Transition-Metal-Catalyzed C-H Functionalization of Heterocycles [2 Volumes] 9781119774136

Table of contents :
Cover: Volume 1
Half Title
Transition-Metal-Catalyzed C-H Functionalization of Heterocycles: Volume 1
Copyright
Contents
Brief Contents
List of Contributors
Preface
1. Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization
1.1 Introduction
1.2 Electrophilic C–H Bond Activation and Concerted Metalation Deprotonation
1.2.1 The (Very) Early Years - from Mercury to the Palladium Era
1.2.2 Modern Concerted Metalation Deprotonation
1.2.3 Classic Electrophilic C–H Activation
1.2.3.1 Electrophilic Auration of Arenes
1.2.3.2 The Shilov Reaction
1.2.3.3 Post-Shilov Electrophilic Activation
1.3 Oxidative Addition
1.3.1 Stoichiometric Oxidative Addition of C–H Bonds
1.3.2 Mechanistic Pathways and the Oxidative Addition Continuum
1.3.3 Catalytic Reactions Proceeding via Oxidative Addition
1.3.3.1 H/D Exchange
1.3.3.2 Alkane Dehydrogenation
1.3.3.3 Alkane Dehydrogenation by High-Oxidation-State Catalysts
1.3.3.4 Applications of Dehydrogenation in Heterocyclic Chemistry
1.3.3.5 Borylation
1.4 Insertion Reactions
1.5 Site-directed C–H Activation
1.6 Sigma-Bond Metathesis
1.6.1 Hydrogenolysis and the Discovery of Four-Centered Transition States
1.6.2 C–H Activation in Actinide Complexes
1.6.3 Identification of a New Mechanism
1.6.4 Emerging Applications of Sigma Bond Metathesis
1.6.5 Hydromethylation of Olefins
1.6.6 Pyridine Hydroalkylation by Orthometalation
1.7 1,2-Addition
1.7.1 Metal Oxos and Imidos
1.7.2 Metal Alkylidenes
1.7.3 Intermolecular C–H Activation by 1,2-Addition
1.8 Sigma Complexes: Unifying Intermediates in C–H Activation
1.9 Base Metals in C–H Activation
1.10 Conclusions and Future Outlook
Acknowledgments
2. Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms
2.1 Introduction
2.1.1 Importance of Pyrrole, Furan and Thiophene Derivatives
2.1.2 General Reactivities of Pyrrole, Furan, and Thiophene
2.2 Transition Metal-Catalyzed C–H Functionalization of Pyrroles
2.2.1 C–H Arylation of Pyrroles
2.2.2 C–H Alkylation of Pyrroles
2.2.3 C–H Alkenylation of Pyrroles
2.2.4 C–H Alkynylation of Pyrroles
2.2.5 C–H Borylation of Pyrroles
2.2.6 C–H Amidation of Pyrroles
2.2.7 C–H Silylation of Pyrroles
2.3 Transition Metal-Catalyzed C–H Functionalization of Furans
2.3.1 C–H Arylation of Furans
2.3.2 C–H Alkenylation of Furans
2.3.3 C–H Alkylation of Furans
2.3.4 C–H Alkynylation of Furans
2.3.5 C–H Borylation of Furans
2.3.6 C–H Silylation of Furans
2.4 Transition Metal-Catalyzed C–H Functionalization of Thiophenes
2.4.1 C–H Arylation of Thiophene
2.4.2 C–H Alkylation of Thiophene
2.4.3 C–H Alkenylation of Thiophene
2.4.4 C–H Alkynylation of Thiophene
2.4.5 C–H Borylation of Thiophene
2.4.6 C–H Silylation of Thiophene
2.4.7 C–H Amidation of Thiophene
2.5 Conclusions and Prospective
3. Functionalization of Five-membered Heterocycles with Two Heteroatoms
3.1 Introduction
3.2 Arylation
3.2.1 Arylation of Oxazole and Thiazole
3.2.1.1 C-2 Arylation of Oxazole and Thiazole
3.2.1.2 C5 Arylation of Oxazole and Thiazole
3.2.1.3 C4 Arylation of Oxazole and Thiazole
3.2.2 Arylation of Imidazole
3.2.2.1 C2 Arylation of Imidazole
3.2.2.2 C5 Arylation of Imidazole
3.2.3 Sequential and Multi-arylation of 1,3-azoles
3.2.4 Arylation of Pyrazole
3.2.5 Arylation of Isoxazole
3.3 Alkenylation
3.3.1 Alkenylation of Oxazole and Thiazole
3.3.1.1 C2 Alkenylation of Oxazole and Thiazole
3.3.1.2 C5 Alkenylation of Oxazole and Thiazole
3.3.1.3 C4 Alkenylation of Oxazole
3.3.2 Alkenylation of Imidazole
3.3.3 Alkenylation of Pyrazole
3.3.4 Alkenylation of Isoxazole
3.4 Alkynylation
3.4.1 Alkynylation with Haloalkynes
3.4.2 Alkynylation with gem-Dihaloalkenes
3.4.3 Alkynylation with Terminal Alkynes
3.5 Alkylation
3.5.1 Alkylation of Oxazole and Thiazole
3.5.1.1 C2 Alkylation of Oxazole and Thiazole
3.5.1.2 C5 Alkylation of Oxazole and Thiazole
3.5.2 Alkylation of Imidazole
3.5.3 Alkylation of Pyrazole
3.6 C–H Heteroatom Bond Forming Reactions
3.6.1 Borylation
3.6.2 Silylation
3.6.3 Thiolation
3.6.4 Amination
3.7 Conclusions
Acknowledgments
4. Transition Metal-Catalyzed C–H Functionalization of Indole Benzenoid Ring
4.1 Introduction
4.2 C4 Functionalization
4.2.1 C4 Alkylation
4.2.2 C4 Arylation
4.2.3 C4 Alkenylation
4.2.4 C4 Alkynylation
4.2.5 C4 Allylation
4.2.6 C4 Acylation
4.2.7 C4 Annulation Reactions
4.2.8 C4 Amidation
4.2.9 C4 Chalcogenation
4.3 C5 Functionalization
4.3.1 C5 Arylation
4.3.2 C5 Selenylation
4.4 C6 Functionalization
4.4.1 C6 Arylation
4.5 C7 Functionalization
4.5.1 C7 Alkylation
4.5.2 C7 Arylation
4.5.3 C7 Alkenylation
4.5.4 C7 Alkynylation
4.5.5 C7 Carbonylation
4.5.6 C7 Amination/amidation
4.5.7 C7 Silylation
4.6 Conclusions and Outlook
Acknowledgments
5. Transition Metal-Catalyzed C2 and C3 Functionalization of Indoles
5.1 Introduction
5.2 C2/C3-Functionalization of Indoles
5.2.1 Arylation of Indoles
5.2.1.1 Non-chelation Assisted C2 Arylation of Indoles
5.2.1.2 Chelation-Assisted C2 Arylation of Indoles
5.2.1.3 C3 Arylation of Indoles
5.2.2 Heteroarylation
5.2.2.1 C2 Heteroarylation
5.2.2.2 C3 Heteroarylation
5.2.2.3 C2 Alkenylation of Indoles
5.2.2.4 C3 Alkenylations of Indoles
5.2.2.5 C2 Alkynylation of Indoles
5.2.2.6 C3 Alkynylations of Indoles
5.2.2.7 C2 Allylation of Indoles
5.2.2.8 C3 Allylations of Indoles
5.2.2.9 C2 Acylation of Indoles
5.2.2.10 C3 Acylations/formylations of Indoles
5.2.2.11 C2 Alkylation of Indoles
5.2.2.12 C3 Alkylation of Indoles
5.2.3 C2 Nitration of Indoles
5.2.3.1 C2 Borylation of Indoles
5.2.3.2 C3 Borylations of Indoles
5.2.4 Cyanation of Indoles
5.2.4.1 C2 Cyanation of Indole
5.2.4.2 C3 Cyanation of Indoles
5.2.5 Annulation of Indoles
5.2.5.1 C2 Amidation of Indoles
5.2.6 Miscellaneous Reactions
5.3 Conclusions
Acknowledgments
6. C(sp2)–H Functionalization of Indolines at the C7-Position
6.1 Introduction
6.1.1 C-H Bond Arylation of Indolines at C7-Position
6.1.2 C-H Bond Alkenylation (Olefination) of Indolines at the C7-Position
6.1.3 C-H Bond Alkynylation of Indolines at the C7-Position
6.1.4 C-H Bond Alkylation of Indolines at the C7-Position
6.1.5 C-H Bond Allylation of Indolines at the C7-Position
6.1.6 C-H Bond Acylation of Indolines at the C7-Position
6.1.7 C-N Bond Formations at the C7-Position of Indolines
6.1.7.1 C7-Amination and/or Amidation of Indolines
6.1.7.2 C7-Nitration of Indolines
6.1.8 C-H Bond Cyanation of Indolines at the C7-Position
6.1.9 C-B, C-O, C-P, and C-S Bond Formation of Indolines at the C7-Position
6.1.9.1 C-B Bond Formation
6.1.9.2 C-O Bond Formation
6.1.9.3 C-P Bond Formation
6.1.9.4 C-S Bond Formation
6.1.10 C-H Bond Halogenation of Indolines at the C7-Position
6.1.11 C-H Bond Trifluoroalkylation of Indolines at the C7-Position
6.2 Conclusions
7. Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms
7.1 Introduction
7.2 C-C Bond Formation
7.2.1 Alkylation
7.2.1.1 Copper Catalysis
7.2.1.2 Nickel Catalysis
7.2.1.3 Palladium Catalysis
7.2.1.4 Rhodium Catalysis
7.2.2 Alkenylation
7.2.2.1 Copper Catalysis
7.2.2.2 Nickel Catalysis
7.2.2.3 Cobalt Catalysis
7.2.2.4 Palladium Catalysis
7.2.2.5 Rhodium Catalysis
7.2.3 Alkynylation
7.2.3.1 Copper-Mediated Reactions
7.2.3.2 Nickel Catalysis
7.2.3.3 Palladium Catalysis
7.2.4 Arylation
7.2.4.1 Copper Catalysis
7.2.4.2 Nickel Catalysis
7.2.4.3 Cobalt Catalysis
7.2.4.4 Iron Catalysis
7.2.4.5 Palladium Catalysis
7.2.4.6 Rhodium Catalysis
7.3 C-N Bond Formation
7.3.1 Copper Catalysis
7.3.2 Iron Catalysis
7.3.3 Miscellaneous
7.4 C-P Bond Formation
7.4.1 Copper Catalysis
7.4.2 Manganese-Mediated Reaction
7.4.3 Silver-Mediated Reaction
7.4.4 Palladium Catalysis
7.5 C-S Bond Formation
7.5.1 Copper Catalysis
7.5.2 Iron Catalysis
7.5.3 Silver Catalysis
7.5.4 Rhodium Catalysis
7.6 C-O Bond Formation
7.7 C-Halogen Bond Formation
7.8 Conclusions and Outlook
Acknowledgments
Cover: Volume 2
Half Title
Transition-Metal-Catalyzed C-H Functionalization of Heterocycles: Volume 2
Copyright
Contents
Brief Contents
List of Contributors
8. Functionalization of Pyridines, Quinolines, and Isoquinolines
8.1 Introduction
8.2 C2-Selective Functionalization
8.2.1 Alkylation
8.2.2 Arylation
8.2.2.1 Pyridine Derivatives as Substrates
8.2.2.2 Pyridine N-oxides as Substrates
8.2.2.3 N-iminopyridinium Ylides as Substrates
8.2.3 Alkenylation
8.2.4 Acylation, Amination, and Aminomethylation
8.3 C3-Selective Functionalization
8.3.1 Alkylation
8.3.2 Arylation
8.3.3 Alkenylation
8.3.4 Borylation
8.4 C4-Selective Functionalization
8.4.1 Alkylation
8.4.2 Arylation
8.4.3 Alkenylation
8.4.4 Borylation
8.5 C8-Selective Functionalization
8.6 Summary and Conclusions
9. Transition Metal-catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives
9.1 Introduction
9.2 Carbon-carbon Bond Formation
9.2.1 C-H Bond (Hetero)arylations
9.2.2 C–H Bond Olefinations
9.2.3 C–H Bond Alkylations
9.2.4 C–H Bond Alkynylations
9.2.5 C–H Bond Carboxylations
9.3 Carbon-nitrogen Bond Formation
9.4 Carbon-oxygen Bond Formation
9.5 Carbon-sulfur Bond Formation
9.6 Carbon-boron Bond Formation
9.7 Carbon-silicon Bond Formation
9.8 Carbon-halogen Bond Formation
9.9 Conclusions
Acknowledgments
10. Functionalization of Chromenes and Their Derivatives
10.1 Introduction
10.2 2H-Chromenes
10.3 2H-Chromene-ones (Coumarins)
10.3.1 C3-Selective Functionalization
10.3.1.1 Alkenylation
10.3.1.2 Arylation
10.3.1.3 Other
10.3.1.4 Annulation/Cyclization
10.3.2 C4–H Selective Functionalization
10.3.3 C5-Selective Functionalization
10.4 4H-Chromene
10.5 4H-Chromenones (Chromones)
10.5.1 C2-Selective C–H Activation
10.5.2 C3-Selective C–H Activation
10.5.3 C5-Selective C–H Activation
10.5.3.1 Alkenylation
10.5.3.2 Alkylation
10.5.3.3 (Hetero)arylation
10.5.3.4 Amination/Amidation
10.5.3.5 Others
10.5.4 C6-Selective C–H Activation
10.5.5 Conclusions
11. Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles
11.1 Introduction
11.2 C–C Bond Formation
11.2.1 Alkylation
11.2.1.1 Fluoro Alkylation
11.2.1.2 Alkoxycarbonyl Alkylation
11.2.1.3 Aryl/heteroaryl Alkylation
11.2.1.4 Amino Alkylation
11.2.1.5 Sulfonyl/Carbonyl/Cyano Alkylation
11.2.2 Alkenylation/Alkynylation/Allenylation
11.2.3 Cyanation/Carbonylation
11.2.4 Arylation/Heteroarylation
11.3 C–S/Se Bond Formation
11.4 C–N Bond Formation
11.5 C–P Bond Formation
11.6 C–Si Bond Formation
11.7 Conclusions
Acknowledgments
12. Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles
12.1 Dehydrogenative Coupling: An Overview
12.2 Importance of Heterocycles and Their Fused Congeners
12.3 Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds
12.3.1 C–C Bond Formation
12.3.1.1 Synthesis of Large-sized Molecules: COTs
12.3.2 Formation of C–N Bonds
12.3.3 Formation of C–B Bonds
12.4 Conclusions
13. C–H Functionalization of Saturated Heterocycles Beyond the C2 Position
13.1 Introduction
13.2 Heterocycle Functionalization with a C2 Directing Group
13.2.1 Carboxylic Acid-Linked C2 Directing Groups
13.2.2 Applications of N-Heterocycle Functionalization with C2 Directing Groups
13.3 Heterocycle Functionalization with C3 Directing Groups
13.3.1 Carboxylic Acid-Linked C3 Directing Groups
13.3.2 Amine-Linked C3 Directing Groups
13.3.3 Alcohol-Linked C3 Directing Groups
13.4 Heterocycle Functionalization with a C4 Directing Group
13.5 Transannular Heterocycle Functionalization with N-linked Directing Groups
13.6 Conclusions
14. Asymmetric Functionalization of C–H Bonds in Heterocycles
14.1 Introduction
14.2 Enantioselective C–H Activation
14.2.1 Activation of C(sp2)–H Bonds
14.2.2 Activation of C(sp3)–H Bonds
14.3 C–H Activation Followed by Enantioselective Functionalization
14.3.1 Intramolecular Coupling
14.3.1.1 Indoles and Pyrroles as Coupling Partners
14.3.1.2 Imidazoles and Benzoimidazoles as Coupling Partners
14.3.1.3 Pyridines and Pyridones as Coupling Partners
14.3.2 Intermolecular Coupling
14.3.2.1 Directing-Group-Free C–H Functionalization
14.3.2.2 Functionalization Assisted by a Directing Group at the C3 Site
14.3.2.3 Functionalization Assisted by a Directing Group at the N-1 Site
14.3.3 Atropo-enantioselective Synthesis of Heterobiaryls
14.4 Conclusions and Perspectives
15. Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases
15.1 Introduction
15.2 Direct Functionalization of the C5-H Bond in Uracil Nucleosides
15.2.1 Cross-Dehydrogenative Alkenylation at the C5 Position
15.2.2 Direct C–H Arylation at the C5 Position
15.2.3 Direct C–H Alkylation at the C5 Position
15.2.4 Miscellaneous Direct C–H Functionalizations
15.3 Direct Functionalization of C6-H Bond in Uracil
15.3.1 Stepwise C6-H Functionalization of Pyrimidine Nucleoside via Lithiation and Alkylation
15.3.2 Direct C6-H Functionalization of the Uracil Base
15.3.2.1 Functionalization with Aryl Halides
15.3.2.2 Cross-Dehydrogenative Functionalization with Arenes
15.3.2.3 Functionalization with Aryl Boronic Acid
15.3.2.4 Intramolecular C6-H Functionalization of Uracil Derivatives
15.4 Inverted C–H Functionalization of Uracil Nucleosides
15.4.1 Inverted C5-H Functionalization of Uracil Nucleosides
15.4.2 Inverted C6-H Functionalization of Uracil
15.5 Direct C2-H Functionalization of Adenosine
15.6 Direct C6-H Functionalization of Purine Nucleoside
15.6.1 Direct C6-H Alkylation
15.6.1.1 With Cycloalkanes
15.6.1.2 With Boronic Acid
15.6.1.3 With Alkyltrifluoroborate
15.6.1.4 With Alkyl Carboxylic Acid
15.6.1.5 With tert-Alkyl Oxalate Salts
15.6.2 Direct C6-H Arylation
15.6.3 Other Direct C6-H Functionalization
15.7 Direct Activation of C8-H Bond in Purine and Purine Nucleosides
15.7.1 Cross-Coupling of Adenine Nucleosides with Aryl Halides
15.7.2 Cross-Coupling of Inosine and Guanine Nucleosides with Aryl Halides
15.7.3 Cross-Coupling of Adenine Nucleosides with Alkanes
15.7.4 Miscellaneous Functionalization of Adenosine-related Substrates
15.8 Conclusions
16. C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides
16.1 General Introduction
16.2 Classical Methods to Prepare C-aryl Glycosides
16.3 Directed C-H Activation Approach
16.3.a Directed Csp2-Csp2 Bond Formation
16.3.a.1 Directing Group Attached to the Aryl Partner
16.3.a.2 Directing Group Attached to the Sugar Nucleus
16.3.b Directed Csp2-Csp3 Bond Formation
16.3.b.1 The Directing Group (DG) Attached to the Coupling Partner
16.3.b.2 The Directing Group Attached to the Sugar Nucleus
16.4 Conclusions and Perspectives
17. Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals
17.1 Introduction
17.2 Synthesis of (±)-Ibogamine
17.3 Synthesis of YD-3 and YC-1 (C–H Arylation of Indazoles)
17.4 Synthesis of Complanadine A
17.5 Synthesis of Diptoindonesin G (C–H Arylation of Benzofuran)
17.6 Synthesis of Dragmacidin D (C–H Arylation of Indoles at the C3 Position)
17.7 Synthesis of Celecoxib (C–H Arylation of Pyrazoles)
17.8 Synthesis of Aspidospermidine
17.9 Synthesis of Pipercyclobutanamide A
17.10 Synthesis of Nigellidine Hydrobromide
17.11 Synthesis of (+)-Linoxepin
17.12 Synthesis of (±)-Rhazinal
17.13 Synthesis of Podophyllotoxin (C–H Arylation)
17.14 Synthesis of (±)-Rhazinilam
17.15 Synthesis of Aeruginosins (sp3 C–H Alkenylation and Arylation)
17.16 Synthesis of Gamendazole
17.17 Synthesis of Beclabuvir (BMS-791325)
17.18 Conclusions
18. Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products
18.1 C–H Methylation and Alkylation
18.2 C–H Arylation and Olefination
18.3 Formation of Other C-C Bonds
18.4 C–H Hydroxylation
18.5 C–H Amination
18.6 C–H Trifluoromethylation
18.7 C–H Difluoromethylation
18.8 C–H Fluorination
18.9 C–H Silylation
18.10 C–H Phosphorylation
18.11 C–H Deuteration and Tritiation
18.12 Conclusions
Index

Citation preview

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles Edited by Tharmalingam Punniyamurthy

Indian Institute of Technology Guwahati Guwahati, India

Anil Kumar

Birla Institute of Technology and Science, Pilani Pilani, India

Volume 1

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Contents List of Contributors xiii Preface xvii 1 1.1 1.2 1.2.1 1.2.2 1.2.3 1.2.3.1 1.2.3.2 1.2.3.3 1.3 1.3.1 1.3.2 1.3.3 1.3.3.1 1.3.3.2 1.3.3.3 1.3.3.4 1.3.3.5 1.4 1.5 1.6 1.6.1 1.6.2 1.6.3 1.6.4 1.6.5 1.6.6 1.7 1.7.1 1.7.2 1.7.3 1.8 1.9 1.10

Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization 1 Tariq M. Bhatti, Eileen Yasmin, Akshai Kumar, and Alan S. Goldman Introduction 1 Electrophilic C–H Bond Activation and Concerted Metalation Deprotonation 2 The (Very) Early Years - from Mercury to the Palladium Era 2 Modern Concerted Metalation Deprotonation 4 Classic Electrophilic C–H Activation 6 Electrophilic Auration of Arenes 6 The Shilov Reaction 7 Post-Shilov Electrophilic Activation 8 Oxidative Addition 9 Stoichiometric Oxidative Addition of C–H Bonds 9 Mechanistic Pathways and the Oxidative Addition Continuum 12 Catalytic Reactions Proceeding via Oxidative Addition 13 H/D Exchange 13 Alkane Dehydrogenation 14 Alkane Dehydrogenation by High-Oxidation-State Catalysts 17 Applications of Dehydrogenation in Heterocyclic Chemistry 18 Borylation 19 Insertion Reactions 21 Site-directed C–H Activation 24 Sigma-Bond Metathesis 26 Hydrogenolysis and the Discovery of Four-Centered Transition States 26 C–H Activation in Actinide Complexes 28 Identification of a New Mechanism 29 Emerging Applications of Sigma Bond Metathesis 29 Hydromethylation of Olefins 29 Pyridine Hydroalkylation by Orthometalation 30 1,2-Addition 32 Metal Oxos and Imidos 32 Metal Alkylidenes 33 Intermolecular C–H Activation by 1,2-Addition 33 Sigma Complexes: Unifying Intermediates in C–H Activation 35 Base Metals in C–H Activation 37 Conclusions and Future Outlook 41 Acknowledgments 41

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Contents

2 2.1 2.1.1 2.1.2 2.2 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.2.6 2.2.7 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.3.6 2.4 2.4.1 2.4.2 2.4.3 2.4.4 2.4.5 2.4.6 2.4.7 2.5 3 3.1 3.2 3.2.1 3.2.1.1 3.2.1.2 3.2.1.3 3.2.2 3.2.2.1 3.2.2.2 3.2.3 3.2.4 3.2.5 3.3 3.3.1 3.3.1.1 3.3.1.2 3.3.1.3 3.3.2 3.3.3 3.3.4

Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms  61 B. Prabagar and Zhuangzhi Shi Introduction  61 Importance of Pyrrole, Furan and Thiophene Derivatives  61 General Reactivities of Pyrrole, Furan, and Thiophene  61 Transition Metal-Catalyzed C–H Functionalization of Pyrroles  63 C–H Arylation of Pyrroles  63 C–H Alkylation of Pyrroles  69 C–H Alkenylation of Pyrroles  74 C–H Alkynylation of Pyrroles  77 C–H Borylation of Pyrroles  80 C–H Amidation of Pyrroles  81 C–H Silylation of Pyrroles  82 Transition Metal-Catalyzed C–H Functionalization of Furans  84 C–H Arylation of Furans  84 C–H Alkenylation of Furans  86 C–H Alkylation of Furans  88 C–H Alkynylation of Furans  89 C–H Borylation of Furans  89 C–H Silylation of Furans  89 Transition Metal-Catalyzed C–H Functionalization of Thiophenes  91 C–H Arylation of Thiophene  91 C–H Alkylation of Thiophene  95 C–H Alkenylation of Thiophene  98 C–H Alkynylation of Thiophene  98 C–H Borylation of Thiophene  100 C–H Silylation of Thiophene  100 C–H Amidation of Thiophene  102 Conclusions and Prospective  102 Functionalization of Five-membered Heterocycles with Two Heteroatoms  109 Jung Min Joo Introduction  109 Arylation  110 Arylation of Oxazole and Thiazole  110 C-2 Arylation of Oxazole and Thiazole  110 C5 Arylation of Oxazole and Thiazole  115 C4 Arylation of Oxazole and Thiazole  117 Arylation of Imidazole  117 C2 Arylation of Imidazole  117 C5 Arylation of Imidazole  119 Sequential and Multi-arylation of 1,3-azoles  121 Arylation of Pyrazole  123 Arylation of Isoxazole  126 Alkenylation  127 Alkenylation of Oxazole and Thiazole  127 C2 Alkenylation of Oxazole and Thiazole  127 C5 Alkenylation of Oxazole and Thiazole  129 C4 Alkenylation of Oxazole  131 Alkenylation of Imidazole  131 Alkenylation of Pyrazole  131 Alkenylation of Isoxazole  133

Contents

3.4 3.4.1 3.4.2 3.4.3 3.5 3.5.1 3.5.1.1 3.5.1.2 3.5.2 3.5.3 3.6 3.6.1 3.6.2 3.6.3 3.6.4 3.7

Alkynylation  134 Alkynylation with Haloalkynes  134 Alkynylation with gem-Dihaloalkenes  135 Alkynylation with Terminal Alkynes  135 Alkylation  136 Alkylation of Oxazole and Thiazole  136 C2 Alkylation of Oxazole and Thiazole  136 C5 Alkylation of Oxazole and Thiazole  139 Alkylation of Imidazole  139 Alkylation of Pyrazole  141 C–H Heteroatom Bond Forming Reactions  141 Borylation  141 Silylation  142 Thiolation  142 Amination  143 Conclusions  143 Acknowledgments  144

4

Transition Metal-Catalyzed C–H Functionalization of Indole Benzenoid Ring  155 Vikash Kumar, Rajaram Maayuri, Lusina Mantry, and Parthasarathy Gandeepan Introduction  155 C4 Functionalization  155 C4 Alkylation  156 C4 Arylation  159 C4 Alkenylation  161 C4 Alkynylation  163 C4 Allylation  163 C4 Acylation  165 C4 Annulation Reactions  165 C4 Amidation  169 C4 Chalcogenation  170 C5 Functionalization  170 C5 Arylation  171 C5 Selenylation  173 C6 Functionalization  174 C6 Arylation  174 C7 Functionalization  174 C7 Alkylation  175 C7 Arylation  176 C7 Alkenylation  176 C7 Alkynylation  177 C7 Carbonylation  182 C7 Amination/amidation  183 C7 Silylation  185 Conclusions and Outlook  185 Acknowledgments  186

4.1 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 4.2.6 4.2.7 4.2.8 4.2.9 4.3 4.3.1 4.3.2 4.4 4.4.1 4.5 4.5.1 4.5.2 4.5.3 4.5.4 4.5.5 4.5.6 4.5.7 4.6 5 5.1 5.2

Transition Metal-Catalyzed C2 and C3 Functionalization of Indoles  193 Pinki Sihag, Meledath Sudhakaran Keerthana, and Masilamani Jeganmohan Introduction  193 C2/C3-Functionalization of Indoles  194

vii

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Contents

5.2.1 Arylation of Indoles  194 5.2.1.1 Non-chelation Assisted C2 Arylation of Indoles  195 5.2.1.2 Chelation-Assisted C2 Arylation of Indoles  197 5.2.1.3 C3 Arylation of Indoles  200 5.2.2 Heteroarylation  201 5.2.2.1 C2 Heteroarylation  201 5.2.2.2 C3 Heteroarylation  203 5.2.2.3 C2 Alkenylation of Indoles  204 5.2.2.4 C3 Alkenylations of Indoles  210 5.2.2.5 C2 Alkynylation of Indoles  211 5.2.2.6 C3 Alkynylations of Indoles  213 5.2.2.7 C2 Allylation of Indoles  213 5.2.2.8 C3 Allylations of Indoles  217 5.2.2.9 C2 Acylation of Indoles  218 5.2.2.10 C3 Acylations/formylations of Indoles  219 5.2.2.11 C2 Alkylation of Indoles  221 5.2.2.12 C3 Alkylation of Indoles  227 5.2.3 C2 Nitration of Indoles  229 5.2.3.1 C2 Borylation of Indoles  229 5.2.3.2 C3 Borylations of Indoles  229 5.2.4 Cyanation of Indoles  230 5.2.4.1 C2 Cyanation of Indole  230 5.2.4.2 C3 Cyanation of Indoles  231 Annulation of Indoles  232 5.2.5 5.2.5.1 C2 Amidation of Indoles  237 5.2.6 Miscellaneous Reactions  238 5.3 Conclusions  240 Acknowledgments  241 6 6.1 6.1.1 6.1.2 6.1.3 6.1.4 6.1.5 6.1.6 6.1.7 6.1.7.1 6.1.7.2 6.1.8 6.1.9 6.1.9.1 6.1.9.2 6.1.9.3 6.1.9.4 6.1.10 6.1.11 6.2

C(sp2)–H Functionalization of Indolines at the C7-Position  251 Neeraj Kumar Mishra and In Su Kim Introduction  251 C−H Bond Arylation of Indolines at C7-Position  252 C−H Bond Alkenylation (Olefination) of Indolines at the C7-Position  260 C−H Bond Alkynylation of Indolines at the C7-Position  265 C−H Bond Alkylation of Indolines at the C7-Position  268 C−H Bond Allylation of Indolines at the C7-Position  279 C−H Bond Acylation of Indolines at the C7-Position  282 C−N Bond Formations at the C7-Position of Indolines  287 C7-Amination and/or Amidation of Indolines  287 C7-Nitration of Indolines  296 C−H Bond Cyanation of Indolines at the C7-Position  298 C−B, C−O, C−P, and C−S Bond Formation of Indolines at the C7-Position  299 C−B Bond Formation  300 C−O Bond Formation  300 C−P Bond Formation  303 C−S Bond Formation  303 C−H Bond Halogenation of Indolines at the C7-Position  306 C−H Bond Trifluoroalkylation of Indolines at the C7-Position  307 Conclusions  308

Contents

7 7.1 7.2 7.2.1 7.2.1.1 7.2.1.2 7.2.1.3 7.2.1.4 7.2.2 7.2.2.1 7.2.2.2 7.2.2.3 7.2.2.4 7.2.2.5 7.2.3 7.2.3.1 7.2.3.2 7.2.3.3 7.2.4 7.2.4.1 7.2.4.2 7.2.4.3 7.2.4.4 7.2.4.5 7.2.4.6 7.3 7.3.1 7.3.2 7.3.3 7.4 7.4.1 7.4.2 7.4.3 7.4.4 7.5 7.5.1 7.5.2 7.5.3 7.5.4 7.6 7.7 7.8

Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms  319 Tanumay Sarkar, Subhradeep Kar, Prabhat Kumar Maharana, Tariq. A. Shah, and Tharmalingam Punniyamurthy Introduction  319 C−C Bond Formation  320 Alkylation  320 Copper Catalysis  320 Nickel Catalysis  321 Palladium Catalysis  322 Rhodium Catalysis  325 Alkenylation  326 Copper Catalysis  326 Nickel Catalysis  326 Cobalt Catalysis  328 Palladium Catalysis  328 Rhodium Catalysis  329 Alkynylation  330 Copper-Mediated Reactions  330 Nickel Catalysis  330 Palladium Catalysis  331 Arylation  333 Copper Catalysis  333 Nickel Catalysis  334 Cobalt Catalysis  337 Iron Catalysis  337 Palladium Catalysis  337 Rhodium Catalysis  340 C−N Bond Formation  340 Copper Catalysis  340 Iron Catalysis  342 Miscellaneous  344 C−P Bond Formation  344 Copper Catalysis  344 Manganese-Mediated Reaction  345 Silver-Mediated Reaction  345 Palladium Catalysis  346 C−S Bond Formation  346 Copper Catalysis  347 Iron Catalysis  348 Silver Catalysis  348 Rhodium Catalysis  349 C−O Bond Formation  349 C−Halogen Bond Formation  349 Conclusions and Outlook  350 Acknowledgments  350

ix

xi

Brief Contents Volume 1: List of Contributors  xiii Preface  xvii 1 Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization  1 Tariq M. Bhatti, Eileen Yasmin, Akshai Kumar, and Alan S. Goldman 2 Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms  61 B. Prabagar and Zhuangzhi Shi 3 Functionalization of Five-membered Heterocycles with Two Heteroatoms  109 Jung Min Joo 4 Transition Metal-Catalyzed C–H Functionalization of Indole Benzenoid Ring  155 Vikash Kumar, Rajaram Maayuri, Lusina Mantry, and Parthasarathy Gandeepan 5 Transition Metal-Catalyzed C2 and C3 Functionalization of Indoles  193 Pinki Sihag, Meledath Sudhakaran Keerthana, and Masilamani Jeganmohan 6 C(sp2)–H Functionalization of Indolines at the C7-Position  251 Neeraj Kumar Mishra and In Su Kim 7 Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms  319 Tanumay Sarkar, Subhradeep Kar, Prabhat Kumar Maharana, Tariq. A. Shah, and Tharmalingam Punniyamurthy

Volume 2: List of Contributors  xiii 8 Functionalization of Pyridines, Quinolines, and Isoquinolines  357 Jun Zhou and Bing-Feng Shi 9 Transition Metal-catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives  393 Christian Bruneau and Rafael Gramage-Doria 10 Functionalization of Chromenes and Their Derivatives  435 Laura Cunningham, Sundaravel Vivek Kumar, and Patrick J. Guiry

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Brief Contents

11 Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles  485 Rajeev Sakhuja and Anil Kumar 12 Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles  543 Neha Jha and Manmohan Kapur 13 C–H Functionalization of Saturated Heterocycles Beyond the C2 Position  567 Amalia-Sofia Piticari, Natalia Larionova, and James A. Bull 14 Asymmetric Functionalization of C–H Bonds in Heterocycles  609 Olena Kuleshova and Laurean Ilies 15 Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases  631 Yong Liang and Stanislaw F. Wnuk 16 C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides  657 Morgane de Robichon, Juba Ghouilem, Angélique Ferry, and Samir Messaoudi 17 Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals  683 Harshita Shet and Anant R. Kapdi 18 Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products  703 François Richard, Elias Selmi-Higashi, and Stellios Arseniyadis

Index  727

xiii

List of Contributors Stellios Arseniyadis Queen Mary University of London Department of Chemistry Mile End Road London, E1 4NS, UK Tariq M. Bhatti Department of Chemistry and Chemical Biology, Rutgers The State University of New Jersey New Brunswick, New Jersey 08903, United States Christian Bruneau Institut des Sciences Chimiques de Rennes UMR6226 University of Rennes, CNRS ISCR-UMR6226, F-35000 Rennes, France James A. Bull Department of Chemistry Imperial College London Wood Lane, London, W12 0BZ, UK Laura Cunningham Centre for Synthesis and Chemical Biology UCD School of Chemistry, University College Dublin Belfield, Dublin 4, Ireland Morgane de Robichon CY Cergy-Paris Université, CNRS, BioCIS Equipe de Chimie Biologique 95000 Neuville sur Oise, France Angélique Ferry CY Cergy-Paris Université, CNRS, BioCIS Equipe de Chimie Biologique 95000 Neuville sur Oise, France Rafael Gramage-Doria Institut des Sciences Chimiques de Rennes UMR6226

University of Rennes, CNRS ISCR-UMR6226, F-35000 Rennes, France Parthasarathy Gandeepan Department of Chemistry Indian Institute of Technology Tirupati Tirupati – Renigunta Road, Settipalli Post Tirupati 517506, India Juba Ghouilem Université Paris-Saclay, CNRS, BioCIS 92290, Châtenay-Malabry, France Alan S. Goldman Department of Chemistry and Chemical Biology, Rutgers The State University of New Jersey New Brunswick, New Jersey 08903, United States Patrick J. Guiry Centre for Synthesis and Chemical Biology UCD School of Chemistry, University College Dublin Belfield, Dublin 4, Ireland Laurean Ilies RIKEN Center for Sustainable Resource Science 2-1 Hirosawa, Wako Saitama 351-0198, Japan Masilamani Jeganmohan Department of Chemistry Indian Institute of Technology Madras Chennai 600036, India Neha Jha Department of Chemistry Indian Institute of Science Education and Research Bhopal Bhauri, Bhopal 462066, India

xiv

List of Contributors

Jung Min Joo Department of Chemistry Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu Seoul 02447, Republic of Korea Anant R. Kapdi Department of Chemistry Institute of Chemical Technology Nathalal Parekh Road, Matunga Mumbai 400019, India Manmohan Kapur Department of Chemistry Indian Institute of Science Education and Research Bhopal Bhauri, Bhopal 462066, India Subhradeep Kar Department of Chemistry Indian Institute of Technology Guwahati Guwahati 781039, India Meledath Sudhakaran Keerthana Department of Chemistry Indian Institute of Technology Madras Chennai 600036, India In Su Kim School of Pharmacy Sungkyunkwan University Suwon 16419, Republic of Korea Olena Kuleshova RIKEN Center for Sustainable Resource Science 2-1 Hirosawa, Wako Saitama 351-0198, Japan Akshai Kumar Centre for Nanotechnology Indian Institute of Technology Guwahati Guwahati 781039, India Anil Kumar Department of Chemistry Birla Institute of Technology and Science, Pilani Pilani 333031, India Sundaravel Vivek Kumar Centre for Synthesis and Chemical Biology UCD School of Chemistry, University College Dublin Belfield, Dublin 4, Ireland

Vikash Kumar Department of Chemistry Indian Institute of Technology Tirupati Tirupati – Renigunta Road, Settipalli Post Tirupati 517506, India Rajaram Maayuri Department of Chemistry Indian Institute of Technology Tirupati Tirupati – Renigunta Road, Settipalli Post Tirupati 517506, India Prabhat Kumar Maharana Department of Chemistry Indian Institute of Technology Guwahati Guwahati 781039, India Natalia Larionova Department of Chemistry Imperial College London Wood Lane, London, W12 0BZ, UK Yong Liang Department of Molecular Medicine Beckman Research Institute of the City of Hope Duarte, CA 91010, US Lusina Mantry Department of Chemistry Indian Institute of Technology Tirupati Tirupati – Renigunta Road, Settipalli Post Tirupati 517506, India Samir Messaoudi Université Paris-Saclay, CNRS BioCIS, 92290, Châtenay-Malabry, France Neeraj Kumar Mishra School of Pharmacy Sungkyunkwan University Suwon 16419, Republic of Korea Amalia-Sofia Piticari Department of Chemistry Imperial College London Wood Lane, London, W12 0BZ, UK B. Prabagar School of Chemistry and Chemical Engineering Nanjing University, Nanjing 210093, China

List of Contributors

Tharmalingam Punniyamurthy Department of Chemistry Indian Institute of Technology Guwahati Guwahati 781039, India François Richard Queen Mary University of London Department of Chemistry Mile End Road, London, E1 4NS, UK Rajeev Sakhuja Department of Chemistry Birla Institute of Technology and Science, Pilani Pilani 333031, India Tanumay Sarkar Department of Chemistry Indian Institute of Technology Guwahati Guwahati 781039, India Elias Selmi-Higash Queen Mary University of London Department of Chemistry Mile End Road, London, E1 4NS, UK Tariq. A. Shah Department of Chemistry University of Kashmir Srinagar 190006, India Harshita Shet Department of Chemistry Institute of Chemical Technology

Nathalal Parekh Road, Matunga Mumbai 400019, India Bing-Feng Shi Department of Chemistry Zhejiang University 38 Zheda Rd., Hangzhou 310027, China Zhuangzhi Shi School of Chemistry and Chemical Engineering Nanjing University Nanjing 210093, China Pinki Sihag Department of Chemistry Indian Institute of Technology Madras Chennai 600036, India Stanislaw F. Wnuk Department of Chemistry and Biochemistry Florida International University Miami, FL 33199, US Eileen Yasmin Department of Chemistry Indian Institute of Technology Guwahati Guwahati 781039, India Jun Zhou School of Chemistry and Chemical Engineering Changsha University of Science and Technology Changsha 410114, China

xv

xvii

Preface Heterocycles are ubiquitous structural scaffolds in bioactive molecules, functional materials and natural products. The complexity in their structural aspect has ensured humanity with a series of diversified novel compounds, unveiling an array of reactivity and stability. Synthesis and modification of heterocyclic compounds is thus an ever-expanding field in synthetic chemistry. Over the past three decades, transition metal-catalyzed C-H bond functionalization has attracted considerable attention as an atom-economical and sustainable technology for the carbon-carbon and carbon-heteroatom bond formations. This approach has allowed rapid access to a library of functionalized heterocyclic compounds from simple substrates via divergent synthetic methodologies. The objective of this book is to focus on the developments in transition metal-catalyzed C-H functionalization of heterocycles. The methods described will allow for unprecedented disconnections in complex heterocyclic molecules. Through its eighteen chapters the reader would get an up-to-date of the C-H bond functionalization developed for a particular type of heterocycle. They are organized according to the type of heterocyclic structural frameworks. A brief history of C-H activation and the mechanistic aspects of transition metal-catalyzed C-H bond activation reactions is presented in chapter 1. In the subsequent chapter, the principal focus is on the developments of C-H arylation, alkenylation, alkynylation, alkylation, borylation, silylation and amidation of five-membered heterocycles with a single heteroatom viz. pyrroles, furans and thiophenes. The transition metal-catalyzed C-H functionalization of five-membered heterocycles with two heteroatoms, viz. oxazoles, thiazoles, imidazoles, and pyrazoles has been emphasized in chapter 3. Key factors for the regioselectivity and mechanistic details are also demonstrated. Chapter 4 pertinently focusses on the transition metal-catalyzed site-selective C-H functionalization of benzene core of indoles. The chapter is organized based on the site of functionalization and subdivided based on the type of reactions. Chapter 5 details the site-selective C-2 and C-3 functionalization of indoles leading to the formation of carbon-carbon and carbon-heteroatom bonds, including arylation, alkenylation, allylation, alkylation, borylation, cyanation, amidation and annulation while the next chapter effectively describes the transition metal-catalyzed site-selective C-7 functionalization of indolines using diverse coupling partners. The transition metal-catalyzed C-H bond functionalization of benzo-fused azoles with two or more heteroatoms is presented in chapter 7. In chapter 8, the transition metal-catalyzed direct C(sp2)-H bond functionalization of pyridine, quinoline, and isoquinoline derivatives is demonstrated in accordance with the mechanism and scope of the methodology. In chapter 9, an in-depth discussion of the transition metal-catalyzed C-H bond functionalization of diazines and benzodiazines has been conferred. Mechanism of selected reactions and late stage C-H bond olefination of Gefitinib (an anticancer drug) are established. Subsequently, chapter 10 discusses the methods developed for the C-H bond functionalization of chromene derivatives using transition-metal-catalysts, also including some key mechanistic cycles. In chapter 11, the C-H functionalization of imidazo-fused heterocycles under transition metal-catalysis has been relevantly disclosed along with the generalized mechanism. Chapter 12 discusses the methodologies of transition metal-catalyzed dehydrogenative annulation of heterocycles leading to generation of fused heterocycles while in chapter 13, the transition metal-catalyzed C(sp3)-H bond functionalization of saturated heterocycles has been covered at positions remote from the heteroatom.

xviii

Preface

In chapter 14, the methods for the asymmetric C-H bond functionalization of heterocycles have been discussed wherein, most of the reactions covered proceed through inner-sphere C-H activation mechanisms. A concise overview of strategies for direct functionalization of nucleobases, including uracil, pyrimidine and purine with alkyl, alkenyl or (hetero)aryl groups is provided in chapter 15. In chapter 16, different strategies to access C-aryl glycosides by C(sp2)-H and C(sp3)-H functionalization under the transition-metal-catalysis has been overviewed. Synthesis of natural products and pharmaceutical drugs employing late-stage C-H functionalization strategy has been emphasised in chapter 17 whereas late-stage C-H functionalization of bioactive molecules, including marketed pharmaceuticals and agrochemicals, clinical candidates, and natural products using transition-metal-catalysis is described in the last chapter of the book. The book is intended to be a valuable reference source for graduate students and researchers working in the field of organic synthesis and process development in academia and industry. The chapters written by an outstanding team of international authors will hopefully be an interesting read and meet the demand of all the readers concerned in further development of C-H functionalization reactions in the field of heterocyclic chemistry. Tharmalingam Punniyamurthy Guwahati, India August 2022 Anil Kumar Pilani, India August 2022

1

1 Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization Tariq M. Bhatti1, Eileen Yasmin2, Akshai Kumar2,3,4, and Alan S. Goldman1 1

Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, United States of America Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam, India Centre for Nanotechnology, Indian Institute of Technology Guwahati, Guwahati, Assam, India 4 Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati, Assam, India 2 3

1.1  Introduction The C–H bond is the most common linkage in organic chemistry and, surely not entirely by coincidence, is also one of the least reactive groups. The bonds of carbon to hydrogen are, of course, terminal bonds in any organic molecule. Therefore, they cannot contribute to the complexity of a molecule in the same way as C–O, C–N, or, most importantly, C–C bonds. This terminal nature is shared, for the most part, with bonds to halogens or alkali metals, but (with the exception of C–F bonds) those bonds are generally far more reactive; indeed, in contrast with C–H bonds, bonds of carbon to halogens, and even more so to alkali (and other) metals, are viewed by organic chemists as particularly desirable points of opportunity to create new bonds and increase molecular complexity. The standard graphical depiction of organic molecules indicates C–H bonds by default, highlighting that the ubiquitous C–H bond is the singular “unfunctional group” of organic chemistry. Thus, the ability to effect transformations of C–H bonds is potentially the most powerful class of reactions in organic chemistry. Yet for most of the history of organic chemistry the selective functionalization of the most common C–H bonds (sp2 and especially sp3) was considered a largely unrealistic goal – however desirable it might be – and was the subject of very little active pursuit. The challenge of functionalizing C–H bonds has been attributed most simplistically to their high bond strength, but this is certainly an incomplete explanation at best. The homolytic bond energy of H–F for example is far greater than that of typical C–H bonds yet no chemist would ever consider H–F to be unreactive. But a high homolytic bond strength combined with very low polarity and the absence of a lone pair of electrons begins to account for their general lack of reactivity. In comparing H–C bonds to other covalent H–element bonds, one observes that cleavage by polar reagents is generally uphill for C–H bonds. Despite this general tendency to be unreactive, however, there are a fair number of reagents that will readily react with C–H bonds. O2 is certainly cheap, abundant, and effective in this respect. But this leads to the next great obstacle toward achieving useful C–H bond functionalization: selectivity. The ubiquitous nature of C–H bonds means that there are often multiple, and often very similar, possible sites of initial attack. And if that challenge is somehow addressed, one then faces the unpleasant fact that an initial C–H bond functionalization generally leads to a molecular product with C–H bonds that are both (a) weaker than those of the starting material, and therefore typically more reactive with respect to homolytic cleavage, (b) more polar, and therefore typically more reactive in a heterolytic sense. Thus, even if one successfully and selectively functionalizes a C–H bond, secondary reactions lie waiting to prey upon the initial product. Thus it is not surprising that for most of the 20th century useful examples of C–H bond functionalization were quite limited. But in part thanks to the groundwork laid at the end of that century in the field of organotransition chemistry, the past few decades have seen an explosion of examples of transition metal chemistry exploited to yield highly valuable and elegant organic transformation. This volume highlights many of the most elegant of such examples. In this introductory chapter we discuss the fertile ground from which they emerged. Our perspective has of course been shaped by that of many Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

2

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

others in the field, including those put forth in numerous excellent reviews [1]. The diversity of these and other reviews reflects the remarkably interdisciplinary range of approaches and perspectives that have been brought to bear on the inspiring challenge of functionalizing C–H bonds.

1.2  Electrophilic C–H Bond Activation and Concerted Metalation Deprotonation 1.2.1  The (Very) Early Years - from Mercury to the Palladium Era In the modern historiography and taxonomy of C–H bond activation, electrophilic chemistry is often considered the earliest class of mechanisms discovered, whereas concerted metalation deprotonation (CMD) is perhaps the most recent important example. The distinction between these two classes of mechanisms, however, is less clear upon careful consideration. In that context we note that this lack of a clear boundary between various classes of C–H activation extends well beyond this particular example; indeed, blurry lines are more the rule than the exception [2]. Although CMD was first described independently in 2005–2006 by Davies and Macgregor [3], Daugulis [4], Maseras and Echavarren [5], its importance was first particularly recognized and exploited by Fagnou [6]. However, despite being recognized relatively recently, CMD is perhaps the operative pathway for the first selective C–H bond functionalizations ever identified. The term is used to refer to a mechanism in which a C–H bond is associated with a vacant site on an electrophilic metal center (typically an electrophilic, late transition metal) through an initial sigma complex (3-center-2-electron bond). This leads to an acidification of the C–H bond, which enables a basic ligand, most classically a carboxylate, to abstract the hydrogen as proton and often dissociate synchronously with carbon-metal bond formation. Selective functionalization of “unactivated” C–H bonds by a transition metal can arguably be dated back to 1891 [7]. BASF used fuming sulfuric acid to oxidize naphthalene to phthalic anhydride, a key intermediate for production of synthetic indigo dye [8]. During one batch, Eugene Sapper, the technician on duty, decided to stir the hot mixture of acid and naphthalene with the nearest object available – a mercury thermometer. The thermometer broke and the mercury entered the reactor, where it was quickly taken into solution. However unplanned, this procedural deviation sharply increased the yield of phthalic anhydride and was quickly commercialized by BASF. It also appears to have initiated academic research into reactions of mercury with aromatic compounds. Thus in 1892, Jacob Volhard, then at Friedrichs-Universität Halle, discovered that aqueous mixtures of mercuric chloride and sodium acetate could mercurate thiophene alpha to sulfur [9]. With a bit of heating, both alpha positions could be substituted. This reaction, however, only afforded modest conversions, and it led to complex mixtures.

S

S

+ HgCl2 + NaOAc

O OH

O +

O

S

HO

(Volhard,1892)

OH

Hg(OAc) +

-O

O N+

Hg(OAc)2

+ Hg(OAc)2

+ AcOH

-O

O N+

HgX + -O

O N+

(Dimroth,1898)

+ -O

O N+

HgX (Westheimer,1950)

HgX Hg(OAc)2 in nitrobenzene, 150 °C:

57%

43%

Hg(CIO4)2 in 60% HClO4, 23 °C:

11%

89%

During his habilitation at the University of Tubingen in 1898, Otto Dimroth observed that boiling benzene with mercury(II) acetate resulted in the formation of phenylmercuric acetate [10]. Acetic acid was formed as the byproduct, accounting for the proton displaced from benzene. Phenol displayed even faster kinetics. It reacts with mercuric acetate at ambient temperature in aqueous media with a bias toward ortho mercuration. Ortho and para mercuration

1.2  Electrophilic C–H Bond Activation and Concerted Metalation Deprotonation

of toluene was also observed [11]. Additionally, thiophene undergoes cleaner mercuration using Dimroth’s conditions. Dimroth noted that this was a general electrophilic reaction for aromatic compounds, akin to sulfonation, nitration, and bromination [12]. But even at this early stage of investigation, there are hints that electrophilic aromatic substitution could not be the entire story. That would not account for the ortho-selectivity in the mercuration of nitrobenzene [12], which overrides the metadirecting tendency of the nitro group. Additionally, in 1907, Reissert reported [13] that the methyl group of nitrotoluene could be mercurated – an sp3 C–H bond functionalization. These early examples remained curiosities for some time, and were seldom the preferred way to access organomercury compounds. Indeed, in 189 pages of preparations of organomercury compounds in Goddard and Goddard’s 1928 textbook Organometallic Chemistry [14], only a handful of preparations involve direct reaction on C–H bonds [15]. And from a theoretical point of view, mechanistic understanding would await the development of physical organic chemistry methods. Starting in the 1920s, significant research was done on the regiochemistry of mercuration of aromatic systems. In 1921, Dimroth studied the mercuration of nitrobenzene, anisole, and phenetole [16]. Burton, Hammond, and Kenner described the orientation of products obtained from mercuration of o-nitrotoluene [17]. Samuel Coffey conducted more detailed studies on the mercuration of nitrobenzene and nitrotoluene [18] and noted deviations from the expected meta substitution pattern. Henry and Sharp described the regioselectivity of mercuration of alkylphenols and alkylphenolaldehydes [19]. Frank Whitmore was particularly prolific in this area during his stay at Northwestern University from 1920 to 1929, reporting the mercuration of a suite of aromatic systems [20]. These early experiments did not consider the intimate role of the anion in forming carbon-mercury bonds. That is, it was assumed that mercuric acetate, mercuric perchlorate, or mercuric acid with perchloric acid catalyst all effected the same transformation. The general assumption was indeed that mercuration occurred simply through electrophilic aromatic substitution. A progression of investigations beginning in the 1950s, however, led to the acceptance of a concerted TS with the acetate ligand of Hg(OAc)2 intimately involved in deprotonation concomitant with carbon-mercury bond formation. In 1950, Frank Westheimer and William Klapproth found that in the mercuration of nitrobenzene with Hg(OAc)2 at 150°C, the ortho and para products (57%) are formed in preference to the meta (43%) product [21]. Mercury perchlorate however conformed to the expected meta-orienting patterns of the nitro group. The anion mattered. After some preliminary studies [22], Herbert C. Brown came into agreement with Westheimer and Klapproth, articulating a difference between Hg(OAc)2 and Hg(ClO4)2, when he wrote: The results indicate that the attacking species in the uncatalyzed [i.e. without perchloric acid] reaction is a less selective agent than that involved in the perchloric acid-catalyzed reaction [23]. Due to the relatively low proportion of ortho product in the mercuration of toluene, Brown noted that the TS must be sterically demanding [24]. Winstein and Traylor elaborated on this observation by studying the kinetics of the reverse reaction, acetolysis of diphenylmercury [25], and proposed a cyclic, concerted TS involving proton transfer to the alkyl ligand concomitant with acetate coordination to mercury. Transition states know no direction, and so this arguably represents the first portrayal of a mechanism which aligns with the modern understanding of the concerted metalation-deprotonation.

R R

Hg

H O

C

O

CH3

R R H

Hg

+ O

C

O

CH3

Kresge and Brennan in 1966 arrived at a similar description of the key TS along the path to carbon-mercury bond formation through kinetic isotope effect (KIE) measurements [26]. In the mercuration of benzene by Hg(OAc)(ClO4), they observed a KIE of 6.0. They interpreted this to indicate that proton transfer from an intermediate sigma complex is the rate-limiting step of mercuration, and furthermore that the acetate group serves as the proton acceptor and

3

4

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

dissociates in concert. They left open the possibility that proton transfer may occur through a cyclic TS or to the solvent medium. Attention to kinetic isotope effects led to an interesting connection. In 1968, Davidson and Triggs surveyed a series of transition metal and post-transition metal acetates [27] – mercury (II), thallium (III), lead(IV), gold(III), palladium(II), platinum(II) – in the metalation of benzene. In some cases, metal aryl complexes could be isolated whereas in others they decomposed to biphenyl – an oxidative cross coupling reaction with precipitation of metal. And along the way, they explicitly identified similarities between the mechanisms of C–H activation by mercury(II) acetate and palladium(II) acetate: It is clear that there is a strong resemblance between palladation and mercuration especially on account of the large primary isotope effect (kH/kD = ca. 5.0). The steady-state treatment, if correct, implies that transfer of a proton from some intermediate containing a benzene molecule and palladium(II) ion is rate-determining. Strong support for Winstein and Traylor’s proposed mechanism eventually arrived in 1980 with the work of Roger Roberts and colleagues [28]. Building on prior low-temperature nuclear magnetic resonance (NMR) studies of arenemercurinium intermediates in sulfur dioxide by George Olah in 1976 [29], they proposed two consecutive pre-equilibria followed by a slow carbon-mercury bond forming step. ArH + HgX 2  [π complex ]  [σ complex ]+ [X− ] → arylmercury product The term sigma complex as used by Roberts refers to a Wheland intermediate, rather than the 3-center-2-electron bonding of metal interactions with C–H bonds. The formation of the π complex is accompanied by a modest entropy loss, and is unaffected by added trifluoroacetate anion in the case of Hg(TFA)2. This argues against ionization as a requirement for reaction. The subsequent steps are associated with a large decrease in entropy to reach the key TS (−20.3 eu±3.0 eu and −31.8 eu±1.9 eu for benzene and toluene, respectively) with rigid geometric requirements. They additionally observed a large primary KIE (kH/kD) of approximately 6 and 7 for benzene and toluene, respectively – indicating rate-limiting proton transfer in the TS (which they concluded was the breakdown of a sigma complex). Hammett analysis indicated a modest buildup of charge in the TS. These factors led them to question whether a discrete sigma complex need be invoked. Instead, the experimental evidence all seemed to agree with the cyclic TSe described by Winstein and Traylor, which resembles the current definitional model of concerted metalation deprotonation. In revisiting these experiments, it’s difficult if not impossible to completely separate concerted metalation deprotonation from proton transfer to solvent, or proton transfer via solvent shuttling. These minor differences in the pathway of proton transfer span either side of the definition of concerted metalation deprotonation and electrophilic insertion. As a credit to the researchers who developed this model, none asserted one pathway (intramolecular versus intermolecular proton transfer) over the other – instead, they left open the possibility for both. Likewise, this work preceded the direct observation of agostic bonding, non-classical dihydrogen complexes, and C–H sigma complexes. These are species that are now recognized as preliminary metal-substrate interactions that are central to C–H activation.

1.2.2  Modern Concerted Metalation Deprotonation The use of mercury reagents is no longer preferred, and in most cases has been superseded by superior methods (with less toxic reagents), and in particular those based on palladium. Early work in cross-coupling, including by Richard Heck [30], utilized arylmercury salts, but the same cross-couplings can be accomplished using organozinc, organomagnesium, and organotin (albeit still toxic) reagents. Organoboron reagents have become particularly preferred with the advance of catalytic C–H borylation methodology. Direct arylation strategies – with transition metals other than mercury – are being heavily researched to eliminate the need for pre-functionalized coupling partners, with a focus on eliminating the organometallic coupling partner. In some instances, the electrophile can be replaced as well, leading to the concept of dehydrogenative cross-coupling [31]. The archetypical dehydrogenative cross-coupling, and certainly the most influential work in concerted metalation deprotonation, is the Fujiwara-Moritani reaction [32]. This is the palladium(II) carboxylate-catalyzed hydroarylation of alkenes followed by β-hydride elimination to form styrene and stilbene derivatives.

1.2  Electrophilic C–H Bond Activation and Concerted Metalation Deprotonation

O

B

Pd (cat.) base

R

Pd (cat.) base

R

+

Pd (cat.) base

R

+

X

O

+

Both coupling partners require prefunctionalization

R X R

R

Suzuki-Miyaura reaction

Mizoroki-Heck reaction Olefin does not require prefunctionalization

Fujiwara-Moritani Neither partner requires prefunctionalization

The reaction was discovered by Yuzo Fujiwara in 1967, while completing his doctorate at Osaka University in the group of Ichiro Moritani, during the course of studies on the stereochemistry of nucleophilic attack on palladium olefin complexes [33]. In the initial example, the complex (di-μ-chlorobis(styrene)dipalladium(II)) was treated with acetic acid in benzene, leading to trans-stilbene formation and alpha phenethyl acetate. Their early description of this process appears to have been influenced by prior work on nucleophilic addition and oxidation of palladium olefin complexes [32a]. Whereas the key role of the acetate anion was quickly appreciated in this oxidative cross-coupling [32c], the connection to the emerging mechanistic understanding of the role of acetate in mercuration may not have been recognized right away. The substrate scope of the Fujiwara-Moritani reaction is fairly broad [34] and it is generally conducted at moderate temperatures (80–110°C). Yields tend to be modest, secondary>tertiary – a trend in which the stronger C–H bonds are more reactive, opposite expectation and trends shown by other reagents that can react with alkanes (e.g. radical), but a trend that ultimately was discovered to be characteristic of C–H activation by transition metal complexes. The work of Garnett and Hodges however had already caught the attention of Alexander Shilov whose group reported in 1969 [56], that exchange of deuterium and hydrogen takes place when methane or ethane was heated with K2PtCl4 in a D2O/CD3CO2D mixture under relatively mild conditions. Methane, notably, has the strongest C–H bond of any alkane. Most importantly, the Shilov lab soon reported actual functionalizations of light alkanes to give the corresponding alkyl chlorides and alcohols [57]. CH4 + [PtCl6] 2- + H2O (Cl-)

[PtCl4]2H2O, 120 °C

CH3OH (CH3Cl) + [PtCl4]2- + 2 HCl

The use of PtIV as a stoichiometric reagent would seem to defeat the economic value of using platinum(II) catalytically, as well as leading to confusion at a purely scientific level. Nevertheless, the efficiency of this system in carrying out selective C–H activation of the most inert of C–H bonds under mild conditions was clearly revolutionary, and ‘Shilov chemistry’ has certainly proven to be one of the most influential developments in the field of C–H activation [58]. Extensive mechanistic investigations of Shilov and related PtII-based systems have since been conducted [59], particularly by Labinger and Bercaw [1b, 60]. In the first step of the mechanistic cycle, methane undergoes C–H activation by a platinum(II) complex to form a methylplatinum(II) intermediate. The product then undergoes oxidation to yield a methylplatinum(IV) species. Nucleophilic attack then occurs at the methyl group by H2O, resulting in the reduction of the platinum center back to give back the platinum(II) species. This generalized mechanism set the basis for various other C–H functionalization reactions involving a platinum center.

7

8

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization Pt II

Pt II

+ RH

R

+ H+

ROH + H + Pt IV

RCl H 2O Pt II

ClPt IV

R

The nature of the C–H activation, the initial step in the Shilov cycle was the subject of a seminal computational study by Siegbahn and Crabtree in 1996 [61]. The authors considered that the platinum(II) center might undergo C–H oxidative addition, followed by deprotonation. This was, however, calculated to have a barrier higher – although not so much higher that it could be ruled out definitively – than an alternative pathway in which, methane, coordinated to Pt(II)Cl2(OH2), transfers a proton to a neighboring chloride. The authors referred to this as a “σ-bond metathesis”. Their nomenclature however may reflect the limited categories of the time recognized for C–H activation reactions. The term σ-bond metathesis (discussed below) had been used to refer to reactions of the type M–X+A–Y=M–Y+A–X (A=H for the most part). Clearly the term is appropriate in such cases, as they are (stoichiometrically) simple examples of two σ-bonded species exchanging partners. In the Siegbahn-Crabtree pathway, however, the chloride that accepts the proton never departs; instead, it loses the proton to solvent and thus the term σ-bond metathesis seems less than ideal. It is our view that CMD would have been a better description, but the term CMD had yet to be coined. Even more descriptive would be a term later coined by Davies and Macgregor, “ambiphilic metal ligand activation” or AMLA[1g]. Most precisely by this nomenclature system, this is an AMLA(4) process, where the number in parentheses refers to the number of atoms involved in the proton-transfer TS, as distinguished from a classic carboxylate-assisted CMD which is an AMLA(6) process. O X M

O

H C

M

AMLA(4)

H C

O

O

M

H

C AMLA(6)

AMLA (ambiphilic metal ligand activation) TSs

Platinum(II) is required to effect the C–H activation step, but the next step, conversion to a Pt(IV) alkyl is required to achieve functionalization. Platinum(IV) is likely unable to effect C–H activation, at least in part because of difficulty accessing a vacant coordination site. This could be envisioned to occur via either transfer of the alkyl from platinum(II) to platinum(IV), or via electron-transfer from the platinum(II) alkyl. Labeling experiments with isotopically enriched 195Pt demonstrate that the reaction proceeds through electron transfer [60g]. The electron-transfer pathway leads to the challenge of avoiding oxidation of the lower oxidation state species prior to alkylation. This problem was initially circumvented, albeit impractically, with the use of platinum(IV) as the oxidant – in that case, any oxidation of unmethylated platinum(II) is a degenerate reaction. The final step involves formation of a bond between carbon and a heteroatom (O or Cl) at the Pt(IV) methyl complex. This step involves nucleophilic attack at the carbon center; several studies have shown that there occurs an inversion of stereochemistry at the carbon center [60c, 60d]. Although the pictorial mechanism depicts the attack to be occurring at a six-coordinate platinum species, there is reason to believe that the nucleophile attacks at a five-coordinate platinum species [1b]. 1.2.3.3  Post-Shilov Electrophilic Activation

The use of an alternative to platinum(IV) as the terminal oxidant in platinum(II)-catalyzed methane functionalization was first reported by Periana and co-workers at Catalytica [62]. The reaction between methane and fuming sulfuric acid was

1.3  Oxidative Addition

catalyzed by a platinum(II) bipyrimidine complex to give methyl bisulfate in 72% yield at 220°C. The oxidant was the sulfuric acid solvent (which may be formally viewed as SO3 plus H2O). The bisulfate anion gave rise to the methyl ester. The ester, in contrast with methanol, was found to be stable under the reaction conditions as it is resistant to oxidation and to further attack by the electrophilic catalyst because it is particularly electron-poor [58c, 62]. CH4 + 2 H2SO4 → CH3OSO3H + 2 H2O + SO2 The ester could be hydrolyzed to give methanol and regenerate sulfuric acid. The oxidation of SO2 to give SO3 (which is perhaps the largest-scale chemical reaction practiced industrially) would complete the cycle with O2 as the ultimate oxidant in the process. Perhaps the biggest obstacle to practical application of this process is not strictly chemical, but separation of the water from the concentrated sulfuric acid [58c]. Apart from platinum, several palladium-based systems have also been developed for oxidation of methane and some lower alkanes. Sen and co-workers reported a bimetallic electrophilic system, comprising Pd/C and CuCl2 using trifluoroacetic acid and water as solvents, that could oxidize methane to methanol and methyl trifluoroacetate in the presence of oxygen and carbon monoxide (used as a co-reductant) [63]. The exact mechanism of this reaction is not very clear, but the studies suggest that free alkyl radicals are probably not involved in this type of reaction. Fujiwara and co-workers had also reported the oxidation of methane to acetic acid with CO, using a system of Pd(OAc)2 and/or Cu(OAc)2 in trifluoroacetic acid with potassium peroxodisulfate as oxidant. Among the co-catalysts, Cu(OAc)2 seemed to be the most effective in converting methane to acetic acid [64]. A report by Strassner showed that palladium(II) N-heterocyclic carbene complexes were able to convert methane to methyl trifluoroacetate in the presence of trifluoroacetic acid and trifluoroacetic acid anhydride using potassium peroxodisulfate as oxidant. Use of peroxydisulfate gives rise to the possibility of a radical pathway; indeed, in the absence of a metal complex, the oxidant itself could convert methane to alcohol via a radical pathway, albeit at higher temperatures [65]. The strategy of using H2SO4 to serve as solvent, nucleophile, oxidant, and protecting group, had been applied by Periana prior to the development of the platinum-based Catalytica system. The greatest success was found with mercury(II), but thallium(III) and palladium(II) were also found to be effective [66]. A one-pass methyl bisulfate yield of 43% was obtained at 180°C. Ess and co-workers investigated this system computationally [67]. In contrast with platinum(II), C–H oxidative addition, to either mercury(0) or mercury(II) was found to be definitively not viable. Rather they calculated a low-energy TS for C–H activation in which methane, coordinated to mercury(II), is deprotonated by a non-coordinating oxygen atom of a (κ1) coordinated bisulfate anion. This TS is completely analogous with the CMD TSs of palladium(II) systems (AMLA(6) in the Davies-Macgregor classification scheme [1g]). A TS that was very slightly (not meaningfully) lower in energy was calculated in which the proton was transferred from coordinated methane to a weakly coordinated bisulfate oxygen atom ligand (AMLA(4) [1g]).

1.3  Oxidative Addition 1.3.1  Stoichiometric Oxidative Addition of C–H Bonds Oxidative addition may be defined as any reaction in which the addition of one or more ligands to a metal center results in an increase in formal oxidation state of the metal center; for example addition of H+ which increases the formal oxidation state by 2 units. The most common usage, however, is for the net insertion of a metal center (regardless of the mechanism) into a bond X–Y to give M(X)(Y) where X and Y each acquire a formal charge of −1 and thus the charge of M is increased by 2. Oxidative addition rose to prominence in organometallic chemistry with the 1962 report of H2 adding, reversibly, to Vaska’s Complex [68]. H

PPh3 Cl Ph3 P

Ir

CO

+ H2

Cl Ph3P

Ir CO

PPh3 H

9

10

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

This reaction caused some consternation in the chemical community which had generally regarded H2 addition (e.g. to olefins) as a reduction (the confusion, which occasionally still arises, derives from the ambiguity of assigning negative or positive charges to H). As inorganic chemists think in terms of electronic structure, however, and the relationship between hydrides and the corresponding halides for example is very clear, Vaska correctly argued that H2 addition should be viewed as (formally) oxidative [68, 69]. Much more questionable, however, was Vaska’s extension of this argument to H2 addition being oxidative in a physical sense – even though much of his own very rigorous data suggested the opposite [69]. Complexes that are more electron-rich generally have a greater tendency to undergo additions that are physically oxidative, e.g. halogenation. But Ir–H bonds are not particularly polar and therefore other factors determine the relative thermodynamics of H2 addition to different complexes. In retrospect, it is clear that the thermodynamics of H2 addition were in many cases less favorable for those derivatives of Vaska’s complex that are more electron-rich [69, 70]. Nevertheless for many years it was accepted that complexes that are more electron-rich would undergo any oxidative addition more favorably. In the context of oxidative addition of C–H bonds; this proved to be misleading. At the very least it contributed to a failure to see the close relationship between various types of reactions that resulted in C–H bond cleavage and metal-carbon bond formation, in particular oxidative addition and electrophilic addition. The first example of oxidative addition of C–H bonds is often attributed to Chatt in 1965 [71], shortly after Vaska’s report. He found that gen erating Ru(0)(dmpe)2 resulted in addition of both C–H bonds of naphthalene and those of the phosphinomethyl groups [72]. H

P Ru

P

“Ru(Me 2PCH 2 CH2 PMe2 )2 ”

P

P P

P

CH2

P

Ru

CH2 P

H

P

P

P

Ru P

H

This surely seemed to support the notion that very electron-rich complexes were key to activating inert C–H bonds. But, ironically enough, it was much later found by Roddick that Ru[(C2F5)PCH2CH2P(C2F5)2]2, a much less electron-rich analogue of Ru(dmpe)2, was apparently more reactive toward the addition of C–H bonds [73]. The year 1965 also saw the report by Cope and Siekman of a cyclometalation of an azobenzene (i.e. the activation of one of the ortho-phenyl C–H bonds) [74]. Whereas the net reaction is not an oxidative addition, and it might perhaps best be described as electrophilic activation, in retrospect at least the possibility of C–H addition followed by loss of HCl can certainly be considered. The value of ortho directing groups and the ambiguity between the usual categories of C–H addition seems to have been foreshadowed by this discovery decades before these concepts came to the fore.

K2 Pt(II)Cl4 + or Pd(II)Cl2

N

N

Cl N r.t. 2 weeks

N

M

M N

N

Cl

M = Pd, Pt

Most of the early examples of C–H activation involved aryl C–H bonds or intermolecular additions, or frequently both (e.g. cyclometalation of a PPh3 ligand) [75, 76].

1.3  Oxidative Addition

PPh3 Ir

Ph3P

Cl

H

PPh3

PPh2 PPh3 Ir Cl PPh3

A particularly notable class of such reactions was discovered by Shaw. With 1,3-bis[(di-t-butyl)phosphino)methyl] benzene, cyclometalation gives rise to an extremely stable pincer structure. Complexes of nickel, palladium, platinum, rhodium, and iridium were all synthesized via cyclometalation of the diphosphine [77]. Pt Bu2 Pt Bu2

MCl 2(NCPh)2 M = Pd, Pt

M

Cl

Pt Bu2

H

M = Pd, Pt

Pt Bu2

Pt Bu2

MCl3 •(H2 O) n M = Rh, Ir

M

Cl H

Pt Bu2

M = Rh, Ir

These complexes and derivatives thereof would ultimately play a supporting role for a vast range of catalytic and other valuable reactions, including many examples involving oxidative addition of unactivated C–H bonds [78]. An important example of intermolecular oxidative addition of a C–H bond was reported in 1970 by Green, who found that benzene undergoes C–H addition to Cp2W. This fragment, which has a valence electron count (VEC) of 16e, was generated from Cp2WH2 either by photolysis [79] or by hydrogenation of olefin [80] (two approaches that were subsequently employed countless times in the field of C–H activation). Note that whereas 16e square planar species like Vaska’s Complex do not add unactivated C–H bonds, and even add H2 relatively slowly and reversibly (i.e. not very exergonically), Cp2W appears to add the benzene C–H bond too rapidly to allow its observation and the thermodynamics of addition are too favorable to allow rapid reversibility.

hν

H

W

H

W

-H2

H

+ C6H6

In 1982 Bergman [81] and Graham [82] independently reported pentamethylcyclopentadienyl (Cp*) iridium complexes that effected the first well characterized examples of oxidative addition of alkane C–H bonds. Thus C–H bond activation had finally been achieved to give well characterized products, with the corresponding metal carbon bonds, without assistance through coordination at another site or the help of π electrons. This breakthrough captured the imagination of the chemical community and brought C–H activation to the forefront unlike any prior reaction.

Ir Me3P

H

+ R-H

Ir OC

hν -H2

H

CO

hν -CO

Ir L

H

R = cycloalkyl, n-alkyl

R

L = PMe3 (Bergman); L = CO (Graham)

11

12

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

In both cases, irradiation was presumed to generate the corresponding 16e species via loss of H2 or CO respectively, which (like Green’s Cp2W fragment [79, 80]) underwent rapid C–H addition. As much as the addition of fully unactivated alkane C–H bonds rightfully attracted attention, arguably the most exciting aspect of this chemistry was the regioselectivity. With Cp*Ir(PMe3), Bergman found kinetic preference for activation that correlated positively, rather than inversely, with C–H bond strength, for example: aryl>1°>2°>>3°. This finding was soon supported and elaborated upon in work by Graham (who observed addition of the very strong methane C–H bond [83]), Jones [84], Flood [85], Field [86] and others – and with metals other than iridium. This selectivity has profound implications. In general, most reagents or catalysts capable of effecting C–H bond cleavage will (not surprisingly) preferentially react with weaker C–H bonds. Thus this chemistry indicated that transition metal complexes could show complementary, orthogonal, selectivity. This suggested particular promise with respect to n-alkanes and more generally n-alkyl groups. Functionalization of the terminal position versus internal position would be more desirable in many cases, but based on normal considerations of bond strengths it is expected to be disfavored. Moreover, the surprising correlation of kinetics with C–H bond strength suggested a way around a potentially formidable barrier to catalytic alkane functionalization: specifically, the initial functionalization of an alkane invariably leads to a product with C–H bonds weaker than that of the parent alkane. Therefore, with the use of any reagent or catalyst which reacts with a preference for weaker C–H bonds, the initial product which will undergo further conversion relatively rapidly, limiting its yield. The conversion of methane to methanol, for example is relatively easy; the hard part is stopping there and not converting the product to CO2. As noted above, the Shilov system had already shown promise in this respect [56–58]; the well characterized stoichiometric reactions now put this on firmer conceptual ground. Aryl and vinyl C–H bonds are stronger than alkyl, but the preference for their addition seemed less surprising than the preference for stronger bonds within the alkyl series; the π-electron system was thought to “pre-activate” these bonds to some extent. Elegant work by Jones indeed demonstrated that coordination of arene π-system preceded aryl C–H bond addition by Cp*Rh(PMe3) [84a, 84b]. On the other hand, Bergman showed that in the case of ethylene (certainly a much better π-donor than arenes), C–H addition was not preceded by π-coordination; in fact, the ethylene π-complex was formed via initial C–H activation(!) [87]

1.3.2  Mechanistic Pathways and the Oxidative Addition Continuum A stoichiometric reaction that results in oxidative addition generally poses no ambiguity, regardless of the mechanistic pathway. But the practical importance of oxidative addition (which applies to any class of organometallic reaction mechanisms) generally derives from reactions in which it describes an intermediate, especially in a catalytic cycle. Intermediates, however, are not typically observed but are usually inferred from experimental mechanistic or computational studies. In many cases, there is little doubt of the intermediacy of the products of oxidative additions, but exceptions are not uncommon. A particular class in which this is often the case is the reaction class that may best be called sigma-bond metathesis (SBM), of which an example of particular relevance to C–H activation is shown below. M − R + R' − H → M − R' + R-H (R, R'=hydrocarbyl or H) However, the term SBM was first used to imply a specific mechanistic pathway (discussed in its own section below), in reference to d0 complexes and this is clearly very distinct from oxidative addition. For complexes in which M has two or more d-electrons, a net SBM can be envisioned to proceed via oxidative addition followed by reductive elimination, concertedly via a four-centered TS as is assumed to be the case for d0 complexes, or on a continuum anywhere in between. In addition to this continuum, which refers to the degree of M–H bond formation along the reaction pathway, there is the question of whether there is any intermediate along the pathway. Thus a species in which the M–H bond is fully formed can be either an intermediate or a TS. Fortunately, as such questions become more difficult to answer they also tend to become less physically significant. The question of whether a reaction proceeds through a species with a very brief but finite lifetime has no obvious significance with respect to the design of a catalyst intended to favor the reaction by lowering the overall barrier (presumably the actual TS has physical properties very similar to a very shallow energy minimum that may precede it).

1.3  Oxidative Addition “classical” σ -Bond Metathesis

H

R’ M

R + R’ H

M

R

σ -CAM

Oxidative Hydrogen Migration

R’

H

R’

H

M

R

M

R

continuum of TSs

M

R’ + R

H

R, R’ = H, hydrocarbyl, etc.

Various nomenclatures have been adopted, with each generally associated with a different degree of M–H bond formation. SBM is clearly the appropriate term (for the mechanism as well as the stoichiometry) in the absence of any M–H bond formation (including d0 metals). For dn metals, terms given crudely in increasing order of the implied M–H bond formation include: Metal-Assisted σ-Bond Metathesis (Hall and Hartwig [88]), σ-Complex Assisted Metathesis (σ-CAM; Perutz and Sabo-Etienne [89]), Oxidatively Added Transition State (OATS; Eisenstein [90]) and, implying a fully formed M–H bond in the TS, Oxidative Hydrogen Migration (OHM) (Goddard and Periana [91]). Love’s review on the continuum of C–H bond activation offers an insightful discussion of this topic [2].

1.3.3  Catalytic Reactions Proceeding via Oxidative Addition 1.3.3.1  H/D Exchange

Whereas the discovery of a stoichiometric reaction may provide the starting point for the development of a catalytic reaction, it is also common for discovery of a catalytic reaction to precede and even lead to the stoichiometric example. In 1970, Parshall at DuPont reported [92] that (η5–Cp)2TaH3 and L2IrH5 (L=PEt3, PMe3, PPhEt2) catalyzed the deuteration of benzene by D2. They proposed that the reactions proceeded via loss of H2 (or D2) from the hydride(deuteride), oxidative addition of a C–H(D) bond, and C–H(D) elimination. This preceded – by a few months – Green’s report of addition of the benzene C–H bond to (η5–Cp)2W (a fragment generated by loss of H2 from (η5–Cp)2WH2). Parshall and other DuPont researchers, including Tebbe, subsequently found a broad range of complexes that catalyzed H/D exchange between D2 and C–H bonds, including TaH5(dmpe)2, (η5–Cp)2NbH3, ReH5(PPh3)3 and RuHCl(PPh3)3 [93]. General principles of arene C–H activation were soon elucidated, including the much greater activity of aryl versus alkyl C–H bonds, and the tendency to avoid activation of C–H bonds ortho to non-coordinating groups such as CH3 or CF3. Electron-withdrawing substituents on the aryl ring generally favored exchange, although the effect was not large (and even absent in the case of (η5–Cp)2TaH3). MHn + H2 - H2 D

D2

MHn-2 D

H M

M

H D

D D M

H

D

M

D

HD

M

RuHCl(PPh3)3 was found to catalyze H/D exchange of both the ortho-aryl and methyl C–H bonds of Ph2P(CH2CH2CH3). The rates were approximately equal, which was explained in terms of the more favorable ring size required for cyclometalation of the methyl versus the aryl (four- versus five-membered, respectively) compensating for the intrinsically higher activity of the aryl C–H bonds. Accordingly, the phenoxy group of Ph2P(OPh) was reported to undergo ortho deuteration

13

14

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

at least 50 times as fast as that of the P-bound phenyl groups. In retrospect, we can see that this work foreshadowed directed catalytic functionalizations of arenes, including the favorability of five-membered metallacycle intermediates for arene functionalization. O

PPh2 CH 2

MLn

PPh2

H

sp3 C-H addition 5-membered ring

MLn

H

sp2 C-H addition 4-membered ring

PPh2 MLn

H

sp2 C-H addition 5-membered ring

Although it was primarily H/D exchange, and thus not a true functionalization, the DuPont work had profound implications. Whereas it may be easier in some sense to appreciate a transformation that gives rise to a stable metal-carbon bond (e.g. simple C–H bond additions), the catalytic H/D exchange reactions highlighted that formation of such intermediates is not necessary for catalysis. Indeed, it highlights the broader point that stable intermediates disfavor catalysis in general. With regard to C–H activation, this reflects a point made by Halpern, who noted that the kinetic barriers to C–H elimination had been well studied and are typically low [94]. Halpern inferred that C–H addition likewise generally has a low kinetic barrier, but is typically unfavorable thermodynamically. As revealed by the DuPont H/D exchange systems, however, an intermediate being slightly uphill does not preclude catalysis; arguably it is better if addition is slightly uphill (and thus difficult or impossible to observe) than downhill in which case the energy of addition must ultimately be paid back to complete a catalytic cycle. It should also be noted that isotopic exchange of C–H bonds has proven to be of value far beyond the mechanistic insight that it offers concerning C–H activation. Exchange with deuterium or tritium has a wide range of valuable applications in the development and study of pharmaceuticals [95]. Transition metal-based compounds, not so unrelated to those in the work discussed above, play a critical role in such work. A relatively recent development has been the discovery by Chirik [96] that organoiron catalysts offer site-selectivity orthogonal and complementary to the standard Ir catalysts [97, 98] used for isotopic labeling of drug molecules. Consistent with the proposal that catalysis of isotopic exchange would suggest an ability to catalyze true chemical transformations, (η5–Cp)2NbH3 was found to catalyze the alumination of benzene, which was proposed to proceed via intermediates similar to those involved in H/D exchange [93].

+ AlEt3

Cp2 NbH 3

AlEt2 + H-Et

1.3.3.2  Alkane Dehydrogenation

In marked contrast with the notoriously inert alkanes, olefins are among the most versatile of organic intermediates. Dehydrogenation of alkanes or alkyl groups is therefore potentially a transformation of tremendous value. Crabtree realized that microscopic reversibility implies that if olefin hydrogenation is very facile, then thermodynamic factors account for the difficulty of catalyzing alkane dehydrogenation to give olefins. To offset the unfavorable thermodynamics, he introduced the use of an olefin as a sacrificial hydrogen acceptor and chose 3,3-dimethyl-1-ethylene (t-butylethylene or TBE), which was considered to have favorable thermodynamics of hydrogenation but would not coordinate too strongly. In addition, Crabtree initially targeted cyclopentane as a substrate, reasoning that formation of a π-cyclopentadienyl complex would provide further driving force for the reaction [99]. [(Me2CO)2lrH2(PPh3)2]+, an extremely good catalyst for olefin hydrogenation, was indeed found to react with cyclopentane and TBE to give [(η5–Cp)Ir(PPh3)2H]+ and the product of TBE hydrogenation (TBA). Its reaction with cyclooctane (COA) yielded the 1,5-COD complex. The assumption that the reaction proceeded via the microscopic reverse of olefin hydrogenation, in which alkane is released via C–H reductive elimination, would imply that the dehydrogenation is initiated by C–H oxidative addition.

1.3  Oxidative Addition BF4 [IrH 2 (Me 2 CO ) 2 (PP h3 ) 2 ]B F 4

or

t

t

Bu (TBE )

Bu (T BA )

Ir Ph3 P

PPh3 H

or

PPh3

BF 4

Ir PPh3

Baudry, Ephritikhine, and Felkin at Gif-sur-Yvette in France then reported a similar reaction of cyclopentane and Re(PPh3)2H7, also with TBE [100]. These workers then extended this to n-alkanes which gave (1,3-diene)Re(PPh3)2H3. The dehydrogenated alkane could be displaced, by P(OMe)3 to liberate – remarkably – not the diene, but rather, free 1-alkene [101]. Both the Crabtree and Gif-sur-Yvette groups shortly thereafter reported multiple catalytic turnovers for the dehydrogenation of COA, using TBE as hydrogen acceptor [102, 103]. The higher activity of COA is undoubtedly related to mediumring transannular repulsions which result in an anomalously low dehydrogenation enthalpy. The COA/TBE couple has since become established as a benchmark for alkane transfer-dehydrogenation catalysis. L AcO tBu

CF3

O

R

L

H H

AcO Ir

L

tBu

O

Ir

L Ir L

H

tBu

L H2

H

L

hν

AcO

H

Ir L

R

Ir L

L AcO

tBu

R

L H H

AcO Ir

H

R

L

AcO = CF3C(O)

Crabtree then reported that complexes IrH2(CF3CO2)(PR3)2 (R=p-C6H4F, cyclohexyl) catalyze thermal alkane/TBE transfer dehydrogenation (at 150°C) and also photochemical (254 nm light) alkane dehydrogenation at room temperature to liberate free H2 [104]. It was proposed that the thermal and photochemical mechanisms shared common steps for alkane dehydrogenation: C–H oxidative addition to Ir(CF3CO2)(PR3)2 and β-H elimination to give IrH2(CF3CO2)(PR3)2. Importantly, it was recognized that C–H oxidative addition was not necessarily the rate-determining step, which might instead be β-H elimination. In the case of transfer dehydrogenation, this sequence was followed by the reverse steps, with TBE undergoing hydrogenation. In the photochemical case, the light was proposed to induce dissociation of H2 from the dihydride to regenerate the active fragment Ir(CF3CO2)(PR3)2. Saito reported in 1990 the first example of alkane dehydrogenation without the use of either a sacrificial acceptor or irradiation. With Wilkinson’s hydrogenation catalyst, the reverse of hydrogenation was achieved with the reaction driven solely by allowing H2 to escape from a refluxing solution of COA (boiling point 151°C) [105]. Crabtree extended the range of catalysts for such acceptorless dehydrogenation to include his previously reported iridium catalyst and well beyond, including Pd/C, (triphos)ReH5 and, notably, a non-precious-metal catalyst, (triphos)WH6 [106]. These critical advances notwithstanding, turnover numbers were low (< ca. 40) and much lower still for alkanes other than COA until 1988; that year Tanaka reported that (PMe3)2Rh(CO)Cl could, under irradiation, effect much more efficient dehydrogenation of COA (930 TO in 3 days) and even give fairly high turnover numbers with cyclohexane and n-hexane (155 TO after 27 h; 99% 2- and 3-hexenes) [107]. A mechanistic study [108] of this unprecedentedly active system by the Goldman lab reached a surprising conclusion. The active fragment was (PMe3)2RhCl, generated by photochemical loss of CO from the starting material. This fragment dehydrogenated the alkane to give (PMe3)2RhClH2 and olefin. The analogy with Crabtree’s report of Ir(CF3CO2)(PR3)2 would suggest that the reaction was driven by photoextrusion of H2 from this

15

16

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization L

H2

hν

L

L Cl

L = PMe3

Cl Rh CO

H

Rh

CO

L L

Cl Rh

H

L

A

CO

Cl Rh CO

L

L R

L Cl

Rh L R

L

H H

Cl

Rh

R

+ H2 - CO + CO - H2

L Cl

H

Rh

H

L

H

R

R

A L Cl

Rh L

R

L

species. Instead, however, it was shown that H2 was displaced by CO to regenerate (PMe3)2Rh(CO)Cl. Thus the photochemical loss of CO provided the energy needed to drive the very endothermic alkane dehydrogenation. A common theme emerging from much of the work described above was the effectiveness of three-coordinate d8 fragments for dehydrogenation. Such fragments were seen to be particularly active towards C–H addition, like those of the type CpML (M  =  Rh, Ir) earlier found to give stable C–H addition products. But addition to the ML2X fragments gave 16e adducts with a vacant coordination site capable of undergoing β-H elimination. In consideration of the mechanism of photochemical dehydrogenation by Rh(PMe3)2(CO)Cl and the key role of Rh(PMe3)2Cl, the Goldman group investigated the thermochemical activity of Rh(PMe3)2(CO)Cl under high pressure of H2 [109]. In accord with microscopic reversibility, H2 was apparently able to displace CO to the extent that olefin was rapidly hydrogenated. Remarkably, the addition of high pressure of H2 also led to alkane dehydrogenation. Apparently, the olefin hydrogenation, via the reverse of all the thermochemical steps in the above cycle, led back to the formation of Rh(PMe3)2Cl, which could then effect alkane dehydrogenation via the same steps in the forward direction. The net result is an H2-catalyzed transfer-dehydrogenation. The system was the first to give high rates and high turnover numbers for thermochemical dehydrogenation of both COA and acyclic alkanes. THF was also dehydrogenated efficiently, to give predominantly 2,3-dihydrofuran. However, in addition to transfer-dehydrogenation, several mol H2-acceptor were hydrogenated per mol of dehydrogenated alkane (an unsurprising side-reaction under such conditions), limiting the potential economic viability of such a system [109, 110]. In an effort to obviate the need for added H2, and thus the undesired hydrogenation of excess acceptor, the Goldman group investigated potential precursors of Rh(PMe3)2Cl that did not contain CO. Rh(PMe3)2Cl itself exists as a dimer. Cleavage of the halide bridge and catalytic activity could be achieved with H2 atmosphere and H2 acceptor, but this defeated the purpose of this line of investigation [111]. In an effort to develop Rh(PMe3)2Cl analogues resistant to dimerization, a pincer-ligated rhodium complex was synthesized. This complex catalyzed alkane transfer-dehydrogenation but much less effectively than the Rh(PMe3)2Cl-based systems [112].

Cl

PR 3

PR2

Rh

Rh

PR 3

PR2

highly active

(RPCP)Rh low activity

PR 3 Cl

Ir PR 3

low activity

PR2 Ir

( RPCP)Ir highly active

PR2

Independently, Jensen and Kaska had found that the iridium complexes Ir(PR3)2Cl showed limited activity for alkane dehydrogenation. In the case of iridium, however, in contrast with rhodium, the pincer-ligated complex (tBuPCP)Ir was found to be highly active for cycloalkane transfer-dehydrogenation, much more so than the monodentate-ligand complexes. The very high activity was observed at high temperatures (150°C–200°C), reflecting the generally high thermal stability of both pincer complexes and iridium complexes [113]. Cyclohexane dehydrogenation resulted in comparably high turnovers of benzene and cyclohexene, and methylcyclohexane likewise gave toluene. (tBuPCP)Ir was also found to be effective for transfer-dehydrogenation of ethylbenzene to give styrene, and THF to give mainly 2,3-dihydrofuran [114].

1.3  Oxidative Addition

A very wide range of pincer-ligated dehydrogenation catalysts have been developed since the initial reports of (tBuPCP) Ir [115], a small fraction of which will be discussed below for illustrative purposes. Jensen, Goldman and co-workers found that (tBuPCP)IrH2 was highly effective for the acceptorless dehydrogenation of COA and even more so for cyclodecane (presumably due to the higher boiling point of the latter) [116]. The iPrPCP analogue was found to be even more reactive for acceptorless dehydrogenation, including n-alkanes [117]. An important advance in this field was the finding that (RPCP)IrH2 (R=tBu or iPr) catalyzes the transfer dehydrogenation of n-alkanes with high rates and turnovers, and with high kinetic selectivity for the terminal position to give the very desirable 1-alkenes [118]. However, double bond isomerization results in the more thermodynamically stable internal olefins. The final yield of 1-alkene is dependent on the nature and concentration of acceptor but in even the most favorable case, the maximum 1-alkene concentration was less than 0.1 M (1.0 mM (tBuPCP)IrH2,1-decene acceptor). Much later, significantly higher concentrations of 1-alkene were obtained, surprisingly, in heterogeneous systems in which the alkane and olefin acceptor (ethylene or propylene) are in the gas phase during the reaction, and the (iPrPCP)Ir catalyst is present as a molecular solid [119]. The higher yields of 1-alkene were not attributed to the unusual catalyst phase. Instead they were explained strictly on the basis of relative concentrations of alkane and olefin and the high activity of ethylene or propylene as acceptors. It was demonstrated that, under typical solution conditions, isomerization was catalyzed by the dihydride (iPrPCP)IrH2; this was present in only very small concentration under ethylene or propylene atmosphere and in the absence of liquid alkane. Isomerization, however, was also catalyzed by an allyl hydride; unfortunately this latter pathway was still fully operational under the reaction conditions and thus the buildup of 1-alkene, although higher than in solution, was still limited [119]. High yields of 1-alkene from n-alkane dehydrogenation, or even monoenes more generally, seemed unattainable due to secondary reactions such as isomerization and secondary dehydrogenation. In part for this reason, attention was turned to tandem systems in which a secondary reaction of olefin was catalyzed, driving the reaction forward. Brookhart and Goldman reported that Schrock-type olefin metathesis catalysts operated in tandem with pincer-Ir dehydrogenation catalysts to effect alkane metathesis or disproportionation [120]. This enabled, for example, the synthesis of valuable n-alkanes in the diesel range (ca. C9–C18) from low-value light n-alkanes such as the formation of n-decane, plus ethane, from 2 mol n-hexane (R=n-C4H9 in the scheme below).

2

dehydrogenation R 2 [Ir]

2 [Ir]H2

2

olefin metathesis R

R

R

+ CH 2 CH 2

hydrogenation

R

R

+ CH 2 CH 2 2 [Ir]H2

2 [Ir]

Huang later showed that cross-alkane metathesis could be used to convert polyethylene and light n-alkanes to diesel range alkanes. Surprisingly, the system was even effective with real-world post-consumer polyethylene such as commercial plastic bags [121]. Perhaps the most promising fulfillment of the promise of tandem dehydrogenation-based catalysis has emerged from the Huang group. In one example a PSCOP-Ir dehydrogenation catalyst was used in tandem with a pincer-iron hydrosilylation catalyst to yield n-alkyl silane [122]. This approach has been extended to convert linear Cn alkanes to linear Cn+1 aldehydes [123] via dehydrogenation/hydroformylation, as well as Cn+1 amines [123] and alcohols [124]. 1.3.3.3  Alkane Dehydrogenation by High-Oxidation-State Catalysts

The dehydrogenation reactions described above generally proceed through C–H oxidative addition to a low valent metal center (especially iridium(I)). More recently, however, Goldberg and Goldman have investigated dehydrogenation with high oxidation state complexes, particularly iridium(III). This work was initiated based on Nishibayashi’s report of alkane C–H activation by (Phebox)Ir(OAc)2 yielding (Phebox)Ir(OAc)(n-alkyl). The Goldberg lab reported that at high temperatures the n-alkyl complex eliminates 1-alkene to give (Phebox)Ir(OAc)H [125]. In a separate reaction, with promising implications for aerobic dehydrogenation, the hydride complex reacted with O2 and HOAc to regenerate (Phebox)Ir(OAc)2 [126]. Acceptorless dehydrogenation of n-alkanes was found to be catalyzed by (Phebox)Ir(OAc)H, with rates significantly increased by the presence of sodium ions [127]. A trifluoromethyl derivative was found to be a highly robust and active, perhaps the most active catalyst for the acceptorless dehydrogenation of n-alkanes reported to date [128].

17

18

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization R

H2

H3C

O

O N

N O

O O[Na+]

Ir

O[Na+]

Ir

H N

N

O

R

O R

The key step of the catalytic cycle shown is a net C–H/M–H SBM, quite distinct from the mechanism of the iridium(I) catalysts. DFT calculations indicate this proceeds concertedly, via a transition state (TS) in which all bond lengths are fully consistent with a C–H oxidative addition [128]; i.e. an (OHM) [91]. Moreover, the calculations (NBO analysis) indicate that this (formal) ‘oxidative addition’ involves a net transfer of charge from the alkane to the iridium center [128]. This may help to explain why the electron-poor trifluoromethyl derivative is more reactive than the dimethyl parent. And whereas the primary role of the sodium cation is to open a vacant coordination site by dechelation of the acetate ligand, the positive charge may additionally promote the reductive oxidative addition [129]. 1.3.3.4  Applications of Dehydrogenation in Heterocyclic Chemistry

The presence of a heteroatom adjacent to a C–C bond thermodynamically favors dehydrogenation of that bond [130]. Thus it is not surprising that THF was one of the first non-alkane substrates dehydrogenated by the early alkane dehydrogenation catalysts [109, 114]. Knapp and Goldman later reported that tertiary amines could be dehydrogenated by (tBuPCP)IrH2 and (MeO–iPrPCP)IrH2 to give enamines [131] (which are often valuable synthons) including several very simple enamines (e.g. N,N-di(isopropyl)vinylamine) not previously reported. On a per C–C bond basis the aminoethyl group was found to be about 160 times more active even than COA. Relatedly, Templeton found that (nacnac)Pt(H) effected dehydrogenation of diethyl ether more readily than pentane [132]. The dehydrogenation of saturated heterocycles has attracted attention both in the context of organic synthesis and in their possible use for hydrogen storage and release. Brookhart reported one of the first examples of the use of a first-row metal for aliphatic-group dehydrogenation [133]: the intramolecular transfer-dehydrogenation of N-silyl piperidines was catalyzed by Cp*Co(olefin)2 under remarkably mild conditions in very high yield. This was extended to a wide range of N-silylated cyclics, including 1,4-piperazines, morpholines, and seven- and eight-membered rings. The reaction was proposed to proceed via C–H oxidative addition; insertion of the silyl vinyl double bond into the resulting Co–H bond then opened a vacant coordination site, allowing β-H elimination to give the enamine product.

Co

X

N

Si

SiMe3 6h, 80 °C

X = CH 2: >99% yield X = O: >99% yield X = NMe: >95% yield

SiMe3

X

N

Si

A wide range of N- and O-containing heterocycles were dehydrogenated by the (PSCOP)Ir catalyst developed by the Huang group using TBE as a hydrogen acceptor [134]. The mechanism is presumably analogous to that of alkane dehydrogenation by the same catalyst.

1.3  Oxidative Addition S

PiPr2

0.5 mol %

Cl

Ir

H

X

O

O

t PiPr2 + NaO Bu

120 °C 12 h

X = O : 84% yield X = NMe: 82% yield X

TBE

O

TBA

Yamaguchi and Fujita reported that Cp*Ir(2-hydroxypyridine) could dehydrogenate tetrahydroquinolines, and then catalyze the reverse, hydrogenation of the quinoline, suggesting promise for an organic hydrogen-storage system. The reaction appeared to proceed via proton and hydride transfer rather than oxidative addition [135, 136]. Note that such a pathway is more likely to be accessible to first-row metals than is oxidative addition. Accordingly, Jones found that an iron complex could catalyze the same reaction, as well as the reversible dehydrogenation of other N-heterocycles through a metal-ligand cooperative (MLC) mechanism. The overall reaction was proposed to proceed through isomerization subsequent to dehydrogenation, and then another dehydrogenation of a HN–CH2 linkage [136, 137]. PiPr2 H N Fe CO H2

N

PiPr2 dehydrogenation

H

PiPr2 H N Fe CO H PiPr2

H

dehydrogenation [Fe]

N

N

N

H

H

H2

N

A related cobalt complex also catalyzed dehydrogenation of tetrahydroquinoline reversibly, although, interestingly, it was proposed that the dehydrogenation proceeded through a MLC mechanism whereas the hydrogenation proceeded through a non-cooperative pathway [138]. 1.3.3.5  Borylation

Suzuki-Miyaura coupling (palladium-catalyzed C–C bond formation using organoboron species) is considered to be the second most commonly applied of all organic reactions used in medicinal chemistry (after the ubiquitous amide bond formation) [139]. Thus there is great demand for a very wide range of organboronates, and the ability to transform C–H bonds to C–B bonds is of corresponding value. In the mid 1990s, Hartwig reported the stoichiometric borylation of alkanes and arenes by irradiation of Cp* carbonyl boryl complexes in the presence of the hydrocarbons [140]. O OC

W

OC

Bcat’ CO

hν

Bcat’ 85%

Bcat’ = B

+

+ HBcat’

OC

W

OC

H

O

CO

The authors proposed that the reaction proceeded via photoextrusion of CO, followed by oxidative addition of a hydrocarbon C–H bond and then B–C reductive elimination – a net σ-bond metathesis). They also considered however a more direct σ-bond metathesis, in which the unsaturated nature of the boryl ligand promoted C–H activation and B–H bond formation.

19

20

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

Moving away from carbonyls, toward much more labile olefin ligands, Hartwig soon developed related, highly effective, catalysts for thermal borylation of alkanes with the use of either boryl ester dimer or hydride [141]. Benzene was found to be even considerably more reactive than alkanes.

O H

B O +

Cp*Rh(C 2H 4 )2 or Cp*Rh(η 4 -C 6Me6 )

or O

O B

H2 +

O B O

150 °C

B O

O

Independently, Smith found that Cp*Ir(PMe3) (the fragment originally reported by Bergman to undergo alkane C–H addition) catalyzed benzene borylation with HBPin [142]. Also, moving to very labile ligands that afforded multiple coordination sites, Smith developed iridium catalysts that were highly effective and regioselective for borylation of aryl C–H bonds [143]. Maleczka and Smith have developed a deborylation process that allows site-selective deuteration and, via diborylation, indirect monoborylation at sites not otherwise selectively accessible [144].

Br

S

Ir catalyst

Br

HBpin or B2pin2

S

Bpin

Ir catalyst

S

Br

Bpin

HBpin or B2pin2

Ir or Pd catalyst

Br

S

H/D

MeOH(D) Bpin

Bpin

Chirik has developed non-precious-metal catalysts for C–H borylation [145]. Remarkably a cobalt-based complex was found to effect diborylation in high yield and even triborylation, at a single methyl group [146], chemistry unprecedented with platinum-group catalysts.

N CH3

R

N Co CH2 SiMe3 R

CH 2SiMe3

2 B2 pin2 or 4 B2pin2 + 3HBPin

Bpin Bpin

Bpin Bpin

95 % yield

or

Bpin

18 % yield

A plausible general mechanistic motif for all of these reactions involves simple B–H or B–B additions, C–H oxidative addition, and B–C eliminations. A persistent question in this field, however, is whether the boryl group assists the C–H activation. At least thus far, it does not appear that there is a generalized answer to this question [147]. Depending on the specific complex or substrate, a simple C–H addition may occur, or there may be substantial contributions to hydride formation from the formally empty p-orbital of the boron, or there may be proton transfer [148] to the electron rich B–M bond. In addition, the O atoms of the boryl ester group may play a significant role by interacting, for example, with the α-C–H bond of an N-ethyl group undergoing of the β-C–H bond [149]. Thus selectivity can be greatly influenced by particular aspects of the C–H activation step. It seems likely that the property of the boryl group that is most responsible for the high activity afforded by so many systems, however, is unrelated to the boryl group’s ability to promote activation of C–H bonds. C–H activation is, after all,

1.4  Insertion Reactions

often a kinetically facile process as indicated by the many examples of rapid H/D exchange. Kinetically, the most important factor with respect to activity may be the unusual ability of the boryl group to undergo rapid B–C elimination subsequent to C–H activation, owing to the planarity at boron and the available p-orbital [147, 149, 150]. Moreover, factors that favor B–C elimination (planarity, vacant p-orbital) also favor the kinetics of B–B and B–H addition to the metal center; these processes are kinetically much more facile than the corresponding C–C or even C–H addition/eliminations. These kinetic factors are complementary with the unusual thermodynamics of boron. Boryl–iridium bonds have been found to be much stronger than the corresponding Ir–C bonds [151]. As Hartwig noted early on [140b], the B–C (112 kcal/ mol) and B–H (111 kcal/mol) bonds formed by C–H borylation with a diboron reagent are much stronger than the C–H (98 kcal/mol) and B–B (104 kcal/mol) bonds broken [152]. The reaction of a C–H and B–H bond is even more unusual, in that H2 (104  kcal/mol) formation is favorable, by ca. 6  kcal/mol. Dehydrogenative couplings are generally uphill; for example, to form a C–C bond (81 kcal/mol) [152], the corresponding thermodynamics are uphill by 11 kcal/mol. The combination of exquisite selectivity and high reactivity has resulted in an explosion in the applications of C–H bond borylation. It is indeed remarkable that this field has progressed from “curious stoichiometric reactions of transition metalboryl complexes” [147] to one with countless applications in the field of organic synthesis and heterocycle chemistry in particular [153].

1.4  Insertion Reactions Insertion of CO into metal alkyl bonds has long been one of the key reaction steps in the largest-scale homogeneously catalyzed reactions such as hydroformylation and the Monsanto acetic acid process. Thus, immediately upon the discovery of alkane C–H addition, CO-insertion was considered as part of a possible route toward incorporating C–H addition into a catalytic cycle. Conversely, prior to these early reports of stoichiometric C–H activation, it seems likely that chemists might have overlooked indications of any such catalytic reactions. Just a year after the initial reports of alkane activation by Bergman and Graham, Eisenberg reported the catalytic carbonylation of benzene to give benzaldehyde upon irradiation of IrH3(CO)(dppe) (dppe=1,2-bis(diphenylphosphino)ethane) [154]. Rh(PPh3)2(CO)Cl was later found to be a more effective catalyst for the same reaction [155]. In all cases, the quantities of benzene produced were small, consistent with a thermodynamic equilibrium for the reaction. Consistent with such an equilibrium, experiments with 13CO demonstrated that the process was reversible. Eisenberg proposed that photoextrusion of a ligand from Rh(PPh3)2(CO)Cl, either CO or PPh3, generated a thermochemical catalyst for the reaction [155]. This proposal received support from elegant flash photolysis studies by Ford [156].

H L Rh

Cl

L Cl

Rh

CO CO

H

L CO

L L = PPh3

hν

L Cl

Rh

CO

Cl

O

H H

L

Rh

CO

Rh CO

CO

O

Cl Ph

Tanaka, considering that PMe3 but not PPh3 was effective for alkane C–H activation by Cp*Ir(PR3), investigated the PMe3 analogue of Eisenberg’s catalyst. Indeed, this was found to catalyze CO insertion with benzene more efficiently, and also effected carbonylation of cyclohexane [157] and n-pentane with high regioselectivity for the terminal position [158]. It was further observed that shorter wavelengths gave higher yields for benzene carbonylation [159] and preferably gave

21

22

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

terminal aldehydes from n-alkane, whereas longer wavelengths yielded branched aldehydes [160]. Given the effect of wavelength and the fact that the thermodynamic equilibrium concentration of any aliphatic aldehyde would be too small to observe, this was clearly a photochemical process (actually, at least two different processes, depending upon wavelength). (short wavelength UV) hν + CO

Cl

trans-Rh(PMe3)2(CO)Cl

hν (long wavelength UV)

H PMe3

higher yields

O

CO

Rh

H

PMe3

O

lower yields

H

O

Studies by Field and Goldman elucidated the key mechanistic features responsible for the selectivity and activity of Rh(PMe3)2(CO)Cl. Whereas CO loss was the dominant photoprocess, this did not lead to efficient carbonylation. Instead, a photoexcited state of Rh(PMe3)2(CO)Cl underwent oxidative C–H addition without ligand loss [159, 161]. A second photon (i.e. irradiation of the resulting C–H addition product) was then required to induce CO-insertion, in competition with the non-productive elimination of benzene. The analogous pathway led to the formation of linear aldehydes from n-alkanes [162]. Further insight into the key C–H addition to the intact excited state complex was obtained through timeresolved spectroscopy by Ford [163]. Work by Bitterwolf extended this chemistry to ethane under supercritical conditions [164]. But ultimately the unfavorable thermodynamics of aryl and especially alkyl C–H bond carbonylation appear to have thus far precluded any highefficiency photocarbonylation (and any high yield thermal carbonylation). If such chemistry is to be rendered useful, it seems likely that coupling carbonylation with a secondary reaction is required. It is also worth noting that CO tends to bind strongly to any vacant coordination site capable of oxidative addition, thus presenting another obstacle to thermochemically catalyzed carbonylation. Isocyanides are isoelectronic with CO, but their insertion reactions are much more thermodynamically favorable. Accordingly, a route analogous to Eisenberg’s carbonylation pathway – the photogeneration of a fragment that thermochemically catalyzes insertion into C–H bonds – can give good yields in the case of isocyanides. Such reactions have been developed by the Jones group, who have successfully employed complexes based on iron, ruthenium, and rhodium [165].

+

R

N

C

[Fe], [Rh], [Ru]

NR

hν

Thermochemical reactions should not necessarily require any photoactivation at all. Accordingly, Jones has found that intramolecular insertion of the isocyanide group into benzylic C–H bonds can be catalyzed by Ru(dmpe)2, thermochemically (140°C), in yields up to 98% [166]. (Ru(dmpe)2)

P

R

R

P Ru P P

R’ N

R’

C

NH

∆

In contrast with the unfavorable thermodynamics of 1,1-CO insertion into C–H bonds, and the very strong binding of CO to vacant coordination sites capable of adding C–H bonds, the 1,2-addition of C–H bonds to olefins is thermodynamically quite favorable. Moreover, olefins generally bind to metal centers much less strongly than CO (or isocyanides). Olefin

1.4  Insertion Reactions

insertion into C–H bonds has seen tremendous success, particularly site-directed with functionalized arenes (see section below). But catalytic olefin insertion into unfunctionalized aryl C–H bonds (olefin hydroarylation) has also seen very significant progress. The metal-catalyzed net addition of aryl C–H bonds to olefins goes back nearly 150 years to the development of FriedelCrafts chemistry. But there has been important motivation to effect this reaction without the intermediacy of carbocations based on tolerance of functionality and especially regioselectivity. In particular, carbocation-based routes lead to Markovnikov regioselectivity whereas transition metal-catalyzed additions often do not. Thus it was an important breakthrough when Matsumoto and Periana reported that a bis-acetylacetonato (bis-acac) iridium complex catalyzed olefin hydroarylation [167]. And indeed, notably, the products from the reaction of propene and 1-alkenes were primarily antiMarkovnikov, n-alkyl benzenes.

O

+

O

R

Ir

O O

R

L

R

+

180 °C, 30min

> 60:40

Soon thereafter, Gunnoe reported the same reaction, with similar regioselectivity and significantly greater activity, catalyzed by TpRu(CO)(NCMe)(Ph) (Tp=κ3-hydridotris(pyrazolyl)borate) [168]. The reaction of heteroarenes catalyzed by the TpRu catalyst was also explored and it was found to selectively result in alkylation at the 2-position (adjacent to the heteroatom) of THF and thiophene [169]. Oxgaard, Goddard and Periana have studied the mechanism of the Ir(bis-acac)-catalyzed reaction in detail. The reaction proceeds (shown below for the reaction of ethylene and benzene) via olefin insertion into the iridium aryl bond to give the corresponding 2-arylalkyl Ir complex. In principle this species could then undergo benzene C–H addition to give an Ir(V) intermediate and then reductive elimination of the arylalkane; however, calculations strongly indicate that it proceeds via a concerted OHM. Interesting, the Gunnoe TpRu-based system seems to proceed very analogously, via OHM rather than a Ru(IV) intermediate [168c, 170].

‡

‡

LnM

LnM

LnM

Ph

LnM

Ph

LnM H2C

H

LnM

+

CH2Ph

Several olefin hydroarylation catalysts based on platinum(II) with bidentate N-coordinating ligands have been reported by others including Tilley [171], Gunnoe [172], and Goldberg [173]. These also appear to operate via olefin insertion into metal-aryl bonds. Rather than a subsequent OHM of an arene C–H bond, however, Goldberg has shown, by isotope labeling studies, that the step following olefin insertion is intramolecular addition of the ortho-C–H bond of the resulting arylethyl group, which is then followed by C–H elimination to give the ortho-alkylaryl complex. This intermediate then effects the intermolecular arene C–H activation. The hydroarylations described above all yield, to some extent, anti-Markovnikov products, strongly arguing against a FriedelCrafts-type carbocation-based mechanism. Anti-Markovnikov selectivity was generally not very high, however, until Gunnoe and

23

24

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

co-workers reported that a simple Rh complex [Rh(μ–OAc)(C2H4)2]2 catalyzes the coupling of arenes and α-olefins to give high selectivity (ca. 10:1) for linear products [174]. The products were not alkyl benzenes but rather, the corresponding alkenylbenzenes [175]. It is therefore proposed that the product of olefin insertion into the metal aryl bond undergoes β–H elimination instead of C–H elimination. Cu(OAc)2 was used to regenerate the rhodium acetate from the resulting rhodium hydride. Copper(II) could be regenerated from the resulting copper(I) with O2 [176]). In view of the value of olefins as intermediates, this can be advantageous versus the formation of the saturated product. Alternatively, the alkenylbenzene can be hydrogenated to give the n-alkylarenes; these are truly linear alkylbenzenes (dubbed “super” linear alkyl benzenes) in contrast with the “linear alkylbenzenes” widely produced from Friedel-Crafts reactions with 1-alkenes which are actually 1-methyl-n-alkylbenzenes [177].

Ph

2 CuX2

H

LnM R

LnM

LnM

Ph R

X

R

L nM

Ph

+

R

R H–X

2 CuX + HX

R

H2 Ph

Ph–H

cat.

R Ph “super” linear alkyl benzene

1.5  Site-directed C–H Activation Except for the simplest hydrocarbons, most organic molecules have some functionality that can coordinate to transition metals. This leads to the concept of directed C–H activation, which is generally thought of as increasing the efficiency of intermolecular reactions by pre-forming reactive organometallic fragments in the microscopic vicinity of target reaction sites while also restraining it from undesired reaction sites [178]. The history of this is almost as old as C–H activation itself. As discussed above, Reissert observed in 1907 that mercuration of ortho-nitrotoluene [13] occurred preferentially at the methyl group. This selectivity likely involves coordination of the nitro group to a mercury center. The related strategy of directed orthometalation was developed in parallel among main group organometallic chemists. Directed metalation using lithium alkyls was discovered independently by Henry Gilman [179] and George Wittig [180], and was the subject of a review by Gilman as early as 1954 [181]. It has seen steady development in the decades since then, receiving particular attention again in the 1980s. The strongly polarized metal-carbon bonds of metal alkyls can deprotonate some C–H bonds, particularly sp2, benzylic, and allylic C–H bonds. The regioselectivity of this deprotonation can be dramatically influenced by coordinating functional groups on the arene ring, such as sulfonate, carbamate, oxazoline, carboxylate, or imido groups. For example, Beak, Hunter, and Jun reported that s-BuLi preferentially deprotonates an allylic site beta to an amide group rather than the significantly more acidic (by 10 pKa units!) site alpha to the amide group [182].

E+

sec-BuLi CONR2

CONR2 Li+

E CONR2

E = CH3 , Si(CH3 )3 , (CH 3 )2 COH

The use of lithium, zinc, and magnesium tetramethylpiperidide (TMP) bases has been particularly successful in these reactions [183]. Within the field of organotransition metal chemistry, multidentate ligands set the stage for directed metalation. The work of Bernard Shaw was influential in this regard. Whereas previous examples relied on hard interactions between electronegative atoms and metal centers to direct metalation, Shaw’s pincer complexes, discussed above, extended this approach to the soft phosphine interaction with late transition metals. The classic, original report involved sp2 aryl C–H activation [77] with nickel, palladium, platinum, rhodium, and iridium. Later, platinum, palladium, iridium, and rhodium were demonstrated to be capable of sp3 C–H activation with an aliphatic bis(phosphine) pincer ligand [184]. Hiraki and colleagues published two interesting papers involving directed metalation around this time as well. The first was a pincer complex formed from a bis(pyridine) aliphatic scaffold and palladium acetate [185]. The second was more

1.5  Site-directed C–H Activation

complex: a cyclopalladation of 4-methyl-4ʹ-nitrodibenzyl sulfide, wherein a thioether directs C–H activation to the more electron-rich toluyl ring instead of the electron poor nitrophenyl ring [186]. This was taken as evidence of electrophilic C–H activation with palladium(II) acetate. CH3

[Pd(O2CMe)2 ] + H3C

(i) 70 °C in HOAc

CH2SCH2

NO2

Cl Pd

(ii) LiCl in THF/H2O

2

S

NO2

A major breakthrough was reported in 1993 when Murai and co-workers developed a useful, catalytic C–H functionalization of arenes [187]. RuH2(CO)(PPh3)3 was used to activate aromatic sp2 C–H bonds adjacent to a ketone functionality. The resulting arylruthenium hydrides could undergo olefin insertion followed by C(sp2)–C(sp3) reductive elimination to produce linearly alkylated products. These reactions are fast, and are often complete within a few hours. Yields are high, and exclusive selectivity for sites ortho to the ketone substituent was observed. Thiophene, furan, and bicyclic aromatic systems were equally amenable to the reaction conditions [188]. DFT calculations indicate that pre-coordination of ruthenium to an arylketone group facilitates ortho C–H activation [189]. O

O R1

R2

RuH2 (CO)2(PPh3)3 +

Y

refluxing toluene

R1

R2

Y R1

Ru(0)

Y O

R2 Ru H

It is difficult to succinctly convey how much directed C–H activation of this nature has emerged and dominated the field of C–H activation writ large, and fundamentally changed the way that synthetic organic chemists think about building molecules. The development of meta-directing templates is a good illustration of the profound impact of this thinking [190]. Ortho-functionalization is certainly the most natural result of directed functionalization of an arene, and myriad examples have been developed. But Murai chemistry, and the great success of ortho-functionalization that followed, inspired chemists to undertake the much more challenging task of directing functionalization to the meta position. Designer structures are installed in order to leash metal centers and steer them exactly where they need to be in a macrocyclic TS [191]. R

Template

DG

C

Pd H Cyclic pre-transition state 6- or 7-membered ring

Pd Cyclophane-like pretransition state >12-membered ring

N

Removable linker

Pd Substrate

Jin-Quan Yu and co-workers Nature, 2012, 486, 518-522

=

R

H

Pd

N

>12-membered ring

25

26

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

The power and modularity of directed C–H activation are represented in a study on late-stage diversification at Pfizer. Olefination, carboxylation, iodination, carbonylation, methylation, and arylation were achieved using sulfonamide as a directing group. This was further demonstrated by making derivatives of the drug Celecoxib, starting from Celecoxib itself [192].

n

R1

S O

10 mol% Pd(OAc)2

NHC6F5 O

R2

+

20 mol% Ac-Leu-OH

n S

R1

O

AgOAc (4 eq.) DMF (10 eq.)

n = 0,1

CH2Cl2, 80°C

NHC6F5 O

Dai, Stepan, Plummer, Zhang, Yu 2011

R2

Yu and colleagues used a directed, dehydrogenative cross-coupling reaction to assemble the two halves of a key intermediate in the synthesis of (+)-lithospermic acid [193].

O

O OMe

CO2 Me

CO 2Me O -K+

O

MeO OMe OMe

O

OMe Pd(OAc)2 / Ligand O2 (1 atm), KHCO 3 (2 eq) tert -amyl-OH 85°C

O

MeO OMe

O O

O-K+ OMe

O OMe

OMe

1.6  Sigma-Bond Metathesis 1.6.1  Hydrogenolysis and the Discovery of Four-Centered Transition States The discovery of SBM is a product of the whirlwind growth of polymerization technologies in the 1950s. In 1953, Karl Ziegler’s team at the Max Planck Institute for Coal Research in Mülheim discovered that mixture of titanium chloride and aluminum alkyls catalyzed the low temperature polymerization of ethylene to high density polyethylene. One year later, Giulio Natta at the Polytechnic Institute of Milan expanded the scope of these systems to stereo-regular polypropylene and synthetic rubbers. And by 1957, Hercules in the US, Montecatini in Italy, and Farbwerke Hoechst AG in Germany had begun commercial production of isotactic polypropylene through Ziegler-Natta catalysis – an amazing five years from discovery to commercial manufacture, with a capstone of Nobel Prizes in 1963 to Ziegler and Natta. These early polymerization processes, however, suffered from low activities. Breslow and Newburg, scientists at Hercules Inc., reasoned that a homogeneous system may offer enhanced activity and control of the polymerization process. The tools for this line of research had only recently become available. Wilkinson’s description of the structure of ferrocene was the harbinger of a broader array of sandwich compounds, which has led to the cyclopentadienyl ligand (and derivatives) becoming mainstays in organometallic chemistry. Early among these was titanocene dichloride, whose synthesis was reported in 1954 [194]. Thus in 1959, Breslow and Newburg reported that Cp2TiCl2, when treated with ethylaluminum dichloride or diethylaluminum chloride, are as catalytically active in solution state as traditional TiCl4/Et3Al systems. The discovery of a molecular catalyst system ushered in a wave of continuing investigations into early transition metal chemistry [195]. This may have been the first instance of an organometallic compound being posited as a model of heterogeneous system, with both commercial value and promise for fundamental insights. In 1962, Hercules patented a new polypropylene process that utilized hydrogen for molecular weight control of polymer product [196]. By adjusting the partial pressure of hydrogen feed into the polymerization reactor, they were thereby able to produce multiple grades of polypropylene product with more adaptable end uses. But the mechanism by which this occurred was unclear. These two discoveries inspired Clauss and Bestian [197], who in 1962 studied the impact of hydrogen on the recently discovered Cp2Ti polymerization systems. They were able to reproduce this effect with their soluble cyclopentadienyl titanium system. Even 5% H2 atmosphere led to low molecular weight, saturated polyethylenes.   The reaction with D2 enabled them to observe isotope incorporation into the alkanes evolved from hydrogenolysis of CpTi(CH3)Cl and CpTi(C2H5).

1.6  Sigma-Bond Metathesis

-δ

+

H

H

M

+ δ

C

-

In retrospect, this experiment was a natural extension of methods developed by main group chemists in preceding decades. For example, there was some understanding of hydrogenolysis for compounds of phosphorus, arsenic, antimony, bismuth, lead, zinc, magnesium [198], aluminum, sodium, and lithium [199]. Podall, Petree, and Zietz [200] studied the product distribution from the hydrogenation of alkylmagnesium, alkylaluminum, alkylzinc, alkylsodium, and alkyllead compounds in the presence of various metal catalysts. They noted a correlation between the polarization of the carbon-metal bond and the rate of hydrogenation: more ionic character imparted faster hydrogenolysis. Based on these findings, they proposed a mechanism for the hydrogenolysis of metal alkyls with a rate-limiting step represented by a four-centered TS (shown). They commented, “To account for the relative ease of this reaction despite the strength of the H–H bond, an important feature of this mechanism would appear to involve the participation of the alkyl-or aryl- carbanion and particularly the metal ion in the loosening of the H–H bond in the transition state.” [200]. Further support for this mechanism came from a deuterium labeling study by Becker and Ashby. Using mass spectrometry, they observed that deuterolysis of Grignard reagents led to incorporation of only one deuterium atom in the alkane product. This ruled out a potential two-step mechanism involving β-hydride elimination followed by hydrogenation of the resulting olefin [198]. But acceptance of a four-centered TS was not reached so soon. Bercaw [201] and Schwartz [202] each studied Zr(IV) alkyl hydrides as models of intermediates in the reductive homologation of carbon monoxide in the Fischer-Tropsch process. The OPEC oil embargo of 1973-1974 shocked economies of the western world, and marked petroleum as a politically unstable energy supply. Improvements to Fischer-Tropsch chemistry, utilizing syngas from low quality (yet reliable) carbon supplies such as garbage or coal, promised energy independence. In 1978, the two arrived at rival interpretations for deuterium scrambling in their model complexes: Cp2Zr(isobutyl)H for Schwartz [202] and Cp*2Zr(cyclohexylmethyl)H for Bercaw [203]. Schwartz measured first order kinetics in the hydrogenolysis of Cp2Zr(isobutyl)H, with the rate found dependent on the partial pressure of H2. A large primary KIE of 5 was also observed when D2 was substituted for H2, and the liberated alkane incorporated label only from the atmosphere – not from the hydride ligand. He further noted scrambling of the zirconium hydride occurring faster than elimination of labeled methylcyclohexane. From these findings, he concluded that H2 coordinates to a vacant site flanking either the hydride or the alkyl group in an endon manner. The zirconium center thereby polarizes the hydrogen molecule and abstracts a hydride (or deuteride) and the proton (or deuteron) reacts with either the existing Zr–H or Zr–alkyl to cleave hydrogen or methane. This is tantalizingly close to the currently accepted mechanism, with some errors reflecting the assumptions of the time. Although Schwartz drew an end-on dihydrogen complex rather than a “non-classical” sigma complex, a kite-shaped TS seems to be implied [202].

Zr

H R

D2

δ- H + Zr R D D δ+

δ+ D δ- D Zr H R

Cp2Zr

Cp2Zr

H D D R

+ R–D

+ H–D

In Bercaw’s study, Cp*Zr(isobutyl)H – even with deuterium labels in the Cp* ligands or with Zr–D – liberates isobutane with only terminal C–H bonds when placed under a hydrogen atmosphere [203]. And under D2 atmosphere, deuterium is incorporated into the terminal carbon of liberated isobutane. This was all in agreement with Schwartz’s observations. The difference emerged under pyrolysis conditions, where Bercaw noted that deuterium from a labeled Cp* ligand was incorporated into the terminal C–H bond of isobutane; and under these conditions, a kinetic isotope effect of ~2 was measured. Like Schwartz, Bercaw dismissed oxidative addition to a d0 zirconium(IV) fragment. But oxidative addition to d2 zirconium(II) was well-known. He therefore postulated a scheme involving reductive elimination of a Cp* ring followed by interception of the resulting zirconium(II) by intramolecular oxidative addition of a Cp* methyl group. Subsequent alkyl–H reductive elimination would produce the alkanes observed in their experiment, and was consistent with the locations of observed deuterium incorporation [203].

27

28

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

The balance was tilted in Schwartz’s favor through extended Huckel calculations by Brintzinger, which identified an energetically accessible direct hydrogen transfer to an alkyl ligand and zirconium center [204]. In this calculated mechanism, H2 coordinates to a vacant site on zirconium in a side-on fashion – a “non-classical” hydrogen bond. Back donation from Zr–H or Zr–alkyl bond into the weakly stabilized Zr(H2) ligand leads to proton transfer to the alkyl ligand to form a sigma alkyl complex (albeit, drawn end-on) followed by alkane release. In the reverse sense – the thermodynamically uphill direction–this is recognizable as C–H activation by SBM [205]. Schwartz conducted additional experiments to confirm the importance of the low-lying, vacant orbital on zirconium into which the sigma bond of hydrogen donates. Diminishing rates of hydrogenolysis were observed in the order: Cp2ZrH(alkyl) >Cp2ZrCl(alkyl)>Cp2Zr(Cl)CH2OZr(Cl)Cp2. Thus, ligands such as oxygen or chlorine, with π electrons that could stabilize the vacant zirconium orbital, inhibit reaction with hydrogen [206].

1.6.2  C–H Activation in Actinide Complexes Research into organoactinide chemistry traces its origins to the development of the atomic bomb [207] and associated industrial-scale uranium isotope separation. It was sustained by the unique properties imparted by high theoretical coordination numbers and strong electrophilicity – consequences of their unfilled f orbitals. Complexes of uranium and thorium thus became important in identifying SBM as a separate mode of C–H activation. Tobin Marks was one of the early pioneers in this field through his research into actinide hydrocarbyl complexes. The metal alkyl bond is highly polarized, with significant anionic character on the alkyl ligand. As a practical matter, such complexes react with ketones to form tertiary alkoxide ligands, and undergo alcoholysis with loss of alkane – reactivity similar to what would be expected with main group metal alkyls. Perhaps the more surprising reactions of Cp3U alkyls [208] and Cp3Th alkyls [209] are their undergoing intramolecular, interligand proton transfer to release alkane. These were viewed in the same polar reaction framework: an alkyl anion deprotonates a cyclopentadienyl ligand, leading to dimerization of two actinide fragments [207, 208]. Hydrogen gas, however, is nonpolar. And the rapid, room-temperature hydrogenolysis of uranium and thorium alkyl complexes was more difficult to explain through polar or even radical mechanisms [210]. The ability of olefins to insert into uranium hydrides, leading to efficient uranium-catalyzed hydrogenation of olefins [211], was likewise difficult to explain. Even more remarkably, Marks reported hydrocarbon metathesis in dialkyl derivatives of Cp*2U and Cp*2Th complexes [211a]. At 100°C, a benzene solution of Cp*2Th(neopentyl)2 exchanges its neopentyl ligands for phenyl ligands. A deeper explanation of this was deferred, however. Andersen played a prominent role in the elucidation of sigma-bond metathesis by organoactinide complexes. As he began his independent career, and assimilating advice from Wilkinson not to “repeat his PhD thesis,” [212] Anderson undertook fundamental studies in actinide chemistry. In 1979, his group reported the preparation of the complexes HU[N(SiMe3)2]3 and HTh[N(SiMe3)2]3, each in the +4 oxidation state [213] and that both complexes undergo complete deuteration of all 55 of their protons(!) when pentane solutions of them are placed under deuterium [214] For uranium, this could be reactions by a sequence of oxidative additions and reductive eliminations through the well-known uranium VI oxidation state. But thorium VI, unknown and unlikely, could not be invoked to explain ligand deuteration. Taking inspiration from Schwartz’s contemporaneous studies of hydrogenolysis in Cp2Zr(H)(isobutyl), Andersen proposed a mechanism that included a four-centered TS for deuterium exchange of the metal hydride. But he also postulated something altogether novel: an ylide intermediate that heterolytically forms and releases H2/D2. Brintzinger’s findings that similar four centered TS were energetically accessible for sp3 C–H bonds had not been fully embraced by this point. In a subsequent work, Anderson elaborated on this proposal by isolating the thorium and uranium metallacylic intermediates and

D2 +

D

[(Me3 Si)2 N]3 M

H

[(Me3 Si)2 N]3 M

D + H

D D

H2 C

[(Me3 Si)2 N] 3M

D

D2 + SiMe2

CH 2

[(Me3 Si) 2N]3 M

SiMe2

CH2

D

SiMe2

[(Me3 Si)2 N] 3M

CH 2D

D

SiMe2

[(Me3Si) 2N]3 M

N

N

N

N

SiMe3

SiMe3

SiMe3

SiMe3

1.6  Sigma-Bond Metathesis

verifying that they, too, undergo perdeuteration under deuterium atmosphere. Although this verified the plausibility of the metallacycles as intermediates, Anderson was now more circumspect in describing the mechanism (likely now influenced by awareness of Brintzinger’s work). It is worth noting that similar metathesis reactions of amide ligands on d0 metals had been observed previously. In 1970, Buerger and Neese observed methane evolution upon thermal pyrolysis of tris(diethylamino)titanium methyl, which was reasoned to proceed by heterolytic dissociation of a methyl anion that abstracts a proton from a diethylammine ligand [215]. In 1974, Bradley and Bennett found that Cp2TiCl2 reacts with Li[N(SiMe3)2] to cyclometalate with release of one equivalent of hexamethyldisilazane [216]. Both of these reactions involve an implicit C–H activation, with the proton departing with a volatile leaving group. Neither of these observations could be explained by the oxidative addition/reductive elimination paradigms of the time.

1.6.3  Identification of a New Mechanism Watson [217], the scientist whose name is perhaps now synonymous with SBM, began her studies of organolanthanide centers in 1979 under the auspices of DuPont Central Research & Development (CR&D). Some comment on DuPont CR&D is due after its dissolution in 2016 [218]. As Whitesides stated simply, “for many years it was arguably the world’s center of fundamental research in organometallic chemistry [219],” It was a product of a time when corporate ownership was more patient for open-ended research with lengthy timelines – and when families like the DuPonts still retained majority ownership of their family enterprises. Pioneers in the field of organometallic chemistry and homogeneous catalysis such as Cramer, Schrock, Tebbe, Milstein, Arduengo, Tolman, and Grubbs (in a consulting role) started their careers here under the leadership of Parshall. Hearkening back to the origins of SBM in the discoveries ofZiegler, Watson’s initial pursuit in lutetium and ytterbium chemistry was motivated by DuPont’s continuing interest in ethylene polymerization [220]. These metals are located near the Group IV metals on the periodic table, and the relevant lutetium(III) and ytterbium(II) complexes are conveniently observable by NMR. But the microscopic steps were slower than for titanium(IV). Thus by using Cp*2Lu(CH3), Watson was able to observe the initial propylene insertion into the Lu–CH3 bond as well as stereoselective enchainment of further propylenes [221]. Similarly, she could observe familiar chain termination by β-hydride elimination and hydrogenolysis as well as a previously undescribed β-methyl elimination (a consequence of microscopic reversibility with respect to olefin insertion). And when the reaction of Cp*2Lu(CH3)(Et2O) with propylene was conducted in toluene-d8, significant isotope exchange occurred between propylene and toluene. Examining this further, it became clear that Cp*2Lu(CH3) and Cp*2LuH were extremely reactive compounds [220]. They reacted with the sp3 C–H bonds of tetramethylsilane and with the sp2 C–H bonds of benzene. Most remarkably, methane undergoes degenerate exchange with Cp*2Lu(CH3) and more quickly with Cp*2Y(CH3) [222]. This was revealed through a simple experiment using 13C-labeled methane: in a cyclohexane-d12 solution at 70°C under 13CH4 atmosphere, 13C satellite signals for the methyl Cp*2Lu(CH3) are seen to grow over 4 hours, whereas the 12CH4 signal for methane also grows concomitantly. Ethane and propane reacted similarly, but the resulting lutetium and yttrium alkyls underwent β-hydride elimination. This was unambiguously shown to occur at d0 transition metals, and some additional considerations showed that 4f orbitals could not be involved. As Hoffmann pointed out, the 4f electrons in lutetium are too low in energy to be involved [223]. Yttrium lacks 4 f electrons entirely but also undergoes methane exchange. Bercaw additionally noted the non-involvement of pi electrons in an apparently general organometallic reaction mode, which led him to coin the name SBM [224].

1.6.4  Emerging Applications of Sigma Bond Metathesis Since the pioneering work by Watson, Schwartz, Bercaw, and Marks, among others, in the 1970s and 1980s, C–H bond activation by early transition metal centers has grown in maturity. Catalytic and practical applications are now beginning to emerge that may impact both commodity organic chemistry as well as fine-chemical applications. We highlight some of these promising trends here.

1.6.5  Hydromethylation of Olefins Watson’s elegant mechanistic studies and the discovery that SBM could be used to activate methane initiated a flurry of research. In 1986, Marks and colleagues reported mechanistic studies on methane activation by thoracyclobutanes [225].

29

30

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

A concerted, four-centered heterolytic SBM pathway was postulated. This was supported by the strong, primary KIE of 6 (±2), the high electrophilicity of the Th(IV) ion, and the strong polarization of the thorium-carbon bond. In 1987, as part of a broader study of the reactions of permethylscandocene derivatives with hydrocarbons, Bercaw and co-workers noted competing reaction outcomes when Cp*2ScMe reacts with olefins [224]. In the case of styrene and isobutylene, vinylic C–H activation occurs to release methane. Propylene, however, undergoes insertion into the Sc–Me bond at 25°C. And in particular, only one propylene inserts – the resulting scandium isobutyl complex undergoes sigma-bond metathesis with the vinylic proton of a subsequent equivalent of propylene. It thus appeared SBM was a general mechanism by which saturated hydrocarbons could be activated and paired with the known reactivity of d0 metals toward olefin insertion. This was achieved by Sadow and Tilley in 2003 [226]. Hydromethylation occurs at ambient temperature, and is accelerated at 80°C albeit with catalyst decomposition. No isobutylene or propylene are observed, indicating that neither β-hydride elimination of the scandium isobutyl complex nor insertion of propylene into possible scandium hydrides is competitive with the desired insertion/SBM pathway.

Sc

CH3

Sc

CH4

The tightrope on which this system walks was illustrated when an ansa-scandocene was used [227]. This modification features a bridging silylene between the two cyclopentadienyl groups that pinches them together to make the metal center slightly more open. Both methane activation and propylene insertion were accelerated, but so too were undesired side reactions such as β-hydride elimination and insertion of a second propylene equivalent. Propylene hydromethylation was thus no longer the dominant reaction. Vinylic and allylic C–H activation are also competitive with methane C–H activation, which leads to noncatalytic scandium complexes [228]. The desired catalytic hydromethylation pathway through SBM / olefin insertion thus requires the right balance of metal Lewis acidity and steric encumbrance such that the usual preference for olefin coordination as opposed to methane C–H activation is reversed [229]. To date, yields approaching a practical level have not been achieved with the use of methane for hydromethylation (and alkanes for broader hydroalkylations) of olefins.

1.6.6  Pyridine Hydroalkylation by Orthometalation Functionalization of pyridines has emerged as a fruitful application of C–H activation by sigma-bond metathesis. Teuben [230] and Watson [231] had separately reported orthometalation of pyridine with titanium (III) and lutetium, respectively. Since then, similar orthometalations have been reported with several other metal complexes including yttrium [232], hafnium [233], scandium [234], lutetium [235], and even calcium [236]. Indeed, this appears to be a general mode of reactivity with d0 transition metal alkyl, aryl, and hydride complexes and pyridines. These intermediates have proven to be gateways to further exciting reactivity. Orthometalation was observed by Jordan in 1988 using the cationic complex [Cp2Zr(CH3)(THF)][BPh4] [237]. This reacted stoichiometrically with alpha-picoline with release of methane. As is generally true in SBM, sp2 C–H bonds react much more rapidly than sp3 C–H bonds. This complex, in turn, slowly inserts propylene in between the zirconium center and alpha carbon of picoline. The resulting metallacycle, however, is more bulky and the rate of further olefin enchainment is thus inhibited. However, this complex is susceptible to hydrogenolysis, and the resulting [Cp2ZrH+][BPh4−] undergoes orthometalation (with release of hydrogen) with alpha-picoline. The overall process is, therefore, the catalytic alpha-alkylation of picoline using propylene. Insertion of other olefins and alkynes is also possible [238], and this insertion may even take place asymmetrically with chiral zirconocene architectures [239]. When 2,6-lutidine is used instead of alpha-picoline, stoichiometric insertions into the methyl C–H bonds with ketones are achieved with ketones, alkynes, and olefins [240].

1.6  Sigma-Bond Metathesis

Cp2 Zr

CH 3

N

+

Cp2 Zr

O

CH 3

O

-CH 4

+

Cp2 Zr

N

N

O Cp2 Zr N

H2

Cp2 Zr N

H Cp2 Zr N Cp2 Zr and isomers

Cp2Zr N

N

N N

H

H2

Cp2Zr

N

N

CH3 Cp2 Zr

O

N

+

Cp2 Zr

O

R = H, Me, CH2 SiMe3

N Ph O

R

H

Cp2 Zr

- THF

O

Cp2Zr

R

R Ph

R Cp2 Zr

Me3 Si

N Cp2Zr

MeC

CMe

Me3 SiC

CH

Cp2 Zr

Advances in this area were perhaps constrained by inertia: the complexes fielded in these studies were metallocene sandwich complexes. These were, at the time, the most well-described d0 metal complexes of an era that stretched back to the early discoveries of molecular polymerization catalysts. Shedding cyclopentadienyl ligands enabled new reactivity and reinvigorated research in this field in 2011. Hou and Guan found that half-sandwich compounds of scandium and yttrium were much more active and versatile in pyridine alkylation [241]. These catalysts allowed olefins such as norbornene, isoprene, and styrene to be used, and showed functional group tolerance for aryl fluorides, chlorides, and methoxy groups. In the case of pyridine, bis-alkylation is seen at extended reaction times. Hou and coworkers further demonstrated that other Cp*Ln (Ln=Sc, Y, La, Sm, Gd, and Lu) complexes were competent in this transformation, but that reducing ligand size

31

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1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

enhanced reactivity [242]. Thus cyclopentadienyl yttrium was identified as the lead catalyst for benzylic linear alkylation of pyridines with dienes, styrenes, and simple alkenes. A chiral scandium complex catalyzes an asymmetric, branched alkylation of pyridines [243]. Allenes [234] have proven to be useful reaction partners for pyridine alkenylation; and alkynes for benzylic alkenylation [233b]. This field continues to grow rapidly, and the reader is referred to more detailed reviews on this topic [244, 245].

1.7  1,2-Addition 1,2-addition involves a M=X species (e.g. a carbene, nitrene, oxo) undergoing a 2π+2σ cycloaddition reaction, resulting in the net insertion of the M–X unit between the sigma bond [246]. This mode of C–H activation tends to occur at π-rich metal complexes with the requisite metal carbon multiple bond, and preferentially at those with strongly polarized metal-heteroatom π bonds which place a partial positive charge on the metal. In these aspects, it is conceptually similar to SBM, which proceeds through a 2σ+2σ cycloaddition at polarized metal-carbon bonds. In fact, a similar kite-like TS occurs in 1,2-addition as in SBM. The discovery of 1,2-addition as a reaction mechanism in organometallic chemistry traces its lineage to two contemporaneous advances in the petrochemicals industry in the 1950s: propylene ammoxidation and olefin metathesis. Both of these catalytic technologies rely on surface metal-ligand multiple bonds, and inspired a generation of mechanistic investigations that led to the discovery of 1,2-addition as a byproduct. We briefly recount these inspirations and mechanistic implications here.

1.7.1  Metal Oxos and Imidos Sohio’s acrylonitrile process transformed an industry when it was commercialized in 1959 [247]. Previously, acrylonitrile was an important but niche monomer. It was manufactured from acetylene and hydrogen cyanide in the presence of Nieuwland catalyst [248] – an aqueous mixture of cuprous chloride, alkali metal chlorides, and hydrochloric acid. This was a painstaking process. In 1953, a team led by Franklin Veatch at Sohio set out to develop a propylene oxidation catalyst. They achieved an early success: oxidizing propylene to acrolein over vanadium pentoxide. In 1957, James Idol and Evelyn Jonak demonstrated production of acrylonitrile in a single step from propylene, air, and ammonia over bismuth phosphomolybdate. This paved the way for rapid scale-up and commercialization, with the first acrylonitrile plant utilizing Sohio’s new technology going online in 1960. This technology was so successful that, within its first decade, it had completely supplanted the legacy acetylene-hydrogen cyanide process for acrylonitrile operated by Monsanto, Union Carbide, DuPont, and American Cyanamid.

O CH3 + O2

cat.

C

H

propene oxidation to acryaldehyde

+ H2O

CH3 + NH3 + 3/2 O 2

cat.

C

N + 3 H2O

propene ammoxidation to acrylonitrile

The guiding hypothesis for propylene ammoxidation, as well as its sibling processes for acrylic acid and acrolein, was that oxides on metal surfaces could be transferred to hydrocarbons and regenerated from air [249]. And as an extension, ammonia could also replace lattice oxygens with isoelectronic imidos which could in turn react with surface allylic intermediates to ultimately form acrylonitrile. One line of mechanistic inquiry was the synthesis of early transition metal d0 organoimido complexes compounds by Nugent of DuPont CR&D. These were intended to be models of the active sites in ammoxidation catalysts [250]. And they did successfully reproduce some of the activity of ammoxidation catalysts such as C–N bond formation [251] They also provided fascinating mechanistic insight. Using a series of tungsten tris(imido) complexes, Nugent and colleagues were able to observe an equilibrium involving an intramolecular alpha hydride migration between imido and ammine ligands [252]. Although this is an example of N–H activation rather than C–H activation, the parallels between the two are clear. This was an important advancement in organometallic bond activation.

1.7  1,2-Addition

NH

NH

L

Mo

O

NR

NR

O

proposed structure of propylene ammoxidation catalyst

W

NH2R

O

O

X2C

CX2

α-H exchange

NHR NHR W O O

NR

X2C

CX2

X = CH3, CF3, Ph

1.7.2  Metal Alkylidenes Olefin metathesis was discovered as a byproduct of research in Ziegler-Natta type coordination polymerization in the 1950s and 1960s. In fact, the earliest metathesis catalysts were simply Ziegler-Natta systems. The first example was patented by Anderson and Merckling at DuPont [253], who unintentionally generated polynorbornene by ring opening metathesis polymerization using a TiCl4/LiAl(heptyl)4 catalyst mixture. “Olefin metathesis” was disclosed by Calderon, Chen, and Scott at Goodyear [254] and also reported as “olefin disproportionation” [255] by Banks and Bailey at Phillips in 1964; and “olefin dismutation” by Bradshaw, Howman, and Turner at BP in 1966. The industrial significance of olefin metathesis was apparent immediately. Banks and colleagues at Phillips used it as the basis of the Phillips Triolefin Process. This reaction, which interconverts propylene with ethylene and 2-butene, continues to serve as an industrially significant “on-purpose” propylene technology. Between 1964 and 1966, Giulio Natta’s team reported its significance in ring opening metathesis polymerization (building on the initial discovery of polynorbornene by Anderson and Merckling), using tungsten hexachloride or molybdenum hexachloride and alkylaluminum combinations to polymerize cyclic alkenes [256]. Mechanistic explanations were not quite as forthcoming, and homogeneous molecular species were critical in developing them. The role of metal carbenes in olefin metathesis was postulated by Chauvin, and experimental validation came from Schrock through the late 1970s and early 1980s. Schrock found that pentamethyltantalum undergoes an explosive bimolecular decomposition above 0°C to release an olefin. In a bid to stabilize this species, he attempted to prepare pentakis(neopentyl)tantalum. Instead, one equivalent of neopentane was lost and a stable tantalum alkylidene was formed [257, 258] Although this fortuitous turn of events was a major advance in our mechanistic understanding of olefin metathesis, its connection to C–H activation is perhaps less appreciated. The intramolecular alpha-hydride abstraction that converts pentakis(neopentyl)tungsten to the tungsten alkylidene is simply the reverse of a 1,2-addition by a metal alkylidene, and is analogous to Nugent’s ammine-imido equilibrium.

CH2CMe3 Me3CCH2

Ta

Cl

Cl CH2CMe3

CH2CMe3 2 LiCH2CMe3 -2 LiCl

Me3 CCH2

Ta

CH2CMe3

CH2CMe3 CH2CMe3

H

CMe4 Me3CCH2 Me3CCH2

C Ta

CMe3

CH2 CMe3

There were subsequent examples of metal-alkyl complexes decomposing by alpha-hydride migration and undergoing follow-up C–H activation reactions. Rothwell reported that under UV irradiation, Ta(CH3)3(OAr)2 loses methane and forms a methylidene, which then also performs an intramolecular 1,2-addition of the aryloxo ligand [259]. Through the use of deuterium labeling, Bercaw and coworkers showed that Cp*2Ti(CH3)2 decomposes to a titanium methylidene and methane by intramolecular α-hydride abstraction [260]. The titanium methylidene then engages a methyl group of a Cp* ligand to form a tuck-in titanium methyl complex. Brubaker successfully trapped titanium alkylidene intermediates generated by thermal decomposition of Cp*2Ti(alkyl)2 using cyclohexene, observing norcarane as the product [261].

1.7.3  Intermolecular C–H Activation by 1,2-Addition Intermolecular reactivity and metal-carbon bond formation are, of course, more exciting than decomposition pathways of hard-earned, reactive metal carbon bonds. And perhaps for this reason, those who were first to achieve it have their names

33

34

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

most closely associated with 1,2-addition. At the 1988 American Chemical Society meeting in Toronto – as well as in back to back J.A.C.S. articles – the activation of hydrocarbons by 1,2-addition was independently reported by two different groups: Cummins and Wolcanzski [262], using (t-Bu3SiNH)2Zr=NSitBu3; and Walsh and Bergman [263], using Cp2Zr=NtBu. Both groups appreciated that dimerization of zirconium imidos was apparently quenching a highly reactive species [264]. Thus, bulky imido ligands unlock the reactivity of the metal-carbon multiple bond toward intermolecular reactivity. This is particularly apparent in the Cummins/Wolczanski complex, which activates methane. Wolczanski and coworkers extended this reactivity to a series of titanium systems. Although methane activation wasn’t achieved, benzene activation was. Theoretical insights were provided by Hoffmann, who identified the importance of electronic saturation of the metal center by strongly π-donating ligands (π-loading) [265].” Over the next decade, extensive experimental and computational studies [266] were undertaken to understand the mechanism and scope of this new mode of C–H activation. Which metals could wield it, and what molecular frameworks could facilitate it? The importance of π-loading of these complexes was recognized [267], but doesn’t by itself confer the ability to undergo 1,2-addition C–H activation. Early mechanistic studies, notably by Wolczanski [268] highlighted the need for a vacant, electrophilic site to polarize a C–H bond. Strong evidence, computational and experimental by Cundari and Wolczanski [266, 269], indicated that a fourcentered TS was preceded by an alkane sigma complex. Regarding selectivity, similar trends are observed as in other organometallic C–H activations: phenyl>methyl>benzyl> alkyl>cycloalkyl. But from these early studies, difficulties in a catalytic process were apparent. Although alkanes could be activated, beta-hydride elimination (the most direct way to functionalize the resulting metal alkyl bond) encounters a higher barrier than simple alkyl–H elimination.

P N

N

P

N CHtBu

Ti P

CH2tBu

Overall reaction: CH2

Ti P

P

CH3

Ti P

P

CH4

+

CH2tBu

P

- CH

2

+

+ PR 3 + CH 4

PR3

N

Ti P

CHtBu

Ph P CH2

N

+

P

Ph

P

Ti P

CH2tBu

N

Ti P

CHtBu

Catalytic alkane dehydrogenation was, however, achieved by Mindiola and colleagues using a titanium alkylidyne system [270]. In this system, a methyltitanium alkylidene eliminates methane to form a reactive titanium alkylidyne. This intermediate reacts with an alkane via 1,2-addition to generate a new alkyltitanium alkylidene. β-hydrogen abstraction from the resulting alkyl group, by the alkylidene, then gives the corresponding olefin. Dissociation of the olefin exposes a vacant site, a step that likely occurs via a spin crossover to a high spin titanium(II) state. This vacant site is then trapped by the methylphosphonium ylide which is ultimately acting as the sacrificial hydrogen acceptor. Transfer of a methylidene forms an alkyltitanium methylidene, and subsequent tautomerization completes the catalytic cycle. Catalysis occurs under very mild conditions: 75°C, albeit slowly and with only a few (3 or fewer) turnovers. Catalyst decomposition occurs at elevated temperatures. Nevertheless, this is noteworthy for being the catalytic incorporation of C–H activation by 1,2-addition.

1.8  Sigma Complexes: Unifying Intermediates in C–H Activation

Perhaps even more unusual is the transfer of β-hydrogen to an alkylidene ligand; thus both H atoms from the alkane are transferred to the alkylidyne ligand without ever forming an M–H bond.

1.8  Sigma Complexes: Unifying Intermediates in C–H Activation The strength (104 kcal/mol) and polarity of H–H bonds is similar to those of aliphatic C–H bonds, particularly for methane (105 kcal/mol at 298 K). Although hydrogen atoms have less specific directionality as a result of their spherically symmetrical 1s orbital, the reaction coordinates that H2 tracks in forming bonds to organometallic complexes resemble those of C–H bonds. This has historically been an important connection, as it laid the theoretical foundations for explaining C–H activation by oxidative addition [68, 69], electrophilic insertion [271], and SBM. Among the multiple modes of C–H activation, unifying mechanistic insight has been provided in the form of sigma complexes, wherein H–H and C–H sigma bonds coordinate to a vacant site on a metal center. Speculation of the existence and nature of sigma complexes long preceded their experimental isolation. In 1971, alongside the earliest reports of sp3 C–H activation by organometallic complexes, Hodges [55] showed through mass spectrometry that unfunctionalized alkanes undergo extensive protium-deuterium (H/D) exchange with K2PtCl4 in 1:1 D2O-acetic acid solvent. An interesting observation was that the logarithm of the rate of H/D exchange was inversely proportional to the ionization of energy of the alkane. Thus the rate of H/D exchange of n-hexane (IE=10.17 eV; 12.7%/hr) was faster than ethane (IE=11.65 eV; 4.0%/hr) which in turn was faster than methane (IE=12.99, 0.2%/hr). On this basis, Hodges speculated that the initial interaction of the catalyst (which he suggested was PtCl2(solv)2 in solution) and alkane involved an electron transfer from a C–H sigma bond to the metal center. In a similar line of reasoning, Shilov and coworkers observed that alkane ionization potentials also correlate with the Taft polar substituent, and that the platinum(II) center in these H/D exchange reactions has modest electron accepting abilities [58a]. They drew an analogy to contemporary work by George Olah in carbonium ions such as CH5+, which had established that sigma bonds could donate electron density in the form of 3-center-2-electron bonds. Singleton and Ashworth remarked that the complex (PPh3)3RuH4, formed by addition of H2 to (PPh3)3RuH2, is likely a ruthenium(II) complex containing a neutral dihydrogen [272]. They drew this conclusion by noting that its reactions all involved initial dissociation of H2. Dihydrogen ligands were also presumed to exist on heterogeneous metal catalysts. Burwell and Stec [273] observed that H2 absorbs onto chromia below −130°C. It is not displaced by helium, but can be displaced by D2 at −196°C. However, above that temperature, D2 and H2 undergo exchange to form HD. Dihydrogen ligands were postulated to explain confounding data on the nature of interaction of hydrogen with nickel centers in zeolites [274]. With sharp intuition in the face of apparently contradictory spectroscopic data, the authors concluded that H2 molecules (and they suggested it was just one per nickel center) coordinate to d9 nickel(I) centers that weakly donate electrons into the antibonding σ* orbital of H2. The direct isolation and characterization of a side-on bonded H2 ligand was achieved by Kubas and colleagues at Los Alamos National Laboratory in 1983 [275]. The complexes W(H2)(CO)3(iPr3P)2 and Mo(H2)(CO)3(Cy3P)2 could be prepared from the respective 5-coordinate carbonyl phosphine complexes under an atmosphere of H2. PiPr3 CO

PiPr3 CO OC

W i

P Pr3

CO

+ H 2 or HD

OC OC

W i

H

P Pr3

H/D 1J

HD =

33.5Hz

free H-D: 43.5 Hz

The HfD coupling constant of 33.5 Hz (versus free H–D, 43.5 Hz), indicated a strong H–H(D) interaction. Taken together with the lack of coupling to the cis-phosphines, as well as with X-ray and neutron diffraction structures and infrared data, a compelling case was made that a dihydrogen complex had been isolated for the first time [276]. “Agostic bonds” is a term coined by Brookhart and Green in a 1983 review of the topic [277]. These are a C–H equivalent to the aforementioned non-classical dihydrogen complexes. Particularly, they are intramolecular entities that occur among

35

36

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

C–H bonds of ligands with another primary attachment point (e.g. the alkyl C–H bonds of a trialkylphosphine ligand). The first direct observation of these was in X-ray crystal structures of (dmpe)TiCl3Me [278] and (dmpe)TiCl3Et (dmpe=1,2bis(dimethylphosphino)ethane) obtained by Green in 1982. In these structures, sp3 C–H bonds were visibly distorted from their ideal bond angles and seemed to be pulled toward the titanium metal center. In the ethyl ligand, a β-hydride was pulled toward the titanium center. They appeared to be aborted α- or β-hydride migrations. Such agostic bonds are in fact presumed to precede intramolecular C–H activation reactions when favorable electronics exist in the structure. But even where they do not continue toward intramolecular oxidative addition or other C–H activation reactions, agostic bonding can help to stabilize coordinatively unsaturated transition metal complexes. Additionally, they can further affect the reactivity of organometallic catalysts. For example, in the Brookhart-Green revision [277] of the classic Cossee-Arlman mechanism for chain growth in Ziegler-Natta systems [279] α-agostic bonds help to open the metal center for coordination of an incoming olefin. This was an elegant theoretical middle-ground between simple olefin 1,2-insertion into the growing polymer chain; and a rival mechanism invoking olefin metathesis of metal alkylidenes formed via alpha-hydride migration, which accounted for the stereofidelity of olefin insertion.

Pol

H Ti

H

P ol

C2 H 4

H

1,2-insertion

H

Ti

H

H

Ti

Cossee-Arlman mechanism

P ol

Pol Ti

Pol

H

Pol Ti

Ti H

Pol

H

H Ti

H

H

α -hydride migration and olefin metathesis pathway

H H

Brookhart-Green modification

Much later it was realized that a small fraction of intramolecular bonding interactions between metal centers and C–H bonds are not the 3-center–2-electron agostic type. Instead they are, or closely resemble, the H-bonding interaction so familiar in main group chemistry, with the C–H bond acting as a H-donor and the metal as acceptor. These are now referred to as “anagostic” [280]. The intermolecular equivalent of agostic bonds, where the sole point of attachment to a metal center is a side-bound C–H bond, are known simply as sigma complexes. Besides the initial speculation of their existence, there were some early attempts to indirectly observe them experimentally from the 1970s and 1980s. In now classic work [281], Perutz irradiated Group 6 metal hexacarbonyl complexes using UV photolysis under cryogenic conditions in different matrices: noble gasses, methane, and mixtures of methane with noble gasses. Photolysis causes one carbonyl ligand to dissociate, leaving behind a square pyramidal metal pentacarbonyl species. The sixth coordination site, however, is filled by the matrix and the resulting complex presents a characteristic UV/ Vis absorption band. Accordingly, Perutz reasoned that there is an interaction between (CO)5Cr and methane. Around the same time and using similar methodology, Kelly and co-workers had identified an interaction between (CO)5Cr and cyclohexane. Isotopic studies, particularly scrambling, have been used to indirectly observe alkane sigma complexes [282]. The intermediacy of the alkane sigma complex is detected by the exchange of the deuterium label into the alkyl ligand. In the notable case of [(Cp)Os(dmpm)(CH3)H+], between −120°C and −100°C the exchange between the hydride and methyl ligand could be observed through line-broadening experiments in NMR [283].

M

CH2 R D

H H C M R D

H D C M R H

unobserved sigma complex intermediates

M

CHDR H

1.9  Base Metals in C–H Activation

In 2007, Ball and coworkers studied the low temperature equilibrium between alkane sigma complexes and alkyl hydrides of the complex CpRe(CO)2(PF3) [284] Solutions of this complex were irradiated with UV light in alkane solvent at −88°C, leading to photoejection of a carbonyl group and interaction with alkane. This interaction is characterized by an equilibrium, observable through NMR and time resolved infrared spectroscopy, between alkylrhenium hydride and rhenium alkane complex. The position of this equilibrium is sensitive to temperature as well as to the alkane: n-pentane, for example, shows both species, but cyclohexane shows only the alkane sigma complex. Low temperature protonation of alkyl ligands is another approach to preparing alkane sigma complexes. This was the approach taken by Bernskoetter, Schauer, Goldberg, and Brookhart in 2009, wherein (PONOP)Rh(13CH3) was treated with H[B(ArF)4]•(Et2O)2 at −105°C in CDCl2F [285]. This complex proved to be relatively long-lived under these conditions, enabling extended spectroscopic studies that were facilitated by 13C isotopic labeling. These measurements were, in turn, paired with theoretical studies. The methane sigma complex was identified by a sharp upfield resonance in 13C-NMR, that was split into a quintet. This indicated fast exchange of C–H bonds: the methane tumbles in the coordination sphere of the cationic rhodium complex. Proton-decoupled 13C-NMR, in turn, showed a single broad resonance – with broadening attributed to weak interactions with the NMR-active nuclei 103Rh and 31P. Methane dissociation from this sigma complex was measured to have an activation barrier of (ΔG‡) of 14.5±0.4 kcal/mol at −87°C. As clever and meticulous as these studies have been, perhaps the most satisfying turn in this decades-long pursuit of sigma complexes appeared in 2012. Abandoning solution phase characterization altogether, Andrew Weller and colleagues hydrogenated a single crystal of the rhodium olefin complex (iBu2PCH2CH2PiBu2)Rh(NBD) (NBD=η,η2-norbornadiene) to accomplish crystal-to-crystal conversion to a norbornane sigma complex. This interconversion could be monitored by solid state NMR. With quick work and low temperatures, the new crystal could be transferred to an X-ray diffractometer, affording the first clear crystal structure of an alkane sigma complex [286]. This was subsequently extended to hydrogenating a pentadiene ligand. Solid-state NMR and ab initio molecular dynamics simulations of the resulting rhodium pentane complex probed the dynamics of alkane complex. Interactions between rhodium and two methylene groups are seen, with equilibration between 2,4-coordination, 1,4-coordination, and 1,3-coordination [287]. The equilibration between alkyl hydride and alkane sigma complexes has been studied in the solid state. Low energy rocking, pivoting, and tumbling occurs in rhodium norbornane complexes. Under an atmosphere of deuterium, scrambling into the bound alkane complex occurs [288]. These solution-state and solid-state studies of alkane sigma complexes have helped to put mechanistic descriptions of sp3 C–H oxidative addition on stronger theoretical footing. The equilibria and low energy dynamic behavior of these complexes is particularly of interest in understanding regioselectivity of C–H functionalization processes. But it should be noted that sigma complexes are presumed to be intermediates to sp3 C–H activation (in some if not all cases) proceeding via all reaction pathways: electrophilic mechanisms, SBM, 1,2-addition, and oxidative addition. To date, detailed studies of these activation modes are lacking, presenting a fundamental challenge that will no doubt require a very thoughtful combination of theoretical and experimental methods to address.

1.9  Base Metals in C–H Activation Homogeneous organometallic catalysts based on the noble 4d and 5d metals have proven their worth over the decades. It’s difficult to imagine modern organic chemistry without palladium, platinum, rhodium, iridium, ruthenium, and osmium catalysts in myriad catalytic applications such as hydrogenation, oxidation, olefin metathesis, cross-coupling, hydroformylation, and C–H functionalization. They’ve helped industry and academia alike move closer toward “ideal syntheses” [289], with precision bond formations reliant on fewer concession steps and with less waste generation. Some of these systems can achieve incredible efficiencies, up to 1 million turnovers or utilizing part per million loadings of catalyst. But even at this optimistic upper end, it only partially offsets the limitations to their use. Noble metals catalysts are a rarity in the Earth’s crust. It is estimated that iridium, rhodium, osmium, and ruthenium are present at ca. 1–2 parts per billion (ppb) by mass. Platinum and palladium are present at 5 and 15 ppb. This is reflected in their prices, which fluctuate daily and are sensitive to market pressures and geopolitical climate. These metals are byproducts of platinum mining, and most of the world’s platinum reserves are located in only two countries: South Africa (63,000 metric tons) and Russia (4,500 metric tons) [290]. Most recently, in 2021 and 2022, the SARS-CoV-2 pandemic and the Russia-Ukraine war have adversely affected the supply and prices of these elements. Molecular catalysts exacerbate this

37

38

1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

inherent rarity in that they are generally non-recoverable in fine chemical processes. A worse scenario for drug manufacturers is if trace metal residues remain in a finished active pharmaceutical ingredient (API). They are, after all, heavy metals of known (or unknown) toxicity [291]. Earth-abundant, or base metals, present enormous and economically viable opportunities for large-scale implementation of homogeneous catalysis. Among the transition metals, these are the elements of groups IV - VI along with manganese, iron, cobalt, nickel, and copper. Iron in particular comprises 5.6% of the mass of earth’s crust. This translates to more facile and less energy intensive extraction and refining. Concerning toxicity, in contrast with platinum group metals, gold, and silver, many base metals are essential parts of our diets [291]. Metalloenzymes have learned to wield base metals for complex multielectron processes [292]. The use of base metals in C–H activation and broader organometallic catalysis has had a lengthy induction period. Only in the past decade has there been an exponential growth in examples and applications [1r]. In some instances, the base metal system outclasses precious metal systems. For example, as discussed above, the anti-Markovnikov hydroarylation of olefins is a desirable reaction to give ‘super-linear’ alkylbenzenes – feedstocks for more efficient and biodegradable detergents. Conventionally, these are prepared by Friedel-Crafts acylation and reduction. Catalytic approaches relying on precious metal-based strategies using hydroarylation, dehydrogenative coupling, and metathesis approaches have been developed, but these systems are either inefficient, unselective, limited scope, themselves produce stoichiometric waste, or assume a second hydrogenation step (e.g. iridium [91, 167], ruthenium [168a], rhodium [174, 176], platinum [173, 293], or the alkane metathesis approach including Ir-based dehydrogenation) [294]. A nickel complex recently reported by Nakao and Hartwig [295] has been a breakthrough: it offers linear-to-branched selectivity of >50:1, broad substrate scope (even isomerizing internal olefins to terminal olefins prior to hydroarylation), and high activity (up to 283 turnovers reported). This particular system was enabled by modern advances in ligand design, namely N-heterocyclic carbenes as organometallic ligands, as well as modern computational methods to characterize a novel ligand-to-ligand hydride transfer pathway [296]. With the modern proliferation of base metal catalysis in the literature, there is some irony in that C–H oxidative addition was likely first observed in iron, with the discovery of ferrocene. the first disclosure of ferrocene was in 1951 by Kealy and Pauson [297]; they prepared it from iron dichloride and cyclopentadienylmagnesium bromide. But although the full history of ferrocene’s discovery and bonding description is something of a Rashoman tale [298], two points are clear: firstly, that Pauson and Kealy were not the first to prepare it; and secondly, that its first preparations were unrecognized instances of C–H activation. Contemporaneously with Pauson and Kealy, a report from Miller, Tebboth, and Tremaine of the British Oxygen Company (and whose work was done three years earlier) described the preparation of ferrocene directly from cyclopentadiene vapors and iron chips at 300°C [299]. This accidental process was actually observed even earlier, in the 1930s as Union Carbide attempted to crack cyclopentadiene. This effort was eventually abandoned when a yellow sludge kept clogging the iron pipes they were using. This sludge was not characterized at the time; but samples of it were retained and, decades later, found to be ferrocene [300]. 2 CpMgBr + FeCl2

2

+

Cp 2F e + MgBr 2 + MgCl2

Fe0

300°C

Fe

+

H2

Pauson and Kealy preparation, 1951

Miller, Teboth and Tremaine, 1952

detected by infrared spectroscopy in matrix isolation studies. Fe H

Ball, Kafafi, Hauge, and Margrave, 1985

In a subsequent study, infrared spectroscopy of iron vapor co-deposited with cyclopentadiene in argon matrix at 14 K revealed characteristic iron hydride stretches, presumed to be from intermediate (C5H5)Fe–H en route to ferrocene [301]. This strongly implicates an initial oxidative addition of Cp–H to Fe(0). A follow-up, redox-neutral C–H activation adds a second cyclopentadienyl ring to the iron(II) center with expulsion of H2 as a byproduct. Right at the dawn of the studies of oxidative addition in the 1960s, several examples of intramolecular C–H activation reactions involving iron(0) were reported. In 1965, Pauson reported the activation of sp2 C–H bonds in imines and

1.9  Base Metals in C–H Activation

azobenzene using iron pentacarbonyl and diiron nonacarbonyl [302]. This showed that iron could form complexes, with formation of metal-carbon bonds, similar to those of palladium or platinum reported by Cope and Siekman [74]. This work, (started prior to Cope and Siekman’s 1965 report) was inspired by Kleiman and Dubeck’s 1963 report of the formation of a complex from dicyclopentadienylnickel and azobenzene [303]. R N N Cl

Cl

M

Ni N

M R

N

O

N

N

R

O

R = Me, OMe

M = Pd, Pt

R

Bagga, Pauson, Preston, Reed 1965

Cope and Siekman 1965

Kleiman and Dubeck 1963

NNN N Fe

Hata, Kondo, and Miyake prepared (dppe)2Fe(C2H4) by reduction of iron(III) acetylacetonate with ethoxydiethylaluminum in the presence of dppe (1,2-bis(diethylphosphino)ethane), and found that it undergoes an intramolecular oxidative addition with a phenyl group under UV light [304]. This is fully reversible, and the intermediate (dppe)Fe0 complex can be trapped using either ethylene (to reform the starting olefin complex) or H2 (to form a dihydride). Ph Ph Ph P Ph P Ph P Fe Ph P Ph Ph

Ph Ph Ph P Ph P H Ph P Fe Ph P

UV -C2 H4 C 2H 4 80°C

Ph Ph Ph P Ph P H Ph P Fe H Ph P Ph Ph

1 atm H2 60 - 70°C

Ph

Hata, Kondo, Miyake 1968

Such dihydrides are further reactive. When exposed to UV light, a similar iron(II) dihydride complex with the ligand tris(dimethylphosphinoethyl)phosphine (“pp3”) reductively eliminates H2, and the resulting (pp3)Fe0 fragment oxidatively adds a ligand methyl group [305]. Examples of intermolecular reactivity also began to appear. Tolman, Ittel, English, and Jesson at DuPont prepared (dmpe)2Fe(napthyl)H [306]. The napthyl hydride was apparently in equilibrium with (dmpe)2Fe and naphthalene. This iron(0) fragment could in turn be trapped in the presence of neutral ligands such as CO, ethylene, diphenylacetylene, and azobenzene [307]. H2 or the C–H bonds of acetonitrile or cyclpentadiene undergo oxidative addition with the Fe(0) intermediate [307]. In 1987, Field and Baker succeeded in activating alkanes using (dmpe)2FeH2 by irradiating a solution under UV light at −90°C [86c]. Oxidative addition occurs at the terminal C–H bond of linear alkanes, and cycloalkanes also under oxidative addition. If the irradiation is done at −30°C in n-pentane, then the initially formed (dmpe)2Fe(1-pentyl)H undergoes β-hydride elimination to reform the starting dihydride with loss of 1-pentene. Unfortunately, product inhibition by the resulting olefin limits the efficiency of this cycle. The same complex, (dmpe)2Fe0, is capable of oxidative addition of methane in a xenon matrix at −100°C [308]. H2 P

P Field, George, and Messerle 1991

P P Fe P

H CH 3

CH 4 (30 mol%) Xe -100°C

P P Fe P

H H

-90°C, hν -30°C

P P P Fe P

H

Field and Baker 1987

39

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1  Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

UV light is not economical for transformations of simple alkanes, but then again, at this point in time, even alkane dehydrogenation systems using Rh and Ir catalysts were reliant on UV light and/or gave very low turnover numbers. This system is remarkable for turning over under cryogenic conditions. In retrospect, the ideal features of this system – the base metal, the fast kinetics, the terminal selectivity – are quite remarkable. Also in 1987, Jones reported the catalytic insertion of isonitriles into arene C–H bonds [165a]. Fe(PMe3)2(CNR)3. As discussed above, this appears to proceed via photogeneration of a thermochemical catalyst, specifically the reversible loss of CNR to give Fe(PMe3)2(CNR)2. The potential practical advantages of base versus precious metals were not particularly appreciated at this time. One advantage of precious metals catalysts is that they were generally more robust. Perhaps a self-fulfilling cycle was operating: as even small advantages of precious metals catalysts led to further research with them, and further success, more and more they appeared to be intrinsically better for catalysis. It seems to have required a conscious effort on the part of the community to return to these roots [309]. Some recent work with iron-based catalysis was initiated by a serendipitous discovery by Nakamura and colleagues in 2008. While pursuing cross-coupling reactions between diphenylzinc and 2-bromopyridine, they detected the formation of an unintended secondary coupling of two phenyl groups [309b]. The origin of this unintended but fortuitous cross-coupling was eventually pinpointed to an air leakage. Excess air or O2, however, led to decomposition of the starting materials. Through some experimentation, dichloroalkanes were found to be cheap and convenient oxidants, with 1,2-dichloro2-methylpropane found to perform best.

FeCl3 (5 mol%) ZnCl 2•TMEDA (1.5 equiv) PhMgBr 3.0 equiv N

Br

N

+

63%

N

N

THF, 50 °C, 3 h (air leakage)

Fe(acac) 3 (10 mol%) ZnCl 2•TMEDA (3 equiv) PhMgBr 6 equiv 1,10-phenanthroline (10 mol%)

Cl

Cl

THF, 0 °C, 16 h

8%

N

2 equiv 99%

This report perhaps arrived at a more receptive time than the earlier report by the Jones group. For one, the scope and efficiency of palladium-catalyzed cross-couplings had grown to the point that they were seeing widespread usage. Two years later, as this work was still being developed by Nakamura, the 2010 Nobel Prize in Chemistry was awarded to Suzuki, Heck, and Negishi for the development of palladium-catalyzed cross coupling. That same year saw major trade disputes emerging concerning export restrictions on rare earth elements. Although palladium is not a rare earth element, this may have been an early alert that organometallic catalysts in synthesis needed some diversification. Additionally, this work occurred concurrently with more widespread growth directed C–H activation strategies (a key enabling strategy). From any academic point of view, this was a system that sat at the intersection of silos of interest. But more than that, the system used off-the-shelf reagents and catalysts. It was easy to use. And the value of this cannot be overstated in synthesis. The above discussion about iron is intended to be representative of base metals in organometallic C–H activation. The earliest reports were confusing, or simply underappreciated. Early attempts at catalysis were not widely reduced to practice. But now that the community understands the value of metal-mediated and catalyzed reactions, has the tools to study them, and appreciates the need for reliable supply chains, there has been vigorous research into base metals. And if ever there was a perception that platinum group metals are unique in C–H activation, that should be dispelled. It appears to be a safer assumption that all transition metals can activate C–H bonds by some mode or another rather than C–H activation

Acknowledgments

being a unique talent of platinum group metals. And whereas the community seems to have focused on platinum group metal catalysis for several decades, it is now applying the knowledge and tools gained along the way to earth-abundant metals with dramatic success.

1.10  Conclusions and Future Outlook The field of organometallic C–H activation, both witting and unwitting, is now over a century old. In the earliest years, the phenomenon was almost begging to be recognized—but neither the state of theory nor experimental methods were amenable to elucidating it. Mercuration pre-dated modern atomic theory, and electrophilic auration preceded the discovery of the neutron. At a time when the most advanced tools for probing molecular structure were combustion analysis, decomposition methods, and the fledgling technique of X-ray crystallography, the solution state behavior of transition metals was a mystery. With the benefit of hindsight, we can only wonder how many missed opportunities there were to accelerate catalysis and organic synthesis in the era between 1920 and 1950. But with the coalescence of physical organic chemistry and its most powerful tools – linear free energy relationships, kinetic isotope effects, TS theory, molecular orbital theory – it was suddenly possible to interrogate reaction mechanisms by the 1950s. The rapid development and widespread availability of scientific instrumentation: microanalytical balances, infrared spectroscopy, ultraviolet spectroscopy, and then NMR and mass spectrometry, aided this effort. The reexamination of old mysteries, such as ethylene coordination in Zeise’s salt, led to new theoretical frameworks – the Dewar-Chatt-Duncanson model for olefin coordination. This would, in turn, advance even beyond the namesake scientists’ imagination. Dewar, for instance, did not imagine that this model would ever apply to sigma bonds [310]. By the 1970s and 1980s, the community realized that strong C–H bonds were not an insurmountable obstacle to C–H activation. Quite the contrary, the ability of transition metals to cleave C–H bonds seemed to increase with increasing C–H bond strength(!). With that insight in mind, C–H activation set out to transform the petrochemicals industry, promising to use methane as a feedstock and stitching together hydrocarbon building blocks to higher value products. Clearly it would be very challenging to effect a functionalization process and stop at the initial products, but if the higher bond strength of methane and simple alkanes was not an impediment, it seemed to be surely ambitious, but perhaps a feasible goal. At the least, it seemed not quite so formidable as the functionalization of more complex organic molecules. In addition to all the problems faced with simple alkanes, the selectivity issue posed by complex molecules possessing many different, yet similar, C–H bonds, was truly daunting; and that is not to even include complications from heteroatoms or functional groups. And yet, whereas commodity scale applications still largely remain an unmet (and inspiring) challenge, C–H activation has had a transformative effect in complex organic synthesis. This is exemplified in the following chapters of this book, which describe the use of C–H activation in various heterocyclic systems. C–H activation is no longer a novelty – it is a tool with evermore ambitious end goals: goals such as stereoselective C–H functionalization [311], atom-economical oxidative cross-couplings using electrochemical oxidation [312], materials synthesis [313], and post-synthetic modification of commodity polymers [314]. The synthetic community is thus transitioning from a discovery phase of C–H activation to an applications phase – at least with stalwart precious-metals catalysts. The synthesis and catalysis communities are rising to backfill useful reactions of these platinum group catalysts with earthabundant metals; and in some cases, developing even more useful systems. We do not pretend to know where the next few decades will take us, but we expect that new technologies, new motifs in ligand design, new methodologies, and new mechanistic frameworks will lead to a wonderfully rich and valuable C–H activation landscape, as different from today’s as today’s is different from that of a few decades past.

Acknowledgments We gratefully acknowledge the U.S. Department of Energy Office of Science (Grant DE-SC0020139) for supporting T.B. and (in part) A.S.G., and funding several aspects of the work discussed in this review. A. K. gratefully acknowledges the funding received from Science and Engineering Research Board, New Delhi, India (Grant No. DST-SERB CRG/2018/000607), Ministry of Education, India (Grant No. STARS/APR2019/CS/629/FS), Ministry of Electronics and Information Technology, GoI, India (Grant No. (5(1)/2021-NANO) & (5(1)/2022-NANO)) and Indian Council of Medical Research, New Delhi, India (5/3/8/20/2019-ITR).

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303 Kleiman, J. P. and Dubeck, M. (1963). The preparation of cyclopentadienyl [o-(phenylazo)phenyl]nickel. Journal of the American Chemical Society 85: 1544–1545. 304 Hata, G., Kondo, H., and Miyake, A. (1968). Ethylenebis(diphenylphosphine) complexes of iron and cobalt. Hydrogen transfer between the ligand and iron atom. Journal of the American Chemical Society 90: 2278–2281. 305 Antberg, M. and Dahlenburg, L. (1987). Oligophosphan-liganden, XXIII. Synthese und chemie des metallacyclischen eisenkomplexes / oligophosphine ligands, XXIII. Synthesis and chemistry of the metallacyclic iron complex. Zeitschrift für Naturforschung B 42: 435–440. 306 Tolman, C. A., Ittel, S. D., English, A. D., and Jesson, J. P. (1978). The chemistry of 2-naphthyl bis[bis(dimethylphosphino) ethane] hydride complexes of iron, ruthenium, and osmium. 1. Characterization and reactions with hydrogen and Lewis base ligands. Journal of the American Chemical Society 100: 4080–4089. 307 Ittel, S. D., Tolman, C. A., English, A. D., and Jesson, J. P. (1978). The chemistry of 2-naphthyl bis[bis(dimethylphosphino) ethane] hydride complexes of iron, ruthenium, and osmium. 2. Cleavage of sp and sp3 carbon-hydrogen, carbon-oxygen, and carbon-halogen bonds. Coupling of carbon dioxide and acetonitrile. Journal of the American Chemical Society 100: 7577–7585. 308 Field, L. D., George, A. V., and Messerle, B. A. (1991). Methane activation by an iron phosphine complex in liquid xenon solution. Journal of the Chemical Society, Chemical Communications 1339–1341. 309 (a) Bolm, C., Legros, J., Le Paih, J., and Zani, L. (2004). Iron-catalyzed reactions in organic synthesis. Chemical Reviews 104: 6217–6254. (b) Shang, R., Ilies, L., and Nakamura, E. (2017). Iron-catalyzed C–H bond activation. Chemical Reviews 117: 9086–9139. 310 Mingos, D. M. P. (2001). A historical perspective on Dewar’s landmark contribution to organometallic chemistry. Journal of Organometallic Chemistry 635: 1–8. 311 Saint-Denis Tyler, G., Zhu, R.-Y., Chen, G., Wu, Q.-F., and Yu, J.-Q. (2018). Enantioselective C(sp3)‒H bond activation by chiral transition metal catalysts. Science 359: eaao4798. 312 Tang, S., Liu, Y., and Lei, A. (2018). Electrochemical oxidative cross-coupling with hydrogen evolution: a green and sustainable way for bond formation. Chemistry 4: 27–45. 313 (a) Li, B., Ali, A. I. M., and Ge, H. (2020). Recent advances in using transition-metal-catalyzed C–H functionalization to build fluorescent materials. Chemistry 6: 2591–2657. (b) Zhang, J., Kang, L. J., Parker, T. C., Blakey, S. B., Luscombe, C. K., and Marder, S. R. (2018). Recent developments in C–H activation for materials science in the center for selective C–H activation. Molecules 23: 922. 314 Williamson, J. B., Lewis, S. E., Johnson III, R. R., Manning, I. M., and Leibfarth, F. A. (2019). C−H functionalization of commodity polymers. Angewandte Chemie International Edition 58: 8654–8668.

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2 Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms B. Prabagar and Zhuangzhi Shi School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China

2.1  Introduction 2.1.1  Importance of Pyrrole, Furan and Thiophene Derivatives Pyrrole, furan, and thiophene derivatives are considered to be highly useful frameworks due to their presence in several biologically active natural products, drugs, and agrochemicals as well as their use in material chemistry. In particularly, these molecules show interesting properties such as antitubercular, anti-viral, analgesic, anti-microbial, anti-malarial, anti-inflammatory, and anticancer acticities in addition to inhibiting enzymes, inhibiting metal corrosion, andfor use in the production of light-emitting diodes in material science [1]. Therefore, diversification of pyrrole/furan/thiophene derivatives has attracted much interest and several effective direct C–H functionalization strategies have been developed for the synthesis of their valuable and fully functional valuable compounds [2]. With the regular improvement of the catalytic system of C–H functionalization reactions [3], several research groups have elegantly described their findings through either direct or directing group assisted C–H activation and functionalization methods for these molecules under transition metal-catalysis. Some of selective examples of pyrrole/furan/thiophenebased drugs/natural products are described in Figure 2.1 and these include atorvastatin (Lipitor), lamellarins, sunitinib, fludioxonil, flufuran, tournefolin B and C, dimethylfuroguaiacin, furopelargone B, suprofen, tiaprofenic acid, clopidogrel, tenoxicam and others (Figure 2.1). In recent years, great advancements have been implemented for the modification of the periphery of the pyrrole, furan, and thiophene derivatives from the various potential research group using several metal-catalysts such as palladium, ruthenium, rhodium, iridium, copper, gold, iron, and cobalt. Therefore, this chapter focuses on the recent developments related to transition metal-catalyzed C–H bond functionalization of pyrroles, furan, and thiophenes (C2, C3, C4 and C5 positions). The chapter is structured to cover the following topics: C–H arylation, alkenylation, alkylation, alkynylation, borylation, silylation, and amination. We, however, strongly believe that this chapter will also assist as an accessible reference for any researcher who is fascinated by emerging novel methods for the formation of C–C and C–heteroatom bonds of existing five-membered heteroarenes and their complex synthesis.

2.1.2  General Reactivities of Pyrrole, Furan, and Thiophene Pyrrole, furan, and thiophenes are undoubtedly more reactive than benzene in electrophilic aromatic substitution reactions due to the presence versus absence of a heteroatom. The C2 position in particular has a high tendency to undergo electrophilic substitution reactions. Whereas electrophilic substitution is much easier than with benzene, nucleophilic substitution reaction with pyrrole, furan, and thiophene is relatively difficult and necessitates an activating group within the molecule. The order of aromaticity as follows; benzene>thiophene>pyrrole>furan (Figure 2.2). All of the π electrons in benzene ring participate fully in forming the aromatic sextet. However, because heteroatoms sulfur, nitrogen, and oxygen are more electronegative than carbon, there is an uneven charge sharing due to electron cloud attraction toward these atoms. Among

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

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2  Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms

Selective pyrrole based drugs/natural products PhHN Ph

OH

HO

N

CH3 OH OH

COOMe

N

N H O

F

F

NH

F

CH3

NC

H 3C

O CH 3

F

NEt2

O

O

N H

N H

R

O

COOH Atorvastatin

Lamellarins

Sunitinib

Fludioxonil

Selective furan based drugs / natural products HO2 C

HO2 C

OH OH

OH

HO

O

O

O

HO

RO

O CH3

OH O

R = Me, Tournefolin B R = H, Tournefolin C

Flufuran

Pri CH3

CHO

Dimethylfuroguaiacin

Furopelargone B

Selective thiophene based drugs/natural products O

HOOC CH 3

Ph

COOH S

O

S

H N

CH 3

O

Cl O CH 3 O

S O

O CH 3 N OH HN N

S

Suprofen

S

Tiaprofenic acid

Clopidogrel

Tenoxicam

Figure 2.1  Selective examples of pyrrole, furan, and thiophene drugs and natural products. Order of Aromaticity

H

H

H

4

3

H 5 S 2 1 Thiophene

H

3

H

4

H

2

5 N1

H

H

H

H

4

3

H 5 O 2 H

Pyrrole

1

Furan

Figure 2.2  General reactivity of pyrrole, furan, and thiophene.

these five membered heterocycles, thiophene has higher aromaticity due to the low electronegativity value of sulfur. Furan has a lower aromaticity because of the higher electronegativity value of oxygen (Table 2.1). As there is negative charge on the carbon atom of thiophene, pyrrole, and furan through electron delocalization, they smoothly undergo electrophilic substitution reactions. Moreover, the electron density of each carbon can be varied depending on the heteroatom present in the ring system. However, these fundamental relativities would not affect much in C–H activation chemistry, which is a positive effect of this strategy [4]. Therefore, the transition metal-catalyzed direct C–H

2.2  Transition Metal-Catalyzed C–H Functionalization of Pyrroles

Table 2.1  Electronegativity values of oxygen, nitrogen and sulfur. Atoms

Electronegativity values

Oxygen

3.44

Nitrogen

3.04

Sulfur

2.56

bond activation and functionalization process for installing a valuable and modifiable functional group in an atom and step economic manner is greatly encouraged. Based on this viewpoint, we here aim to discuss the recent advancements and challenges of C–H functionalization reactions involving pyrrole, furan, and thiophenes.

2.2  Transition Metal-Catalyzed C–H Functionalization of Pyrroles 2.2.1  C–H Arylation of Pyrroles Transition metal-catalyzed direct C–H cross-coupling reactions with no use of prefunctionalization is the most important strategy in constructing highly valuable organic compounds. These reactions are considered environmentally attractive, cost-effective, and atom economical. In 2010, Jafarpour and coworkers reported the direct regioselective C2 arylation of pyrroles in the presence of palladium catalysis. The reactive free NH-pyrroles have effectively participated in the catalytic system providing 2-arylated pyrrole derivatives 1 in good yields. Transformation involving free NH-pyrroles is highly notable as it avoids the need of installing the protecting groups and potential functionalities for the formation of this C–C bond. To obtain the desired product, this reaction requires the catalytic system of Pd(OH)2/C (10 mol%) and triethanolamine (0.2 M) at 100 oC for 24 h (Scheme 2.1A) [5]. Similarly, in 2012, Doucet’s group demonstrated the coupling between N-tosylpyrroles and arylbromides for the construction of 2-arylated pyrrole 1. This reaction condition is also viable with heteroarylbromides to give the corresponding pyrrole coupled product in good yield. A wide range of functional groups on aryl bromides are well tolerated under this catalytic condition. Overall, the N-tosylpyrrole provided increasing yield whereas free NH-pyrrole ended with poor yield. Comparatively, N-alkyl pyrroles are much more reactive than tosyl and free NH-pyrroles (Scheme 2.1B) [6]. Jafarpour, 2010

N

I

H

R

Pd(OH)2 /C (10 mol%) Triethanolamine (0.2 M) 100 o C, 24 h

R1

(A)

N R

R1 1

R = H, Ar, alkyl

22-80% yield

Doucet, 2012

N Ts

H

Br

[PdCl(C 3H5 )] 2 (1.0 mol%)

Ar

KOAc (2.0 equiv) DMAc, 20 h, 130 oC

R1 Ar = aryl/heteroaryl

DMAc = Dimethylacetamide

N

(B)

Ar

Ts

R1 1

> 15 examples 40-68% yield

Scheme 2.1  Palladium-catalyzed regioselective C2 arylation of pyrroles.

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2  Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms

The Hu and Yu group have discovered an expedient synthetic method for the C2 arylation of pyrroles using arylboronic acids in the presence of iron catalyst (Scheme 2.2). The challenging site-selectivity at the C2 position using free NH-pyrroles and the involvement of electron-deficient pyrroles are great features of this transformation. Thus, the combination of polyamine macrocyclic ligand 3 and Fe-catalyst are greatly facilitated this direct Suzuki-Miyaura coupling between electronrich and electron-deficient N-heterocyclic compounds and arylboronic acids. Based on experimental study and DFT (Density-functional theory) calculation, the mechanism was described as follows. First, the oxoiron I species was generated by oxidation of iron complex under oxygen. The newly-formed iron-complex prefers to perform an electrophilic attack on the C-2-position of pyrrole in regioselective manner with the assistance of a nitrogen atom. Then, deprotonation of tertiary metal-complex I gave 2-metalated pyrrole complex-II. Finally, transmetalation with arylboronic acid followed by reductive elimination delivered the anticipated coupling product 2 in a very good yield. Hence, the initial step coordination of nitrogen atom with the iron-complex is highly responsible for the C2 selectivity. (Scheme 2.2) [7]. Hu and Yu, 2010

FeC 2O 4·2H2O (0.2 equiv)

B(OH)2 N H

H

R

N

N H

3 (0.2 equiv) 130 oC, 10 h, Air

NH

R

HN

2

H N

up to 86% yield

3

Proposed mechanism

Ar

N H

III

O2

FeL

N H

FeL O

Fe L Ar

N H

H N

Fe O L

B(OH)3 ArB(OH) 2

H

I

Fe L O H

N H II

Scheme 2.2  Iron-catalyzed C2 arylation of pyrroles using arylboronic acids.

In 2011, the arylchlorides were successfully used as an arylating agent for the regioselective direct arylation of pyrroles and furans under palladium catalysis. The combination of 2-(dicyclohexylphosphino)-biphenyl ligand 4 and K3PO4 base along with Pd(OAc)2 catalyst provided the targeted C2 arylated pyrrole 1 in moderate to good yields. Notably, the electronpoor and electron-rich aryl chloride coupling partners worked nicely for this catalytic condition. Moreover, the indole and furan heteroarenes also reacted with aryl chlorides and delivered the corresponding arylated product effectively with little modification to the reaction condition (Scheme 2.3) [8]. In 2011, Sanford reported the direct C–H arylation of 2,5-substituted pyrroles using diaryliodonium salts 5 under palladium catalysis. Utilizing the developed catalytic condition (MeCN)2PdCl2 (2.5 mol%), Ar2IBF4 (1.0 equiv) in 1,2-dichloroethane (DCE) solvent at 84°C for 2 h, numerous trisubstituted pyrrole derivatives 6 were successfully synthesized up to 88% yield. Depending on the size of substituents on second and fifth position of pyrrole molecules, the yield fluctuated.

2.2  Transition Metal-Catalyzed C–H Functionalization of Pyrroles

Daugulis, 2011 Pd(OAc)2 (5.0 mol%) 4 (10 mol%)

Cl

R1 N

H

R2

R

R1 N R

K3PO4 (2.0 equiv) o

NMP, 125 C, 24 h

R

1 yield 42-78%

PCy2 4

Scheme 2.3  Palladium-catalyzed C2 arylation of pyrroles using arylchlorides.

Therefore, the steric factors play a major role in the regioselectivity in this protocol. Also, this method is effective to prepare tetra and penta substituted pyrroles, which shows the high functional group tolerance (Scheme 2.4) [9]. Sanford, 2011 R4 H R3

H N R1

BF4

I

R2

Ar R4

H

(MeCN)2 PdCl2 (2.5 mol%) DCE, 84 °C, 2 h

R3

R2

5

N R1 6

(1.0 equiv)

up to 88% yield

Scheme 2.4  Palladium-catalyzed selective C3-arylation of 2,5-substituted pyrroles using diaryliodonium salts.

Cobalt-porphyrin catalyzed direct C–H arylation of unactivated pyrroles with aryl iodides/bromides was reported by Chan’s group in 2012 for the construction of 2–arylated pyrrole derivatives 2 in an efficient manner (Scheme 2.5). The proposed reaction mechanism is generation of aryl radical I from the carbon–halogen homolytic cleavage of arylhalides with the help of cobalt(II)(tap). The formed aryl radical adds to the pyrrole to give the arylated-pyrrole radical intermediate II. Tert-butoxide or hydroxide anion performs deprotonation of the radical intermediate to deliver the heteroaryl-radical-anion species III. Finally, the desired product is obtained by intermolecular dissociative electron transfer process between heteroaryl-radical-anion and aryl halides. The C2 and C3 selectivity appears to result from the resonance structures of the C2 and C3 arylated heterocyclic radical intermediates. Therefore, the reason for the high C2-selectivity is that the corresponding arylated radical intermediate has more resonance structures than the C3 arylated product (Scheme 2.5) [10]. In 2014, Flepin’s group showcased the copper catalyzed Meerwein-type radical C2 aryalation of pyrroles using anilines as an arylating agents with the help of CaCO3. This reaction proceeded through the in situ generated aryldiazonium salts I, which undergoes copper(I)-catalyzed homolytic dediazoniation to generate highly reactive aryl radical II. The formed aryl radical immediately reacted with pyrrole and gave the int-III, which is oxidized in the presence of copper(I) to the corresponding cationic species Int-IV and finally deprotonated to give the desired product (Scheme 2.6A). The control experiments revealed the role of CaCO3, as it acts as a buffer additive defeating the formation of azo compounds and also steps in the catalytic cycle to increase the reaction proficiency (Scheme 2.6A) [11]. In the same year, Doucet and coworkers reported phosphine-free palladium-catalyzed desulfitative arylation. The variety of pyrroles such as 1-phenyl-, methyl-, and 1-benzylpyrroles were positively combined with benzenesulfonyl chlorides and provided the respective pyrroles in

65

66

2  Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms

Chan, 2012 X

N H

CoII(tap) (5.0 mol%) KOH (10 equiv)

H

N H

tBuOH (10 equiv)

N2, dark, 200 o C

R1

2

15-60 minutes

upto 74% yield

X = I, Br proposed mechanism X-

KOH

H N

Ar

+

H 2O 2

Ar

H 2O + 1/2 O2

Co II(tap)

ArX H N

R1

CoIII(tap)OH

ArX

-

KX

Co III(tap)X III

KOH

H2O/t BuOH

Ar I

OH-/ tBuO -

H N

Ar H

H

H N

(tap = tetrakis-4-anisylporphyrinato dianion)

II

Scheme 2.5  Cobalt-catalyzed C2 arylation of pyrroles.

good yields with high regioselectivity. Interestingly, the bromo- and iodo-benzenesulfonyl chlorides successfully delivered the expected product by not cleaving the sensitive C–Br or C–I bonds which could be further readily transformed to the valuable products (Scheme 2.6B) [12]. Itami and Yamaguchi have developed the regioselective C3 arylation of pyrrole under Rh-catalysis (Scheme 2.7). Installation of an aryl moiety at the C3 position of pyrroles (6) is highly important as these scaffolds are present in many natural products and drug molecules. Here the authors successfully showcased the preparation of polycyclic marine pyrrole alkaloids, lamellarins C, and other important derivatives by utilizing this developed C3 selective arylation of pyrroles with aryl iodides (C−H/C−I coupling) followed by a new double C−H/C−H cross-coupling reaction as a key steps. The N-substituents of pyrrole have made a high impact in providing regioselectivity at the C3 position. The larger N-substituents increase the trend of C3-selectivity of pyrroles (7) rather than int-8. For example, the order of increasing C3-selectivity is Me 98:2 42%

O

NMe 2

CO 2Me E :Z = 79:21 61%

Scheme 6.25  Palladium(II)-catalyzed C7-olefination of N-carbamoyl indolines with various alkenes. Source: Modified from Jiao and Oestreich [35].

In 2014, Shibata’s group reported the first [IrIIICp*Cl2]2-catalyzed site-selective C7- alkenylation of N-acetylated indolines with various terminal olefins (Scheme 6.26) [36]. Cu(OAc)2 was used to reoxidize iridium(I) to iridium(III) in the catalytic cycle. The effect of different carbonyl functionalities (e.g. Me, Et, iPr, tBu, cyclopropyl, NMe2, NEt2, and piperidinyl) as DGs on the nitrogen atom of indoline were studied and it was observed that N-acetyl (N-COMe) group underwent C7−H olefination at a much faster rate than the others. The protocol could be extended with a range of substituted N-acetylated indolines, including sterically congested C6-F substituted indoline. On the other hand, different electron-donating and electron-withdrawing groups bearing styrenes, ethyl, and cyclohexyl acrylates were good coupling olefinic sources for this transformation. Interestingly, the hydrogenation and DDQ oxidation were performed to obtain the corresponding C7-alkylindoline (91%) and C7-alkenylated indole compound (62%), respectively (Scheme 6.27).

R1

R

+

N O

Me

R2

[Cp*IrCl2]2 (5 mol %) AgOTf (20 mol %)

N O Ph

R

N

Cu(OAc)2 (10 mol %) DCE, 100 o C, 48 h

O

Me

R2

R1

R

R1

96% (R = 2-Me) 88% (R = 3-Me) 64% (R = 5-Br) Me 61% (R = 6-F)

N O

59% (R = 3-OMeC6H 4) 94% (R = 4-MeC6H4) Me 75% (R = CO2Et) 89% (R = CO2c-Hex)

R

Scheme 6.26  Iridium(III)-catalyzed C7-olefination of N-acetyl indolines with terminal olefins. Source: Modified from Pan et al. [36].

6.1  Introduction

a) Pd/C, H2

b) DDQ N O Ph

Me

N

1,4-dioxane reflux, 24 h

62%

O

N

MeOH, rt overnight

Me

Ph

O Ph

Me

91%

Scheme 6.27  Synthetic transformations of C7-olefinated indolines. Source: Modified from Pan et al. [36].

The reaction mechanism involves a catalytic dehydrogenative cross-coupling in which C7-metallation of N-acetylated indoline takes place by an active cationic iridium(III) complex A (generated by the addition of [IrCp*Cl2]2 with AgOTf), which results in the formation of a six-membered aryliridium intermediate B. After olefinic coordination as well as migratory insertion to the carbon-iridium bond of B along with β-hydride elimination, intermediate B transforms into the final C7-alkenylated indoline product and iridium(I) species, which is oxidized to an active iridium(III) complex by copper(II) (Scheme 6.28).

[Ir IIICp*Cl2]2 2HX Air 2CuIX

H 2O

2CuIIX2

AgOTf AgCl

N

IrIIICp*Xn

O

A X = OTf , OAc

Me HX

IrICp*Xn-2 D

N Me Ir Cp* X O n-1 B

N

N O R

+ HX

Me

Me

H R

Ir

R2

O

Xn-1

Cp* C

Scheme 6.28  Proposed reaction mechanism. Source: Modified from Pan et al. [36].

Similarly, the removable N-pyridinyl DG-assisted C7-alkenylation of various substituted indolines with different styrenes and other alkenes under the rhodium(III) catalyst was reported by Loh group. The reaction might have been initiated by the formation of a monomeric rhodium(III) complex [RhCp*(OAc)2] generated by the ligand exchange between neutral [RhIIICp*Cl2]2 catalyst and Cu(OAc)2 oxidant (Scheme 6.29) [37]. In the same manner, other groups also reported using the N-pivaloyl DG with different transition metal catalysts to produce cross-coupling reactions between various substituted indolines with α,β-unsaturated acceptor acrylates as the olefinic source. For example, Zhao and Huang used the [RuIICl2(p-cymene)]2 catalyst for this transformation (Scheme 6.30) [38], whereas Ravikumar, in 2020, efficiently utilized the [Cp*Co(CO)I2] catalyst for this C7-alkenylation of indolines (Scheme 6.31) [39]. In both of these transformations, the proposed reaction mechanism is similar to the previously reported works [34, 36]. Complementarily, a powerful protocol for the [RuIICl2(p-cymene)]2-catalyzed direct C–H alkenylation of N-pivaloyl indolines with a series of internal alkynes to afford the C7–H alkenylated indolines was also reported by Koley’s group in 2021 (Scheme 6.32) [40]. The catalytic system tolerates various functional groups at C2-, C3-, and C5-positions on the indoline frame. Notably, the tolerance of this reaction system for bromine, chlorine, iodine, cyanide, and nitrogen dioxide

263

264

6  C(sp2)–H Functionalization of Indolines at the C7-Position

[RhCp*Cl2] 2 (4.5 mol %) Cu(OAc) 2 (2 equiv.)

R2

R1

+

N

R

DCE, 100

o

N

C, 12 h N

N

R (R = aryl and alkyl) H 3CO

R N

R2

R1

R N

N

CH 3

N

N

CH 3

N N

N R

75% (R = H) 75% (R = Ph)

84%

62% (R = Br) 76% (R = p-OAc) 86% (R = F) 81% (R = o -CH 3 )

Scheme 6.29  Rhodium(III)-catalyzed C7-olefination of N-pyridinyl indolines with styrenes. Source: Modified from Yang et al. [37].

[Ru(p-cymene)Cl2]2 (5 mol %) Cu(OAc) 2 H2O (1 equiv.)

R2

R1

+

N O

R

AgSbF6 (20 mol %) THF, 100 oC, 20 h, Ar

(R = EWG)

tBu

R2

R1

N t Bu O R (up to 92% yield)

Scheme 6.30  Ruthenium(II)-catalyzed C7-olefination of N-pivaloyl indolines with acrylates. Source: Modified from Zhang et al. [38].

R2

R1

O

OR 2

+

N

[CoCp*(CO)I2] (10 mol %) AgSbF6 (20 mol %) Cu(OAc) 2 H2O (1 equiv.) HFIP (0.1 M), rt, 20 h (up to 92% yield)

O

tBu

R2

R1

N O

tBu

CO 2R 2

Scheme 6.31  Cobalt(III)-catalyzed C7-olefination of N-pivaloyl indolines with acrylates. Source: Modified from Banjare et al. [39].

R2 R1

+

N H

O

R3

R4

N t Bu

O

tBu

O 78% (R = H) Ph 67% (R = Me)

R3

Ph 62% (R = Me) Ph 52% (R = NO2) Br

N

O

tBu

NPhth CO2Me

NPhth tBu 78%

48% (R 3, R4 = 4-Me-Ph) 66% (R 3, R4 = 2-thienyl)

N

Ph

O

N

R3 R4

R

R

Ph

PivOH (5 equiv.) DCM (0.16 M), 100 oC, 12 h

tBu

N Ph

R2

[Ru(p-cymene)Cl2]2 (5 mol %) R1 AgSbF6 (20 mol %)

O

O

O

O 71%

Ph

60% (R 3 = Me, R 4 = Ph)

R4

N

H N

tBu

BnO tBu

OBn O OMe

O Ph CH2OBn

N O

tBu

72% (rr = 3:1)

Scheme 6.32  Ruthenium(II)-catalyzed C7-olefination of N-pivaloyl indolines with internal alkynes. Source: Modified from Raziullah et al. [40].

6.1  Introduction

groups is of interest as these moieties can provide a versatile synthetic handles for further transformation of the synthetic products. This reaction is also suitable for the annulated indolines. The sterically hindered C6-substituted indoline was not compatible with this reaction. However, both symmetrical and unsymmetrical alkynes participated smoothly in this direct C7-alkenylation cross-coupling reaction. Interestingly, this protocol was extended to alkyne derivatives bearing pharmaceutically acceptable heteroarenes (piperonyl, quinoline, indole, thiophene, and benzothiophene) and active pharmacophores to form active pharmaceutical ingredients (APIs) such as quinoxalinone (caroverine, a muscle relaxing drug), carbazole (carprofen, a nonsteroidal anti-inflammatory drug), pyridone (pirfenidone, a drug for idiopathic pulmonary fibrosis), and quinolone (aripiprazole, drug for schizophrenia and bipolar disorder) and furnished the single regioisomeric products in 17–88% yields. Subsequently, this approach was also applied to late stage modification of natural products, drugs, and API molecules tethered with internal alkynes. For example, indole-containing amino acids (tryptamine, serotonin receptor agonist), 4-hydroxycoumarin (an active pharmacophore of warfarin), phenylalanine (amino acid), mannose (carbohydrate), and cholesterol (a steroid) resulted in the formation of the corresponding C7-alkenylated indolines in good to high yields. Moreover, DG removal, the gram-scale experiment, and DDQ oxidation of indoline to indole, showed the synthetic application and practicality of this methodology. The mechanism of the reaction pathway was proposed on the basis of kinetic isotope value (kH/kD=~1), suggested that the C–H bond cleavage might not involve in the rate-limiting step. Mechanistically, authors suggested that first the combination of a neutral [RuIICl2(p-cymene)]2 catalyst, AgSbF6 additive, and pivalic acid generates an active [RuII(OPiv) (p-cymene)](SbF6)n catalyst A. Electrophilic ruthenation of indoline with catalyst A formed a six-membered ruthenacycle intermediate B. Then the coordination and insertion of alkynes into the Ru–C bond leading to the formation of an eightmembered C(sp2)−Ru species D. Finally, the desired C7-alkenylated indoline product can be liberated by protodemetallation (Scheme 6.33). [Ru(p-cym)Cl2] 2 PivOH, AgSbF6 HCl

N Ph

+

tBu

O Ph

[Ru(OPiv)(p-cym)](SbF6)nA C-H act iv at ion

N H

protodemetallation

PivOH

PivOH

N Ph Ru

t Bu

O

N

tBu

O

L

Ru

O B

t Bu

D alk yne insert ion

Ph

N L Ph

Ru

O Ph

Ph

t Bu

C

Scheme 6.33  Proposed reaction mechanism. Source: Modified from Raziullah et al. [40].

6.1.3 C−H Bond Alkynylation of Indolines at the C7-Position Carbon-carbon triple bonds (alkynes) are among the most important functional groups in organic molecules which can be easily transformed into other moieties because of the diverse reactivity of the triple bonds [41]. Alkynes are widely found in a range of synthetic bioactive compounds, natural products and functional materials [42]. Traditionally, the Sonogashira cross-coupling reaction was widely utilized for the alkyne incorporation to get the alkynylated (hetero)arenes and was accomplished with various major challenges [43]. To overcome these challenges, several approaches have been involved

265

266

6  C(sp2)–H Functionalization of Indolines at the C7-Position

for the addition of alkyne functionality into heterocycles and, among them, transition metal-catalyzed C−H cross-coupling has been recognized as one of the most powerful methods [44]. This part is focused on C7−H alkynylation of indolines. In 2012, Chang’s group first introduced a single example of site-selective C7−H alkynylation of indoline having a pyridine DG with (triisopropylsilyl)acetylene as alkyne reagent under a cost-effective palladium(II)-catalyst in 9% yield (Scheme 6.34) [45]. Mechanistically, the formation of a six-membered palladacycle by the arylpalladium π-complex underwent ligand exchange with the addition of alkyne and provide an arylpalladium acetylide intermediate. Finally, reductive elimination afforded the desired C7-alkynylated indoline product and palladium(0) species, which could be re-oxidized to palladium(II) with the help of benzoquinone (BQ) and acid additive.

Pd(acac) 2 (10 mol %) TsOH/H 2O (10 mol %)

H N

+

N

Si(i-Pr)3

N

benzoquinone (2 equiv.) benzene, 80 o C, 12 h 9%

N Si(i-Pr)3

Scheme 6.34  Palladium(II)-catalyzed C7-alkynylation of N-pyridyl indolines with silyl acetylenes. Source: Modified from Kim et al. [45].

To accommodate the pyridine as a removable DG with the nitrogen of indolines and to allow the insertion of alkyne group at the C7-position of indolines, Loh and coworkers designed another protocol for the C7-alkynylation of indolines in 2016. The combination of a neutral [RhIIICp*Cl2]2 catalyst with CuII(OTf)2 was found to be most effective catalytic system in the C7–H alkynylation of indolines through the formation of a indoline bearing six-membered rhodacycle complex (Scheme 6.35) [37]. With the optimized catalytic system in hand, a series of indolines having a variety of electron-rich and halogen substituents at the C2- to C5-positions were evaluated. Generally, due to the steric hindrance, the less reactive C6-position was also tolerable in this system and the C7-alkynylated product was obtained in a respectable yield. Not only the TIPS-alkyne (TIPS-EBX), but other hypervalent alkynyl iodine reagents such as TES-EBX, TBS-EBX, TBDPSEBX, and tBu-EBX also successfully furnished the corresponding products in good-to-high yield with high regioselectivity. It is noteworthy that phenyl-based hypervalent alkynyl iodine Ph-EBX, which is usually unsuccessful in C−H functionalization to facilitate the alkynylation reaction, resulted in the desired product in good yield even at room temperature and less reaction time. [RhCp*Cl2] 2 (4 mol %)

R2

R1

N

+ R 3-EBX

Cu(OTf)2 (20 mol %)

R2

R1

N

DCE, 50 o C, 12 h

N

N R3

N

N

N TIPS 77%

N R

72% (R = TES) 83% (R = TBS) 74% (R = TBDPS) 72% (R = tBu)

R3

I O O

R 3 EBX

Scheme 6.35  Rhodium(II)-catalyzed C7-alkynylation of N-pyridyl indolines with TIPS-EBX alkynes. Source: Modified from Yang et al. [37].

Although a detailed catalytic pathway on the mechanism was not proposed, the preparation of a thermodynamically stable six-membered rhodacycle complex, derived from N-pyridinyl indoline suggested a key intermediate in the catalytic cycle. A scale-up experiment and the deprotection of pyridinyl DG to get the free (NH)-C7-alkynylated indolines have been showcased by the authors (Scheme 6.36). In 2015, similar work by Li and coworkers appeared in which [IrIIICp*Cl2]2 was employed as a catalyst and a hypervalent iodine reagent (TIPS-EBX) was used as an alkyne source. A screening of suitable DGs was challenging, as it seemed that

6.1  Introduction

1) MeOTf , CH 3CN 2) NaBH 4, MeOH

N

N H

3) TBAF, THF (semi-one-pot)

N

62%

TIPS

Scheme 6.36  Deprotection of pyridinyl and TIPS groups into free (NH)-C7-alkynylated indoline. Source: Modified from Yang et al. [37].

the steric, electronic, and metal coordination effect played a crucial role in this transformation. The DGs such as acetyl, carbamoyl, acyl, and sulfonyl, however, exhibited no directing effect towards the C7-alkynylation. The pyridine and pyrimidine ligands as DGs were found to support the catalytic system to furnish the C7-alkynylated indoline product at room temperature (Scheme 6.37) [46]. This method yielded a wide range of N-pyrimidyl indolines that could be coupled with various hypervalent iodine reagents. Even indoline bearing the strong electron-withdrawing groups such as NO2 and ester underwent the desired coupling reaction in high yield. O N H

+

N

N

O

[Cp*IrCl2]2 (2.5 mol %) AgNTf 2 (10 mol %)

R2

I

EtOH, rt, 10 h

N

2 (R2 = TIPS, TMS, TES, t Bu)

1

N N

R2 3

Scheme 6.37  Iridium(III)-catalyzed C7-alkynylation of N-pyridyl indolines with TIPS-alkynes. Source: Modified from Wu et al. [46].

Two mechanistic paths have been proposed (Scheme 6.38). First, a cationic [IrIIICp*(NTf2)2] catalyst was formed to promote the catalytic cycle, generated from the ligand exchange between a neutral [IrIIICp*Cl2]2 catalyst and AgNTf2 additive. In path a, the formation of a six-membered iridium(V)-metallacycle intermediate B takes place, followed by the oxidative addition of hypervalent iodine alkyne into intermediate A that subsequently undergoes to reductive elimination to form species C. Although other possibilities cannot be ruled out, the alternative path b also forms species C by migratory

N

2 path b *Cp

N

path a

R 1 IrCp*(NTf 2)2

N

III N

I O

A

N

2 ox idative addition

H+

N R

Ir III

Ir Cp*

AgCl AgNTf 2

D

N *Cp

Ir V

N R

reductive elimination N N

N

N

VN

E

N

B O(CO)PhI

(IrCp*Cl2)2

O

N

Ir

C p* O(CO )P

hI

1,2-aryl migration

R Ir(III)Cp* C O(CO)PhI

3

Scheme 6.38  Proposed reaction mechanism. Source: Modified from Wu et al. [46].

267

268

6  C(sp2)–H Functionalization of Indolines at the C7-Position

insertion of the alkyne, α-elimination of 2-iodobenzoic acid, formation of iridium vinylidene species E, aryl-migration and elimination. Finally, alkyne dissociation from species C generates the desired C7-alkynylated indolines. In the same year, Zhu and coworkers employed hypervalent iodine reagents (TIPS-EBX) as alkynylating agents with N-acylated indolines under Rh(III)-catalysis (Scheme 6.39) [47]. The catalytic pathway is similar to previous reports [46]. However, MnO2 (manganese dioxide) was applied for the oxidation of indoline to convert it into indole and the removal of DG took under DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) conditions.

R2 R1

+

N H

O

O

I

[RhCp*Cl2 ] 2 (5 mol %) AgNTf 2 (20 mol %)

TIPS

N

MS (4Å) DCM, 50 oC, 16 h, Ar

R

O (R = Me, Et, Bn, Ph)

R2 R1

O

TIPS-EBX

R

TIPS

Scheme 6.39  Rhodium(III)-catalyzed C7-alkynylation of indolines with TIPS-EBX alkynes. Source: Modified from Jin et al. [47].

Later, by employing the hypervalent iodine reagents (TIPS-EBX) as alkyne donors, Zhao’s group reported only two examples for the C7-alkynylation of N-pivaloyl indolines under a [RuIICl2(p-cymene)]2 catalyst and using Cu(OAc)2·H2O as a suitable oxidant (Scheme 6.40) [38].

Br R N O

tBu

+ TIPS

[Ru(p-cymene)Cl2]2 (5 mol %) Cu(OAc) 2 H 2O (1 equiv.) KPF6 (20 mol %) H2O, 100 oC, 20 h, Ar

R N t Bu

O

75% (R = H) TIPS 71% (R = Me)

Scheme 6.40  Ruthenium(II)-catalyzed C7-alkynylation of N-pivaloyl indolines with TIPS-EBX alkynes. Source: Modified from Zhang et al. [38].

6.1.4 C−H Bond Alkylation of Indolines at the C7-Position Traditionally, the synthesis of alkylated (hetero)arenes relies on Friedel–Crafts reactions [48] or radical alkylations [49, 50]. These protocols have several limitations (Scheme 6.41a) [51]. As a consequence of these limitations, research efforts have been directed towards the development of transition metal-catalyzed cross-couplings between unactivated alkyl (pseudo)-halides and organometallic nucleophiles, which enables a streamlining of organic synthesis as well as a minimization of overall waste formation (Scheme 6.41b) [51]. In consideration of the challenge and biologically importance of C7-alkylated indolic scaffolds, we aim to provide here an overview of the C7−H alkylation of indolines.

(a) traditional alkylation

R2

X H

M R1

R1

H H cat.[TM] -MX

R1

H

R2 H

cat.[TM] R2 -HX H H (b) direct alkylation X

Scheme 6.41  Traditional cross-coupling versus direct alkylation reaction. Source: Modified from Ackermann [51b].

6.1  Introduction

In this context, the transition metal-free direct C7–H alkylation of N-Boc protected indoline with alkyl halide was reported for the first time by Coldham and Leonori in 2009. In this reaction, the authors reported a single example between indoline and an electrophilic bromo propane as an alkyl source, generating a 73% yield of N-Boc-7-propylindoline (Scheme 6.42) [13]. The reaction proceeded in an SN2 fashion through the formation of a organolithium species A that was generated by the treatment of N-Boc-indoline with sec-BuLi/TMEDA and then the direct addition of bromopropane to species A delivered the N-Boc-7-propylindoline product. This reaction represented a real breakthrough and a valuable tool for the further study of the directed C7–H alkylation of indolines. After this report, a number of researchers, including our group, efficiently utilized a different coupling partners for the transition metal-catalyzed C7-alkylation of indolines. sec-BuLi (1.2 equiv.) TMEDA (1.2 equiv.) N Boc

Et2O, -78 oC, 2 h

N Boc

Li

Me

Br N Boc

Me

A

73%

Scheme 6.42  Transition metal-free C7–H alkylation of N-Boc protected indoline with alkyl halide. Source: Modified from Leonori et al. [13].

In 2013, Sanford and coworkers disclosed a single example of a direct oxidative Suzuki-Miyaura type cross-coupling reaction between unsubstituted indoline and a organoboron reagent (i.e. potassium organotrifluoroborate) under a Pd(OAc)2 catalyst (Scheme 6.43) [52]. The combination of CH3BF3K, MnF3, and a palladium(II) catalyst was found to provide an effective catalytic system in C7–H methylation. This example was an advance and the desired product was produced in good yield. The authors utilized the widely used acetyl group as the DG to control the site-selectivity of methylation, particularly at the C7-position of indoline. Based on the previous reports and experimental results, a catalytic pathway was proposed involcing the formation of palladium(II)/palladium(IV) species. In this pathway, potassium organotrifluoroborate plays a dual role, both as methyl source and as terminal oxidant to generate the palladium(IV) intermediate. Pd(OAc) 2 (10 mol %) CH3BF3 K (2 equiv.) MnF 3 (4 equiv.)

N O

Me

TFE/H2O/AcOH 25-40 oC, 3 h

N Me

O 83%

Me

Scheme 6.43  Palladium(II)-catalyzed C7-methylation of N-acetyl indoline with CH3BF3K. Source: Modified from Neufeldt et al. [52].

One year later, Shibata and coworkers reported the direct C–H alkylation of N-substituted indolines using cationic [IrI(cod)2]BF4 as a catalyst and rac-BINAP as a ligand. The one-pot alkylation of various substituted N-acetylindolines was achieved by the simple addition of olefins at the C7-position (Scheme 6.44) [53]. It is noteworthy that, except for acetyl groups, other N-carbonyl DGs such as Boc, Cbz, COtBu, COPh, and carbamoyl failed to facilitate the desired alkylated products. The use of a variety of olefins such as acrylates and other terminal olefins was capable of providing the desired C7-alkylated product in good to high yields. para-Trifluoromethyl-substituted styrene showed low tolerance, but styrene itself delivered the corresponding C7-alkylated indoline in high yield. These results indicated that electronic effect play an important role in this transformation. This protocol was then successfully used for the DDQ oxidation for the conversion of indoline to indole. The authors proposed a simple reaction mechanism followed by the formation of a iridium(III) alkyl species. In contrast, Zhou, Yang, and coworkers described the rhodium(III)- and iridium(III)-catalyzed direct alkylation of N-pyrimidyl indolines with a broad range of diazomalonates and Meldrum’s diazoester. This approach employed the catalytic system of [RhIIICp*Cl2]2/AgSbF6 with diazomalonates and [IrIIICp*Cl2]2/AgNTf2 with Meldrum’s diazoester and C2-, C3-, C4-, and C5-substituted indolines gave moderate-to excellent yields of the corresponding C7-alkylated indolines (Scheme 6.45) [54]. It is notable that this protocol is also suitable for use with sterically congested C6-substituted indoline, providing the desired C7-alkylated indolines in high yield. The facile release of N2 as an environmentally benign byproduct

269

270

6  C(sp2)–H Functionalization of Indolines at the C7-Position

R N Ac (Ac = COMe)

R1

+

R

[Ir(cod) 2]BF4 (5 mol %) rac-BINAP (5 mol %)

N Ac

o

dioxane, 135 C, 24 h R1

R N Ac

R N Ac

COOEt 91% (R = H) 92% (R = CH 3) 98% (R = Ph)

N Ac

F

COOEt

COOEt 86% (R = Br) 86% (R = OMe)

97%

N Ac

COOR 94% (R = Et) 95% (R = c-Hex) 85% (R = Ph)

Scheme 6.44  Iridium(I)-catalyzed C7-alkylation of N-acetyl indoline with olefins. Source: Modified from Pan et al. [53].

N2 O

O O

R N pym

(pym = pyrimidine )

or R 2O

EtO2C

R

70% (R = H) 95% (R = CO2Et)

N2

[RhCp*Cl2]2 (2.5 mol %) R3

O R

N pym

AgNTf 2 (10 mol %) R1OH, 100 o C, 6 h

O

+

[IrCp*Cl2]2 (2.5 mol %)

AgSbF6 (10 mol %) EtOH, rt, 24 h

R N pym

R1O2C R R2O2C

R3

N pym

R

N N N pym pym pym RO2C EtO2C EtO2C CO2Et 94% (R = OMe) 77% (R = iPr) 70% (R = OMe) 84% (R = Br) 72% (R = Br) 57% (R = tBu)

Scheme 6.45  Iridium(III)-catalyzed C7-alkylation of N-pyrimidyl indoline with diazoesters. Source: Modified from Ai et al. [54].

and oxidant-free conditions make this protocol an important advancement in the C7-functionalization of indolines. Furthermore, the DDQ oxidation, and subsequently the C2-alkynylation of the newly-obtained C7-alkylated indole, showcases the robustness of this cross-coupling reaction. On the basis of the deuterium exchange experiment and KIE value (KIE, KH/KD=1.45), the proposed reaction pathway included the generation of isolable six-membered rhodium(III)-complex, coordination of diazo compound, 1,2-migratory insertion of the aryl group, release of N2, and the protonolysis to generate the final product. In 2015, a palladium(II)-catalyzed decarboxylative C(sp2)–C(sp3) cross-coupling reaction between N-pyrimidyl indolines and easily accessible aliphatic carboxylic acids as the alkyl source was disclosed by Jain and coworkers (Scheme 6.46) [55]. PhI(OAc)2 was found to be a suitable terminal oxidant, which significantly promoted the reaction at lower temperature (40 oC) under solvent-free conditions. A range of tertiary/secondary α-substituted and acyclic as well as cyclic aliphatic carboxylic acids efficiently introduced the related alkyl groups at the C7-position of C2-substituted and unsubstituted N-pyrimidyl indolines in good-to-high yields. The practicability of this method was further demonstrated by the ortho-alkylation of 2-phenylpyridines and azobenzenes with aliphatic carboxylic acids. The authors proposed a radical pathway for the reaction mechanism. Radical trapping experiments using radical scavengers such as TEMPO and ascorbic acid were performed, which prohibited the yield of product and suggested the radical pathway for this reaction. Thus, the oxidative addition of in situ generated pivaloyl radical (facilitated by the thermal decomposition of PhI(OAc)2) to six-membered palladacycle A leads to the formation of a palladium(III)/palladium(IV) species B. The reductive elimination of B resulted in the formation of final C7-alkylated indoline product and a palladium(0) complex, which can be reoxidized by external oxidant to liberate the active palladium(II) catalyst to participate in the next catalytic cycle (Scheme 6.47).

6.1  Introduction

H

N pym

N pym

Pd(OAc) 2 (10 mol %) PhI(OAc)2 (2 equiv.)

CO2H

R1 +

R2 Me R3

R

Me Me Me Me 92% (R = H) 89% (R = Me)

Me

40 oC, 2 h

N pym Me

( )3

79%

Me

Me R2 R3 Me N pym

R1 N pym

Me

73%

N pym

89%

Scheme 6.46  Palladium(II)-catalyzed C7-alkylation of indolines with aliphatic carboxylic acids. Source: Modified from Premi et al. [55].

oxidant Pd(0) C

N Me N Me Me

N

N

Pd(OAc)2 H

reductive elimination

AcOH

N

N Me

Pd

N

N

N

carbopalladation

N

Pd

Me Me OAc B

2

OAc

N

N

A

oxidative addition Me Me

-CO2 COOH -AcOH + PhI(OAc)2 Me -PhI Me Me Me

Scheme 6.47  Proposed reaction mechanism. Source: Modified from Premi et al. [55].

Reports confirming that C7-alkylation of indolines using allylic alcohol were unexplored during those period. Therefore, in 2015, this encouraged Kim and coworkers to adopt the allylic alcohol as alkyl donor for regioselective C7-alkylation of indolines under a rhodium(III) catalyst (Scheme 6.48) [56]. Kim used an N-acetyl group as the directing auxiliary in performing the C7-alkylation of indolines. Other DGs such as N-pivaloyl, benzoyl, and N,N-dimethyl carbamoyl, exhibited moderate to good or even no directing effect toward the C7-position. However, the pyrimidine ligand was found to be tolerable for this reaction. The combination of a neutral [RhIIICp*Cl2]2 catalyst with AgSbF6 and Cu(OAc)2 additives favored the construction of desired C7-alkylated product with a range of electron-donating and electron-withdrawing functionalities at the different positions of N-acetylated indolines. It is noteworthy that the sterically more congested C6-substituted indolines delivered the desired alkylated product with moderate to excellent yields. A similar reactivity was also observed with annulated indoline. This methodology extended the various α-substituted allylic alcohols as alkyl sources. However, no formation of desired product was detected when α-aryl-substituted allylic alcohol as well as β- and γ-substituted allylic alcohols were used. Synthetic utility of the protocol was further highlighted by the transformation of indolinic carbonyl scaffolds into biologically relevant tricyclic indolinic motifs through intramolecular aldol reaction and basic dehydration (Scheme 6.49).

271

272

6  C(sp2)–H Functionalization of Indolines at the C7-Position

R2

R1

N

+

N

AgSbF 6 (10 mol %)

OH

R3

H

[RhCp*Cl2] 2 (2.5 mol %)

R

R2

R1

R3

Cu(OAc)2 (30 mol %) DCE, 60 oC, 20 h

O

O O

R Me

89% (R = Me) 85% (R = tBu) 66% (R = Ph) R 5% (R = NHOMe) N. R. (R = NHOMe)

N O O

Me

N

O

Me 17%

O O

Me

Me

Me 51%

O

Me 71%

O

N

N

N

Me

O

O 62% (R = H) R 77% (R = Et) O 57% (R = Oct)

Me

O

Me N

Ph

N

N

N

Me

Me

O O

O

60%

Ph

21%

Scheme 6.48  Rhodium(III)-catalyzed C7-alkylation of indolines with allylic alcohols. Source: Modified from Han et al. [56].

N Me O O

Me

K2CO3 (150 mol %)

N

MeOH, 80 oC, 16 h 59%

Me MeOH, rt, 12 h 70% Me

O

N

10% Pd/C, H 2

Me O

Me

Scheme 6.49  Intramolecular aldol reaction and basic dehydration of C7-alkylated indolines. Source: Modified from Han et al. [56].

Mechanistically, a kinetically favored six-membered cyclorhodated intermediate A controlled the C7-selectivity of alkylation that involved the coordination and subsequent 1,2-migratory insertion of allylic alcohol to generate the sterically congested intermediate B. Then β-H elimination afforded the corresponding alkylated indoline through the keto−enol tautomerization of allylated enol product (Scheme 6.50).

N

N Me HO

Me

[RhCp*(OAc)]+SbF6-

O C

Me

H

O HOAc

+ N

N Me O O

Me

Me

Rh OH B

+

Me N

O

Cp* Rh O

Me

A OH Me

Scheme 6.50  Proposed reaction mechanism. Source: Modified from Han et al. [56].

6.1  Introduction

Encouraged by this result, the Kim group further extended a similar strategy to the N-pivaloyl directed C7(sp2)–H alkylation of indolines with various α,β-unsaturated carbonyl compounds (enones and enals) for the synthesis of C7-alkylated β-indolinic ketones using the [RhIIICp*Cl2]2 as the catalyst combined with AgSbF6 and Cu(OAc)2 as the additives (Scheme 6.51) [57]. This method has excellent functional group tolerance and the chemoselectivity toward halogen groups that can allow postfunctionalization into the cross-coupling reactions. R2

R2 O

R1 N H

O

tBu

+ R1

R2

1 [RhCp*Cl2]2 (2.5 mol %) R AgSbF6 (10 mol %)

N R 1O

Cu(OAc)2 (10 mol %) DCE, 60 oC, 20 h

O

tBu

R2

Scheme 6.51  Rhodium(III)-catalyzed C7-alkylation of N-pivaloyl indolines with enones and enals. Source: Modified from Oh et al. [57].

An oxidative approach for the C7-alkylation of pyrimidine directed indolines with various alkyl substituted cyclopropanols via rhodium(III)-catalyzed cleavage of C7(sp2)–H/C–C bonds was also studied by the Li group (Scheme 6.52) [58]. In this reaction, the use of CsOAc is crucial to the reaction because the formation of monomeric [RhCp*(OAc)2] derived from [RhCp*(Cl)2]2 and CsOAc, is the active catalyst. It has been proposed that the reaction proceeds by the formation of rhodium(III) alkoxide species B followed by the ligand exchange with cyclopropanol into the Rh–C bond of the metallacycle A. Subsequent β-carbon elimination forms a homoenolate species C that can undergo reversible β-H elimination. Then migratory insertion of the Rh−C bond into the olefin unit and C−H reductive elimination furnishes the alkylated product (Scheme 6.53).

R1

R H

+ N pym

HO

R2

[Cp*RhCl2]2 (4 mol %) CsOAc (25 mol %)

Bn

R1

O

N pym

OEt O Me N pym EtO

N pym

Cu(OAc)2 H2O (2.1 equiv.) MeOH, rt, N2, 17 h R2

R O

R

Me N pym O 85% (R = H) 86% (R = OMe) Bn 77% (R = CO2Me)

75%

71%

Scheme 6.52  Rhodium(III)-catalyzed C7-alkylation of N-pyrimidyl indolines with alkyl cyclopropanols. Source: Modified from Zhou et al. [58].

Kim and coworkers developed ruthenium(II)- and rhodium(III)-catalyzed Grignard-type C–H additions of pyrimidine directed N-heterocycles with activated aldehydes and ketones to afford the corresponding hydroxy alkylated derivatives. Among these N-heterocycles, a number of coupling reaction of pyrimidine DG-appended indolines with ethyl glyoxalate and CF3 containg activated ketone have been achieved (Scheme 6.54) [59]. The alkylation reaction of indolines employs a [RuII(p-cymene)Cl2]2/AgSbF6 and NaOAc catalytic system consisting of a cationic active complex [RuII(p-cymene)(OAc)] [SbF6]. Based on H/D exchange experiments, the mechanism of the alkylation reaction is proposed to involve the pyrimidine-directed C7-metalation, which undergoes coordination and subsequent irreversible insertion of α-keto aldehydes into the Ru−C bond and finally the protonation of the formed intermediate, producing the C7-α-hydroxyalkylated indoline. In past few years, the DG-assisted transition metal-catalyzed C–H functionalization and construction of (hetero)arenes by using the internal olefins such as maleimides for the formation of succinimide containg pharmaceutically important molecules have been well explored [60]. Many of them have an impressive approach and medicinally valuable N-containing heterocycles if the starting materials bear heteroatoms. In this context, Pan, Yu, and coworkers reported a cationic rhodium(III)-catalyzed C7-alkylation reaction between various substituted N-acetylated indolines and N-alkyl/N-aryl

273

274

6  C(sp2)–H Functionalization of Indolines at the C7-Position

[RhCp*Cl2] 2 N pym

CsOAc Cu(I) N pym

O Bn

H

[RhCp*(OAc) 2]

Cu(II)

HOAc

Cp*Rh(I) N AcO Rh N Cp* A

N

Bn O *Cp Rh H

N

N

N HO

E

HOAc N

Bn

N

O Rh N Cp* B

N Pym Rh H Cp* D

O

Bn

Bn

N Bn O

N

Rh N Cp* C

Scheme 6.53  Proposed reaction mechanism. Source: Modified from Zhou et al. [58].

R2

R1

O

N H

+

N

N

R2

[Ru(p-cymene)Cl2]2 (2.5 mol %) AgSbF6 (10 mol %)

CO2Et R (R = H, COCF3)

R1 N EtO2C

NaOAc (50 mol %) DCE, 60 oC, 20 h Me

N EtO 2C

OH

N

82% (X = N) 78% (X = C)

EtO 2C

O OH

R

10% (R = NMe 2) 14% (R = Me)

OH

EtO 2C

OH

85% (R = F) 46% (R = Cl)

EtO 2C

OH 79%

N

N EtO 2C

OH

N

N

Ph N

N

N

OH

95% (R = OMe) 83% (R = Br)

93%

N N

N EtO2C

N

Me R

N

N EtO 2C

N

R

N X

OH

N

N

89% (dr = 1.1:1)

N EtO2C N F 3C N OH

N

39%

Scheme 6.54  Grignard-type C7-alkylation of N-pyrimidyl indolines with aldehydes and ketones. Source: Modified from Jo et al. [59].

substituted maleimides C(sp2)–H bonds to build succinimide containg indolines in the presence of AgOAc and AcOH (Scheme 6.55) [61]. In addition, the DDQ oxidation for the synthesis of C7-succinimide induced indole and the removal of N-acetyl group under acidic (HCl) conditions have also been successfully developed.

6.1  Introduction

R3

R4

R2 R1

N R

+

N O

[RhCp*Cl 2]2 (5 mol %) AgSbF6 (20 mol%) AgOAc (20 mol %)

O

O R = H, alkyl, Bn, allyl

R3

R4

R2 N

HOAc (2 equiv.) DCE, 120 oC, 2 h

O

R1

O N

O

R

Scheme 6.55  Rhodium(III)-catalyzed C7-alkylation of indolines with substituted maleimides. Source: Modified from Pan et al. [61].

Inspired by the above report, Ravikumar and coworkers have extended a similar strategy to install the succinimide unit at the C7-position of indolines using the [CoIIICp*(CO)I2] catalyst combined with AgSbF6 and Zn(OTf)2 as additives. Zinc(II) plays a unique ligand role to facilitate the formation of the more electrophilic [CoIII(Cp*)OTf]+ complex (Scheme 6.56) [62]. This method has excellent functional group compatibility toward the indolines and maleimides as well as methyl acrylate and exhibited different properties from the rhodium(III)-catalyzed reaction. It is noteworthy that a weakly coordinating amide carbonyl group proved to be a superior DG to facilitate the reaction followed by the coordination and insertion of maleimide into the C7–Cobalt bond of the six-membered cobalt(III) species formed.

Cp*Co(CO)I2 (10 mol %) AgSbF6 (20 mol %) Li2CO3 (20 mol %)

R2

R1 N O

X

+ Me Me

O

O

R

Me Me Me

N O

O O

Br N

N

Zn(OTf )2 (20 mol %) TFE, 80 oC, 24 h

O X = O, N

Me

R2

R1

Me Me Me

X

MeO N

O

O

R

75% (R = H) 76% (R = Me) 44% (R = Ph)

N

Me Me Me

N O

Me Me

O

Me

N

R O 73% (R = H) 68% (R = Me) 59% (R = Bn)

O 79% (R = H) 60% (R = Me) 51% (R = Ph)

N O CO2Me

Me Me Me

Scheme 6.56  Cobalt(III)-catalyzed C7-alkylation of N-pivaloyl indolines with maleimides. Source: Modified from Banjare et al. [62].

A unique reactivity of paraformaldehyde as an abundant C1 feedstock for the C7-alkylation of indolines under ruthenium(II) catalyst was disclosed by Mishra, Kim, and coworkers. In the presence of combined catalysts of [Ru(p-cymene)Cl2]2/PCy3 and Zn(OAc)2, a site-selective hydroxymethylation at the C7-position of indolines was occurred in moderate to high yields in DCE solvent (Scheme 6.57) [63]. The use of an electron-rich basic phosphine ligand [i.e. tricyclohexylphosphine (PCy3)] in the R2 R1

+ (HCHO) n N DG

H

[Ru(p-cymene)Cl2]2 (5 mol %) R1 PCy 3 (10 mol %) Zn(OAc) 2 (50 mol %) DCE, 40 oC, 24 h

HO

R2 N DG

F Me

N HO

N

N

X HO

82% (X = C) 45% (X = N)

N

N 3h, 58%

HO

N 3f, 70%

R HO

N N

3r, 67% (R = OMe) 3s, 27% (R = Br)

Scheme 6.57  Ruthenium(II)-catalyzed C7-hydroxymethylation of indolines with maleimides. Source: Modified from Lee et al. [63].

275

276

6  C(sp2)–H Functionalization of Indolines at the C7-Position

catalytic system acts a crucial role to enhanced the nucleophilicity of the Ru−aryl species generated during the catalytic cycle. An excellent level of regioselectivity was observed with a variety of electron-withdrawing and electron-donating functional groups located at the different positions of N-pyridinyl indolines. However, C6-substituted substrates are also not restricted in this transformation and form the desired products in moderate-to-high yield. The catalytic cycle proceeded by the formation of a six-membered ruthenacycle A followed by an oxidative addition of a indolic C7–H bond with in situ formed active ruthenium(II) complex, which was generated by the dissociation of one end of a chlorine ligand. Then coordination and migratory insertion of zinc-coordinated formaldehyde into the Ru–C bond and the removal of Zn(OAc)2 forms the eight-membered ruthenacycle intermediate C, which can be protonated by HOAc to give the final product and a ruthenium(II) catalyst (Scheme 6.58).

[Ru(p-cymene)Cl2]2 N HO

N

Zn(OAc) 2, PCy 3 H

N

N

Ru(II)Ln(OAc) 2 Ln = p-cymene and PCy 3

HOAc HOAc

N

N

N

O Ru Ln OAc

Ln

C H Zn(OAc) 2

H

N

Ru O N Ln OAc Zn(OAc)2 B

Ru

N OAc A Zn(OAc) 2 O

H (HCHO)n ∆

H HCHO

Scheme 6.58  Proposed reaction mechanism. Source: Modified from Lee et al. [63].

Whereas the C7-alkylation of indolines discussed above commonly involves a migratory insertion step, Punji and coworkers developed a different approach in 2020 through iron(II)-catalyzed C7-alkylation of N-pyridinyl indoline with a wide range of unactivated alkyl chlorides as an efficient alkyl auxiliary (Scheme 6.59) [64]. By employing a combination of catalytic amount of Fe(OTf)2, LiHMDS, and the bidentate diphosphine ligand Xantphos in tert-butylbenzene as the solvent, the desired C7-alkylated indolines were produced in good to excellent yields. This method displayed high regioselectivity for both primary and secondary alkyl chlorides. Moreover, not only the linear alkyl chlorides, branched, cyclic, and (hetero) aryl-substituted alkyl chlorides were also introduced as the alkyl source to successfully delivered the desired products. The generality of this protocol was further demonstrated by using the biologically relevant polycyclic molecules such as cholesterol-, stigmasterol-, and estrone-linked alkyl chlorides, producing the corresponding alkylated indolines in moderate yields. The importance of this chemistry in C7-alkylation has prompted computational (DFT) and experimental mechanistic studies of their reactivity. The result of XPS analysis and DFT energy calculation suggested that Fe(I) catalyst might be the active catalyst in catalytic system. However, both kinetic as well as EPR studies supports the direct alkylation of indolines via radical pathway. Overall, the initial C–H bond metalation is rate limiting, consistent with an observed KH/KD KIE of about 3.2. Based on these results, a cooperative mechanism was proposed as shown in Scheme 6.60. The (Xantphos)FeII complex might undergo for ligand exchange with LiHMDS via one-electron reduction to form the iron(I) active species. Coordination of indolic C7–H bond with iron(I) species lead to the formation of electron-rich organometallic iron(I) complex A, which liberated the iron(II) intermediate B followed by the addition of a halogen atom of electrophile alkyl chloride, generating through a single electron process the alkyl radical (R•). Furthermore, the alkyl radical recombined with B to give Fe(III) intermediate C. Finally, the C7-alkylated product was formed by reductive elimination and active catalyst was regenerated in the presence of LiHMDS.

6.1  Introduction

R2

R1

N 2-py

H

H

H

(py = pyridine)

R 89% (R = 68% (R = 69% (R =

LIHMDS (2 equiv.) tBu-benzene, 140 oC, 12 h

H H

O

O

N yp-2

H

H

( )6

H

54%

R2 N 2-py R

O

N 2-py

Me Si Me Me

nC H ) 6 13 nC H ) 8 17 nC H ) 12 25

R1

R

+ Cl

N 2-py

Fe(OTf) 2 (5 mol %) Xantphos (5 mol %)

Me

N 2-py ( )n 61% (n = 1) 65% (n = 2) 79% (n = 3)

53%

Scheme 6.59  Iron(II)-catalyzed C7-alkylation of N-pyridinyl indolines with alkyl chlorides. Source: Modified from Jagtap et al. [64]. P

Fe(II)(OTf) 2

P

R

LiN(SiMe3)2

P

N 2-py

Fe (I)

X

LiN(SiMe3)2

P [X = N(SiMe 3) 2/OTf /Cl]

LiX + HX

R P Fe P

Cl

N N

C

Me P = P

P

Me

P

Fe (I) N

N

A

O PPh2

PPh 2 Cl

R

P

R P

Cl

Fe(II) N

N

R

B

Scheme 6.60  Proposed reaction mechanism. Source: Modified from Jagtap et al. [64].

Very recently, Nishii, Miura, and coworkers disclosed a mild reaction condition for the C7-formylmethylation of pyrimidine directed indolines based on the use of a cationic active [RhIIICp*(MeCN)3][SbF6]2 catalyst and vinylene carbonate as alkyl donor in dichloroethane (DCE) solvent (Scheme 6.61) [65]. The coupling reaction was demonstrated for a wide range of substituted indolines and other heteroarene based substrates. However, substrate bearing electron-donating group (OMe) at C5-position and substituent at C6-position provide only low yields of the alkylated product, which suggested the possible importance of electronic and steric effect on the efficiency of this transformation. Experimentally, the acid mediated synthetic transformation, DDQ oxidation, and subsequently deprotection of pyrimidine DG of C7-alkylated indoline, showing both its versatility and applicability. Later, in the same year, Zhu, Hao, and coworkers followed the Miura’s procedure and reported the same work but replaced the DCE solvent with toluene (Scheme 6.62) [66]. Additionally, these challenging C7-alkylation of indolines were also independently highlighted by other research groups using different transition metals. For example, in 2018, Borah and Shi used [RhI(coe)2Cl]2 catalyst for a single reaction of sterically hindered N-PtBu2 directed indoline with methyl (E)-pent-2-enoate as a Michael acceptor (Scheme 6.63) [67].

277

278

6  C(sp2)–H Functionalization of Indolines at the C7-Position

R

R [Cp*Rh(MeCN)3 ][SbF6]2 (6 mol %)

O N

+ N

N

O

N

DCE, 130 oC, 16 h

O

H

N

N O

R

Me N Cl H N 76% (R = H) N 77% (R = Me) O 12% 59% (R = Cl)

N H

N

N O

N H

N

N O

53%

Scheme 6.61  Rhodium(III)-catalyzed C7-formylmethylation of indolines with vinylene carbonate. Source: Modified from Kato et al. [65].

R1

R2

N N

N

O + O

O

[Cp*Rh(CH 3CN) 3][SbF6]2 (5 mol %) toluene, 110 oC, 14 h, Ar

R1

R2

N

H

N

N O

Scheme 6.62  C7-formylmethylation of N-pyrimidyl indolines with vinylene carbonate in toluene. Source: Modified from Hu et al. [66].

H

N PtBu 2

[Rh(coe)2Cl] 2 (5 mol %) Ligand (5 mol %) toluene, 120 oC, Ar Ligand = biphenyl-2,2'-diol H

N PtBu 2

MeOOC 61%

COOMe

Scheme 6.63  Rhodium(I)-catalyzed C7-alkylation of indolines with methyl (E)-pent-2-enoate. Source: Modified from Borah and Shi [67].

Gandon and Bour showed a typical example for the C7-alkylation reaction of (NH)-free indoline with electrophilic styrene as the alkyl source under a univalent [InI(PhF)2][Al(OC(CF3)3)4] catalyst via a tandem hydroamination/Hofmann-Martius rearrangement (Scheme 6.64) [68]. Very recently, Xu and coworkers also demonstrated the C7-alkylation reaction of a simple derivative of N-methylated indoline with allylbenzene as alkyl donor under the combined catalytic system of anilido-oxazoline ligand supported scandium and [PhNHMe2][B(C6F5)4] catalysts (Scheme 6.65) [69].

N H

+

[In(PhF)2][Al(OC(CF3)4] (5 mol %) Ph

PhF, 110 oC, 12 h 99%

N H Me

Ph

Scheme 6.64  Indium(I)-catalyzed C7-alkylation of free (NH)-indolines with styrene. Source: Modified from Li et al. [68]. Sc-catalyst n =0 O

Sc-catalyst (10 mol %) [PhNHMe 2]B(C 6F5)4] (10 mol %) N Me

toluene, 80 oC, 12 h Ph

N Me

Ph Me 54%

PPID

N

N Sc

i Pr (THF) n

Si Si

Scheme 6.65  Scandium/ borane-catalyzed C7-alkylation of N-methyl indoline with allylbenzene. Source: Modified from Su et al. [69].

6.1  Introduction

6.1.5 C−H Bond Allylation of Indolines at the C7-Position The allylation reaction is one of the important transformation in organic synthesis because allyl moieties are easily employed to access various versatile functional groups. There are several methods to synthesized the allylated compounds. A straightforward and useful approach is the Lewis acid-promoted Friedel–Crafts allylation reaction because it eliminates the prior preparation of the aryl metal compounds [70]. However, the classical method for the synthesis of allylated motifs is palladium-catalyzed allylic substitution of activated nucleophiles is termed the Tsuji–Trost reaction [71]. This type of coupling reaction is restricted to electron-rich (hetero)arenes and harsh reaction conditions. In past decades, particularly, DG assisted C–H bond allylation process is become a powerful tool in where various olefins that contain allylic surrogates undergo direct C–H allylation instead of the Heck-type olefination reaction followed by β-oxygen or β-X elimination over β-hydride elimination [8e, 72]. In 2015, Kim and coworkers established an elegant example of a rhodium(III)-catalyzed intermolecular C7–H allylation reaction of indolines with allylic carbonates (Scheme 6.66) [73]. By using N-butyl carbamoyl as a removable DG, it successfully avoided the problem to enhanced the yield due to the strong coordination property with the cationic rhodium(III)catalyst in t-AmOH solvent. This method could be applied to various substituted indolines with allyl methyl carbonate to

X N H

O

N O

+

R1 R2

NHnBu

t-AmOH, rt, 20 h

O R1

Cl

NHnBu

N

(81%, >50:1)

N O

NHnBu

(89%, E:Z = 1:2.7)

O ph

N

NHnBu

N

NH nBu O (62%, >50:1) N

NH nBu

R2

O

(79%, >50:1)

NH nBu

Y N

Boc N

O

Me

X

[RhCp*Cl2]2 (2.5 mol %) AgSbF6 (10 mol %) OCO2R Cu(OAc) 2 (30 mol %)

Y

NH nBu

(82%, >50:1)

Me

(85%, E:Z = >50:1)

Me

Me

O

(84%, E:Z = 1:2.8), 40 h

N NHnBu

Scheme 6.66  Rhodium(III)-catalyzed C7-allylation of N-carbamoyl indolines with allyl methyl carbonate. Source: Modified from Park et al. [73].

yield the regioisomeric mixture (E/Z) of terminal C7-allylated indolines with excellent level of E-selectivity as major products. However, the allylation reaction was not inhibited by a substituent at the C6-position. It suggested that steric factor was not important in this catalytic system. Additionally, the reaction proceeded smoothly when the monosubstituted allyl alkyl carbonates were used as the allyl reagent with indolines and formed the (Z)-crotylation products as major isomers in high yields. However, α-phenyl-substituted allyl carbonate provided the trans-selective alkenylated product in 85% yield. The key feature of this approach is that in case of branched allylic carbonates, the reaction proceeded with complete γ-selectivity without migration of double bond and a high regioisomeric ratio of product was characterized. Moreover, no formation of C7-allylated product was observed with α,α-dimethylsubstituted allylic carbonate. It is noteworthy, this transformation was not only limited with allylic carbonates. 2-Vinyloxirane was also coupled with indoline to formed a mixture of C7-allylated alcohol indoline (E/Z=3:1) in 69% yield through olefin insertion and epoxide ring-opening, which is in agreement with the formal SN-type reaction mechanism (Scheme 6.67). Interestingly, the synthetic product was successfully applied to synthesized a diverse array of tricyclic diazepine compound via aza-Michael reaction. Further, the deprotection of N-butyl carbamoyl DG, free (NH)-allylated indolines was formed which undergoes the transfer hydrogenation process to provide C7 allylated indole compounds (Scheme 6.68).

279

280

6  C(sp2)–H Functionalization of Indolines at the C7-Position

N H

NHnBu

[RhCp*Cl2]2 (2.5 mol %) AgSbF6 (10 mol %) Cu(OAc) 2 (30 mol %)

O

+

N NH nBu O

t-AmOH, rt, 20 h

O

OH

69% (E :Z = 3:1)

Scheme 6.67  Rhodium(III)-catalyzed C7-allylation of N-carbamoyl indolines with 2-vinyloxirane. Source: Modified from Park et al. [73].

N O

Hoveyda-Grubbs 2 nd generation NH nBu

+

N

toluene 100 oC, 24 h EtO2C

O

O

s-EtOH NH nBu

N H

100 oC, 20 h

N

NaH, DMF

O

rt, 1 h

N

EtO2C

60% yield (E :Z = 50>1)

CO2Et

N

NH nBu

nBu

45% yield

10% Pd/C, acetone

N H

80 oC, 20 h

Me 70% yield (E :Z = >50:1)

Me 75% yield (E:Z = >50:1)

Scheme 6.68  Synthetic transformations of C7-allylated N-carbamoyl indolines. Source: Modified from Park et al. [73].

The KIE (KH/KD) shows that the rate-limiting step is C–H bond activation of the aryl ring. Thus, the mechanism was initiated by the reaction of rhodium(III) with indoline to form the cyclorhodacycle species A, which on migratory insertion of an olefin into Rh−C bond affords an eight-membered rhodium(III) intermediate B. Subsequent, β-oxygen elimination from B leads to the formation of desired product. However, other possibilities such as coordination of allyl methyl carbonate to the cyclorhodated species A followed by nucleophilic substitution, cannot be ruled out as components of the catalytic cycle (Scheme 6.69).

N H

O R = NH nBu

coordi nation

R

N [Rh]

NHnBu

O A

N [Rh] O

Rh III

nucleophilic subst itution

O

olef in insert ion

NHnBu

O OMe C N

N O

NH nBu

β−oxygen elimination O

NHnBu

O [Rh] O OMe

B

Scheme 6.69  Proposed reaction mechanism. Source: Modified from Park et al. [73].

6.1  Introduction

The Kim group further explored the allylation reaction of indolic scaffolds using cyclic allyl sources such as 4-vinyl1,3-dioxolan-2-one under rhodium(III) catalysis (Scheme 6.70) [74]. For the reaction of C7(sp2)–H allylation, the use of [RhCp*Cl2]2, AgSbF6, Cu(OAc)2, and t-AmOH and a wide variety of electron-rich and electron-poor functional groups bearing indoline derivatives were formed in E/Z- isomeric form with excellent level of Z-selective as major C7-allylated indoline derivatives. The reaction did not proceed in the absence of AgSbF6, because the corresponding active cationic [RhIIICp*OAc]+SbF6- catalyst that facilitates the C–H allylation reaction could not be generated. Various N-protected DGs such as acetyl, pivaloyl, benzoyl, and pyrimidine are also tolerated in the reaction. It is noteworthy that a highly congested C6-substitiuted indoline, which is often problematic in the catalytic C7–H functionalization of indolines, was compatible in this coupling reaction.

R R

R1 +

N

O

DG

H

O

[RhCp*Cl2]2 (2.5 mol %) AgSbF 6 (10 mol %)

O

Cu(OAc)2 (30 mol %) t-AmOH, rt, 20 h

R1 N DG

OH E/Z

N O

83% 59% R 63% 50%

(5:1, R = (3:1, R = (3:1, R = (4:1, R =

NH nBu) Me) tBu) Ph)

N Pym

O

OH 81% (1:1.5)

OH

N O

OH

N

NHnBu 54% (10:1, R = Cl) 54% (10:1, R = Cl)

NHnBu

OH 67% (7:1)

O

N NHnBu

O

60% (10:1) OH

Me

Me

Me R

N

NHnBu

68% (10:1) OH

Scheme 6.70  Rhodium(III)-catalyzed C7-allylation of indolines with 4-vinyl-1,3-dioxolan-2-one. Source: Modified from Sharma et al. [74].

The presence of a trifluoromethyl group (-CF3) into pharmaceutical molecules often enhances and modifies their biological activities [75]. In this context, in 2016, Kim and coworkers highlighted the first report on rhodium(III)catalyzed formal SN-type C–H allylation reaction using readily obtainable CF3-containing allylic carbonates for the γ-trifluoromethylallylation of various heterocyclic C–H bonds to access the γ-trifluoromethylallyl frameworks in a regioisomeric mixture (E/Z) with excellent E-selectivity in moderate to good yields. This protocol involves the oxidative addition of indolines to trifluoromethylated allylic carbonate using N-acetyl as DG for the synthesis of C7-functionalized trifluoromethylallylated indoline scaffolds (Scheme 6.71) [76]. The nature of the DG plays a vital role in this reaction. Along with acetyl, both pivaloyl and carbamoyl were suitable as DGs for this C7-allylation. However, pyrimidine groups failed to react under the same conditions. A broad substrate scope for both indolines and indoles was compatible with this oxidative catalytic transformation. At this stage, Kapur’s group focused a different route for the allylation of various indolic derivatives by utilizing the [RuCl2(p-cymene)]2, Cu(OAc)2, and AgBF4 catalytic system in DCE solvent. With controlled reaction conditions, a single reaction between N-pyridyl indoline and allyl alcohol was conducted that delivered the terminal allylated indoline product in 43% yield (Scheme 6.72) [77]. Inspired by the preliminary reports on the efficient utilization of Morita–Baylis–Hillman (MBH) adducts in C–H activation [78], in 2019, Punniyamurthy and coworkers developed an efficient strategy for the one-pot allylation of various

281

282

6  C(sp2)–H Functionalization of Indolines at the C7-Position

R R

R1

CF3 +

N

OCO2Et

DG

H

N DG

Cu(OAc) 2 (50 mol %) THF, 120 oC, 24 h F3C

R

F 3C

N. R.

N

N Me

O

O

71% (>50:1)

F3C

Me N O

37% (>50:1, R = NMe 2) F3C 58% (>50:1, R = Me) 56% (>50:1, R = tBu) Me Cl

F3C

E /Z

N Pym

N O

R1

[RhCp*Cl2]2 (2.5 mol %) AgSbF6 (10 mol %)

F3C

Me

64% (>50:1)

61% (>50:1)

N

F

O F3C

Me

Me

64% (>50:1)

Scheme 6.71  Rhodium(III)-catalyzed C7-allylation of N-acetyl indolines with CF3-allyl carbonate. Source: Modified from Choi et al. [76].

H

OH

N + Py

[RuCl2(p-cym)]2 (5 mol %) Cu(OAc) 2 (2 equiv) AgSbF6 (20 mol %) DCE, 85 oC, 20 h

43%

N Py

Scheme 6.72  Ruthenium(II)-catalyzed C7-allylation of N-pyridyl indoline with allyl alcohol. Source: Modified from Kumar et al. [77].

substituted indolic scaffolds using electrophilic MBH adduct under an active cationic [RhCp*(CH3CN)3](SbF6)2 catalyst without using external additives and oxidants. The utility of MBH adduct was also successfully applied to the facile access of a single example of C7-allytated indoline using acetyl DG (Scheme 6.73) [79].

OAc N O

Me

+

CO2Me

[RhCp*(CH3CN)3][SbF 6]2 (3 mol %) DCE, 120 oC, 12 h

N MeO 2C

O 71%

Me

Scheme 6.73  Rhodium(III)-catalyzed C7-allylation of N-acetyl indoline with MBH adducts. Source: Modified from Pradhan et al. [79].

6.1.6 C−H Bond Acylation of Indolines at the C7-Position Acyl-containing molecules have attracted much attention of the chemist due to their potential biological activities, pharmaceutical significance, presence in natural products, use in agrochemicals and wide application in other functional materials [80]. Generally, they are synthesized by Friedel–Crafts acylation using a stoichiometric amount of Lewis acids [81]. In the past few years, the transition metal-catalyzed C–H acylation of (hetero)arenes has beenwidely studied [82]. In particular, a classical approach for the C7-acylation of (NH)-free indoline was first achieved by Lo and coworkers in 1980, who employed benzonitrile as an acyl source by using a Lewis-acid catalyst such as BCl3 and AlCl3 in toluene solvent followed by a Friedel–Crafts type acylation reaction (Scheme 6.74) [83].

6.1  Introduction

1) BCl3 (1.1 equiv.) AlCl3 (1.1 equiv.) dry-toluene, 5-10 oC to reflux, 16 h

CN +

N H

2) 2N HCl, reflux, 2.5 h

N H O 80%

Scheme 6.74  Lewis acid-catalyzed C7-acylation of (NH)-free indoline with benzonitrile. Source: Modified from Lo et al. [83a].

In contrast, Chatani’s group suggested that CO and ethylene (CH2=CH2) gas could be applied as an acyl source in the acylation reaction of indolines using a ruthenium(0) complex such as Ru3(CO)12 as the catalyst. The significance of this seminal work included the first catalytic C7–H carbonylation reaction of indolines, which is distinct from the classical Friedel−Craft acylation reactions. The use of a pyridine ligand as a DG and N,N-dimethylacetamide (DMA) as the solvent played a crucial role in this reaction (Scheme 6.75) [84]. A tentative catalytic cycle includes the formation of a N-bounded ruthenium-complex, which formed the six-membered ruthenacycle complex. Subsequently, electrophilic addition of ethylene into the H–Ru bond gives the ethyl-Ru-complex where the insertion of CO takes place to provide an acyl-Ru intermediate, followed by reductive elimination provide the C7-carbonylated indoline product (Scheme 6.76).

Ru 3(CO)12 (5 mol %) CH 4=CH4 (5 atm)

R

N N

CO (10 atm) Me 2NCOMe 160 oC, 20 h

R1

N O

R R1

Et N

R = R 1 = H (41%) R = R1 = Me (58%)

Scheme 6.75  Ruthenium(0)-catalyzed C7-acylation of N-pyridyl indolines with CO gas and ethylene. Source: Modified from Chatani et al. [84].

N

H

N

N Et

Ru

N

N

N

Ru

Ru N

H

N

CO Ru

O

N

CH 2=CH2

Ru

-Ru

N O

Et N

Et

Scheme 6.76  Proposed reaction mechanism. Source: Modified from Chatani et al. [84].

The palladium-catalyzed decarboxylative C7-acylation of indolines with α-oxocarboxylic acids was described by Kim and coworkers. They suggested that the combination of Pd(TFA)2 catalyst and (NH4)2S2O8 as an external oxidant in DCE solvent efficiently catalyzed the first decarboxylative C7-allylation of indolines bearing an easily removable N-benzoyl as DG (Scheme 6.77a) [85]. N-Benzoyl groups were not the only suitable DGs. Acetyl, pivaloyl, or N,N-dimethylcarbamoyl were also comparatively effective with decreased formation of desired product. However, the nitrogen DG, such as pyrimidine ligand, was completely unsuccessful in coordinating with the palladium(II) catalyst. This procedure tolerates with both electron-donating and electron-withdrawing substituents on the indolines and α-keto acids. In addition, the heterocyclic and alkyl substituted α-keto acids were also favored with somewhat decreased reactivity. It is interesting to note that onepot gram-scale experiment along with DDQ oxidation and the deprotection of benzoyl group under basic hydrolysis shows the applicability of this methodology (Scheme 6.77b).

283

284

6  C(sp2)–H Functionalization of Indolines at the C7-Position

(a)

Y +

N H

O

N Ph

OO

Y

O

X

Pd(TFA)2 (5 mol %)

R1

HO

65% (R = Me) 30% (R = t-Bu) 33% (R = NMe2) R 73% (R = Ph) Ph

Ph

Ph

OO

O

85%

N

N Ph

Ph Ph

OO 60%

S

Ph

Ph

OO 76%

N

N

Ph OO 49% (X = F) 34% (X = Cl)

R

OO

Me

N Pym N.R.

X

R1

Br

Me

N

N

(NH 4) 2S2O8 (200 mol %) DCE, 80 oC, 15 h

O

R

X

N Ph

OO

Me

Ph

OO 15%

30%

Scheme 6.77a  Palladium(II)-catalyzed C7-acylation of N-benzoyl indolines with α-oxocarboxylic acids. Source: Modified from Kim et al. [85]. (b) N H Ph

s-KOH, EtOH

O 81%

DDQ, DCE

N

100 oC, 12 h Ph

OO

N

120 oC, 18 h

Ph

Ph

OO 62%

Ph

Scheme 6.77b  DDQ oxidation and basic hydrolysis of C7-acylated N-benzoyl indolines. Source: Modified from Kim et al. [85].

Mechanistically, ligand exchange between the carbonyl group of N-benzoyl indoline and the palladium(II) catalyst affords the six-membered O–palladium(II) species. Reaction with an α-keto acid forms the dimeric palladium(III) or palladium(IV) intermediate along with (NH4)2S2O8 mediated decarboxylation, which then furnishes the final C7-carbonylated indoline product via reductive elimination and regenerates the palladium(II) catalyst via protodepalladation. However, the authors also suggested that the involvement of other possibilities, such as a palladium(0)/palladium(II) catalytic cycle, cannot be ruled out (Scheme 6.78).

Pd(TFA)2 N Ph

OO

N Ph

Ph O HO2CCF3

H

HO2CCF3 N Ln

N Ph

Pd

O

O Ln 2 dimeric Pd(III) or Pd(IV)

PdII

O A

Ph

Ph B

O

(NH 4) 2S2O8

Ph

HO CO2

O

Scheme 6.78  Proposed reaction mechanism. Source: Modified from Kim et al. [85].

6.1  Introduction

Shortly thereafter, the Kim group extended this Pd(TFA)2-catalyzed acylation strategy by employing the aldehydes and alcohols as acylation sources to the indolines, providing C7-carbonylated indolines in moderate to good yields (Scheme 6.79) [86]. Unlike the previous report, N-pivaloyl was employed as an effective DG and tert-butyl hydroperoxide (TBHP) was optimized as an external oxidant to accomplish the catalytic cycle. Indolines, aromatic aldehydes, and aromatic alcohols with all electronic characters at various positions including electron neutral, poor, and rich are suitable in this transformation to provide the C7-acylated indolines. Heterocyclic and aliphatic aldehydes as well as aliphatic alcohols show low reactivity. Although the catalytic reaction pathway was not schemed, the result of two parallel experiments with KIE (KH/KD=2.79) value revealed that C7–H bond cleavage might be involved in the rate-limiting step. O Y X

N H

or OH

+ tBu

O

R

H

H

Y

Pd (TFA)2 (5 mol %) TBHP (2 equiv.)

X

R

R

H

N

DCE, 80 oC, 16 h

Me

R N Ph

t Bu

OO

Ph

Me 78% (R = H) 61% (R = OMe) N 61% (R = Cl) tBu OO

46% Me

N

N O

tBu

Me O O 81% a 83% (from benzyl alcohol) (a = TBHP = 3 equiv)

OO

Me Ph

Ph

OO 49% Me

Me

tBu

N

Me

tBu

tBu

N

Me

Ph

OO

OO

tBu

11%

28%

Scheme 6.79  Palladium(II)-catalyzed C7-acylation of N-pivaloyl indolines with aldehydes. Source: Modified from Shin et al. [86].

The limitation of the nitrogen-directed acylation of indolines as indicated above was overcome by the Kim and coworkers shortly thereafter by using a pyrimidine DG instead of carbonyl group under a ruthenium(II) catalyst. When Cu(OAc)2 additive was used in an open reaction vessel with α-keto aldehydes as acyl source, the pyrimidine directed C7-indolinyl ketoester products were produced exclusively in moderate to good yields (Scheme 6.80) [87]. A variety of indoline substrates bearing synthetically useful functional groups were compatible with this procedure. However, the strong electronwithdrawing groups such as esters and NO2 were comparatively less reactive. It is noteworthy that the Cu(OAc)2 additive R2

R1 N H

N

O + H X

CO2Et

[Ru(p-cymene)Cl2]2 (2.5 mol %) AgSbF6 (5 mol %) Cu(OAc)2 (50 mol %) DCE, 60 oC, 20 h

R

ON

N X

N EtO 2C

85% (X = N) 18% (X = C)

N EtO 2C

ON

X

R

N EtO 2C

R2

R1

ON

82% (R = OMe) 83% (R = Br)

N

EtO2C

ON

83% (R = Me) 50% (R = NO 2)

R N EtO2C

N ON

N

78% (R = F) 31% (R = Cl)

Scheme 6.80  Palladium(II)-catalyzed C7-acylation of N-pyrimidyl indolines with α-keto aldehydes. Source: Modified from Jo et al. [87].

285

286

6  C(sp2)–H Functionalization of Indolines at the C7-Position

with a ruthenium(II)-catalyst played a very important role for the oxidation of secondary alcohols to ketones in the presence of air O2 as a terminal oxidant to provide the desired C7-acylated indoline product. Based on this experimental evidence, a plausible reaction mechanism was proposed (Scheme 6.81). First, the generation of cationic [Ru(p-cymene)(OAc)][SbF6] takes place through ligand exchange between [RuII(p-cymene)Cl2]2/AgSbF6 and Cu(OAc)2, which coordinate to pyrimidine ligand to give the ruthenacycle intermediate A followed by C7–H activation of indoline. Subsequent ethyl glyoxalate coordination and migratory insertion led to the eight membered ruthenacycle species C. Then, protonation and oxidation of the alcohol group in the alkylated product by an external Cu(OAc)2 additive release the desired C7-indolinyl ketoester and active ruthenium(II) catalyst to participate in next catalytic cycle.

N EtO2C

O2

Cu(II)

Cu(I)

N

[Ru(p-cymene)OAc][SbF6]

N

ON

H HOAc

+ N EtO2C

HOAc N

C

+

N

EtO2C

N

O

N

N

OH

N

N

N

Ru

Ru

N

N

Ln A

Ln

+ O N Ln

Ru

H

CO2Et

N

N

O H

CO2Et

B

Scheme 6.81  Proposed reaction mechanism. Source: Modified from Jo et al. [87].

In 2021, Gong and coworkers employed the 1,2-diketones and α-keto acids as acyl reagents at the C7-position of pyrimidine directed indolines under palladium(0/II) catalyst to generate the C7-acylated indolines (Scheme 6.82) [88]. 1,2-Diketones were found to be reactive substrates with Pd(OAc)2 catalyst and TBHP oxidant in THF solvent, whereas a similar reaction with α-keto acids generated the desired products under Pd2(dba)3 catalyst and PhI(OAc)2 as the oxidant in CHCl3, thus revealing the important roles of catalyst and oxidant in this oxidative coupling reaction. This method allowed a wide range of functional groups bearing indolines to couple with various symmetrical and unsymmetrical aromatic and aliphatic 1,2-diketones as well as with various substituted aromatic α-keto acids. Thiophene-based 1,2-diketone and α-keto R1 Pd(OAc) 2 (10 mol %) TBHP (4 equiv.) R1

R2

N

R4

+ R3

N H

O

N

O

THF (1.5 mL) air, 95 oC, 16 h R3/R4 = aryl, alkyl

N R 3/ R 4

ON

R1

Pd2(dba) 3 (10 mol %) PhI(OAc) 2 (2 equiv.) CHCl3 (2.0 mL) air, 80 oC, 16 h R 3 = aryl; R 4 = OH

R2

N R2

N R3

ON

N

Scheme 6.82  Palladium(II)-catalyzed C7-acylation of N-pyrimidyl indolines with 1,2-diketones. Source: Modified from Xie et al. [88].

6.1  Introduction

acid were also suitable for this transformation. As expected, a mixture of products was obtained with unsymmetrical 1,2-diketones as acyl donors. However, no reaction was observed when C6-substituted indolines were used as starting materials, indicating the steric influence on this methodology. Based on the experimental results of detailed mechanistic investigations such as a series of control experiment for radical inhibition and KIE values 0.9 (with 1,2-diketone) and 2.2 (with α-keto acid), a plausible mechanism was proposed (Scheme 6.83). Initially, the reaction proceeds by the formation of a palladacycle intermediate A via C7–H bond palladation of N-pyrimidinyl indoline, which undergoes to the oxidative addition with benzoyl radical (formed in the presence of a radical initiator), generating a potential intermediate of six-membered trivalent palladacycle B. Subsequently, C7-acylated indoline product is formed by reductive elimination and the active palladium catalyst is regenerated in the catalytic cycle.

N Ph

ON

N N

Pd(0/II)

H

N

N

H+

N Pd Ph N Ln O B

N N

Ln

Pd

N

N

A O

O Ph t BuOOH

Ph O

O

OH

PhI(OAc) 2 Ph O

Ph

Scheme 6.83  Proposed reaction mechanism. Source: Modified from Xie et al. [88].

6.1.7 C−N Bond Formations at the C7-Position of Indolines 6.1.7.1  C7-Amination and/or Amidation of Indolines

Several aforementioned carbon−nitrogen bond formation strategies have been established such as copper-catalyzed Ullmann-Goldberg and palladium-catalyzed Buchwald-Hartwig amination reactions [89]. Although most of these are powerful approaches for C−N bond formations into (hetro)arenes, these methods are unable to provide a direct route for site-selective C−N bond formations. Therefore, the C−H activation process has been successfully applied to construct a C−N bond that can directly functionalize a hydrocarbon substrate without preinstallation of a reactive group for the synthesis of nitrogen-containing bioactive heterocyclic molecules [90]. These considerations encourage various research groups to investigate the possibility for direct and site-selective C−N bond formation at the C7-position of indolines. In 2010, Yu reported on the first realization of C7-amination of N-acetylated indoline as a single example along with the ortho-amination of various anilides by using N-nosyloxycarbamates as amine donors under a palladium(II) catalyst (Scheme 6.84) [91]. Although other palladium(II) catalysts were tested, [Pd(OTs)2(MeCN)2] was found to be the most effective catalyst in this transformation. In this reaction, N-nosyloxycarbamate produced the nitrene that might react with a cyclopalladated complex to give the aminated product. Alternatively, the authors also assumed that the C−N bond formation may involve a palladium(IV) or a dimeric palladium(III) complex that would lead to the reductive elimination to afford the final aminated product. [Pd(OTs)2(MeCN) 2 (10 mol %) N O

N

1,4-dioxane, 80 oC, 6 h EtO NsONH(CO)OEt Me

NH

O

Me

O

Scheme 6.84  Palladium(II)-catalyzed C7-amination of N-acetyl indolines with N-nosyloxycarbamates. Source: Modified from Ng et al. [91].

287

288

6  C(sp2)–H Functionalization of Indolines at the C7-Position

In 2014, Zhu and coworkers reported a ruthenium(II)-catalyzed C7-amidation of indoline C–H bonds. The authors employed a [RuCl2(p-cymene)]2 as catalyst and AgSbF6 additive with AgOAc to conduct the desired transformation using sulfonyl azides as the amidation reagent (Scheme 6.85) [92]. AgOAc might be rationalized as both an acetate source and a Lewis acid to enhance the amidation process in the catalytic cycle. Control experiments showed that omitting either the catalyst or the Ag additives led to no formation of the desired product. The reaction can tolerate a variety of functional groups, including electrondonating and electron-withdrawing groups bearing N-acetylated indolines and aryl sulfonyl azides under the electronic control. In the present conditions, not only the acetyl group but also N-benzoyl, N-pivaloyl, and N-1-butyryl indolines readily show the DG effect and smoothly coordinate with the ruthenium(II) catalyst to facilitate the C7 indoline amidation product in good yields. Heterocyclic and aliphatic sulfonyl azides give good yields of corresponding amidated products. R2 R 3

R 2 R3 R1

R4 N H

O

O + Ar

S N3 O

Me

R

[RuCl2(p-cymene)]2 (5 mol %) AgSbF6 (20 mol %)

N O NH Me N O S O Ar NH O 76% (R = H) S O 56% (R = NO2) Ar O 86% Ar = (p-MeC6H5)

N O

Me R

R4 N

O NH S O Ar O

AgOAc (50 mol %) DCE, 80 oC, 10 h

Me Me

R1

NH S O O

Me

79% (R = H) 75% (R = CF3)

S

N O NH O S O

Me

Me

81%

Scheme 6.85  Ruthenium(II)-catalyzed C7-amidation of N-acetyl indolines with sulfonyl azides. Source: Modified from Pan et al. [92].

Similarly, Li and Zhou reported a cationic iridium(III)-catalyzed preparation of C7-amidated indolines from the coupling of a range of substituted indolines with various azides such as sulfonyl-, aryl-, and acyl azides in good to high yields under a pH-neutral (i.e. room temperature) reaction conditions. Herein, acetyl group was found to be a better DG for the reaction (Scheme 6.86) [93]. It is mentioned that the C7-aminated indoline could be oxidized with MnO2 into 7-aminoindoles and also undergo for palladium(II)-catalyzed intramolecular oxidative C–C coupling reaction to yield the biologically active tetracyclic pyrrolo[2,3-a]carbazole derivative (Scheme 6.87). The authors proposed a simple reaction mechanism followed by the in situ generation of active [IrIIICp*NTf2]2 catalyst, which leads to a six-membered cyclometalated iridium(III) complex A. The resulting complex interacts with azide that is converted into iridium(III) amido species C followed by a concerted migratory insertion or through high valent iridium(V) nitrenoid species D in an oxidative manner with the release of N2 and subsequently protonolysis liberated the C7-amidated indoline product (Scheme 6.88). R2

R1

N H

O

+ R

N3

Me

[IrCp*Cl2]2 (2.5 mol %)

R2

R1

N AgNTf2 (10 mol %) NH Me O DCE, rt, 3-6 h R R = sulf onyl, acyl or aryl

Scheme 6.86  Iridium(III)-catalyzed C7-amidation of N-acetyl indolines with various azides. Source: Modified from Hou et al. [93].

Pd(OAc)2 (10 mol %) K2CO 3 (10 mol%)

N NH O 2N

O

Me

PivOH (49 equiv.) O2N TFA, 120 oC, 8 h

N NH 74%

O

Me

Scheme 6.87  Palladium(II)-catalyzed intramolecular C–C coupling of C7-aminated N-acetyl indolines. Source: Modified from Hou et al. [93].

6.1  Introduction

[IrCp*Cl2]2 AgNTf2 N Ts

NH

O

N

AgCl Me

IrCp*(NTf 2)2

H

Me

O

H+

H+ N2

N N N Ir (V) Me Ts N Me Ts (III) O Ir O Cp* Me D NTf 2 Cp* Ir (III) O Cp* C NTf 2 A NTf 2 N

N2 N2 N N (III) Ir Ts Me Cp* O NTf2- B

TsN 3

Scheme 6.88  Proposed reaction mechanism. Source: Modified from Hou et al. [93].

In contrast, Punniyamurthy and coworkers showed an efficient protocol for the ruthenium(II)-catalyzed direct C7–H amination at the C7-position of indolines having pyrimidine DG using various acyl azides as amine donor. A combined catalytic system of 5 mol % of [Ru(p-cymene)Cl2]2 and 20 mol % of AgSbF6 with the addition of substoichiometric amount of NaOAc was employed (Scheme 6.89) [94]. Interestingly, both electron-deficient and electron-rich acyl azides were efficiently coupled even at room temperature without undergoing the Curtius rearrangement. The hereocyclic azides possess less reactivity under these reaction conditions. Intermolecular and parallel KIEs were measured to be 1.17 and 1.29 for C7–H bonds, respectively, indicating that C–H bond cleavage was not the rate-determining step. [Ru( p-cymene)Cl2 ]2 (5 mol %)

O

R H

+ N R1 2-pym

N3 AgSbF6 (20 mol %) NaOAc (30 mol %) CH 2Cl2, rt, 12-14 h

R

N 2-pym NH

R1 O

X

Ph

N 2-pym NH O 61%

N Ph NH 2-pym 61% (X=Br) X 66% (X=Me) O

N 2-pym NH 69% (X=O) O 71% (X=S)

Scheme 6.89  Ruthenium(II)-catalyzed C7-amidation of N-pyrimidyl indolines with acyl azides. Source: Modified from Banerjee et al. [94].

Interestingly, in the continuation of his great success on C–N bond formation reactions, Chang and coworkers developed an iridium(III)-catalyzed amidation of unactivated methyl C(sp3)−H and aromatic or olefinic C(sp2)−H bonds with the use of azidoformates as a readily deprotectable amino source. In this protocol, the authors showcased two representative examples of amidation of N-acetyl- and N-Boc protected indolines at the C7-position under optimized reaction conditions using Boc−N3 and Cbz−N3 as efficient amine sources (Scheme 6.90) [95]. In 2016, Kim’s group reported the use of a readily accessible dioxazolone as electrophilic amide source for decarboxylative C7–H amidation of a range of indolines. Using the commercially available catalyst [RhIIICp*Cl2]2 in 2.5 mol % and AgNTf2 (10 mol %) additive in DCE solvent, N-pyrimidine directed indoline derivatives reacted smoothly with dioxazolones to produce the desired C7-amidated indolines in good-to-excellent yields with high regioselectivity (Scheme 6.91a) [96]. However, other DGs such as carbamoyl, acetyl, pivaloyl, and benzoyl were found unsuccessful in promoting this

289

290

6  C(sp2)–H Functionalization of Indolines at the C7-Position

[IrCp*Cl2]2 (5 mol %) AgNTf 2 (20 mol %)

N 3 Boc or + N N3 Cbz R

N

NaOAc (30 mol %) DCE, 60 oC, 24 h

or

N

NHBoc R

NHCbz R

99% (R = COMe) 63% (R = BOc)

Scheme 6.90  Iridium(III)-catalyzed C7-amination of indolines with azidoformates. Source: Modified from Kim et al. [95].

coupling reaction. In the case of indolines, two types of reaction conditions (room temperature and 80 oC) were developed to achieve a broad substrate scope ranging from electron-poor to electron-rich indolines including sterically-congested C6-substituted indoline. The optimized reaction conditions were also compatible for the amidation with various electronrich to electron-neutral substrates of aromatic dioxazolones. Heterocyclic and 3-alkylsubstituted dioxazolones tolerated the conditions to give the C7-amidated products in high yields. This method can be attributed to the synthetic versatility of amidated indolines by demonstrating the DDQ oxidation of indoline to indole and basic hydrolysis of amide group to furnished the C7-amino indoline with a good yield (Scheme 6.91b). Interestingly, considering the wide utility of the amidated indoline motifs in pharmaceutics, in vitro anticancer activity evaluation against various human cancer cell lines was studied and some of them were found to be highly cytotoxic comparable with anticancer agent doxorubicin. O

R2 R1

+

O

N H

O

NH

N X O

N

Ph

N

NH

O

N

96%

N NH

DG

N.R. (R N.R. (R R N.R. (R N.R. (R

R

= Me) = tBu) = Ph) O = NHnBu)

Ph

N O

NH

O

NH S

Ph 59%

N

N

N

N

N NH

N

Ph 70% (R = OMe) 57% (R = Br)

Me Ph

Me

N NH

O R

Ph 95% (X = N) 90% (X = C)

O

DCE, rt, 24 h

R

N O

R1

N

DG

R2

[RhCp*Cl2]2 (2.5 mol %) AgNTf 2 (10 mol %)

N

N

N O

59%

NH Me

N

N

97%

Scheme 6.91a  Rhodium(III)-catalyzed C7-amidation of N-pyrimidyl indolines with dioxazolones. Source: Modified from Jeon et al. [96].

O Ph

NH 66%

N Pym

DDQ (2 equiv.) dioxane O 100 oC, 4 h

NH Ph

N Pym

10% KOH in MeOH 90 oC, 24 h

N NH2 Pym 60%

Scheme 6.91b  DDQ oxidation and basic hydrolysis of C7-amidated indolines. Source: Modified from Jeon et al. [96].

The accepted catalytic cycle for this transformation involves an initial formation of a seven-membered rhodium(III)amido intermediate C, followed by the coordination and migratory insertion of dioxazolone to six-membered Rh–C7(aryl) complex A with subsequent release of CO2 that finally undergoes protonation to release the desired product (Scheme 6.92). Later, Prabhu and coworkers (Scheme 6.93) [97] and Niu, Yang, and coworkers (Scheme 6.94) [98] independently utilized the dioxazolones as a nitrene source for the pivaloyl or pyrimidine directed C7–H amidation of indolines under ruthenium(II) and cobalt(III) catalysis instead of rhodium(III) catalyst. The substrate scopes, applications, and reaction mechanisms are similar to previous report [96] and thus will not be discussed herein.

6.1  Introduction

+

O

N Pym

NH Ph

Cp*Rh(III)

N Pym

H

H+

H+

+

+ N

N O Ph

N C

N

N

Rh

*Cp

Rh

N

A

N

Cp* + Ph

CO2

O

N O

O

O O

N Rh Cp* B

N

O

N

N

Ph

Scheme 6.92  Proposed reaction mechanism. Source: Modified from Jeon et al. [96].

R2

R1

+ O

N O

O

tBu

O N

R

[Ru(p-cymene)Cl2]2 (5 mol %)

R2

R1

N AgSbF6 (20 mol %) t Bu O NH PivOH (20 mol %) O TFE (2 mL), 30 oC, 24 h R

Scheme 6.93  Ruthenium(II)-catalyzed C7-amidation of N-pivaloyl indolines with dioxazolones. Source: Modified from Hande et al. [97]. R2

R1 N H

N

O + O

N R

O N

R2

[Cp*Co(MeCN)3 ](SbF6) 2 R1 (5 mol %) HFIP, 100 oC, 12 h, air

N

R

NH

N

N

O

Scheme 6.94  Cobalt(III)-catalyzed C7-amidation of N-pyrimidyl indolines with dioxazolones. Source: Modified from Yan et al. [98].

In their efforts to prepare the synthetically useful C7-amidated indolic motifs, the Kim group disclosed in 2017 the C7-amination of indolines with the use of anthranils as amination auxiliaries in the presence of strongly coordinating pyrimidine ligand as DG under a rhodium(III) catalyst (Scheme 6.95a) [99]. In this method, the screening of DGs was crucial. Except pyrimidine and pyridine ligands, other DGs such as carbonyl or carbamoyl exhibited no formation of product. Both indolines and anthranils having electron-donating or withdrawing functionality at different positions were compatible with this coupling reaction. However, the reaction is found to be sensitive to steric effects as C6-substituted indoline exhibited a lower yield of desired product. The formed 2-formylaniline ring containg indoline made it possible to get further extension of the π-conjugated system followed by acid mediated inter- and intramolecular cycloaddition to generate the bioactive indole alkaloids (Scheme 6.95b). The isolation of six-membered rhodacycle complex A suggested that this complex is most likely to coordinate with anthranil and subsequently after migratory insertion give rhodium(III)amino species C, which might undergo for protonation and delivered the C7-aminated indoline product (Scheme 6.96). Almost at the same time, the Xu’s group achieved similar outcomes on C7(sp2)–H amination of various substituted N-pyrimidyl indolines with anthranils using the combination of [RhCp*Cl2]2/AgSbF6 catalysis and MesCOOH acetate additive in THF solvent (Scheme 6.97) [100].

291

292

6  C(sp2)–H Functionalization of Indolines at the C7-Position

R2

R1 R2

R1

+

N H

N Cl

NH

DCE, 120 oC, 24 h

R

DG

N

[RhCp*Cl2]2 (2.5 mol %) AgSbF6 (10 mol %)

O

DG

O

Cl R

Me N NH

N X

N

NH

O

Cl

Cl Ph 96% (X = N) 92% (X = C)

NH

32%

Ph Br

Ph

Me) t-Bu) Cl Ph) NH nBu)

N Pym

O

Cl

NH (R = (R = (R = (R =

N

N

O Ph 82%

MeO2C

NH

O

Cl

R N.R. N.R. N.R. N.R.

O

O

N Pym

F

N

N Pym

NH

NH O

O

Cl

85% Ph

86%

N Pym

H 86%

Ph

Scheme 6.95a  Rhodium(III)-catalyzed C7-amidation of N-pyrimidyl indolines with anthranils. Source: Modified from Mishra et al. [99].

N Pym

N

TFA

NH

o

80 C 24 h

BF3 Et2 O (1.5 equiv.) CH2Cl2, rt, 0.5 h

N Pym

N2

N Pym

OEt

O

71%

N

74% CO2Et

O

H

Scheme 6.95b  Lewis acid mediated inter- or intramolecular cyclization of C7-aminated indolines. Source: Modified from Mishra et al. [99].

+

N NH

N

N

N

Cp*Rh(III)

H

N

N

O H

H+

H+ +

+

N N

N Rh O Cp*

N

N *Cp

Rh

N

N

A

H

+

C

N

N Rh

N O

B

Cp*

N

N

O

Scheme 6.96  Proposed reaction mechanism. Source: Modified from Mishra et al. [99].

6.1  Introduction

R2

R1

O

N H

+ N

N

[Cp*RhCl2]2 (3 mol %) N AgSbF (12 mol %) 6

R2

R1 N

MesCOOH (2 equiv.) THF, 90 oC, Ar R

R

NH

N

N

CHO

Scheme 6.97  Rhodium(III)-catalyzed C7-amination of N-pyrimidyl indolines with anthranils. Source: Modified from Li et al. [100].

Whereas the amidation reactions discussed above commonly involved only the incorporation of amine functionality at the C7-position of indolines, in 2017, Kim and coworkers disclosed a different approach for the generation of N-aroylurea functionality at the C7-position of indolines by the addition of polar π-bond of electrophilic isocyanates as amidation source under the combination of [RhIIICp*Cl2]2 and AgNTf2/Cu(OAc)2 as a catalytic system (Scheme 6.98a) [101]. Importantly, the authors found that when they increased the temperature (120 oC) and the amount of isocyanates (5 equivalents) in the reaction, the installed C7-N-aroylurea auxiliary would play the role of DG as well as serve as a valuable synthetic intermediate for the formation of biologically relevant pyrroloindolidione products via sequential C6–H amidation and intramolecular cyclization of C7-amidated indolines under the slightly modified reaction conditions (Scheme 6.98b). The reactivity of both electron-poor and electron-rich substituents at the indolines is almost same. Furthermore, this reaction protocol can tolerate isocyanate substrates bearing alkyl and aryl substituents to afford the corresponding C7-amidated indolines in good yields. However, the process is restricted to sterically congested C6-substituted indolines and resulted in lower formation of desired products. It is noteworthy that all of the synthesized products were also evaluated for the anticancer activity and the linear alkyl side chains bearing products were found to be highly cytotoxic.

R2

R1 N H

+

tBu

O

R

N

C

O

[RhCp*Cl2]2 (2.5 mol %) AgNTf 2 (10 mol %) Cu(OAc) 2 (30 mol %) DCE, rt, 20-40 h

R2

R1 O Et

N H

N N Et

OO

tBu

R N

O Et

N H

N

OO

Et

Me

N H

tBu

N OO Et 95%

N H

N OO Et 70% ( R = Me) 72% (R = Cl) 90% (R = CO2Me)

Et

N H

N Et

OO

tBu

N Et

OO

tBu

Et N H 28% (R = Me) 29% (R = Cl)

Me

N

O

N

O Et

R Et 92% ( R = tBu) trace (R = Me) 71% (R = Ph) trace (R =NHnBu)

N

R O

N

O

N

O tBu R

72%

N H

tBu OO R 23% (R = cyclo -pentyl) 78% (R = Ph)

N

Scheme 6.98a  Rhodium(III)-catalyzed C7-amidation of N-pivaloyl indolines with isocyanates. Source: Modified from Jeong et al. [101].

[RhCp*Cl 2] 2 (2.5 mol %) AgNTf 2 (10 mol %) Cu(OAc) 2 (30 mol %) O

N

H6 H7

t

O

Bu

DCE, 120 oC, 20 h R-N=C=O (5 equiv.)

N R

57% 40% N 32% t Bu 45% O O

(R (R (R (R

= Et) = n-butyl) = n-pentyl) = n-octyl)

Scheme 6.98b  Rhodium(III)-catalyzed C6-functionalization and intramolecular cyclization of synthesized C7-aroylurea directed indolines for the synthesis of pyrroloindolidiones. Source: Modified from Jeong et al. [101].

293

294

6  C(sp2)–H Functionalization of Indolines at the C7-Position

The catalytic cycle first includes the formation of a cationic [RhIIICp*(OAc)][NTf2] catalyst that produced a rhodacycle intermediate C followed by the coordination and migratory insertion of isocyanate to complex A and then protonation with AcOH to deliver the C7-amidated indoline species. Next, in path a, the N-aroylurea product can generated from intermediate C via nucleophilic addition to isocyanate and and protonation (Scheme 6.99a). The authors believe that a metal-mediated and/or base-mediated coupling reaction pathway between C7-amidated indoline species and isocyanate to form the N-aroylurea product is also operating in this process based on the results of control experiments. The formation of pyrroloindolidione might takes place through the intramolecular cyclization of bis-amidated indoline species H via sequential C−H activation of C7-amidated indolines, coordination, and migratory insertion of isocyanate at 120 oC (Scheme 6.99b). (a) < plausible reaction pathway forming N-aroylureas at room temperature> AcOH N H [RhCp*Cl2] 2

Cu(OAc) 2

AgNTf 2

Rh

Cp*

tBu

O

Et N C O

N tBu

O A

[RhIIICp*(OAc)][NTf 2]

N

AgCl

Rh

Cp*

AcOH

O

N O N Et

N H

t Bu

OO D

Et

Et

N H

Et-N=C=O

N N Et

OO

N Et O C

C

AcOH O

N

B C

Rh Cp*

[RhCp*(OAc)][NTf2] path b Cu(OAc) 2 Et-N=C=O

Et

tBu

O

N

t Bu

O

t Bu

pat h a

N Et O

N N Et

OO Rh

t Bu

Cp*

E

(b) < plausible reaction pathway forming pyrroloindolidiones at 120 o C >

D

Et

[RhCp*(OAc)][NTf2] Cp* Rh

N O F

t Bu

NH O

N

C

O

O Et

N

N

tBu

O Rh O NH Cp* G Et

Et

AcOH O Et NH

N

O N Et

O O

tBu

N O

tBu

NH O H Et

Scheme 6.99  Proposed reaction mechanism. Source: Modified from Jeong et al. [101].

6.1  Introduction

In 2018, Wang, Cui, and coworkers reported the C7-amidation of N-pyrimidyl indolines with nitrosobenzenes using a rhodium(III) catalyst with the aid of a stoichiometric amount of 1-adamantanecarboxylic acid (Scheme 6.100) [102]. The efficient utilization of commercially available aryl sulfonamides and trifluoroacetamide for sulfonamidation and amination at the C7-position of N-acetyl indolines was also accomplished by Sun’s group under rhodium(III) catalysis (Scheme 6.101) [103]. R2

R1

N N H

O

+ N

N

R2

[Cp*Rh(MeCN)3][SbF6 ]2 (5.0 mol %) R

R1 N

1-AdCO2H (1.0 equiv.) THF, 30 oC, 16 h

NH N R

N

Scheme 6.100  Rhodium(III)-catalyzed C7-amination of N-pyrimidyl indolines with nitrosobenzenes. Source: Modified from Xiong et al. [102].

[Cp*RhCl2] 2 (5 mol %) AgOTf (20 mol %) AgOAc (20 mol %)

N O

ArSO2NH2

Me PhI(OAc) 2 (1 equiv.) HOAc (3 equiv.) THF, 90 oC, Ar

N O NH S O Ar O

Me

N CF3CONH2 F C 3

NH

O

Me

O

Scheme 6.101  Rhodium(III)-catalyzed C7-amidation of N-acetyl indolines with amides. Source: Modified from Dong et al. [103].

Later, Koley and coworkers highlighted the cross-dehydrogenative coupling of C7–H bond of indolines with nucleophilic phthalimides as amine agent, employing CuOAc as the catalyst and molecular oxygen (O2) as oxidant (Scheme 6.102) [104]. The strongly binding, but easily removable and highly electron-deficient pyrimidine, was employed as DG. The use of 1,2-dichlorobenzene (DCB) as bulky solvent was necessary to facilitate the reaction. Various substituted indolines and phthalimides were coupled smoothly. However, -NO2 as a strong electron-withdrawing group at the C5-position of indoline produced low yield, indicating that electronically rich indolines showed better reactivity. Notably, not only the phthalimides, but also both maleimide and succinimide were also found to be suitable amine substrates in this transformation. It was found that the resulting C7-aminated indoline were prone to further transformation, thus protocols for deprotection of DG, oxidation into indole and ring opening of C7-phthalimide functionality were developed.

H

O

N 2-pym

N

+

R1 NH

DCE, O 2, 130 o C, 30 h

R2

N R O O 81%

CuOAc (20 mol %) R1

N

N R O O

N

57% 35% R = pyrimidine

N R O O

N

N 2-pym R2

N N

O

R

20%

Scheme 6.102  Copper(I)-catalyzed C7-amination of N-pyrimidyl indolines with phthalimides. Source: Modified from Raziullah et al. [104].

295

296

6  C(sp2)–H Functionalization of Indolines at the C7-Position

The authors then investigated the catalytic cycle, where a step involving the oxidation of copper(I) into active copper(II) occurred to provide a copper(II)-pyrimidinyl species A that participates in the disproportionative C–H functionalization to provide the cyclometalated aryl–Cu(III) species B. This is followed by a ligand exchange with phthalimides to provide a six-membered species C that undergoes reductive elimination to release the copper(I) salt and C7-aminated indoline product (Scheme 6.103). However, the authors also worried about the possibility of a single-electron transfer (SET) pathway, which cannot be ruled out.

Scheme 6.103  Proposed reaction mechanism. Source: Modified from Raziullah et al. [104].

Following up on this study, the same group further reported almost similar work on the copper(II)-mediated crossdehydrogenative coupling of pyrimidine directed indoline with sulfonamides, carboxamides, and anilines for the amidation and amination at the C7-position of indolines. The reaction was smoothly promoted when a combination of Cu(OAc)2 and 2,6-di-tert-butyl-4-methylpyridine along with toluene solvent was used (Scheme 6.104) [105]. The reaction was compatible with various functional groups and the synthesized products can be used as a unique intermediate for the synthesis of biologically relevant heterocyclic compounds.

R1

H

N 2-pym

1 RSO 2NH R Cu(OAc)2 (25 mol %) 2,6-di-tert-butyl-4RO2SHN methylpyridine (25 mol %) RCONH 2 1 R toluene, 140 oC, 36 h

ArNH 2

RO 2CHN

N 2-pym

N 2-pym

R1 ArHN

N 2-pym

Scheme 6.104  Copper(II)-catalyzed C7-amidation of N-pyrimidyl indolines with various amines. Source: Modified from Kumar et al. [105].

6.1.7.2  C7-Nitration of Indolines

The nitration of indolines can also be achieved using C–H bond functionalization. This reaction is highly depending on the reaction conditions, electronic property of aromatic ring of indolines, and the nitration sources. In this context, Bose and Mal reported that both C5- and C7-position of indolines can be nitrated via electrophilic aromatic (EArS) nitration using Cu(NO3)2 or AgNO3 as the –NO2 donor with the aid of stoichiometric amount of potassium persulfate (K2S2O8) as an oxidant in the presence of trifluoroacetic acid (TFA) as catalyst (Scheme 6.105) [12]. In this protocol, KNO3 and NaNO3 as nitration sources completely failed to delivered the desired products because of the soft acid–soft base nature (HSAB approach) [106]. The formation of Cu2+/Ag+–aryl ring interaction was preferred via cation-π interaction over the formation of the K+/Na+ (hard acid)–aryl ring (soft base) interaction. Bi(NO3)3.5H2O furnished a lower yield of C5–H nitrated product, indicating the inferior activation of the aromatic ring by the relatively hard acid (Bi3+) in compare to the softer

6.1  Introduction

A: Cu(NO3)2 (1.1 equiv.) B: AgNO3 (1.5 equiv.)

R N R1

H

K2S2O 8 (1.5 equiv.) TFA (20 mol %) DCE, 80 o C, 2 h tBu

Ph

R

NO 2

O2N

N NO2

Me

N R1

N O

NO 2 A: 52%, 1 h Me B: 50%, 1 h

A: 72%, 2 h B: 73%, 2 h

NO2

N

tBu

O

O A: 63%, 4 h B: 55%, 4 h

Scheme 6.105  Oxidative C7-nitration of indolines using Cu(NO3)2 or AgNO3 as nitration source. Source: Modified from Bose and Mal [12].

Cu2+/Ag+ system (Scheme 6.106). The reason that highly polar solvents such as acetonitrile (CH3CN), DMF, and DMSO cannot deliver the products might be due to the absence of weak cation-π interactions; however, Cu2+/Ag+ ions in the nonpolar solvent 1,2-dichloroethane (DCE) led to the optimized results. However, N-methyl or NH-free indoline failed to give any product and this was probably due to the protonation of nitrogen atom. The authors also suggested that EArS nitration takes place at the C5-position over the C7-position, possibly due to the steric effect of N-acetyl DG and the comparatively electron-rich tendency of C5-position. When the authors blocked the C5-position, the C7-position of indolines was preferentially nitrated in moderate to good yields. Importantly, the di-nitration reaction was unsuccessful even though excess amount of nitration sources and catalyst was used. Various C5-blocked indolines reacted well for C7-nitration, but the scope of the C2- or C3-substituted indolines was limited.

N R

H 3O +

N

N H R

R = -H, -Me no ArSE

n

π*CO O no protonation

reaction inhibtion

Scheme 6.106  Indolines N-centre with π-acceptors and solvent effect on the arene ring activation. Source: Modified from Bose and Mal [12].

On the basis of his previous report, in 2019, the group of Mal further investigated and found that tert-butyl nitrite (TBN) can also act as an efficient –NO2 donor to the aryl ring of indolines CH3CN solvent only without the use of inorganic salts as nitration sources under acid free condition. The C–H bond nitration occurred preferentially at the C5-position. In contrast with C5-substituted indolines, the C7-nitration of N-acetylated indolines was selectively highlighted under the reported reaction conditions (Scheme 6.107) [107]. Based on the reaction inhibition by radical scavengers, Mal suggested R O

Ar H Me

N R1

N

O

tBu

(1.2 equiv.)

NO2 Me

N NO 2 S O O Tol 78%

R

CH3CN, 60 oC, 6 h

N R1

Ar

NO2 76%

N R = acetyl R

N R

NO2 72% (Ar = (p-CF3C6H5) 77% (Ar = (p-EtC 6H 5)

Scheme 6.107  C7-nitration of indolines with tert-butyl nitrite (TBN) followed by aerobic oxidation. Source: Modified from Sau et al. [107].

297

298

6  C(sp2)–H Functionalization of Indolines at the C7-Position

that radical process is involved in reaction as presented in Scheme 6.108. A reactive NO2 radical generated from the thermal decomposition of tBuONO followed by aerobic oxidation of a NO radical. Subsequently, the single-electron transfer (SET) process by the assistance of tBuO radical, the N-acetylated indoline give a radical cation species B or B’, which can undergo the radical addition with NO2 radical and followed by aromatization provides the corresponding product. The site-selective nitration between the C5- and C7-positions of indolines can be rationalized by the electronic density and steric effect of N-acetyl group during the electrophilic radical addition step. Later, a similar reaction was also reported by Li and Xie, who used a ferric nitrate (Fe(NO3)3.9H2O) as the nitrating reagents in acetonitrile solvent (Scheme 6.109) [108]. tBu O

NO

O2

N TBN

aer obic

O

ONOO

∆ NO

tBu O + NO

ONOONO

2NO 2

tBu O

N R R = -COCH 3

A

B

N R

N B' R

NO

O2 N

N NO2

N R

O

N R

Me

steric control

NO 2

N R

Scheme 6.108  Proposed reaction mechanism. Source: Modified from Sau et al. [107].

R

R R2 N R1

Fe(NO3) 3 9H2O (50 mol%) CH3CN (3 mL), 40 oC

NO2

N R1

R2

Scheme 6.109  C7-nitration of indolines with ferric nitrate (Fe(NO3)3.9H2O). Source: Modified from Li et al. [108].

6.1.8 C−H Bond Cyanation of Indolines at the C7-Position The cyano group acts as a versatile intermediate for the synthetic transformations into a useful functional groups such as carboxyl, carbamoyl, aminomethyl, carbonyl, and heterocycles. Therefore, a great deal of effort has been made in cyanation reactions in the past century. An alternative route for the cyanation of heteroarenes is transition metal-catalyzed cyanation [109]. However, the direct cyanation of C7-indolines was investigated much less [6]. A successful example with rhodium(III)-catalyzed cyanation of indolines was disclosed by Kim’s group. They suggested that a cationic rhodium(III)-catalyst can efficiently undergo cyanation of the C7–H bond of indolines with N-cyano-N-phenylpara-methylbenzenesulfonamide (NCTS) as a user-friendly CN donor, leading to the production of C7-cyanated indoline derivatives (Scheme 6.110a) [110]. A range of carbonyl-auxiliary as DGs and various electron-rich functional groups on indolines are tolerated in the reaction. Among the DGs examined, N-pivaloyl was found to be a superior DG. Interestingly, the authors subjected the C7-cyanated indoline product to further transformations involving the synthesis of free-(NH)-indoline in 62% yield concomitant with the basic hydrolysis of a nitrile group along with a simple oxidation of indoline to indole (Scheme 6.110b). A deuterium exchange and a KIE value of 2.76 support the reversible process. The authors proposed that in situ-generated cationic rhodium(III) catalyst cyclomatalate the indoline, followed by C–H activation, coordination of NCTS, and insertion of CN group into the C(sp2)–Rh bond give the key intermediate D, then rapid rearrangement of D provides the C7-cyanated product and a rhodium species E that finally undergoes ligand exchange to liberate the PhNHTs as a side intermediate of NCTS and the active rhodium(III) catalyst (Scheme 6.111).

6.1  Introduction

Y X N H

+

O

77% (R 72% (R 70% (R 62% (R

O

R

Ts

N

X

NaOAc (30 mol%) DCE, 130 oC, 40 h

Ph

R

N CN

NC

Y

[RhCp*Cl2]2 (5 mol%) AgSbF6 (20 mol %)

= tBu) Cl = Me) = Ph) = NMe2)

N CN

O 40%

N CN

O Me Ph

R

Me N

tBu

tBu

CN

O 65%

Scheme 6.110a  Rhodium(III)-catalyzed C7-cyanation of N-protected indolines with NCTS. Source: Modified from Mishra et al. [110].

N H COOH

s-KOH, EtOH

DDQ, dioxane

N

100 oC, 3 h 62%

CN

tBu

O

100 oC, 16 h 65%

N CN

t Bu

O

Scheme 6.110b  DDQ oxidation and basic hydrolysis of C7-cyanated indolines. Source: Modified from Mishra et al. [110]. [Cp*RhCl2] + AgSbF6 + NaOAc

AgCl + NaCl

H Ts

Ph N

[Cp*RhOAc]+SbF6A

HOAc

N H

t Bu

O

H+ *Cp Ph

+ Rh N

+ Ts

N

E *Cp

N CN

O

RhIII

tBu

O B

tBu

Ts NC N Ph +

+ N Ph

N t Bu

O N N Rh D S O O Cp* Tol

Rh *Cp

tBu

Ts O N C N Ph C

Scheme 6.111  Proposed reaction mechanism. Source: Modified from Mishra et al. [110].

6.1.9 C−B, C−O, C−P, and C−S Bond Formation of Indolines at the C7-Position In past few decades, the site-selective C−B, C−O, C−P, and C−S bond formations of various (hetero)arenes, most of which are the essential links in these feedstock chemicals, has reached an impressive level of edification and efficiency [111]. They act as an important synthetic intermediates that have a key role in the direct construction of natural products, pharmaceuticals, and organic materials. Recently, a few groups investigated the regioselective incorporation of these groups on indolic scaffolds by direct C−H functionalization reaction.

299

300

6  C(sp2)–H Functionalization of Indolines at the C7-Position

6.1.9.1 C−B Bond Formation

In particular, the C−B bond formation strategy thereafter provides a simple way to construct the various C−C and C–heteroatom bonds. A simple method for the direct C7–H borylation of indolic scaffolds without the use of metal catalysts was published by Houk, Shi and coworkers. With the installation of pivaloyl group at the N1 position of indoline, the reaction represents one of the single example of C7–H borylation of indoline via the formation of tetrahedral species A initiated by the coordination of BBr3, where the central B atom is chelated by the oxygen of N-pivalate. Furthermore, the treatment of dibromoborane species with a K2CO3 base and pinacol as a borane source successfully converted this species to a C7-boronated indoline product followed by the formation of a pinacol boronate ester intermediate B (Scheme 6.112) [112]. In this protocol, the density functional theory (DFT) calculations indicating that BBr3 can be act as both a reagent and a catalyst.

BBr 3

N H

O

tBu

N

tBu 0 DCM, rt B O Ar, 1 h Br A Br

K2CO3 pinacol oC-rt,

Me

O

B 1 h Me O O Me Me B

N tBu

N BPin O

tBu

Scheme 6.112  C7–borylation of N-pivaloyl indoline by the coordination of BBr3. Source: Modified from Lv et al. [112].

6.1.9.2 C−O Bond Formation

The classical approach for C−O bonds on heteroarenes has been studied using oxidative electrophilic aromatic substitution reactions by using strong Brønsted/Lewis acids in the presence of super stoichiometric amount of oxidants. These strategies are mainly restricted to the site-selective C−O bond formations. To overcome these disadvantages, significant efforts have been dedicated to the direct catalytic C−O bond formations (especially acetoxylation and hydroxylation) on certain heteroarenes [111]. Deb and coworkers developed a direct approach for the synthesis C7-acetoxylated indoline scaffolds from the reaction between N-pyrimidyl indolines and nonmetallic phenyliodine(III) diacetate [PhI(OAc)2] as a acetoxy reagent in good to high yields, in preference to the electron-rich substrates under rhodium(III) catalyst (Scheme 6.113) [113]. However, R2

R1 N H

N

N

R2

PhI(OAc) 2 (1.2 equiv.) 1 [Cp*Rh(MeCN)3 ](SbF6 ) 2 (5 mol%) R Ac 2O (16.0 equiv.), DCE (0.1 M) N 2, 40 o C, 12 h

N OAc

N

86% 65% 62% N 89%

(R 1 = H) (R 1 = 3-Me) (R 1 = 2-Ph) (R 2 = 4-OMe)

Scheme 6.113  Rhodium(III)-catalyzed C7-acetoxylation of N-pyrimidyl indolines with [PhI(OAc)2]. Source: Modified from Mishra et al. [113].

the stoichiometric amount (2.0 equivalents) of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) as an additive is required to facilitate the oxidative reaction of C7-acetoxylated product and the pyrimidine auxiliary could subsequently be removed under basic conditions to provide the NH-free C7-hydroxy indole. Using a very similar procedure, Wang successfully extended the methodology to synthesized C7-acetoxylated indoline derivatives by using the combination of [RhCp*Cl2]2 and AgF2 catalyst instead of [RhCp*(MeCN)3](SbF6)2 (Scheme 6.114a) [114]. Under the slight modification of the reaction medium, such as use of DMF instead of acetic anhydride, the authors successfully obtained C7-hydroxylated indoline products. The aid of H2O was essential as it act as OH donor in this protocol (Scheme 6.114b). In addition to the C7-hydroxylation of indolines, some other hydroxyl sources, such as sodium perborate tetrahydrate (NaBO3.4H2O) [112] and p-toluenesulfonic acid monohydrate (TsOH.H2O), also coupled with indoline C7−H bonds to form the corresponding C−OH bonds under appropriate catalysts (Scheme 6.115) [115]. In a subsequent communication, a unique example of direct acetoxylation at the C7-position of indolines was showcased by the Punniyamurthy and coworkers. Indolines bearing an electron-deficient and easily removable pyrimidine DG could be acetoxylated with diversely substituted (hetero)aryl and alkyl carboxylic acids in the presence of [RuII(p-cymene)Cl2]2/ AgSbF6 catalyst and Ag2CO3 oxidant (Scheme 6.116) [116]. The nature of DG and oxidant was crucial for the success of this protocol, possibly due to the stability of the alleged ruthenacycle intermediate. The electron-rich groups on the indoline

6.1  Introduction

R2 R1

R2 [RhCp*Cl2]2 (5 mol %) AgF2 (20 mol %) R1

R3 N

(a)

PhI(OAc) 2 (120 mol %) Ac2O, 30 oC, 6 h, air

N

N

CO2Me N OAc

N N

N

OAc

94%

R3 N

N

N OAc

N 99%

73%

OAc

N

N

(b)

39%

R2 R3 N

N

N

N

R2 R1

N

N

O 2N

Ph N

N

OAc

[Cp*RhCl2]2 (5 mol %) AgF 2 (20 mol %) R1

R3

N

PhI(OAc) 2 (120 mol %) DMF, H 2O (10 equiv.) 30 oC, 2 h, Ar

OH

N

N

Scheme 6.114  Rhodium(III)-catalyzed C7-acetoxylation and hydroxylation of N-pyrimidyl indolines. Source: Modified from Zhai et al. [114]. Pd(OAc)2 (5 mol %) TsOH H2O (0.25 equiv.)

N O

AcOH, 30 oC, 20 h 52%

Me

N OH

O

Me

Scheme 6.115  Palladium(II)-catalyzed C7-hydroxylation of N-acetyl indolines with (TsOH.H2O). Source: Modified from Mulligan et al. [115]. R2

R1

N H

+ RCOOH N

N

R2

[Ru(p-cymene)Cl2 ] 2 (5 mol %) R1 AgSbF 6 (20 mol %) Ag2 CO3 (2 equiv.) DCE, 100 oC, 16-18 h, air

N

R

O

N

N

O N Ph

O

N

O 77%, 16 h

N

S N

O

N

O 64%, 18 h

N N tBu

O

N

O 69%, 18 h

N

Br N Ph

O O

N

N

77%, 16 h

Scheme 6.116  Ruthenium(II)-catalyzed C7-acetoxylation of N-pyrimidyl indolines with carboxylic acids. Source: Modified from De et al. [116].

were found to be the most favorable for C7-acetoxylation due to electronic reasons. Additionally, the C6-substituted substrates showed no steric hindrance, producing the desired products in good yields. A catalytic cycle was proposed on the basis of deuterium-labeling and KIE experiments. Both intermolecular and parallel kinetic isotope effect (kH/kD) were measured to be 6.7 and 2.65 for C7−H bond, respectively, indicating that C7−H bond cleavage was the rate-determining step. The KIE value for intermolecular experiment was calculated by 1H NMR analysis and parallel experiment value was estimated by the ratio of the obtained yields (KIE=43%/18%/90%=2.65). The proposed mechanism for the reaction involves the formation of six-membered ruthenacycle intermediate B followed by the C−H activation of indoline and coordination of the active ruthenium(II) carboxylate to pyrimidyl-nitrogen. Reductive elimination results in the formation of an C7-acetoxylated product (Scheme 6.117).

301

302

6  C(sp2)–H Functionalization of Indolines at the C7-Position

[{RuCl2(L)}2] 2 Ag + RCO2H 2 AgCl N N

O

N

C O RCO 2H, Ag 2CO3

N

N

H

Ru

N N

N

L[Ru](RCO2)n[SbF6]n n = 1 or 2 L = p-cymene

R

N N

N [Ru] B

N [Ru(O 2CR)n] A

O 2CR RCO2H

Scheme 6.117  Proposed reaction mechanism. Source: Modified from De et al. [116].

In 2018, Koley and coworkers also reported using copper(I) oxide (Cu2O) as a catalyst to catalyze the oxidative cross-dehydrogenative coupling of N-pyrimidyl indolines with a variety aryl and alkyl carboxylic acids to produce to C7-acyloxylated indolines. A key to the success of this reaction was the utilization of molecular oxygen (O2) as the terminal oxidant. The influence of steric effects is observed depending on the reagent and catalyst used (Scheme 6.118a) [117]. Based on the detailed mechanistic investigations, a catalytic cycle was proposed by the authors (Scheme 6.118b). Cu2O might undergo R2 R1 N 2-pym

H

+

Cu2O (20 mol %)

R2

R1

RCOOH CH 3CN, O2 R = aryl, o hetaryl, alkyl 130 C, 18 h

RCOO

N 2-pym

Br

R N OBz 2-pym

N 2-pym OBz 67%

84% (R = H) 85% (R = Ph)

OBz

N 2-pym

N 2-pym OBz

R

0% (R = Cl) 0% (R = NO2)

67%

Scheme 6.118a  Copper(I)-catalyzed C7-acetoxylation of N-pyrimidyl indolines with carboxylic acids. Source: Modified from Ahmad et al. [117]. Cu 2 O O 2 + BzOH

Cu IOBz

N

CuII(OBz)2

acive catalyst regeneration

metal coordination

H

N

N

N BzO

N

N

reductive elimination

N H (OBz)2CuII

BzO BzO

N Cu III N C

N

CuIOBz

dispropor tionation

A BzOH

N

CuII N BzO Cu II(OBz)2 B

N

N

N

Scheme 6.118b  Proposed reaction mechanism. Source: Modified from Ahmad et al. [117].

6.1  Introduction

for oxidation to generate the active copper(II) catalyst CuII(OBz)2, which coordinates with indoline and to form the six membered copper(II) species B through the C−H activation of an intermediate A. Next, the disproportionation reaction of the copper(II) ion leads to the formation of an active copper(III) species C. Species C liberated Cu(I)OBz and the C7-acyloxylated indoline product, which is followed by a reductive elimination process. Finally, in the presence of oxygen, the oxidation of Cu(I)OBz takes place to regenerate the active copper(II) catalyst to participate in the next catalytic cycle. Furthermore, DDQ oxidation was performed smoothly to provide the corresponding indole, which served as an intermediate for the removal of DG and de-esterification of the acyloxyl group into a hydroxyl group (Scheme 6.119a). The importance of these modifications was also demonstrated by the formation of an indoloisochromenone scaffold through an intramolecular Heck-type cross-coupling reaction (Scheme 6.119b). LiOH H 2 O (2 equiv.) THF:MeOH:H 2O

(a)

rt, 3 h, 94%

DDQ, dioxane N 90 oC, 12h 92% OBz 2-pym

(b)

I

N

100 oC, 5 h NaOEt 20% in EtOH DMSO, Ar, 63%

Pd(OAc) 2 (10 mol%) NaOAc (2 equiv.)

N O

N 2-pym OBz

N

N OH 2-pym

OH

N H

N

DMF, 130 o C, 5 h 57%

O

O

N

N

O

Scheme 6.119  Synthetic transformations of C7-acyloxylated indolines. Source: Modified from Ahmad et al. [117].

6.1.9.3 C−P Bond Formation

The potential of P-based nucleophiles in the rhodium(III)-catalyzed cross-dehydrogenative coupling of various heteroaromatics under anodic oxidation was reported by the research group of Xu, Zhang, and Wen. With the assistance of the pyridine DG, an electrochemically driven monomeric RhIIICp*(OAc)2-catalyzed C−H phosphorylation of a single example of indoline with diphenylphosphine oxide proceeds to produce the corresponding C7−phosphonated indoline in excellent yield (Scheme 6.120) [118].

N H

N

+

O P H Ph Ph

RVC

Pt

RhCp*(OAc) 2 (5 mol %) KPF6 (1 equiv.), MeOH reflux, 65 o C, 3 mA, 5.9-8.0 h

N Ph P N Ph O 96%

Scheme 6.120  Electrochemically rhodium(III)-catalyzed C7-phosphorylation of N-pyridyl indoline. Source: Modified from Wu et al. [118].

6.1.9.4 C−S Bond Formation

The C−S and C−Se bond formation are of great interest in organic synthesis and pharmaceutical industry also in material sciences [119]. The traditional methods for achieving this goal are transition metal-mediated cross-coupling reactions between different sulfur and selenium sources. The other effective protocol is Chan-Lam-type coupling, which is a very useful procedure to prepare C−S and C−Se bonds in the presence of borates and boronic acids as substrates [120]. Considering the generality and practicality of Chan-Lam-type coupling, the site-selective introduction of C−S and C−Se bond on (hetero)arenes under transition metal catalysts are also reported [119]. Of particular special interest with respect to indoline heterocycle C7-bond functionalization, Wang reports on the in situ generated cationic [RhIIICp*(OTf)2]-catalyzed intermolecular C7-thiolation and selenation of N-pyrimidyl indolines under mild conditions where sulfur and selenium functionalities can be oxidatively incorporated at the C7-position of indolines by employing different substituted aromatic and alkyl disulfides and diselenides as coupling reagents (Scheme 6.121) [121], and the sulfenylated product can be selectively

303

304

6  C(sp2)–H Functionalization of Indolines at the C7-Position

R1 N H

+ N

N

R1

[Cp*RhCl2 ]2 (5 mol %) AgOTf (20 mol %)

R2Z 2 (Z = S, Se)

N

Ag2CO 3 (1.0 equiv.) toluene, 130 o C, 12-24 h under air

Z

N

N

Br N ZPh

N

N N

N

ZPh

95% (Z = S) 81% (Z =Se)

N

N

97% (Z = S) 58% (Z = Se)

N

Cl N

SPh

38% (Z = S) 25% (Z = Se)

17%

ZBn

N

N

N

Scheme 6.121  Rhodium(III)-catalyzed C7-sulfenylation and selenylation of N-pyrimidyl indolines. Source: Modified from Xie et al. [121].

converted into sulfonyl indolines by treatment with m-CPBA. Mechanistic studies revealed that this process involves various steps such as the formed six-membered rhodacycle complex A that might undergo nucleophilic substitution reaction with disulfide to give the product and rhodium(III) species B, which further undergoes for C−H activation to produce indoline, forms intermediate C and, after a reductive elimination process, releases the desired C7-sulfenylated or selenylated indoline product (Scheme 6.122). Later, the Jana group applied the same procedure as an application for the formation of C7−S and C7−Se bond on the synthesized C2-arylated indoline [122]. [Cp*RhCl2]

[Cp*RhCl2 ] 2 AgORf

Ag 2CO3

[Cp*Rh(OTf) 2]

N H

N

N

HOTf

Rh(I) N SPh

N

N

reduct iv e elimination TfO

PhS

N Rh

N Rh

SN

C [PhSRhCp*]OTf B

HOTf N H

N

A

N

N

N

N

N SPh

N

PhS SPh

N

N

Scheme 6.122  Proposed reaction mechanism. Source: Modified from Xie et al. [121].

On the other hand, a very unique redox system in the reaction pathway involving copper(II)/copper(III)/copper(I) oxidation states was reported by Ackermann and coworkers. They have extensively studied the reactivity between N-pyrimidinyl indolines and substituted diaryldisulfides and diaryldiselenides with copper(II) [Cu(OAc)2·H2O] as an

6.1  Introduction

air-stable and user-friendly catalyst in mesitylene solvent and successfully obtained the C7-thiolated and selenylated indoline derivatives (Scheme 6.123) [123]. Many functional groups at the C2-, C3-, and C4-positions on indoline substrates were well tolerated, producing the corresponding products in moderate to good yields. In mechanistic experiments, when radical scavengers BHT and galvinoxyl were added, no formation of product was detected. However, in the presence of TEMPO, the yield of product was decreased to 23%, suggesting that the reaction proceed through a free radical mechanism. On the basis of these observations including deuterium exchange results, a copper(II)/copper(III) catalytic cycle via a SET-type mechanism was proposed. In situ generated sulfenyl radical via a SET step of a disulfide in air oxygen reacts with cyclometalated copper(II) complex A, which undergoes oxidation into copper(III) species B. After reductive elimination, the C7-sulfenylated indoline product and copper(I) salt is generated. The formed copper(I) species is reoxidized by disulfide and O2, regenerating the sulfenyl radical and starting copper(II) complex to complete the catalytic cycle (Scheme 6.124). R2

H

N 2-pym

R1 + Ar 2 X2 (X=S, Se)

mesitylene 140 oC, air, 20 h Me Me

N

R2

Cu(OAc)2 H2O (20 mol %)

N XAr 2-pym F

N

XPh 2-pym 66% (X = S) 57% (X = Se)

N

N SPh 2-pym

XPh 2-pym 72% (X = S) 56% (X = Se)

R1

XPh 2-pym 69% (X = S) 62% (X = Se)

52%

Scheme 6.123  Copper(II)-catalyzed C7-sulfenylation and selenylation of N-pyrimidyl indolines. Source: Modified from Gandeepan et al. [123].

N O2

PhS

N N

[CuX2 ]

H

X=OAc

PhSSPh

XH

N

[CuX] N

PhS

N

[CuX] A

N SPh

N

N

N N

[CuX]

N B

SPh

Scheme 6.124  Proposed reaction mechanism. Source: Modified from Gandeepan et al. [123].

Additionally, the research group of Shi and Song recently reported a similar reaction on the chelation-assisted C7-sulfonylation of N-pyrimidinyl indolines with arylsulfonyl chlorides via the formation of sulfonyl radical. Under Cu(II) catalyst and Na2CO3 additive with Ag2CO3 as oxidant in HFIP solvent, the SET mechanism is operative and the C−H sulfonylation occurs selectively at C7-position of the aromatic ring of indoline (Scheme 6.125) [124].

305

306

6  C(sp2)–H Functionalization of Indolines at the C7-Position

R2 R1

N H

N

N

SO 2Cl +

Cu(OAc)2 H 2O (20 mol %) Na 2 CO3 (2.0 equiv.) Ag2CO3 (0.5 equiv.)

R2 R1

HFIP, 110 o C, 8 h under air

R

N

O S O N

N

R

Scheme 6.125  Copper(II)-catalyzed C7-sulfonylation of N-pyrimidyl indolines with sulfonyl chlorides. Source: Modified from Zhi et al. [124].

6.1.10 C−H Bond Halogenation of Indolines at the C7-Position Some N-halosuccinimides as halogen sources, such as NBS, NCS, and NIS, also coupled at the C7−H bond of indolines to form the corresponding C7−halogen bonds under the suitable catalytic conditions. The reported examples are illustrated as mention in below the Schemes. The application of heterogeneous palladium(0) nanoparticles [Pd@MOF], generated from the Fe based metal–organic framework (MOF), namely Pd@MIL-88B-NH2(Fe) and chromium (Cr) based metal–organic framework (MOF)Pd@MIL101-NH2(Cr), was reported by the group of Martín-Matute in the synthesis of C−H halogenated (hetero)arenes. Along with the halogenation of various C(sp2)−H bonds with electrophilic N-halosuccinimides, by taking the advantage of an N-acetyl DG, a single example of C2-methylated indoline for the halogenation (bromination and iodination) at C7-position was also examined. However, it was found that N-chlorosuccinimide (NCS) could not generate the desired chlorinated product (Scheme 6.126) [125].

N H

O

Me

Pd@MOF (4 mol %) NXS (2.3 equiv.)

N

o

Me

HOAc, 40-50 C, 3-6 h air atmosphere

X

O

Me 95% (X = I) >99% (X = Br) trace (X = Cl) Me

Scheme 6.126  Palladium(0) nanoparticles catalyzed C7-halogenation of N-pyrimidyl indolines. Source: Modified from Pascanu et al. [125].

In 2020, Koley and coworkers employed a variety of indoline substrates, bearing N-pyrimidyl DG, reacted smoothly with N-halosuccinimides in a palladium(II)-catalyzed transformation into C7-halogenated indolines. The challenge here was the selectivity at C7-position instead of the acid mediated electrophilic aromatic substitution (SEAr) product at the electron rich C5-position of indolines. The authors tried various reaction conditions and controlled the C7-selectivity with the use of 10 mol % of Pd(OAc)2 and CuO-additive in DCE solvent, delivering the C7-halogenated indolines in good to high yields (Scheme 6.127) [126]. O R1 H

N + 2-pym

N X O

Pd(OAc)2 (10 mol %) CuO (1 equiv.) R1 DCE, 90 o C, 24 h

X

X=Cl N X=Br 2-pym

Scheme 6.127  Palladium(II)-catalyzed C7-halogenation of N-pyrimidyl indolines. Source: Modified from Ahmad et al. [126].

In 2021, a similar approach for C7−halogenation of indolines was disclosed by Sharma and coworkers. As standard conditions, the substrates with [RhCp*Cl2]2 (5 mol %), Ag2O (2 equiv.), Tf2O (30 mol %), and THF were warmed to 100 oC for 3h. Moderate to good yields of desired C7-halogenated indoline products were obtained (Scheme 6.128) [127]. The reaction tolerated various functional groups on indoline, including esters and phenyl derivatives. However, the influence of steric effects was observed with the C6-substituted indolines. The reaction can be carried out at gram scale and the C7-halogen groups can be transformed into other functionalities. Based on the various mechanistic studies, two mechanistic pathways shown in Scheme 6.129 were proposed. In an initial step, a ligand exchange takes place to form the active cationic rhodium(III) species, which can form a six-membered rhodium(III)-complex called Rh-A. This reacts with N-bromosuccinimide and can undergo either oxidative addition followed by reductive elimination (path a) or nucleophilic

6.1  Introduction

R

R

R1 N H

+

N

N

N X

X

Br CO 2Et

N N

N

X

84% (X = Br) 46% (X = I) 64% (X = Cl)

X

85% (X = Br) 63% (X = I) 71% (X = Cl)

X

N

N

N

N

Tf2O (30 mol %) THF, 100 o C, 3 h

O X = Br, I, Cl

N

R1

[RhCp*Cl2]2 (5 mol %) Ag2O (2 equiv.)

O

N

F X

N

N

N

N

N

N

58% (X = Br) 64% (X = I)

75% (X = Br) 48% (X = I)

Scheme 6.128  Rhodium(III)-catalyzed C7-halogenation of N-pyrimidyl indolines. Source: Modified from Manisha et al. [127].

[RhCp*Cl2] 2

O

AgOTf

N

N H +

Br

O (detected in NMR)

Ag2O + Tf 2O

N

N

N

[RhCp*OTfCl or [RhCp*(OTf )2 ]

TfOH

H

N

N TfOH

N Br Cp* O

N

N

RhIII N

O

isolated

C

Cp* Rh-A

nu cl e op P at h hi l ic b su bs

reductive elimination

Br O

Rh V N

titu

N

N

tio

n

HO

Br

N N

N O

N

O

N Cp*

N Rh III

B

Path a Br oxidative N addition O

O

Rh III

N

N

A

Scheme 6.129  Proposed reaction mechanism. Source: Modified from Manisha et al. [127].

substitution (path b) to give intermediate C. Finally, protodemetallation affords the C7-brominated indoline. To confirm the suggested pathways some control experiments were performed, suggesting that nucleophilic type substitution reaction (path b) is more energetically favorable. This conclusion is further supported by the theoretical study on the nucleophilic type substitution reaction for halogenations [128].

6.1.11 C−H Bond Trifluoroalkylation of Indolines at the C7-Position Because the fluorinated indolic scaffolds are important cores in pharmaceutical industry and material sciences [129], a transition metal-catalyzed C−H cross-coupling reaction on trifluoroalkylation of these substrates, particularly indolines, has been less reported. Novák and coworkers has reported a direct sp2 C−H trifluoroethylation of heteroaromatics using

307

308

6  C(sp2)–H Functionalization of Indolines at the C7-Position

Pd(OAc)2 catalyst and mesityl(trifluoroethyl)iodonium triflate as an electrophilic trifluoroethylation reagent. The developed method was also applied for the trifluoroethylation of a representative example of N-acetyl indoline selectively at the C7-position in excellent yield (Scheme 6.130) [130]. The reaction was efficiently promoted when Brønsted acid such as trifluoroacetic acid (TFA) was present in the reaction mixture. In 2017, the same group expanded this approach for the ortho-trifluoroethylation of arylureas as well as a C7−H trifluoroethylation of a carbamoyl group assisted indoline [131]. Later, a chelation-controlled rhodium(III)-catalyzed method for the CF3-carbenoid C7-functionalization of indolines from the fluorinated diazo esters methyl-3,3,3-trifluoro-2-diazopropionate as a CF3-carbene donor has been developed by Osipov and coworkers (Scheme 6.131) [132]. However, iridium(III) and cobalt(III) catalyst were ineffective in this coupling reaction. The indolines bearing methyl, nitro, phenyl, and halogen groups were efficiently tolerated in the presence of N-pyrimidine DG as chelation supporter in the catalytic cycle. The method was successfully applied for DDQ oxidation of C7-trifluoropropanoated indolines to transform into a diverse array of indoles. CF 3 I + Me

N O

Pd(OAc) 2 (7.5 mol %) TFA (1-3 equiv.)

OTf Me

R

CH 2Cl2, 25 o C, 1.5 h-3 h 93% (R = Me) 93% (R = NMe2)

Me

N F3C

R

O

Scheme 6.130  Palladium(II)-catalyzed C7-trifluoroethylation of N-protected indolines. Source: Modified from Tόth et al. [130]. R2

R1

N N

R3

+

[Cp*RhCl2]2 (2 mol %) CO2Me AgSbF6 (10 mol %)

F3C

N

Me N Pym

MeO 2C CF3 R=H (91%) R=NO 2 (79%)

R3 N Pym

DCE, 80 oC, 4 h

N2

MeO2C

R

R2

R1

N Pym MeO 2C

MeO2C CF3 70%

Me N Pym CF3 MeO2C 94%

CF3

Ph N Pym

CF3 28%

Scheme 6.131  Rhodium(III)-catalyzed C7-trifluoropropanoation of N-pyrimidyl indolines with diazoesters. Source: Modified from Iagafarova et al. [132].

A unique reactivity of β-trifluoromethyl-α,β-unsaturated ketones to provide the CF3-alkylated products was highlighted by Sharma’s group in 2018. This protocol proved to be a direct access to pharmaceutically important indolic derivatives bearing a stereogenic carbon center with a CF3 functionality. A representative example of CF3-alkylation at the C7-position of indoline was also included by the authors. It is noteworthy that the reaction condition was very simple, which performed in the presence of a low loading of 1 mol % of [RhCp*Cl2]2 catalyst and 4 mol % of the AgSbF6 as counter anion with the exclusion of additives or external oxidants (Scheme 6.132) [133]. Interestingly, this methodology easily shows the scalability to provide the excellent yield of desired product even though use of only 0.5 mol % of rhodium(III) catalyst with 2.5 mol % of silver(I) salt. Under the treatment of para-toluenesulfonic acid (p-TSA), the method was smoothly applied to synthesized a medicinally important pyrroloindole compound in a good yield.

6.2  Conclusions Over the last decade, the transition metal-catalyzed C−H functionalization has emerged as an interesting area for the functionalization of indolic scaffolds especially for a highly challenging C7-functionalization of indolines. In this chapter, we have summarized the achievements in catalytic and direct C−C, C−(CR=O), C−N, C−CN, C−B, C−O, C−P, C−X, and

References

Me N N

N

+ F3C

[Cp*RhCl2]2 (1 mol %) AgSbF6 (4 mol %)

N F3C

DCE, 70 oC O Me

N

N

O 30%

Scheme 6.132  Rhodium(III)-catalyzed C7-CF3-alkylation of N-pyrimidyl indolines. Source: Modified from Chaudhary et al. [133].

C−(CR)−CF3 bond formation reactions at the C7-position of indoline derivatives using various coupling sources to provide the C7-functionalized indoline products. In addition to ruthenium- and palladium-catalyzed functionalizations, several other transition metals such as rhodium, iridium, cobalt, manganese, iridium, cobalt, manganese, nickel, iron, and copper were also employed. Selectively, to activate the C7-position of aromatic ring of indolines, the N-centre of the indoline was protected with π-acceptors such as –SO2 (tosyl, mesyl), –CQO (acetyl, pivaloyl, benzoyl) or electron-deficient pyrimidine and pyridine ligands as DGs. On the other hand, the established methods have demonstrated the high reactivity, good selectivity, and broad substrate scopes of indolines and coupling partners. Furthermore, the mechanistic studies, oxidation of indolines into indoles, gram-scale results and the transformation of C7-functionalized indolines are also highlighted. However, as a remaining part of direct C7−CF3 reactions unexplored and will be expected in this rapidly evolving new challenging area.

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7 Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms Tanumay Sarkar1, Subhradeep Kar1, Prabhat Kumar Maharana1, Tariq. A. Shah2, and Tharmalingam Punniyamurthy1 1 2

Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, India Department of Chemistry, University of Kashmir, Srinagar, India

7.1  Introduction Benzo-fused azoles represent an important class of heterocycles that offer a common scaffold to a plethora of derivatives exhibiting diverse bioactive and pharmaceutical properties. Within the realm of design and discovery of medicinal compounds, they are regarded as privileged sub-structures owing to their importance as anticancer, antiviral, antiinflammatory, antiulcer, antihelmintic, antimicrobial, and antidiabetic agents (Figure 7.1) [1]. Hence, for the advancement of synthetic chemistry and pharmaceutical maneuvers, the sustainable and handy accessibility of these bioactive scaffolds is of the utmost significance. The functionalization of various distinctive sites on their molecular topology has been well elaborated for decades by primitive and classical methods including cyclocondensation, metalation with strong bases such as nBuLi, cross-coupling, and others [2]. However, the limitations associated with these methodologies rendered their applicability and productivity problematic. For instance, cyclocondensation demands repetition of each step for every molecule to be synthesized, thereby limiting its potential for the construction of a complete chemical library [3]. The classical metalation methods demand sophisticated reaction conditions and often suffer from low atom economy and selectivity (chemo-/ regioselectivity) [4]. Although, cross-coupling reactions offered greater access to a plethora of heterocyclic motifs in minimal steps, their potential use has been discouraged by serious drawbacks: prefunctionalization, organometallic reagent preparation, and stoichiometric metalation [5]. Consequently, the continuous demand for biologically active benzo-fused azoles has pushed synthetic chemists to require sustainable and advantageous approaches, mainly based on C–H functionalization. Transition metal-catalyzed C–H functionalization has emerged as an effective synthetic tool for streamlining the benzofused scaffolds [6]. Pertinently, even the transition metal-catalyzed functionalization is not absolute when it comes to benzo-fused azoles. The ligating ability of heteroatoms with a transition metal catalyst and the inherent electrophilic nature of azoles offer challenges in C–H activation [7]. The ligation of heteroatom with a transition metal makes the functionalization difficult and substrate specific. The electrophilic nature of azoles invites either a nucleophilic attack via ringopening or a direct attack in the company of metal catalysts. Moreover, β-hydride elimination, hydrodehalogenation, and homocoupling using transition metal catalysts coupled with the instability of moisture-sensitive triflates and iodides offers a challenge. To surmount this proclivity, synthetic chemists have come up with certain strategies such as directing group- (DG)assisted regioselective C–H functionalization, fine-tuning of the inherent reactivity of azoles, and/or the use of moisturesensitive coupling partners such as phosphates and carboxylic acids. However, the field provides ample synthetic space and demands the development of efficient and sustainable catalytic systems along with stable and electrophilic coupling partners. Numerous reviews have addressed the functionalization of C–H bonds [8]. Ackermann and co-workers reviewed the transition metal-catalyzed alkylation and alkenylation of azoles, whereas Evano and Theunissen highlighted the alkylation Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

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CO2 H

Me

HO

O

O N

N

HO

N

O

OH MeCO2 C

O Caboxamycin

Me

HO2 C

N Me

F

H N

MeO

N

Flunoxaprofen

OMe Me

N

Me

Boxazomycin B Me N Me N CO 2H

S

Omeprazole

N

N

CH3

Nataxazole

O

CONH2 HO N

O

N N

nPr

Telmisartan

Figure 7.1  Representative examples of biologically active benzo-fused azoles.

of heteroarenes [9]. Pertinently, the increasing demand for bioactive benzo-fused azoles demands an effective catalytic system with regioselectivity. To substantiate the importance of the transition metal-catalyzed C–H functionalization of benzo-fused azoles, we present herein the important developments and mechanistic insights related to direct C–C/C–heteroatom bond formations.

7.2 C−C Bond Formation The formation of the C−C bond lies at the heart of synthetic chemistry owing to the omnipresence of this bond in a wide spectrum of structurally important molecules and complex architectures found in natural products and potent pharmacophores. However, the majority of the conventional synthetic strategies known to date utilize organometallic compounds containing alkaline metals, thereby limiting their practicality in sustainable synthesis. To overcome this shortcoming, the transition metal-catalyzed functionalization of C−H bond has piqued attention with its potential to revolutionize organic synthesis. In lieu of pre-defined reactive handles, this strategy can enable step- and atom-economical gains in the formation of C–C bonds.

7.2.1  Alkylation 7.2.1.1  Copper Catalysis

The alkylation of benzo-fused azoles using transition metal-catalysis is a straightforward method for accessing diverse structural frameworks. The copper catalyzed C–H benzylation and allylation has been found to be successful for benzo-fused azoles with N-tosylhydrazones as a secondary alkyl source (Scheme 7.1) [10]. The reaction of a broad array of N-tosylhydrazones has been demonstrated in moderate to good yields. The less acidic benzothiazoles were found compatible with higher catalyst loading. In this transformation, the migratory insertion of copper carbene plays a crucial role. This strategy has been extended to direct alkylation of benzo-fused azoles using ferrocenyl ketone-derived N-tosylhydrazones [11]. The reaction utilizes CuBr and tolerates a wide range of substituents to afford the functionalized ferrocenyl-derived azoles in moderate to good yields. The scope of the procedure has been extended to the reaction of substituted 1,1′-ferrocenyl di-ketone-derived N-tosylhydrazones. Further, a copper catalyzed cross-coupling of benzoxazoles with bis(trimethylsilyl)diazomethane has been established to access 1,1-bis(trimethylsilyl)-methylated heteroarenes via a metal carbene migratory insertion (Scheme 7.2) [12]. The reaction of diverse benzoxazoles and benzothiazoles has been accomplished. The base promoted deprotonation and the follow up transmetalation provides copper(I) species I, which reacts with diazo compound to afford the carbene species II. Subsequent migratory insertion and protonation delivers the disilylated product with regeneration of the copper(I) catalyst. Later, the copper-catalyzed dehydrogenative C–H/C–H cross-coupling of benzothiazoles with cyclic

7.2  C−C Bond Formation

N

CuI (10 mol %) t BuOLi (2.5 equiv)

NNHTs +

R

X

R

N X

toluene/dioxane, 110-120 o C, 1-1.5 h X = O, S

N X

R

N Cu

Cu

X

Scheme 7.1  Benzylation and allylation of benzoxazoles and benzothiazoles.

TMS

N

R

+

N2

X

TMS

CuI (20 mol %) LiOt Bu (1.5-2 equiv)

R toluene, 110-120 C, 8 h o

N

TMS

X

TMS

X = O, S Represenative examples MeO

N

TMS

O

TMS

F

77%

O

TMS

Br

TMS

S

TMS

TMS

N X

Cu(I)

N2

TMS

I

H

N

79%

BuOH

N

t

TMS

59%

t

X

N

N2

+ BuOLi

TMS

N Cu(I)

X

Cu(I) TMS

II N

TMS

X

TMS N H

Cu(I)

TMS X TMS III

Scheme 7.2  Alkylation using bis(trimethylsilyl)diazomethane.

ethers has been accomplished utilizing K2S2O8 as the oxidant (Scheme 7.3) [13]. Ethers such as tetrahydrofuran, 1,4-dioxane, and 1,3-dioxolane participated in moderate to good yields. Benzothiazoles with electron-rich functionalities produced superior results compared to those bearing the strong-withdrawing substituents. The reaction involves a radical pathway and DFT calculations rationalized the mechanistic pathway. 7.2.1.2  Nickel Catalysis

Alkyl halides are efficient alkylating agents in metal-catalyzed heteroarenes functionalization. A nickel catalyzed alkylation of benzoxazoles and benzothiazoles has been reported with alkyl halides using CuI as a co-catalyst (Scheme 7.4) [14].

321

322

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms

N

R

S

H

+

Cu(OTf)2 (10 mol %) K 2S 2 O8 (2 equiv)

X Y O

n

R

o

60 C, 14 h

N

X Y

S

O

n

Represenative examples N

N S 92%

MeO

O

O2 N

O

N

S

O

S

0%

O

86%

Scheme 7.3  Alkylation using cyclic ethers. A. Hu (2010) Y Alkyl (Y = Br, Cl, I) C1 (5 mol %), CuI (5 mol %) LiOt Bu (1.4 equiv) 1,4-dioxane, 140 o C, 16 h

NMe2 R

N Ni Cl

N Alkyl

X X = O, S

NMe2 C1

B. Ackermann (2011) R (Y = Br, Cl) Y N R

X

[(diglyme)NiBr 2] (5 mol %) diglyme (15 mol %)

R CuI (7.5 mol %), NaI (20 mol %) t LiO Bu (2 equiv), 1,4-dioxane 140 o C, 16 h C. Herbert (2020) R Br C2 (5 mol %), LiO t Bu (1 equiv) 1,4-dioxane, 140 o C, 16 h

R

N X

R X = O, S CF3 Me

N O

R Me2 N

N Ni Cl C2

N

Scheme 7.4  Alkylation with alkyl halides.

Subsequently, the use of [(diglyme)NiBr2] has been demonstrated for the alkylation using tBuOLi base [15]. The reaction of a broad range of β-hydrogen containing alkyl halides has been covered. Later, a N,N,N-chelation-assisted benzannulated phenanthridine-supported nickel(II) C2 was used for the alkylation of benzoxazoles [16]. Alkyl bromides having ester, carbazole, aryl, arylether, thioether, and alkenyl substituents have been explored and have produced good yields. Olefins have been employed as effective coupling partners. For instances, a bimetallic nickel/aluminum-synergistic catalyzed regioselective alkylation of benzimidazoles has been accomplished with styrenes using amino N-heterocyclic carbene (NHC) L1 as a ligand (Scheme 7.5) [17], whereas a Ni–NHC–catalyzed hydroheteroarylation of vinylarenes has been successful with benzoxazole to give 1,1-diarylethanes [18]. A similar type of transformation utilizing Ni(IMes)[P(OEt)3]Br2 has been achieved for branched products and sterically encumbered Ni(IPr*OMe)[P(OEt)3]Br2 produced the linear products with the aid of magnesium turnings as reductant [19]. The reaction of diverse styrenes has been explored with wide functional group tolerance. Further, hydrazones are found to be appealing alkylating agents. Thus, a NiBr2/phen-catalyzed alkylation of benzoxazoles has been successful with N-tosylhydrazones bearing carbocyclic, heterocyclic, and long chain aliphatic substituents in moderate to good yields (Scheme 7.6) [20]. This strategy has been extended to a cobalt-catalyzed alkylation of benzothiazoles. Control experiments obviated the involvement of a carbene insertion pathway. 7.2.1.3  Palladium Catalysis

A palladium-catalyzed direct alkylation of benzoxazoles with unactivated alkyl halides has been developed (Scheme 7.7) [21]. Alkyl bromides and chlorides having alkenyl, benzyl ether, silyl ether, phthalimide, and pivaloyl ester groups reacted in moderate to good yields. In addition, the C2-alkylation of benzoxazoles and benzimidazoles has been found to be successful with secondary and tertiary alkyl halides utilizing Pd/dppp-complex [22]. Further, the cyclopropylation of

7.2 C−C Bond Formation A. Ong (2012) Ni(COD) 2 (10 mol %) L1 (10 mol %) w or w/o AlMe3 (10 mol %) toluene, 100-150 o C, 2-15 h

Me

N

R

N or

N R

Ar

B. Mandal (2017) Ar

C3 (5 mol %), Ni(COD)2 (5 mol %)

+ R

N X X = NR, O, S

hexane, 80 o C, 6 h

Me

O

Ar

Ar

iPr

Pr i N

Ph Pr i

N

C. Sun (2019) C4 (5 mol %) or C5 (10 mol %)

Me

N R

X

Ar

P(OEt) 3 Br Ni Br Me Me

Me Me Me NH N

Mes

Me

N

N

Me

L1

Ph C3

i

Mg (1 equiv), THF 60-100 o C, 48-60 h X = S, NMe, NBn

N

R

N

N R

R

Pr

N or

X

R

Ar

P(OEt) 3 Ph Br Ni Br Ph Ph Ph Me MeO

N

Me

N

OMe

Ph Ph Ph

C4

Ph

C5

Scheme 7.5  Alkylation using olefins.

NiBr 2 (10 mol %) 1,10-phenanthroline (10 mol %) t

R

N X X = O, S

+ TsHNN

R R'

BuOLi (3 equiv) 1,4-dioxane, 100 oC, 8 h

R

CoBr2 (10 mol %) 1,10-phenanthroline (10 mol %) t

BuONa (3 equiv) DMF, 120 oC, 7 h

R

N

R

O

R'

N

R

S

R'

Scheme 7.6  Reaction with N-tosylhydrazones.

benzoxazoles has been achieved utilizing cyclopropyl halides as alkyl surrogates [23]. The reaction offers the stereoretentive coupling of the three-membered rings. The reaction involves oxidative addition of palladium(0)-complex to the alkyl halide, followed by transmetalation of in situ-generated anionic azole to afford V. Reductive elimination yielded the target product with regeneration of the catalyst. Benzyl chlorides have been utilized as a versatile coupling partner for accessing mono-, di- and tribenzylated benzoxazoles by tuning the base and reaction conditions under palladium-catalysis (Scheme 7.8) [24]. One sp2 C–H bond and two sp3 C–H bonds are cleaved sequentially to enable the synthesis of a broad spectrum of tribenzylated benzoxazoles with a quaternary carbon center. Oxidative addition of palladium(0) species with benzyl chloride gives palladium(II) species VI, which undergoes transmetalation with lithiumazole species to generate VII. Reductive elimination delivers the monobenzylated compound. Sequential nucleophilic substitution with aid of base affords the di- and tri-benzylated products. The substrate scope has been extended to the use of benzyl carbonates for the alkylation of benzoxazoles [25]. The reaction occurred efficiently using a palladium complex in the presence of NaOAc to afford the diarylmethanes in moderate to good yields. The double benzylation was accomplished via a base free benzylic C(sp3)-H activation. This strategy has been

323

324

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms A. Miura (2010) Y Alkyl (Y = Br, Cl, I) [{PdCl( 3-C 3H5)}2] (3.75 mol %) P( nBu)3 (30 mol %)

N

R

Alkyl

O

t

BuOLi (3 equiv), diglyme 120 oC, 4 h B. Zhou (2014) Y Alkyl (Y = Br, I) [Pd(PPh3)4] (5 mol %) dppp (7 mol %)

N R

O

N

R

Cs2CO3 (2 equiv), PhCF3 110 oC, 24 h

Alkyl

O

R

C. Zhou (2015) [Pd(PPh3)4] (5 mol %)

I R

NaOMe (2 equiv) PhCF3, 110 oC, 24 h

O R

N R

Na

O

L2(I)Pd

R

N

N O

IV Represenative examples Decyl

N

V

Ph

N

O 95% trans:cis = 26:1

PdL2

Cy

N

O 93% trans:cis = >100:1

O 89% trans:cis = >100:1

Scheme 7.7  Reaction of benzoxazoles with alkyl halides. Ar

N

R

O N

R

O

+ ArCH2Cl

Pd(MeCN) 2Cl2 (5 mol %) dppp (6 mol %)

N

R

solvent, base, 60-120 oC 16 h

Ar R

O

Ar

O

Ph

Ar

N O Ar N O

Cl Ar Ar

Ph

Ar

Cl

Ph

O

Cl

Ar

Ph

N

Ph 90% with BuOLi and DMF

81% with Cs2CO3 and DMA

base

Ar

O

Me

89% with Na2CO 3 and DMF

base

Ph

N

Ar

O

Represenative examples N

Ar

N

t

N O

Pd(0)

Ar

Ar N O VII

PdCl

Ar

Pd

Cl

VI

Ar

Ar N O

Scheme 7.8  Alkylation of benzoxazoles with benzyl chloride.

Li

t BuOLi

N O

7.2 C−C Bond Formation

utilized for the synthesis of triarylmethanes using benzoxazoles with diarylmethyl carbonates or pivalates utilizing PdCl2(MeCN)2/PPhCy2 (Scheme 7.9) [26]. The procedure has been explored for a broad array of diarylmethyl carbonates with functional group diversities. In addition, the palladium-catalysis was found to be successful for the desulfonative cross-coupling of benzoxazoles with benzyl sulfones [27]. Benzoxazoles bearing methyl and N,N-dimethylaminocarbonyl groups have been explored. The reaction of symmetric or unsymmetric sulfones comprising electron-rich and electron deficient functionalities reacted in good to excellent yields.

N

R

+

O

PdCl 2 (MeCN)2 (10 mol %) PPhCy2 (20 mol %)

Ar RO

t

Ar' R = Boc or Piv

N

Ar

O

Ar'

R

BuOLi (2 equiv) 1,4-dioxane, 120 oC, 6 h

Representative examples OMe

CN

N

N

O

O

Ph

N O

S

83%

53%

76%

Scheme 7.9  Reaction with diarylmethyl carbonates or pivalates.

7.2.1.4  Rhodium Catalysis

α-Substituted acrylates have been explored for the asymmetric C2-alkylation of benzoxazoles using [Rh(cod)OAc]2/chiralphosphine (Scheme 7.10) [28]. Among the phosphine ligands surveyed, CTH-(R)-Xylyl-P-Phos L2 furnished the best enantioselectivity. This hydroheteroarylation proceeds via a sequential rhodium-catalyzed C–H activation, migratory insertion, β-H elimination, and protonation. A wide range of acrylates having benzyl, n-butyl, and sterically encumbered isobutyl

N

R

[Rh(cod)OAc]2 (5 mol %) L2 (10 mol %)

EWG

O

R

N

Rh

O

P

P P GWE Rh H

EWG

R

R

N

H

O

P P L Rh GWE H R

Representative examples Me

Me

Me N O

88%, 94% ee

CO2 Et

N

N

CO2 Et

O 93%, 95% ee

O

OMe

nBu

N

EWG

O

CsOAc (25 mol %) MeCN, 100 oC, 48 h

R

P

R N

MeO MeO

P(m-xylyl)2 P(m-xylyl)2 N

L2 OMe

Scheme 7.10  Alkylation of benzoxazoles with α-substituted acrylates.

325

326

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms

groups at the α-position afforded the alkylated benzoxazoles in high enantioselectivity. Later, the use of rhodium catalysis has been explored for the alkylation of benzimidazoles with acrylates [29]. A rhodium(I) complex bearing an electronically deficient ligand using K3PO4 as the base provided the best results. The protocol paves a pathway for the production of electronically divergent alkylated benzimidazoles and the amide functionality in the product could be used as an efficient precursor for biological uses.

7.2.2  Alkenylation 7.2.2.1  Copper Catalysis

The alkenylation of benzo-fused azoles has received considerable attention owing to their potential application in materials sciences. A CuCl-catalyzed C2-alkenylation of benzoxazoles with allyl halides (allyl bromide, chloride, and iodides) as alkenylating agents has been successfully demonstrated (Scheme 7.11) [30]. A variety of substituted benzoxazoles were coupled to deliver the alkenylated products in good yields. The reaction proceeds through the base-mediated deprotonation, followed by cupration on the C2-position of benzoxazole, producing intermediate IX. Later, IX reacts with allyl halide to afford π-allyl complex X, which undergoes subsequent reductive elimination and isomerization to deliver the product with concomitant regeneration of the catalyst.

CuCl (10 mol %) t BuOLi (3 equiv)

N R

Br

O

R''

N R

O

toluene, reflux, N 2

R'

R'

Representative examples Me

N O 90%

N

N O

Me

O

F3C

Me

73% N

R O N

Me Me

Me

89%

R''

O

XI CuCl

t -BuOLi

Isomerization

O

Product

VIII

N

Li

O IX

O

Cu X

N X

Br

N

Cu

R

R

Scheme 7.11  Coupling of benzoxazoles with allyl halides.

7.2.2.2  Nickel Catalysis

A C2-selective alkenylation of functionalized benzothiazoles and benzimidazoles has been accomplished using alkenyl bromides under Ni-catalysis [31]. Mechanistic studies confide that the C−H bond cleavage is reversible and the reaction proceeds via a single-electron transfer (SET). The substrate scope has been expanded to the coupling of esters as alkenyl source utilizing Ni/dcype-catalyzed C–H/C-O coupling [32]. The scope of the procedure was investigated for C5-substituted

7.2 C−C Bond Formation

benzoxazoles having methyl, methoxy, and tert-butyl groups employing styryl pivalate, carbamate, and phenyl cinnamates as the alkenylating agents. Further, the reaction of heteroaryl esters proceeded efficiently to deliver the products in 80–86% yields. Later, a nickel-catalyzed regioselective C7-alkenylation of triazolopyridines was achieved employing alkynes as the alkenyl source (Scheme 7.12) [33]. The method tolerates a wide range of aryl and alkyl substituted alkynes wherein the regioselectivity is attributed to the steric-bulk of the substituents. Pertinently, the electron-withdrawing as well as terminal- and silyl-substituted alkynes showed inferior results. The stoichiometric usage of AlMe3 as the Lewis acid is crucial. Mechanistic studies reveal the crucial interplay of Lewis acid within the catalytic manifold. The reaction involves the formation of XII by the chelation of triazolopyridine with AlMe3. Subsequent coordination with Ni-catalyst produces XIII, which leads to the oxidative addition at the C7-position to afford XIV. Regioselective alkyne insertion and the reductive elimination deliver the products. The synthetic utility was illustrated by accessing 2,6-disubstituted pyridines. This strategy has been use to perform the C5-selective C–H alkenylation of imidazo[1,5-a]pyridines with synergistic nickel/aluminum catalysis (Scheme 7.13) [34]. Notably, the C3-alkenylated products were achieved without using AlMe3. The scope of the procedure was explored with a broad range of imidazo[1,5-a]pyridines and alkynes having electronically varied groups.

R

N N

Ni(COD) 2 (10 mol %) R' PPh3 (10 mol %)

N

AlMe3 (1.2 equiv) toluene, 70 o C

R

H

N

N N

H

Ph

N

Ph

p-OMeC 6H 4

94%

H

Rs

RS

[Ni] RL

XV

RS = R small RL = R large

p-FC6 H4

N N N AlMe3 H XII

N N N C7 AlMe2 H

RL

RL

RL

N N N Ni H AlMe3 PPh3

N

H

51%

[Ni] XIII

Rs

H

N N Me

Rs

N N N AlMe3 [Ni] H

Rs

N

Substrate + AlMe3

RL

N

R

75%

N N AlMe3

N N

R'

Et

86%

N

R

Ph

H

Ph

or

R'

N N

H

Me

N

H

R

Representative examples Ph

Ph N N

N N

R

XIV

Scheme 7.12  Alkenylation of triazolopyridines with alkynes.

turnover limiting step

327

328

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms R

R'

R''

N

N

R

R R''

R''

Ni(COD) 2 (5 mol %) IMes (5 mol %) AlMe3 (60 mol %) toluene, rt, 6 h

R'' R''

N

N

R'

R''

R'' R''

Representative examples

p-CF3C 6H 4

p-t BuC 6H 4 Me

nPr

N

N

N

N

N

nPr

nPr

N

nPr

nPr 97%, E/Z = 99/1

nPr 89%, E/Z = 94/6

N

N

Ni(COD)2 (5 mol %) R' IMes (5 mol %) toluene, rt, 6 h

90%, E/Z = 99/1

Scheme 7.13  Regioselective alkenylation of imidazo[1,5-a]pyridines with alkynes.

7.2.2.3  Cobalt Catalysis

Cobalt-catalyzed diphosphine ligand assisted approach has been developed for the C2-alkenylation of benzoxazoles and benzothiazoles (Scheme 7.14) [35]. The addition of Grignard reagent was found to be crucial. The reaction tolerates a wide variety of internal alkynes with good functional group tolerance. The oxidative addition of the C2-H bond with the metal center, subsequent alkyne insertion, and reductive elimination leads to the formation of the product.

R

N +

X

R'

R'

CoBr2 (10 mol %) DPEphos/Xantphos (10 mol %) Me3 SiCH 2 MgCl (50 mol %)

H R'

N

R

X

THF, 20 oC, 12 h

R'

X = O, S Representative examples Pr

N S

Cl

Pr

74% (E/Z = 5/1)

Pr

N O

Pr

85% (E/Z = 12/1)

N O

nBu nBu

97% (E/Z = 99/1)

Scheme 7.14  Alkenylation with alkynes.

7.2.2.4  Palladium Catalysis

A palladium-catalyzed C2-alkenylation of benzoxazoles has been accomplished employing alkenyl tosylates as the alkenylation source in the presence of ppm level of Pd source [36]. The reaction using PhMezole-Phos as the ligand produced the best results. A diverse array of substituted alkenyl tosylates ranging from sterically hindered to vinyl tosylate were coupled efficiently. The strategy has been extended to the palladium-catalyzed decarboxylative cross-coupling of α-alkoxyacrylic acids [37]. PdCl2 was used as the catalyst with CuCO3 as the additive and either dppe or dcpe as the ligand at an elevated temperature. The scope of the procedure was examined with varied α-alkoxylated acrylic acids and benzoxazoles and was shown to produce α-heteroarylated vinylethers in moderate to good yields. In the case of benzothiazoles, CuI played a crucial role by forming a [Cu]-heterocycle pre-complex and thereby facilitating the catalytic transformation. Recently, a palladium-catalyzed trisallylation of azoles has been developed with alkynes using RuPhos as ligand via a sequential C(sp2)-H allylation/olefin isomerization/double C(sp3)-H allylation (Scheme 7.15) [38]. The reaction involves the formation of a palladium-hydride species, which leads the isomerization of alkyne to allene and produces the π-allylpalladium complex XVI. The latter undergoes reaction with azole to furnish the mono-allylated XVII. Then, subsequent isomerization and sequential two-fold C(sp3)–H allylation delivers the target product. Later, a

7.2 C−C Bond Formation Ph Me

N R

O Ph

MeO

N O

Pd(OAc) 2 (2.5 mol %) RuPhos (5 mol %)

N R

KOAc (0.6 equiv) HOPiv (10 mol %)

OHC N O

Me 60% Olefin Migration

50%

N

Me

PdL2

Ar sp3 C-H allylation Pd Ar

Ar

R'

O

N Ar

O

Ph

R' =

Ph

Representative examples Me N R' O

R'

O

R'

toluene, 120 o C, 24-48 h

95%

Ar

O

H

HOPiv

O N XVII

N

HPdOPiv

Ar

HOPiv PdOPiv N O

Ar

H XVI

Me

Ar

Scheme 7.15  Trisallylation with alkynes.

cross-dehydrogenative coupling of benzoxazoles was reported using olefins to synthesize C2-alkenylated benzoxazoles using Pd(TFA)2/1,10-phenanthroline in the presence of AgTFA as the oxidant [39]. The method features a distinctive level of E-selectivity with a broad substrate scope. 7.2.2.5  Rhodium Catalysis

A rhodium–catalyzed pyrimidine-directed C5-olefination of benzimidazoles with acrylic esters has been achieved [40]. The protocol utilizes Cu(OAc)2 and O2 as the oxidants. A variety of acrylic esters were compatible with C2-substituted benzimidazoles in moderate to good yields. Later, a rhodium/copper co-catalytic system was used to achieve trans-selective tetra(hetero)-arylethylenes via the C–H oxidative coupling of benzoxazoles with internal alkynes [41]. The reaction involves the insertion of alkyne into the Rh–C bond of azolylrhodium complex, followed by transmetalation with the azolylcopper complex. The second C–C bond is formed as a result of the intramolecular trans-nucleophilic addition. The reaction tolerates a wide variety of functional groups in the substrates. Recently, our group developed a convenient strategy for the regioselctive construction of indazoloquinolines using Cu(OAc)2•H2O as oxidant (Scheme 7.16) [42]. This method utilizes two-fold C–H activation/dual C–C bond formation under rhodium–catalysis employing a variety of 2-aryl-2H-indazoles with alkynes. Symmetrical alkynes comprising both electron-rich as well as withdrawing groups both efficiently produced good yields. Pertinently, the blue emission and high quantum efficiency, as determined by late-stage photophysical investigations, highlight the practical applicability of the transformation.

329

330

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms R'

Ar

N

N +

R'

R'

[Cp*RhCl2 ]2 (4 mol %) Cu(OAc) 2 H 2O (1.2 equiv)

R'

N N

K 2CO3 (1 equiv) (CH2 Cl)2 , 100 oC, 6 h

R

R

Representative examples OMe

MeO

Pr

Ph MeO

Pr Ph N N

N N

N N

66%

63%

73%

Scheme 7.16  Synthesis of indazoloquinolines with alkynes.

7.2.3  Alkynylation 7.2.3.1  Copper-Mediated Reactions

Alkynylated benzo-fused azoles are among the most essential and fundamental π-conjugated scaffolds in synthetic chemistry. In this realm, transition metal-catalysed alkynylation has paved the pathway for the synthesis of a wide range of acetylated azoles. An efficient strategy for the alkynylation of activated C–H bonds of benzoxazoles has been developed with copper acetylide (Scheme 7.17) [43]. In presence of LitOBu and 1,10-phenanthroline, the relatively acidic C–H bond of benzoxazoles can be readily alkynylated at room temperature. The functional group tolerance, mild reaction condition, and formation of complex scaffolds are important advantages. N R

Cu

R'

X X = O, S

1,10-Phenanthroline t

BuOLi, O2 , CH 3CN, rt, 48 h

N R

X

R'

Representative examples Me

N Me

O 54%

N

N

O

S

42%

Me 52%

Scheme 7.17  Coupling of benzoazoles with copper acetylides.

7.2.3.2  Nickel Catalysis

A nickel-based approach has been accomplished for alkynylating benzoxazoles with alkynyl bromides [44]. The reaction shows a wide versatility and proceeds quite efficiently, demonstrating the C–H/C-Br cross coupling. Subsequently, a bimetallic nickel-catalyzed concise method has been developed for the alkynylation of azoles with terminal alkynes (Scheme 7.18) [45]. The reaction exhibited notable substrate scope for benzo-fused azoles as well as alkynes. In this reaction, the terminal alkyne reacts with an in situ-generated nickel(II) complex XVIII to afford the (alkynyl)nickel intermediate XIX, whereas the deprotonation of C2-H of benzo-fused azole using tBuOLi generates the heteroaryllithium XX. Transmetallation of XIX with XX and the subsequent reductive elimination furnishes the target product along with nickel(0) complex that, in turn, oxidizes to XVIII and thereby completes the catalytic cycle. However, if there is preferable reaction of the alkyne with XIX, then the undesired homo-coupled product would be obtained via a bis(alkynyl)nickel XXII.

7.2 C−C Bond Formation

R

N +

O

H

R'

NiBr 2 diglyme (5 mol %) dtbpy (5 mol %) t BuOLi (3 equiv)

N

R

o

toluene, 50-120 C, 1-3 h O2 (1 atm)

R'

O

Representative examples Me Ph

Cl

N

N

O

O

55 %

61 %

Ni

R', t BuOLi

II

N

R'

Si(i-Pr)3

Me 45 % R', t BuOLi

R'

XIX

N O N O XXI

Ni(II) XVIII

O2

Ni(0)

Me

O

Ni

O

R'

Li XX R'

N

Ni XXII

R'

R'

R'

Scheme 7.18  Reaction of benzoxazoles with terminal alkynes.

7.2.3.3  Palladium Catalysis

A palladium-catalysis has been successfully utilized for the alkynylation of benzoxazoles with 1-bromoalkynes in the presence of LiOtBu at moderate temperature [46]. The reaction utilizes Pd(OAc)2/Xantphos and the substrate scope could be extended to benzothiazoles and N-alkylbenzimidazoles in moderate yields. Later, the oxidative alkynylation of benzofused azoles has been accomplished (Scheme 7.19) [47]. The procedure utilizes air as the oxidant with terminal alkynes under palladium-catalysis to afford the 2-alkynylazoles in good yields. A wide range of benzo-fused azoles having electronically varied functionalities were coupled. Electronically rich alkynes exhibited better conversions than electronically deficient counterparts. In this transformation, the base deprotonates the C2-H of the azole moiety, forming a lithium azolate, which transmetalates into a palladium(II) species generated in situ and further affords a Pd(II)azolyl complex XXIII. The formation of Pd-acetylide species XXIV minimizes the expected dimerization of XXIII. Subsequent reductive elimination of XXIV produces the 2-alkynylazole along with palladium(0), which oxidizes under air to complete the catalytic cycle. Further, the alkynylation of benzo-fused azoles has been demonstrated utilizing gemdichloroalkenes [48]. The procedure was well tolerated for substituted gem-dichloroalkenes to give the alkynylated benzoxazoles bearing both electron-donating and withdrawing groups. However, the alkynylation of the benzothiazoles only proceeds well in the presence of co-catalytic amounts of CuI as an additive. In addition, the oxidative coupling of azoles has been accomplished with terminal alkynes through a combined use of palladium and silver salts (Scheme 7.20) [49]. The expected imidazo[1,5-a]-pyridines could be accessed by finely tuning the dropwise addition of the terminal alkyne. The catalytic system was found to be compatible with a variety of benzo-fused azoles to afford the desired C2-alkynylated azoles.

331

332

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms N

R

+ H

R'

X X = O, S, NR

N

Pd(PPh3) 4 (5 mol %)

R

tBuOLi (4 equiv) toluene, 100 °C, 12 h

R'

X

Representative examples N

N

N

Ph

O

OMe

O

74%

CF 3

O

67%

50%

Pd(0)

N H

X

tBuOLi

Pd(II)

air Pd(0)

N

Pd

Dimer

X XXIII Pd

Product

R X

N

H

R tBuOLi

XXIV

Scheme 7.19  Coupling with terminal alkynes.

N

N

R

X X = O, S, NR'

N X

R'

N

R' H

C5 (0.5 mol %) Ag2CO3 (1.5 equiv) R AcOH (1 equiv) DMF + DMSO (5 % v/v) 120 o C, 40 min-2 h

Ar

Ar

R"

N

Pd(OAc)2 (2.5 mol %) Ag2CO3 (1.5 equiv) AcOH (1 equiv) DMF + DMSO (5 % v/v) 120 o C, 50 min-4 h

R

N R"

Representative examples OMe Ph

N N

Ph

O 2N N O

Ph

NO 2

N S

N AcO

68%

Scheme 7.20  Alkynylation using alkynes.

59%

51%

Pd C5

N OAc

7.2 C−C Bond Formation

7.2.4  Arylation 7.2.4.1  Copper Catalysis

A copper-catalyzed arylation of benzoxazoles has been carried out using 2-nitrobenzoic acids via decarboxylation [50]. As a series of benzoxazoles were subjected to this treatment, electron-rich substrates yielded good results. Investigation of the substrate scope implied the vital role of coordinating groups in the ortho-position for the desired decarboxylation. Soon after, a relatively sustainable method was demonstrated for the decarboxylative arylation of benzo-fused azoles with benzoic acids using molecular oxygen (Scheme 7.21) [51]. This copper-mediated protocol proceeded smoothly with benzothiazoles, benzoxazoles, and N-methyl benzimidazoles in presence of electron deficient benzoic acids, affording the anticipated hetero-biaryl scaffolds in good yields. The catalytic cycle involves the initial decarboxylation to afford XXV. With benzoxazole under the influence of a base and oxidant, this generates a copper(I) or copper(II) intermediate. Either of the two copper species undergoes further oxidation to generate the copper(III) intermediate XXVII, which upon reductive elimination produces the target product.

R

N X

+

Ar-COOH

X= S, O, NMe N Cl

O O 2N 78%

CuBr (30-60 mol %) 1,10-phenanthroline (30-60 mol %) K 2 CO 3 (1 equiv), toluene O 2 ,140 o C, 24 h Representative examples F N F O F 29% N

N Ar

X

N

I

Cu

N

III

Cu

N N

O 2N N Me 74%

CO2 N

N X XXVII

I

Cu Ar

N XXV

N

II

Cu

N

Ar

X N XXVIa N

or

+ base

X

metalation N

Ar

Ar CO2 H + base

N

oxidation

X

N

decarboxylation

reductive elimination Ar

N R

I

Cu

Ar

N XXVIb N

X

Scheme 7.21  Decarboxylative arylation using benzoic acids.

The substrate scope has been further extended to arylazines as the aryl source for the coupling with benzo-fused azoles using copper catalysis [52a]. This chelation assisted reaction involves sequential C(sp2)-H metalation of benzo-fused azole, C–H activation of arylazine, and reductive elimination to afford the biaryl products in good yields. Further, a one-pot protocol for synthesizing benzofused heteroaryl azoles was demonstrated via cross-coupling of benzoazoles with gem-dihaloolefins [52b]. Later, a 2-pyrimidyl (DG) assisted oxidative C2-arylation of indoles was achieved with benzoxazoles in presence of stoichiometric amount of Cu(OAc)2 and AcOH under air (Scheme 7.22) [53a]. The reaction proceeds through carboxylate ligand-assisted cupration of azole to produce XXVIII, which leads to the formation of bis(heteroaryl)copper species XXIX via chelation assisted C–H activation. Oxygen-promoted reductive elimination of the latter delivers the product with concomitant regeneration of the copper complex. Similarly, a C6-selective heteroarylation of 2-pyridones with

333

334

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms R' N

Cu(OAc)2 (0.2-3 equiv) AcOH (1-4 equiv)

X

o-xylene, 150 o C, 4-6 h

+

R'' N

R

2-Pym

R' N R'' N 2-Pym

X = O, S, NMe

X

R

Representative examples NO2

N

MeO

CN

N

N O 2-Pym

N

N

O

N

2-Pym 75%

67%

O

2-Pym 81% N

N , H 2O

N X 2-Pym

X

L nCu(OAc)2

AcOH, O2

AcOH Ln Cu

N XXIX N

N

N

X

X XXVIII

N

Cu(OAc)Ln

AcOH N 2-Pym

Scheme 7.22  Oxidative C2-arylation of indoles with benzo-fused oxazoles.

benzo-fused azoles was documented in presence of Cu(OAc)2 using removable pyridyl DG (Scheme 7.23) [53b]. Further, a copper-mediated oxidative C(sp3)-H/C(sp2)-H coupling of carboxamide-pyridine N-oxides has been shown with azoles via N,O-bidentate chelation (Scheme 7.24) [54]. Diversely substituted benzoxazoles and amides were found to be compatible in moderate to good yields. The removal of the DG provides a straightforward route to access potent β-azolyl propanoic acids. 7.2.4.2  Nickel Catalysis

A nickel-catalyzed arylation of benzothiazoles and benzoxazoles has been achieved using aryl bromides [55]. A bulkier (2,9-dimethyl-1,10-phenanthroline hydrate) with NiBr2·diglyme and zinc powder produced the best results. The substrate scope could be extended to aryl iodides, chlorides, and triflates using Ni(OAc)2/2,2-bipyridine [56]. Later, the arylation of benzo-fused azoles was successful using trimethoxyarylsilane (Scheme 7.25) [57]. Using NiBr2•diglyme/2,2ʹ-bipyridyl, a set of trimethoxyarylsilanes was surveyed. Electron-rich and sterically congested arylsilanes displayed grater reactivity over electron-withdrawing ones. The adequacy of the hypothesis was extended to benzothiazoles and N-substituted benzimidazoles. Initial metalation of benzoxazole in presence of CsF gives nickel(II) intermediate XXX. The in situ generated silyl species XXXII undergoes transmetalation with XXX to afford XXXI, which upon reductive elimination offers the biarylated product and nickel(0) species.

7.2 C−C Bond Formation R

R O

N

N

Cu(OAc)2 (3 equiv) PivOH (1 equiv)

X

o-xylene, 150 o C, 20 h

+ N

R'

O

N

N N

X

X = O, S, NMe Me

O

R'

Representative examples CF3

CF3 O

N

N N

N

N

O

N

N

S

N

66%

O

N

N

Me 34%

37%

Scheme 7.23  Dehydrogenative C6-heteroarylation of 2-pyridones with benzo-fused azoles.

R'

N

N H

R''

Cu(OAc) 2 H 2O (1.5 equiv) K 2CO3 (2.2 equiv)

N

O

+ X

O

H

R

X = O, S, NR"'

O R'

N H N

R''

PivOH (0.5 equiv) o-xylene, 140 o C, 24 h

Py

X

Representative examples O Me

N H N

Et

O

O

Py

n

Pr Pr

N H N

n

O

Ph

Py

N H N

Me O

O

70%

66%

72%

Scheme 7.24  Direct oxidative coupling of carboxamide-pyridine N-oxides with azoles.

N R

+

X

ArSi(OR)3

X = S, O, NMe

NiBr 2 diglyme (10 mol %) 2,2'-bipyridyl (10 mol %) CsF (3 equiv), CuF2 (2 equiv) DMAc, 150 oC, 2.5 h

N

R

X ArSi(OR)3

N N

CsF

NiBr

X XXX

+ CsF

(RO) 3Si Ar F XXXII

X N X

NiBr2

CuF2

NiAr XXXI

Ni(0)

N X

Scheme 7.25  Arylation using trimethoxyarylsilane.

Ar

Ar

Py

t Bu

335

336

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms

The substrate scope of nickel-catalyzed arylation has been further extended to carbonates as aryl source [58]. Using Ni(cod)2/1,2-bis-(dicyclohexylphsophino)ethane, the arylation of benzoxazole and benzothiazole has been successfully achieved. Gratifyingly, several aryl carbonates including those bearing reactive functional groups were found to be amenable to this treatment. This method could be utilized for the coupling quinine triflate as the aryl source. Subsequently, the arylation has been found to be successful with aryl esters (Scheme 7.26) [59]. Aryl esters comprising hetero-aryl scaffolds such as thiophenyl, furyl, and pyridinyl could be coupled. The oxidative addition of nickel(0) to the C-O bond of phenyl ester affords XXXIII, which upon subsequent CO migration generates XXXIV. C–H nickelation of benzoxazole with XXXIV generates XXXV and the reductive elimination of XXXV delivers the target product. Later, a relatively greener approach for the arylation of benzimidazoles has been achieved using aryl methyl ethers as the electrophilic aryl surrogates under nickel-catalysis (Scheme 7.27) [60]. DFT studies confirmed that the synergistic effect of nickel and Grignard reagent accomplished the task of C-O cleavage. The sterically bulkier Grignard reagents lower the energy barrier for the C-O bond cleavage to promote the arylation. Under these conditions, substrates possessing electron withdrawing groups were unsuccessful.

N

R

+ ArCOOPh

O

Ni(cod)2 (10 mol %) dcype (20 mol %)

N

R K 3 PO 4 (2 equiv) o 1,4-dioxane, 150 C, 24 h

Ar

O

[Ni]0

CO

(CO)n n = 0 or 1

ArCOOPh

[Ni]0 O

(CO) n+1

Ar

PhO [Ni]

XXXIII (CO)n

N

Ar

O

N O XXXV

Ar [Ni]

Ar PhO [Ni] XXXIV (CO) n+1

(CO) n+1

N

PhOH

O

Scheme 7.26  Arylation using aryl esters.

N

R

N Me

+

Ar-OMe

Ni(cod)2 (10 mol %) IPr (10 mol %) o-tolylMgBr (1.5 equiv) LiCl (1 equiv) m-xylene, 90 oC, 16 h

R

N N Me

Ar

Representative examples N

N

N Me

N Me

92%

TMS

50%

Scheme 7.27  Arylation using aryl methyl ethers.

N N Me 66%

Me

7.2 C−C Bond Formation

7.2.4.3  Cobalt Catalysis

A cobalt(II)-catalyzed oxidative C–H/C–H coupling of benzo-fused azoles with carboxamides has been demonstrated with 8-aminoquinolinamide DG (Scheme 7.28) [61]. A variety of benzoxazole substrates were used efficiently. The H/D exchange, the kinetic isotope effect, radical trapping, and electron paramagnetic resonance (EPR) studies provided insight into the reaction pathway.

O

N +

N H

Ar/ Het

Co(OAc) 2 4H2 O (0.5-6 mol %) Ag2 CO 3 (1.5 equiv)

R X = NR', O, S

N Q H N O 81%

N Q H N

S Me O 87%

N H N

Ar/ Het

N

X R

Representative examples O

O S

PivOH (1.0 equiv), toluene, 120-150 o C, 6-24 h

X

N

O

O N Q H N

S MeO O 74%

Scheme 7.28  Arylation using 8-aminoquinoline amide directing group.

7.2.4.4  Iron Catalysis

Iron-catalyzed arylation of benzothiazoles has been accomplished with boronic acids [62]. The reaction utilizes Fe(NO3)3 as the catalyst and K2S2O8 as oxidant under air. The reaction is scalable and coupling of a broad range of boronic acids has been covered. 7.2.4.5  Palladium Catalysis

A palladium-catalyzed arylation of benzoxazoles has been achieved utilizing aryl tosylates as the arylating agent [63]. Screening of aryl tosylates revealed that both electron-donating and withdrawing substituents on the aryl motif were equipotent in producing the target products in good to excellent yields. The substrate scope has been extended towards mesylates as the potential arylating agent to generate the C2 arylated benzoxazoles. Subsequently, a palladium-catalyzed decarboxylative arylation of benzothiazole has been accomplished with substituted benzoic acids [64]. PdCl2 along with PPh3 was chosen as the catalytic system and a set of benzoic acids with diverse substituents proved compatible with benzothiazoles and benzoxazoles. However, N-methyl benzimidazole was an unsuccessful substrate. Later, a palladium-catalyzed decarboxylative arylation of benzothiazoles and benzoxazoles has been reported implementing 1,2,3-triazole tethered carboxylic acids as arylating agent (Scheme 7.29.) [65]. Among several substituted carboxylic acids tested, functional groups on the N-1-aryl ring of the trizole motif had a more significant effect compared with the C-4 aryl one. Furthermore, a palladium-catalyzed arylation of benzoxazoles and benzothiazoles has been described with aryl iodides [66]. A cationic [Pd(phen)2](PF6)2 in presence of a base showed tremendous activity towards this arylation. An array of aryl iodides with distinct electronic functionalities on the aryl ring furnished the product in excellent yield. Heteroaryl iodides such as pyridyl and thienyl could be coupled efficiently. Further, the arylation of benzimidazoles using readily available aryl chlorides has been demonstrated [67]. NHC-Pd(II)-Im complex was identified as the promising catalytic system. A variety of N-substituted benzimidazoles and substituted aryl chlorides were subjected to this treatment to produce good to excellent yields. Further, the arylation of benzoxazole has been successful using aryltrimethylammoinum triflate as a potential arylation source (Scheme 7.30) [68]. The reaction utilized [Pd(π-allyl)Cl]2 with aryltrimethylammonium salts derived from naphthyl, anthracenyl, and electron-rich phenyl moieties. In case of phenyltrimethylammonium salts with electron withdrawing group IPr•HCl produced superior results versus PCy3. Moreover, benzothiazole could be arylated with 1-naphthyltrimethylammonium triflate using PCy3. The palladium(0) species XXXVI undergoes oxidative addition with aryltrimethylammonium triflates to give XXXVII. The base promoted C–H palladation of benzo-fused azole with XXXVII generates XXXVIII, which upon reductive elimination yields the C2-arylated product.

337

338

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms

N

R

+

X X = O, S

COOH

PdCl 2 (10 mol %) PPh3 (20 mol %)

N N N

Ag2CO3 (3 equiv) DMSO, N2 , 150 oC

Ar

N

S

O2 N

N N N

N

R

Representative examples N

N

N

S

O

Ar

N N N

N N N

F

N

X N

F

74%

58% Me

63%

Scheme 7.29  Decarboxylative arylation using 1,2,3-triazol carboxylic acids.

N R

+ Ar-NMe3 OTf

X X= O, S

[Pd(π-allyl)Cl]2 (5 mol %) L5 (5 mol %)

N

R

t

NaO Bu (2 equiv) DMF, 120 o C, 12 h

L5 = PCy3 or IPr HCl Representative examples

N OMe

O 82%

N

O

N

O

Ph

S

80% [Pd(π-allyl)Cl] 2 NaO t Bu

NMe3 OTf

Pd0 L XXXVI N

Ar

X

Oxidative addition

Ar

X L Pd

NMe3 L Pd

X

N XXXVIII

OTf

XXXVII C-H Palladation

NaOTf + t BuOH

N X

+ NaOt Bu

Scheme 7.30  Arylation using aryltrimethylammoinum triflate.

97%

7.2 C−C Bond Formation

The C2-heteroarylation of benzoxazoles with varied azole moieties containing nitrogen, oxygen, and sulfur atoms was reported (Scheme 7.31) [69]. This versatile cross-coupling occurs under palladium-catalysis and the regioselectivity is administered by the acidity of the C–H proton at the C2-position of the azoles. A combination of Cu2+, Ag+, and acetate ions under air produced the unsymmetrical 2,2ʹ-bisheteroaryls in good to excellent yields. The presence of the silver salt attenuated the homo-coupling and favoured the formation of the cross-coupled product under ambient conditions. This direct oxidative C–H/C–H cross-coupling methodology showed wide substrate scope and good functional group tolerance. The strategy has been extended to the oxidative C–H/C–H coupling of benzothiazoles with thiazoles/thiophenes [70]. This cross-dehydrogenative coupling successfully generated the coupled bi-heteroarenes in excellent yields when carried out under palladium-catalysis and was found to be air and moisture stable, exhibiting broad functional group tolerance. A wide variation of the substrate scope was observed for both of the coupling partners, with both electron-donating and withdrawing groups being well tolerated.

N

R R

N

Y

N R''

N

R'

N R''

S

Y N

Conditions A or B Cu(OAc)2 (2 equiv) DMF, air, 120 o C

S

N Me 86 %

N

R'

Representative examples Br

Me Me

N

Y

S

N

Condition A : Pd(OAc)2 (5 mol %) KF/AgNO 3 (3 + 1.5 equiv), 24 h

Condition B : Pd(OAc) (10 mol %), AgF (2 equiv), 24-48 h

N

N

N

O

S 71 %

N

N

Me N

S

N

Cl

95 %

Scheme 7.31  Dehydrogenative coupling using azoles.

An efficient method for the synthesis of 2-arylbenzoxazoles under palladium-catalysis via simple cross-coupling between benzoxazoles and arenes has been developed (Scheme 7.32) [71]. Optimization studies revealed the inevitable role of CuBr2 in carrying out the reaction in which it acts not only as an oxidant to palladium but also to accelerate the reaction by enhancing the C–H acidity of the benzoxazole. The demonstrated protocol could successfully be applied to a set of benzoxazoles as well as arene moieties to give the bis-arylated product in good to excellent yields under air.

R

N

Ar-H

O

Pd(OAc) 2 (10 mol %) CuBr2 (2 equiv), O2 (1 atm)

R

K 3 PO 4 (2 equiv), PivOH (3 equiv) DMA, 120 o C, 48 h

N O

Representative examples tBu

N O 94 %

CF3 Ph

N O

Ph

Me

66 %

Scheme 7.32  Dehydrogenative cross-coupling using arenes.

Ar

F N O 76 %

F

339

340

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms

7.2.4.6  Rhodium Catalysis

Transition metal-catalyzed regioselctive C–H arylation is a potent synthetic route to furnish 2-aryl benzo-fused azoles. A rhodium(I)-catalyzed arylation of benzo-fused azoles has been investigated using aryl bromide as the aryl source (Scheme 7.33) [72]. The procedure is compatible for aryl bromides having functional groups like sulfonyl, chloro, acetamide, hydroxy, and amines to afford C2-arylated compounds in good to excellent yields. The possible involvement of N-heterocyclic carbene rhodium-intermediate that has been discussed, that might be formed as a result of C–H activation/ tautomerization.

t

N

R

+

[RhCl(coe) 2] 2 (20 mol %) L3 (0.15 equiv)

ArBr i

X X= NR', O, S

Pr2iBuN (3 equiv), THF W (200 oC), 2 h

R

Bu P

N X

Ar L3

Representative examples N N H 93%

CF3

O S Me

N N H

60%

N

Ph

O 66%

Scheme 7.33  Arylation using aryl bromides.

7.3 C−N Bond Formation Aza-(hetero)aromatic compounds have acquired importance in organic synthesis owing to their omnipresence in bioactive molecules [73]. For example, the compounds having aza motif are utilized as the dopamine antagonists, anti-inflammatories, and antibiotics [74]. In this context, much attention has been devoted for the development of effective synthetic tools for their preparation [75]. Transition metal-catalyzed cross-coupling reaction has provided a robust and effective approach for the amination of (hetero)aryl halides or sulfonates [76]. However, the requirement of pre-functionalized substrates limits their potential applications. Therefore, a recent surge in interest has been observed for performing C–H functionalization of at least one of the two coupling partners. This will not only improve the efficacy of the coupling-based methods but also obviate the necessity of a pre-functionalized substrate.

7.3.1  Copper Catalysis A copper-catalyzed oxidative amination of benzoxazoles has been accomplished via C–H/N-H dehydrogenative cross-coupling (Scheme 7.34) [77]. The reaction used Cu(OAc)2 with PPh3 as the catalyst and oxygen as the oxidant at elevated temperature. The substrate scope can be extended to benzothiazoles and 2-methylbenzimidazoles. The reaction of a series of aliphatic amines including piperidine and diethylamine has been explored. The base-promoted C–H activation of azole produces an organocopper XXXIX, which undergoes nucleophilic substitution by the amine to give XL. Subsequent reductive elimination generates the product along with copper(I) species, which is oxidized to copper(II) to complete the catalytic cycle. Later, the oxidative C–H amination of benzo-fused azoles with a set of aliphatic and aromatic amines has been achieved in good yields [78]. This reaction utilized Cu(acac)2 as the catalyst and molecular oxygen as the oxidant at an elevated temperature (140°C). CuBr2catalyzed amination was later documented using oxygen as the oxidant in the presence of AcOH at a moderate temperature [79]. Furthermore, copper(II)-exchanged zeolite, Cu/H-USY, has been used to accomplish the amination in HFIP at moderate temperature [80]. The advantages of this approach include the recyclability of the catalyst and the aerobic conditions. Efforts have been made to develop the copper-catalzyed electrophilic amination of benzoxazoles employing O-benzoyl hydroxylamines (Scheme 7.35) [81]. The reaction utilized CuCl with PPh3 as the catalyst and tBuOLi as the base at room temperature. O-benzoyl hydroxylamine derived from a secondary amine exhibited greater reactivity compared to that produced from a primary amine. In this reaction, copper(I) complex reacts with tert-butoxide to generate the copper(I)-tert-butoxide XLI, which reacts with the benzoxazole to give the copper(I) species XLII. The oxidative addition of XLII with O-benzoylhydroxylamine can lead to the formation of XLIII, which can give the product by reductive elimination. Later, the amination of benzoxazole has been accomplished using dialkyl formamide as the amine source via decarbonylation at elevated temperature [82]. This reaction involved

7.3 C−N Bond Formation N

R

HN

X

R'

Cu(OAc)2 (20 mol %) PPh3 (40 mol %)

R''

O2 (1 atm), xylene, 140 oC, 40 h

X = NR''', O, S

N

S

N

X

R' R''

Representative examples n

N

N

R

N

Pr

Ts

65%

N X

O 71% + Base

N

N

Me Ph

N 51% Me

N

X

Me Ph

BaseH+X -

Ar LnCuII XXXIX X R' HN + Base R''

LnCuII X2

N

N

BaseH+X -

R' R''

Ar

LnCuII

1/2O2 + 2BaseH +X-

XL NR'R''

Scheme 7.34  Amination using amines.

Cu(OAc)2•H2O as the catalyst and aryl carboxylic acid as the additive under molecular oxygen. The substrate scope has been expanded to N-methyl benzimidazoles using two-step and one-pot process at room temperature (Scheme 7.36) [83]. In this reaction, N-methyl benzimidazole reacts with Zn(tmp)2 to produce organozinc, which reacts with BzONRR using copper(II) catalysis to produce the 2-aminobenzimidazoles. The strategy has been found to be expedient for both electron-rich and electron-deficient benzimidazoles. Functionalities such as halide, ester, nitro groups, and nitriles are well tolerated due to selective zinc metalation.

O R

O

N

Ph

O

R' N

CuCl (5 mol %) PPh3 (10 mol %) t BuOLi (3 equiv) R''

O

R

THF, rt, 1h

N

N

Representative examples O

O

N

N

N

Me N

O Ph

75%

91%

N

O2 N

N

61% CuCl/PPh3 LiOtBu LiOBz

LiOtBu

LiCl I

[Cu ]OtBu XLI

[CuI]OBz O N

N

O N

R' R''

O N

[CuIII ] XLIII

OBz

HOtBu

O

N R' R''

N O Ph

O

R' N

[CuI] XLII

R''

Scheme 7.35  Amination using o-benzoyl hydroxylamines.

R' R''

341

342

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms

R

N

1) Zn(tmp)2, THF, rt

N Me

2) BzO-NR'R'' (1 equiv) Cu(OAc)2 (10 mol %), rt

R

N N Me

R' N R''

Representative examples N N Me 67%

N

N

N

NBoc

N

N Me

N Me 80%

N

O

96%

Scheme 7.36  Zn/Cu-catalyzed amination of benzimidazoles.

Furthermore, the C–H functionalization of benzimidazoles has been accomplished via a copper(II)-mediated oxidative coupling with diverse nitrogen nucleophiles [84]. The reaction used 20–200 mol % Cu(OAc)2 with pyridine as the additive and Na2CO3 as the base at elevated temperature. Cyclic amides, urea, and carbamate nucleophiles showed superior reactivity compared with acyclic secondary amines. Later, the amination of benzoxazoles was achieved using tertiary amines via oxidative C–H and C-N bond activation (Scheme 7.37) [85]. The reaction employed CuBr2 as the catalyst, AcOH as the additive, and molecular oxygen as the oxidant at elevated temperature. Tertiary amines having α-H adjacent to the nitrogen atom can be used as the substrates. The reaction well-tolerates simple alkyl as well as unsaturated allyl amines and is more facile with less sterically hindered alkyl substituents.

N

R

+

R'

O

N R "'

R''

CuBr2 (10 mol %) AcOH (20 mol %) O 2 (1 atm), 1,4-dioxane

R

N O

N

R '' R "'

Representative examples N O

N

Ph Ph

0%

t-Bu

N O 32%

N

N O

Et N Et

87%

Scheme 7.37  Oxidative amination of benzoxazoles by tertiary amines.

Our group accomplished a tandem ring-opening/annulation of aziridines with benzimidazoles using copper(II)-catalysis (Scheme 7.38) [86]. The ring-opening was achieved using Cu(OTf)2 at moderate temperature, whereas the oxidative C-H/ N-H dehydrogenative coupling was found to be effective employing Cu(OAc)2/PCy3 with Na2CO3 as the base and air as the oxidant at elevated temperature. Reverse selectivity was observed in case of alkyl aziridines, where ring opening and further cyclization occurred selectively at the sterically less hindered position. Optically active aziridines could be coupled stereospecifically with high enantiomeric purities. Further, a copper-catalysed cascade two-fold C-N bond formation has been accomplished via Ullman type C-N bond formation followed by C–H amination (Scheme 7.39) [87]. The reaction utilized Cu(OAc)2•H2O as the catalyst and oxygen as the oxidant under heating. The reaction of (hetero)aromatic and aliphatic bromides having both electron-donating and withdrawing groups has been accomplished in moderate to good yields. The substrate scope has been extended to the N-aryl ring of the indazole with diverse substituents. This strategy has been extended to the domino synthesis of heterocycle-fused benzimidazole and 1,2,4-benzothiadiazine 1,1-dioxides (Scheme 7.40) [88]. The reaction involves intermolecular N-arylation followed by the C–H/N-H dehydrogenative coupling at elevated temperature. Substrates with electron-donating substituents show greater reactivity compared to those bearing electron-withdrawing groups.

7.3.2  Iron Catalysis A FeCl3-catalyzed C–H amination of benzoxazoles has been accomplished utilizing formamide as the nitrogen source, imidazole as the additive, and air as the oxidant (Scheme 7.41) [89]. Benzoxazoles with electron-donating substituents

7.3 C−N Bond Formation

Ts N

1. Cu(OTf)2 (10 mol %) toluene, 80 o C, 2-3 h

N

R

N

2. Cu(OAc)2 (10 mol %) PCy3 (20 mol %) R Na2CO3 (2 equiv) m-xylene, 120 o C

N H

R' R' = alkyl or aryl

N

R or

N

Ts R' = aryl

R' N N

N

Ts R' = alkyl R'

Representative examples N N

N

N

Ts

N

71%

82%

N

N

Ts

N

N

Ts

71%

OMe

Scheme 7.38  Tandem ring-opening/cyclisation of aziridines with benzimidazoles.

Cu(OAc)2 H2 O (20 mol %) X-Phos (5 mol %)

N N R

+ R'

Br

DMF, 100 o C, 8h

R

H 2N N

N

N R'

Representative examples N

N

N

N

N

N

70% Me

72%

Br OMe

N

N N

70%

Scheme 7.39  Cascade two-fold C-N bond formation for synthesizing benzoimidazoindazoles.

O

S

O N H

Ar

Br

H N

CuI (20 mol %), L - Proline (20 mol %)

N

CH 3 ONa (2 equiv), O2 DMF, 130 o C,

R

O O S Ar N N

N

R Representative examples CF3

O O S N N

84%

N

OMe

O O S N N

95%

N

O O S Ph N

O O S Ph N N

N

OMe

N

MeO

95 %, (1:0.87)

Scheme 7.40  Synthesis of fused benzimidazole and 1,2,4-benzothiadiazine 1,1-dioxides.

343

344

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms O

O R

N

H

O

Me

FeCl3 (0.25 equiv)

R' N R''

O R

Imidazole (2 equiv) 12 h, 130 oC

N

N

R' R''

Representative examples

N

N

O

Me

O N

O

N

N

82%

63% O

O2

III

[Fe ]

tBu

72% O

Formamides

N

H N

N

R' N R''

II

[Fe ]

[FeIII] O N FeCl3 XLIV

O H

R' N R''

N H XLV

R' N R''

O [Fe] heat

H

N R"

R'

Scheme 7.41  Amination using Amides.

showed greater reactivity compared to those having electron withdrawing groups. Of the formamides, N,N-disubstituted formamide and a cyclic amino moiety gave the best results. Lewis acid chelates the benzoxazole to form XLIV, which undergoes addition with an amine to produce XLV. The latter undergoes oxidation to produce the target product. Iron(III) plays a dual role as a Lewis acid as well as a redox catalyst to furnish the 2-aminobenzofused azoles.

7.3.3  Miscellaneous Few studies are focused on the oxidative coupling of secondary amines with benzo-fused azoles to furnish 2-aminobenzofuzed azoles. A cobalt-catalyzed oxidative amination of benzoxazoles and benzothiazoles has been accomplished using aqueous tert-butyl hydroperoxide (TBHP) as oxidant and benzoic acid as additive [90]. Further, a nickel-catalyzed amination has been found to be successful using TBHP as the oxidant [91]. These reactions are effective at moderate temperature with broad substrate scope and functional group diversities.

7.4 C−P Bond Formation C-P bond forming reactions hold a special space in the synthetic domain owing to the omnipresence of organo-phosphorous motif in plethora of bioactive compounds and matrials [92]. In addition, phosphonates and their synthetic congeners have tremendous utility in synthetic chemistry [93].

7.4.1  Copper Catalysis The oxidative copper-catalyzed phosphonation of benzo-fused azoles has been performed using dialkyl phosphites in good yields (Scheme 7.42) [94]. The catalytic system having Cu(OH)2 with K2S2O8 as the oxidant is utilized for the reaction of

7.4 C−P Bond Formation O H P OR' OR'

N R

X

Condition A

MeO

N

MeO

S

Conditions A-B

X

Representative examples O N P O nBu O O n Bu

O iPr

OMe

O P OR' OR'

Condition B X= N-Pym CuBr (20 mol %) DTBP (3 equiv) (CH 2Cl) 2, 120 o C, 6 h

X= S, O Cu(OH) 2 (10 mol %) K2 S 2O 8 (3 equiv) MS 4Å, MeCN 120 oC, 2 h O P O iPr

N

R

44%

Me

N

Me

N O iPr Pym

66%

O P OiPr

59%

Scheme 7.42  Phosphonation using dialkyl phosphites.

benzoxazoles and benzothiazoles, whereas the CuBr-catalysis with DTBP as the oxidant has been employed for N-pyrimidyl benzimidazoles with moderate to good yields.

7.4.2  Manganese-Mediated Reaction A solvent free approach for the phosphorylation of benzothiazoles has been developed utilizing the ball milling technique (Scheme 7.43) [95]. This Mn(OAc)3-mediated reaction has been found to be successful for benzothiazoles in high yields; however, benzoxazoles and benzimidazoles are unsuccessful substrates. The reactions of diphenyl, dicyclohexyl, and dibutylphsophine oxides has been investigated. The phosphine oxide with manganese(III) may produce phosphoryl radical XLVI, which undergoes addition reaction to produce the radical XLVII. The latter can undergo oxidation using manganese(III) to produce the phosphorylated product via single electron transfer (SET).

S

R

N

MeO

N S

+

O H P(R')2

O PPh2

Mn(OAc)3 2H2 O ball mlling, 1.5 h under air Representative examples N N O PPh2 S S

Me 96%

90%

R

O P(R')2

S N

O P(4-FC 6H 4 )2

N S

O P(R')2

R' = Cyclohexyl, 66% = n-Butyl, 73%

94% S

O H P(R')2

Mn(III) -AcOH

O P(R')2 XLVI

N

S N XLVII

O P(R')2

Mn(III)

Product

-H

Scheme 7.43  Phosphorylation utilizing the ball milling strategy.

7.4.3  Silver-Mediated Reaction A silver-mediated phosphorylation of benzothiazoles has been investigated using diarylphosphine oxides at moderate temperature (Scheme 7.44) [96]. The reaction of a series of benzothiazoles with diverse substituents has been shown. The procedure shows great compatibility with mono- and di-substituted diarylphosphine oxides, whereas diethyl phosphonate

345

346

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms O + H P (R')2

N

R

S

AgNO3 (1 equiv) CH3 CN, 90 o C, 24h

N

R

S

O P (R')2

Representative examples N S

MeO

O P(Ph)2

MeO2 C

N S

86%

N

S 71%

92% Ag(I)

S

Ag(I)

H N

OH P(Ar) 2

S XLIX

N

Ag(I)

S XLVIII

O P(p-MeC 6H 4 )2

N

O P(Ph)2

O P(Ar)2

Ag(I) Product Ag(0)

O H P(Ar)2

Scheme 7.44  Phosphorylation using phosphine oxides.

ester produced inferior results. The coordination of the substrate to silver(I) can generate XLVIII, which undergoes nucleophilic addition of diphenylphospine oxide to give XLIX. The latter can undergo oxidation using silver(I) to yield the target product.

7.4.4  Palladium Catalysis A palladium-catalyzed phosphonation of benzoxazoles and benzothiazoles has been shown with dialkyl phosphites (Scheme 7.45) [97]. The reaction using Pd(OAc)2/L-proline is found to be effective for the reaction of benzothiazoles, whereas the Pd(OAc)2/2,2ʹ-bypridine produced the best results for benzoxazoles. The reactions have utilized K2S2O8 as the oxidant at 100°C with broad substrate scope and functional group diversities.

O H P (OR')2

N R

X X= O, S

Pd(OAc)2 (5 mol %) L5 or L6 (30 mol %) K 2 S2 O8 (3 equiv) MeCN, 100 o C, 24 h

N R

X

O P (OR') 2

L5 = L-proline, L6= 2,2'-bipyridine Representative examples N S

Me

O P(OEt) 2

41%

N S

O P(Oi Pr)2

64%

tBu

N O

O P(OEt)2

83%

Scheme 7.45  Phosphonation using dialkyl phosphites.

7.5 C−S Bond Formation Thiolated heteroaryls and their synthetic congeners are unique class of compounds having widespread occurrence in a plethora of bio-active natural products and synthetic materials [98]. In particular, C2-thiolated benzothiazoles are important structural motifs having a range of pharmaceutical activities [99].

7.5 C−S Bond Formation

7.5.1  Copper Catalysis The thiolation of benzoxazoles has been investigated utilizing diaryl disulphide as the sulfide source (Scheme 7.46) [100]. The reaction used CuI/2,2ʹ-bipyridine as the catalyst and Cs2CO3 as the optimal base under molecular oxygen. Diverse diaryl disulfides having both electron-donating and withdrawing groups successfully coupled in moderate to good yields. CuI with benzoxazole and Cs2CO3 can produce L, which reacts with diaryl disulfide to generate the copper(I) species LI. The latter can oxidize to copper(II) species LII, which can react with substrate to yield the product and copper(0) species that can be oxidized using molecular oxygen. The substrate scope has been expanded to benzothizoles utilizing CuO nanoparticles at elevated temperature [101]. The reaction of broad range of diaryl and dialkyl disulfides has been demonstrated in good yields.

CuI (20 mol %) 2,2'-bipyridine (20 mol %)

N

R

+ ArSSAr

O Me

Ph

N O

Cs2 CO 3 (4 equiv) DMF, O2 , 80 oC, 2 h Representative examples N

S

O

49%

S

p-OMeC6 H 4

N

S

p-ClC 6 H4

O 54% N

O 2, I CuI Ar

S

O

71%

N

Ar

N

R

O

and Cs2CO3 Cs2 CO3 •HI

Cu(0)

S

O N

N O

Cu

SAr

LIII

L

O

Cu ArSSAr

Cs2 CO 3 • HI N O and Cs2CO3

N ArSCuI LII

ArSCu LI

Ar S

O

O2 , I

Scheme 7.46  Thiolation of benzoxazoles utilizing diaryl disulphide.

Efforts have been made to use of thiols for the thiolation of benzo-fused azoles. The CuBr2/2,2ʹ-bipyridine catalytic system has been utilized for the thiolation of benzoxazoles with arylthiols in presence of Cs2CO3 as a base [100]. Subsequently, the combination of Cu(OAc)2 and CuO has been explored for the thiolation benzoxazoles, benzothiazoles, and benzimidazoles with aliphatic thiols at elevated temperature [102]. The reaction of primary and secondary aliphatic thiols has been accomplished, whereas aryl and sterically demanding aliphatic thiols produced inferior results. Meanwhile, CuI/2-2ʹbipyridine has been utilized for thiolation of benzothiazoles with alkyl/aryl thiols at elevated temperatures [103]. This procedure efficiently coupled both alkyl/aryl thiols with benzothiazoles and benzimidazoles in good to excellent yields. Later, the thiolation of benzothiazoles was studied employing NHC–CuI in the presence of K2CO3 as the base [104]. Both aryl/alkyl thiols successfully coupled under air to produce the thioethers in quantitative yield.

347

348

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms

Effort is being made to develop methods for the direct C2-thiolation of benzothiazoles using aryl iodides and sulfur powder (Scheme 7.47) [105]. p-Substituted aryl iodides exhibited greater reactivity compared to m- and o-substituted ones. Aryl iodide with sulfur produces diaryl disulphide, which reacts with LIV to produce the thioether. Furthermore, LV can oxidize to LVI, which can react with benzothiazole to afford LVII. The latter can undergo reductive elimination to give the product and copper(0) species, which can be oxidized to CuI to complete the catalytic cycle.

S

R

ArI

+

N

S CuI (30 mol %) 1,10-phenanthroline (30 mol %)

S

OMe

54%

SAr

N

Representative examples S O 2N S N CF 3 38%

S N

S

R

KOH (4 equiv), DMSO O2 , 130 oC, 7 h

S N

SPh

41% S

CuI

O2 , I S N

KOH,

N KI, H2 O

SAr

S

S N

ArI + S

Cu(0)

Cu

N LIV

SAr

LVII

Cu KOH

ArSSAr

DMSO S

KI, H 2O

N

SAr

ArSCu S KOH,

N

LV

ArSCuI LVI O2 , I

Scheme 7.47  Thiolation of benzothiazoles in presence of iodobenzene and sulphur.

7.5.2  Iron Catalysis A recyclable Fe3O4-nano-catalyzed thiolation of benzothiazoles has been accomplished using diaryl disulphides [106]. The reaction has been performed using K2CO3 as base at 120°C and scalable. The reaction of diverse disulfides and benzothiazoles has been covered.

7.5.3  Silver Catalysis A base-free, silver(I)-catalyzed thiolation of benzoxazoles has been achieved utilizing thiols under neutral conditions [107]. In presence of stoichiometric Cu(OAc)2 as mediator/oxidant a library of benzothiazoles, benzoxazoles, and benzimidazoles were converted to their respective thioethers in good yields. It is worth mentioning that aliphatic, aryl, benzyl, and heteroaryl thiols smoothly afforded the desired products.

7.7 C−Halogen Bond Formation

7.5.4  Rhodium Catalysis Rhodium catalysis has been utilized for the C2-thiolation of benzothiazoles and benzoxazoles with α-(phenylthio)isobutyrophenones (Scheme 7.48) [108]. The unsubstituted and p-tolylthio substrates showed superior reactivity. The transformation was successful with various six-substituted 1,3-benzothiazoles in high yield. In case of five- and six-substituted 1,3-benzoxazoles, the substrate with the electron-donating substituent delivered superior reactivity over that having the electron-withdrawing group.

O

N R

X

+ Ph

X= S, O N

RhH(PPh3 )4 (4 mol %) Me dppe (8 mol %) Me C 6H 5 Cl, reflux, 3 h SR'

X

SR'

Representative examples N

S

S

N

R

S

CF3

91%

N SPh

O

MeO

92%

SPh

70%

Me

Scheme 7.48  Thiolation using α-(phenylthio)isobutyrophenone.

7.6 C−O Bond Formation Development of synthetic routes for C-O bond formation is important as this motif is present in numerous natural products and biologically active compounds [109]. Copper(I) catalysis has been utilized for the C2-H functionalization of benzofused azoles with alcohols under oxidative conditions (Scheme 7.49) [110]. Intramolecular alkoxylation of benzimidazoles has been successful using CuCl with di-tert-butyl peroxide (DTBP) at moderate temperature. Tertiary alcohol supported the alkoxylation reaction, whereas primary and secondary alcohols were unsuccessful substrates. The substrate scope has been extended to the intermolecular reaction of benzothiazoles and benzimidazoles with 2-phenylethanols using phenanthroline ligand. Me R

R

N

n

N

OH CuCl (5 mol %) ( tBuO) 2 (2 equiv) o

toluene, 80-100 C 6-12 h HO

R

X N X = S, -NMe

R

N

n

Me R O

N

R'

CuCl (5 mol %) (t BuO)2 (2 equiv) L7, toluene, 100-115 o C 12 h

R

X

O

R'

N

L7= 3,4,7,8-tetramethyl-1,10-phenanthroline

Scheme 7.49  Intra- and intermolecular alkoxylation of benzoxazoles.

7.7 C−Halogen Bond Formation Halogenated heteroarenes are easy targets for transition metal-catalyzed cross-couplings to generate functionalized biaryls, which have great significance in the synthetic domain [111]. In this realm, LiTMP/ZnCl2•TMEDA mediated

349

350

7  Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms

iodination of benzoxazole and benzothiazole has been performed with molecular iodine [112]. A similar iodination has been demonstrated using the combination of LiTMP and CdCl2•TMEDA, which uses (TMP)3CdLi as the active species [113]. These procedures solely depend on strong basic conditions, thus limiting their potential applications. A copper-catalyzed direct iodination of functionalized 1,3-benzofuzed azoles has been performed using iodine (Scheme 7.50) [114]. In this reaction, a mixture of LiOtBu and 1,10-phenanthroline in presence of CuBr2 efficiently transformed a series of benzoxazoles to their C2-iodination products. Compared with electron-donating groups, electron-withdrawing groups at the 5-position of benzoxazoles produced lower yields. In addition, benzothiazole and benzimidazole can be iodinated in moderate yields. Coordination of copper salt to the benzoxazole and subsequent deprotonation in presence of LiOtBu/1,10phenanthroline can produce copper species LVIII that can react with iodine to produce the target product.

t

BuOLi (2 equiv) 1,10-phenanthroline (1 equiv)

N

R

I2

X

CuBr2 (10 mol %) 1,4-dioxane, 60-80 oC

X= S, O, NMe

N

R

I

X

Representative examples t-Bu

N

N O

I

N

I

S

74%

55%

15%

N Me

I

N [Cu] N X

tBu

O

Li

N

H

N X LVIII

+δ −δ Cu I I [Cu]

N

I

X I

Scheme 7.50  Iodination of benzoxazoles using iodine.

7.8  Conclusions and Outlook This chapter highlights the notable advancements in C–H functionalization of benzo-fused azoles. Further, these C–H functionalization reactions have demonstrated a high tolerance to reactive functional groups, particularly halo, nitro, and ester moieties. A large library of C−C/N/P/S/O/I bonds have been successfully formed, coupled with mechanistic rationalizations of the key methodologies that provide a better understanding of the chemical process. The insertion of a DG, modulation of the steric/electronic impact of substrates, and/or catalytic system have helped to alleviate regioselectivity concerns. A variety of third-row and precious late transition metal catalysts are commonly utilized and the exploitation of eco-benign techniques (photocatalysis, electrocatalysis, biomass-derived solvents, and reusable heterogeneous catalysts) will be an important research topic in future study. Further, the chiral ligand enabled asymmetric syntheses are still in their infancy and offer a synthetic gap for investigation. Finally, we foresee that this chapter will address new ideas, stimulate further advancements, and assist broad readers in taking it to the next level.

Acknowledgments One of us (T.A.S.) thanks the science and engineering research board (SERB) for the national postdoctoral fellowship (PDF/2017/2653).

References

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100 Fukuzawa, S., Shimizu, E., Atsuumi, Y. et al. (2009). Copper-catalyzed direct thiolation of benzoxazole with diaryl disulfides and aryl thiols. Tetrahedron Letters 50 (20): 2374–2376. 101 Rosario, A. R., Casola, K. K., Oliveira, C. E. S. et al. (2013). Copper oxide nanoparticle-catalyzed chalcogenation of the carbon-hydrogen bond in thiazoles: synthesis of 2-(organochalcogen)thiazoles. Advanced Synthesis and Catalysis 355 (14–15): 2960–2966. 102 Zhou, A. X., Liu, X. Y., Yang, K. et al. (2011). Copper-catalyzed direct thiolation of azoles with aliphatic thiols. Organic and Biomolecular Chemistry 9 (15): 5456–5462. 103 Ranjit, S., Lee, R., Heryadi, D. et al. (2011). Copper-mediated C–H activation/C–S cross-coupling of heterocycles with thiols. The Journal of Organic Chemistry 76 (21): 8999–9007. 104 Inomata, H., Toh, A., Mitsui, T. et al. (2013). N-heterocyclic carbene copper(I) complex-catalyzed direct C–H thiolation of benzothiazoles. Tetrahedron Letters 54 (35): 4729–4731. 105 Wang, X., Li, Y., and Yuan, Y. (2013). The direct thiolation of benzothiazole catalyzed by copper complex in superbase system. Synthesis 45 (9): 1247–1255. 106 Rafique, J., Saba, S., Frizon, T. E. A. et al. (2018). Fe3O4 nanoparticles: A robust and magnetically recoverable catalyst for direct C–H bond selenylation and sulfenylation of benzothiazoles. ChemistrySelect 3 (1): 328–334. 107 Dai, C., Xu, Z., Huang, F. et al. (2012). Lewis acid-catalyzed, copper(II)-mediated synthesis of heteroaryl thioethers under base-free conditions. The Journal of Organic Chemistry 77 (9): 4414–4419. 108 Arisawa, M., Toriyama, F., and Yamaguchi, M. (2011). Rhodium-catalyzed phenylthiolation reaction of heteroaromatic compounds using α-(phenylthio)isobutyrophenone. Tetrahedron Letters 52 (18): 2344–2347. 109 Delost, M. D., Smith, D. T., Anderson, B. J. et al. (2018). From oxiranes to oligomers: Architectures of U.S. FDA approved pharmaceuticals containing oxygen heterocycles. Journal of Medicinal Chemistry 61 (24): 10996–11020. 110 Takemura, N., Kuninobu, Y., and Kanai, M. (2013). Copper-catalyzed C–H alkoxylation of azoles. Organic Letters 15 (4): 844–847. 111 Alberico, D., Scott, M. E., and Lautens, M. (2007). Aryl−aryl bond formation by transition-metal-catalyzed direct arylation. Chemical Reviews 107 (1): 174–238. 112 L’Helgoual’c, J.-M., Seggio, A., and Chevallier, F. (2008). Deprotonative metalation of five-membered aromatic heterocycles using mixed lithium-zinc species. The Journal of Organic Chemistry 73 (1): 177–183. 113 L’Helgoual’ch, J. M., Bentabed-Ababsa, G., Chevallier, F. et al. (2008). Deprotonative cadmation of functionalized aromatics. Chemical Communications (42): 5375–5377. 114 Zhao, X., Ding, F., Li, J. et al. (2015). Direct C–H iodination of 1,3-azoles catalysed by CuBr2. Tetrahedron Letters 56 (3): 511–513.

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles Edited by Tharmalingam Punniyamurthy

Indian Institute of Technology Guwahati Guwahati, India

Anil Kumar

Birla Institute of Technology and Science, Pilani Pilani, India

Volume 2

This edition first published 2023 © 2023 John Wiley & Sons, Inc. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Tharmalingam Punniyamurthy, Anil Kumar to be identified as the author(s) of the editorial material in this work has been asserted in accordance with law. Registered Office John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats. Trademarks: Wiley and the Wiley logo are trademarks or registered trademarks of John Wiley & Sons, Inc. and/or its affiliates in the United States and other countries and may not be used without written permission. All other trademarks are the property of their respective owners. John Wiley & Sons, Inc. is not associated with any product or vendor mentioned in this book. Limit of Liability/Disclaimer of Warranty In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. A catalogue record for this book is available from the Library of Congress Hardback ISBN: 9781119774136; Set ISBN: 9781394180981 (Volume 2); ePub ISBN: 9781119774150; ePDF ISBN: 9781119774143; oBook ISBN: 9781119774167 Cover image: © zhengshun tang/Getty Images; Courtesy of Tharmalingam Punniyamurthy and Anil Kumar Cover design by Wiley Set in 9.5/12.5pt STIX Two Text by Integra Software Services Pvt. Ltd, Pondicherry, India

v

Contents List of Contributors 8 8.1 8.2 8.2.1 8.2.2 8.2.2.1 8.2.2.2 8.2.2.3 8.2.3 8.2.4 8.3 8.3.1 8.3.2 8.3.3 8.3.4 8.4 8.4.1 8.4.2 8.4.3 8.4.4 8.5 8.6 9 9.1 9.2 9.2.1 9.2.2 9.2.3 9.2.4 9.2.5 9.3 9.4 9.5 9.6 9.7

xiii

Functionalization of Pyridines, Quinolines, and Isoquinolines Jun Zhou and Bing-Feng Shi Introduction 357 C2-Selective Functionalization 358 Alkylation 358 Arylation 361 Pyridine Derivatives as Substrates 361 Pyridine N-oxides as Substrates 363 N-iminopyridinium Ylides as Substrates 365 Alkenylation 365 Acylation, Amination, and Aminomethylation 367 C3-Selective Functionalization 370 Alkylation 370 Arylation 371 Alkenylation 374 Borylation 377 C4-Selective Functionalization 378 Alkylation 378 Arylation 380 Alkenylation 381 Borylation 382 C8-Selective Functionalization 382 Summary and Conclusions 387

357

Transition Metal-Catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives 393 Christian Bruneau and Rafael Gramage-Doria Introduction 393 Carbon-carbon Bond Formation 394 C-H Bond (Hetero)arylations 394 C–H Bond Olefinations 406 C–H Bond Alkylations 415 C–H Bond Alkynylations 418 C–H Bond Carboxylations 419 Carbon-nitrogen Bond Formation 420 Carbon-oxygen Bond Formation 424 Carbon-sulfur Bond Formation 424 Carbon-boron Bond Formation 425 Carbon-silicon Bond Formation 425

vi

Contents

9.8 9.9

Carbon-halogen Bond Formation  427 Conclusions  428 Acknowledgments  429

10

Functionalization of Chromenes and Their Derivatives  435 Laura Cunningham, Sundaravel Vivek Kumar, and Patrick J. Guiry Introduction  435 2H-Chromenes  435 2H-Chromene-ones (Coumarins)  437 C3-Selective Functionalization  437 Alkenylation  437 Arylation  438 Other  441 Annulation/Cyclization  442 C4–H Selective Functionalization  449 C5-Selective Functionalization  456 4H-Chromene  459 4H-Chromenones (Chromones)  462 C2-Selective C–H Activation  462 C3-Selective C–H Activation  463 C5-Selective C–H Activation  468 Alkenylation  468 Alkylation  471 (Hetero)arylation  473 Amination/Amidation  474 Others  477 C6-Selective C–H Activation  478 Conclusions  478

10.1 10.2 10.3 10.3.1 10.3.1.1 10.3.1.2 10.3.1.3 10.3.1.4 10.3.2 10.3.3 10.4 10.5 10.5.1 10.5.2 10.5.3 10.5.3.1 10.5.3.2 10.5.3.3 10.5.3.4 10.5.3.5 10.5.4 10.5.5 11 11.1 11.2 11.2.1 11.2.1.1 11.2.1.2 11.2.1.3 11.2.1.4 11.2.1.5 11.2.2 11.2.3 11.2.4 11.3 11.4 11.5 11.6 11.7

Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles  485 Rajeev Sakhuja and Anil Kumar Introduction  485 C–C Bond Formation  486 Alkylation  486 Fluoro Alkylation  486 Alkoxycarbonyl Alkylation  488 Aryl/heteroaryl Alkylation  489 Amino Alkylation  493 Sulfonyl/Carbonyl/Cyano Alkylation  496 Alkenylation/Alkynylation/Allenylation  498 Cyanation/Carbonylation  503 Arylation/Heteroarylation  509 C–S/Se Bond Formation  525 C–N Bond Formation  532 C–P Bond Formation  533 C–Si Bond Formation  535 Conclusions  535 Acknowledgments  536

Contents

12 12.1 12.2 12.3 12.3.1 12.3.1.1 12.3.2 12.3.3 12.4 13 13.1 13.2 13.2.1 13.2.2 13.3 13.3.1 13.3.2 13.3.3 13.4 13.5 13.6 14 14.1 14.2 14.2.1 14.2.2 14.3 14.3.1 14.3.1.1 14.3.1.2 14.3.1.3 14.3.2 14.3.2.1 14.3.2.2 14.3.2.3 14.3.3 14.4 15 15.1 15.2 15.2.1 15.2.2 15.2.3 15.2.4

Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles  543 Neha Jha and Manmohan Kapur Dehydrogenative Coupling: An Overview  543 Importance of Heterocycles and Their Fused Congeners  545 Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds  546 C–C Bond Formation  546 Synthesis of Large-sized Molecules: COTs  549 Formation of C–N Bonds  550 Formation of C–B Bonds  557 Conclusions  562 C–H Functionalization of Saturated Heterocycles Beyond the C2 Position  567 Amalia-Sofia Piticari, Natalia Larionova, and James A. Bull Introduction  567 Heterocycle Functionalization with a C2 Directing Group  567 Carboxylic Acid-Linked C2 Directing Groups  567 Applications of N-Heterocycle Functionalization with C2 Directing Groups  580 Heterocycle Functionalization with C3 Directing Groups  586 Carboxylic Acid-Linked C3 Directing Groups  586 Amine-Linked C3 Directing Groups  590 Alcohol-Linked C3 Directing Groups  592 Heterocycle Functionalization with a C4 Directing Group  594 Transannular Heterocycle Functionalization with N-linked Directing Groups  598 Conclusions  603 Asymmetric Functionalization of C–H Bonds in Heterocycles  609 Olena Kuleshova and Laurean Ilies Introduction  609 Enantioselective C–H Activation  609 Activation of C(sp2)–H Bonds  609 Activation of C(sp3)–H Bonds  611 C–H Activation Followed by Enantioselective Functionalization  615 Intramolecular Coupling  615 Indoles and Pyrroles as Coupling Partners  615 Imidazoles and Benzoimidazoles as Coupling Partners  618 Pyridines and Pyridones as Coupling Partners  618 Intermolecular Coupling  619 Directing-Group-Free C–H Functionalization  619 Functionalization Assisted by a Directing Group at the C3 Site  621 Functionalization Assisted by a Directing Group at the N-1 Site  623 Atropo-enantioselective Synthesis of Heterobiaryls  624 Conclusions and Perspectives  627 Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases  631 Yong Liang and Stanislaw F. Wnuk Introduction  631 Direct Functionalization of the C5-H Bond in Uracil Nucleosides  632 Cross-Dehydrogenative Alkenylation at the C5 Position  632 Direct C–H Arylation at the C5 Position  634 Direct C–H Alkylation at the C5 Position  635 Miscellaneous Direct C–H Functionalizations  636

vii

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Contents

15.3 15.3.1 15.3.2 15.3.2.1 15.3.2.2 15.3.2.3 15.3.2.4 15.4 15.4.1 15.4.2 15.5 15.6 15.6.1 15.6.1.1 15.6.1.2 15.6.1.3 15.6.1.4 15.6.1.5 15.6.2 15.6.3 15.7 15.7.1 15.7.2 15.7.3 15.7.4 15.8

Direct Functionalization of C6-H Bond in Uracil  637 Stepwise C6-H Functionalization of Pyrimidine Nucleoside via Lithiation and Alkylation  637 Direct C6-H Functionalization of the Uracil Base  637 Functionalization with Aryl Halides  637 Cross-Dehydrogenative Functionalization with Arenes  638 Functionalization with Aryl Boronic Acid  639 Intramolecular C6-H Functionalization of Uracil Derivatives  639 Inverted C–H Functionalization of Uracil Nucleosides  640 Inverted C5-H Functionalization of Uracil Nucleosides  640 Inverted C6-H Functionalization of Uracil  641 Direct C2-H Functionalization of Adenosine  641 Direct C6-H Functionalization of Purine Nucleoside  642 Direct C6-H Alkylation  642 With Cycloalkanes  642 With Boronic Acid  643 With Alkyltrifluoroborate  643 With Alkyl Carboxylic Acid  643 With tert-Alkyl Oxalate Salts  644 Direct C6-H Arylation  644 Other Direct C6-H Functionalization  645 Direct Activation of C8-H Bond in Purine and Purine Nucleosides  645 Cross-Coupling of Adenine Nucleosides with Aryl Halides  645 Cross-Coupling of Inosine and Guanine Nucleosides with Aryl Halides  647 Cross-Coupling of Adenine Nucleosides with Alkanes  648 Miscellaneous Functionalization of Adenosine-related Substrates  649 Conclusions  650

16

C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides  657 Morgane de Robichon, Juba Ghouilem, Angélique Ferry, and Samir Messaoudi General Introduction  657 Classical Methods to Prepare C-aryl Glycosides  657 Directed C-H Activation Approach  658 Directed Csp2-Csp2 Bond Formation  659 Directing Group Attached to the Aryl Partner  659 Directing Group Attached to the Sugar Nucleus  661 Directed Csp2-Csp3 Bond Formation  662 The Directing Group (DG) Attached to the Coupling Partner  662 The Directing Group Attached to the Sugar Nucleus  675 Conclusions and Perspectives  679

16.1 16.2 16.3 16.3.a 16.3.a.1 16.3.a.2 16.3.b 16.3.b.1 16.3.b.2 16.4 17 17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8 17.9

Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals  683 Harshita Shet and Anant R. Kapdi Introduction  683 Synthesis of (±)-Ibogamine  684 Synthesis of YD-3 and YC-1 (C–H Arylation of Indazoles)  685 Synthesis of Complanadine A  685 Synthesis of Diptoindonesin G (C–H Arylation of Benzofuran)  686 Synthesis of Dragmacidin D (C–H Arylation of Indoles at the C3 Position)  687 Synthesis of Celecoxib (C–H Arylation of Pyrazoles)  688 Synthesis of Aspidospermidine  689 Synthesis of Pipercyclobutanamide A  690

Contents

17.10 17.11 17.12 17.13 17.14 17.15 17.16 17.17 17.18

Synthesis of Nigellidine Hydrobromide  691 Synthesis of (+)-Linoxepin  691 Synthesis of (±)-Rhazinal  692 Synthesis of Podophyllotoxin (C–H Arylation)  693 Synthesis of (±)-Rhazinilam  694 Synthesis of Aeruginosins (sp3 C–H Alkenylation and Arylation)  694 Synthesis of Gamendazole  696 Synthesis of Beclabuvir (BMS-791325)  697 Conclusions  698

18

Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products  703 François Richard, Elias Selmi-Higashi, and Stellios Arseniyadis C–H Methylation and Alkylation  704 C–H Arylation and Olefination  705 Formation of Other C−C Bonds  711 C–H Hydroxylation  714 C–H Amination  715 C–H Trifluoromethylation  716 C–H Difluoromethylation  716 C–H Fluorination  718 C–H Silylation  718 C–H Phosphorylation  719 C–H Deuteration and Tritiation  720 Conclusions  723

18.1 18.2 18.3 18.4 18.5 18.6 18.7 18.8 18.9 18.10 18.11 18.12

Index  727

ix

xi

Brief Contents Volume 1: List of Contributors  xiii Preface  xvii 1 Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization  1 Tariq M. Bhatti, Eileen Yasmin, Akshai Kumar, and Alan S. Goldman 2 Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms  61 B. Prabagar and Zhuangzhi Shi 3 Functionalization of Five-membered Heterocycles with Two Heteroatoms  109 Jung Min Joo 4 Transition Metal-Catalyzed C–H Functionalization of Indole Benzenoid Ring  155 Vikash Kumar, Rajaram Maayuri, Lusina Mantry, and Parthasarathy Gandeepan 5 Transition Metal-Catalyzed C2 and C3 Functionalization of Indoles  193 Pinki Sihag, Meledath Sudhakaran Keerthana, and Masilamani Jeganmohan 6 C(sp2)–H Functionalization of Indolines at the C7-Position  251 Neeraj Kumar Mishra and In Su Kim 7 Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms  319 Tanumay Sarkar, Subhradeep Kar, Prabhat Kumar Maharana, Tariq. A. Shah, and Tharmalingam Punniyamurthy

Volume 2: List of Contributors  xiii 8 Functionalization of Pyridines, Quinolines, and Isoquinolines  357 Jun Zhou and Bing-Feng Shi 9 Transition Metal-Catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives  393 Christian Bruneau and Rafael Gramage-Doria 10 Functionalization of Chromenes and Their Derivatives  435 Laura Cunningham, Sundaravel Vivek Kumar, and Patrick J. Guiry

xii

Brief Contents

11 Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles  485 Rajeev Sakhuja and Anil Kumar 12 Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles  543 Neha Jha and Manmohan Kapur 13 C–H Functionalization of Saturated Heterocycles Beyond the C2 Position  567 Amalia-Sofia Piticari, Natalia Larionova, and James A. Bull 14 Asymmetric Functionalization of C–H Bonds in Heterocycles  609 Olena Kuleshova and Laurean Ilies 15 Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases  631 Yong Liang and Stanislaw F. Wnuk 16 C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides  657 Morgane de Robichon, Juba Ghouilem, Angélique Ferry, and Samir Messaoudi 17 Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals  683 Harshita Shet and Anant R. Kapdi 18 Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products  703 François Richard, Elias Selmi-Higashi, and Stellios Arseniyadis

Index  727

xiii

List of Contributors Stellios Arseniyadis Queen Mary University of London Department of Chemistry Mile End Road London, E1 4NS, UK Tariq M. Bhatti Department of Chemistry and Chemical Biology, Rutgers The State University of New Jersey New Brunswick, New Jersey 08903, United States Christian Bruneau Institut des Sciences Chimiques de Rennes UMR6226 University of Rennes, CNRS ISCR-UMR6226, F-35000 Rennes, France James A. Bull Department of Chemistry Imperial College London Wood Lane, London, W12 0BZ, UK Laura Cunningham Centre for Synthesis and Chemical Biology UCD School of Chemistry, University College Dublin Belfield, Dublin 4, Ireland Morgane de Robichon CY Cergy-Paris Université, CNRS, BioCIS Equipe de Chimie Biologique 95000 Neuville sur Oise, France Angélique Ferry CY Cergy-Paris Université, CNRS, BioCIS Equipe de Chimie Biologique 95000 Neuville sur Oise, France Rafael Gramage-Doria Institut des Sciences Chimiques de Rennes UMR6226

University of Rennes, CNRS ISCR-UMR6226, F-35000 Rennes, France Parthasarathy Gandeepan Department of Chemistry Indian Institute of Technology Tirupati Tirupati – Renigunta Road, Settipalli Post Tirupati 517506, India Juba Ghouilem Université Paris-Saclay, CNRS, BioCIS 92290, Châtenay-Malabry, France Alan S. Goldman Department of Chemistry and Chemical Biology, Rutgers The State University of New Jersey New Brunswick, New Jersey 08903, United States Patrick J. Guiry Centre for Synthesis and Chemical Biology UCD School of Chemistry, University College Dublin Belfield, Dublin 4, Ireland Laurean Ilies RIKEN Center for Sustainable Resource Science 2-1 Hirosawa, Wako Saitama 351-0198, Japan Masilamani Jeganmohan Department of Chemistry Indian Institute of Technology Madras Chennai 600036, India Neha Jha Department of Chemistry Indian Institute of Science Education and Research Bhopal Bhauri, Bhopal 462066, India

xiv

List of Contributors

Jung Min Joo Department of Chemistry Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu Seoul 02447, Republic of Korea Anant R. Kapdi Department of Chemistry Institute of Chemical Technology Nathalal Parekh Road, Matunga Mumbai 400019, India Manmohan Kapur Department of Chemistry Indian Institute of Science Education and Research Bhopal Bhauri, Bhopal 462066, India Subhradeep Kar Department of Chemistry Indian Institute of Technology Guwahati Guwahati 781039, India Meledath Sudhakaran Keerthana Department of Chemistry Indian Institute of Technology Madras Chennai 600036, India In Su Kim School of Pharmacy Sungkyunkwan University Suwon 16419, Republic of Korea Olena Kuleshova RIKEN Center for Sustainable Resource Science 2-1 Hirosawa, Wako Saitama 351-0198, Japan Akshai Kumar Centre for Nanotechnology Indian Institute of Technology Guwahati Guwahati 781039, India Anil Kumar Department of Chemistry Birla Institute of Technology and Science, Pilani Pilani 333031, India Sundaravel Vivek Kumar Centre for Synthesis and Chemical Biology UCD School of Chemistry, University College Dublin Belfield, Dublin 4, Ireland

Vikash Kumar Department of Chemistry Indian Institute of Technology Tirupati Tirupati – Renigunta Road, Settipalli Post Tirupati 517506, India Rajaram Maayuri Department of Chemistry Indian Institute of Technology Tirupati Tirupati – Renigunta Road, Settipalli Post Tirupati 517506, India Prabhat Kumar Maharana Department of Chemistry Indian Institute of Technology Guwahati Guwahati 781039, India Natalia Larionova Department of Chemistry Imperial College London Wood Lane, London, W12 0BZ, UK Yong Liang Department of Molecular Medicine Beckman Research Institute of the City of Hope Duarte, CA 91010, US Lusina Mantry Department of Chemistry Indian Institute of Technology Tirupati Tirupati – Renigunta Road, Settipalli Post Tirupati 517506, India Samir Messaoudi Université Paris-Saclay, CNRS BioCIS, 92290, Châtenay-Malabry, France Neeraj Kumar Mishra School of Pharmacy Sungkyunkwan University Suwon 16419, Republic of Korea Amalia-Sofia Piticari Department of Chemistry Imperial College London Wood Lane, London, W12 0BZ, UK B. Prabagar School of Chemistry and Chemical Engineering Nanjing University, Nanjing 210093, China

List of Contributors

Tharmalingam Punniyamurthy Department of Chemistry Indian Institute of Technology Guwahati Guwahati 781039, India François Richard Queen Mary University of London Department of Chemistry Mile End Road, London, E1 4NS, UK Rajeev Sakhuja Department of Chemistry Birla Institute of Technology and Science, Pilani Pilani 333031, India Tanumay Sarkar Department of Chemistry Indian Institute of Technology Guwahati Guwahati 781039, India Elias Selmi-Higash Queen Mary University of London Department of Chemistry Mile End Road, London, E1 4NS, UK Tariq. A. Shah Department of Chemistry University of Kashmir Srinagar 190006, India Harshita Shet Department of Chemistry Institute of Chemical Technology

Nathalal Parekh Road, Matunga Mumbai 400019, India Bing-Feng Shi Department of Chemistry Zhejiang University 38 Zheda Rd., Hangzhou 310027, China Zhuangzhi Shi School of Chemistry and Chemical Engineering Nanjing University Nanjing 210093, China Pinki Sihag Department of Chemistry Indian Institute of Technology Madras Chennai 600036, India Stanislaw F. Wnuk Department of Chemistry and Biochemistry Florida International University Miami, FL 33199, US Eileen Yasmin Department of Chemistry Indian Institute of Technology Guwahati Guwahati 781039, India Jun Zhou School of Chemistry and Chemical Engineering Changsha University of Science and Technology Changsha 410114, China

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8 Functionalization of Pyridines, Quinolines, and Isoquinolines Jun Zhou1 and Bing-Feng Shi2 1 2

School of Chemistry and Chemical Engineering, Changsha University of Science and Technology, Changsha, China Department of Chemistry, Zhejiang University, 38 Zheda Rd., Hangzhou, China

8.1  Introduction Pyridines, quinolines, and isoquinolines are a common family of heterocycles. Because of their unique role in pharmaceuticals, agrochemicals, and other biologically active molecular scaffolds (Scheme 8.1), the development of efficient methods for the rapid synthesis of these hetereoarenes is extremely important [1]. Apart from the construction of sp2-hybridized nitrogen-containing six-membered aromatic structures through intra- and intermolecular condensation reactions, the other way to access substituted pyridine derivatives is the direct introduction of substituents to pyridines. However, due to the low reactivity and poor regioselectivity, direct functionalization of the pyridine ring is a significant challenge. For example, electrophilic aromatic substitution is difficult and Friedel–Crafts reactions usually proceed under harsh reaction conditions. Pyridine derivatives without a good leaving group are usually unreactive toward aromatic nucleophilic substitution. Furthermore, the inherent instability and difficulties during the synthesis of pyridyl organometallics severely limits their application in cross-coupling reactions [2]. In recent years, transition metal-catalyzed C–H activation reactions have emerged as one of the most important strategies for the synthesis of these heterocycles [3]. In this chapter, the direct functionalization of pyridine, quinoline, and isoquinoline derivatives through transition metal-catalyzed Csp2–H activation process is reviewed. The examples in each section are organized according to C2-, C3-, C4-, C8- selective functionalization and various transformations, including

H N

O Cl

N H

N

epibatidine (analgesic)

HO OH

NH2

N N

N

N

Nicotine

Oxerine

Isoniazid

OMe O N

S

N HN

esomeprazole (antiulcerant)

O OMe

S HN

HO O

O pioglitazone (antidiabetic)

N

H

N

MeO Quinine

N

Scheme 8.1  Selected examples of natural products, pharmaceuticals, and biologically active compounds with pyridine derivatives.

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

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8  Functionalization of Pyridines, Quinolines, and Isoquinolines

alkylation, alkenylation, arylation, acylation, and others. The reaction scopes and proposed mechanisms will be discussed when necessary. Note that the functionalization of pyridines derivatives involving radical processes (metal free or visible light initiated or metal involved) are considered to be out of the scope of this chapter [4, 5].

8.2  C2-Selective Functionalization 8.2.1  Alkylation In 1989, Jordan and Taylor reported that a cationic alkylzirconium complex effected C2-selective alkylation of 2-picoline through a reaction with propene under an atmospheric pressure of hydrogen (Scheme 8.2) [6a]. The presumed catalytic cycle involves the hydrogenolysis of the alkylzirconium complex, exchange of the coordinating 2,6-dialkylated pyridine with 2-picoline, metalation of the C2–H bond of 2-picoline with co-liberation of hydrogen (H2 elimination/C–H abstraction), and migratory insertion of the 2-picolyl group across propene to regenerate the cationic alkylzirconium complex. Several stoichiometric experiments were performed to fully support the proposed catalytic cycle. The use of a chiral zirconium catalyst with an ethylenebis(tetrahydroindenyl) ligand allowed for enantioselective variants of the alkylation reaction (Scheme 8.3) [6b].

N

Cp 2 Z rL H2

+

N

DCM

Cp2 Zr

N H2

N Cp2 Zr

Cp 2 Z r

N

H Cp2 Zr

N

N

N H

H2

Cp 2 Zr

N N

Scheme 8.2  Zirconium-catalyzed coupling of propene and α-picoline.

N +

Zr N - BPh

4

+ N

H

Bu

N

∗ Bu

(3 mol%) H2,DCM, 50 °C

Scheme 8.3  Stoichiometric experiments.

58 % ee, TON = 6.2

8.2  C2-Selective Functionalization

In 2007, Bergman, Ellman, and coworkers developed a method for the rhodium(I)-catalyzed alkylation of pyridines and quinolines (Scheme 8.4) [7a]. Steric interactions provided by the alpha-position substituent presumably increase the equilibrium from an N-bound to a C-bound rhodium complex. This strategy was applied to intramolecular cyclization of pyridines with alkenes in 2010 by the same group [7b], and provides a new reaction pathway for the efficient preparation of underrepresented classes of complex bicyclic pyridines and tricyclic. a) N

R1

R L

H

+

THF, 165 C

N H Rh L

R

Cl

b)

O R1

N

[RhCl(coe)2]2 (3 mol% ) PCy3 (15 mol%)

R2

R2

H

N

L Rh Cl HL

N

R1

R

o

THF, 165 C

L Rh L

N H

[RhCl(cod)] 2 (5 mol%) PCy3 (15 mol%)

R2

O R1

Cl

R2

N

Scheme 8.4  Rhodium(I)-catalyzed alkylation of quinolines and pyridines via C–H bond activation.

The rare-earth catalysts are complementary to late transition metal catalysts in terms of selectivity, functional group tolerance, and substrate scope. In 2011, the Hou group demonstrated that the cationic half-sandwich rare-earth alkyl complexes served as excellent catalysts for ortho-selective C − H alkylation of pyridines. The combination of (C5Me5) Ln (CH2C6H4NMe2-o)2 (Ln = Sc, Y) with B(C6F5)3 showed excellent activity and selectivity for the ortho C − H addition of 2-subsituted pyridines to various olefins such as ethylene, 1-hexene, 1,3-cyclohexadiene, and norbornene, affording the corresponding alkylated or allylated pyridine derivatives in high yields. (Scheme 8.5) [8a]. The computational studies are also being investigated lately[8b]. In 2014, The same group examined the asymmetric C−H bond addition to alkenes by chiral half-sandwich rare-earth complexes and reported the synthesis of the first chiral half-sandwich rare earth alkyl complexes and their application to the catalytic enantioselective C−H addition of p ­ yridines to alkenes [8c].

N

H

R1

+

R2

C5Me5Ln (CH2C6H4NMe2-o)2 (2 mol%) B(C6F5)3 (2 mol%), toluene, 70 °C Ln= S c, Y

N R1

H +

Alkyl

[Sc]/L *(5mol%) [Ph 3C]B(C6 F5) 3 (5 mol%), toluene, 40 C 20 examples, 63-98% yield, up to 98:2 er

N

R2

R1

N

Alkyl ∗

R1

Scheme 8.5  Rare-earth-catalyzed C2 selective alkylation.

In 2013, Fu and coworkers developed an unexpected palladium(II)-catalyzed ortho-alkylation of pyridine N-oxides using of nonactivated secondary and tertiary alkyl bromides as coupling reagents (Scheme 8.6) [9a]. The author proposed that the radical-type of C-Br cleavage was engaged in the palladium-catalyzed C–H functionalization reaction, which was consistent with the fact that the primary bromides were less reactive during the transformation. The reaction showed good compatibility with many synthetically relevant functional groups, presenting a good method for the preparation of alkylpyridine derivatives. However, only C2-substituted pyridine N-oxides reacted efficiently and C2-substituents were necessary to prevent double alkylation. Herein, in 2014, the Zhou group reported a simple [Pd/dppp] catalyst which allows regioselective alkylation of various families of heteroarenes using secondary and tertiary alkyl halides [9b].

359

360

8  Functionalization of Pyridines, Quinolines, and Isoquinolines R2

Br Me

N

+

H

N

Me

O

Me

O

Me

O

R2

N

100 C, 24h

N

n

n=0, trace n=1, 52% n=2, 56% n=3, 88% n=4, 62% n=5, 61%

Cs2CO3, toluene

R1

O

Me

Pd(OAc)2dppf 5 mol% R1

N O

O

26%

70% CHO N

Me

O

H

N

O

Cy

O

58%

70% H

N

N THBDMSO N MeO

H

H

R

O

O R=Me, 52% R=Ph, 47%

82%

Scheme 8.6  Palladium-catalyzed C2 selective alkylation of pyridine N‑oxides.

Actually, pyridine N-oxides are good substrates for C2 selective alkylation. Apart from palladium, other metals can also be good catalysts including iridium, and copper. In 2014, Takanoa and coworkers discovered that the cationic iridium catalyst combining with a rac-BINAP ligand could accomplish C–H alkylation of 2-substituted pyridine N-oxides with acrylates (Scheme 8.7) [10]. The preliminary mechanism study revealed that the steps of C–H bond cleavage and alkene insertion are reversible. In 2016, Jain and coworkers reported the first copper-catalyzed microwave-assisted C2 alkylation of azine N-oxides, including the quinoline N-oxide, with tosylhydrazones (Scheme 8.8) [11]. This reaction, catalyzed by copper(I) iodide, was revealed to be an efficient and selective route towards the synthesis of both primary and secondary C2-alkyl-substituted azines. The reaction is highly regio- and chem-selective, and affords azine cores that bear both ­primary and secondary alkyl side chains which are otherwise difficult to prepare by using the precedent C–H alkylation methodologies.

O N R1

H

+

CO2

R2

O

cationic Ir cat. R

O

O N MeO

82%

C F3

75% O

O N

CO 2Et

N

CO2 Et 67%

MeO

CO 2R 2

N 1

CO 2Et

N

CO 2Me 14%

Scheme 8.7  Cationic iridium-catalyzed C–H alkylation of 2-substituted pyridine N-oxides.

8.2  C2-Selective Functionalization

Ar

+ N

H

10 mol % CuI 3.5 eq. LiOtBu

NNHTs R

O

R'

F N

O

O

N O

85%

Ph

73%

N

N

OMe

O

N O

63%

R

O

MW , 1 h, PhMe,110o

N

O

R'

N

OMe

92%

Ar

50%

56%

MeO

Scheme 8.8  CuI-catalyzed ortho-alkylation of azine N-oxides with N-tosylhydrazones.

8.2.2  Arylation 8.2.2.1  Pyridine Derivatives as Substrates

Early in 2000, Sasson and coworkers disclosed that heterogeneous palladium on carbon could catalyze the regiospecific coupling of aryl halides and pyridine under moderate conditions (Scheme 8.9) [12a]. This system enables the clean formation of 2-phenylpyridine in good yields without requiring expensive and wasteful boron or tin reagents. The ease of product and catalyst separation promotes this approach as a potential alternative pathway to the conventional cross-coupling methods. In 2005, the Sames group extended this novel protocol further for site-specific phenylation of pyridine (Scheme 8.10) [12b], which demonstrates the potential of bi- and polynuclear metallic species in catalysis.

N

H

+ Cl-Ph

Pd/C (0.5 mol% ) N

Ph

52%

Zn,H2 O,115 C, 20h

Scheme 8.9  Pd/C-catalyzed regiospecific cross-coupling of haloaryls and pyridine.

I + N

[Ru].PPh 3 (2 mol%) Cs2 CO 3 (1.2 eq) t BuOH,150 oC

N

Ph

Scheme 8.10  Ruthenium-catalyzed arylation of heteroarenes with aryl chloride.

Apart from palladium and ruthenium catalysts, other metals could also proceed with this transformation. In 2008, Bergman, Ellman and coworkers developed a rhodium(I)-catalyzed strategy for the direct arylation of pyridines and quinolines, which represented an expeditious route to an important class of substituted heterocycles and should be of broad utility (Scheme 8.11) [13a]. In 2009, Hua and coworkers developed the direct C–H arylation of pyrazine and pyridine with a wide range of aryl bromides catalyzed by Cy3PAuCl in the presence of t-BuOK as base. However, a mixture of C2/C3/C4 arylation was obtained (Scheme 8.12) [13b]. In the same year, Yamakawa and coworkers demonstrated the nickel-catalyzed direct C–H arylation of pyridine using aryl halides to generate a mixture of C2/C3/C4 arylation products (Scheme 8.13) [13c]. Arylzinc reagents are common organometallic reagents. In 2009, the Chatani group developed a catalytic 1,2-addition-based approach to the arylation of electron-deficient hetero aryls, which are instead notoriously poor substrates in catalytic direct ­arylation reactions (Scheme 8.14) [14]. In 2010, the Knochel group reported new frustrated Lewis pairs or tmp-zinc and tmpmagnesium bases with BF3·OEt2 that allows an efficient, regioselective metalation of various N-heterocycles (Scheme 8.15) [15].

361

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8  Functionalization of Pyridines, Quinolines, and Isoquinolines [RhCl(CO)2 ] 2 5mol%

Br R1

N

H

+

dioxane, 175-190 C ,24h

R2

Ph

N 53%

R1

N

N

N

51%

86%

R2

Scheme 8.11  Rhodium(I)-catalyzed direct arylation of pyridines and quinolines.

Br N

H

R

+

Cy3PAuCl 5mol% t-BuOK,100oC,24h

N

R

Mixture of C2/C3/C4

N

N

C2/C3/C4=24/14/11

N

C2/C3/C4=14/8/4

C2/C3/C4=22/17/9

Scheme 8.12  Gold(I)-catalyzed direct C–H arylation of pyrazine and pyridine with aryl bromides.

Ar-X

N

Cp 2Ni (5.0 mol) KOt -Bu,PPh3 ,100o C, 12 h

As solvent

Ar N

Mixture of C2/C3/C4

Scheme 8.13  Cp2Ni-catalyst system for direct C–H arylation.

N

H

+

EtZ n

Ni(cod)2 / PCyp3

R

N

toluene, 130 C

R

Scheme 8.14  Nickel-catalyzed reaction of arylzinc reagents with N-aromatic heterocycles.

via

1) tmpMgCl BF3 LiCl,THF 2) a)ZnCl2; b) Ar-I, Pd cat.

N

N N

F

Cl

N 72%

thf

Ar

75%

Mg F

CN

N CO2Et

F B F

N CO2 Et

72%

OMe

Scheme 8.15  Highly selective metalations of pyridines and related heterocycles.

8.2  C2-Selective Functionalization

The complexation of pyridine with tmpMgCl·BF3·LiCl furnishes an intermediate complex, followed by transmetalation with ZnCl2 and a subsequent Negishi cross-coupling with ethyl iodobenze yields the 2-arylated pyridines. Recently, Jiang and Zhang and coworkers developed an iridium(III)-catalyzed direct α-arylation of non-activated N-heteroarenes with both aryl and heteroaryl boronic acids by a H2O-mediated H2-evolution cross-coupling strategy in 2021(Scheme 8.16) [16]. This chemical avenue to 2-(hetero)aryl N-heteroarenes proceeds with broad substrate scope and excellent functional compatibility under redox neutral conditions, and is operationally simple, scalable, and applicable for structural modification of biomedical molecules.

Ar

+ N

H

[Cp*IrCl2 ]2 L-proline (20 mol%)

ArB(OH) 2

Ar N

Dioxane /H 2O,110 C 24 h

N

Ph

N

N

78%

60%

OMe

Ph

N

F

45%

N

N

N

31%

Ar

X=O, 45% X=S, 41%

26%

X

Scheme 8.16  Iridium-catalyzed direct α-arylation of N-heteroarenes.

Catalytic oxidative C–H/C–H cross-coupling between two (hetero)arenes would be one of the most attractive approaches to forge these bi(hetero)aryl units. In 2013, the You group developed for the first time a palladium(II)-catalyzed C−H crosscoupling strategy of non-oxidized pyridines with various heteroarenes to selectively synthesize a variety of C2-coupled unsymmetrical biheteroarenes, streamlining previous approaches that require the activated azine N-oxide as the coupling partner (Scheme 8.17) [17].

N

N

+

HetAr

S 62%

Ph

Pd(OAc)2, Phen H2 O H AgOAc, PivOH, 140 C, 24 h

N

O 55%

N

HetAr

N

N 40%

Scheme 8.17  Palladium-catalyzed oxidative C–H/C–H cross-coupling of pyridines with heteroarenes.

8.2.2.2  Pyridine N-oxides as Substrates

Pyridine N-oxides often serve as important intermediates for the activation and functionalization of the pyridine ring. In 2005, Fagnou and coworkers described palladium-catalyzed regioselective direct arylation of pyridine N-oxides that occurs in high yield with a wide range of aryl bromides (Scheme 8.18) [18a-c]. The resulting 2-arylpyridine N-oxides can be easily reduced to the free pyridine via palladium-catalyzed hydrogenolysis. This direct arylation of pyridine N-oxides at C2 for the preparation could be applied to the synthesis of analogues in medicinal chemistry. Also, aryl triflates could also be helpful instead of aryl halides [18d].

363

364

8  Functionalization of Pyridines, Quinolines, and Isoquinolines a) 1) Pd(OAc)2 /Pt Bu3-HBF4 K 2CO3 , toluene,110 oC

Br

R1 N

H

+

R2

O

N

R2

2) Pd/C,HCOONH4 ,MeOH,rt

b)

Cl N N

R1

H

O

N

As above

O

N

O

O

O

64%

64% aporphine analogues

c) R1 N

H

+

Pd(OAc) 2 /HPRBF4 K 2 CO3 ,PhMe

TfO

R1 N

R2

R2

O

R = Cy3 or t Bu 2 Me

O

Scheme 8.18  Palladium-catalyzed direct arylation of pyridine N-oxides.

Copper could also catalyze this kind of C2 selective arylation. In 2008, Daugulis developed a general method for coppercatalyzed arylation of sp2 C–H bonds (Scheme 8.19) [19]. The method employs aryl halide as the coupling partner, lithium alkoxide or K3PO4 base, and DMF, DMPU, or mixed DMF/xylenes solvent. A variety of electron-rich and electron-poor heterocycles can be arylated.

CuI/phenanthroline R1 N

H

+

I R2

O

N

N

O

O

58%

41%

LiO t Bu or K 3 PO 4

N N

R1 N

solvent 120-125 C ,1-12 h

R2

O

Ph

O 43%

N O 91%

Scheme 8.19  Copper-catalyzed arylation of pyridine N-oxides.

Considering their broad applications, potassium aryltrifluoroborates have the potential to serve as the ideal aryl sources for C–C bond-forming reactions via C–H bond activation. Herein, in 2016, Li and Wei and coworkers reported the first example of a palladium-catalyzed system for the direct arylation of pyridine N-oxides using potassium aryl- and heteroaryltrifluoroborates without requiring the addition of any ligand (Scheme 8.20) [20]. Importantly, this method provides the desired 2-arylpyridine N-oxides in moderate to high yields with good functional group tolerance and high regioselectivity. The mechanism involves ortho-C–H activation, transmetalation and reductive elimination. In 2010, the You group demonstrated the first palladium(II)-catalyzed regioselective oxidative C–H/C–H cross-coupling between two heteroaromatic compounds (Scheme 8.21) [21]. A diverse set of electron-deficient heteroarenes including pyridine N-oxides were effective substrates to couple with either electron-rich thiophenes or furans. The density functional theory (DFT) study supported that a SEAr process could be involved in the initial palladation of thiophene, and the second C–H activation might undergo a concerted metalation-deprotonation (CMD) process.

8.2  C2-Selective Functionalization Pd(OAc)2 /Ag2 O, TBAI, Dioxane,90o C

R1 N

H

+

R1

(Het)Ar-BF3 K

N

(Het)Ar

O

O

N

N

O

O

OMe

89%

O

N

N

92%

S

O

O

F

83%

59%

Scheme 8.20  Palladium-catalyzed direct arylation with potassium aryltrifluoroborates.

R1

+ N

HetAr

H

H

Pd(OAc)2 /Cu(OAc) 2 • H 2O

R1

pyridine,additive,dioxane

O

O

N

O

N

O

CHO

O 77%

60%

S

N

O

O

HetAr

N

41%

Scheme 8.21  Palladium(II)-catalyzed oxidative C–H/C–H cross-coupling of heteroarenes.

8.2.2.3  N-iminopyridinium Ylides as Substrates

N-iminopyridinium ylides were also shown to be useful precursors to various novel heterocyclic compounds, mainly through 1,3-dipolar cycloaddition reactions and photochemical rearrangments. In 2008, Charette and coworkers revealed that in presence of Pd(OAc)2 and P(t-Bu)3 a wide range of aryl and heteroaryl bromides could be readily coupled to the N-iminopyridinium ylides in moderate to excellent yields (Scheme 8.22) [22].

Pd(OAc) 2 / PtBu3

Br

R1 N

H

+

R2

R1

K 2 CO3, toluene, 125 C

N NBz

NBz

N NBz

R2

R2 =OMe,77% R2 =CO2 Me,76%

F

N

NBz

NBz 53%

F

N

N

50%

N

R2

N NBz N 50%

Scheme 8.22  Palladium-catalyzed direct C–H arylation of N-iminopyridinium ylides.

8.2.3  Alkenylation In 2003, Hori and coworkers developed a novel ruthenium-mediated regio- and stereoselective alkenylation reaction of pyridines (Scheme 8.23) [23]. A number of aryl- and alkyl-alkynes were shown to take part in the reaction with 3- and 4-substituted pyridines. An initially proposed mechanism was similar to that of the previously described chemistry: [2+2] cycloaddition to ruthenaazetidine followed by β-hydride and reductive eliminations.

365

366

8  Functionalization of Pyridines, Quinolines, and Isoquinolines

R1

Me 3Si

+ N

R2

CpRu(PPh 3 ) 2 C l (20 mol%) NaPF 6 (22 mol%)

R1 N

150 C ,7-24 h N

+ pyridine R

Cp

Me 3Si

Ru+ L L

R2

R2 + pyridine

L= PPh 3

N H

N

Cp

R Cp

PF6 -

Ru L N

L

H R

Ru N

Cp L

N H

.

H R PF6 -

H

Ru N

HR

PF6-

N

Scheme 8.23  Ruthenium-mediated regio- and stereoselective alkenylation of pyridine.

In 2007, Hiyama and coworkers demonstrated nickel-catalyzed E-selective alkenylation of pyridine-N-oxides at C2 by means of C2-H activation followed by stereoselective insertion of an alkyne under mild conditions (Scheme 8.24) [24]. The resulting adducts are readily deoxygenated to give 2-alkenylpyridines, demonstrating that the sequence of reactions provides a novel route for C2 functionalization of pyridine derivatives. R2 R1 N

Ni(cod) 2/PCyp 3 toluene, 35 o C

R3

N

H+

O

R3

O

PCl3 (1.2 eq) toluene, RT,15 min

R1

R1

N

Pr Pr

R2 CO 2Me

N O

Pr Pr

67%,E /Z=93:7

Pr

N O

Pr

59%,E/Z =93:7

N O

Pr Pr

66%,E /Z>99:1

N O

Pr Pr

81%,E /Z>99:1

N

Pr

O 56%,E /Z >99:1

Scheme 8.24  Nickel-catalyzed addition of pyridine-N-oxides across alkynes.

In 2008, Chang and coworkers found that the oxidative cross-coupling reaction of pyridine N-oxides with olefins could take place using a catalytic system comprised of Pd(OAc)2 and Ag2CO3 (Scheme 8.25) [25]. Treatment of pyridine N-oxides with olefins regioselectively furnished the ortho-alkenylated products in moderate-to-good yields with moderate to good mono/diselectivity, depending on the steric effect. In 2009, Cui, Wu and coworkers revealed for the first time that N-oxidized quinolines, served as both the inducing platform and the oxidant, could successfully direct palladium-catalyzed C2 alkenylation with acrylates, leading to 2-alkenylated quinolines and 1-alkenylated isoquinolines under external-oxidant-free conditions (Scheme 8.26) [26]. Considering that the enhanced reactivity of pyridine-N-oxides is apparently attributed to an electron-deficient nitrogen that increases the acidity of the C2-H bond, a similarly activated pyridine species could also be generated catalytically in situ by the coordination of the nitrogen to a Lewis acid catalyst. In 2008, Hiyama enabled the use of simple

8.2  C2-Selective Functionalization

R1

N

H

+

Pd(OAc) 2 (10 % mo l) Ag 2 CO3 ,1, 4-dioxane

R2

O

R1

100-130 C

N O

R2

Ph N

CO2 tBu

O

91%

N O

CO2tBu 88%

N O

N O

53%

Ph 64%

Scheme 8.25  Palladium-catalyzed C–H functionalization of pyridine N-oxides. O N +

R

N

CO 2Et

Pd(OAc) 2

CO2 Et

N

N

CO2 Et

R

CO 2 nBu

N

CN 65%

80%

86%

Scheme 8.26  Palladium-catalyzed alkenylation of quinoline-N-oxides.

pyridines in the hydroarylation of alkynes through a cooperative nickel/Lewis acid catalysis, leading to a wide variety of 2-alkenylated pyridines products; some of the substituted pyridines also participated in the dienylation reaction under nickel-AlMe3 catalysis (Scheme 8.27) [27]. R2 L A cat .

R1 N

R1

R3

Ni(cod) 2 (3mol%), i-Pr 3 P(3 mol%)

H

R2

ZnMe 2 or ZnPh 2 (6 mol%)

LA

(E / Z = 93:7 to > 99: 1)

toluene, 50-100 C, 7-24 h R

Pr

Ni(cod) 2 (3 mol%)

R

Pr Pr

i-Pr 3 P (12 mol%) + N

H

Pr

Me 3 Al (6 mol%) toluene, 50 C

R3

N

H

N

H

R1

Pr

N

R = H: 80% R = 4-OM e: 4 6%

Pr

Scheme 8.27  Direct C2 selective alkenylation of pyridines by nickel/Lewis acid (LA) catalysis.

Charette and coworkers studied the C2 selective alkenylation of pyridines with inexpensive copper salts. In 2010, they found that treatment of N-iminopyridinium ylides with alkenyl iodides in the presence of 10 mol % CuBr2 using K2CO3 as a mild base gave a range of C2-alkenylated products in good to excellent yields. The authors postulated that the reaction ­proceeds through a copper(I)/copper(III) manifold. The reaction is the first ligand-free copper-catalyzed direct alkenylation of electron-deficient heteroarenes, and it is highly chemoselective towards alkenyl iodides, introducing the possibility of ­preparing a scaffold from which a library of biologically interesting compounds could be constructed (Scheme 8.28) [28].

8.2.4  Acylation, Amination, and Aminomethylation In 1992, Moore and co-workers reported that a catalytic amount of triruthenium dodecacarbonyl [Ru3(CO)12] effected C2-selective acylation of pyridine through a reaction with alkenes under an atmosphere of carbon monoxide (Scheme 8.29) [29a]. Ethylene, hex-2-ene, and cyclohexene were successful alkenes for the reaction. Triruthenium dodecylcarbonyl could

367

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8  Functionalization of Pyridines, Quinolines, and Isoquinolines

N

I

+

NBz

CuBr 2 (10 mol%) K2 CO3 (3 eq) PhCl,125 oC

R1 R2

R1 N

R2

NBz

N

N

N

NBz

NBz 93%

NBz

MeO

CF3

71%

93% Ph N

N NBz

NBz

53%

OPMB 30%

Scheme 8.28  Copper-catalyzed direct alkenylation of N-iminopyridinium ylides.

+ N

H

C4H9

Ru3(CO)1 2 (cat.) CO(10 atm), 150 oC, 16h

Ru(CO)4

N

C4H9

O 65% (n/ i=13:1)

H via

(CO)3Ru

Ru(CO)3 N

Scheme 8.29  Catalytic and regioselective acylation of aromatic heterocycles.

selectively activate the ortho positions in pyridine to form ortho-metalated species, which is the key intermediate for this reaction. The mechanism proposed previously by Laine and coworkers [29b] would further involve the migratory insertion of alkenes into the ruthenium–hydrogen bond followed by carbonylation of the resultant alkyl ligand and reductive ­elimination to give 2-acylpyridines and regenerate a catalytically active species. In 2015, Zhang, Li, and coworkers reported the first example of a palladium-catalyzed dual C–H activation of ­isoquinoline and quinoline N-oxides with formamides leading to the synthesis of isoquinoline-1-carboxamides and quinoline-2-­carboxamides (Scheme 8.30) [30]. This method provides a new way to construct a new carbon–carbon bond. In the same year, Wu developed a Cu(OAc)2-catalyzed electrophilic amination of quinoline-N-oxides with R2N (+) synthons provided by O-benzoyl hydroxylamines (Scheme 8.31) [31]. This development provides a new strategy for the synthesis of 2-aminoquinoline compounds in moderate to excellent yields via aryl C–H bond activation. The electrophilic amination can also be performed in good yield on a gram scale. In 2015, Tsurugi and Mashima and coworkers found that group 3 metal triamido complexes can catalyze the reaction of pyridines with imines; they developed the first catalytic C−H bond addition of pyridine derivatives coupled with a nonactivated C-N double bond to afford aminomethylated products of pyridines (Scheme 8.32) [32]. This reaction is initiated by the coordination of pyridine to the catalyst. Abstraction of the o-hydrogen atom of the pyridine ring with an amidometal moiety affords the corresponding pyridylmetal intermediate. The resulting pyridylmetal then reacts with the imine to give the product.

8.2  C2-Selective Functionalization R2 N

1

R

O +

H O

Pd(MeCN) 2Cl2,n-Bu4 NOAc Yb2 O3 , neat or PhMe air,120 oC

R2 N R3

O

O

NMe2

NMe 2

O

O

R3

N

R1 NMe 2

N

N

N

N

MeO

nC6 H13 50%

61%

56%

OMe O

O

N

O

N

N

O F3 C

N Ph

NHM e N

Ph

51%

Ph

64%

71%

Scheme 8.30  Palladium-catalyzed oxidative carbamoylation of isoquinoline N-oxides.

O

Cu(OAc)2(10 mol%), Ag2 CO 3(10 mol%) t BuOH, 80 C, 24 h

N R

N-OBz

O N

N R

O O N

O

O N

N

O N

N

N

N N

90%

52%

58%

80%

Scheme 8.31  Copper(II)-catalyzed electrophilic amination of quinoline N-oxides.

R1

N

R2

+

Ln = Gd,Y, etc. N R3

HN Ph

N

90%

Ln[N(SiMe 3)2]3 (10 mol%) HNBn 2 (10 mol%

R1

N

R2 R3

Toluene

Cy

HN Ph

HN

N

Cy

OMe

Cy

Cy

HN Ph

70%

N

Cy 81%

Scheme 8.32  Aminomethylation reaction of ortho-pyridyl C−H bonds.

O

369

370

8  Functionalization of Pyridines, Quinolines, and Isoquinolines

8.3  C3-Selective Functionalization 8.3.1  Alkylation The C3 selective alkylation of pyridine derivatives is usually performed by introducing a directing group (DG) in the C4 or C2 position. Early in 1997, Grigg and coworkers found that heating 4-acetyl pyridine with alkenes in toluene in the presence of RulI2CO(PPh3)3 afforded mixture of mono- and di-alkylated products in 60 and 9% yield respectively (Scheme 8.33) [33]. O

O Si(OEt)3

+

O

RuH 2(CO)(PPh 3 )3 toluene

Si(OEt)3 +

9%

60 %

N

N

(EtO)3 Si

Si(OEt)3 N

Scheme 8.33  Ruthenium-catalyzed alkylation of pyridines.

In 2012, the Chang group described Rh−NHC–catalyzed double C(sp2)-H hydroarylation of 2,2′-bipyridines by a rollover cyclometalation pathway (Scheme 8.34) [34]. Mechanistically, it was proposed that N-heterocyclic carbene (NHC) is bound to a metal center I as a strong σ-donating ligand; it may exert a high trans-effect to weaken a metal-pyridyl bond trans to L allowing for the facile decomplexation of I leading to II, thus enabling subsequent rotation around the bipyridyl axis and then C−H bond activation eventually to afford a metalacycle species III. This work elucidated for the first time the dramatic NHC effects on the rollover cyclometalation pathway enabling highly efficient and selective bisfunctionalization of 2,2′-bipyridines and 2,2′-biquinolines.

Rh(acac) 3 /IMes HCl

N

H N

R

H

+

t-BuONa,toluene 130 C, 2h

N

R

R

N

trans-effect N Rh N I

NHC X

N N

NHC Rh H X

N

NHC Rh

N

II

X

III

Scheme 8.34  Dramatic NHC effects in alkylation of pyridines.

The non-directing C3 alkylation of pyridine derivatives was achieved by Shi and coworkers. In 2011, the Shi group reported an iridium-catalyzed activation of pyridine C–H bond and its nucleophilic addition to benzaldehydes (Scheme 8.35) [35]. The reaction was applicable to various pyridine derivatives and aryl aldehydes. An independently synthesized silyl iridium complex [(dtbpy)Ir(H)(Cl)(SiEt3)]2 was able to catalyze the reaction, indicating that a bulky silyl iridium intermediate might be responsible for the novel reactivity and the unusual selectivity. Recently, Donohoe and coworkers described a novel rhodium-catalyzed C3/5 methylation of pyridines using temporary dearomatisation strategy (Scheme 8.36) [36]. Initially electron deficient pyridine rings were activated by in situ reduction caused by metal hydride addition, in this case nucleophilic enamine intermediates are formed which enable new C–C bond formation; finally the C3/5 methylation products were obtained through temporary dearomatisation. In particular,the 4- substituted pyridines were doubly methylated at the C3/5 positions whereas the monomethylated product was obtained only when the C3/5 position was already blocked.

8.3  C3-Selective Functionalization H R1

+ N

O R2

H

OSiEt 3

Ir4(CO)12(2 mol%),1,10-phen (4 mol%) HSiEt 3,benzene,135 oC,12h

R2

R1 N

H2

LnIr- SiEt 3

H

Ln=1,10-phen,CO, and/or SiEt 3

HSiEt3

N

LnIr-H

Ln

OSiEt3 Ar Ln

N

Ir

H

Ir

N OSiEt 3

H SiEt 3

O H

Ar

Ar

N

Scheme 8.35  Iridium-catalyzed highly selective addition of pyridyl C–H bonds to aldehydes. R' R' N X

1) [RhCp*Cl2] 2,MeOH,CH2 O NEt3 ,65o C,16 h H 3C

N

R' CH 3

2) CsF,65 oC,1 h

N

PITSO CF3

MeO

CH 3

CH 3 N 58%

N

CO2 Me

CO2Me

H3 C

N 52%

H3 C

CH 3

CH3

N

N

38%

68%

Scheme 8.36  Rhodium-catalyzed C-3/5 methylation of pyridines.

8.3.2  Arylation Intramolecular cyclization reactions have been employed for the preparation of a variety of pyridine derivatives for C3 selectivity. This strategy mainly relies on the introduction of a link at C2 or C4 position. In 1984, Ames and Opalko employed 2-(2-bromophenoxy) pyridine as a tether for directing arylation to C3, resulting in the synthesis of a benzofuropyridine (Scheme 8.37) [37]. Despite a high reaction temperature and a relatively high catalyst loading, the target compound was only obtained in 10% yield, and 25% of the starting material was recovered unreacted. Br N

O

Pd(OAc) 2, ( 8 mol%) Na2 CO3 ,DMAc,170 oC, 48 h N

O

10 %

Scheme 8.37  Palladium-catalyzed cyclisation of 2-substituted halogenoarenes.

Several C4-substituted tethers have also been used for directing arylation at C3 position. Both five- and six-membered rings have been formed using this reaction. LaVoie and co-workers used this method to prepare biologically active compounds (Scheme 8.38) [38]. The cyclized products were generally obtained in moderate yields (22–55 %). Furthermore,

371

372

8  Functionalization of Pyridines, Quinolines, and Isoquinolines a)

Y

Y

N X O

N

W

O

O

R 1,R2 = Alkyl X = NH2, H, Y= H, NH2, W = Br, I

R 2 RN

1

R 2 RN

MeO

OMe N

I

O

N

1

MeO

N

Pd(OAc)2, P(o-tol)3 Ag2 CO 3,DMF

O

O

b)

X

O

N O

O

N

Pd(OAc)2 , P(o-tol) 3 Ag 2CO3 ,DMF

M eO O

N O

R 1 ,R 2 = Alkyl

O

1 R2 RN

1 R 2RN

Scheme 8.38  Palladium-catalyzed cyclisation of 4-substituted halogenoarenes.

in 2009, Beccalli and coworkers developed a practical and efficient direct arylation reaction of pyridines using ligandfree conditions with the mixture of Pd(OAc)2 and TBAC as catalytic system, providing a straightforward synthesis of azapolycyclic systems (Scheme 8.39) [39]. a) O

Pd(OAc)2 (5 mol%) AcOK (2 equive.)

N Z

O

TBAC (1 equive.) DMA, 100 oC

X

N

X = Br, I Z = C,N, 58-69 % Yield

N Z N

b) I N N

T he Same as above N 90 % Yield

O

N

O

Scheme 8.39  Palladium-catalyzed direct arylation using ligand-free conditions.

Maes and co-workers prepared cryptolepine derivatives using (2-chlorophenyl) quinolin-4-ylamine or (3-chloropyridin-2-yl) pyridin-4-ylamine as reactants (Scheme 8.40) [40]. For these cyclizations, the electron-rich phosphine ligand P(tBu)3 was used Cl

N

Pd2(dba)3 , (10 mol%), P(t Bu)3 K 3 PO4 ,Dioxane,120 oC, 36 h

N H N

N

Cl N H

N N H

N

Pd2 (dba) 3, (2.5 mol%), P(t Bu)3 K 3PO 4,Dioxane,120 oC, 3 h

52 %

N N H

95 %

Scheme 8.40  Palladium-catalyzed cyclisation of 4-substituted pyridine derivatives.

8.3  C3-Selective Functionalization

alongside [Pd2(dba)3] as catalyst. The reaction of (2-chlorophenyl) quinolin-4-yl-amine gave the expected product with formation of a five-membered ring in 95% yield, with only 2.5 mol% catalyst. However, cyclization of (3-chloropyridin-2-yl) pyridin-4-ylamine gave the desired compound in only 52% yield, with 10 mol% catalyst. In the presence of a pyridine substituted at C4 by a 2-bromoaniline, the cyclization proceeded in 72% yield, with 5 mol% ligand-free Pd(OAc)2 as catalyst (Scheme 8.41) [41]. This improvement in yield is due to the easier oxidative addition of aryl bromides to palladium. Intramolecular cyclization of a pyridine substituted at C4 by a 2-bromophenol gave the desired cyclized product in only 21% yield; this low yield is probably due to the formation of side products.

Br

N

Pd(OAc)2, (5 mol%) Na2 CO 3,DMF ,165o C, 20 h

N H

72 %

N H

Br

N

N

O

Pd(OAc) 2, (5 mol%) K 2 CO 3,TBAB,DMF,150 oC, 3 h

O N

O

21 %

O

Scheme 8.41  Palladium-catalyzed cyclisation of 4-substituted pyridine derivatives with aryl chloride.

There have, to date, been very few examples of palladium-catalyzed intermolecular C3 or C4 arylation of pyridines with aryl halides. One of the rare cases, described by Cetinkaya and co-workers in 2005 (Scheme 8.42) [42], involved the coupling of pyridine-2-carbaldehyde and 4-chloroacetophenone in the presence of Pd(OAc)2 with a N-heterocyclic carbene ligand. The 3-arylated pyridine product was obtained in 88% yield. COMe + N

Pd(OAc) 2 (1 mol%) SIMes· HCl (2 mol%) Cs2 CO3,Dioxane,80o C, 16 h

CHO

COMe

88%

Cl

N

CHO

Scheme 8.42  Selective palladium-catalyzed arylation(s) of benzaldehyde derivatives.

In 2010, The Yu Group developed the first example of directed transition metal-catalyzed C–H arylation of a pyridine ring at the 3-positions. The N-3,5-dimethylphenyl amide protecting group gave the excellent overall yield of the DGs tested under the Pd0/PR3-catalyzed system, a variety of nicotinic and isonicotinic acid derivatives could be arylated with good yields. (Scheme 8.43) [43]. ArHN

O H

+

R Br

N

Pd(OAc)2 (10 mol %) ArHN PCy 2 tBu HBF4 (10 m ol %) Cs2 CO 3, 3A MS Toluene, 130 oC, 48 h

O R

N

OMe HN

HN

O

N

86%

HN

O

N

94%

O

N

68%

Scheme 8.43  Pd0/PR3-catalyzed arylation of nicotinic and isonicotinic acid derivatives.

373

374

8  Functionalization of Pyridines, Quinolines, and Isoquinolines

Apart from developing this directing strategy, in 2011, the Yu group also developed the first non-directed C3-selective arylation of unprotected pyridines. The catalyst was considered to be generated in situ from Pd(OAc)2 and phen. With this methodology as a key step, a concise synthesis of the drug molecule (±) preclamol has been completed with 67% yield for 3 steps. (Scheme 8.44) [44]. Pd(OAc)2 (5 mol%) Phen (15 mol%)

H R

R'

+

X

N

R' R

Cs 2CO3 , 140 C

(C3 /C 4/C 2)

N

OH

OMe + N MeO

Br

67% f or 3 steps

N

N

Preclamol

Scheme 8.44  Ligand-promoted C3-selective arylation of pyridines with palladium catalysts.

8.3.3  Alkenylation In 2011, the Li group reported chelation-assisted rhodium(III)-catalyzed oxidative annulation of pyridines with alkynes for the direct synthesis of quinolines, a process that involves 2-fold C–H activation. The selectivity of the coupling reaction is oxidant-dependent; different products could be formed when Ag2CO3 or Cu(OAc)2 was used as an oxidant (Scheme 8.45) [45]. This coupling reaction is the first example of chelation-assisted 2-fold C–H functionalization of pyridine rings at the 2- and/or 3-positions and the six-member-ring formed. O N

DG

R R DG=amide,R=Ph,45% DG R R

[RhCp*Cl2]2

+ N

N

Ag2CO 3 1.1 eq

R

R

2-4 mol%

Cu(OAc)2 2.2 eq

p-Tol

N

R R DG=amide,pyridine,imidazole 24 examples, up to 90%

Scheme 8.45  Synthesis of quinolines via rhodium(III)-catalyzed oxidative annulation of pyridines.

In 2012, the Li group found that the the five-member-ring could also form under the [RhCp*Cl2]2/Cu(OAc)2 system with secondary isonicotinamides and activated olefins (Scheme 8.46) [46]. The selectivity can be controlled by the solvent; the mono-alkenylation and two-fold oxidation reaction is the major pathway in MeCN, whereas this reaction gave mostly O NR

N R'O2C

CO 2R'

O [Rh Cp *Cl 2 ] 2 (2 m ol% ) C u(OA c ) 2

(4 .2 eq )

C H 3 C N, 110 o C

NHR N

+ CO2 R'

[Rh Cp *Cl 2 ] 2 (2 m ol% ) C u(OA c ) 2

O

(6 eq)

T H F ,1 10 o C

NR

N R'O 2C

Scheme 8.46  Rhodium(III)-catalyzed oxidative mono- and di-alkenylation of isonicotinamides.

8.3  C3-Selective Functionalization

dialkenylation products in THF. However, the coupled products contain an exocyclic C=C bond in both cases. By introducing the amide group at the C2 position, in 2014, Xi and coworkers achieved rhodium(III)-catalyzed intermolecular oxidative alkenylation/cyclization of picolinamides and alkenes with high regio- and stereoselectivity to furnish pyrido pyrrolone derivatives in good to excellent yields (Scheme 8.47) [47]. O N

[RhCp*Cl2 ] 2 (5 mol%) Cu(OAc) 2 (2 eq)

NHR

CO 2R'

+

O

N

NR

130 C R'O 2C O

O

O

O

N

N

N NnBu

NnBu 92%

nBu O2 C

NnBu

82%

nBuO2 C

90%

nBu O 2C

NnBu

N

MeO

Ph

0%

Scheme 8.47  Rhodium(III)-catalyzed cascade oxidative alkenylation/cyclization.

Our group has been devoted to the selective functionalization of pyridine derivatives for many years. In 2013, our group reported a rhodium(III)-catalyzed C3 selective oxidative alkenylation of pyridines and quinolines relying on the introduction of the pivalamide at the C2 position (Scheme 8.48a) [48]. This protocol is operationally simple and has been successfully applied to the multigram-scale synthesis of naphthyridinones with a low catalyst loading (0.1 mol %). The good reactivity of this reation might result from the competitive coordination of Cu(OAc)2 with the pyridine nitrogen, which may facilitate the following rhodium(III)-catalyzed C–H activation. Subsequently, a series of 3,4-dihydro1,8-naphthyridin-2(1H)-ones have been prepared from 3-alkeny pyridines in one pot via two steps, including catalytic hydrogenation and intramolecular cyclization. Afterward, we extended this method to picolinamide derivatives successfully. and, futhurmore, obtained olefination–cyclization products when secondary picolinamides were coupled to ethyl acrylate. (Scheme 8.48b). a)

O

H3 C N NHPiv

[Cp*RhCl2] 2 H AgSbF6 , Cu(OAc) 2

N

N CH 3

NHPiv N

120 o C, DCE

N

R

R1

N

FabI inhibitor

R

R1

O

N

N

O

N H

N H

O

R

Antibacterial agents

b) CONR 1 R2

[Cp*RhCl2] 2 AgSbF6 , Cu(OAc)2

H

N

+ 3

R

R

o

120 C, DCE

CONR 1R2

O R

N R3

or

N

R2 N R

Scheme 8.48  Rhodium(III)-catalyzed C3 selectively oxidative alkenylation of pyridines and quinolines.

Given that the oxidative alkenylation was limited to terminal activated olefins above, such as styrenes and acrylates, that only give E-linear alkenes (such as Scheme 8.48a), to afford trisubstituted (pyridin-3-yl) alkenes, our group developed a rhodium(III)-catalyzed hydroarylation of a broad range of internal alkynes with picolinamides in 2014 (Scheme 8.49) [49]. The current hydroarylation protocol offers a complementary approach to access the branched products.

375

376

8  Functionalization of Pyridines, Quinolines, and Isoquinolines R'

R' R''

N

O

R1

Rh(III)-cat, Cu(OAc)2 HOAc

+

N

O

O

R2 R

N

Ph Ph

N

O

N

Ph Ph

N Br

92%

Br

R1

N

R2

R

N

N

R''

O

Ph Ph

N Br

90%

87%

Scheme 8.49  Rhodium(III)-catalyzed regioselective hydroarylation of alkynes.

In the same year, we also developed rhodium(III)-catalyzed oxidative annulation of picolinamides with alkynes for an efficient synthesis of isoquinolines using Cu(OAc)2 as an oxidant (Scheme 8.50) [50]. The scope of the reaction was studied with a selection of various picolinamides and alkynes, and the desired isoquinolines were obtained in good to excellent yields. Inspired by our work, some other groups developed a few examples using different DGs (Scheme 8.51) [51]. R'

R' R''

N

O

R1 +

N

O

R1 R2

N

120 o C, DCE

R2

R

N

R''

[Cp*RhCl2] 2 AgSbF6 , Cu(OAc)2

R2 R

1

Cy N

O

N

Ph Ph

N

O

Pr

N

Ph 92%

Cy

Pr

N

O

Ph

N

Ph

Pr 41%

Ph

Ph

94%

Pr

Ph

Scheme 8.50  Rhodium(III)-catalyzed oxidative annulation of picolinamides with alkynes. R2

O N

HN n

R R

N

R R Carretero, 2015

O

N

R R

N

R R Xu, 2018

R R

N R'

O

Zhu, 2020

R R

N

R R

N

R'

R Li, 2021

R

Scheme 8.51  Rh (III)-catalyzed oxidative annulation of pyridine derivatives.

There is one example for the non-directed C3 selective alkenylation of pyridine derivatives. In 2011, the Yu group reported a new palladium-catalyzed C3-H alkenylation of pyridines using air and catalytic Ag2CO3 as the oxidants. The bispyridine ligands play a key rule in this reaction process by a strong trans-effect (Scheme 8.52) [52]. Excess of pyridines are needed for the reaction and the resulting C3-olefination products are useful building blocks for the synthesis of drug molecules.

8.3  C3-Selective Functionalization H +

N

Pd(OAc)2 (10 mol% ), Phen (13 mol%) Ag2CO 3, DMF, air,140o C,12 h

R

CO2Et

Ph

N

N

73%(12/1/1)

R N F

CO2Et

CO2Et

N

F

61%(10/2/1)

45%(30/3/1)

(C3/C2/C4)

N 57%

Scheme 8.52  C3 selective C–H alkenylation of pyridines with palladium catalysts.

8.3.4  Borylation In the absence of coordinating functionalities, selective borylation of pyridine at the C3-position has been difficult to achieve. This is evident in the iridium-catalyzed borylation of pyridine reported by Ishiyama, Miyaura, and coworkers in early 2002. This reaction results in a mixture of C3- and C4-borylated pyridines, whereas quinoline exclusively yielded a 3-borylated product. (Scheme 8.53) [53]. a) + B(pin)-B(pin)

[IrCl(cod)]2 (1.5 mol%) 4,4'-(t-Bu)2 bpy (3 mol%)

b)

+ N

N H + diborylation products (12-17%)

octane,100o C, 6 h

N

[IrCl(cod)]2 (1.5 mol%) 4,4'-(t-Bu)2 bpy (3 mol%) + B(pin)-B(pin)

42% (2:1)

(nip)B

o

octane,100 C, 6 h

N

B(pin)

B(pin)

84% (> 99%)

N

Scheme 8.53  Iridium-catalyzed C–H borylation of pyridine derivatives.

In 2006, Marder and coworkers achieved borylation of pyridine derivatives ortho to the N atom or ortho to a MeO substituent for the first time; the complete regioselectivity could be attributed to either electronic or steric control. (Scheme 8.54) [54]. Excellent regioselectivity can be achieved with a pyridine that has a substituent at the C3-position to direct the MeO

OMe

N

t Bu

N

N

Ph

B(pin) N

t Bu

t Bu

N

B(pin)-B(pin) Hexane,80 oC, 16 h

B(pin)-B(pin) Hexane, 16 h

OMe

N

[Ir(cod)(m-OMe)] 2 (5 mol%) dtbpy (10 mol%)

[Ir(cod)(m-OMe)] 2 (2.5 mol%) dtbpy (5 mol%) N

MeO (pi n ) B

B(pin)-B(pin) Hexane,80 oC, 16 h

N

t Bu

[Ir(cod)(m-OMe)] 2 (5 mol%) dtbpy (10 mol%)

N

(pi n )B

B(pin)

B(pin)

(pin)B +

N

Ph

N

Scheme 8.54  Iridium-catalyzed borylation of C–H bonds in N-containing heterocycles.

Ph

377

378

8  Functionalization of Pyridines, Quinolines, and Isoquinolines

iridium-catalyzed borylation at the C5-position, presumably owing to steric reasons. This particular transformation was elegantly demonstrated in a key step in the total synthesis of complanadine A by Sarpong and Fischer (Scheme 8.55) [55].

[IrCl(cod)] 2 (1.5 mol%) 4,4'-(t-Bu) 2bpy (3 mol%)

BocN H H

BocN (nip)B H

B(pin)-B(pin) THF,80 oC, 5.5 h

N

N 75%

N

BocN

H

H

NBoc

Complanadine A

N

Scheme 8.55  Iridium-catalyzed pyridine C–H functionalization.

8.4  C4-Selective Functionalization 8.4.1  Alkylation Early in 1997, Grigg at al. found that heating 3- or 4-acetyl pyridine with alkenes in toluene in the presence of RulI2CO(PPh3)3 afforded the mono- or a mixture of mono- and dialkylated products in good yield (Scheme 8.56) [33]. H

O

R' R

+

R'

N

R = Me, Ph

R'

O

RuH 2 (CO)(PPh 3) 3 (10 mol%) toluene

O R

R + N

N

R'

Scheme 8.56  Ruthenium-catalyzed alkylation of pyridines.

A bulky group serving as a Lewis acid can trigger the C4 alkylation formation. In 2010, Nakao and Hiyama and coworkers reported direct C4-selective addition of pyridine across alkenes for the first time. This transformation was achieved by nickel/Lewis acid cooperative catalysis with an N-heterocyclic carbene ligand (Scheme 8.57) [56]. Both alkenes and pyridine bearing a variety of substituents could give linear 4-alkylpyridines in modest to good yields. On the other hand, the addition across styrene gives branched 4-alkylpyridines. To develop this kind of strategy, in 2013, Matsunaga, Kanai, and coworkers developed a new catalyst system for the C4-selective direct alkylation of pyridines (Scheme 8.58) [57]. They found a catalytic amount of CoBr2 in combination with LiBEt3H could give branched adducts from styrene derivatives and linear adducts from aliphatic alkenes.

N H

+

R

Ni(cod) 2 (5 mol%), IPr (5 mol%) N MAD (20 mol%), toluene o

130 C, 5-23 h

N

IPr

N

+

N

R

O

O Al Me MAD

Scheme 8.57  Selective C4 alkylation of pyridine by nickel/Lewis acid catalysis.

R

8.4  C4-Selective Functionalization

N

R1 +

R2

CoBr (1 mol%) LlBEt3H, Et3B(20 mol%)

N

R1

toluene, 70 o C, 20h

R2 +

N

R1

R2

R1 =Me,OMe, etc R2=Ph,nBu,nOctyl, etc

Scheme 8.58  Cobalt-catalyzed C4-selective direct alkylation of pyridines.

There are rare examples for the asymmetric functionalization of pyridine derivatives. In 2018, the Buchwald group disclosed a noval C−C bond-forming dearomatization of pyridines and pyridazines catalyzed by a chiral copper hydride (CuH) complex at room temperature (Scheme 8.59) [58]. The reaction process starts directly on free heterocycles and generates the nucleophiles in situ, eliminating the need for stoichiometric preactivation of either reaction partner. The dearomatization/reoxidation protocol is one of very few methods available for the enantioselective 1,4-dearomatization of heteroarenes. Aryl alkene (1.1-2 equiv) Cu(OAc) 2 6%, (S,S)-Ph-BPE

R1

R2

R2

O2 or air

R1

Ar R1

PhMe,rt

DMM S ( 3 equiv) THF,rt, 20-24 h

N

Ar

N

N

SiMe(OM e)2 OMe

N

N

72% yield, 93% ee

TES

OMe

F N

61% yield, 82% ee

N

73% yield, 94% ee

55 % yield, 82 % ee

Scheme 8.59  Asymmetric copper-catalyzed 1,4-dearomatization of pyridines and pyridazines.

In the same year, the Shi group reported the first example of enantioselective C−H cyclization of pyridines to chiral annulated products (Scheme 8.60) [59]. They developed a highly regio- and enantioselective nickel(0)-catalyzed endoselective C−H cyclization of pyridines with alkenes. An unprecedented enantioselective C−H activation at pyridyl 3- or 4-positions was enabled by bulky chiral N-heterocyclic carbene ligands. This protocol provides expedient access to a series of optically active 5,6,7,8-tetrahydroquinolines and 5,6,7,8-tetrahydroisoquinolines in moderate to high yields (up to 99% yield) and enantioselectivities (up to 99% ee).

R1

Ni(cod) 2 (5 mol%) (R,R,R,R)-SPIE/HCl (5 mol%) NaOt Bu (10 mol%)

R3

N R2

MAD (1,2 equive) CPME (0.5 M), 80 oC, 24 h

R1

R3

N R2 R1

N OMe 97%, 93% ee

N

N

tBu 79%, 93% ee

90%, 95% ee

Scheme 8.60  Regio- and enantioselective C−H cyclization of pyridines with alkenes.

379

380

8  Functionalization of Pyridines, Quinolines, and Isoquinolines

8.4.2  Arylation Early in 2005, Maes and co-workers also studied the cyclization of 3-substituted quinolines (Scheme 8.61) [60]. During the course of this reaction, the C4 arylation occurred selectively. Several reactions conditions were tested and microwave heating was found to improve the yield. To have a more general protocol for the synthesis of indoloquinolines, they also studied the reactivity of a few other substrates. Br

PdCl2 (PPh3 )2 , ( 8 mol%) NaOAc,DMAc,180 oC, MW, 10min

R N

R

R= H,Me, Cl, CF3 45-76% Yield

N

Scheme 8.61  Palladium-catalyzed intramolecular arylation.

Apart from intramolecular C4 selective arylation, the intermolecular examples have also been developed. In 2006, Fagnou and coworkers reported catalytic intermolecular direct arylation of perfluorobenzenes, in which there was one example for pyridine derivative (Scheme 8.62a) [61a]. 2,3,5,6-tetrafluoropyridine reacted with bromobenzene in excellent yield and required only a slight excess of the fluorobenzene. Later, they extended the reactant scope to aryl chloride under the combination of Pd(OAc)2 with S-Phos in the presence of K2CO3 in iPrOAc at 80°C (Scheme 8.62b) [61b]. In 2010, Su and coworkers demonstrated that benzene could also be feasible. Deuterium-labeling experiments suggested that C–H bond cleavage of the simple arenes rather than the polyfluoroarenes is involved in the rate-limiting step (Scheme 8.62c) [61c]. a)

F

Br F

N

Pd(OAc)2 (10 mol %), Pt Bu2 Me HBF4 (10 mol %) K 2 CO 3 (1.1 equiv), DMA,120 °C

F +

F

F

N

F

Pd(OAc)2 /S-Phos K2 CO3, iPrOAc,80 °C

Cl

+ F

F

1.0 equiv F

F

F

F

86% Yield

1.5 equiv b)

N

F

N

F

F F

97%

1.5 equiv

c)

F

N

H

F +

F

Pd(OAc) 2 (20 mol %), Cu(OAc)2 (2 equiv) Na 2CO3 , PivOH, DMA,110 °C, 24 h

F 0.2 mmol

F F

N

F F

70% Yield 0.8 mL

Scheme 8.62  Direct arylation of perfluorobenzenes.

The first example of directed transition metal-catalyzed C–H functionalizations of a pyridine ring at the 4-positions was achieved in 2010, when the Yu Group developed a Pd(0)/PR3-catalyzed arylation procedure for nicotinic and isonicotinic acid derivatives (Scheme 8.63) [43]. Later, the Sames group reported a novel palladium-catalyzed C3/4-selective C–H arylation of pyridines containing electron-withdrawing substituents (NO2, CN, F and Cl) (Scheme 8.64) [62]. There is repulsion between the nitrogen lone pair and polarized C-Pd bond at C2-/C6-positions and acidity of the C–H bond. Hence, the regioselectivity could be rationalized on the basis of the key electronic effects in combination with steric effects (sensitivity to bulky substituents).

8.4  C4-Selective Functionalization PhHN

O R

H +

Pd(OAod)2 /Pcy2 tBu HBF4

O

R

O

F

Cs2CO3, 3A MS,

Br

N

PhHN

toluene 130 o C, 48 h Ar=3,5-Me2Ph PhHN

N

N

O

PhHN

N

N 60%

50%

58%

Scheme 8.63  Pd0/PR3-catalyzed arylation of nicotinic and isonicotinic acid derivatives.

Pd(OAc)2 (5 mol%)/L EWG

+

Ar

PivOH,Ag2CO3 (Cs2CO3), toluene,120 °C

ArBr

N

EWG N

CO 2Et Ph

NO2 Ph

CN

CN

O2N N

N

N 58 %

41 %

Ph N

55 %

51 %

Scheme 8.64  Palladium-catalyzed selectively C–H arylation of pyridines.

8.4.3  Alkenylation In 2010, The Ong group presented a new amino-NHC nickel-aluminum system that mediates para-C–H bond activation of pyridine and quinoline derivatives. They also isolated the structure of a bimetallic η2, η1-pyridine nickel(0)-aluminum(III) intermediate prior to the C–H bond activation step (Scheme 8.65) [63].

via H

Pr +

R N

Pr

Ni(cod)2 (10 mmol%) amino-NHC(10 mmol%) Me 3Al (20 mmol%) o toluene,80 C

Pr Pr

AlMe3 N NHt-Bu Ar N

R N

t-BuHN

Ni

N

N N Ar

Ar=2,4,6-Me 3 Ph

Scheme 8.65  Bimetallic nickel aluminun mediated para-selective alkenylation of pyridine.

At exactly the same time, Nakao and Hiyama and coworkers reported the selective C-4 alkylation of pyridine by nickel/ Lewis acid catalysis (Scheme 8.66) [56]. In this article, a single example of C4-selective alkenylation is also described. During this reaction, IMes was used as the ligand and slow addition of an excess amount of 4-ocytne was found effective, giving a mixture of C4 and C3 cis-alkenylated pyridines.

381

382

8  Functionalization of Pyridines, Quinolines, and Isoquinolines Pr N

+ H

Ni(cod) 2 (5 mol%), IMes (5 mol%) AlMe 3 (20 mol%), toluene

+ Pr

110 o C, 5 h

Pr

Pr

N

53%

Pr

Pr

N 15%

Scheme 8.66  Selective C4 alkenylation of pyridine by nickel/Lewis acid catalysis.

8.4.4  Borylation In 2000, Smith III demonstrated general and selective borylations in arene functionalization (Scheme 8.67) [64], There is only one example for pyridine derivatives; borylation of 2,6-dimethylpyridine showed the para selectivity using the active pre-catalyst Cp*Rh(η4-C6Me6).

+

N

HBPin

Cp*Rh( 4-C 6Me 6) 2 mol % 150 o C,6 h

BPin

N

41%

Scheme 8.67  Steric and chelate directing efffects in aromatic borylation.

In 2007, the Hartwig group disclosed regioselective synthesis of halogenation of 2,6- disubstituted and 3-substituted pyridines in one-pot using a sequence of iridium-catalyzed arene borylation, followed by ipso halogenation with copper(II) salts (Scheme 8.68) [65].

[Ir(COD)(OMe)] 2 0.1 mol% H + B 2pin 2 dtbpy 0.2 mol% , THF,80o C R then evaporation

R N

X R

Bpin N

CuX 2 MeOH/H 2O=1:1

N Me

X N

X X=Br:51% Cl:46%

Me

N

X=Br:72% Cl:72%

Me

Scheme 8.68  Meta halogenation of 1,3-disubstituted arenes.

8.5  C8-Selective Functionalization The first example of complete regiocontrol for direct catalytic functionalization of unmodified quinolines at the 8-postion was reported by the Chang group in 2011 (Scheme 8.69) [66]. They developed rhodium (NHC)-catalyzed C8 selective arylation of quinolines with an excellent regioselectivity. In achieving high activity and selectivity, the choice of NHC ligand in combination with the rhodium catalyst source were found to be essential. It is also proposed that the formation of a bimetallic and monomeric rhodium species could both be responsible for the outcomes. In 2014, Sawamura and coworkers reported a heterogeneous iridium catalyst system based on the silica-supported cagetype monophosphane ligand silica-SMAP enabled catalytic site-selective C–H borylation of quinolines at the C8 position (Scheme 8.70) [67]. The C8-borylated quinaldine can be used for various transformations including oxidation, one-carbonhomologation/oxidation sequences, rhodium-catalyzed Heck-type reactions, and Suzuki–Miyaura coupling. The synthesis of a CRF1 receptor antagonist based on a late-stage C–H borylation strategy demonstrated the utility of the C8 borylation.

8.5  C8-Selective Functionalization H N R

+

ArBr

Rh 2(OAc)4 (3 mol %) IMes HCl (6 m ol %) t-BuONa (2.5 equiv)

Ar N R

toluene, 95 o C, 24 h Ph

Ph

Ph

N

N

N

O OtBu

90%

94%

81%

N

R N

Rh N

R

Rh

or

Ph

N Rh

N N

R

Bimetallic Intermediate I

R Monomeric Intermediate II

Scheme 8.69  Rhodium (NHC)-catalyzed direct arylation of quinolines at the 8-position.

+ Bpin-Bpin

R

Ir(OMe)(cod)2 (2 mol %) Silica-SMAP (2 mol %) MTBE,60 o C, 12 h

R N

N

P

Bpin Ph

N

N

Bpin

Bpin

Bpin

91%

N

M eO

71%

86%

SiMe 3

Si

O

O

Si O O O

O

Si O O

SiO 2 Silica-SMAP

N N 1) Ir(OMe)(cod) 2 M eO

N

2) Pd(PPh3 )4

MeO

N

CRF1 receptor antagonist

57% for two steps Cl

Scheme 8.70  Meta C–H Borylation of quinolines at the C8 position.

N-oxides could also be applied to the C8- selective C–H functionalization of quinolines. In 2015, Larionov developed a noval C8-selective C–H homocoupling of quinoline N-oxides (Scheme 8.71) [68]. The reaction proceeds with a high degree of site-selectivity to give 8,8ʹ-biquinolyl N, N’-dioxides that can serve as precursors to a number of 2,2ʹ-substituted 8,8ʹ-biquinolyls. Preliminary mechanistic analysis shows that the higher oxidation state palladium and the crucial role of acetic acid could be helpful for the C8-regioselectivity.

383

384

8  Functionalization of Pyridines, Quinolines, and Isoquinolines

Pd(OAc) 2 (10 mol %) AgOAc (4 equiv) AcOH/H 2O,120o C

R N O

R

R O

N

N

O

N X

Conditions

X

N

R X = H, OMe, NHtBu,Cl, iPr

R

Scheme 8.71  Palladium-catalyzed oxidative C8-selective C–H homocoupling of quinoline N-oxides.

Aryldiazonium tetrafluoroborates are a convenient aryl group donor also working as an oxidant via C−N2 bond cleavage in organic chemistry. In 2015, the Chang group reported the development of a mild and external oxidant-free Cp*Ir(III)catalyzed direct C−H arylation of arenes and alkenes. On the basis of the experimental and theoretical (DFT) studies, a catalytic pathway involving the formation of an iridium(V)-aryl intermediate via oxidative N2 extrusion is proposed (Scheme 8.72) [69].

R1 N O

+

R2

[IrCp*Cl 2]2 ( 5 mol %) AgNTf 2 ( 20 mol %)

N2BF4

CF3CH2OH 45 oC,12 H

R1 N O R2

MeO 2C N O

F

49%

N O

Br 62%

N O

CF3 54%

N O

N O

Cl 58%

Cl

Ph

50%

Scheme 8.72  Cp*Ir (III)-catalyzed C−H arylation of arenes with aryldiazonium salts.

Aryl halides are commercially available and widely used in organic chemistry. In 2015, Larionov described the palladium-catalyzed regioselective C8 arylation of quinoline N-oxides on synthetic, mechanistic and computational studies (Scheme 8.73) [70a]. The reaction could be carried out under thermal or microwave conditions on a gram scale and a number of functional groups in quinolines and iodoarenes could be tolerated. Mechanistic studies show the key role of the C−H bond cleavage step. DFT study points to the C8 cyclopalladation as the lower energy pathway under phosphine-free conditions with acetic acid as a non-innocent solvent/ligand. In addition, arylboronic acids are also important coupling partners. The application of C8 arylation of quinoline N-oxides was developed by Liu, Song, and Wang. (Scheme 8.73) [70b–c]. C-8 selective alkenylation of quinoline N-oxides has been also achieved by the Shibata group with cationic rhodium(I)catalysis in the reaction of diarylacetylenes (Scheme 8.74a) [71a]. This is a rare example of the use of an N-oxide as a DG and provides a new protocol for regioselective functionalization of the C-8 position of quinolines. A variety of 8-alkenylated quinoline N-oxides was obtained in moderate to high yields. Moreover, the N-oxide moiety can be readily removed by reductive treatment. A possible reaction mechanism was also proposed. C–H bond cleavage occurs at both the C-2 and C-8 positions to give intermediates A and B. However, alkyne insertion proceeds from A and the stable five-membered

8.5  C8-Selective Functionalization

metallacyle C is generated. Subsequent reductive elimination affords alkenylated products. In addition, C8 selective alkenylation of quinoline N-oxides could also be achieved by rhodium(III)-catalyzed direct C8 olefination of quinoline N-oxide with acrylates, styrenes, and aliphatic olefins (Scheme 8.74b) [71b-c]. a)

R1

R1

Pd(OAc) 2 (5 mol %) Ag 3PO4 (4 equiv) AcOH/H 2O

I

+

R2

N

N O

120 oC (T) or 180 oC (MW)

O

R2

N O

O

CF3

CF3

Br 90%(T),

78%(T), >20:1 83%(MW),>20:1

93%(T),C8/C2=17:1 87%(MW),C8/C2=16:1 b)

N

N O

R1

15:1

R1 +

[Cp*RhCl 2]2

ArBF 3K or ArB(OH) 2

N O

N O

Ar

Scheme 8.73  Palladium-catalyzed C8-selective C−H arylation of quinoline N‑oxides. a)

Ar

O

Ar

N

[Rh(cod) 2]OTf (10 mol%) xylyBINAP (10 mol%)

+

R

Ar

N R

Shibata's work

Ar

Ar H

Rh

O N

H H R

R A

O

H

N

Rh

O

Ar

H O

Rh

N R

B

C

b) R1 N O

+

R2

Rh(III) Cu(OAc) 2 H2O or O2 Sharma's work

R1 N O R2

Scheme 8.74  C–H alkenylation of quinoline N-oxides at the C-8 position.

H

385

386

8  Functionalization of Pyridines, Quinolines, and Isoquinolines

In 2014, the Chang group developed the rhodium(III)-catalyzed direct alkylation and alkynylation of quinoline N-oxides for C8 selective C−C bond formation (Scheme 8.75) [72]. The regioselective C-8 alkylation was explored successfully using quinoline N-oxides with diazo compounds and the desired C−H alkynylation of quinoline N-oxides occurred smoothly with TIPS-EBX. This example demonstrates the synthetic utility of the N-oxide DG as a stepping stone for remote C−H functionalization of quinolines. N2 R1

R2

N R1

Cp*Rh(III) H

I

O

H

N

R2

O

R3

O

O

N O R3

Scheme 8.75  Rh (III)-catalyzed C−C bond formation of quinoline N‑oxides at the C8 position.

In the same year, the Chang group succeeded in the direct introduction of heteroatomic groups at the C8 position of quinoline N-oxides for the first time (Scheme 8.76) [73]. In this article, rhodium-catalyzed iodination and iridium-catalyzed amidation of quinoline N-oxides were developed. Both reactions were highly regioselective, occurring at the C8 position under mild conditions with excellent functional group tolerance. In this approach, N-oxide was utilized as a stepping stone for the remote C−H functionalization. The present protocol is anticipated to be an important synthetic tool due to the utilities of the iodinated and amidated products accessible through the present study.

R

Cp* M

R H

N O

III

N

M = Rh

I

R

O

Zinquin ethyl ester (fluorescent sensors for Zn2+) O

N

H M *Cp

O

M = Ir

O

R N R'

NH

O

O N NHTs

Scheme 8.76  Introduction of heteroatoms at the C8 position of quinoline N‑oxides.

In 2016, Sundararaju developed a cobalt-catalyzed C–H and C–O coupling of quinoline-N-oxide with internal alkynes via a C–H activation/OAT process (Scheme 8.77) [74]. Such a catalytic transformation is witnessed for the first time with a cobalt catalyst and using N-oxide as a traceless DG, in contrast to the existing literature. In this reaction, various substituted quinoline-N-oxide structures can be coupled with symmetrical and unsymmetrical internal alkynes. Preliminary studies have revealed that the reaction likely undergoes irreversible cyclometallation. The above acylmethylation of quinoline N-oxides could also be accessed from rhodium-catalyzed regioselective C8-H acylmethylation of quinoline N-oxides with sulfoxonium ylides. In 2018, Pi, Cui, and coworkers addressed this transformation (Scheme 8.78) [75]. Sulfoxonium ylides probably work as precursors to obtain transition metal–carbene complexes. Reactions to introduce succinimides on quinoline N-oxides at the C8 position through C–H activation still remain scarce. Recently, similar reactions through rhodium(III)-catalyzed C8-alkylation of quinoline N-oxides with maleimides as alkylating agents were reported by the Sharma, Kim, and Lee groups(Scheme 8.79) [76].

References R1 +

R2

N

R1

Cp*Co(CO)I 2 NaOPiv CF3CH 2OH 120 oC, 24 h

R3

O

N O

R2 R3 S

Ph

N O Ph 80%

N O

N O

Ph

95%

Ph

89%

Ph

Scheme 8.77  Cobalt(III)-catalyzed C8 selective C–H and C–O coupling of quinoline N-oxide with internal alkynes. R1 O

R1

O S

+

R2

N O

[Cp*RhCl 2]2 AgNTf 2, NaOAc o HFIP,120 C, 12 h

N O R2

Scheme 8.78  Rhodium(III)-catalyzed selective C8−H acylmethylation of quinoline N-oxides.

O

O R1

R3 N

N R2

+

N R3 O

[Cp*RhCl 2]2 AgSbF 6 Sharma, Kim, and Lee

O R1

O O N R2

Scheme 8.79  Installation of diverse succinimides at the C8 position of quinoline N-oxides.

8.6  Summary and Conclusions Over the last 10 years, many achievements have been fulfilled on functionalization of pyridines, quinolines and isoquinolines. This chapter focused on the transformation via transition metal-catalyzed direct C–H activation processes including alkylation, alkenylation, arylation, acylation and others. Although the established methods have demonstrated high reactivity, good selectivity, and broad substrate scope, in contrast to the metal-catalyzed C–H activation of common aromatics, many challenges still need to be overcome: a) The reaction mode is almost limited to C–C bond formation and, although many examples are shown above, there are only a few reports about the formation of C–O, C–N, C–X, and similar bonds; b) C3, C4, and C8 selective functionalization need to be exploited further; and c) The application of asymmetric catalysis in functionalization of pyridines, quinolines, and isoquinolines is still a challenge; a breakthrough might be made from C2 selective functionalization because of its wide development. We anticipate that the development of new strategies and catalytic systems will further contribute to the C–H activation of pyridines, quinolines, and isoquinolines in the future.

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71 (a) Shibataa, T. and Matsuoa, Y. (2014). Directed C-H alkenylation of quinoline N-oxides at the C-8 position using a cationic rhodium(I) catalyst. Advanced Synthesis & Catalysis 7 (356):1516–1520. (b) Sharma, R., Kumar, R., Sharma, U. et al. (2015). RhIII-catalyzed dehydrogenative coupling of quinoline N-oxides with alkenes: N-oxide as traceless directing group for remote C–H activation. European Journal of Organic Chemistry 24 (2015):7519–7528. (c) Sharma, R., Kumar, R., Sharma, U. (2019). Rh/O2-catalyzed C8 olefination of quinoline N-oxides with activated and unactivated olefins. The Journal of Organic Chemistry 5(84): 2786–2798. 72 Jeong, J., Patel, P., Chang, S. et al. (2014). Rhodium (III)-catalyzed C−C bond formation of quinoline N‑oxides at the C‑8 position under mild conditions. Organic Letters 16 (17): 4598–4601. 73 Hwang, H., Kim, J., Chang, S. et al. (2014). Regioselective introduction of heteroatoms at the C‑8 position of quinoline N‑oxides: Remote C−H activation using N‑oxide as a stepping stone. Journal of the American Chemical Society 136 (30): 10770–10776. 74 Barsu, N., Sen, M., Sundararaju, B. et al. (2016). Cobalt (III) catalyzed C-8 selective C–H and C–O coupling of quinoline N-oxide with internal alkynes via C–H activation and oxygen atom transfer. Chemical Communications 7 (52): 1338–1341. 75 You, C., Pi, C., Cui, X. et al. (2018). Rh(III)-catalyzed selective C8−H acylmethylation of quinoline N-oxides. Advanced Synthesis & Catalysis 21 (360): 4068–4072. 76 (a) Thakur, A., Dhiman, A. K., Sharma, U. et al. (2021). Rh(III)-catalyzed regioselective C8-alkylation of quinoline N-oxides with maleimides and acrylates. The Journal of Organic Chemistry 9 (86):6612–6621. (b) An, W., Mishra, K., Kim, I. S. et al. (2021). Site-selective C8-alkylation of quinoline N-oxides with maleimides under Rh(III) catalysis. The Journal of Organic Chemistry 11 (86):7579–7587. (c) Nale, S. D., Aslam, M., Lee, Y. R. (2021). Installation of diverse succinimides at C-8 position of quinoline N-oxides via Rhodium(III)-catalyzed C-H functionalization. ChemistrySelect 32(6): 8244–8248.

393

9 Transition Metal-Catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives Christian Bruneau and Rafael Gramage-Doria Univ Rennes, CNRS, ISCR-UMR6226, Rennes, France

9.1  Introduction Diazines and benzodiazines are important building blocks that have found, and are increasingly finding, a wide range of applications from material sciences to medicinal chemistry [1–8]. They comprise a fully aromatic heterocyclic six-membered ring containing two nitrogen atoms at different positions (Figure 9.1). Their synthesis has been extensively reviewed and it clearly highlights that multi-functionalized diazines (and benzodiazines) are typically prepared via long condensation reaction sequences starting from highly functionalized (and sometimes very sensitive) carbonyl- and amine-containing derivatives [9–12]. In addition, the poor chemical stability and lack of reaction predictability they present over a range of conditions makes them difficult to directly functionalize [13–20]. As such, the straightforward functionalization of diazines (and benzodiazines) is challenging and new methodologies based on metal-catalyzed C-H bond functionalization have just started to appear [21–24]. It is relevant to note that such heterocycles are considered as electron-poor species [25, 26]. Nevertheless, C-H bond functionalizations by means of metal catalysts can give access to otherwise impossible to form, highly functionalized diazine (and benzodiazine) derivatives, besides being an excellent atom- and step-economy transformation from a sustainability perspective [27–35]. In the following chapter, we will present and discuss the most notable examples related to the metal-catalyzed C-H bond functionalization of diazines and benzodiazines. Note that examples involving the formal use of metals for radical-mediated transformations such as Minisci-type ones are not herein included [36, 37]. An alternative strategy of the core functionalization of diazines is the prior formation of diazine oxide (or other N-activated fragment) where the oxygen atom behaves as a metal-directing group to assist in the further catalytic events [38–41]; however this is beyond the scope of the current book chapter as the directing group (DG) has to be cleaved/ N

N N

N

pyridazine (1,2-diazine)

N N

N

N

pyrimidine (1,3-diazine)

pyrazine (1,4-diazine)

N N

N

N

N N

quinazoline quinoxaline cinnoline phthalazine (benzopyrimidine) (benzopyrazine) (benzo[c]pyridazine) (benzo[d]pyridazin )

Figure 9.1  Molecular structures of the family of unfunctionalized diazines and benzodiazines.

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

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9  Transition Metal-Catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives

transformed in subsequent steps to release the nitrogen-free diazine (or benzodiazine). Note that functionalizations of C-H bonds in which the diazine serves as a DG are not herein discussed because the diazine core remains chemically unchanged.

9.2  Carbon-carbon Bond Formation 9.2.1  C-H Bond (Hetero)arylations The synthesis of biphenyl derivatives via transition metal-catalyzed C-H bond functionalization strategies is highly relevant due to the ubiquitous presence of the biphenyl motifs [42]. Consequently, it is hardly surprising that most efforts devoted to the functionalization of diazines and benzodiazines have focused on developing C-H bond (hetero)arylation methodologies using transition metal catalysts. In this context, the first successful methodology was reported by Daugulis and coworkers in 2008 [43]. They showed that a copper/phenanthroline-based catalytic system enabled the C–H bond arylation of unfunctionalized pyridazine and pyrimidine in the presence of iodobenzene as an arylating source and Et3COLi as a base (Scheme 9.1, top). Although in modest yields, the functionalization selectively occurred in the most acidic sites (C4 for pyridazine and C5 for pyrimidine). Some mechanistic investigations indicated the catalytic formation of organocopper species upon C–H bond activation (Scheme 9.1, bottom). When CuCl2 was employed as the catalyst in the presence of an atmosphere of oxygen, the homocoupling product resulting from C–H bond functionalization was obtained in the case of 2-methoxypyrazine (Scheme 9.2) [44]. A similar finding of 42% yield for homo-dimerization of 2-methoxypyrazine was later evidenced using MnCl2 in catalytic quantities (7 mol%) [45].

H

Y N

X

CuI (10 mol%) phenantroline (10 mol%) Et COLi

+ I

o

DMPU, 125 C, 12 h

N

1 equiv.

2 equiv.

H vi a N

Y X

+ CuL

Y X

X = N, Y = CH, 60% X = CH, Y = N, 31% CuL

- BH

N

Y X

+ Ph I

Ph

- CuL

N

Y X

Scheme 9.1  Copper-catalyzed C–H bond arylation of pyridazine and pyrimidine. L=phenanthroline, B=Et3CO. N H

N

CuCl2(10 mol%), iPrMgCl.LiCl,ZnCl2

MeO

N

r.t., 1 h

OMe N

N MeO

N

50%

Scheme 9.2  Copper-catalyzed C–H bond homocoupling with pyrazine derivative.

Regarding the C–H bond arylation of diazines, nickel catalysts proved particularly effective as shown by the group of Chatani in 2009 [46]. The C2-arylation of unfunctionalized pyrazine was achieved upon reaction with Ph2Zn as the arylating reagent and a nickel catalyst formed upon in situ combination of Ni(cod)2 with tricyclohexylphosphine (Scheme 9.3, top). The corresponding 2-phenyl pyrazine was obtained in 81% yield. In the presence of an excess of the arylzinc reagent, bis-arylation is feasible as demonstrated for the functionalization of quinoxaline (Scheme 9.3, top) [47]. The fact that dihydropyrimidine derivatives undergo C(sp3)-H bond arylation (Scheme 9.3, bottom) and further mechanistic investigations suggested the reaction mechanism displayed in Scheme 9.4. The initial nickel(0) catalyst reacts with diphenylzinc-diazine adduct forming a postulated azanickelacyclopropane that undergoes intramolecular transmetallation between nickel and zinc and further reductive elimination with regeneration of the nickel(0) species. A fast oxidative rearomatization afforded the C2-arylated products and formation of metallic zinc and benzene as side-products.

9.2  Carbon-carbon Bond Formation

N

H

N or

N

H

N

H

Ph2Zn (n equiv.) Ni(cod)2 (5 mol% ) PCy3 (10 mol%)

N

toluene 10 0 C, 20 h

N

Ph

81% (n = 1.5)

N R

Ph2Zn (n equiv.) Ni (cod)2 (5 mo l%) PCy 3 (10 mol%)

H H

N H

N

toluene 60 C, 20 h

H Ph

N H

R

N

Ph

N

Ph

or 74% (n = 3)

N

DDQ

R

N

Ph

R = Me, 54% R = 4-Me-C6H4, 78%

Scheme 9.3  Nickel-catalyzed C–H bond arylation of unfunctionalized pyrazine and quinoxaline (top) and nickel-catalyzed C–H bond arylation of unfunctionalized dihydropyrimidine derivatives (bottom). N

N Ph N H Zn Ph

Zn(0) + PhH

N ZnPh2

[Ni]

N N N

Ph

N

H N [Ni] Ph Ph Zn

H N [Ni] Ph Zn Ph

Scheme 9.4  Reaction mechanism proposal for the nickel-catalyzed C–H bond arylation of unfunctionalized pyrazine.

Related C–H bond arylations of dihydroquinazolines were reported early under rhodium catalysis in the presence of aryl halides by Bergman, Ellman and coworkers, although with a different regioselectivity (Scheme 9.5, top) [48, 49]. In stark contrast, the same reaction conditions applied to the fully aromatic quinazoline has not provided any C–H bond functionalization so far (Scheme 9.5, top). These observations emphasize the difference of reactivity between the aromatic and non-aromatic families of diazines and benzodiazines. On the other hand, the C–H bond arylation of dimethylated pyrimidine and pyrazine at the C2 site was successfully achieved under rhodium catalysis using aryl bromides albeit with low yields (Scheme 9.5, bottom) [50]. The mechanism, which is depicted in Scheme 9.6, takes benefit of the proximal nitrogenrhodium coordination to assist the selective ortho-C–H bond activation. The formation of tautomerizing rhodium-carbene

H

N

NH

N

H

( 6 equiv.)

N 78%

H N

(6 equiv.)

Ph

N

NEt 3 (4 e quiv.) THF 150 C, 6 h

N or

N

PhI (2 equiv.) [RhCl(coe)2]2 (5 mol%) PCy 3 (40 mol%)

ArBr (1 equiv.) [RhCl(CO)2]2 (5 mol %) dioxane 175 C, 24 h

PhI (2 equi v.) [Rh Cl(coe)2] 2 (5 mol %) P Cy 3 (40 mol%)

H

N N

NEt 3 (4 equiv.) THF 150 oC, 6 h

N

N

Ar or

N 26%

Ar N

33%

Scheme 9.5  Difference of reactivity between unfunctionalized dihydroquinazoline and quinazoline in rhodium-catalyzed C–H bond arylations (top), and rhodium-catalyzed C–H bond arylation of dimethylated diazines (bottom). coe=cyclooctene, ArBr=2-bromonaphthalene.

395

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9  Transition Metal-Catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives

species as intermediates was postulated that further underwent oxidative addition upon reaction with aryl bromide and final reductive elimination to yield the C–H bond arylated diazines and regeneration of the rhodium(I) catalyst. N [RhCl(CO)2]2 +

Ar

N R

X

R

X

OC Rh X

H R

Y

X

OC Ar CO Rh N Br YS X

R

Ar-Br

Y

CO

Y

R = Me, X = N, Y = CH R =H, X = C-Me, Y = N

H

N N

X

R

H

Y

N R

R

X

OC H CO Rh X Y

H N R

X

OC CO Rh X Y

+S - HX

OC CO Rh N S Y X

Scheme 9.6  Reaction mechanism proposal for the rhodium-catalyzed C–H bond arylation of methylated diazines. S=solvent and/or heterocycle capable of N-coordination.

In 2011, Chang and coworkers demonstrated that phenazine, a scaffold that might be regarded as a pi-extended quinoxaline derivative, underwent a selective and unique C8-arylation under rhodium catalysis [51]. The key for the success of the reaction was the use of IMes carbene ligand in combination with the dimeric Rh2(OAc)4 complex (Scheme 9.7). Interestingly, bimetallic intermediates were evoked to explain the observed selectivity and reactivity according to some preliminary mechanistic investigations. H N N (2 equiv.)

PhBr (1 equiv.) Rh2(OAc)4 (3 mol%) IMes.HCl (6mol%) t

BuONa (2.5 equiv.) toluene 95 oC, 24 h

N R

Ph N

R

N Rh

N

N

73%

N

Rh

Scheme 9.7  Rhodium-catalyzed C–H bond arylation of phenazine. IMes=1,3-dimesitylimidazol-2-ylidene, R=2,4,6-trimethylphenyl.

The previously-described examples are rather selective and they are actually more general for electron rich heteroaromatics (i.e. substrates containing a single nitrogen atom). The first general methodology for the C–H bond arylation of diazines was probably reported in 2009 by the Hua group, which used gold(I) catalysis [52]. At the expense of excess amounts of diazine, the reaction conditions were compatible with a large number of functional groups at the aryl bromide partner (Scheme 9.8). Whereas electron-rich aryl bromides reacted smoothly with pyrazine, addition of catalytic amounts of silver were necessary when using electron-poor ones. Details regarding the reaction mechanism remain to be studied. Among the many metal-based catalysts employed in C–H bond functionalization, the palladium-based systems are particularly powerful [53, 54]. Consequently, they have also been used for the C–H bond (hetero)arylations of diazines and benzodiazines. An intermolecular C–H bond arylation concerning diazines as substrates was reported by Guchhait and coworkers in 2012 [55]. The highly functionalized 3-aminoimidazopyrazine derivatives, which are relevant from a biological point of view, delivered the corresponding C6-arylated products upon reaction with different bromoarenes using a palladium/triphenylphosphine/pivalic acid catalytic system (Scheme 9.9). Besides a large scope with respect to the bromoarene partner, the catalysis was

9.2  Carbon-carbon Bond Formation

N

+

R

(10 equiv.)

N

t BuO K (2

equiv.) 10 0 C, 12-24 h

Br

N

R

N

(1 equiv.)

N

N N

Cy3 PAuCl (2 mol%) Ag BF4 (0 o r 2 mol%)

H

N

56%

N

N

R

N

24%

N N

40%

R= H, 81% R = 2-Me, 58% R = 3-Me, 86% R = 2,4-Me, 44% R = 2- OMe, 64% R = 4-OMe, 60% R = 2-Cl, 25% R = 4-Cl, 36% R = 2-CF3, 31%

Scheme 9.8  Gold-catalyzed C–H bond arylations of unfunctionalized pyrazine.

also compatible with different functional groups at the amino site. Preliminary theoretical calculations indicate that the C–H bond being arylated provides the most thermodynamically accessible pathway for a plausible concerted metalation deprotonation (CMD) key step (Figure 9.2), which is in line with previous and pioneering reports from Fagnou’s group [56, 57]. Pd(OAc)2 (10 mol% )

H

N

R3

+ N

NHR 2

R1

K2CO3 (2 equiv.) toluene, 110 C

Br

N

PPh3 (20 mol% ) PivOH (3 0 mol%)

N N

R1 and R2 = alkyl, aryl

(1 equiv.)

N NHR2

R1

(2.5 equiv.)

(22 examples)

CHO

Cl N

N N

N

N

NH

48%

R3

N NH

N N

N NH

MeO 72%

53%

Scheme 9.9  Palladium-catalyzed C–H bond C6-arylations of 3‑aminoimidazo[1,2‑a]pyrazine derivatives.

Very similar reaction conditions were later applied by Marder and coworkers for the C–H bond arylation of dicyano- and dinitroquinoxalines, respectively, which were conceived as strong electron acceptors relevant for material sciences [58]. In this case, bis-functionalized quinoxaline derivatives at the C5 and C8 sites were primarily obtained (Scheme 9.10). Two different palladium pre-catalysts with different oxidation states (+2 or 0) were employed depending on the starting materials considered. For instance, Pd(OAc)2 was preferred for the C–H bond arylation of dicyanoquinoxalines whereas Pd2dba3 was suited for functionalization of dinitroquinoxalines. This strategy is particularly useful because it overcomes the issues encountered in the classical pre-functionalizations with stannyl, boryl, or other metallic derivatives that generate large amounts of chemical wastes and impose additional synthetic steps to produce these materials.

Ar N

PPh3 O Pd H

N R1

O

N NHR2

Figure 9.2  CMD transition state relevant for the palladium-catalyzed C–H bond C6-arylation of 3‑aminoimidazo[1,2‑a] pyrazine derivatives.

397

398

9  Transition Metal-Catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives ArBr Pd(O Ac) (10 mol%) P Bu Me.HBF (20 mol %)

H Et

N

CN

Et

N

CN

Ar Et

N

CN

Et

N

CN

(6 examples) PivOH (1 eq uiv.) K CO (3 equiv.) toluene , 120 C

H

Ar

R

N

ArBr P d dba ( 10 mol% ) NO2 P Bu Me.HB F (20 mol% )

R

N

NO2

H

Ar R

N

NO2

R

N

NO2

(6 examples) Pi vOH (0.5 equi v.) K PO (2.2 eq uiv.) toluene, 1 20 C

H NMe2

Ar

F

SiMe3 S

Et

N

CN

H

N

NO2

Et

N

NO 2

Et

N

CN

H

N

NO2

Et

N

NO 2 S

NMe2 80%

SiMe3

F 72%

68%

Scheme 9.10  Palladium-catalyzed C–H bond arylations of dicyano- and dinitroquinoxaline derivatives.

In 2019, Zhang, Feng, Lin, and coworkers reported a sequential cross-coupling/annulation of ortho-vinyl bromobenzenes with (hetero)aromatic bromides under palladium catalysis [59]. They reported an example involving a quinoxaline substrate leading to a polycyclic heteroaromatic derivative (Scheme 9.11). Although the yield was modest, a complex structure involving selective formation of two new bonds was realized. An important parameter was the choice of an appropriate ligand for the palladium-based catalytic system, in this case bis[(2-diphenylphosphino)phenyl]ether (DPEphos).

Ph

H N

Br

Ph

+

Pd(OAc)2 (5 mol%) DPEphos (10 mol%)

N

K2CO3 (3 equiv.) dioxane,130 C

N

Br

N

37%

Scheme 9.11  Palladium-catalyzed sequential Heck/C–H bond arylation of 7-bromoquinoxaline.

B H N

Pd L N

R1N

X

Ar

HB+ Figure 9.3  Key transition state involving a palladated species with a dearomatized 2-aminopyrimidine ring for the C–H bond arylation. B=base.

2-Aminopyrimidine derivatives were found to undergo regioselective C5-H bond arylation via palladium catalysis in the presence of aryl halides [60]. The C–H bond arylation methodology was general and tolerant to electron-rich as well as electronpoor substituents in the aryl halide (Scheme 9.12). It was noted that the reactivity of aryl halides increased in the order Ar-Cl80% yield observed in products 110h-m. Notably, thioxanthones and acridinones (xanthones in which the B-ring oxygen is replaced with S or N, respectively) were successfully applied, suggesting that analogues of chromenone in which the oxygen is substituted with other heteroatoms would likely furnish the desired products if applied in this methodology. More recently, building upon Kim’s initial work with maleimides 108 and chromenone derivatives 81, Song was able to succeed by employing ruthenium(II)-catalysis (Scheme 10.72) [108]. A wider range of chromenones was examined than in Kim’s work and showed that electron-donating and withdrawing groups on the chromenone backbone had no impact on the yields for the formation of products 110p–r. Given Kim’s demonstration that substitution at the 6-position was too sterically hindering, it is unsurprising that no such examples were reported in Song’s work. Maleimide derivatives were also explored, and once again, neither electron-donating nor withdrawing groups exhibited significant impact on the yield of the reaction.

10.5  4H-Chromenones (Chromones)

R2 N H

O

1

R

+ O

O 81 Et

O N

O

O

R1 O

R2 N

O

108

[Ru(p-cymene)Cl2]2 (2.5 mol %) AgNTf 2 (10 mol %)

O

PhCOOH (0.8 equiv) Neat, 80 oC

R1

110i, R1 = H, 91% 110n, R1 = 2-Me, 75% O 110o, R1 = 3-Me, 93% 110p, R1 = 7-Me, 89% 110q, R1 = 7- OMe, 87% 110r, R1 = 7-OAc, 85%

R2 N

O O

110

O

O O

O

110g, R2 = H, 79% 110k, R2 = Cy, 89% 110l, R2 = Bn, 90% 110s, R2 = 4-Br-C6H4, 89% 110t, R2 = (CH2)2CO2Me, 87%

Scheme 10.72  Ru(II)-catalyzed C5-alkylation of 4-chromenone 81.

10.5.3.3  (Hetero)arylation

Whereas oxidative arylation and heteroarylation methods exist within the toolbox of C–H activation applications, there is still a dearth of techniques available for the C5-arylation of chromenones. Whereas classic examples such as Suzuki couplings have proven to be exceptionally powerful techniques, the atom-economy of oxidative C–H/C–H couplings makes them highly sought-after approaches. Although oxidative ortho-heteroarylations have been successfully demonstrated, these catalytic systems primarily employ palladium, ruthenium, rhodium, cobalt, and nickel catalysts whose success largely relies on strongly coordinating DGs such as quinolyl amides and often require high temperatures to affect good yields (>160oC) [112–115]. Of course, as discussed already throughout this chapter, the ability of ketones as DGs has been successfully demonstrated to be highly effective with a broad range of transition metal catalysts. Further building upon this, You has recently reported the application of an iridium(III) catalytic system that demonstrated amenability to a remarkably broad range of DGs, and the ability to effect greater activity than the analogous rhodium(III)-system [116]. In cases where the employed DG was a ketone, as in the single chromenone example 81 (Scheme 10.73), elevated temperatures of 120oC were necessary. CO2Et

H

O H

O

+

PivOH (1 equiv) DCE, 120 oC, 24 h

O 81

CO 2 Et

[IrCp*Cl2]2 (5 mol %) AgSbF6 (20 mol %) Ag2O (3 equiv)

111

O

O

O 112, 46%

Scheme 10.73  C5-Selective oxidative heteroarylation of 4-chromenone 81.

It was identified that the crucial, and often limiting, step of similar transformations is reductive elimination. In the case of the iridium(III) species, the high stability of the pre-reductive elimination intermediate precludes product formation. To overcome this, the addition of excess oxidant gives rise to a highly active iridium(V) species, which readily undergoes reductive elimination, furnishing the arylated product and regenerating the active iridium(III) catalyst. This process, known as oxidatively induced reductive elimination (ORE), enables catalytic systems to overcome an effective thermodynamic blocking of the catalytic cycle, which is typically resolved through necessarily high temperatures. Although a chemical oxidant was employed in this example, it is also possible to electrochemically oxidize the metal center to invoke ORE, as has been recently demonstrated by the Chang group [117]. In Chang’s 2019 work, an extensive investigation into the mechanism of ORE-dependant C–H activation/arylation was performed. A combination of DFT

473

474

10  Functionalization of Chromenes and Their Derivatives

calculations and experimental data was able to demonstrate that reductive elimination failed to occur in their catalytic system, even at elevated temperatures, unless a suitable oxidant such as silver fluoride was present to enable ORE. Furthermore, the effect of ORE allowed the majority of the substrates in this work to undergo arylation at room temperature. In the case of ketone DGs, such as in the only example of a 4-chromenone derivative, elevated temperatures of 50 oC were required (Scheme 10.74). CF3

H

O

Bpin + F3 C

O 81

[IrCp*Cl2] 2 (5 mol %) AgF (2.2 equiv) AgNTf 2 (20 mol %)

O

Cu(OAc)2 (0.5 equiv) DCE, 50 oC, 12 h

O

113

114, 81%

Scheme 10.74  ORE-mediated C–H activation/arylation of 4-chromenone 81 with boronic ester 113.

However, this is still a remarkably low temperature when one considers that all examples of C–H activation involving 4-chromenone 81 discussed vide supra required a minimum of 80oC, with the majority exceeding 100oC. Indeed, it is quite likely that this work, successfully demonstrating the amenability of rhodium, ruthenium, and iridium to ORE, will pave the way for various catalytic systems to enable the synthesis of compounds previously inaccessible through such step- and atom-economical methods as allowed through C–H activation. 10.5.3.4  Amination/Amidation

In 2013, Chang described the direct amination of 4-chromenone derivatives 81 as part of a larger body of work on amination of ortho-benzamides, ketones, or ketoximes [118]. In conjunction with a silver additive to generate the active catalyst, rhodium(III)-successfully catalyzes the C–H activation/amination of a range of substrates in moderate to high yield. Increased steric demand around the carbonyl species was shown to be particularly detrimental to the yield, and the yield drops significantly in the case of C2-substituted chromenone derivatives 115b and 115c, even with increased catalyst loadings (Scheme 10.75). Eighteen azide derivatives were demonstrated to be effective (43–86% yield) with their model substrate; however only the bis-trifluoromethyl benzyl azide 115 was applied in the case of 4-chromenones. H

O

R1

O 81

a

+ R2

Ar

N3

[RhCp*Cl2]2 (4 mol %) AgSbF6 (16 mol %) DCE, 110 C, 24 h

115 Ar = 3,5-(CF3)2C6H3

Ar

NH O

R1

O

R2

115a, R1 = R2 = H, 95% 115b, R1 = H, R2 = Ph 60%a 115c, R1 = OAc, R2 = Ph, 66%a

8 mol % [RhCp*Cl2]2, 32 mol % AgSbF6

Scheme 10.75  Direct C–H amination of 4-chromenone 81 with azides 115.

In the same year, Sahoo described the C–H activation/amidation at the 5-position of 4-chromenones 81. Chang followed shortly afterwards by employing a similar system (Scheme 10.76) [119, 120]. Both reports focused primarily on the orthoamidation of aryl esters and ketones; however both successfully demonstrated the applicability of their systems with 4-chromenone. Chang employed an iridium catalyst in combination with multiple additives, allowing for room temperature reactions via CMD with relatively short reaction times (Scheme 10.76, condition set A).

10.5  4H-Chromenones (Chromones)

H

O + O

R1

O Ph S N3 O 116

81

[IrCp*Cl2] 2 (4 mol %) AgNTf 2 (16 mol %) HOAc (15 mol %) Li2CO3 (15 mol %) DCE, 25 oC, 12 h A or [RuCl2(p-cymene)] 2 B (4 mol %) AgSbF6 (20 mol %) Cu(OAc)2 H2O (50 mol %) DCE, 100 oC, 24 h

O S NH O O

Ph

O

R1

117a, R1 = H, 97% (A), 65% (B) 117b, R1 = Ph, 95% (A)

Scheme 10.76  Direct amidation of 4-chromenone 81 with tosyl azide 116.

In contrast, Sahoo reported the use of a considerably cheaper ruthenium catalyst. However, this required high loadings of additives and temperatures of 100oC (Scheme 10.76, condition set B). Although neither group investigated the impact of replacing the tosyl moiety in the case of 4-chromenone substrates, we note that a range of sulfonyl azides 116 was employed with other substrates in both reports with great success, including alkyl-, benzyl-, thiophenyl-, and a range of substituted phenyl-sulfonyl azides. Employing virtually unchanged reaction conditions, Chang also reported two examples of 4-chromenone-derived phosphoramidites 118 by simply replacing the sulfonyl azide 116 (Scheme 10.76, condition set A) with a phosphoryl azide, furnishing the desired products 118 in good to excellent yields (Scheme 10.77) [121]. Longer reaction times and elevated temperatures were required compared to the application of sulfonyl azides. Once again, these examples were simply part of a larger substrate scope exploiting the weakly coordinating carbonyl DG. Only the simple phosphoryl azide 117 was used in conjunction with 4-chromenone substrates 81.

H

O

O 81

O + PhO P N3 OPh R1 117

[IrCp*Cl2]2 (5 mol %) AgNTf 2 (20 mol %) HOAc (15 mol %) Li2CO 3 (15 mol %) DCE, 60 oC, 24 h

O PhO P PhO NH O

O

R1

118a R1 = H, 76% 118b R1 = Ph, 90%

Scheme 10.77  Synthesis of phosphoramidites 118 via C–H activation/amidation.

Notably, attempts to replace the iridium catalyst with either ruthenium or rhodium, as described by other groups, failed to furnish the products in greater than trace quantities. However, in this report Chang employed AgNTf2 in all cases, whereas previous reports with 4-chromenone substrates that successfully applied ruthenium or rhodium catalysts, utilized AgSbF6, including their own work on amination (Scheme 10.76). This may potentially explain the apparent lack of reactivity despite chemically similar systems. However, in another publication by Chang on ortho-amidiation of aryl ketones, the use of AgNTf2 together with ruthenium proved highly successful [122]. Kim further expanded the C5-amidation of 4-chromenones 81, continuing with the application of ruthenium catalysis, but with a significantly broader substrate scope (Scheme 10.78) [123]. Employing lower loadings of catalyst and silver additive than Sahoo (2.5 mol % and 10 mol %, respectively, versus 4 mol % and 20 mol %), Kim reported shorter reaction times with more dilute conditions (0.3 M versus 0.5 M). The scope of sulfonyl azides 116 was restricted to phenyl derivatives whereas previous work by Sahoo and Chang incorporated alkyl and heteroaryl sulfonyl azides. This work demonstrated a significant variety of complex substitution patterns around the chromenone backbone, in addition to the sulfonyl azide (Scheme 10.78). Substitution at the 2- and 3-positions appeared to have a surprisingly profound affect (see examples 117h and 117i), whereas substitution changes to the sulfonyl azide 116 had no discernible electronic effect. Notably, no sterically demanding substrates were investigated in this scope.

475

476

10  Functionalization of Chromenes and Their Derivatives

H

O

O + R S N3 O

R2 R

R1

O

[RuCl2(p-cymene)]2 (2.5 mol %) AgSbF6 (10 mol %)

4

3

116

81

O R4 S NH O O

R2

3

R

Cu(OAc)2 . H2O (50 mol %) DCE, 100 oC, 6 h

O

R1

117

X O2S

Ts

NH O

Ts

NH O

Ts

NH O

Br O

O 117a, X = H, 61% 117c, X = 4-MeO, 54% 117d, X = 4-NO2, 58% 117e, X = 3-Cl, 48% 117f, X = 2-F, 54%

NH O OMe

Me O CO 2Bn

117g 42%

Ph

O OMe

117h 76%

117i 34%

Scheme 10.78  C–H activation/amidation of 4-chromenones 81.

One more example of C5-selective C–H activation/amidation of 4-chromenone 81 is a manganese-based system, once again employing sulfonyl azides 116 as the nitrogen source [124]. Excellent yields and good functional group tolerance were observed with benzophenone derivatives including 4-chromenone (Scheme 10.79).

H

O + O 81

O Ph S N3 O

O O S Ph NH O

MnBr(CO)5 (5 mol %) Me2Zn (2 equiv) Cu(OAc)2 (1.5 equiv) 1,4-dioxane, 80 oC, 6 h

O

116

117a, 89%

Scheme 10.79  Manganese-catalyzed C–H amidation of chromenone 81 with sulfonyl azide 116.

Recently, Maji showed a single example of rhodium(III)-catalyzed C5-amidation of chromenone 81 in which dioxazolone 119 was utilized as a nitrogen source to deliver amidated product 120 in 53% yield (Scheme 10.80) [98]. H

O

81 + O

O

O O N

Ph

Me

[Cp*RhCl2]2 (5 mol %) AgSbF6 (20 mol %) Cu(OAc)2.H2O (15 mol %) DCE, 100 oC, 20 h

O

NH O

O 120, 53%

Me

Ph

119

Scheme 10.80  Rhodium(III)-catalyzed C5-amidation of chromenone 81 using dioxazolone 119.

Together, these similar publications detailing the installation of nitrogen-containing functional groups at the C5-position present a clear picture of the range of reaction conditions and substrate modifications that are compatible with this methodology.

10.5  4H-Chromenones (Chromones)

10.5.3.5  Others

Alkynes are important synthetic intermediates in organic synthesis, but C5-selective alkynylation of 4-chromenone was not reported until six years after the alkenylation work described by Jeganmohan[94] In 2017, Jiang described the iridiumcatalyzed C–H-alkynylation of carbonyl compounds, where 4-chromenones also effectively participated in the reaction with triisopropylsilyl (TIPS)-protected alkynyl bromide 48 to form C5-selective alkynylated products 121a–b in 75–77% yield (Scheme 10.81) [125]. Notably, common catalytic systems such as palladium(II), ruthenium(II), and rhodium(III) were found to be ineffective. Furthermore, only TIPS-protected alkynyl bromide was studied and once again the 4-chromenones scope also limited. Alkynylation takes place selectively at the C5-site with the aid of the carbonyl DG, while the electronically competing C=C is completely inert under these conditions. TIPS H

O

Br R

+

O

TIPS

[IrCp*Cl2]2 (4 mol %) AgNTf 2 (16 mol %) NaOAc (30 mol %)

O

AgOAc (2 equiv) DCE/HFIP (9:1) 120 oC, 24h

O

48

81

R

121a, R = H, 75% 121b, R = Ph, 77%

Scheme 10.81  Direct alkynylation of 4-chromenone 81 by iridium(III)-catalysis.

In 2015, Hong devised a formal hydroxylation of flavones and 4-chromenones 81 (Scheme 10.82). Employing a ruthenium(II)-catalyst in conjunction with hypervalent iodine as an oxidant, generally high yields were observed. The concentration of TFA in the reaction medium had a significant impact on the reactivity. For example, using a ratio in which TFA was in excess gave a very low yield (12%), and a lower ratio of TFA/TFAA of 1:9 provided the product in only 34% yield. However, a ratio of 1:65 in favour of TFAA provided considerably higher yields of hydroxylated chromenone or flavanone product 122, up to 87%. H

O

[Ru(p-cymene)Cl2]2 (5 mol %) PhI(CF3CO2)2 (2 equiv)

R1 O

R2

TFA/TFAA (1:65), 80 oC

OH O R1 O

R2

H

O

122

81 OH O

H X

O 122a, X = H, 87% 122b, X = 3-F, 84% 122c, X = 3-CF3, 85% 122d, X = 3-OCF3, 84% 122e, X = 3-NO2, 80%

O

X O

Ph

122f, X = 7-Me, 78% 122g, X = 7-F, 67% 122h, X = 7-OTf, 64% 122i, X = 7-OH, 70% 122j, X = 6-Me, 84%

X O 122k, X = 7-OH, 80% 122l, X = 7-OTf, 72% 122m, X = 3-Me, 46% 122n, X = 3-Br, 71% 122o, X = 6-Me, 84%

Scheme 10.82  C5-Hydroxylation of 4-chromenone and flavanone derivatives 81.

A variety of functionalized chromenones proved to be suitable in this methodology, including free hydroxy groups, triflates, nitro groups, and halides. Whereas the majority of products were obtained in high yield, only meta-substitution in the flavanone aryl ring was properly investigated in the case of 122a-e,. Two examples of other substitution were investigated, 3,4-dimethoxy or 3,4-dihydroxy, and these gave considerably lower yields of 44% and 49%, respectively. No remark was made about the obvious impact of substitution patterns on reactivity, nor whether the low yields arise from regioselectivity issues as a consequence of increasing the electron density at the 3-position of the flavanone scaffold.

477

478

10  Functionalization of Chromenes and Their Derivatives

The formal hydroxylation proceeds via standard C5-directed C–H activation through a weak coordination to the carbonyl, followed by oxidation of the rhodium complex to generate a rutheniun(IV) species, which subsequently reductively eliminated to regenerate the active ruthenium(II) catalyst and a 5-trifluoroacetate chromenone. Subsequent aqueous work-up cleaves the acetate to liberate the hydroxylated chromenone. It is abundantly clear that functionalization at the C5-position of 4-chromenone derivatives represents the vast majority of C–H activation-based methodologies. Whereas other sites on the chromenone backbone offer greater nucleo- or electrophilicity, the formation of a 5-membered metallacycle through chelate-directed C–H activation through coordination with the carbonyl group clearly enables a robust approach to overcoming possible regioselectivity issues.

10.5.4  C6-Selective C–H Activation Only one report could be found involving the C–H functionalization of 4-chromenone at the C6-position. The Yu group described a non-directed oxidative alkenylation of arenes using a bimetallic rhodium-(II) catalyst, representing one of the few non-directed examples of C–H activation with an arene loading of only one equivalent, whereas previous work by Glorius, Sanford, and others employed the arene in substantial excesses [126–128]. Poor regioselectivity in the metalation step also represents a significant shortcoming of many previous reports, which is, to some extent, overcome in this work [129]. They showcased a sole example of chromenone 81 affording the alkenylated product 123 in 62% yield in a regioselective manner (Scheme 10.83), whereas other arenes exhibited poor selectivity. O H O 81 + nBuO 2C

[Rh2(OAc)4] (5 mol %) PCy3 (5 mol %) Cu(TFA)2 (1 equiv) V2O5 (1 equiv) 5Å MS DCE, 80 oC

O nBuO 2C O 123, 62%

53b

Scheme 10.83  C6-Selective C–H oxidative alkenylation of chromenone 81.

This report represents the single example to date of regioselective C6–H functionalization of 4-chromenone. This underscores the inherent challenges of affecting C–H activation at the C6, C7 or C8-position, all of which remain almost entirely unexplored.

10.5.5  Conclusions Methodologies based on the transition metal-catalyzed C–H functionalization of chromenes have progressed impressively over the last two decades and some have been utilized in natural product synthesis. The majority of the examples reported have been focused on the functionalization of 2H-chromen-2-one (coumarin) and 4H-chromen-4-one (chromone) systems, whereas functionalization of 2H-chromenes or 4H-chromenes is still in its infancy. Substantial efforts have been made to develop a diverse range of reactions such as alkenylation, alkynylation, arylation, alkylation, annulation/cyclization, and amination. Among these, most of the transformations rely on the noble metal catalysts such as palladium, ruthenium, rhodium, and iridium. However, cheap metal catalytic systems such as copper, cobalt, and manganese have also been employed. In particular, palladium-catalysis is ideal for the functionalization of the C3- or C4-position of coumarins and the C2- and C3-position of chromones, whereas rhodium-catalysis is best for the functionalization of C5 in coumarin or chromones. Despite the many advancements in this field, it is not without issues. In particular, these include likely limited substrate scope, regioselectivity, and some transformations that need large excesses of oxidants and higher reaction temperature. Recent efforts to perform the reactions using environmentally benign O2 as oxidant have met with some success, although there is room for improvement. In addition, the functionalization of C7 and C8 has not been explored whereas the non-directed C6-functinalization of chromane proved to be successful. Similarly, enantioselective C–H activation is one of the challenging and fastest growing strategies, but these kinds of transformation in chromene frameworks have not been studied and thus breakthroughs are expected in the future.

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Synthesis of succinimide-containing chromones, naphthoquinones, and xanthones under Rh(III) catalysis: Evaluation of anticancer activity. The Journal of Organic Chemistry 81 (24): 12416–12425. 112 Wang, X., Xie, P., Qiu, R., Zhu, L., Liu, T., Li, Y., Iwasaki, T., Au, C. T., Xu, X., Xia, Y., Yin, S. F., and Kambe, N. (2017). Nickel-catalysed direct alkylation of thiophenes via double C(sp3)-H/C(sp2)-H bond cleavage: The importance of KH2PO4. Chemical Communications 53 (59): 8316–8319. 113 Tan, G., He, S., Huang, X., Liao, X., Cheng, Y., and You, J. (2016). Cobalt-catalyzed oxidative C−H/C−H cross-coupling between two heteroarenes. Angewandte Chemie International Edition 55 (35): 10414–10418. 114 Gao, D. W., Gu, Q., and You, S. L. (2016). An enantioselective oxidative C–H/C–H cross-coupling reaction: Highly efficient method to prepare planar chiral ferrocenes. Journal of the American Chemical Society 138 (8): 2544–2547. 115 Wencel-Delord, J., Nimphius, C., Wang, H., and Glorius, F. (2012). Rhodium(III) and hexabromobenzene-a catalyst system for the cross-dehydrogenative coupling of simple arenes and heterocycles with arenes bearing directing groups. Angewandte Chemie International Edition 51 (52): 13001–13005. 116 Tan, G., You, Q., and You, J. (2018). Iridium-catalyzed oxidative heteroarylation of arenes and alkenes: Overcoming the restriction to specific substrates. ACS Catalysis 8 (9): 8709–8714. 117 Kim, J., Shin, K., Jin, S., Kim, D., and Chang, S. (2019). Oxidatively induced reductive elimination: Exploring the scope and catalyst systems with Ir, Rh, and Ru complexes. Journal of the American Chemical Society 141 (9): 4137–4146. 118 Shin, K., Baek, Y., and Chang, S. (2013). Direct C–H amination of arenes with alkyl azides under rhodium catalysis. Angewandte Chemie International Edition 52 (31): 8031–8036. 119 Kim, J. and Chang, S. (2014). Iridium-catalyzed direct C–H amidation with weakly coordinating carbonyl directing groups under mild conditions. Angewandte Chemie International Edition 53 (8): 2203–2207. 120 Bhanuchandra, M., Ramu Yadav, M., George, R. K., Rao Kuram, M., and Sahoo, A. K. (2013). Ru(II)-catalyzed intermolecular ortho-C–H amidation of aromatic ketones with sulfonyl azides. Chemical Communications 49 (45): 5225–5227. 121 Kim, H., Park, J., Kim, J. G., and Chang, S. (2014). Synthesis of phosphoramidates: a facile approach based on the C–N bond formation via Ir-catalyzed direct C–H amidation. Organic Letters 16 (20): 5466–5469.

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122 Kim, J., Kim, J., and Chang, S. (2013). Ruthenium-catalyzed direct C–H amidation of arenes including weakly coordinating aromatic ketones. Chemistry—A European Journal 19 (23): 7328–7333. 123 Shin, Y., Han, S., De, U., Park, J., Sharma, S., Mishra, N. K., Lee, E.-K., Lee, Y., Kim, H. S., and Kim, I. S. (2014). Ru(II)catalyzed selective C−H amination of xanthones and chromones with sulfonyl azides: Synthesis and anticancer evaluation. The Journal of Organic Chemistry 79: 9262–2971. 124 Kong, X. and Xu, B. (2018). Manganese-catalyzed ortho-C–H amidation of weakly coordinating aromatic ketones. Organic Letters 20 (15): 4495–4498. 125 Li, X., Wu, G., Liu, X., Zhu, Z., Huo, Y., and Jiang, H. (2017). Regioselective C–H bond alkynylation of carbonyl compounds through Ir(III) catalysis. The Journal of Organic Chemistry 82 (24): 13003–13011. 126 Ye, M., Gao, G. L., and Yu, J. Q. (2011). Ligand-promoted C–3 selective C–H olefination of pyridines with Pd catalysts. Journal of the American Chemical Society 133 (18): 6964–6967. 127 Patureau, F. W., Nimphius, C., and Glorius, F. (2011). Rh catalyzed C–H activation and oxidative olefination without chelate assistance: On the reactivity of bromoarenes. Organic Letters 13 (24): 6346–6349. 128 Kubota, A., Emmert, M. H., and Sanford, M. S. (2012). Pyridine ligands as promoters in Pd II/0-catalyzed C–H olefination reactions. Organic Letters 14 (7): 1760–1763. 129 Vora, H. U., Silvestri, A. P., Engelin, C. J., and Yu, J.-Q. (2014). Rhodium(II)-catalyzed nondirected oxidative alkenylation of arenes: Arene loading at one equivalent. Angewandte Chemie International Edition 53 (10): 2683–2686.

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11 Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles Rajeev Sakhuja and Anil Kumar Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan, India

11.1  Introduction Imidazole-fused heterocycles constitute an interesting class of unique chemical entities found in natural products and several marketed drugs. These azaheteroaromatic compounds also form the backbone for the construction of complex organic architectures that have exhibited profound applications in medicinal and materials chemistry in the past [1–4]. In the commonly explored imidazo-fused heterocycles, the imidazole ring is fused with another five- or six-membered heterocyclic moiety possessing one or more nitrogen or sulfur atoms at varied positions. Some common examples of this family include: imidazo[1,2-a]pyridine (I), imidazo[1,5-a] pyridine (II), 3H-imidazo[4,5-b]pyridine (III), 1H-imidazo[4,5-c]pyridine (IV), imidazo[1,5-a]quinoline (V), imidazo[4,5-c]quinoline (VI), imidazo[1,2-a]pyrazine (VII), imidazo[1,2-b]pyridazine (VIII), imidazo[1,2-a]pyrimidine (IX), 1H-imidazo[1,2-a]imidazole (X), 9H-imidazo[1,2‑a]benzimidazole (XI), imidazo[2,1-b]thiazole (XII), benzo[d]imidazo[2,1-b]thiazole (XIII), imidazo[4,5-d]thiazole (XIV), imidazo[2,1-b][1,3,4]thiadiazole (XV), and imidazo[1,2-α][1,8]naphthyridine (XVI) (Figure 11.1).

N

H N

N

N

N

N

Imidazo[1,2-a]pyridine (I)

Imidazo[1,5-a]pyridine (II)

N

N H

N

3H-Imidazo[4,5-b]pyridine (III)

N

1H-Imidazo[4,5-c]pyridine (IV)

HN N

N

N

N

N Imidazo[1,5-a]quinoline (V)

N

Imidazo[4,5-c]quinoline (VI)

N Imidazo[1,2-a]pyrimidine (IX) S

N N

Benzo[d]imidazo[2,1-b]thiazole (XIII)

N

Imidazo[1,2-a]pyrazine (VII)

N

N

Imidazo[1,2-b]pyridazine (VIII)

N

HN

H N

N

N

N

N

S

N

N

N N

1H-Imidazo[1,2-a]imidazole (X) 9H-Imidazo[1,2-a]benzimidazole (XI) Imidazo[2,1-b]thiazole (XII)

S

N

S

N

N H

N N

N

4H-Imidazo[4,5-d]thiazole (XIV) Imidazo[2,1-b][1,3,4]thiadiazole (XV)

N

N

N

Imidazo[1,2-a][1,8]naphthyridine (XVI)

Figure 11.1  Molecular structures for the family of imidazo-fused heterocycles. Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

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11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

From time to time, synthetic methods for these molecules have been developed at the expense of conventional and modern flourishing chemistry, some of which have been extensively reviewed in recent times [5–13]. In most of the bicyclic imidazo-fused heterocycles, the imidazo-ring (ring B) is π-excessive and thus prone to undergo electrophilic addition/substitution, whereas ring A (fused-heterocyclic moiety) is usually π-deficient and subjected to nucleophilic attack. However, the reactivity may vary depending upon the size of the fused heterocyclic moiety (ring A) and/or/ the heteroatom(s) present in ring A. Accordingly, the C(sp2)–H bond functionalization in different imidazo-fused heterocycles has been explored under transition metal-free and transition metal-catalyzed conditions. However, C–H bond functionalizations by means of transition metal catalysts have given access to highly functionalized imidazo-fused heterocyles in high yields. Notably, imidazo[1,2-a]pyridine is the most popular and extensively chemically functionalized imidazofused heterocycle due to its prevalence in several marketed drugs such as miroprofen, alpidem, olprinone, zolimidine, and minodronic acid. In the following chapter, we will discuss the C(sp2)–H functionalization strategies of imidazofused heterocycles with different coupling partners in the order of C–C, C–S/Se, C–N, C–P, and C–Si bond formations under metal catalysis in a systematic manner. The generalized mechanism proposed/proven for the disclosed functionalization will also be presented/discussed. However, the functionalization of appropriately positioned aryl group and/or subsequent annulation with specific coupling partners by exploiting the directing group ability of imidazo-heterocycles is out of the scope of this chapter.

11.2  C–C Bond Formation 11.2.1  Alkylation 11.2.1.1  Fluoro Alkylation

Direct and regioselective C3 trifluoromethylation of 2-arylimidazo[1,2-a]pyridines was first achieved with Langlois reagent (sodium trifluoromethanesulfonate) by using catalytic amounts of AgNO3 and TBHP under aerobic conditions at room temperature. Notably, C2 aryl substituted imidazo-pyridines possessing electron-donating substituents gave superior yields over electron-deficient substrates. The reaction mechanism was proposed to be evoked with the attack of imidazo [1,2-a]pyridine on CF3 radical generated by the reaction of AgNO3 with sodium trifluoromethanesulfonate. TBHP was used to oxidize the imidazo-pyridyl radical intermediate to produce C3 trifluoromethyation product, along with the regeneration of Ag(I) for the next catalytic cycle. The protocol was also applied to prepare trifluoromethylated derivatives of imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazoles (Scheme 11.1A, Table 11.1: entry i) [14]. Subsequently, Cu(OAc)2 has been used for the trifluoromethylation of imidazo[1,2-a]pyridines, imidazo[2,1-b]thiazoles, benzo[d] imidazo[2,1-b]thiazoles and imidazoles using Langlois reagent in a mixture of [Bmim]BF4 and water at room temperature. The reaction was believed to proceed by Cu-catalyzed generation of t-butoxyl radical that in turn generated CF3 radical from sodium trifluoromethanesulfonate (Scheme 11.1B, Table 11.1: entry ii) [15]. Langlois reagent has also been used for regioselective C3 trifluoromethylation of 1-alkyl/aryl/heteroaryl imidazo[1,5-a]quinolines under Cu(I) catalysis. Moderate yields of the C3 trifluoromethylated products were obtained with 1-arylimidazo[1,5-a]quinolines possessing electrondonating and electron-withdrawing substituents on aryl or quinoline moieties and the position of these groups had an appreciable effect. Heteroaryl and alkyl substituents on imidazo[1,5-a]quinolines produced inferior results. Notably, unsubstituted imidazo[1,5-a]quinoline afforded a regioisomeric mixture of C1 and C3 trifluoromethylated products in 31% and 20% yields, respectively. The mechanistic pathway initiates with a single electron transfer (SET) promoted reaction between Cu(I) catalyst and TBPB to furnish Cu(II)COOPh and t-butoxy radical, which on reaction with NaSO2CF3 produced trifluoromethyl radical. In parallel, the earlier generated Cu(II)COOPh on reaction with imidazo[1,5-a]quinolines produced organocopper(II) species, which on addition of trifluoromethyl radical followed by reductive elimination afforded the desired product (Scheme 11.1C, Table 11.1: entry iii) [16]. Togni’s reagent has also been used for the C3 trifluoromethylation of imidazo[1,2-a]pyridines under copper-catalysis in moderate to good yields. The reaction was believed to proceed by copper-catalyzed generation of a CF3 radical from Togni reagent via a single-electron transfer (SET), which reacted in a similar way as described above (Scheme 11.2A, Table 11.2: entry i) [17]. The C3 trifluoromethylation of imidazo[1,2-a]pyridines have also been achieved by using iodotrifluoromethane (CF3I) under nickel-catalyzed conditions. The protocol was extended to the trifluoromethylation of indoles and thiophenes under described conditions. The reaction involves the generation of trifluoromethyl radical via a single-electron oxidation of CF3I by in situ generated nickel(I) species (Scheme 11.2B, Table 11.2: entry ii) [18].

11.2  C–C Bond Formation

Scheme 11.1  Silver/copper-catalyzed trifluoromethylation of imidazo-heterocycles.

Table 11.1  Silver/copper-catalyzed strategies for trifluoromethylation of imidazo-heterocycles. Entry

Reaction Conditions

Representative Products

i.

AgNO3 (20 mol %), TBHP (20 mol %), DMSO, 12 h, r.t., air

N

Examples and Yields

NO2

S

S

N

Cu(OAc)2 (5 mol %), TBHP (3 equiv), [Bmim]BF4/H2O, 25 o C, 24 h

Et

N

N

iii.

CuCl (20 mol %), TBPB (3 equiv), DMSO, r.t., 30 min

N

CF3 20%

S

N

65%

F

N

CF3

N

F

N

O

S

EtOOC

CF3

74%

51% CF3

N

45%

N

N

38% CF3

13 examples 38–74%

N

N

N

S

O

71% CF3

69% CF3

ii.

3 examples 68–71%

N N

N

n-Pr

17 examples 63–78%

78% CF3

71% CF3

63% CF3

OMe

N

N

N

N

N

N

N N

CF3

CF3 N 44%

11 examples 45–81%

81% CF3

CF3

N N 67%

28 examples 20–67%

487

488

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Scheme 11.2  Copper/nickel-catalyzed trifluoromethylation of imidazo[1,2-a]pyridines. Table 11.2  Copper/nickel-catalyzed strategies for trifluoromethylation of imidazo[1,2-a]pyridines.

Entry

i.

ii.

Reaction Conditions

CuI(PPh3)4 (5 mol %), K3PO4 (3 equiv), 1,4-dioxane, r.t., 6 h NiCl2(dppp) (10 mol %), DABCO (2 equiv), dioxane, 60 oC, 12 h

Examples and Yields

Representative Products N

N

N

SO2Me

N

47% CF3

N N 50%

CF3

56% CF3

NO2

23 examples 47–87%

N N 87% CF3

N N 60% CF3

S

N N

OMe

20 examples 50–82%

82% CF3

Regioselective ethoxycarbonyl-difluoromethylation at C3 position of 2-(hetero)arylimidazo[1,2-a]pyridines has been achieved with BrCF2CO2Et in acetonitrile under ambient copper-catalyzed conditions. Notably, smooth ethoxycarbonyldifluoromethylation of imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazoles under the described conditions exemplified the generality of this protocol. The reaction was proposed to initiate by oxidative insertion of Cu(I) to BrCF2CO2Et to afford (CF2COOEt)Cu(III)X species, which on nucleophilic attack by imidazo[1,2-a]pyridine generated a stabilized copper(III) carbocation. Subsequently, base-mediated elimination of proton followed by reductive elimination produced the desired product with the regeneration of the copper catalyst (Scheme 11.3) [19]. 11.2.1.2  Alkoxycarbonyl Alkylation

Regioselective C3 alkoxycarbonylmethylation of imidazo[1,2-a]pyridines could be achieved by coupling ethyl diazoacetate with imidazo[1,2-a]pyridines under rhodium(II)-catalyzed conditions at room temperature. The reaction involves the generation of a carbene complex by the reaction between diazo ester and rhodium(II) catalyst, which on electrophilic attack at the C3 carbon of the imidazo[1,2-a]pyridine gave the alkoxy-carbonlymethylated product via formation of a rhodiumbased zwitterionic intermediate (Scheme 11.4A, Table 11.3: entry i) [20]. The method has been used to prepare zolpidem in 85% yield using 2-diazo-N,N-dimethylacetamide. Ruthenium(II)-catalyzed, visible light-promoted reaction between imidazo-heterocycles and diazo compounds can also be used to afford alkoxycarbonlymethylated products. Under these conditions, blue LED irradiated transformation of Ru(bpy)32+ complex to its excited state initiates the reaction by

11.2  C–C Bond Formation

N

R1

N

Cu1+ R2

or S

N N

R2

N

R1

BrCF2CO2Et Cu2 O (10 mol %)

N

R2

12 examples 42-85% S

EtOOCF2 C

R2 CF2 CO 2Et

R1

3 examples 80-85%

N 42%

CF2 CO2Et

N

78% CF2CO2 Et

N 85% CF2 CO2Et

N

CuX

N R

N

2

BrCF2 COOEt

R1

N

EtOOCF2 C

Representative Products S

N

Cu X

N N

N

R2

N

CF2 CO2Et

1,10-Phen (12 mol %) K2 CO 3 (2 equiv) CH3 CN, 80 °C, 10 h, air

N

N

R1

OMe

S

S

N N

Cu X

N N

Me 85% CF2 CO 2Et

R2

82%

Ph CF 2CO2 Et

Scheme 11.3  Copper-catalyzed ethoxycarbonyl-difluoromethylation of imidazo-heterocycles.

interacting with the protonated form of diazo compound to afford alkoxycarbonylmethyl radical via single-electron reduction. Thereafter, electrophilic attack of radical at the C3 position of imidazo[1,2-a]pyridine followed by subsequent oxidation by Ru(bpy)33+ and deprotonation produces the desired alkoxycarbonylmethylated product (Scheme 11.4B, Table 11.3: entry ii) [21]. Zolpidem was synthesized in 51% yield using this approach.

Scheme 11.4  Rhodium/ruthenium-catalyzed C3 alkoxycarbonylmethylation of imidazo[1,2-a]pyridines.

11.2.1.3  Aryl/heteroaryl Alkylation

Biheterocycles are frequently found in several natural products, drug candidates, and functional materials. The synthesis and application of bis(heteroaryl)methanes have received special attention in recent years. For decades, formaldehyde has been commonly employed as a methylene source in several conventional organic transformations. However, for the past few years, the direct dehydrogenative coupling involving different methylene synthons has witnessed remarkable

489

490

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Table 11.3  Rhodium/ruthenium-catalyzed strategies for C3 alkoxycarbonylmethylation of imidazo[1,2-a]pyridines. Entry

Reaction Conditions

i.

Rh2(oct)4 (10 mol %), CHCl3, r.t., 4 h, N2

Representative Products N

Ru(bpy)3Cl2.6H2O (2 mol %), MeOH/ H2O (10:1), r.t., 36–72 h, Blue LED, N2

N

N

MeOOC

ii.

Examples and Yields

COOEt 92%

N

N N CONMe2

Zolpidem

N

COOEt

55%

N 51%

OCF3

N

COOEt 65% COMe

28 examples 55–95%

N

95%

COOEt

29 examples 51–88%

N N 88%

COOEt

interest. In this realm, synthesis of bis(imidazo[1,2-a]pyridin-3-yl)methane was achieved by VO(acac)2-catalyzed C3 methylenation of imidazo[1,2-a]pyridines using N,N-dimethylacetamide (DMA) as methylene source. A wide variety of imidazo[1,2-a]pyridines furnished their respective methylene bridged dimerized heterocycles in high yields. The method was also applicable for 2-arylindoles and corresponding bis(2-arylindolyl)methanes were obtained in good yields. Using this strategy, the synthesis of an unsymmetrical bis(imidazo[1,2-a]pyridin-3-yl)methane derivative was achieved in 56% yield by using equimolar amounts of two different substrates with DMA. The reaction was believed to proceed via VO(acac)2 and IBD-mediated oxidation of DMA to form an iminium intermediate, which on nucleophilic attack by imidazo[1,2-a]pyridine furnished N-methyl-N-((imidazo[1,2-a]pyridin-3-yl)methyl)acetamide. This intermediate on elimination of N-methylacetamide followed by electrophilic substitution at the C3 position of a second molecule of imidazo[1,2-a]pyridine produced the bis(imidazo[1,2-a]pyridin-3-yl)methanes (Scheme 11.5A, Table 11.4: entry i) [22]. Alternatively, Cu(OAc)2 in combination with K2S2O8 can be used to prepare bis(imidazo[1,2-a]pyridin-3-yl)methane by coupling substituted imidazo[1,2-a]pyridines with DMA. The formation of an iminium cation and dimethylamine by the oxidation and cleavage of DMA by Cu(OAc)2 and K2S2O8 was presumed to trigger the reaction. Dimethylamine generated later undergoes complexation with imidazo[1,2-a]pyridine and copper(II) salt to furnish a copper-bridged cationic intermediate that subsequently attacked the generated iminium cation to give N-methyl-N-((imidazo[1,2-a] pyridin-3-yl)methyl)acetamide that produced the methylene linked product as explained above (Scheme 11.5B, Table 11.4: entry ii) [23].

Scheme 11.5  Vanadium/copper-catalyzed synthesis of bis(imidazo[1,2-a]pyridin-3-yl)methanes.

11.2  C–C Bond Formation

Table 11.4  Vanadium/copper-catalyzed strategies for bis(imidazo[1,2-a]pyridin-3-yl)methanes.

Entry

Reaction Conditions

Representative Products

Examples and Yields

i.

VO(acac)2 (10 mol %), IBD (2 equiv), 100–150°C, 6h

19 examples 29–90%

ii.

Cu(OAc)2 (20 mol %), K2S2O8 (2 equiv), 120°C, 6–12 h

20 examples 53–81%

N,N-Dimethylformamide (DMF) has been used as a methylene source for the coupling of imidazo[1,2-a]pyridines with indoles or N,N-dimethylaniline under copper catalysis to afford a series of 3-(1H-indol-3-ylmethyl)imidazo[1,2-a]pyridines or (4-imidazo[1,2-a]pyridin-3-ylmethyl)(phenyl)dimethylamines in high yields. The substrate scope was studied using electron-withdrawing and electron-donating groups on imidazo[1,2-a]pyridines. The reaction was initiated by with the formation of an iminium ion from DMF using CuI and K2S2O8, which on attack by imidazo[1,2-a]pyridine generated N-methyl-N-((imidazo[1,2-a]pyridin-3-yl)methyl)formamide. Further, elimination of N-methylformamide followed by nucleophilic attack by C3 position of indole or C4 position of N,N-dimethylaniline produced methylene bridged products (Scheme 11.6) [24]. In a strikingly similar manner, decarboxylative coupling of 3-indoleacetic acids with imidazo[1,2-a]pyridines afforded 3-(1H-indol-3-ylmethyl)imidazo[1,2-a]pyridines under copper-catalyzed conditions using 4,4′-di-tert-butyl-2,2′-bipyridine as a ligand. The method was also sucessfully extended for the alkylation of other heteroarenes such as 2-phenylbenzo[d] imidazo[2,1-b]thiazoles, 2-phenylindolizines and 4H-chromen-4-ones. A broad substrate scope on imidazo-heterocycles and the use of several alkyl carboxylic acids highlights the success of this C(sp2)–C(sp3) bond forming protocol. The reaction mechanism was triggered by copper(II)-mediated decarboxylation of 3-indoleacetic acid to give an active copper(II)alkylated species, which on electrophilic substitution on imidazo[1,2-a]pyridine generated a copper(II)-briged alkyl-heteroaryl intermediate via the formation of an arenium ion intermediate. Subsequently, MnO2-mediated oxidation to the corresponding copper(III) species, followed by reductive elimination of the copper(I) species, delivered the C3 indolyl alkylated product (Scheme 11.7) [25]. Alkylation of 2-arylimidazo[1,2-a]pyridines with substituted isochromans at the C3 position has been achieved under cobalt catalysis using oxygen as an oxidant. The reaction was compatible with a number of substituted imidazo-heterocycles, whereas other cyclic ethers, including isothiochroman and tetrahydroisoquinoline were incompatible under the described conditions. Two mechanisms were proposed for the desired transformation. One mechanism involves the CoCl2/ O2-mediated reaction of isochroman to generate oxonium ion cobalt species, furnished the desired product on attack by imidazo[1,2-a]pyridine. The other mechanism initiated with the CoCl2/O2-mediated formation of oxonium ion via two subsequent SETs from isochroman, followed by deprotonation via the formation of a radical cation species. Thereafter, C3 electrophilic substitution of imidazo[1,2-a]pyridine on the oxonium ion produced the desired C3 alkylated product (Scheme 11.8) [26].

491

492

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles R2 N N

N

1

R

R2

N

Cu1+

OR

R1 13 examples 55-82%

K2 S2O 8 (1 equiv) DMF, 80 °C, 24 h

N

R2

R1

R3 N

R3

CuI (10 mol %)

+

N

N

R3 N

OHC N

N R1

OR

R

N

2

N

N

R1

N

R1 8 examples 75-88% Representative Products N

N

S N

N HN

N

R1

N

R2

N N

CHO

N

N

NC

R2

OHC N

CuI/K2 S2O8

N

N

N

DMF

N

N

R2

N

OMe

N

N

HN

N 82%

72%

55%

N

75%

88%

Scheme 11.6  Copper-catalyzed synthesis of methylene linked 2-(hetero)arylimidazo[1,2-a]pyridines. R2

N

R5

R1

N N

N R3 N

R5

R1

S

N N

R1

Cu(OTf)2 (5 mol %)

OR

R4 +

HOOC

R

N

R4

Cu 2+

2

Ar

dtbpy (10 mol %) MnO2 (1 equiv) DMF, 120 °C, 24 h

N

NH

N

N

N

R3 N

R5

N

N R3 R2

N Cu II-OTf R4

R4

R5

N

N R3 S

N

N

R5 R4

CuII

COOH

Repr esentat iv e Pr oducts S

R2

Cu II

R1

MnO2

O

N

N R3

R

N

2 examples 43-51% Cl

R4

5

N

R1

R5

CuI

22 examples 34-91%

S

N

N

N

MnO2

Cu II

N R3

Ar

R2

N N

HO HN 34%

HN 81%

HN Br

91%

HN 43%

HN OMe

51%

Br

Scheme 11.7  Copper-catalyzed synthesis of methylene linked indolyl imidazo[1,2-a]pyridines.

A regisoselective C5 alkylation of imidazo[1,2-a]pyridine has been achieved by manganese(II)-catalyzed oxidative decarbonylation coupling with aliphatic aldehydes. In addition, cyclic alkanes, ethers, thioether and alcohols have been also used to affix functionalized or unfunctionalized alkyl groups via cross-dehydrogenative coupling at C5 position on different imidazo-heterocycles in decent yields under similar manganese(II)-catalyzed conditions. A number of other N-heterocycles including benzothiazole, benzoxazole, pyridine, quinoxaline, phthalazine, benzothiazole, and isoquinoline

11.2  C–C Bond Formation Co 2+ N R1

N

R2

+ R3

N

R1

O

CoCl2 .H2 O (10 mol %)

n

140 °C, 15 h, O2

N

SET OH [Co]

O NO2

N N

52%

Ph

.

O

R3

85%

70%

SET

[Co]/O 2 N

N

62%

O

R3

O N

N

Ph

O

R3

O

R2

N

n 21 examples 52-85%

Repr esentat iv e Pr oducts

O

N

R1

R3

O

R3

N

O

n = 0,1

Cl

N

R2

Scheme 11.8  Cobalt-catalyzed synthesis of 3-isochromanylimidazo[1,2-a]pyridines.

could be alkylated under described conditions using one of the earlier mentioned coupling partners. The reaction was proposed to be initiated by homolytic cleavage of di-t-butyl peroxide (DTBP) to furnish t-butoxyl radical and t-butoxy Mn(III) species. Thereafter, aldehydic hydrogen on abstraction by t-butoxyl radical generated acyl radical that undergoes decarbonylation to produce an alkyl radical, which is attacked by C5 position of imidazo[1,2-a]pyridine to provide a C5 alkylated radical intermediate. Oxidation of this radical intermediate followed by deprotonation afforded the C5 alkylated product along with the regeneration of the manganese(II) catalyst. In contrast, t-butoxyl radical abstracted the C(sp3)-H proton adjacent to the oxygen atom of ether, alcohol, or cycloalkane to generate an alkyl radical, which was attacked by imidazo [1,2-a]pyridine to produce the desired product (Scheme 11.9). Notably, C5 functionalization probably occurred due to its activation by electron-donating ability of imidazolium nitrogen [27].

Mn2+ N R1

N

R3 CHO R2

+

OR R4

N

N

R1

N R2

R1

N

Repr esentat iv e Pr oducts

35%

S

R3 /R 4 R1

N

77%

MnIIIOt-Bu

N O 89%

O

MnII

R2 R3

R3 N

R2

N

N

O

OH

75%

R1

N

N N

N

R2

R3 /R 4

R 3/R 4 35 examples 35-89%

N

O O

N

DTBP (3 equiv) H 1,2-Dichlorobenzene, 120 °C, 6-8 h

N

Cl

Mn(OAc)2 (5 mol %)

-C O

or R4

R3 CHO R4

H

O

Scheme 11.9  Manganese-catalyzed synthesis of 5-alkylimidazo[1,2-a]pyridines.

11.2.1.4  Amino Alkylation

Aminomethylation of imidazo[1,2-a]pyridines has been achieved using N,N-dimethylformamide (DMF) under copper(II) catalysis using an excess of TBHP. Through this process, a series of C3 aminomethylated imidazo[1,2-a]pyridines in good-toexcellent yields were prepared by varying electron-donating and withdrawing substitutents on aryl and pyridyl moieties of the substrate. The reaction was assumed to proceed by the oxidation of DMF under Cu(II)/O2 conditions following a series of intermediates to generate iminium species, which on attack by imidazo[1,2-a]pyridine through the usual aromatic electrophilic mechanism to produce the desired aminoalkylated product (Scheme 11.10A, Table 11.5: entry i) [28]. In striking contrast, methanol has been used as a methylene source for the C3 N-pyridyl aminomethylation of imidazo[1,2-a]pyridines

493

494

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

with 2-aminopyridines via an iron-catalyzed protocol using water as a co-solvent. Use of uncommon methanol as a methylene source, environmentally benign aqueous conditions and broad functional diversity on the two substrates, furnishing C3 functionalized imidazo[1,2-a]pyridines in moderate-to-good yields, highlights the benefits of the strategy. The reaction was initiated by the reduction of TBHP by FeCp2 to produce an Fe(III)(OH)-complex and the t-butoxyl radical that abstracted a hydrogen from methanol to afford the hydroxymethyl radical. This hydroxymethyl radical on attack by imidazo[1,2-a] pyridine followed by oxidation and deprotonation produced 3-hydroxymethylimidazo[1,2-a]pyridine. Subsequently, with the help of the Fe(III)(OH)-complex, 3-hydroxymethylimidazo[1,2-a]pyridine generated its corresponding ether that is polarized by the Fe(III)(OH)-complex to generate an allyl-type carbocation, which yielded the dication intermediate on attack by 2-aminopyridine. Deprotonation followed by Dimroth rearrangement afforded the desired product (Scheme 11.10B, Table 11.5: entry ii) [29].

Scheme 11.10  Copper/iron-catalyzed synthesis of 3-aminomethylimidazo[1,2-a]pyridines.

Regioselective C3 aminoalkylation of imidazo[1,2-a]pyridines has also been achieved by decarboxylative coupling of N-substituted glycines with imidazo[1,2-a]pyridines under copper-catalyzed conditions using 4,4′-di-tert-butyl-2,2′bipyridine (dtbpy) as a ligand. The same conditions could also be used for the aminoalkylation of benzo[d]imidazo[2,1-b] thiazole derivative. A copper(II)-mediated decarboxylation of N-substituted glycines produced an active copper(II)-alkylated species, which on electrophilic substitution on imidazo[1,2-a]pyridine generated copper(II)-briged alkyl-heteroaryl intermediate. Finally, MnO2-mediated oxidation and subsequent reductive elimination delivered C3 aminomethylated product (Scheme 11.11) [25]. Table 11.5  Copper/iron-catalyzed strategies for aminoalkylation of imidazo[1,2-a]pyridines.

Entry

Reaction Conditions

i.

Cu(OTf)2 (10 mol %), TBHP (6 equiv), 90°C, 12 h

N N

FeCp2 (25 mol %), TBHP (2.5 equiv), 2,2′-bipyridine (25 mol %), MeOH: H2O (2 mL), 90°C, 30 h, Air

N

N

87%

N

N

OMe

N

N HN

N

N

72%

30%

HN N

N CN

15 examples 72–92%

N

S

N SO2Me

N

ii.

Examples and Yields

Representative Products

92%

N HN

62%

39 examples 30–82%

N

N

82%

11.2  C–C Bond Formation Cu2+ 3

R

N

R4

N

+ R1

N

HOOC

R2

dtbpy (10 mol %) MnO 2 (1 equiv) DMF, 120 °C, 24 h

N

N

NC

Cu(OTf) 2 (5 mol %)

41%

R2

N

N

MnO2

R1

N R4 22 examples 41-89%

Cu+ MnO 2

CuII

N R4 R3

Cu

N OMe N

N R4 R3

N

R1

R2

N

2+

CuII-OTf

R4

R3 N

R2

N

CuII

N N

N

N

N

R1

R2

R3

Representative Products S N

N

N

R1

N

R4

HOOC

41%

89%

Scheme 11.11  Copper-catalyzed synthesis of 3-aminomethyl imidazo-heterocycles.

The nucleophilic behavior of C3 position of imidazo[1,2-a]pyridine has been explored for its oxidative coupling with N-methylmorpholine oxide under vanadium(IV)-catalyzed conditions to obtain Mannich type product. A variety of substituents on imidazo[1,2-a]pyridine moiety delivered their respective C3 aminomethylated products in moderate-to-excellent yields; electron-rich substrates showed better reactivity than electron-deficient ones. The methodology was extended to obtain few derivatives of 3-aminomethylated indoles. A non-radical mechanism was inferred that was triggered by the oxidation of VO(acac)2 with N-methylmorpholine oxide to generate an iminium ion along with the generation of hydroxyl vanadium oxide ion species. This abstracted a proton from imidazo[1,2-a]pyridine and facilitated its attack on iminium ion to produce the desired aminomethylated product and dihydroxy vanadium species, which eliminated water to regenerate the catalyst for the next catalytic cycle (Scheme 11.12) [30].

N

R1

N

N N

R2

V

4+

dioxane. 120 °C, 12 h N

N

O

O Representative Products NO2 Br N

R2

HO

OMe

HO

N 63%

O

N

R1 O

N

OH V(acac)2

N

O

O

O (caca) 2V

O

R2

N

O V(acac)2

ac) 2

N O

N

19 examples 56-90%

N

N

56%

N

R1

N

N

N O

R2

N

VO(acac)2 (20 mol %)

+ O

N

R1

ac O((

O

N

O

V

90%

Scheme 11.12  Vanadium-catalyzed synthesis of 3-morpholinomethyl imidazo[1,2-a]pyridines.

A copper-catalyzed C3 aminoalkylation of imidazo[1,2-a]pyridine has also been developed by coupling with N-benzyloxycarbonylamino sulfones in DMSO. Various N-benzyloxycarbonylamino sulfones derived from aliphatic, aromatic, and heteroaromatic aldehydes underwent smooth transformations to produce the C3 (benzyloxycarbonylamino) alkylated imidazo[1,2-a]pyridines in moderate yields. The reaction proceeded through the formation of an N-acyliminium ion intermediate (Scheme 11.13) [31]. Carboxylated derivatized amino alkylated derivatives of imidazo[1,2-a]pyridines can be prepared by coupling imidazo[1,2-a] pyridines with N-arylglycine esters under copper(II) catalysis either by conventional heating at 40–60oC or at room temperature by using visible light. A variety of electron-donating substituents on both coupling partners smoothly underwent cross-dehydrogenative coupling to deliver α-imidazo[1,2-a]pyridyl-α-amino esters in excellent yields. Under conventional conditions, the reaction was initiated by the formation of an imine intermediate formed by Cu(OTf)2-catalyzed oxidation of

495

496

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

N R1

R2

N

+ HN R3

Cbz

Cu2+ Cu(OTf )2 (10 mol %)

N

DMSO, 100 °C, 24 h

Repr esentat iv e Pr oducts N

N

n-pentyl

Cbz N O H 52%

N

R1

N

R2

N

N

N

31%

R2

NHCbz R3 10 examples, 31-66%

Ts

Cbz N H

N

R1

HN

N Cbz

Cbz N H 66%

R3

Cbz

R3

NH Ts

Scheme 11.13  Copper-catalyzed synthesis of 3-(benzyloxycarbonylamino)methyl imidazo[1,2-a]pyridines.

N-arylglycine ester via SET along with the generation of Cu(OTf). Thereafter, the attack of imidazo[1,2-a]pyridine on imine intermediate afforded the desired product (Scheme 11.14A, Table 11.6: entry i) [32]. In contrast, the photoredox transformation was initiated by copper(II)-promoted generation of a [copper(I)-radical cation] intermediate from N-arylglycine ester via SET, which subsequently under visible light-mediated conditions in the presence of oxygen gets oxidized to the imine intermediate. This intermediate on attack by imidazo[1,2-a]pyridine produced the desired product (Scheme 11.14B, Table 11.6: entry ii) [33].

Scheme 11.14  Copper-catalyzed synthesis of 3-(N-phenylamino)methyl imidazo[1,2-a]pyridines.

11.2.1.5  Sulfonyl/Carbonyl/Cyano Alkylation

Tosylmethylation of imidazo[1,2-a]pyridines has been achieved by coupling it with p-toluenesulfonylmethyl isocyanide (TosMIC) in a solvent mixture of H2O/PEG-400 using iron-catalyzed conditions. The two proposed mechanistic pathways involves FeCl3-mediated generation of either a toluenesulfonylmethyl radical or carbonium ion intermediates from TosMIC, which afforded the desired product on attack by imidazo[1,2-a]pyridine followed by elimination of H• or H+. The strategy exemplified broad substrate compatibility and was extended to regioselective tosylmethylation of other imidazo-heterocycles such as benzo[d]imidazo[2,1-b]thiazole, imidazo[2,1-b]thiazole, and imidazo[1,2-a]quinoline (Scheme 11.15) [34]. Mn(OAc)2.4H2O has been used for the C3 carbonylalkylation of imidazo[1,2-a]pyridine with methyl ketones via cross-dehydrogenative C(sp3)–C(sp2) coupling using excess of dicumyl peroxide (DCP). A number of substituted imidazo[1,2-a]pyridines with electron-donating and electron-withdrawing groups reacted smoothly with acetone, whereas other methyl ketones, including butanone, acetophenone, and cyclohexanone, showed moderate reactivity. The reaction pathway involves the homolysis of DCP to furnish a radical that in turn generated a methyl ketone radical by proton abstraction. Subsequently, C3 attack of imidazo[1,2-a]pyridine on methyl ketone radical produced the C3-alkylated radical intermediate, which on oxidation by Mn3+ afforded a C3 carbonylalkylated carbocation that produced the desired product on proton elimination (Scheme 11.16) [35]. Bromoacetonitriles or iodoacetonitrile have been used for the C3 cyanomethylation of imidazo[1,2-a]pyridines under visible light-promoted iridium-catalysis. Moderate-to-excellent yields of the products were obtained by using a variety of

11.2  C–C Bond Formation

Table 11.6  Copper-catalyzed strategies for aminoalkylation of imidazo[1,2-a]pyridines.

Entry

i.

Reaction Conditions

Cu(OTf)2 (10 mol %), CH3CN, 40–60°C, 3–24 h, Air

Representative Products

Examples and Yields

N N

Br

H N

O

Cu(OTf)2 (10 mol %), CH3CN, r.t., 3–12 h, Air, Blue LED

H N OEt 70%

OEt 97%

82% N

F

N

N

F

N O OEt 80%

20 examples 70–97%

H N

NH

O

26 examples 30–97%

H N

O

OEt

N

OMe

N

NH

O CF3

N O

N

N

OEt 30%

ii.

OMe

N

OEt 97%

Scheme 11.15  Iron-catalyzed synthesis of tosylmethyl substituted imidazo-heterocycles.

electron-donating and withdrawing substituents on imidazo[1,2-a]pyridines. The reaction was initiated by visible light induced excitation of [faC–IrIII(ppy)3] to generate excited iridium(III)-photocatalyst, which produced a cyanomethyl radical from haloacetonitrile and [faC–IrIV(ppy)3]+ via SET. Further, attack of imidazo[1,2-a]pyridine on electron-deficient cyanomethyl radical furnished the cyanomethyl substituted imidazo[1,2-a]pyridyl radical that on oxidation via another SET process generated its corresponding carbocation, which on deprotonation produced the desired product. Cyanomethylation of 2-phenylbenzo[d]imidazo[2,1-b]thiazole and 6-phenylimidazo[2,1-b]thiazole have also proceeded under optimized conditions in high yields (Scheme 11.17) [36]. Acetonitrile has also been used for the C3 cyanomethylation of imidazo[1,2-a]pyridines by iron(II)-catalyzed C(sp2)– C(sp3) coupling between 2-arylimidazo[1,2-a]pyridines with acetonitrile to produce 2-(imidazo[1,2-a]pyridine-3-yl)acetonitriles. The reaction was initiated with the reduction of dicumyl peroxide (DCP) by FeCp2 to furnish an iron(III) complex and cumyloxyl radical that abstracted a hydrogen from acetonitrile to produce a cyanomethyl radical. Attack of cyanomethyl radical at C3 position of imidazo[1,2-a]pyridine followed by oxidation and subsequent deprotonation released the desired product (Scheme 11.18A, Table 11.7: entry i) [37]. Alternatively, diazoacetonitrile has been employed to achieve cyanomethylation of imidazo[1,2-a]pyridines under an iron(III)-catalyzed ligand- and oxidant-free conditions. The reaction pathway was initiated by the reaction of diazoacetonitrile with FeCl3 to generate iron carbene species that on attack by imidazo[1,2-a]pyridine produced a zwitterionic intermediate, which on subsequent β-elimination and protonation afforded the desired product (Scheme 11.18B, Table 11.7: entry ii) [38].

497

498

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles Mn2+ N

R1

N

O R2

+

R

3

DCP (3 equiv) 120 °C, 24 h, Air

R4

Cl

N

Mn(OAc)2 .4H 2O (10 mol %) R1

N

O

R

N

Mn3+

2

R

R3

4

39%

O

O

Ph

R2 O

R4

R3

Mn2+

N

R4

Ph heat

O

R2

R1

78%

R3

R3

R2

N O

Ph

O

N

O

O

N

N

R1

R1

O

7%

N

1

N

N

N

R

Ph

O

17 examples 7-78% R 4

Repr esentat iv e Pr oducts Cl N

N

R2

O R4

R3

Scheme 11.16  Manganese-catalyzed synthesis of 3-carbonylmethyl imidazo[1,2-a]pyridines.

R

N

1

R

N

+

OR S

Ir 3+

2

X

CN

N N

R

N

R1

N

R1

R2

N N

CN 24 examples, 12-96%

[fac-Ir(ppy)3] (2 mol %) NaHCO 3 ( 2 equiv) DMSO, r.t., 12 h, Ar 5W Blue LEDs

S

R2

N

CN

CN IrIV

N N

2

N

R

fac-Ir(ppy)3

R2

Blue LEDs

CN 2 examples, 84-88%

1

N N

R2

CH 2 CN [fac-Ir(ppy)3]*

BrCH 2CN

Repr esentat iv e pr oduct s N N NC

CF3

N Cl 12%

NC

70%

N

N NC

S

N

N

N

86%

NC

N

NC

N N

N

96%

S

84%

NC

84%

Scheme 11.17  Iridium-catalyzed synthesis of 3-cyanomethyl imidazo-heterocycles.

Scheme 11.18  Iron-catalyzed synthesis of 3-cyanomethyl imidazo[1,2-a]pyridines.

11.2.2  Alkenylation/Alkynylation/Allenylation The regioselective C3 alkenylation of imidazo[1,2-a]pyridines can be achieved with acrylate under ruthenium(II)-catalysis using Cu(OAc)2 as an oxidant. Different acrylates such as ethyl acrylate, methyl acrylate, butyl acrylate, 2,2,2-trifluoroethyl acrylate, and 2-ethylhexyl acrylate underwent smooth coupling with a variety of substituted imidazo[1,2-a]pyridines to furnish moderate to good yields of 3-alkenylimidazo[1,2-a]pyridines. Substrates possessing electron-donating groups have shown higher reactivity compared to the ones with electron-withdrawing groups. The reaction was triggered by ruthenium(II)-catalyzed imidazo[1,2-a]pyridyl C3 metalation, followed by migratory insertion of acrylate into the

11.2  C–C Bond Formation

Table 11.7  Iron-catalyzed strategies for cyanoalkylation of imidazo[1,2-a]pyridines. Entry

Reaction Conditions

i.

FeCp2 (10 mol %), DCP (2 equiv), 100°C, 20 h, Ar

Representative Products N Cl

N

FeCl3 (5 mol %), CH3CN, 60 oC, 6 h

N NC

38%

N

N F3C

30%

NC

23 examples 38–79%

N N

O

NC

41%

79%

30 examples 30–76%

N

S

N

N NC

OEt

N

Cl

NC

ii.

Examples and Yields

N 40%

NC

76%

ruthenium-carbon bond, which on subsequent reductive elimination gave C3 β-alkenylated product along with the elimination of ruthenium hydride. The latter is re-oxidized by Cu(OAc)2 to the active ruthenium species to continue the catalytic cycle (Scheme 11.19A, Table 11.8: entry i) [39]. In contrast, Pd(OAc)2 has been used for the selective α-alkenylation of imidazo[1,2-a]pyridines with styrenes via aerobic cross-dehydrogenative coupling using molecular oxygen as an oxidant and tetrabutyl ammonium bromide (TBAB) as an additive. The reaction was believed to proceed by the palladium-catalyzed activation of styrene, which, followed by the attack of imidazo[1,2-a]pyridine and subsequent β-hydride elimination, generated C3 α-vinylated product (Scheme 11.19B, Table 11.8: entry ii) [40]. Similarly, C(sp2)–H olefination of imidazo[1,2a]pyridines with acrylates and vinylarenes has also been achieved by using slightly modified palladium-catalyzed conditions using silver carbonate as an additive and molecular oxygen as terminal oxidant. Here again, vinylarenes resulted in the formation of α-alkenylated products, whereas acrylates resulted in β-alkenylated products; the formation of these was proposed by two plausible pathways very similar to the mechanisms described above. For the coupling with acrylates, C3 palladation of imidazo[1,2-a]pyridine followed by migratory insertion of acrylate into the palladium–carbon bond at the β-position and subsequent reductive elimination gave the C3 β-alkenylated product. On the other hand, for the coupling with vinylarenes, coordination of palladium(II) with vinyl π-electron cloud followed by intermolecular attack of imidazo[1,2-a]pyridine at α-position of vinylarene and subsequent β-hydride elimination furnished the C3 α-alkenylated product (Scheme 11.19C, Table 11.8: entry iii) [41].

Scheme 11.19  Ruthenium/palladium-catalyzed synthesis of 3-alkenylated imidazo[1,2-a]pyridines.

499

500

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Table 11.8  Ruthenium/palladium-catalyzed strategies for C3 alkenylation of imidazo[1,2-a]pyridines.

Entry

Reaction Conditions

i.

[RuCl2(p-cymene)]2 (3 mol %), AgSbF6 (40 mol %), Cu(OAc)2.H2O (2 equiv), DCE, 120°C, 24 h

N

N

N

Pd(OAc)2 (5 mol %), Bu4NBr (2 equiv), DMAc, 100°C, 16 h, O2, (101.3kPa)

N

N

N

Pd(OAc)2 (5 mol %), Ag2CO3 (5 mol %), AcOH/ Ac2O, dioxane, 120°C, 24 h, O2

78%

60%

COOEt

N

N

N

N

N

N 70%

16 examples 72–86%

86% COOMe

77% COOEt

N

64%

N

N

72% COOBu

18 examples 59–78%

N N

N

N

75% COOBu

S

N

N

24 examples 50–75%

N

COOCH2CF3

61%

59%

iii.

N

N

50% CN

ii.

Examples and Yields

Representative Products

But

18 examples 64–77%

77%

Dehydrogenative C2 alkenylation of 3,6-disubstituted imidazo[2,1-b]thiazoles with a variety of acrylates can be achieved in the presence of Pd(OAc)2/AgOAc. 2,5-Dialkenylated products were obtained by the reaction of 3,6-dimethylimidazo[2,1b]thiazole with acrylates or N,N-dimethyl acrylamide under these conditions. The reaction pathway commenced with the generation of Pd(OPiv)2 by the reaction of Pd(OAc)2 and PivOH that eventually deprotonated the C2 proton of imidazo[2,1b]thiazole to give the C2-palladated intermediate, which was inserted into the alkene to yield the C2 alkyl palladium intermediate. Thereafter, reductive elimination of this intermediate produced the C2 arylated product, which further underwent the second cycle of palladation, deprotonation, oxidative addition, and reductive elimination to afford 2,5-dialkenylated product (Scheme 11.20) [42]. Nickel and aluminum-based bimetallic catalytic system has been used for remote C(sp2)–H activation of imidazo[1,5-a] pyridines with alkynes to furnish a series of C5 alkenylayted imidazo[1,5-a]pyridines in moderate to excellent yields (Scheme 11.21D). However, the exclusion of AlMe3 from the catalytic system accomplished C3 alkenylation in appreciable yields by coupling substituted imidazo[1,5-a]pyridines with oct-4-yne under similar reaction conditions (Scheme 11.21C). Predominantly, the E isomer was found to be formed in major amounts in both the C3 and C5 alkenylated products. Furthermore, the use of the same bimetallic catalytic system produced C5 alkylated imidazo[1,5-a]pyridines with a variety of alkene derivatves at higher temperature conditions. In addition, the coupling of C3 or C5 arylated imidazo[1,5-a]pyridines with alkynes produced C8 alkenylated imidazo[1,5-a]pyridines in appreciable yields by exploiting the synergistic interaction between nickel, aluminum, and different ligands to induce remote C–H activation (Scheme 11.21A–B). The labeling studies indicated the possibility of two different mechanisms for the observed C3 and C5 alkenylated products based on the observed KIE value; however the exact mechanism was not proposed [43, 44].

11.2  C–C Bond Formation R3

S

R3

N

R2

N Pd S

N

3

R

AgOAc (3 equiv) PivOH, 80 o C, 24 h

R1

R3

18 examples, 65-94% OR R3

S

S

R2

N

Pd(OAc) 2

PivOH

S

R3

NC

S

(EtO)2 OP Ph

N N 65%

S

N

BuO t

S

Ph

N

S

N N

N

Ph

CO2Et

78%

CONMe2

84%

Scheme 11.20  Palladium-catalyzed synthesis of 3,6-dialkenylated imidazo[2,1-b]thiazoles.

(A) Ni 0 N

N+

R2

R3

Ni(cod) 2 (5 mol %) AlMe3 (20-60 mol %) IMes (5 mol %)

R3

R

0

N

Ni0

R2 R 3 Ni Ni(cod)2 (5 mol %) (C) IMes (5 mol %)

R1 N R2

R1 N

toluene, r.t., 6 h

N

N N

N

N n-Pr

99%

R2 R2

or

Me

N

Ph 17%

N

N

R3

n-Pr

Ph

N

3

N

N

N

N

N

N

Ph Ph 53%

T MS 82%

TMS

98%

R1

R1 OR

AlMe 3 (60 mol %) R2 IMes (5 mol %) R3 toluene,r.t.-130 oC, 6-18 h 25 examples 53-99%

N

N

N

C8 H 17 74%

TBSO 70%

Scheme 11.21  Nickel/aluminum-catalyzed synthesis of alkenylated imidazo[1,5-a]pyridines.

96%

N R2

R3 16 examples 52-96%

Representative Products

Ph N

Me

(D) Ni(cod) (5 Rmol %) 2

R3 17 examples 23-99%

Representative Products But But

n-Pr

R1 19 examples, 17-98%

83%

CF3

n-Pr

N

N

N

30%

2

toluene, 60-100 oC, 6-12h

R1

N

N

R3

Ni0 N + R2

Ph

N

R1 10 examples 30-83%

(B)

t -Bu

Ph

N

toluene, 100-130 oC, 6h

R1

N

Ni(cod) 2 (5 mol %) R2 AlMe3 (1 equiv) PCy 3 (20 mol %)

Representative Products

t -Bu

R3

R2

R3

N Me 2NOC

S

Ph

N 94%

74%

EtO 2C

N

N

R2 R1 PdOPiv

R1

Representative Products

Pd(OPiv)2 N

N

R2

R1

S

N 6 examples, 78-89%

N N

R3

PdOPiv R3

N

PivOPd

R1

N

R1

S

R2

N

S

N

R3

N

Pd(OPiv)2

R1

Pd(OAc) 2 (10 mol %)

R2

N

2+

PivOPd

N

N

501

502

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Direct C2 alkenylation of 3H-imidazo[4,5-b]pyridines has been achieved by coupling with bromoalkenes under microwave-assisted palladium/copper co-catalysis [45]. Low-to-good yields of the C2 alkenylated products were obtained by varying the substituent nature and position of the two substrates. However, the electronic effects of the substituents did not have a direct reactivity correlation with the observed yields of the corresponding products. Interestingly, copper-catalyzed coupling of gem-dibromoalkenes with 3H-imidazo[4,5-b]pyridines afforded C2 alkynylated 3H-imidazo[4,5-b]pyridines in low-to-good yields [46]. Dehydrobromination of dibromoalkene in the presence of t-BuOLi produced bromoalkyne that reacted with the 2-cuprio-3H-imidazo[4,5-b]pyridine intermediate produced from 3H-imidazo[4,5-b]pyridine by deprotonation metalation to generate C2 alkynylated products (Scheme 11.22).

Br Cu1+

N 1

R

R

N PG

N

2

27 examples 19-74% N

R1

N PG

N

Br CuBr·SMe 2 (10 mol %)

N

Pd2+ Pd(OAc) 2 (5 mol %) CuI (10 mol %)

N PG

phenanthroline (20mol%) t -BuOLi (2.0 equiv) dioxane, MW, 120 oC, 30 min.

1

R

DPEPhos (20 mol %), t-BuOLi (6 equiv) dioxane,120 o C, 4 h

N

R2

R2 R2

Br

Br

t-BuOLi

Br

1

N

Ph

N

Br Cu III L

N PG

Cu I L

M-Cu I-L

Cl

N PG 23 examples 9-79% N

R2

R1 N

(M = Br or t-BuO)

N

N

N PG

N 19%

Ph

N MEM

S

N

79%

Br

N

Br

N Bn

N

R2

N

R1

Representative Products

N R

Br

R2

N Bn 59% N N Bn

N

77%

Scheme 11.22  Palladium/copper-catalyzed synthesis of alkenylated/alkynylated 3H-imidazo[4,5-b]pyridines.

Oxidative coupling of 1-alkynylated or unsubstituted imidazo[1,5-a]pyridines with terminal alkynes has been achieved using Pd(OAc)2/Ag2CO3 catalytic system. A large number of 1,3-bis(arylethynyl)-imidazo[1,5-a]pyridines or 3-arylethynylimidazo[1,5-a]pyridines were obtained in decent yields (Scheme 11.23) [47]. In case of unsubstituted imidazo[1,5-a]pyridines, the formation of dimeric alkynes (18–51%) and traces of imidazopyridine dimers were also observed along with C3-alkynylated products. A concerted metalation-deprotonation (CMD) pathway was predicted involving the palladation of low acidic C(sp2)–H bond of imidazo[1,5-a]pyridine. The UV-vis and fluorescence spectra of the 1,3-bis(arylethynyl)-imidazo[1,5-a]pyridines suggested that the arylethynyl groups influence the emission maxima, which was evident from linear correlations observed with the Hammett substituent constants on the arylethynyl groups.

CF3

R2 N

Pd2+

N

N H

N

N

R1 Pd(OAc)2 (2.5 mol %) Ag2 CO 3 (1.5 equiv) AcOH (1 equiv) DMF + DMSO, 120 °C, 1-3 h

Representative Products

OMe

R1

N 6 examples 7-68%

R2

N

N N

N R1 5 examples 53-78%

42%

N

N

N

N

N

68% Ph

N

78% Ph

Scheme 11.23  Palladium-catalyzed synthesis of alkynylated and bis(alkynylated) imidazo[1,5-a]pyridines.

OMe

53%

11.2  C–C Bond Formation

Zn(OTf)2 has been used for the selective allenyation of several imidazo-heterocycles by coupling them with 1,1,3-triphenylprop2-yn-1-ol under simple heating conditions (Scheme 11.24) [48]. The generality of this methodology was studied by varying substituents on pyridyl and aryl rings of imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, benzo[d]imidazo[2,1-b]thiazoles and imidazo[2,1-b]thiazoles. The C3 allenylated product was presumed to be formed by the SN2′ type attack of imidazo[1,2-a]pyridine on the species obtained by the coordination of Zn(OTf)2 on 1,1,3-triphenylprop-2-yn-1-ol followed by proton elimination. X X

Zn2+

N

R1

R2

N

Ph

OR S

Ph OH Ph

Zn(OTf) 2 (10 mol %) Toluene, 110 °C, 9-16 h

N N

R

N N

Ph

R1

C Ph

2

N

Ph

N

Ph Ph 97%

S

C Ph

N Ph

N

R2 C

R1

C Ph

Ph Ph 77%

Ph

C

Ph F1

(Tf O)2 Zn

Ph

O Ph Ph

Ph X R1

Representative Products S N N Ph N N

Ph

R2

N

Ph

Ph 16 examples, 77-97% N S R2 N Ph C Ph Ph 3 examples, 75-97%

Ph 78%

N

C Ph

N

R2

N

S

N Ph Ph Ph 75%

N N C Ph

Ph

Cl

97%

Scheme 11.24  Zinc-catalyzed synthesis of allenylated imidazo-heterocycles.

11.2.3  Cyanation/Carbonylation The remarkable applicative value of formylated hetero(arenes) in synthetic chemistry has attracted special attention of organic chemists and classical formylating methods such as Vilsmeier–Haack, Reimer–Tiemann, Rieche, and Friedel–Crafts acylations have been developed in the last century. However, most of these reactions are moisture sensitive and require high temperature and strong acidic or basic conditions to succeed. In contrast, several new transition metal-catalyzed strategies for the formylation and carbonylation of aromatic and heteroarmatics have been developed in the past decade via flourishing C–H functionalization. For example, copper-mediated formylation at C3 position of imidazo[1,2-a]pyridine has been achieved using DMF as a formylation reagent. In constrast, C3 cyanation was achieved by using ammonium iodide in combination with DMF that provided nitrogen and carbon atoms respectively for the in situ generation of cyano group [49]. Excellent functional group tolerance was exhibited with respect to electron-donating and withdrawing substituents on imidazo[1,2-a]pyridine, furnishing moderate-to-excellent yields of the C3 formylated/cyanated imidazo[1,2-a] pyridines. Cyanation can also be carried on benzo[d]imidazo[2,1-b]thiazole and imidazo[2,1-b]thiazole under described conditions. Imidazo[1,2-a]pyridines with 2-(4-chlorophenyl) substituents were converted to saripidem, a commercial drug, over four steps in good yields. Detailed mechanistic investigation suggested a sequential cyanation pathway in which C3 iodination of imidazo[1,2-a]pyridine using ammonium iodide followed by its cyanation using the in situ generated cyanide ions under copper-mediated conditions. It was proposed that oxidation of DMF first produced N-methyl-N-formyl iminium ion that on subsequent reaction with ammonia produced amidinyl species, which could be the source of cyanide ions. On the other hand, addition of imidazo[1,2-a]pyridine to N-methyl-N-formyl iminium ion produced C3 methyl aminated intermediate, which upon oxidation to C3 methylene radical species via a single electron-transfer (SET) followed by dioxygen trapping generated peroxy radical. This subsequently gave the desired formylation product (Scheme 11.25). On similar grounds, DMSO has also been used for the formylation of imidazo[1,2-a]pyridines under copper-catalysis [50] or iron catalysis [51], employing molecular oxygen as the terminal oxidant. Using these strategies, formylation of different susbstituted imidazo[1,2-a]pyridines has smoothly afforded good-to-excellent yields of C3 formylimidazo[1,2-a]pyridines. The copper-catalyzed strategy was proposed to trigger by the copper(II)-mediated oxidation of imidazo[1,2-a]

503

504

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles N N

R

1

Cu

N

R2

N

2+

, R1 Ac I O H H4 N

DMF

CN 18 examples 45-90%

N

N

OMe

R

N

R1

CHO

R2

N

O

O2

O

R1

N

R2

N

S

55%

N

Me CHO

S

85%

N

N

90%

Cu, O2 SET

R2

N

22% CHO

N

CHO

N

N N

CN

CN

N

R2

N

N

N 1

N

N

N

R1

R2

N

N

45% CN

I

CHO Cu(NO 3) 2

19 examples CHO 22-85% Representative Products S MeOOC N

N

CHO

NH 4I + HOAc

N

N R1

N

HN

R2

N

R2

N

Cu(NO 3) 2.H2 O 130 oC, O2

R1

[CN]

CHO

60% CN

40%

Scheme 11.25  Copper-catalyzed synthesis of 3-cyanated/carbonylated imidazo-heterocycles.

pyridine and DMSO via SET to generate a radical intermediate and methyl radical, which upon intermolecular coupling gave 2-methylimidazo[1,2-a]pyridine. Subsequently, another copper-mediated SET step followed by capturing of oxygen furnished peroxy radical that ultimately produced the desired product (Scheme 11.26A). A similar mechanism involving SET oxidation process with the assistance of ferric chloride and oxygen, has been proposed for iron(III)-catalyzed C3-formylation of imidazo[1,2-a]pyridines (Scheme 11.26B).

Cu2+ Cu(OAc)2 (5 mol%)

(A) R1

N

AcOH (1 equiv) 120 °C, 24 h, O2

R2

N

(B)

DMSO

R2

CH 3COOH (20 mol %) 100 °C, 12 h, O2 Fe 3+

O

R2

N

FeCl3 (5 mol%)

N

N

N

N

O

H

12 examples 66-86%

N

N 72%

CHO

CHO 80%

N

N

-H +

I1

N

CH3

Representative Products (B)

N N

Cu2+/Fe 3+, O 2 SET

N

Cu 2+, O 2 SET

Representative Products (A) N

O

OR Fe3+ [O] SET

O S

N

O2

N

15 examples 72-84%

N N 84%

N CHO

N

N

66%

CHO

N

N

N

CHO 77%

86%

CHO

Scheme 11.26  Copper/iron-catalyzed synthesis of C3 formylimidazo[1,2-a]pyridines.

The regioselective C3 alkoxycarbonylation of imidazo[1,2-a]pyridines and other imidazo-heterocycles such as benzo[d] imidazo[2,1-b]thiazoles and imidazo[2,1-b]thiazoles can be accomplished by using carbazates under Fe catalysis [52]. Using this protocol, a variety of 2-arylimidazo[1,2-a]pyridines having electron-withdrawing and donating groups afforded their corresponding alkoxycarbonylated products in good-to-excellent yields. However 2-alkyl substituted substrates (2-Me,

11.2  C–C Bond Formation

2-i-Pr) could not furnish any desired product. The reaction was proposed to be initiated by a SET between methyl carbazate and iron(III) species, which on subsequent deprotonation furnished an azo alkoxy radical intermediate. Subsequently, a second SET and deprotonation generated an azo alkoxycarbonyl radical that upon loss of molecular nitrogen resulted in an alkoxycarbonyl radical. Thereafter, attack of imidazo[1,2-a]pyridine on alkoxycarbonyl radical followed by oxidition by S2O82− and deprotonation afforded the 3-alkoxycarbonylated imidazo[1,2-a]pyridine (Scheme 11.27A, Table 11.9: entry i). Alteranatively, C3 alkoxycarbonylation of imidazo[1,2-a]pyridines can be carried out by using a combination of alcohol and CO gas under palladium-catalyzed conditions in DMF [53]. Excellent functional group tolerance was exhibited with respect to substituents on imidazo[1,2-a]pyridines and a variety of cyclic and acyclic alcohols including natural products such as leaf alcohol, phytol, nerol, and tetrahydrogeraniol produced their corresponding 3-alkoxycarbonylated imidazo[1,2-a]pyridines in appreciable yields. The reaction was proposed to be initiated by the C(sp2)–H bond palladation followed by CO insertion to generate imidazo-pyridyl carbopalladium intermediate, which on coordination with alcohol followed by reductive elimination furnished the C3 carbonylation product (Scheme 11.27B, Table 11.9: entry ii). Similarly, substituting CO by W(CO)6 as a CO surrogate produced 3-alkoxycarbonylated imidazo[1,2-a]pyridines with alcohols under palladium-catalyzed conditions [54]. Moderate-to-good yields of the products were obtained by using a wide range of imidazo[1,2-a]pyridines and alcohols. However, benzyl alcohol and phenol were found to be unreactive under optimized conditions. A slighlty modified mechanism involving C3 metalation followed by ligand exchange with alcohol before CO insertion into the palladium–carbon bond using W(CO)6 and subsequent reduction was proposed to afford the desired product (Scheme 11.27C, Table 11.9: entry iii).

Scheme 11.27  Iron/palladium-catalyzed synthesis of alkoxycarbonylated imidazo-heterocycles.

Carbonylation at the C3 position of imidazo[1,2-a]pyridines can also be introduced by its cross-coupling with methyl-heteroarenes under copper-catalysis using trifluoroacetic acid (TFA) [55]. Various substituted 2-methylpyridines, 2-methylquinolines, 2-methylpyrazines, and 2-methylthiazoles were successfully employed to accomplish carbonylation of imidazo[1,2-a]pyridine in moderate to good yields. TFA was presumed to react with 2-methylpyridine to give pyridinium salt, which on oxidation via SET followed by attack of imidazo[1,2-a]pyridine and another SET furnished a C3 alkylpyridinium intermediate. Subsequently, another SET followed by O2 capture gave peroxy radical that ultimately afforded the desired product (Scheme 11.28). In the realm of introducing carbonyl functonality on imidazo-heterocycles, N, N-disubstituted acetamide or acetone have been used to accomplish dicarbonylation of imidazo[1,2‑a]pyridines under copper-catalyzed conditions in the presence of acetic acid as additive and molecular oxygen as oxidant [56]. Imidazo[1,2-a]pyridines with electron-donating groups underwent smooth transformation to afford corresponding C3 dicarbonylated imidazo[1,2-a]pyridines in moderate-to-good yields, whereas electron-withdrawing bearing substrates did not react at all. The best results were obtained when the coupling of imidazo[1,2-a]pyridine with acetone was performed in DCE as an additional solvent. The reaction was proposed to be initiated with the copper(II)-catalyzed formation of a radical intermediate from DMF via SET oxidation mechanism, which on attack by imidazo[1,2-a]pyridine following another SET proton transfer generated another intermediate. Subsequently, another SET oxidation and dioxygen trapping generated peroxy radical species. Protonation and water elimination from this species produced the desired product (Scheme 11.29A–B).

505

506

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Table 11.9  Iron/palladium-catalyzed strategies for alkoxycarbonylation of imidazo-heterocycles. Reaction Conditions

Entry

Representative Products

FeCl2.4H2O (20 mol %), (NH4)2S2O8 (60 mol %), DMSO, 55°C, 6h

i.

S

Examples and Yields S

N N

32%

N N

COOMe

COOMe

70%

Br

N

iii.

Pd(OAc)2 (10 mol %), Cu(OAc)2 (2 equiv), DCE, 100 oC, 16 h

N

N COOEt

O

O

45%

O

84%

N

N

N COOt-Bu O

R1

N

R2

+ N

Cu 2+

R

R

N

Cu(OAc)2 (10 mol %)

COOMe

O

R

2

N

N

O

N

O

O

N

55%

70%

R

N

O

R1

N

N R2

R1

N

R2

N

SET

O2

NH

NH

CF3 COO

CF3 COO

CF3 COO NH

N

O

S 35%

2

SET

N

N

N

N

Br

N

N

N

1

O

R3 35 examples 35-80% Representative Products N

91%

O

N

TFA (3 equiv) Toluene, 130 °C, 12 h, O2

R3

Cl

N

1

24 examples 57–91%

N

N

N

O

95%

83%

N

50 examples 45–95%

N

N

N

57%

COOMe 92%

74%

N

20 examples 55–92%

S

N

COOMe

55%

COOMe N

CF3

COOMe

Pd(OAc)2 (5 mol %), Cu(OAc)2 (1.1 O2N equiv), DMF, 100 oC, 24 h

72%

N

N

5 examples 32–72%

N N

N

ii.

S

OMe

80%

TFA N

Cu, O2 N SET H CF3 COO

N

R1 N CH2 R1 H CF3 COO

N N

N

R2 CF3 COO

R2

NH

Scheme 11.28  Copper-catalyzed C3 carbonylation of imidazo[1,2-a]pyridines.

Other methyl ketones have been used as a dicarbonyl source for the synthesis of C3 dicarbonylated imidazo[1,2-a]pyridines under copper-catalyzed conditions in presence of molecular oxygen [57]. The reaction was not compatible with imidazo[1,2-a]pyridines possessing strong electron-withdrawing groups, whereas electron-donating groups and weakly electron-withdrawing halogens on acetophenones showed good to moderate reactivities. The reaction was initiated with the copper(II)-catalyzed formation of a methyl ketone and imidazolium cationic radical from acetophenone and imidazo[1,2-a]pyridine via SET oxidation mechanisms, which upon radical coupling generated the C3 aralkylated intermediate. Another SET proton transfer from this intermediate followed by dioxygen trapping afforded a peroxy radical species, which subsequently gave the desired product (Scheme 11.30A, Table 11.10: entry i). Similarly, magnetic copperdoped nano-composite iron oxide catalyst [Cu4O3@Fe3O4_C(II)] can also be used for the C3 dicarbonylation of imidazo[1,2a]pyridines with methyl ketones under similar reaction conditions [58]. Various imidazo[1,2-a]pyridines with electron-donating and weakly electron-withdrawing groups underwent smooth transformations to corresponding

11.2  C–C Bond Formation O N

R

N

N

(B )

O

O N R 20 examples R 45-81%

R

N

R

O

O 17 examples O 15-84%

N 45%

O

NEt

R

O

N R

R

R

Cu, O SET

O R

N R

Cu, O SET R

N

81% O

N

68%

R

O R

N

O

O

N R

N R

N

O

15%

NMe

R

N R

Cu, O SET

N

R

O

N

R

N

O

N R

N

N

Cl

O

NMe

O

O

N

N O

67%

N R

N

N

O

N

OH

O R

R

Representative Products (B)

Representative Products (A) N

N

O

R

N

R1

DCE

R

N

O

Cu(OAc) (10 mol %) R + Cu AcOH (10 mol %) t-AmOH, 120 °C, 24 h, O O

R

N

N

N R

(A )

R N

N

R

R

O

84% O

O

Scheme 11.29  Copper-catalyzed synthesis of C3 dicarbonylated imidazo[1,2-a]pyridines.

1,2-dicarbonyl imidazo[1,2-a]pyridines in moderate-to-good yields. With the help of an external magnetic field, the catalyst was separated and reused up to 6 times with negligible change in its performance. The mechanism was proposed to be similar to that of copper(II)-catalyzed dicarbonylation discussed above (Scheme 11.30B, Table 11.10: entry ii).

Scheme 11.30  Copper/copper-nanoparticle-catalyzed synthesis of dicarbonylated imidazo[1,2-a]pyridines.

Table 11.10  Copper/copper-nanoparticle-catalyzed strategies for dicarbonylation of imidazo[1,2-a]pyridines. Entry

Reaction Conditions

i.

Cu(OAc)2 (5 mol %), AcOH (10 mol %), toluene, 140°C, 12 h, O2

Representative Products

Examples and Yields

N

N

N O O

O

O

93%

80%

10%

O

O

OH

44 examples 10–93%

N

N

N

Et

ii.

Cu4O3@Fe3O4_C (10 mol %), AcOH (10 mol %), toluene, 120°C, 16 h, O2

N

27 examples 53–85%

N

N O O

N

N O

N O

O O

53%

76% OH

O 85%

507

508

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Dicarbonylation of imidazo[1,2-a]pyridine has also been achieved by using aryl acetaldehydes via copper-catalyzed aerobic oxidative cross-dehydrogenative coupling under base-free conditions. The scope of this strategy was further extended to the dicarbonylation of imidazo[1,2-a]pyrimidine, imidazo[2,1-b]thiazole, and benzo[d]imidazo[2,1-b]thiazole [59]. A radical mechanism was proposed involving a Cu(I)/O2-mediated attack of imidazo[1,2-a]pyridine on carbonyl carbon of aryl acetaldehyde to give a C3 hydroxylethylene intermediate via SET pathway, which on oxidation furnished a C3 carbonylmethylene intermediate. Subsequently, its copper-mediated conversion to super oxide radical by oxygen insertion eventually produced the dicarbonylated product (Scheme 11.31A, Table 11.11: entry i) Alternatively, aryl glyoxals can accomplish dicarbonylation of imidazo[1,2-a]pyridines under via iron-catalyzed dehydrogenative coupling under ligand-free conditions [60]. This dicarbonylation proceeded on a variety of other imidazo-heterocycles such as benzo[d]imidazo[2,1-b]thiazoles and imidazo[1,2-a]pyrimidines. Notably, the use of benzaldeyde under the described conditions gave bis-imidazo[1,2-a] pyridine in good yield. In this case, a non-radical pathway was proposed that involved the FeCl3-catalyzed addition of aryl glyoxal on imidazo-heterocycle to produce a iron(III)-chelated imidazo-heterocyclic intermediate, which is oxidized to iron(IV)-oxoimidazo-heterocyclic complex via aerial oxidation. Subsequently, its reductive elimination gave the C3 dicarbonylated product (Scheme 11.31B, Table 11.11: entry ii).

Scheme 11.31  Copper/iron-catalyzed synthesis of dicarbonylated imidazo-heterocycles. Table 11.11  Copper/iron-catalyzed strategies for dicarbonylation of imidazo-heterocycles. Reaction S. No. conditions

i.

CuBr (10 mol %), 2,2ʹ-bipyridine (10 mol %), toluene, 100°C, 12–17 h, Air

Examples and Yields

Representative Products

N

Ph

N

Br

N

Ph

N O

O

N Ph

N

O

O

O

N

N

N

NO 2

22 examples 55–85%

O O

O 78%

55%

85% F N

S

N

S

S

N

N

O

O O

O

68%

74%

70% F

2 examples 68–74%

11.2  C–C Bond Formation

Table 11.11  (Continued) Reaction S. No. conditions

ii.

FeCl3 (10 mol %), toluene, 80°C, 6 h, Air

Examples and Yields

Representative Products

NO2

N N

N

Ph

N

O

O O

O

68%

82%

77%

N

S

O

71%

N

S

N O

Ph

N

O

O

12 examples 68–82%

N

N

S

N O O 78%

N

S

Cl

N

15 examples 71–86%

O O 86%

11.2.4  Arylation/Heteroarylation A number of palladium catalysts in the absence or presence of an appropriate ligand/additive have been used to affix aryl and heteroaryl groups at C3 position of imidazo[1,2-a]pyridines. Two generalized mechanisms have been proposed for this protocol. Mechanism A involves the C–H palladation of imidazo[1,2-a]pyridine with Pd(OAc)2 to generate imidazo[1,2-a] pyridyl-palladium intermediate. This on oxidative addition with aryl halide and then subsequent reductive elimination gives the desired product while regenerating the palladium(0) catalyst that is oxidized to palladium(II) catalyst for the next catalytic cycle. In mechanism B, the oxidative addition of palladium(0) catalyst to aryl halide is followed by electrophilic substitution of Ar-Pd-Cl species at the C3 position of imidazo[1,2-a]pyridine involving base-mediated proton abstraction and reductive elimination of the palladium(0) catalyst (Scheme 11.32). Work on the palladium-catalyzed arylation of imidazo[1,2-a]pyridine was started by Sames and coworkers using a palladium-based catalytic system (L1L2PdX2). Three examples of 3-arylimidazo[1,2-a]pyridines were synthesized in 51–98% yields through this protocol in DMA using CsOAc as a base [61]. The complex L1L2PdX2, consisting of N-heterocyclic carbene (NHCs) and phosphine ligands, was designed and identified as a promising catalyst from a series of related catalysts based on the steric and electronic properties of the carbene ligand. The authors did not shed any light on the mechanism of the reaction (Scheme 11.32, Table 11.12: entry i). Subsequently, the exploitation on the use of commercially available palladium-based catalysts for the C3 arylation of imidazo[1,2-a]pyridines became significant. For example, the Pd(OAc)2/PPh3 catalytic system was used to carry out direct C3 arylation and heteroarylation of imidazo[1,2-a]pyridines under conventional heating (Method A) or microwave-induced conditions (Method B) using K2CO3 as a base in dioxane and dioxane-EtOH solvent systems, respectively [62]. Various aryl or heteroaryl bromides were cross-coupled with a range of substituted imidazo[1,2-a]pyridines to furnish their corresponding C3 arylated/heteroarylated products in good-to-excellent yields (Scheme 11.32, Table 11.12: entry iiA-B). The application of this microwave-assisted approach was extended for the synthesis of 2,3,6-trisubstituted imidazo[1,2-a]pyridines by one-pot, two-step Suzuki/heteroarylation conducted using arylboronic acids and 3-bromopyridine under palladium-catalyzed similar conditions [63]. Another application of the conventional palladium-catalyzed C3 arylation protocol has been exemplified using catalytic amounts of Pd(OAc)2/PPh3 or Pd(OH)2 on carbon during the multistep synthesis of 3-(3-aryloxyaryl)imidazo[1,2-a]pyridine sulfones as potential liver X receptor agonists [64]. Along similar lines, the Pd(OAc)2/Phen catalytic system has been used for the C3 arylation of imidazo[1,2-a]pyridines with arylboronic acids using Cu(OAc)2/O2 as oxidant/ co-oxidant system [65]. Electron-donating and electron-withdrawing groups on aryl boronic acid had little effect on the product yield. However, the position of substituent showed pronounced effects due to steric hindrance. A variety of substituted imidazo[1,2-a]pyridines were well tolerated and afforded good-to-excellent yields of the arylated products with high regioselectivity. The reaction was believed to proceed by the generalized mechanism involving incorporation of palladium catalyst in

509

510

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Scheme 11.32  Palladium-catalyzed synthesis of 3-(hetero)arylimidazo[1,2-a]pyridines.

C(sp2)–H bond of imidazo[1,2-a]pyridine, which on coupling with arylboronic acid followed by reductive elimination of palladium catalyst generated the product. The presence of oxidant regenerated palladium(II) catalyst for the next catalytic cycle (Scheme 11.32, Table 11.12: entry iii) Also, C3 arylation of imidazo[1,2-a]pyridines has been achieved by relatively less reactive aryl chlorides by using Pd(OAc)2/BuAd2P catalytic system in NMP using Cs2CO3 as a base [66]. A series of functional groups on aryl chlorides were well tolerated under the optimized conditions. However, aryl halides possessing strong electron-withdrawing groups (NO2, OCH3) and heteroaryl chloride did not yield products. Oxidative addition to aryl chloride, followed by electrophilic substitution of Ar-Pd-Cl species at the C3 position involving base-mediated proton abstraction and reductive elimination of the palladium catalyst were the key steps involved for the described transformation (Scheme 11.32, Table 11.12: entry iv). Furthermore, the use of Pd(OAc)2/PivOH catalytic system has demonstrated regioselective C3 arylation of imidazo[1,2-a] pyridine with unactivated arenes using Ag2CO3/O2 as oxidants [67]. This cross-dehydrogenative-coupling proceeded preferentially at a less hindered position of the arene. However, the reactions were drastically retarded with sterically-hindered substrates. In this case, electrophilic C3 palladation of imidazo[1,2-a]pyridine followed by C–H activation of arenes through a CMD process were the key steps that resulted in aryl-heteroaryl bond formation (Scheme 11.32, Table 11.12: entry v). Subsequently, aryl tosylates and mesylates have also been used for C3 arylation of unsubstituted imidazo[1,2-a]pyridines using Pd(OAc)2 in combination with SPhos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) and an indole-based phosphine ligand (2-(2-(diisopropylphosphino)-phenyl)-1-methyl-1H-indole), respectively [68]. Notably, the Pd−SPhos catalyst system was found to be ineffective for the mesylate-functionalized arenes. Electronically neutral and functionalized aryl mesylates possessing CN, keto, and benzodioxolyl groups were well tolerated under the described conditions, whereas highly sterically hindered mesylate did not afford the desired product (Scheme 11.32, Table 11.12: entry vi). Further, palladium-catalyzed C3 (hetero) arylation of imidazo[1,2-a]pyridines with (hetero)aryl chlorides could be achieved in a mixture of dioxane/H2O [69]. Differently substituted imidazo[1,2-a]pyridines with electron-donating and withdrawing groups, and sterically hindered aryl and heteroaryl chlorides comfortably coupled under the described conditions to produce 3-(hetero)arylimidazo[1,2-a]pyridines in good-toexcellent yields (Scheme 11.32, Table 11.12: entry vii). Water has been used as the only greener solvent for the C3 arylation of imidazo[1,2-a]pyridines with aryl halides under ligand-free palladium-catalyzed conditions [70]. Use of environmentally benign solvent and reasonable functional group tolerance including electron-donating and electron-withdrawing aryl and heteroaryl halides highlighted the effectiveness of this methodology (Scheme 11.32, Table 11.12: entry viii). Very interestingly, 1 mol% of Pd/C in 3-methylbutan-1-ol has been used for the direct arylation of imidazo[1,2-a]pyridines and other heteroarenes such as thiophenes, furans, pyrroles, thiazoles, imidazoles, and isoxazoles with aryl bromides using KOAc as a base [71]. Other green solvents such as diethyl carbonate, DMA, pentan-1-ol, and cyclopentyl methyl ether were also used to perform arylation

11.2  C–C Bond Formation

511

with a few electron-deficient and electron-rich aryl bromides. The mechanism of the reaction was not proved, but desorption of palladium from Pd/C after oxidative addition of the aryl halide on the Pd/C surface to furnish a soluble palladium(II) species was postulated to be the key step (Scheme 11.32, Table 11.12: entry ix). The C(sp2)–H heteroarylation of 2-arylimidazo[1,2-a] pyridines have been achieved with (E)-1-(5-bromothiophen-2-yl)-3-arylprop-2-en-1-ones using Pd(OAc)2/P(Cy)3 catalytic system to furnish a series of C3 thienylated products that were evaluated for their in vitro cytotoxic anticancer activity against a panel of four human cancer cell lines (A549, MCF7, HeLa and DU145) [72]. Oxidative addition of substituted thiophen-2-yl bromide with PCy3-activated Pd(0) complex, followed by base-mediated electrophilic substitution and reductive elimination of palladium(0) activated complex, produced the heteroarylated product (Scheme 11.32, Table 11.12: entry x). Recently, an efficient approach for the C3 arylation of 6-phosphoryl-imidazo[1,2-a]pyridines was disclosed with aryl bromides in moderate-tohigh yields under ligand-free palladium-catalyzed conditions [73]. Previously, imidazo[1,2-a]pyridine substituted phosphonates, phosphinates, and phosphine oxides were prepared by carrying Hirao coupling at C3, C5, and C6 positions under palladiumcatalyzed conditions (Scheme 11.32, Table 11.12: entry xi). Fascinatingly, regioselective C3 arylation of imidazo[1,2-a]pyridine has occured with aryl bromides using carbon nitride (gCN) supported nanosized metallic palladium, where oxidative addition of aryl bromide by palladium(0)-nanoparticles, base-mediated electrophilic aromatic substitution via Wheland intermediate, and subsequent reductive elimination were the key steps for the reaction pathway (Scheme 11.32, Table 11.12: entry xii) [74]. Also, the application of bimetallic Ni@Pd core@shell nanoparticles assembled on reduced graphene oxide (rGO) has carried C3 arylation of imidazo[1,2-a]pyridines using a variety of electron-deficient and electron-rich aryl bromides and iodides [75]. High functional group tolerance on the substrates was attributed to the synergistic effect between two metals in the core@shell structure and beneficial properties of rGO as a support material in organic reactions. Coordination and oxidative addition of aryl halide by palladium shell of the rGO-Ni@Pd nanocatalyst, followed by C(sp2)–H bond activation of imidazo[1,2-a]pyridine by base-mediated electrophilic aromatic substitution involving the Wheland intermediate and then subsequent reductive elimination and reproduction of the rGO-Ni@Pd nanocatalyst was the proposed mechanism (Scheme 11.32, Table 11.12: entry xiii). Very interesingly, dimetallic palladium(II)–NHC complexes possessing 9,10-anthracenyl spacer sandwiched between two imidazole rings have been used for the direct arylation of several heterocycles including imidao[1,2-a]pyridine [76]. Notably, this dimetallic palladium-complex was found to be more effective than the related mononuclear palladium-complex in catalyzing the direct arylation reactions of heterocycles with aryl halides. Apart from the acceptable homogenous catalysis mechanism, involving electrophilic aromatic substitution (SEAr) and a CMD process, the possibility of heterogeneous catalysis mechanism was also indicated from the studies carried (Scheme 11.32, Table 11.12: entry xiv). Similarly, using a combination of Pd– and Cu–NHC based catalytic systems, one example of C3 arylation of imidazo[1,2-a]pyridine with 4-methyhe lbromobenzene was achieved in 70% yield [77]. The proposed mechanism consisted of toverlap of dual catalytic cycles involving CsOH-mediated, copper-catalyed C(sp2)–H activation of the C3 proton of imidazo[1,-a]pyridine and palladium-catalyzed oxidative addition of the aryl halide over a common transmetallation step, leading to the formation of aryl-heteroaryl bond formation upon reductive elimination (Scheme 11.32, Table 11.12: entry xv).

Table 11.12  Palladium-catalyzed strategies for C3 arylation/heteroarylation of imidazo[1,2-a]pyridines.

Entry Reaction Conditions

Examples and Yields

Representative Products

i.

N

N

N O

N

N

(2.5 mol %)

N

N

COOEt

N

N

93%

98%

COOEt

3 examples 51–98%

PdI 2PPh 3

CsOAc (2 equiv), DMA, 125°C, 24 h

51% COOMe

iiA.

Pd(OAc)2 (5 mol %), PPh3 (10 mol %), K2CO3 (2 equiv), dioxane, 100°C, 48 h Cl

N

N

N N

Cl

N

Cl

96%

80%

79% N Pr

N

OMe

6 examples 79–96%

512

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Table 11.12  (Continued) Entry Reaction Conditions

iiB.

Examples and Yields

Representative Products

Pd(OAc)2 (5 mol %), PPh3 (10 mol %), K2CO3 (2 equiv), dioxane/EtOH, MW, 130–150°C, 1–3.5 h

F

N

Cl

N

N

Cl

N

96%

94%

64%

20 examples 64–96%

N

N

N

N

N Pr

iii.

Pd(OAc)2 (5 mol %), Cu(Oac)2 (10 mol %), Phen (10 mol %), dioxane, 120°C, 24 h, O2

N

N

N

50%

33 examples 50–83%

N

N

N

77%

83% Cl

iv.

Pd(OAc)2 (2.5 mol %), BuAd2P (10 mol %), Cs2CO3 (1.5 equiv), NMP, 120°C, 24 h

N

N CF3

N

69%

N

N

F

80%

89%

Cl

v.

Pd(OAc)2 (5 mol %), PivOH (15 mol %). Ag2CO3 (1.2 equiv), DMF, 130°C, 20 h, O2

N

26%

vi.

t-Bu

N N

Pd(OAc)2 (10 mol %),

N

72%

79%

N

N

24 examples 38–88%

N

N

N

N

PCy2 OMe

38% OR

SPhos (8 mol %)

20 examples 26–79%

N

N

N

MeO

27 examples 69–89%

N

O

57%

i-Pr 2P

88%

O

N

t-Bu

L1 (8 mol %)

K3PO4.H2O (1.5 equiv), t-BuOH, 120°C, 18–24 h, N2 vii.

Pd(OAc)2 (5 mol %), BuAd2P (10 mol %), K2CO3 (3 equiv), Dioxane/H2O (2: 1), 110°C, 24 h, N2

Pd(OAc)2 (5 mol %), KOH (3 equiv), H2O, 100°C, 24 h, N2

NH2

86%

N

33%

N

F3C

S

N

29 examples 26–99%

N

N

26%

viii

N

N N

99%

N

N

N 64%

N NH 92%

27 examples 33–92%

11.2  C–C Bond Formation

513

Table 11.12  (Continued)

Entry Reaction Conditions

ix.

Examples and Yields

Representative Products

10% Pd/C (1 mol %), KOAc (2 equiv), 3-methylbutan-1-ol, 150 oC, 16 h

N

N

N

5 examples 73–96%

N

N

N CN 94%

73%

N

96% COMe

x.

Pd(OAc)2 (2.5 mol %), P(Cy)3 (5 mol %), K2CO3 (2.0 equiv), DMA, 90°C, 18 h

N

N

Ph

N

N

S

81%

xi.

xii.

Pd(OAc)2 (2.5–10 mol %), KOAc (2 equiv), DMAc (0.1 M), 140–160 0C,4–60 h, N2 OR Pd(OAc)2 (2.5–10 mol %), KOAc (2 equiv), DMAc (0.1 M), MW, 170–190 OC, 0.5–1 h Pd-gCN nanocatalyst (5 mg), KOAc (2 equiv), DMAc, 130 oC, 24 h

CN

O 91%

OMe

Me2OP

S O

N

85%

63%

rGO-Ni@Pd nanocatalyst (10 mg), KOAc (2 equiv), DMA, 130 oC, 24 h

N

N

98% CN

N

N

95%

74%

98%

N

CN

OMe

xiv.

Ph

N Cl N

Pd

COOEt

N

2 examples 64–75%

N

N

O N

N

N Cl

Cl

O Pd Cl

(0.75 mol %)

75%

64%

N Ph

N

15 examples 74–98%

N

N

N N

13 examples 65–98%

N

OH

xiii.

Ph

13 examples 21–100%

100%

N

N

Ph

N

Ph2OP

N

N

O

97%

75%

21%

18 examples 81–97%

Ph

N N

Ph

N

S

N N

N

NO 2

CN

CN

K2CO3 (2 equiv), PivOH (30 mol %), DMA, 130 oC, 18 h xv.

iPr

iPr

N iPr iPr Pd Cl N

Ph [Pd(Cl)(cin)(SIPr) (1 mol %)

N N

N Cu Cl

[Cu(Cl)ItBu)] (1 mol %)

CsOH (1.3 equiv), Toluene, 110 oC, 15 h

N

70%

1 example 70%

514

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

In addition, other transition metal catalysts can be used for arylation of imidazo[1,2-a]pyridine derivatives. For example, ruthenium-arene complex carried out regioselective C3 arylation of imidazo[1,2-a]pyridines with aryl halides to afford polysubstituted imidazo[1,2-a]pyridines under ligand free conditions. In this process, p-substituted aryl halides resulted in higher yields than their corresponding o-substituted analogues. Also, electron-donating groups on aryl halides showed higher reactivity than the aryl halides with electron-withdrawing groups. Activation of the C(sp2)–H bond of imidazo[1,2a]pyridine by ruthenium(II) via formation of an unstable cationic three-member cyclic intermediate, followed by basemediated proton abstraction, reversible oxidative addition of aryl halide, and subsequent reductive elimination afforded the C3 arylated products in good-to-excellent yields (Scheme 11.33A, Table 11.13: entry i) [78]. In striking contrast, C3 arylation of imidazo[1,2-a]pyridine with aryl halides has also been achieved using an inexpensive CuI/1,10-phenanthroline catalytic system [79]. The strategy was feasible with different aryl iodides, aryl bromides, and aryl triflates with a range of imidazo[1,2-a]pyridines affording the arylated products in good-to-excellent yields. However, the heteroaryl halides could not generate the desired product. The reaction was believed to proceed through base-mediated C(sp2)–H proton abstraction in imidazo[1,2-a]pyridine, followed by copper(I)-catalyzed transmetalation, aryl halide oxidative addition and finally reductive elimination (Scheme 11.33B, Table 11.13: entry ii). A [Rh(cod)Cl]2/PPh3 catalytic system has been utilized to perform C3 arylation of imidazo[1,2-a]pyridines with aryl bromides or triflates in excellent yields using NMP as a solvent [80]. Oxidative addition by rhodium(I) into aryl halide generated an aryl-rhodium halide intermediate, which followed by base-mediated electrophilic substituion at C3 position furnished a rhodium-bridged aryl-heteroaryl species. This underwent reductive elimination to gave the desired product (Scheme 11.33C, Table 11.13: entry iii). A catalytic amount of CoCl2⋅6H2O has also accomplished C(sp2)–H arylation of imidazo[1,2-a]pyridine with aryl/heteroaryl iodide under ligandfree conditions using KOAc as a base to afford 3-arylated imidazo[1,2-a]pyridines in good yields [81]. Reaction was performed in a Screw-top V-Vial® and electronically-rich and deficient aryl iodides showed decent reactivity. Although the mechanistic aspect of cobalt-catalyzed arylation reaction was unclear, the authors speculated that the first step involved cobalt-catalyzed homolysis of aryl iodide to generate an aryl radical that subsequently formed an aryl-cobalt complex on which imidazo[1,2-a]pyridine underwent oxidative addition to generate a cobalt-bridged aryl-heteroaryl species. Finally, 3-arylimidazo[1,2-a]pyridine was obtained by reductive elimination along with regeneration of cobalt(II)-species (Scheme 11.33D, Table 11.13: entry iv), and C3 azolylation of imidazo[1,2-a]pyridines has succeeded using 2-bromoazoles under visible light-mediated Ir-catalyzed mild conditions [82]. Moderate-to-good yields of the heteroarylated products were obtained by using a variety of substituent scope on the two heteroaromatic coupling partners. Other heteroaryl bromides including thiophene and furan derivatives showed lower reactivity under the described conditions as compared to thiazoles and benzothiazoles derivatives. Reasonable yields of thiazolation products were obtained with other imidazo-heterocycles such as 6-phenylimidazo[2,1-b]thiazole and 2-phenylimidazo[1,2-a]pyrimidine. It was postulated that oxidative quenching of 2-bromothiazole by an excited state catalyst [Ir(ppy)2(dtbbpy)]PF6* generates a thiazolyl radical that underwent addition to imidazo[1,2-a]pyridine to furnish a heterocyclic radical, which loses a hydrogen radical to furnish the C3 athiazolted product (Scheme 11.33E, Table 11.13: entry v). Along similar lines, an oxidative strategy has been reported for the copper(I)-catalyzed C(sp2)–H homocoupling of imidazo[1,2-a]pyridine to synthesize bi-imidazo[1,2-a]pyridines in DMSO using bipyridine as a ligand [83]. A reasonable number of substrates furnished their corresponding dimeric products connected through C3 position in good-to-excellent yields. Exclusion of radical or SET pathway was indicated by a radical trapping experiment using TEMPO as radical scavenger. Thus, the formation of C3 metallated imidazo[1,2-a]pyridine species by the coordination of copper(I) to imidazo[1,2-a]pyridine followed by the attack of second molecule resulted in the formation of copper(I) linked species, which generated the homo-coupled product on reductive elimination (Scheme 11.34). As far as the other imidazo-pyridines are concerned, affixing (hetero)aryl groups at different positions has been accomplished using different transition metals, with palladium remaining a dominant metal for this purpose. For example, C1 arylation of 3-substituted imidazo[1,5-a]pyridines was achieved with 4-trifluoromethylphenyl iodide using Pd(OAc)2/PPh3 catalytic system as a ligand in DMA (Scheme 11.35A) [84]. The use of PPh3 as a ligand in the above coupling reaction significantly improved the yield of corresponding C1 arylated product. In contrast, the use of cationic palladium-complex bearing the bipyridyl type ligand, [Pd(phen)2(PF6)2] afforded quantitative amounts of C1 arylated product. When there was no substituent at the C3 position, arylation proceeded selectively at the C3 position to afford C3 arylated products in moderate to excellent yields (Scheme 11.35B) [85]. Regioselective C2 arylation of N3-MEM-protected imidazo[4,5-b]pyridines using aryl halides has been achieved by Pd(OAc)2 in combination with stoichiometric amounts of CuI under two different reaction conditions [86]. When Pcy3·HBF4 was used as an additive, the reaction temperature reduced from 140 to 120°C. However, this in turn had an impact on lowering the

11.2  C–C Bond Formation

Scheme 11.33  Transition metal-catalyzed C3 (hetero)arylation of imidazo[1,2-a]pyridines. Table 11.13  Transition metal-catalyzed C3 (hetero)arylation of imidazo[1,2-a]pyridines.

Entry

Reaction Conditions

i.

[RuCl2(p-cymene)]2 (5 mol %), Cs2CO3 (2 equiv), DMF, 120°C, 15 h

CuI (5 mol %), 1,10-phenanthroline (10 mol %), t-BuOK (2.5 equiv), DMF, 140°C, 24 h

N

N

CF3

N

N

70%

ii.

Examples and Yields

Representative Products

CN

92%

tBu

N

93%

N

N N

N

72%

82% CN

CF3

13 examples 70–93%

N

29 examples 72–89%

N N

89% Et

515

516

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Table 11.13  (Continued)

Entry

Reaction Conditions

iii.

[Rh(cod)Cl]2 (2.5 mol %), PPh3 (8 mol %), K2CO3 (1.0 equiv), NMP, 100°C, 20 h

N

N t-Bu

N

CoCl2.6H2O (20 mol %), KOAc (2 equiv), DMF, 150°C, 24 h

N

Cl

80%

iv.

Examples and Yields

Representative Products

OMe

N

42%

N

33 examples 42–92%

91%

N

N

27 examples 80–91%

N

Cl

86%

N

N

N

92%

84% NO2

Ir(ppy)2(dtbbpy)PF6 (2 mol %), Cy2Nme (2 equiv), 5W Blue LEDs, MeCN, r.t., 20 h, Ar [dtbbpy: 4,4′-Di-tert-butyl-2,2′dipyridyl]

v.

N

N

N

N S

28%

83%

29 examples 28–83%

N N

N

S 83%

S

N

OMe

Cu2+ R1

N

R2

N

CuI (5 mol %)

N N 60%

N R2

R1

bipy (10 mol %) N R2 DMSO, 120 °C, 8 h, O2 20 examples N 60-84%

N

N

N

Representative Products N

N I

N R1

N

N N 68%

t -Bu

N

R1

N

R2

t-Bu

N

I

N

Cu

R1

R1

R2

N

R1

N 84%

Ln Cu I

N R1

N

N N N

R2

R2

CuL n

R2

Scheme 11.34  Copper-catalyzed synthesis of bi-imidazo[1,2-a]pyridines.

reaction rate. Electron-deficient aryl halides showed lower reactivity than the corresponding electron-donating derivatives. Two mechanisms were postulated by the authors, of which their observations were consistent with a CMD mechanism that involves the pre-coordination of CuI to nitrogen atom of imidazo-pyridine, which lowers the pKa of the C–2H, followed by base-assisted C–H palladation and reductive elimination of the palladium(0) catalyst (Scheme 11.36A–B). Subsequently, a catalytic amount of Cu(OAc)2 in combination with bathophenanthroline has been used for C2 arylation/ alkylation of imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines with aryl/heteroaryl/alkyl boronic acids in DMF/H2O solvent system under microwave-assisted conditions [87]. Electron-rich and electron-deficient aryl boronic acids reacted smoothly with a variety of regioisomeric imidazo-heterocycles, whereas heteroaryl, vinyl, and cyclopropyl boronic acid analogues displayed moderate reactivity under the optimized conditions. However, methyl and ethyl boronic acids

11.2  C–C Bond Formation

Ar

(B) Pd2+

Pd(OAc)2 (5 mol %)

N

N

(A)

Pd2+

ArI +

PPh 3 (5 mol %) Cs 2CO3 (1.1 equiv) DMA, 150 o C, 24 h

R1 2 examples 34-56%

N

N

R1

N

N

Cs 2CO3 (1.1 equiv) DMA, 150 oC, 20-40 h

14 examples 50-98%

1

R =H

Representative Products (B) N

Representative Products (A) N

N

Ar

Pd(phen)(PF6 )2 (5 mol %)

MeO

CF3

N

N N N

MeO

CF3

56%

N

CF 3

34%

N

N

N

50%

N

82%

N 98%

Scheme 11.35  Palladium-catalyzed synthesis of 1- and 3-(hetero)arylimidazo[1,5-a]pyridines.

Scheme 11.36  Palladium-catalyzed synthesis of C2 (hetero)arylimidazo[4,5-b]pyridines.

produced the desired alkylated products in trace amounts only. The reaction was believed to initiated with the transmetallation from aryl boronic acid with Cu(OAc)2 to yield aryl copper(II) species, which reacted with the imidazo-pyridyl anion (generated by base-mediated abstraction of C2 proton) to furnish a copper(III) species via copper(II) bridged aryl imidazopyridyl species; reductive elimination of this produced the arylated product (Scheme 11.37).

R 2X Cu(OAc) 2 (5 mol %) Bathophenanthroline (10 mol %)

Cu2+ N Het

N R1

Cs 2 CO 3, DMF/H 2O, MW 110 oC, 30 min.

N 41%

N

N 69%

N Ph

N

N Het

2

R

Het

N R1 X = B(OH)2, BF3K

Represenatative Products N S N

N N

N

CuIII X

Cu IIX2 N

Cu IX N

R2

Het

N N

Ph

R 2B(OH) 2 XB(OH) 2 II

71%

N R2

91%

Cu X2

CuII R2

Cs 2CO3

R 2CuIIX

Scheme 11.37  Copper-catalyzed (hetero)arylation of imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines.

N R1

N Het

N R1

517

518

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

In continuation, single and double C(sp2)–H arylations at C9 or/and C6 position(s) of imidazo[1,2-a][1,8]naphthyridines with aryl iodides (introduced sequentially) have been achieved using a Pd(OAc)2/PPh3 catalytic system, affording two series of RO8191 analogues for anti-HCV activity in low to excellent yields [88]. Promising anti-HCV activities was observed for some of the synthesized products. The reaction mechanism involved the oxidative addition of palladium(0) to aryl iodide followed by electrophilic palladation with imidazo[1,2-a][1,8]naphthyridines to generate an aryl-palladadium-imidazo-heterocyclic intermediate, which on deprotonation and subsequent reductive elimination produced the C9 arylated product and palladium(0) catalyst. However, in presence of a second molecule of aryl iodide, the C9 arylated product continued the second catalytic C–H arylation pathway to produced 6,9-diarylimidazo[1,2-a][1,8]naphthyridines (Scheme 11.38A–B).

R 1I (1.3 equiv) Pd(OAc) 2 (10 mol %). (A) PPh 3 (10 mol %) Ag2 CO3, DMF, 130 oC, 3-6 h CF 3

CF3

CF3

N

CF3

N

12 examples 12-91%

Pd2+

N

R1 I (2 equiv), Pd(OAc)2 (10 mol %), PPh3 (10 mol %), Ag2 CO3 (4 equiv), DMF, 130 o C, 6-12 h (B) OR

CF3

CF3

N

N

CF3

N

R 2 /R 1-Pd-I

R1

R 1/R 2

CF3

N

CF3

N

N

N

N

Pd

N

C F3 CF3

R2 Pd N

N

N

R1

Pd

N

N

N

N R 1 -Pd-I

R2 Pd

CF3

CF3

Reducti elimiatiove n

Pd0

N

N

CF3

N

N

N

R1

CF 3 N

N

R1I

CF3

N

N

N

R1 6 examples 38-89%

CF3 CF 3

1

R

N

CF3 N

N

R1

Representative Products (A)

N

N

CF3

CF3

Ag2 CO 3

CF3

CF3

R 1I (1.3 equiv), Pd(OAc) 2 (10 mol %), PPh3 (10 mol %), Ag2 CO3 (1 equiv), DMF, 130 o C, 3 h and then R 2I (2.0 equiv), Ag 2CO3 (2 equiv), 6-12 h (i)

N

CF3

Reductive elimiation

Representative Products (B) CF3

N

N

C F3

N

N

N

O 12%

S 40%

NO 2

91%

Cl

38%

89%

Scheme 11.38  Palladium-catalyzed C9/C6 (hetero)arylation of imidazo[1,2-a][1,8]naphthyridines.

Direct C3 (hetero)arylation of imidazo[1,2-b]pyridazines has been carried with (hetero)aryl bromides and chlorides under phosphine-free palladium-catalyzed conditions in DMA or 1-pentanol as solvents [89]. A wide variety of aryl bromides with both electron-donating and withdrawing substituents and aryl chlorides with electron-withdrawing substituents were proven to be excellent arylating agents under described conditions, affording 3-(hetero)arylimidazo[1,2-b]pyridazines with high TOFs and TONs in excellent yields. A few heteroaryl bromides were also fruitful in delivering C3 heteroarylated products, albeit in comparatively lower yields (Scheme 11.39). Aryl and heteroaryl groups have been affixed at different positions on imidazo[1,2-a]pyrazine nucleus under palladiumand rhodium-catalyzed conditions. For example, direct C3 arylation of imidazo[1,2-a]pyrazines can be performed with aryl bromides using Pd(OAc)2/PCy3·HBF4 catalytic system in DMF. Subsequently, a second arylation at C5 position was achieved using a second mole of aryl bromide using Pd(OAc)2/Phen catalytic system in DMA (Scheme 11.40A–B) [90]. A variety of substituted aryl bromides and heteroaryl bromides, including pyridyl, quinolinyl, pyrimidinyl, thienyl, pyrazolyl, and furyl were used for the described arylations in moderate to good reactivities. One representative example was carried out for consecutive C3/C5 arylations of imidazo[1,2-a]pyrazines in a one-pot, two-step operation to afford 3-(4-ethylphenyl)5-(3-quinolinyl)imidazo[1,2-a]pyrazines in 40% yield over two steps.

11.2  C–C Bond Formation

R1

N

N

ArX

X = Br, Cl

N

58%

N

N Ar

31 examples 58-97%

Representative Products N N

N N

N

DMA (or pentan-1-ol), 1 R 150 oC, 16 h

+

Cl

Pd(OAc)2 (5 mol %) KOAc (2 equiv)

Pd2+

N

N

N

CN

72%

N

N

N

N

N

N

97%

79%

CHO

NO2

Scheme 11.39  Palladium-catalyzed synthesis of C3 (hetero)arylimidazo[1,2-b]pyridazines.

Pd2+ N

N

R1

N

N

N

R 2Br Pd(OAc)2 (5 mol %)

(A)

N

N

PCy3 .HBF4 (10 mol %) PivOH (30 mol %) K2CO3 (1.5 equiv) DMF, 100 o C

N

N N

21%

HN

46%

CN 90%

OMe

N 24%

N

N N

N

R1

R2 R3 10 examples 24-50%

Representative Products (B) N N N N

S COCH3

(B)

phen (20 mol %) Cs 2CO3 (3 equiv) DMA, 140 o C

R2 18 examples 21-90%

N

N

R1

N

Representative Products (A) N N N N

N

R3 Br Pd(OAc) 2 (10 mol %)

N N

N

N 35%

SEt

N

Et 50%

Scheme 11.40  Palladium-catalyzed sequential synthesis of 3,5-di(hetero)arylimidazo[1,2-a]pyrazines.

One-pot sequential functionalization at C3 and C6 positions of 8-methoxy- or 8-methylthio-substituted 6-bromoimidazo [1,2-a]pyrazines have been achieved via palladium-catalyzed Suzuki-Miyaura cross-coupling with arylboronic acids, followed by direct C–H arylation/vinylation/benzylation with aryl/vinyl/benzyl halides, respectively (Scheme 11.41) [91]. 2-(Dicyclohexylphosphino)biphenyl (cyJohnPhos) was found to be an ideal ligand amongst a number of other phosphine based ligands screened for the desired transformation. In addition, electron-donating and withdrawing groups on arylboronic acids and aryl halides underwent smooth arylation to furnish good-to-high yields of C3-C6 substituted imidazo-pyrazines. On the other hand, two examples of regioselective arylations of imidazo[1,2-a]pyrazine at C3 and C8 positions with phenyl iodide and diphenyl zinc were reported under palladium and rhodium-catalyzed conditions, respectively (Scheme 11.42) [92]. Notably, arylation at C3 position occurs via electrophilic substitution, whereas oxidative nucleophilic substitution was proposed to be involved for the arylation at C8. Similarly, Pd(OAc)2 in combination with PPh3 has been used for the C6-arylation of 3-aminoimidazo[1,2-a]pyrazines with aryl bromides using PivOH as an additive serving as proton shuttle (Scheme 11.43) [93]. The electron-rich and deficient aryl bromides possessing chloro, cyano, nitro, methoxy, formyl, and amine groups smoothly reacted with imidazoheterocycles under optimized conditions to afford 6-aryl-3-aminoimidazo[1,2-a]pyrazines in moderate-to-good yields. The reaction mechanism was proposed to proceed by oxidative addition of aryl bromide to generate ArPdBr that on reaction with PivOK furnished ArPd(OPiv) complex, which activated C6−H bond of imidazo[1,2-a]pyrazine to form aryl-Pd-imidazopyrazine complex. Subsequently, its reductive elimination produced C6 arylated imidazo[1,2-a]pyrazine along with

519

520

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Pd2+ Y N

N N

Br

Y = O, S X = Br, Cl, I

N

N

R 2X

N CyJohnPhos (10 mol %) 120 oC, 18 h R1 R2 Cs 2CO3 (5 equiv) o 27 examples dioxane, 90 C, 3 h 30-93%

Representative Products S

O

O

N

N

N

N

N

N N

N

N MeO

Y

R 1B(OH) 2 Pd(OAc)2 (5 mol %)

Br 63%

30%

93%

N OMe

Scheme 11.41  Palladium-catalyzed sequential functionalization at C3 and C6 positions of imidazo[1,2-a]pyrazines.

Pd2+

Rh1+ Ph

Ph2 Zn {RhCl(cod)}2 (5 mol %) N PCy 3 (10 mol %) toluene, 100 oC, 20 h

N

N N

40%

PhI Pd(OAc)2 (5 mol %)

N N

N

N N

PPh3 (10 mol %) Cs 2 CO 3 (2 equiv) dioxane, 120 oC, 20 h

99%

Ph

Scheme 11.42  Palladium/rhodium-catalyzed synthesis of 3- or 8-aryl/heteroarylimidazo[1,2-a]pyrazines.

N

N N +

Pd(OAc) 2 (5 mol %)

R2

HN R1

R3 Br N

t-Bu OMe

N

N

N PPh3 (20 mol %) R3 PivOH (30 mol %) NH R1 K2 CO3 (2 equiv) 22 examples toluene, 110 oC, 24-36 h 46-74% Representative Products N N N N

MeO

N

Pd 2+

N NH 46%

NH

R3

R2

N

N Pd

N HN

PPh3

R2 R1

R3 Ph 3P Pd O

N

N H

R2

O tBu

N

N N

Cl R3 Br

R1

N H

R2

HN R1

Pd(0)Ln R3 Pd-Ln

74%

PivOK

O R3 [Pd] Ph 3P O

tBu

Scheme 11.43  Palladium-catalyzed synthesis of 6-aryl-3-aminoimidazo[1,2-a]pyrazines.

palladium(0) for the next catalytic cycle. The computational studies conducted on the transition states arising out of the possible arylations at different positions were found to be in agreement with the proposed CMD mechanism. Catatlytic amounts of Pd(OAc)2/(t-Bu)2PMe·HBF4 have accomplished the C5 arylation of 3-methylimidazo[1,5-a]pyrazines with electron-rich and electron-deficient aryl halides to produce 5-aryl-3-methylimidazo[1,5-a]pyrazines in goodto-excellent yields (Scheme 11.44) [94]. However, cyano and nitro-substituted aryl bromides and mesityl bromide failed to arylate under described conditions. The lack of involvement of electronic effects of the substituents on the observed yields

11.2  C–C Bond Formation

R1

R1

Pd2+

N N

Pd(OAc)2 (10 mol %)

N

(t -Bu) 2PMe • HBF4 (20 mol %) Cs 2CO3 (3 equiv) DMF, 120-130 oC, 4-36 h

+ 2

R Br

OMe N N MeOOC

N N

47%

N

N

R2 28 examples 47-99%

R1

N

N R1

H R2 N Pd

Representative Products N

NMe 2 N

N

BrPd N

N F 74%

N

N N 99% R2 Br

N

2 Br H R

R1

N

N

Pd 0L n

N

R2 Pd-Br

OMe

Scheme 11.44  Palladium-catalyzed synthesis of 5-aryl-3-methylimidazo[1,2-a]pyrazines.

excluded the possibility of an electrophilic palladation mechanism, thereby suggesting a Heck-type mechanism involving a carbopalladation step. Li and coworkers disclosed the first report on C3 arylation of unsubstituted imidazo[1,2-a]pyrimidines under basemediated palladium-catalyzed conditions using triphenylphosphine as a ligand. A series of 3-arylimidazo[1,2-a]pyrimidines were furnished in 39–96% yields from a variety of aryl bromides possessing electron-donating and withdrawing substituents; the former displayed lesser reactivity than the latter. Electrophilic attack by arylpalladium halide on imidazo[1,2-a]pyrimidine followed by deprotonation generated a aryl(imidazopyrimidyl)palladium(II) intermediate, which on subsequent reductive elimination produced the C3 arylated product along with the regeneration of palladium(0) catalyst (Scheme 11.45A, Table 11.14: entry i) [95]. In a similar microwave-assisted palladium-catalyzed similar strategy was developed for the arylation/heteroarylation of 2-substituted imidazo[1,2-a]pyrimidines using a variety of diversely functionalized aryl and heteroaryl bromides to afford C3 arylated imidazo[1,2-a]pyrimidines in good-toexcellent yields. These also included arylation of imidazo[1,2-a]pyrimidine-2-carboxylic acid derivatives (Scheme 11.45B, Table 11.14: entry ii) [96]. Very interestingly, BODIPY functionalized ruthenium-nitrogen doped grapheme nanosheet photocatalyst [fRuNDGNs] has been used for the C(sp2)–H arylation of imidazo[1,2-a]pyrimidines. Electronrich and deficient aryl bromides delivered high yields of desired C3 arylated products in high selectivity under visible light irradiation in acetonitrile. The reaction was proposed to be initiated with the formation of excited state catalyst PC* via irradiation with light, which in turn generated an aryl radical by the oxidative quenching of bromoarene along with the conversion of PC* to PC+. The aryl radical upon addition to imidazo[1,2-a]pyrimidine furnished a C3 imidazo radical species. Further, concurrent triethylamine-mediated reduction of PC+ to PC produced triethylamine radical cation that captured a hydrogen radical from C3 imidazo radical species to yield C3 arylation product (Scheme 11.45C, Table 11.14: entry iii) [97]. C2 Arylation of 3-substituted benzo[4,5]imidazo[2,1-b]thiazoles with aryl iodides has been achieved in good-to-excellent yields using a Pd(OAc)2/PPh3 catalytic system. Prior to this, the substrates were synthesized by a copper-catalyzed protocol involving coupling between trans-1,2-diiodoalkenes, 1H-benzo[d]imidazole-2-thiols. The usual mechanism involving Pd(OAc)2/PPh3-catalyzed oxidative addition, base-mediated C2 aryl palladation, and reductive elimination was proposed to achieve the desired C2 arylated product (Scheme 11.46A, Table 11.15: entry i) [98]. In contrast, a CuCl2/PPh3-catalytic system was used for C2 arylation of substituted imidazo[1,2-b]thiazoles with aryl iodides using t-BuOLi as a base. Notably, the arylation occurred in thiazolyl moiety in moderate to good yields by coupling electron-rich and electron-deficient imidazo[1,2-b]thiazole with aryl iodides possessing both electron-donating and withdrawing substituents. However 4-nitrophenyl iodide failed to produce the desired arylation under optimized conditions. The reaction was proposed to be initiated by t-BuOLi mediate deprotonation of C2 proton, which on transmetalation generated the organocopper intermediate that subsequently underwent reversible oxidative addition to aryl iodide and reductive elimination to give the desired arylation product (Scheme 11.46B, Table 11.15: entry ii) [99].

521

522

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Scheme 11.45  Palladium/ruthenium-catalyzed synthesis of 3-aryl/heteroaryl imidazo[1,2-a]pyridines.

In contrast to the above finding, arylation at the C5 position of imidazo[2,1-b]thiazoles has been achieved with a range of aryl bromides under palladium-catalyzed microwave-assisted conditions. A variety of differently positioned electron-withdrawing groups on aryl bromides coupled smoothly with 2-phenylimidazo[2,1-b]thiazoles, benzo[d]imidazo[2,1-b]thiazoles, and 5,6,7,8-tetrahydrobenzo[d]imidazo-[2,1-b]thiazoles, furnishing their corresponding arylated imidazo-heterocycles Table 11.14  Ruthenium/platinum-catalyzed strategies for C3 arylation/heteroarylation of imidazo[1,2-a]pyridines.

Entry

Reaction Conditions

i.

Pd(OAc)2 (2 mol %), PPh3 (4 mol %), Cs2CO3 (2 equiv), dioxane, 100 oC, 18 h

Examples and Yields

Representative Products

N

N

N

N

N N

N

N

96%

39%

12 examples 39–96%

N

96%

NMe2

ii.

Pd(OAc)2 (8 mol %), PPh3 (16 mol %), Cs2CO3 (1.1 equiv), dioxane, MW 150W, 145–160 oC, 20–60 min.

N

N

N N

86% t-Bu

fRuNDGNs (5 mg), NEt3 (2 equiv), CH3CN, Visible Light Irradiation, 12 h

N

98%

N

N N

45 examples 46–96%

96% CF3

N

N N

CONHBn

N

46%

iii.

N

N

N N

N

98%

99%

NO 2

NMe 2

9 examples 98–99%

N

N

11.2  C–C Bond Formation

Scheme 11.46  Palladium/copper-catalyzed synthesis of 2-aryl benzo[4,5]imidazo[2,1-b]thiazoles and imidazo[1,2-b]thiazoles.

Table 11.15  Palladium/copper-catalyzed strategies for C2 arylation benzo[4,5]imidazo[2,1-b]thiazoles and imidazo[1,2-b]thiazoles.

Entry

Reaction Conditions

i.

Pd(OAc)2 (5 mol %), PPh3 (10 mol %), Cs2CO3 (2 equiv), p-xyleme, 135°C, 24 h, N2

ii.

CuCl2 (10 mol %), PPh3 (10 mol %), t-BuOLi (2 equiv), DMA/xylene (1:1), 140 oC, 12 h

Examples and Yields

Representative Products

N

S N 75%

F

F

OMe CF3

N 78%

96%

80%

N

S

N

N

F

15 examples 75–96%

N

S

N

S

N 95%

N

S

N

S

Ph

Ph

N

25 examples 78–96%

96%

in moderate-to-good yields. Notably, the arylation proceeded exclusively in less π-electron rich imidazole ring over comparitiively more π-electron rich thiazole ring, suggesting a crucial role of C(sp2)–H acidity in the observed regioselectivity. In detailed density functional theory calculations were performed to confirm the proposed arylation to proceed via a CMD pathway, which involved the attack of acetate ion on Ar-Pd-Br species obtained by oxidative addition of aryl bromide to palladium(0) catalyst. Thereafter, attack of imidazo[2,1-b]thiazole on Ar-Pd-acetate ion species followed by reductive elimination produced atylated product along with the regeneration of palladium(0) (Scheme 11.47) [100]. Similarly, C5 arylation of 2-arylimidazo[2,1-b][1,3,4]thiadiazoles has been achieved by palladium-catalyzed coupling with aryl bromides using excess of Cs2CO3 as a base. The presence of electron-withdrawing and donating groups on imidazo-thiadiazoles greatly affected its reactivity, affording low-to-excellent yields of the desired C5 arylated products. Also, a one-pot two-step strategy was exemplified to afford trisarylimidazo[2,1-b][1,3,4]thiadiazole by carrying the first arylation at C2 position via Suzuki-Miyaura cross-coupling with arylboronic acid followed by C5 arylation with alkyl bromide under palladium catalysis. Oxidative addition of aryl bromide with palladium(0), followed by C–H palladation and subsequent reductive elimination was the proposed mechanism (Scheme 11.48) [101].

523

524

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles Pd2+

S

N N

R2

+ ArBr S

S

Pd(OAc)2 (5 mol %) PPh3 (10 mol %) K2CO3 (3 equiv) DMF, 130 °C, 1.5 h

N

N

S

S

N N

2

R

26 examples Ar 20-91%

Representative Products S N N

N

S

N

R

Ph 3P Pd

F3 C

R2

H

Ar

O

Pd PPh3 O Ar

N N

Pd0 (PPh3 )2

S

ArBr

20%

N N

2

85% CF3

91%

Ar

Ar-Pd(PPh3 )-Br

PPh3 Pd O

NO2

N N

R2

O

Scheme 11.47  Palladium-catalyzed synthesis of 5-aryl imidazo[2,1-b]thiazoles and other imidazo[2,1-b]thiazoles.

Pd2+ N

S 1

R

N

N

R2

+ ArX

Pd(OAc) 2 (10 mol %) Xantphos (20 mol %) Cs 2CO3 (3 equiv) dioxane, toluene, 150 o C, 1 h, Ar Representative Products

S Me

N Me

N N

MeO

S R1

N

R1

R2

N N

OMe

N R2

N N Pd

Ar 19 examples 10-92% S

R1

N

Ar S

N

N N H Ar Pd

N N

Cs 2CO3

92%

10%

S

NO2

Pd

0

ArX

Ar-Pd-X

O

R2 O O Cs

S R1 N

N N

R2

Scheme 11.48  Palladium-catalyzed synthesis of 5-aryl imidazo[2,1-b][1,3,4]thiadiazoles.

The arylation/heteroarylation in imidazo[1,2-b]pyrazoles with aryl bromides proceeded preferencially at the C3 position under microwave-assisted palladium-catalyzed conditions using PCy3 as an additive. A variety of aryl bromides possessing electron-withdrawing (CN, COOMe, CF3) and electron-donating substituents (Me, OMe) delivered 3-arylimidazo [1,2-b]pyrazoles in good-to-excellent yields. Thienyl and furyl bromides underwent C3 arylation in quite low yields, while 4-pyridyl bromide afforded 3-pyridyl substituted imidazo[1,2-b]pyrazoles in good yields. Further, arylation of the NH-imidazopyrazole under optimized conditions afforded corresponding C3 arylylated product in 40% yield using 4 equivalents of potassium carbonate (Scheme 11.49A) [102]. However, C7 arylation/heteroarylation was achieved if the arylation was carried with aryl and heteroaryl bromides and chlorides with 3-aryl substituted imidazo[1,2-b]pyrazoles under similar microwave-assisted palladium catalysis. The above two strategies were combined to accomplish C3 and C7 diarylation of imidazo[1,2-b]pyrazoles in one pot by using two equivalents of aryl halides under slightly modified palladium-catalyzed conditions in good yields. No reactivity improvement by using acetate or pivalate ions or aryl iodide indicated the possibility of carbonate-assisted metalation–deprotonation mechanism (CMD) [103]. Through these strategies, C2/C6/C7 trisubstituted, C2/C3/C6 tri(hetero)arylated, and C2/C3/C6/C7 tetrasubstituted imidazo[1,2-b]pyrazoles were synthesized and studied for their in vitro anticancer activities against different cell lines (Scheme 11.49B) [104]. The arylation of C2 unsubstituted imidazo[1,2‑a]imidazoles with aryl and heteroaryl bromides under palladium-catalyzed conditions proceeded at C3 position (Scheme 11.50A). C6 Thienyl or aryl substituted imidazo[1,2‑a]imidazoles reacted smoothly with electron-rich and electron-deficient aryl/heteroaryl bromides to afford their corresponding C3 arylated imidazo[1,2‑a]imidazoles in moderate-to-good yields, whereas C6 pyridyl substituted imidazo[1,2‑a]imidazoles did not produced the desired C3 arylated products under optimized conditions. Using the same palladium-catalyzed

11.3  C–S/Se Bond Formation Pd2+

(A ) N Ph

Pd(OAc)2 (10 mol %)

R1

N N +

Ph

PCy3 (20 mol %) K2CO3 (2 equiv) dioxane, MW, 160 oC, 1 h

R2Br

R1

N

N

19 examples 18-94%

Ph N

R2

N Ph

NC

3

X = Br, Cl

PCy3HBF4 (20 mol %) Cs2CO3 (2 equiv) dioxane, MW, 160 oC, 4 h

N Ph

Ph N

N

R1

R2 16 examples 41-95%

Representative Products (B)

OMe

N N 94%

60%

R2

N

N

OMe Ph

N N

N

Pd(OAc) 2 (10 mol %)

+ R X

Representative Products (A)

R1

N

R3

Pd2+

(B )

N

N

OMe

N N

Ph

Tol

41%

N N N 95%

OMe

Tol

Scheme 11.49  Palladium-catalyzed synthesis of C2/C6/C7 trisubstituted, C2/C3/C6 tri(hetero)arylated, and C2/C3/C6/C7 tetrasubstituted imidazo[1,2-b]pyrazoles.

conditions, C2 arylation of 6-arylated 3-(hetero)arylated imidazo[1,2-a]imidazoles with a few aryl/heteroaryl bromides was achieved in good yields (Scheme 11.50B). Finally, the methodology was employed for a sequential one-pot two-step arylation using two different aryl bromides to afford C2 and C3 arylation of 6-substituted imidazo[1,2-a]imidazole in comparatively better yield over successive double C−H arylation sequence [105].

R1

N

Pd2+

(A)

PMB N

PMB

Pd(OAc)2 (10 mol %)

N

R1

K2CO3 (1.5 equiv) toluene, 150 oC, 12 h

+ R2Br

PMB N

N

F3C

PMB N

N N

R3

R2 7 examples 50-73% PMB N N

73%

80% CF 3

N

R1

N

N

MeO 46%

K2CO 3 (1.5 equiv) toluene, 150 oC, 12 h

R2 22 examples 46-80%

N

PMB

Pd(OAc)2 (10 mol %)

N

Representative Products

N N

N

(B) Pd2+ R3Br

OMe

Scheme 11.50  Palladium-catalyzed synthesis of C2 and C3 arylated imidazo[1,2‑a]imidazoles.

11.3  C–S/Se Bond Formation Chalcogenylated heterocycles occupies a special locus in the hierarchy of pharamacological and industrially useful chemicals. In 2011, the Zhou group reported the first protocol for chalcogenylation of imidazo[1,2-a]pyridines with dichalcogenides using CuI in DMSO. Imidazo[1,2-a]pyridines bearing electron-donating groups were found more reactive than those bearing electron-withdrawing groups. Interestingly, all the disulfides including dialkyl sulfides were equally reactivite irrespective of their electronic environment. In addition, imidazo[1,2-a]pyrimidine and indole derivatives underwent smooth thiolation and selenylation under optimized conditions. The reaction was proposed to be initiated by copper(I)-catalyzed dissociation of disulfides and diselenides to form an arylsulfur/selenium cationic intermediate on attack by imidazo[1,2-a] pyridine produced imidazolenium(II) ion, which on deprotonation afforded chalcogenated products along with the regeneration of the copper(I) catalyst. Consequently, air oxidation of aryl thiol/selenol reproduced dichalcogenides (Scheme

525

526

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

11.51A, Table 11.16: entry i) [106]. A very similar strategy was exhibited for the synthesis of thioalkyl ether-decorated imidazo[1,2-a]pyridines by thiolation of imidazo[1,2-a]pyridines with alkyl thiols using CuI as the catalyst and O2 as the oxidant. Aliphatic primary and secondary thiols reacted efficiently with a variety of diversely substituted imidazo[1,2-a]pyridines to afford enormous C3 thioalkyl substituted imidazo[1,2-a]pyridines in good-to-excellent yields. The reaction mechanism involved the attack of CuI on alkyl thiol to generate CuSR, which through CMD with imidazo[1,2-a]pyridine furnished Cu(II)-bridged thioalkyl imidazo[1,2-a]pyridine intermediate. On reductive elimination, this generated the desired product (Scheme 11.51B, Table 11.16: entry ii) [107]. Subsequently, C3 sulfenylated imidazo[1,2-a]pyridines were prepared by the thiolation of imidazo[1,2-a]pyridines with (hetero)aryl thiols using Cu(OAc)2 as catalyst. Through this process, a variety of aliphatic, aromatic and heteroaromatic thiols, including benzo[d]thiazole-2-thiol, benzo[d]oxazole-2-thiol, 1-methyl1H-imidazole-2-thiol, pyrimidine-2-thiol coupled well with imidazo[1,2-a]pyridines to deliver thioether-decorated imidazo[1,2-a]pyridines in moderate-to-excellent yields. The computational study by Gaussian03 has suggested a high electron density distribution at C3 (−0.125) over C2 (−0.054), which provided a rationale for regioselective thiolation at C3 position over C2 (Scheme 11.51C, Table 11.16: entry iii) [108]. CuI/PPh3 catalytic system has been used for the C3 sulfenylation of imidazo[1,2-a]pyridines using sulfonyl chlorides as a benign sulfenylating agent. Through this process, a variety of imidazo[1,2-a]pyridines and 2-phenylbenzo[d]imidazo[2,1-b]thiazole coupled smoothly with electron-rich and deficient sulfonyl chlorides to produce 3-thioarylated imidazo-heterocycles in moderate-to-good yields. The formation of aryl hypochlorothioite by the reaction between aryl sulfonyl chloride and PPh3 initiated the reaction pathway to which oxidative addition of CuI produced highly electrophilic Cu(III) complex. This on addition by imidazo[1,2-a]pyridine-generated carbocation intermediat, which on oxidation afforded the sulfenylimidazo[1,2-a]pyridine (Scheme 11.51D, Table 11.16: entry iv) [109]. Sodium thiosulfate in combination with alkyl and aryl halides has been used for the C3 sulfenylation of 2-arylimidazo[1,2-a]pyridines in DMF under copper-catalyzed conditions. Several primary and secondary alkyl bromides and chlorides and aryl iodides reacted efficiently with a variety of imidazo[1,2-a]pyridine to furnish their corresponding alkyl and aryl thioether derivatives (Scheme 11.51E, Table 11.16: entry v) [109]. Structurally diversified aryl chalcogen substituted imidazo[1,2-a]pyridines were synthesized in good yields by C3 chalcogenation of imidazo[1,2-a]pyridines with sulfur or selenium powder using arylboronic acids under copper-catalyzed conditions. The reaction was proposed to proceed by electrophilic substitution in imidazo[1,2-a]pyridine by copper(III)-tetracoordinated square planar sulfate complex generated by the reaction of CuI with disulfide and the diselenide, which in turn were obtained by the reaction between arylboronic acids and S8 or Se. Finally, elimination and aromatization produced the chalcogenated product along with the regeneration of thiol/selenol and CuI for the next catalytic cycle. Interestingly, two of the products of this series exhibited better in vitro antiproliferative activities than the 5-fluorouracil against PC–9 and H1975 with IC50 values of 6.68±0.82 and 15.30±1.18 μM on human-derived lung, stomach, esophageal, and breast cancer cell lines (Scheme 11.51F, Table 11.16: entry vi) [110]. C3 Arylthiolation of 2-arylimidazo[1,2-a]pyridines has also been achieved with S-aryl arenesulfonothioate as the arylthiolating agent in moderate-to-good yields under Cu-mediated conditions. The reaction was proposed to proceed by the reaction of Cu(OAc)2 with S-phenyl 4-methylbenzenesulfonothioate to generate two Cu complexes: PhSCuOAc and ArSO2CuOAc; each of these underwent a process of coordination, metalation-deprotonation and reductive elimination to deliver arylthiolated product (Scheme 11.51G, Table 11.16: entry vii) [111]. The synthesis of 2-aryl-3-(arylselenyl)imidazo[1,2a]pyridines has been executed in a one-pot two-step manner by coupling between triarylbismuthanes and diimidazopyridyl diselenides formed from imidazo[1,2-a]pyridines and selenium powder under copper-catalyzed conditions. Moderate-toexcellent yields of 3-selenylimidazopyridines were obtained by using a variety of triarylbismuthanes that showcased higher reactivity over phenyl iodide and boron, silicon, and tin based phenyl donors. Although the exact mechanism was not determined, it was postulated that the reaction commenced with the formation of selena-copper(II)-imidazo intermediate via copper-catalyzed electrophilic substitution imidazo[1,2-a]pyridine with selenium, which on oxidative homocoupling produced the diselenide intermediate. Consecutively, a copper-mediated transmetalation in triarylbismuthane furnished an aryl-copper(I) species, which on oxidative addition to the diselenide generated previously afforded bisimidazo diselenide aryl-copper(III) species. Next, an iodide ion attack on the bisimidazo diselenide aryl-copper(III) species gave an imidazoselenide aryl-copper(III) iodide species that undergoes successive reductive elimination to give the 3-selenylimidazo[1,2-a] pyridines along with the regeneration of the copper(I) species (Scheme 11.51H, Table 11.16: entry viii) [112, 113]. Further, the synthesis of C3 benzothiazolyl sulfenylated imidazo[1,2-a]pyridines was carried out by copper-catalyzed coupling between imidazo[1,2-a]pyridines and o-iodo/bromoanilines using carbon disulfide as a sulfur source. 1,10-Phenanthroline (1,10-Phen) showed maximum efficiency for the desired transformation among a number of ligands screened. Electrondeficient o-haloanilides showed higher reactivity as compared to electron-rich analogues. Nitro substituted imidazo[1,2-a] pyridine and NHCOMe, COMe and SMe substituted o-haloanilines failed to react under described conditions. The reaction

11.3  C–S/Se Bond Formation

Scheme 11.51  Copper-catalyzed synthesis of 3-chalcogenyl imidazo[1,2-a]pyridines.

Table 11.16  Copper-catalyzed strategies for C3 chalcogenylation of imidazo[1,2-a]pyridines.

Entry

Reaction Conditions

i.

CuI (10 mol %), DMSO, 110°C, 10–18 h

Examples and Yields

Representative Products

N N 42% S Et

N

N

N N

66% Se

N S

20 examples 42–97%

97%

(Continued)

527

528

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Table 11.16  (Continued)

Entry

Reaction Conditions

ii.

CuI (5 mol %), DMSO, 100°C, 20 h, O2

N

N t-Bu

N

Cu(OAc)2 (10 mol %), DMA, 80°C, 20 h, O2

S

N

N

CuI (10 mol %), PPh3 (3 equiv), Toluene, 130°C, 24 h

N

N

tBu

S

N

N S

S

Ph

N N 34%

N

N

N

Br

81%

51% F

N

N S

77%

N Ph

Se Ph

N Se 60%

16 examples 42–81%

S

Se

N

68%

N

Br

N

42%

(a) CuI (10 mol %), 1,10-Phen (10 mol %), DMSO, 130°C, 1–4 h, Air. (b) R3Bi, 1–2 h

N

N

N S

viii.

85%

NO2

N

24 examples 58–85%

S

70%

58%

Cu(OAc)2 (1 equiv), K2CO3 (1 equiv), DMSO, 120°C, 6 h, N2

N

N Cl Br

N

25 examples 40–99%

99%

S

vii.

MeO

65%

N

CuI (20 mol %), Phen (20 mol %), K2CO3 (50 mol %), Ag2CO3 (50 mol %), DMF, 130°C, 10 h, Air

MeO

N

S

S

40%

vi.

Cl

N

S

CuI (20 mol %), DMF, 120°C, 12 h

92%

N

N

v.

S

S n-Pr

79%

N

39 examples 72–92%

N

N S

11

93%

N

N

72%

iv.

N

85% S

N

76 examples 72–93%

N

N

S

72%

iii.

Examples and Yields

Representative Products

Cl

89%

N

Ph S

S

N

Ph

Ph

9 examples 68–89%

27 examples 34–80%

80% Se Ph

commenced with the formation of o-halocarbamodithioic acid by the nucleophilic addition of o-haloanilides on carbon disulfide, which on copper-catalyzed intramolecular S-arylation afforded benzothiazole-2(3H)-thione that isomerizes to 2-mercaptobenzothiazole. Consecutively, copper(III)-imidazo[1,2-a]pyridine complex is formed by base-mediated C–H activation that subsequently reacted with 2-mercaptobenzothiazole to furnish benzothiazolyl sulfenylated copper(III)-imidazo[1,2-a]pyridine complex, which on reductive elimination produced the desired C3 sulfenylated product. An alternate mechanism involving the formation of copper-thiolate complex has also been proposed (Scheme 11.52) [114]. Other transition metal catalysts have also been employed for chalcogenylation of imidazo[1,2-a]pyridines. For example, a catalytic amount of Pd(OAc)2 in combination with stoichiometric amounts of CuI/Phen system has been

11.3  C–S/Se Bond Formation N R1

R2

N +

NH 2

R3 X N CF3

N S 60%

Cu1+ CS2 , CuI (10 mol %) 1,10-Phen (20 mol %) DBU (3 equiv) DMSO, 110 °C, 6 h, O2

N S

R2

N

24 examples 60-88%

N

R2

N

N

S

Cu

CuI

R3

S

III

S

R1

DBU N

S

S

N

H3CO

N N

S S

70%

N N S 88%

SH

X

N Cl

CS2

NH2

HN S

X SH

CuI

S

DBU

N H

R2

CuIII

CuI DBU, O2 R1

Ph

S

N N

Representative Products

N Ph

R1

N R1

S

N N

R2

Scheme 11.52  Copper-catalyzed synthesis of benzothiazolyl sulfenylated imidazo[1,2-a]pyridines.

used for the C(sp2)–H sulfenylation of few imidazo[1,2-a]pyridines and a large number of indoles with arylboronic acids and elemental sulfur. The reaction was initiated by the palladation of imidazo[1,2-a]pyridine to generate vinylpalladium intermediate, which on reaction with organocopper thiolate complex intermediate obtained from arylboronic acid and S8 under copper-mediated conditions upon transmetalation produced another intermediate. This on reductive elimination furnished the target product along with the regeneration of palladium(0) that was oxidized by silver(I) to palladium(II) active species to continue the catalytic cycle (Scheme 11.53A, Table 11.17: entry i) [115]. CoCl2.6H20 has been used to prepare arylthiosubstituted imidazo[1,2-a]pyridines by three-component reaction between imidazo[1,2-a]pyridines, inorganic S8, and arylboronic acids using DABCO as a base. Notably, substituted arylimidazo[1,2-a]pyridines reacted smoothly with arylboronic acids possessing electron-donating and withdrawing groups to furnish C3 sulfenylated imidazo[1,2-a]pyridines in good yields. The reaction was initiated by the reaction between DABCO, CoCl2, and arylboronic acid to generate an arylcobalt complex intermediate that on reaction with S8 powder generates diaryl disulfide dicobalt complex. Nucleophilic attack of imidazo[1,2-a]pyridine on this complex followed by deprotonation afforded the imidazo[1,2-a]pyridyl cobalt thioaryl intermediate which subsequently on reductive elimination produced the eried product along with the generation of cobalt(I) that was oxidized back to cobalt(II) by air or S8 (Scheme 11.53B, Table 11.17: entry ii) [116]. The synthesis of C3 sulfenylated imidazo[1,2-a]pyridines using thiols have also been performed under iron(III)-catalyzed conditions under oxygen atmosphere. Through this protocol, C2 unsubstituted and substituted imidazo[1,2-a]pyridines underwent sulfenylation with a variety of aliphatic and aromatic thiols in moderate to good yields. Notably, differently fluorinated 3-sulfenylimidazo[1,2-a]pyridines exhibited good anticancer activity safety profiles. The reaction commenced by iron-promoted oxidation of thiol to generate disulfide intermediate that subsequently produced the thio radical, which upon radical addition to imidazo[1,2a]pyridine followed by a single-electron oxidation and aromatization afforded the desired product. Alternatively, iron(III)-mediated C3 attack of imidazo[1,2-a]pyridine on disulfide resulted in the formation of SR-Fe–C bonded intermediate that upon reductive elimination and deprotonation produced the product (Scheme 11.53C, Table 11.17: entry iii)[117]. Finally, NiBr2/2,2-bipyridine catalytic system has also accomplished aryl- and alkyl-selenation at C3 position of imidazo[1,2-a]pyridines with arylboronic acids and alkyl halides, respectively using selenium powder. Imidazo[1,2-a]pyridines with electron-withdrawing substituents displayed lower reactivity than those with electrondonating substituents, whereas secondary or tertiary alkyl halides afforded lesser or no yields of the corresponding selenated products. A nickel(II)-catalyzed reaction between selenium powder and arylboronic acid or alkyl halide generates diselenide, which was proposed to initiate the reaction mechanism in presence of base. This on subsequent reaction with LNiIIBr2 furnished a dialkylselenyl nickel(III) bromide intermediate. Electrophilic attack of imidazo[1,2a]pyridine on dialkylselenyl nickel(III) bromide followed by deprotonation provided nickel(III)-aromatic intermediate, which on reductive elimination gave the desired product and nickel(I) that is oxidized by air to nickel(II) for the next catalytic cycle (Scheme 11.53D, Table 11.17: entry iv) [118]. In this realm, Adimurthy and coworkers reported an interesting disulfenylating strategy, whereby 2,3-disulfenylimidazo [1,2-a]pyridines were prepared by three-component reaction between imidazo[1,2-a]pyridines, elemental sulfur, and a variety of haloarenes under copper catalysis [119]. This reaction commenced with a copper-catalyzed reaction between

529

530

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Scheme 11.53  Palladium/cobalt/iron/nickel-catalyzed synthesis of 3-chalcogenyl imidazo[1,2-a]pyridines. Table 11.17  Palladium/cobalt/iron/nickel-catalyzed strategies for C3 chalcogenylation of imidazo[1,2-a]pyridines.

Entry

Reaction Conditions

i.

Pd(OAc)2 (5 mol %), CuI (1 equiv), phen (1.1 equiv) Cs2CO3 (2 equiv), Ag2CO3 (2 equiv), [Bmim]Cl, 80 oC, 6 h

ii.

CoCl2.6H20 (20 mol %), DABCO (2 equiv), DMF, 130 oC, 20 h, Air

Examples and Yields

Representative Products N

N N

N 72%

N

76% S

S F N

N

S Cl

20% Cl

93%

N

N

N S

8 examples 71–83%

N

65% S

OMe

N N

S 94%

16 examples 20–94%

11.3  C–S/Se Bond Formation

Table 11.17  (Continued)

Entry

Reaction Conditions

iii.

FeCl3 (5 mol %), CH3COOH (20 mol %), DMF, 80°C, 12 h, O2

Examples and Yields

Representative Products

t-Bu

N S

NiBr2 (20 mol %) K3PO4 (2 equiv) 2,2-bipyridine (30 mol %) DMO, 135 oC, 20 h, Air

iv.

N

N 76%

75%

S

S

90%

N

N

N

N

Br

N

OMe

N Se

Se Me

30%

24 examples 75–90%

N

N

N

Se Bu 92%

tBu

52%

26 examples 30–92%

iodoarene and sulfur powder to generate copper acetate and diaryldisulfide in acetic acid medium that was converted to thiophenol and the copper intermediate. The aryl thiophenol on reaction with the imidazo-pyridyl-CuOAc intermediate (itself obtained by the reaction of imidazo[1,2-a]pyridine with Cu(OAc)2) furnished another copper complex. The subsequent reaction of this copper complex with acetic acid and thiophenol gives C3 aryl sulfenylated C2 arylthio copper intermediate via C3 aryl sulfenylated C2 copper acetate (Scheme 11.54).

Cu1+

N R1

+ R2

N

N N

N

t-BuOK(3 equiv) DMF: AcOH, 130 °C, 24 h

R1

N

S NO2 Cl NO2

N N 45%

S

N N

S

R2 S

S R2 26 examples 15-99%

Representative Products

S 15%

I

S8 CuI (40 mol %)

S 99%

B(OH)2

N R1

I R +

CuI/AcOH

R2

S

S

S8

N R1

N

N

R2

R2

B(OH) 2

N R1

CuOAc

S R2

N Cu(OAc) 2 R1

SH

Cu(OAc) 2

t-Bu t-Bu

R2

S R2

Cu0

2

S

N

R2 S Cu

SCuOAc R1 R2

SH

Base/AcOH N N

H

Cu S R2

N CuOAc

Scheme 11.54  Copper-catalyzed synthesis of 2,3-disulfenylated imidazo[1,2-a]pyridines.

An interesting protocol to synthesize bis(imidazo[1,2-a]pyrid-3-yl)selenides and diselenides has been reported by double C–H selenation of imidazo[1,2-a]pyridine with selenium powder under copper-catalyzed aerobic conditions using 1,10-phenanthroline as a ligand [120]. The reaction pathway was initiated with the copper-mediated electrophilic substitution of imidazo[1,2-a]pyridine with selenium to generate an intermediate, which on oxidative homocoupling afforded the diselenide product. On the other hand, oxidative addition of another molecule of the imidazo[1,2-a]pyridine on the same intermediate, followed by the aromatization and reductive elimination, produced selenide product (Scheme 11.55). Also, a copper-catalyzed strategy for the preparation of bis(imidazo[1,2-a]pyridin-3-yl)sulfanes has been reported using isothiocyanate as the sulfur source and DMAP as a base [121]. The reaction commenced with the formation of iodo-substituted imidazo[1,2-a]pyridine, which on oxidative addition by copper(I) yielded a copper(III)-imidazo intermediate. Thereafter, proton abstraction from nitrogen of thiourea followed by DMAP-promoted nucleophilic substitution gave a copper(III) intermediate, which underwent reductive elimination to provide a thiourea-substituted imidazo[1,2-a]pyridine intermediate. Elimination of diphenylmethanediimine from this intermediate produced the C3 thiol intermediate, which attacked the copper(III)-imidazo intermediate formed earlier followed by reductive elimination to deliver the final product (Scheme 11.56). Chalcogenylation of other imidazo-heterocycles has also been developed. A copper-catalyzed coupling of imidazo[2,1-b] thiazoles and differently substituted diorganyl diselenides possessing

531

532

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles Cu1+ N R1

N

R2

Se N

R1

N 6 examples 78-90%

Se (0.5 equiv) CuI (10 mol %) 1,10-Phen (10 mol %)

R2

DMSO, 130 °C, 2.5-6 h, Air

R2

N

N

DMSO, 130 °C, 3 h, Air

R

N

Se (1 equiv) CuI (10 mol %) 1,10-Phen (10 mol %) = L

N

Representative Products N N Ph Ph N N Se Se 90% 77% Se N N Ph Ph MeO N N

F MeO

78%

N

MeO F

N

N

[O]

2

N Se

Se Se

1

N

R2

R1

CuII

N

N

N

OMe

N

I

R2

N

Se Cu(I)L

L R2

R1

R1

N

2

R

Se I Cu III L N

Se 89% Se

CuII

L

N R1

Se

I

N

R2

N

N

R1

R1

N

R2

R

N 6 examples 77-89%

N Se

N R1

R1

R1

Cu1+

R

N

N

N

N

L

N R1

R1

N

R2

Se

Se I Cu III

N

N N

2

R

N

1

R2

Scheme 11.55  Copper-catalyzed synthesis of bis(imidazo[1,2-a]pyrid-3yl)selenides and diselenides.

Cu1+ N R1

N

R

2

S

N

DMAP (0.5 equiv) DMF, 90 °C, 12 h

N

S

S N

N 14%

N

O

N 63%

S

N R

1

N

CuI

N

Cu I

N

S N N 88%

N R1 R

N

1

R1

R1

R

N

2

N

R

2

CuI2

N

R1

PhNCS

CuI/DMAP N

R1

SH

CuI2 N

N R1

PhNHCSNHPh

N I

N S

R2

R2

N

R2

N

R1

CuI/DMAP

N

N

N

N

23 exmaples 14-88% yields

Representative Products N O

R2

R2

N

N R1

N

R2

R2

PhNCS CuI (20 mol %)

R2 NPh NHPh

Cu S

PhHN

NPh

Scheme 11.56  Copper-catalyzed synthesis of bis(imidazo[1,2-a]pyrid-3yl)sulfanes.

undergoing copper catalysis in DMSO furnished C5 aryl/heteroaryl/alkyl selenylated imidazo[2,1-b]thiazoles in good-toexcellent yields [122]. The reaction commenced with the coupling between CuBr and diorganyl diselenide to yield a cationic intermediate, which on attack by imidazo[2,1-b]thiazole followed by deprotonation produced C5 selenyl product, organylselenol and CuBr for the next catalytic cycle. Subsequently, organylselenol is oxidized to diorganyl diselenides using DMSO and air, which continued the next catalytic cycle (Scheme 11.57A, Table 11.18: entry i). Similarly, C5 sulfenylation of imidazo[2,1-b]thiazoles was achieved with thiols under copper-catalyzed conditions. Good-to-excellent yields of the sulfenylated products were obtained by using a variety of alkyl and (hetero)aryl thiols. Two mechanistic pathways have been worked out for the reaction. The first pathway involved the formation of a copper(I)-thiolate intermediate by the reaction of copper(I) salt with thiols and ligand, which on coordination with nitrogen atom of imidazo[2,1-b]thiazole and subsequent oxidation generated C5 bonded copper(II)-thiolate intermediate complex. Finally, the C5 sulfenylated product was obtained by reductive elimination of copper(0) from the copper(II)-thiolate intermediate complex and its re-oxidization to copper(I) by O2. The second pathway involved the formation of disulfides by the oxidation of thiols, which subsequently generated RS+ cation species through the reaction between CuI/L and disulfides. Thereafter, electrophilic attack of RS+ cation on imidazo[2,1-b]thiazole furnished the imidazolenium intermediate, which on deprotonation provided the C5 thiolated product (Scheme 11.57B, Table 11.18: entry ii) [123].

11.4  C–N Bond Formation Despite the importance of nitrogen-functionalized heterocycles, only one report could be traced under metal-catalysis. This interesting example of C–N bond formation is the coupling of imidazo[1,2-a]pyridines with saccharin using Selectfluor as an oxidant under copper-catalysis. Through this process, C2 unsubstituted imidazo[1,2-a]pyridines gave very low or no

11.5  C–P Bond Formation

Scheme 11.57  Copper-catalyzed synthesis of 5-chalcogenyl imidazo[2,1-b]thiazoles. Table 11.18  Copper-catalyzed strategies for C5 chalcogenylation of imidazo[2,1-b]thiazoles. Entry

Reaction Conditions

i.

CuBr (20 mol %), DMSO, 90°C, 20 h

Representative Products

Cl

N Ph

Se

71%

13 examples 71–96%

N

S

N

S

N

S

Examples and Yields

N

N n-Bu

Se

Se

90%

96%

S

ii.

CuI (20 mol %), Phen (20 mol %), DMF, 120°C, 12 h, O2

N

S

N

S

N

N Se

81%

n-Pr

24 exmples 59–90%

N

S N

Se

84%

Se

N

72%

S Cl

yields of the desired products. The reaction mechanism involved the generation of an imidyl radical via copper-mediated oxidation of saccharin with Selectfluor that underwent an additional reaction at the C3 position of imidazo[1,2-a]pyridine to afford a carbon radical intermediate, which on subsequent oxidative aromatization produced the C–N functionalized product (Scheme 11.58) [124].

11.5  C–P Bond Formation Phosphonylation of at its C3 position can be accomplished by using dialkyl phosphites under manganese(III) catalysis. A wide range of imidazo[1,2-a]pyridines and dialkyl phosphites were well tolerated under the optimized conditions to afford C3 phosphonylated imidazo[1,2-a]pyridines in good-to-excellent yields. In addition, C(sp2)–H phosphonylation of other

533

534

11  Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles

Cu2+

O R1

N

NH

R2 +

N

O

S

O

Cu(OAc) 2 (30 mol %) Selectfluor (2 equiv) Na2 CO3 (2 equiv) DCE, 120 o C, 12 h

N

R1

N O

-H +

R2

N

R1

N

O N S O

O

R2

O N S O

-e -

19 examples 27-85% yields Cl

N N O 27%

Representative Products N S

O N S O

N O 80%

O N S O

Cl

R1

N N O 85%

O N S O

R1

N N

N N

O Selectfluor Saccharin R2

R2

O N S O

Scheme 11.58  Copper-catalyzed synthesis of C3 saccharinyl imidazo[1,2-a]pyridines.

heteroarenes including indoles, 7-azaindoles, and pyrroles could be achived under similar conditions. The reaction was believed to proceed by manganese(III)-mediated one-electron oxidation of dialkyl phosphate to generate a dialkyl phosphonate cation radical, which upon deprotonation and attack by imidazo[1,2-a]pyridine furnished the product via generation of phosphonylated imidazo-pyridyl radical intemrediate (Scheme 11.59A, Table 11.19: entry i) [125]. In contrast, a Pd(OAc)2/Phen catalytic system can be used for phosphonylation of imidazo[2,1-b]thiazoles with dialkyl phosphites to afford C5 phosphonated products in moderate to good yields. Other palladium catalysts including PdCl2, Pd(TFA)2, and Pd(OPiv)2 were found to be less effective. The reaction mechanism was proposed to involve a monocationic palladium complex formed by the nucleophilic coordination of the phosphite to a palladium(II) species, which on C5 nucleophilic attack by imidazo[2,1-b]thiazole generated another imidazo-thiazolyl-palladium complex. Subsequently, K2S2O8-mediated oxidation followed by reductive elimination produced C5 phosphonated imidazo[2,1-b]thiazole via formation of a palladium(IV) species (Scheme 11.59B, Table 11.19: entry ii) [126].

Scheme 11.59  Manganese/palladium-catalyzed phosphonylation of imidazo-heterocycles.

11.7  Conclusions

Table 11.19  Manganese/palladeium-catalyzed phosphonylation of imidazo-heterocycles. Entry

Reaction Conditions

Representative Products

i.

Mn(OAc)3.2H2O (1.5 mol %), NMP, 80°C, 16 h, N2

N N

Pd(OAc)2 (5 mol %), Phen (20 mol %), K2S2O8 (2 equiv), CH3CN, 100°C, 12 h

N

R1

R3

N + H Si

R4

R2

EtO P 54% O

N

S Cl

N

N O P OiPr 88% OiPr

O P OiPr 75% OiPr

N

S

F

N NO2

N

Ph

N

OEt EtO P O 73%

Zn2+ Zn(OTf) 2 (40 mol %)

DTBP (3 equiv) C6 H5 CF3, 120 o C, 36 h, Ar

R5 CONH 2 N N

65%

Si R4

R5

-H

R2

N

33 examples 53-80% yields

+

N

R1

N

R3

Representative Products

N N

SiPh3

R3

Zn(OTf) 2

N

R1

SiMe2 tBu 60%

Si

R2

Zn(OTf) 2 N

R1

R5

R3 R3

OMe

N

O

R2

N

R4

N

SiMe2 tBu

16 examples 48–73%

N

S

Ph

OEt Ph EtO P O 72%

OEt

17 examples 45–88%

N

N

O P OiPr 45% OiPr

ii.

Examples and Yields

H Si

R4

Si

R4

R5

R5 O

O

80%

Scheme 11.60  Zinc-catalyzed synthesis of 5-silyl-imidazo[1,2-a]pyridines.

11.6  C–Si Bond Formation Cross-dehydrogenative coupling between imidazo[1,2-a]pyridines and silanes using zinc triflate as a Lewis acid and dit-butyl peroxide as the oxidant, is the only example reported to afford C–5 silylated imidazo[1,2-a]pyridines in moderate to high yields [127]. Different silanes including triisopropylsilane, trihexylsilane, t-butyldimethylsilane, dimethylphenylsilane, methyldiphenylsilane, and triphenylsilane accomplished C5 silation on a variety of C2 alkyl/aryl/heteroaryl substituted imidazo[1,2-a]pyridines under the described conditions. The reaction mechanism involves the formation of t-BuO. radical by the thermal decomposition of DTBP, which abstracts a hydrogen from sliane to generate a silyl radical. Thereafter, Zn(OTf)2-promoted attack of imidazo[1,2-a]pyridine on nucleophilic silyl radical furnished silated imidazopyridyl radical intermediate, which on oxidation and deprotonation delivered the product (Scheme 11.60).

11.7  Conclusions Significant advancement has been made toward transition metal-catalyzed C–H functionalization of various imidazofused heterocycles. Of these, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazole, and benzo[d]imidazo[2,1-b]thiazole have been extensively explored for the one-pot atom-economical C–C, C–S/Se, C–N, C–P, and C–Si bond formations, whereas other known imidazo-fused heterocycles are either not functionalized or functionalized only to a limited extent, to the best of our knowledge. On most occasions, a combination of π-electron availability in imidazo-ring and acidity of a particular C(sp2)–H bond dictates the functionalization at that position. However, there are a few instances in which only one of these

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factors predominates and results in selective functionalization on one position over another. Although different 3d transtion metal-catalyzed cross-couplings have been documented without the pre-functionalization of imidazo-fused heterocycles, palladium(II) catalysts have been prominently utilized for C–arylation/heteroarylation, C–alkenylation, and C–alkynylation at different positions, whereas chacogenylation has been primarily achieved at the expense of inexpensive copper(I)/copper(II)-catalysis. The absence or presence of additives and use of atmospheric oxygen or external oxidants had an impact on the product yields and sometimes a specific catalyst/additive catalytic system has driven the functionalization at remote locations. In a nutshell, the presented catalytic processes are expected to pave a path for the discovery of new metal-catalyzed functionalization and annulation strategies, which would be helpful to the scientific community worldwide for the development of pharmacological active drug candidates.

Acknowledgments Financial support from SERB, India is acknowledged.

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Palladium-catalyzed microwave-assisted direct arylation of imidazo[2,1-b] thiazoles with aryl bromides: Synthesis and mechanistic study. Organic and Biomolecular Chemistry 12: 5773–5780. 101 Copin, C., Henry, N., Buron, F. et al. (2016). Palladium-catalyzed direct arylation of 2,6-disubstituted imidazo[2,1-b][1,3,4] thiadiazoles. Synlett 27: 1091–1095. 102 Grosse, S., Pillard, C., Massip, S. et al. (2012). Efficient synthesis and first regioselective C–3 direct arylation of imidazo[1,2-b]pyrazoles. Chemistry – A European Journal 18: 14943–14947. 103 Grosse, S., Pillard, C., Bernard, P. et al. (2013). Efficient C–7 or C–3/C–7 direct arylation of tri- or disubstituted imidazo[1,2-b]pyrazoles. Synlett 24: 2095–2101. 104 Grosse, S., Mathieu, V., Pillard, C. et al. (2014). New imidazo[1,2-b]pyrazoles as anticancer agents: synthesis, biological evaluation and structure activity relationship analysis. European Journal of Medicinal Chemistry 84: 718–730. 105 Grosse, S., Pillard, C., Massip, S. et al. (2015). Ligandless palladium-catalyzed regioselective direct C–H arylation of imidazo[1,2-a]imidazole derivatives. The Journal of Organic Chemistry 80: 8539–8551. 106 Li, Z., Hong, J., and Zhou, X. (2011). An efficient and clean CuI-catalyzed chalcogenylation of aromatic azaheterocycles with dichalcogenides. Tetrahedron 67: 3690–3697. 107 Cao, H., Chen, L., Liu, J. et al. (2015). Regioselective copper-catalyzed thiolation of imidazo[1,2-a]pyridines: An efficient C–H functionalization strategy for C–S bond formation. RSC Advances 5: 22356–22360. 108 Zheng, Z., Qi, D., and Shi, L. (2015). Copper-catalyzed thiolation of imidazo[1,2-a]pyridines with (hetero)aryl thiols using molecular oxygen. Catalysis Communications 66: 83–86. 109 Ravi, C., Chandra Mohan, D., and Adimurthy, S. (2016). Dual role of p-tosylchloride: Copper-catalyzed sulfenylation and metal free methylthiolation of imidazo[1,2-a]pyridines. Organic and Biomolecular Chemistry 14: 2282–2290. 110 Guo, T., Wei, X.-N., Zhu, Y.-L. et al. (2018). Copper-catalyzed one-pot synthesis of chalcogen-benzothiazoles/imidazo[1,2-a] pyridines with sulfur/selenium powder and aryl boronic acids. Synlett 29: 1530–1536. 111 Sharma, P. and Jain, N. (2019). S-aryl arenesulfonothioate and copper acetate mediated arylthiolation of 2-arylpyridines and heteroarenes. The Journal of Organic Chemistry 84: 13045–13052. 112 Kondo, K., Matsumura, M., Kanasaki, K. et al. (2018). Synthesis of 2-aryl-3-(arylselanyl)imidazo[1,2-a]pyridines: Copper­catalyzed one-pot, two-step Se-arylation of selenium with imidazopyridines and triarylbismuthanes. Synthesis 50: 2200–2210.

References

113 Matsumura, M. (2020). Development of a general synthetic method for organoselenium compounds utilizing copper catalyzed cross coupling and C–H bond activation. Yakugaku Zasshi 140: 1101–1106. 114 Gan, Z., Yan, Q., Li, G. et al. (2019). Copper-catalyzed domino synthesis of sulfur-containing heterocycles using carbon disulfide as a building block. Advanced Synthesis and Catalysis 361: 4558–4567. 115 Li, J., Li, C., Yang, S. et al. (2016). Palladium-catalyzed oxidative sulfenylation of indoles and related electron-rich heteroarenes with aryl boronic acids and elemental sulfur. The Journal of Organic Chemistry 81: 7771–7783. 116 Zhu, W., Ding, Y., Bian, Z. et al. (2017). One-pot three-component synthesis of alkylthio-/arylthio- substituted imidazo[1,2-a]pyridine derivatives via C(sp2)–H functionalization. Advanced Synthesis and Catalysis 359: 2215–2221. 117 Qin, L., Wu, H.-B., Weng, L. et al. (2020). Aerobic iron(III)-catalyzed direct thiolation of imidazo[1,2-a]pyridine with thiols. SynOpen 04: 17–22. 118 Zhu, J., Zhu, W., Xie, P. et al. (2018). Nickel-catalyzed C(sp2)-H selenation of imidazo[1,2-α]pyridines with arylboronic acids or alkyl reagents using selenium powder. Tetrahedron 74: 6569–6576. 119 Semwal, R., Ravi, C., Saxena, S. et al. (2019). Copper-catalyzed multicomponent reactions (MCRs) for disulfenylation of imidazo[1,2-a]pyridines using elemental sulfur and arylhalides and intramolecular cyclization of haloimidazo[1,2-a] pyridines. The Journal of Organic Chemistry 84: 14151–14160. 120 Matsumura, M., Takahashi, T., Yamauchi, H. et al. (2016). Synthesis and anticancer activity of bis(2-arylimidazo[1,2-a] pyridin-3-yl) selenides and diselenides: The copper-catalyzed tandem C–H selenation of 2-arylimidazo[1,2-a]pyridine with selenium. Beilstein Journal of Organic Chemistry 20: 1075–1083. 121 Tian, -L.-L., Lu, S., Zhang, Z.-H. et al. (2019). Copper-catalyzed double thiolation to access sulfur-bridged imidazopyridines with isothiocyanate. The Journal of Organic Chemistry 84: 5213–5221. 122 Santos, K. S., Sandagorda, E. M. A., Cargnelutti, R. et al. (2017). Copper-catalyzed selective synthesis of 5-selanylimidazo[2,1-b]thiazoles. ChemistrySelect 2: 10793–10797. 123 Liu, W., Wang, S., Jiang, Y. et al. (2015). Copper-catalyzed regioselective C5 sulfenylation of imidazo[2,1-b]thiazoles with thiols. Asian Journal of Organic Chemistry 4: 312–315. 124 Sun, K., Mu, S., Liu, Z. et al. (2018). Copper-catalyzed C–N bond formation with imidazo[1,2-a]pyridines. Organic and Biomolecular Chemistry 16: 6655–6658. 125 Yadav, M., Dara, S., Saikam, V. et al. (2015). Regioselective oxidative C–H phosphonation of imidazo[1,2-a]pyridines and related heteroarenes mediated by manganese(III) acetate. European Journal of Organic Chemistry 6526–6533. 126 Liu, W., Wang, S., Yao, H. et al. (2015). Regioselective palladium-catalyzed phosphonation of imidazo[2,1-b]thiazoles with dialkyl phosphites. Tetrahedron Letters 56: 6100–6103. 127 Li, Y., Shu, K., Liu, P. et al. (2020). Selective C–5 oxidative radical silylation of imidazopyridines promoted by Lewis acid. Organic Letters 22: 6304–6307.

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12 Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles Neha Jha and Manmohan Kapur Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhauri, Bhopal, India

12.1  Dehydrogenative Coupling: An Overview The development of novel methodologies for the formation of C–C bonds has long been the aim of synthetic chemists to enable the construction of numerous molecular scaffolds [1–3]. In this regard, numerous strategies have evolved over the years to increase the product selectivity, resourcefulness, and operational simplicity while reducing the overall environmental impact of such transformations. Conventional protocols usually involve nucleophilic additions, substitutions, and Friedel-Crafts reactions, among others, for combining two simpler molecular units to form a complex structure. Therefore, the advent of pericyclic [4], and transition metal-mediated C–C bond formation has greatly increased the efficacy and overall scope of modern organic chemistry. Modern cross-coupling reactions such as the Suzuki coupling and Negishi coupling still necessitate the pre-functionalization of the coupling partners. Transition metal-catalyzed C–H bond functionalization has gained universal acceptance owing to its advantages over these procedures. C–C bond formation via C–H bond functionalization eliminates the need for the pre-functionalization of substrates with enhancement in selectivity [5, 6]. The concept of transition metal-catalyzed C–H functionalization has therefore gained the limelight because it is perceived as highly regioselective; step- and atom-economical; and capable of generating reduced amounts of waste. As evident in Figure 12.1, extra steps (introduction of FG) are required to synthesize the starting materials for the transformation required to form single C–C bond. Additionally, the above-mentioned protocols have limited applications in the construction of molecules containing C–Z bonds (where Z=N, O, S). This bottleneck is addressed by dehydrogenative coupling reactions in which a direct C–H and Z–H bond coupling occurs under oxidative conditions. In this regard, dehydrogenative coupling/annulation constitutes a class of C–H bond functionalization reaction that results in the formation of C–C and C–Z bonds (where Z=N, S, O) directly from two unmodified C–H bonds [7–14]. The reaction formally occurs with the loss of one equivalent of H2, which is thermodynamically unfavorable and therefore requires the use of an oxidant (e.g. DDQ, benzoquinone, O2, hypervalent iodine) to provide the driving force (Figure 12.2). These reactions usually fall under cross-dehydrogenative couplings (CDC), a term initially proposed by Professor Chao Jun Li of McGill University, Canada [15–17]. In their initial work, Li and coworkers described a copper-catalyzed CDC of C(sp3)–H bonds adjacent to nitrogen atoms. In this manner, they synthesized a wide spectrum of nitrogen-containing compounds under mild conditions (Figure 12.3) [18]. CDCs can be further categorized into four subgroups depending upon the mechanism: Heck type-, direct arylation, ionic intermediate, and radical intermediate [8, 13]. Enantioselective CDC reactions have also gained their share of the limelight in the past decade [19]. In this process, a ­chiral-metal complex is employed that is usually prepared in situ from a metal salt and a chiral ligand in the presence of an oxidant. This technique is useful in the synthesis of various non-natural α-amino acids, which itself is of particular interest in the fields of proteomics and drug-discovery. The first report of this approach was published by Wang and coworkers which described a catalytic CDC in the functionalization of N-aryl glycine esters with β-keto esters (Scheme 12.1) [20].

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

544

12  Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles

FG 2 C FG1introduction

C H

C F G1

C C

(TM catalyzed)

Figure 12.1  Pre-functionalization of substrates in transition metal-catalyzed modern coupling reactions.

C H

+

cat.M [O]

H Z

C Z

Z = O , N, S, C

Figure 12.2  Dehydrogenative coupling reaction.

R

R3

1

N R2

R4

H H

+

N

R4

N

+

CO2R

Ar

Ar

R3

1

r.t., overnight

CO2R

+

N

5 mol% CuBr, 1.2 equiv. TBHP

NO 2

Ar

R

N R2

NO2 R4

5 mol% CuBr,1-1.2 equiv. TBHP r.t., overnight

N RO2C

5 mol% CuBr,1-1.2 equiv. TBHP 100 °C, t h

CO2R

R4

R

Ar

N

10 mol% DABCO, 5 mol% CuBr, TBHP

+

Ar

N

50 °C, overnight

Ar

R 3

Figure 12.3  Copper-catalyzed CDC reaction of C(sp )–H with various coupling partners.

O

O

R1 H R

2

O OR3

+

ArHN H H

OR4

Cu(OTf)2 (10 mol%) L (12 mol%), DDQ (1.0 equiv.) THF, -40 °C

O

CO 2R4

R1 NHAr R3O2C R2

upto 82% yield, 19:1 d.r., 96% ee

O

O NN

L

Scheme 12.1  Catalytic asymmetric activation of C–H bonds adjacent to nitrogen atoms.

12.2  Importance of Heterocycles and Their Fused Congeners

Another field of dehydrogenative coupling includes acceptorless dehydrogenative coupling reactions (ADCs) (Figure 12.4) which, in recent times, are quite prevalent because they impede the usage of stoichiometric quantities of oxidants along with the sole liberation of hydrogen (a greener by-product). The term originates from the fact that the reactions are performed in the absence of acceptors of H2 [21, 22]. Some other types of dehydrogenative couplings involve radical [23], photo-catalytic [24–30], and electrochemical pathways [31–35], which further lead to the enhancement of the synthetic procedures. For example, molecular oxygen can be used instead of external oxygens such as DDQ in the radical pathway. Thus, waste generation and by-product formation are minimized [36–38]. Photo-catalytic reactions, on the other hand, restrict the use of expensive and toxic transition metals and eliminate the generation of copious side-products. Heterocyclic annulated products can be formed by applying photo-induced electron transfer processes [39, 40]. A similar purpose can be served via electro-oxidative methods that make use of electricity to couple unactivated C–H bonds in an environmentally-friendly manner and without much difficulty [41]. Hence, these types of transformations have come a long way since their inception and ample opportunities have surfaced to develop economical methods of bond formation. In this chapter, we shall focus on transition metal-catalyzed dehydrogenative coupling reactions of heterocyclic substrates leading to fused heterocycles via C–H bond activation and discuss broadly the various mechanistic pathways underlying them.

12.2  Importance of Heterocycles and Their Fused Congeners Aromatic heterocyclic cores are present in diverse molecular scaffolds and find immense utility in pharmaceuticals, agrochemicals, and fragrances [42–44]. Their wide applicability motivates chemists to develop newer methodologies despite having many classical methods for the synthesis of these compounds. Usually, metal-catalyzed multi-component coupling [45, 46], and annulation reactions [47–49], although viable, generate copious side-products, sometimes resulting in low yields. Therefore, several efficient methods for synthesizing such heterocyclic cores and their congeners employ the dehydrogenative annulation reactions that form the crux of this chapter. Various methods have been put forth that vary in the metal catalyst used, types of C–Z bonds formed, and mechanisms engaged. A few examples depicted here show examples of top-selling and important drugs that contain fused heterocyclic skeletons and are used to treat various types of chronic diseases (Figure 12.5).

Transition-metal catalyzed dehydrogenative coupling

Acceptorless dehydrogenative coupling

Photo-induced dehydrogenative coupling Dehydrogenative coupling

Radical-mediated dehydrogenative coupling

Figure 12.4  Types of dehydrogenative coupling reactions.

Electro-oxidative dehydrogenative coupling

545

546

12  Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles HO O O

N

H N

N

HO H N

N

N

H2N

N

N

NH

N

OH N

O

N

N

N N

N

OH

NH2 N

O palbociclib (anti-cancer agent) H N

trastuzumab (Used in treating breast cancer)

GSK812397 (anti-HIV)

MeO

HO O O antitumor agent

N

N

OH

Et

N

N N

O

N

N

N O

O

Me divaplon

fasiplon (anxiolytic)

Figure 12.5  Examples of important drugs containing fused-heterocyclic cores.

12.3  Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds 12.3.1  C–C Bond Formation Heterocycles and their benzo-fused analogues demonstrate a wide spectrum of pharmacological, pharmaceutical, and medicinal properties. Benzothiophenes [50] and benzo-fused indoles [51], in particular, show antibacterial, anti-inflammatory, anti-tumor, and cytotoxic properties. In general, the properties of heterocycles differ significantly from their fused analogues, especially in terms of optical-electronics [52, 53]. A viable example was given by Szostak and coworkers in 2019 [54] in which template-assisted benzothieno[2,3]coumarins were synthesized using palladium(II) as the active catalytic system. In this case, coumarins act as templates for the thiophenyl fragments whereas double C–H bond activation and subsequent annulation pave the way for highly functionalized benzothiophenes. 4-arylthiocoumarins undergo intramolecular cross-dehydrogenative annulations using Pd(OAc)2 as the catalyst and AgOAc as the oxidant. A wide range of substrate scope has been screened with varying substituents both at the aryl subunit and at the coumarin template; some representative examples are shown (Scheme 12.2, top). The reaction mechanism involves palladium(II)-catalyzed reversible C–H activation at the C3 position of the thiol-tethered coumarin to give the intermediate I followed by electrophilic aromatic substitution to generate the intermediate II. This, upon further deprotonation (palladacycle III) and reductive elimination, yields the annulated benzothiophene product (Scheme 12.2, bottom). In 2016, Hajra and coworkers [55] described the synthesis of indole-fused coumarins via palladium-catalyzed crossdehydrogenative coupling reactions. These fused annulated heterocycles find widespread applications in organic light emitting diodes (OLEDs). 4–Hydroxy coumarins are used in conjugation with aniline derivatives which in presence of Pd(OAc)2 (catalyst), oxygen (oxidant), and DMF (solvent) give the fused indolyl-coumarin ring system (Scheme 12.3, top). A benefit of this protocol is the replacement of stoichiometric external oxidant with molecular oxygen, thereby reducing by-product generation. Some representative examples highlight the dependence of yields on the electronic environment of the arene ring containing the indolyl group: an electron-withdrawing group diminishes the yield, whereas an electrondonating group increases it. Aniline derivatives containing nitro- or cyano-groups do not yield the desired product under the standard conditions owing to the reduced nucleophilicity of anilines. The plausible mechanism involves a one-pot condensation of the coumarin and aniline derivatives to give intermediate I, which after electrophilic interception by palladium(II) gives intermediate II. This compound, upon subsequent tautomerization to enamine III, undergoes a palladium(II)-catalyzed C–H functionalization to give the palladacycle V via the transition state IV. Further reductive elimination gives the annulated product (Scheme 12.3, bottom). Hence, this approach produces a varied spectrum of indole-fused coumarins using metal-catalyzed dehydrogenative coupling reactions.

12.3  Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds H R2 H

Pd(OAc)2 (10 mol%)

O

EtCO2 H, 140 °C, 24 h

AgOAc (2 equiv)

O

R1

R2

S

S R1

O

O

Cl S

S

S

Me O

Cl

O

O

(82%)

O

O

(75%)

S

Me

F

O

O

(70%)

O

O

(74%)

Ag0 1+

S OMe O (66%)

SPh 2+

Ag

[Pd]

O

O

0

[Pd]

S O

H

O

R2 S

2+

PdOAc S

O

2+

Pd III

O

I

O

E

O S

2+

Pd O II

O

Scheme 12.2  Thiol-tethered coumarins with their annulated thiophene products (top) and the plausible catalytic cycle (bottom).

A similar approach has been utilized by Cheng’s group [56] in which a one-pot, two-step synthesis of fused benzofuran skeletons was undertaken via subsequent palladium-catalyzed O-arylation of 4-hydroxy heterocycles and their dehydrogenative couplings with iodoarenes. The fused benzo[4,5]furo heterocycles and their dibenzo analogues carry immense medicinal value and can be obtained with high levels of regioselectivity. An example of a pharmaceutically-important molecule containing the benzo[4,5]furo and dibenzofuran skeleton has been provided in Scheme 12.4. Both electronwithdrawing and electron-donating substituents at the para position of the phenyl group are well-tolerated. Ortho substituents, heterocyclic, and meta substituents provide products with good yields. In case of meta substituents, cyclization is achieved at the less hindered side. The mechanism proceeds with the oxidation of the arene iodide into iodonium ion in the presence of hydroxyl-substituted aromatic compound (Int1) followed by isomerization to the O-aryl intermediate (Int2). Subsequent palladium-catalyzed C–H activation and annulation (coupling) yield substituted benzofurans in a single pot (Scheme 12.4). A similar report by DeBoef and coworkers describes the intramolecular annulation of a benzimidazole derivative that is carried out via dehydrogenative coupling catalyzed by a palladium(II)/copper(I) system [57]. In this case, a benzyl system is tethered to the imidazole ring, thereby facilitating a close proximity between the coupling partners and also minimizing dimerization. A CDC then causes the tethered substrate to annulate and gives the fused ring (Scheme 12.5, top). A wide

547

548

12  Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles

Scheme 12.3  Dehydrogenative coupling of 4-hydroxycoumarins with aniline derivatives (top) along with the probable mechanism (bottom).

array of substrates has been screened and this has shown that electron-donating substituents increase yields whereas electron-withdrawing substituents diminish yields. The reaction failed with other heteroaromatic tethered groups such as furans. Also, the success of the reaction is controlled by variation in the tethered chain length (seven-membered rings failed to provide the coupled product). The plausible mechanism involves two independent metal-catalyzed C–H activation pathways: copper(II) disproportionates into copper(I) and undergoes electrophilic metalation with benzimidazole to form the copper(I)-benzimidazole complex I. Meanwhile, palladium(II) activates the C–H bond of the arene ring, producing acetic acid as a byproduct. Further transmetalation generates a biaryl palladium(II) complex III that gives the cyclized product upon reductive elimination (Scheme 12.5, bottom). Construction of C–C bonds via CDC was efficiently achieved by Wang and coworkers in 2019. In this approach, a palladium (II)-catalyzed intramolecular cross-coupling between the vinyl and arene C(sp2)–H of tertiary enamides leads to

12.3  Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds 1) m-CPBA (1 equiv) CF3CO2H (2 equiv) CH3CN,70 °C,4 h

OH H

H +

X

O

2) Pd(OAc)2 (5 mol%) K2CO3 (3 equiv) NaCl (1 equiv) DMF, 130 °C, 24 h

I

X

[O ]

[Pd]

O

O I

I

X Int 1

X Int 2 F

O O O2 N (70%)

N

(94%)

O

N

CO 2CH 3

(61%)

O

N (67%)

O O O coumestan (72%)

Scheme 12.4  Dehydrogenative coupling of 4-hydroxyquinolines with iodoarenes: some representative examples.

the formation of 7,8-dihydro-5H-benzo[4,5]azepino[2,1-a]-isoindol-5-one derivatives (Scheme 12.6, top) [58]. The reaction proceeds under mild conditions by employing Pd(OAc)2 as the catalyst and O2 as the oxidant at 80°C. A few representative examples with varying substitutions have been provided to illustrate the effects of electronic and steric parameters upon the reaction outcome. To improve the efficiency of the transformation, the authors have attempted synthesis of aporhoeadane alkaloids such as palmanine, lennoxamine, and chilenamine in only three to four steps (Scheme 12.6, bottom). Analogously, efficient C–C bond formation for the construction of indeno[2,1-c]chromene-6,7-diones was achieved by Weng and coworkers in 2020 by employing a palladium(II)-catalyzed intramolecular CDC of 3-benzoyl substituted coumarins (an electron-deficient system) [59]. The scope of the transformation included the screening of the various steric and electronic factors, representative examples of which have been provided. The reaction is sensitive toward steric congestion because product yield is reduced upon moving the Me-group from the 4- to the 2-position of the phenyl ring. Also, electronwithdrawing groups such as –F and –CF3 afforded the desired products in lower yields compared with electron-donating groups (Scheme 12.7, top). The plausible mechanism involves a palladium(II)-catalyzed ortho C4–H activation of the coumarin assisted by the weakly coordinating ketone group. A five-membered palladacycle intermediate I is generated, which remains in equilibrium with II. An additional C–H bond activation occurs, which leads to the six-membered palladacycle intermediate III. Subsequent reductive elimination of III generates the desired product molecule along with palladium(0), which is regenerated upon oxidation triggered by Ag2O (Scheme 12.7, bottom). 12.3.1.1  Synthesis of Large-sized Molecules: COTs

Arene-fused cyclooctatetraenes (COTs) form a special group of cyclic compounds with unique structural and electronic properties [60]. Its saddle-shaped three-dimensional skeleton, although symmetric, can be transformed into a versatile chiral π-conjugated system via the introduction of substituents in the benzene ring or by substituting the benzene system with heteroarenes. These heteroarene-containing COTs are shuffled from tub to planar forms through redox pathways [61]. The COTs can be planarized by forming either 6π dication or 10π dianion, so therefore they exhibit potential applications in asymmetric synthesis and supramolecular chemistry [62]. In agreement with this finding, Miura and coworkers in 2017 reported a palladium(II)-catalyzed two-fold dehydrogenative coupling (4-fold C–H

549

550

12  Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles N

R1

H

N

H

20 mol% Pd(OAc)2 0.5 equiv CuOAc 1.5 equiv Cu(OAc)2.H2O 2.0 equiv CsOPiv dioxane, 3 h, 150 °C (MW)

N R1

N

R2

2

R

N

N Me

N

N O 2N

N

N N

N

O

N

N

Me (58%)

(62%)

(29%)

(0%)

trace

N N

[Pd]

Cu(OA c)2

0

N CuOAc

electrophilic metalation

2+

Pd

N

H

N

H

A cOH Pd(O Ac)2

N III

N

1+

[Cu]

N N

1+

CuOAc

[Cu] N

H AcOH

I

2+

Pd(OAc) II

Scheme 12.5  Intramolecular dehydrogenative coupling in a tethered benzimidazole (top); mechanistic cycle showing dual and independent C–H bond activation (bottom).

activation) of 3,3ʹ-bithiophene to dimeric COT coupled product (Scheme 12.8, top) [63]. A plausible mechanism suggested by the control experiments in which C–H activation acts as the rate limiting step (kH/kD=2.96) and upon subsequent dimerization gives rise to a high-valent palladacycle intermediate palladium(IV) (II in Scheme 12.8, bottom). The role of silver pivalate remains crucial for the catalytic cycle to continue because palladium(II) is oxidized to palladium(IV) via the supposed involvement of carboxylate-bridged palladium(III)-dinuclear species [64]. This intermediate II upon reductive elimination generates a nine-membered complex III, which then paves the way to the dimerized product and results in a dehydrogenative reaction.

12.3.2  Formation of C–N Bonds Azole-fused quinazolines have recently been in the limelight in OLEDs and pharmaceuticals owing to their structural and electronic characteristics [65]. Synthesis of such fused heterocycles has long been the target of various chemists [66]. Kumar and coworkers reported a one-pot, two-step synthesis of azole-fused quinazolines via sequential Ullman coupling [67] and a palladium-catalyzed dehydrogenative C–N bond formation [68]. The protocol involves Pd(OAc)2 as the catalyst

12.3  Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds

H R1

H

R2 R2

N

Pd(OAc)2 (20 mol%), Cu(OAc)2 (2.0 equiv) DMSO, 80 °C, O2

1

R O O Me

N O

CF 3

Me

Cl N

N

O

N

O

( 66 %)

N

O

( 62 %)

O

( 52 %)

OMe

O O Me

( 55 %)

O

O

O

HO N MeO

O Me O p alm a nine

N MeO

N MeO

O Me (±)- ch ilena m ine

OMe O ( ±)- len nox am in e

Scheme 12.6  Palladium(II)-catalyzed intramolecular CDC of tertiary enamides leading to fused N-heterocyclic scaffolds (top); examples of aporhoeadane alkaloids (bottom).

and CuI as the co-catalyst that catalyzes the ortho-directed C–N type Ullman coupling (Scheme 12.9). A variety of palladium catalysts have been screened, out of which Pd(OAc)2 is favored owing to the efficiency of deprotonation of palladiumbound acetate during the C–H activation step. In this manner, the dual catalytic system effectively aides in the facile synthesis of various quinazoline scaffolds from azoles such as 1H-imidazole and 2-(2-bromophenyl)-1H-imidazole/benzimidazoles. The substrate scope has been screened with various substituents both at the imidazole as well as at the benzimidazole sub-units, with electron-withdrawing substituents giving increased yields compared to electron-donating groups (p–F vs p–OMe). The plausible mechanistic pathway involves a copper-catalyzed Ullman type ortho C–N coupling of the two starting materials that form the intermediate compound I, which in the presence of base binds with Pd(OAc)2 to give II. This further undergoes C–H activation and deprotonation to produce intermediate IV via III. Finally, reductive elimination paves the way for formation of the annulated product. Here, Cu(OAc)2 acts as the oxidant to convert palladium(0) to palladium(II) (Scheme 12.9). Various groups have worked toward the synthesis of benzo[e]pyrido[10,20:1,2]imidazo[4,5-g]isoindole derivatives, which exhibit a broad spectrum of biological activities synergistic to their parent molecules as they are hybrid scaffolds of imidazo[1,2-a]pyridines and maleimides. In 2021, Reddy and coworkers reported a ruthenium(II)-catalyzed dehydrogenative annulation of 2-arylimidazo[1,2-a]pyridine with maleimides to construct a diverse range of benzo[e] pyrido[1ʹ,2ʹ:1,2]imidazo[4,5-g]isoindoles in a simple and step-economical fashion (Scheme 12.10, top). This oxidative [4+2] cycloaddition occurs via a ruthenium(II)-catalyzed ortho C–H activation of imidazo[1,2-a]pyridine and its concomitant dehydrogenative annulation with cyclic maleimides in presence of Cu(OAc)2 (oxidant) in toluene. Varied substrates participated well in the reaction with substitutions on the aryl group of imiazo[1,2-a]-pyridines. Replacing the alkyl group of the maleimide with –tBu results in a slight decrease in the yield, whereas no product formation takes place at all (0% yield) in the case of N–Ph.

551

552

12  Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles

H

O

R2

H

R1

Pd(OAc)2 (10 mol%), Ag2O (2.0 equiv)

R2 O

TFA, 150 °C, 48 h

O

O

R1 O Me

O

Me

Me O O

O

O

O

(89 %)

O

O

O

(48% ) F

O

O

O

(6 0% )

O

(92 % )

F3C

O O

O

O

O

(56 %)

Me

O

O

O

(trace)

O

(9 3% ) H

O

O

O

Ag+H2O PdX2

Ag2O

X = CF 3C O 2

Pd(0)

O

X

HX

O

2+

Pd O

O O

I

O

2+

Pd

X O

O III

2+

Pd

O

O O

II

O

Scheme 12.7  palladium (II)-catalyzed construction of indeno[2,1-c]chromene-6,7-diones (top); plausible mechanistic cycle involving dual C–H bond activation (bottom).

From a mechanistic aspect, [Ru(p-cym)Cl2]2 undergoes ligand exchange with Cu(OAc)2 to form the active catalyst [Ru(pcym)(OAc)2], which proceeds to give a cyclometalated species I via ortho C–H activation of imidazo[1,2-a]pyridine. The ruthenacycle thus formed, after an oxidative insertion of maleimide into the Ru–C bond of the tethered phenyl group, generates the intermediate II. This is followed by a ruthenium-mediated –N to –C rollover to generate a seven-membered

12.3  Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds R X

Pd(OAc)2 (10 mol%) AgOPiv (2.0 equiv)

R

PhCO2H (50 mol%) toluene, 120 °C, 16 h

R X

R Ph

S

Ph

S

Ph

X

X

X

X

S

S

N O

Ph

O

Ph

R Ph

N S

Ph

R

(42%)

S

Ph

(27%) S

R

R 2Ag 0

Pd(OCOR)2

S 2RCO 2H

2AgO CO R

L S

Pd

0

2+

L

Pd

R

S R

I

2AgOCOR

product

2Ag 0 Pd(OCOR)2

R

S

R

S

R

R

R S S

2+

R

S

Pd L

L III

S

R

4+

Pd L L S

S

II

R possibly via carboxylate bridged Pd(III)-dinuclear species

Scheme 12.8  Palladium-catalyzed synthesis of heteroarene-fused cyclooctatetraenes (top); plausible mechanistic pathway showing a high-valent palladacycle (bottom).

ruthenacycle III via elimination of AcOH. Reductive elimination of III then affords the annulated intermediate species IV, which further oxidizes to yield the target molecule. The active catalytic species is then regenerated back after oxidation with Cu(OAc)2 (Scheme 12.10, bottom). In the quest to synthesize N-containing annulated heterocycles having pyrimidine units, Tiwari and coworkers reported a palladium(II)-catalyzed intramolecular dehydrogenative annulation of benzimidazole derivatives using oxygen as the oxidant [69]. Fused imidazo[1,2-a]pyrimidines and pyrazolo[1,5-a]pyrimidines are formed in good yields, thereby facilitating one-pot condensation and dehydrogenative coupling reactions (Scheme 12.11). Although concrete evidence has not been provided by the authors, a putative mechanism has been put forth that involves condensation of the pyrazolo amine with the free aldehyde, twice concomitantly, to yield the intermediate I. Further

553

554

12  Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles N +

N Br

N

1. CuI (20 mol%), K2CO3 (2.0 equiv), DMF, 150 °C, 1 h

N

N H

2. Pd(OAc)2 (5 mol%), Cu(OAc)2 (2.0 equiv), 150 °C, 2 h

N N N

F N

MeO

N

N

N

N N

N (71%)

N

N N

N

N N

F

MeO

N

(62%)

(81%)

N +

N Br N

N

N

(56%)

N

N

CuI, K 2CO3

N H

C−N coupling

Pd

N N

N N N

Cu(OAc)2

0

I

Pd(OAc)2

N A cOH

N

N

N 2+

Pd N

N

N

N

N IV

O O

H N 2+

Pd N

N 2+ Pd AcO

II

N

N III

Scheme 12.9  Palladium(II)/copper(I) dual-catalyzed synthesis of azole-fused quinazolines along with their mechanistic pathway.

electrophilic metalation with palladium(II) yields II, which then undergoes a proton shift to give III. This is followed by the formation of a seven-membered palladacycle IV, after which a 1,2-palladium migration gives the intermediate V- a six-membered aza-cycle. A β–H elimination step yields back palladium(II) and releases the intermediate VI, which lies in equilibrium with structure VII. A tandem Wacker-Tsuji type oxidation follows that undergoes attack by H2O at the C-terminal to give the corresponding alcoholic intermediate X. Further β–H elimination yields a palladium(II)–H species that, after reduction in presence of K2CO3. gives palladium(0). The alcohol XI and palladium(0) thus obtained undergoes oxidation with molecular oxygen to give the ketonic product XII along with palladium(II), which continues the catalytic cycle. A copper-catalyzed C–H activation and subsequent dehydrogenative annulation of a C3-substituted pyrrole-azole system has been reported by Singh and coworkers in which they synthesized six- and seven-membered annulated pyrroles (Scheme

12.3  Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds R1

+

N

NR3

O

O

N

[Ru(p-cym)Cl2]2 (5 mol%)

NR 3

O

N

Cu(OAc)2 (9 mol%), toluene, 120 °C,14 h

R1

O

N R2

R2

O

Et N

Me N

O

O

N

O

O

N

N

Cyclohexyl N O Me

O

N

N

Cl

(90%)

(87%)

tBu N

O O

N

N

N

OMe (90%)

O

N

N

Ph N

OMe (75%)

(0%)

N N 1/2 [Ru(p-cym)Cl2]2 Cu(OAc)2

O NR 3

O

CuCl2

N

[RuL(OAc)2] [O]

N 1

L = p-cym

N

AcOH

N Cu(OAc) O O

NR3 IV

AcO O

L

NR 3

2+

2+

L

Ru

Cu(OAc)2

N N

O

I

Ru

N N

III

O NR3 2 O O OAc L 2+ Ru N

AcOH

NR 3 O

N II

Scheme 12.10  Ruthenium(II)-catalyzed annulation of 2-arylimidazo[1,2-a]pyridines with maleimides(top); plausible mechanistic pathway (bottom).

555

556

12  Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles

12.12, top). As per literature reports, a copper-mediated intramolecular dehydrogenative annulation is far more restricted compared to its intermolecular counterpart [70]. Also, the preferential reactivity of the C2–H of pyrroles over C5–H has not been extensively explored. Hence, this enhancement in the regioselectivity of the oxidative cross-coupling reaction owes its prevalence to the fine-tuning between the pKa of the C2 and C5–H owing to the presence of C3-substitution. It has been observed during optimization that formation of the dimer becomes prominent in most of the cases. Therefore, to circumvent this challenge, upon optimization, it is found that the optimum result is obtained in presence of 20 mol% Cu(OAc)2 as the catalyst with Ag+ salt as the oxidant. To further increase the selectivity of the annulated product over the dimer, NMO/ TBAB has been used in their respective stoichiometry to obtain the best yield. The ratios depicted in the substrate scope represent the annulated product to the dimeric side-product. Upon screening the substrate scope, it was found that substituting –CHO to the more electron-withdrawing –NO2 group at C3 of the pyrrole unit improves the given ratio. Inclusion of an electron-donating group such as –Me in the imidazole counterpart slightly increases the yield with an increment of the relative ratio of the two products. The best yield and selectivity occurs in case of dimethyl-substituted imidazole where both an electron-donating group and an electronwithdrawing group at the pyrrole subunit are present. The substrate scope can be extended to seven-membered annulated

PdCl2 (5 mol%) K 2CO3 (1 mmol)

X

R1

Y N H

NH 2 +

X

O

N

Y N

O 1 atm O2, 80 °C, 4 h

N N

Ph Ph

H 2O

O N N H

Ph Ph

(80%)

X = CH/N Y = CH/N

NH 2 +

O

N

H Ph

N

Ph N Ph

N

I

Pd(II)

H Pd(II) Ph

N N

[O] N

II

Ph

Pd(0)

Ph

N

Ph

N N XII

[O]

Ph

N

Ph

N

O

N

Ph

N

XI

III

HPd(II)X N Ph H Ph

N N

Ph

X

Ph N

Ph

N

IX

VIII

X

N

N Ph

N (II)Pd

Pd(II)X

HPd(II)X

Ph

N N

N

N

N Pd(II)OH X

N N

Ph

N

K 2 CO3

OH

Pd(II)

N

HX

H 2O

(II)Pd Ph

N N N H VII

Ph

Ph

N N N

Ph

X

Ph H

Ph V

VI

Scheme 12.11  Palladium(II)-catalyzed pyrimidine formation via tandem condensation and dehydrogenative annulation.

Ph Pd(II) IV

12.3  Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds

pyrroles, where moderate yield and selectivity has been observed. Based on experimental evidence, a putative mechanism has been chalked out. Owing to the high acidity of the –H flanked by the two N-atoms of the azole counterpart, copper(II) activates this C2–H to form the intermediate I. The formation of I can be confirmed by the isolation of a dimer obtained during optimization of the annulated product. Intermediate I then undergoes disproportionation with Cu(OAc)2 to form an intermittent copper(I) species II, which again undergoes a second C–H activation at the C2 of the pyrrole counterpart to afford III via oxidative addition. The copper(III) thus formed is further stabilized by its interaction with the aldehydic carbonyl group by Cu–O coordination. Further reductive elimination of III affords the annulated product B with the generation of copper(I) that is further oxidized by Ag2CO3 (Scheme 12.12, bottom). A similar report, put forth by Pal and coworkers in 2021, utilizes a palladium-catalyzed intramolecular CDC of tethered isoxazole derivatives for the construction of highly π-conjugated benzimidazo[1,2-a]quinoline-fused isoxazole skeletons [71]. A simple and efficient protocol for the construction of imidazopyridine-fused indoles has been developed by Kumar and coworkers where a one-pot tandem Knoevenagal condensation and an intramolecular CDC coupling prevail. A palladium(II)-catalyzed double C–H activation takes place in presence of Cu(OAc)2 as the sole oxidant (Scheme 12.13, top) [72]. The plausible mechanism involves a Knoevenagel condensation of the 3-formyl indole with a substituted imidazole unit to yield the condensation intermediate A in the presence of piperidine. This undergoes a regioselective palladation to yield the intermediate I. Subsequent formation of the seven-membered palladacycle II occurs via a concerted metalation–deprotonation process. Further reductive elimination yields the annulated product B in comparable yields for a variety of substrates. Thus, a variety of azole-annulated indoles can be constructed (Scheme 12.13, bottom). In 2019, Dabiri and coworkers achieved an efficient tandem coupling and annulation reaction between aldehydes and arylquinazolinones to access variably substituted hydroxyisoindolo[1,2-b]quinazolinone scaffolds [73]. The methodology anchors upon tandem formation of C–C and C–N bonds in a one-pot fashion. The reaction employs Pd(OAc)2 as the catalyst and TBHP as the oxidant to provide optimal yields. Diverse substitutions are well-tolerated at both the ends of the coupling congeners with substrates containing electron-withdrawing groups reacting sluggishly compared to electrondonating group-containing substrates. Sterics also play a vital role in the reaction outcome with the ortho substituents providing decreased product yields. A few representative examples have been provided to clarify the reaction results produced using diverse substrates (Scheme 12.14, top). The plausible mechanism involves palladium(II)-catalyzed arene C–H activation as the initial step, leading to the formation of a five-membered palladacycle I. A rollover cyclometalation of the intermediate I occurs that leads to the intermediate II. The resulting palladacycle II undergoes an acyl radical mediated oxidation (generated in situ by TBHP) to generate either a palladium(IV) or a dimeric palladium(III)-intermediate III. Subsequent reductive elimination affords the formation of a C–C bond with palladium(II) attaching to the amide N- of phenylquinazolinone (IV). Upcoming intramolecular nucleophilic attack at the carbonyl center forms the palladium alkoxide (V), which after protonation produces the annulated hydroxyisoindolo[1,2-b]quinazolinones (Scheme 12.14, bottom).

12.3.3  Formation of C–B Bonds Carboranes constitute a significant class of polyhedral molecular cluster, constituting C and B bonds. Functionalizing such three dimensional molecular structures opens up various opportunities, especially in fields of medicinal research. In 2021, Xie and coworkers reported the first example of an iron-catalyzed formation of C,B-substituted carborane-fused phenanthroline derivatives via an intramolecular B–H/C–H dehydrogenative coupling strategy [74]. The resulting skeleton also finds application in various catalytic systems by acting as a bidentate ligand having an 8-aminoquinoline moiety as an integral part of its structure. The reaction utilizes a 3d-transition metal iron(III) as the catalyst and generates products in a single step in good to moderate yields. The substrate scope involves the screening of diversified substituents, ranging from electron-withdrawing group to electron-donating group, and also highlights the steric effects. A substituent at the C2 positon of the cage is well-tolerated, and so is substitution at the other position of the carborane cage. An electron-withdrawing group such as –CF3 at the quinolinyl unit gave comparatively lower yield, thereby exhibiting an electronic effect upon the product formation. A substituent such as bromine at the C6-position of quinolinyl fragment also displays a lower yield, thereby revealing a steric effect (Scheme 12.15, top).

557

558

12  Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles H/Ph

R

N Ph/H

N

N

n

n

Y N

Cu(OAc)2 (20 mol%), Ag2 CO3 (1 equiv.)

Y

NMO (2 equiv,.), K2 CO3 (2 equiv.), TBAB (50 mol%) xylene, 150 °C, 36 h

X

X = CHO, NO2, CN; Y = C, N

N N

R

X

N Ph/H

+

X

N

Y N

R

R

N Y

N

(dimer) N H/Ph

OHC

O2N

O2N N

N N

N

(51%, 7:1)

Me N

N

O2N

N N

Me

Me

(56%, 11:1)

N

N

N

N

Me (61%, 12:1)

Ph

O2N

Ph

N N

X

(88%, 18:1)

N

(35%, 4:1)

OHC Ag(I)

N N

N

Ag(0)

CHO

Cu(I)

B Cu(II)

N

N N A

H

CHO O Cu(III)

N C(2) vs C(5); C(2)-activated

N N

N

N

III

N I

Cu(II)

Cu(OAc)2 CHO

AcOH

Cu (I) N

N

Cu(OAc)

N II

Scheme 12.12  pKa/directing-group-controlled intramolecular C–H activation with copper (top); mechanistic pathway (bottom).

The plausible mechanism involves generation of an active iron(III) species I, produced as a result of the reaction between Fe(acac)3 and Grignard reagent ArMgCl. This metal species further chelates with the 8-aminoquinoline derivative to form the intermediate II. This is followed by subsequent electrophilic attack of iron(III) at the electronically richer B4–H unit, thus generating the key intermediate III.

12.3  Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds

R2 CHO N R1

O

+

N

R2

N

O

i) Piperidine (1.5 equiv.), toluene reflux, 3h N ii) Pd(OAc)2 (10 mol%) Cu(OAc)2 H 2 O (50 mol%) AcOH(30 mol%), 12-24 h, open air

N

N N R1

OR

O CHO

N Me

O N

+

N

Piperidine

R2

Ph N

Knoevenagel condensation Cu(OAc)2

N R1

N

O

N A Me

Pd(OAc)2

N

O Ph

Pd(0)

AcOH O

N N B

N

Ph N

Me

2+

N N Pd Me OAc I O

Ph N 2+

N Me

Pd II

N

O

Ph N 2+

N Pd O

N H O Me TS: deprotometalation

Scheme 12.13  Synthesis of 5-aroyl-11H-imidazo[1ʹ,2ʹ:1,2]pyrido[3,4-b]indoles via dehydrogenative coupling (top); plausible mechanism for the same (bottom).

The trans effect of the cage boron initiates a rotation of the bidentate directing group, thus leading to the formation of a [B−Fe(III)−C] intermediate IV via C–H bond activation. A value of 1.33 is obtained for kH/kD upon performing parallel experiments to check for a kinetic isotope effect, suggesting that the C–H activation step is non-turnover limiting. This is followed by subsequent reductive elimination to afford the annulated species. The iron(I) formed is transformed back to iron(III) upon oxidation with 2,3-DCB, thus further continuing the catalytic cycle (Scheme 12.15, bottom).

559

560

12  Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles O

O NH H

N

H

R2

+

Pd(OAc)2 (10 mol%), TBHP (4.0 equiv)

N

DCE, 80 °C, N 2, 16 h

R1

R2

O HO

N OMe

R1 MeO

NO2

O HO

O HO

O HO

MeO O HO

N

N

N

N

N

N

(71%)

N (68%)

N (trace)

(55%)

O HO

O HO

O HO

O HO

N

N

N

N

N

N

Me

N

NO2

N MeO

(74%)

(trace)

Br

(trace)

O HO Ph N

O

N

N

(62%)

NH

H Pd(OAc)2

c

AcOH O

O Ph 2+ OAc O Pd N

NH N

N V

2+

AcO

O

OAc N

N

Pd

2+

Pd

O O Ph

N

IV O

N

I

OAc 2+ N Pd II

O

Ph OAc N Pd III

putative Pd(3 ) or Pd(4 ) intermediate

O

O

H

TBHP

Scheme 12.14  palladium(II)-catalyzed synthesis of hydroxyisoindolo[1,2-b]quinazolinone via CDC showing some representative examples (top); plausible mechanistic cycle (bottom).

12.3  Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds R3

R3

N

B H

R2

NH

2,3-DCB (4.0 equiv), THF/PhCl (1:4) 140 C, 2 h

O

R2

N

NH

N

NH B

O Me

F3 C

Ph

O

B

(70%)

R1

N

NH B

O

Ph

O

N

NH

Bn

(80%)

B

R2

R1

N

B

R4

AlEt 3 (1.0 equiv), p-TolMgCl (3.0 equiv)

NH R2

N

Fe(acac)3 (10 mol%), dppen (10 mol%)

R4

Br

NH B

O

Me

Me

(58%)

O Me

(43%)

(60%)

F e(acac)3 ArMgCl

N

dppen 2,3-DCB AlEt 3

3+

2,3-DCB Ar MgCl

NH

+ B H

Ar3[Fe]Ln I

O Me

1+

N

-EtH -AlEt 2Ar

[FeLn]

NH B

P

O

3+

P Ar

Me

Fe H

II

P 3+ Fe P

N

B

N

Ar O Me

N N AlEt 2 Ar

B O

Ar

Fe

P

Me IV

P ArH

III

H

N 3+

B

ArH

N O Me

Scheme 12.15  Construction of carborane-fused phenanthroline derivatives employing iron(III)-catalyzed C–H activation as a key step (top); plausible mechanistic cycle (bottom).

561

562

12  Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles

12.4  Conclusions Various methodologies have been developed over the years to discover newer aspects of dehydrogenative coupling reactions, thereby paving ways to develop innumerable heterocyclic cores. In an advancement over conventional synthetic protocols, these developments eliminate the requirement of pre-functionalizing the substrate. Furthermore, these approaches offer enhanced productivity, step-economy, and reduced formation of by-products. Improved synthetic utility of the methodologies can be obtained by employing an additive-free, greener route. Moreover, an acceptor-less dehydrogenative coupling reaction to synthesize fused heterocyclic scaffolds would form a transformative future research direction. Further exploration might involve 3d transition metal-assisted dehydrogenative couplings that can provide an economical route to access large-scale synthesis of heterocycles, especially at an industrial level. Moreover, the medicinal values of such fused-heterocyclic scaffolds demand easy accessibility of these products. Progress in the fields of transition metal-free catalysts and photo-catalysis that eliminates the many drawbacks of these transformations is underway.

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45 de Graaff, C., Ruijter, E., and Orru, R. V. A. (2012). Recent developments in asymmetric multicomponent reactions. Chemical Society Reviews 41 (10): 3969–4009. 46 Wan, J. P., Gan, L., and Liu, Y. (2017). Transition metal-catalyzed C–H bond functionalization in multicomponent reactions: A tool toward molecular diversity. Organic and Biomolecular Chemistry 15 (43): 9031–9043. 47 Nakamura, I. and Yamamoto, Y. (2004). Transition-metal-catalyzed reactions in heterocyclic synthesis. Chemical Reviews 104 (5): 2127–2198. 48 Nandakumar, A. et al. (2015). Transition-metal-catalyzed hydrogen-transfer annulations: Access to heterocyclic scaffolds. Angewandte Chemie International Edition 54 (38): 11022–11034. 49 Xiang, Y. et al. (2019). Diazo compounds: versatile synthons for the synthesis of nitrogen heterocycles via transition metal-catalyzed cascade C–H activation/carbene insertion/annulation reactions. Advanced Synthesis and Catalysis 361 (5): 919–944. 50 Bolognese, A. et al. (2008). Antitumor agents 6. Synthesis, structure-activity relationships, and biological evaluation of spiro[imidazolidine-4,3′-thieno[2,3-g]quinoline]-tetraones and spiro[thieno[2,3-g]quinoline-3,5′-[1,2,4]triazinane]-tetraones with potent antiproliferative act. Journal of Medicinal Chemistry 51 (24): 8148–8157. 51 Hamid, H. A., Ramli, A. N. M., and Yusoff, M. M. (2017). Indole alkaloids from plants as potential leads for antidepressant drugs: A mini review. Frontiers in Pharmacology 8: doi: 10.3389/fphar.2017.00096. 52 Grigalevicius, S. et al. (2016). Polymers containing diphenylvinyl-substituted indole rings as charge-transporting materials for OLEDs. Journal of Electronic Materials 45 (2): 1210–1215. 53 Wang, C. et al. (2012). Semiconducting π-conjugated systems in field-effect transistors: a material odyssey of organic electronics. Chemical Reviews 112 (4): 2208–2267. 54 Zhang, J. et al. (2019). Palladium-catalyzed synthesis of benzothiophenes via cross-dehydrogenative coupling of 4-arylthiocoumarins and pyrones. Advanced Synthesis and Catalysis 361 (24): 5709–5714. 55 Dey, A. et al. (2017). Palladium-catalyzed synthesis of indole fused coumarins via cross-dehydrogenative coupling. Tetrahedron Letters 58 (4): 313–316. 56 Hong, F. et al. (2016). One-pot assembly of fused heterocycles via oxidative palladium-catalyzed cyclization of arylols and iodoarenes. Advanced Synthesis and Catalysis 358 (3): 353–357. 57 Pereira, K. C., Porter, A. L., and Deboef, B. (2014). Intramolecular arylation of benzimidazoles via Pd(II)/Cu(I) catalyzed cross-dehydrogenative coupling. Tetrahedron Letters 55 (10): 1729–1732. 58 Zhu, W. et al. (2019). Intramolecular arylation of tertiary enamides through Pd(OAc)2-catalyzed dehydrogenative crosscoupling reaction: construction of fused N-heterocyclic scaffolds and synthesis of isoindolobenzazepine alkaloids. Journal of Organic Chemistry 84 (5): 2870–2878. 59 Yang, T. et al. (2020). Pd-catalyzed cross-dehydrogenative coupling of 3-benzoyl substituted coumarins: Efficient access to Indeno[2,1-c]chromene-6,7-diones. Asian Journal of Organic Chemistry 9 (11): 1765–1768. 60 Huang, H. et al. (2009). Hydroxytetraphenylenes, a new type of self-assembling building block and chiral catalyst. Organic and Biomolecular Chemistry 7 (7): 1249–1257. 61 Mouri, K., Saito, S., and Yamaguchi, S. (2012). Highly flexible π-expanded cyclooctatetraenes: cyclic thiazole tetramers with head-to-tail connection. Angewandte Chemie International Edition 51 (24): 5971–5975. 62 Sygula, A., Fronczek, F. R., and Rabideau, P. W. (1996). The first example of η8 coordination of lithium cations with a cyclooctatetraene dianion: crystal structure of Li2(dibenzo[a,e]cyclooctatetraene)(TMEDA)2ʹ. Journal of Organometallic Chemistry 526 (2): 389–391. 63 Fukuzumi, K., Nishii, Y., and Miura, M. (2017). Palladium-catalyzed synthesis of heteroarene-fused cyclooctatetraenes through dehydrogenative cyclodimerization. Angewandte Chemie International Edition 56 (41): 12746–12750. 64 Powers, D. C. and Ritter, T. (2009). Bimetallic Pd(III) complexes in palladium-catalysed carbon-heteroatom bond formation. Nature Chemistry 1 (4): 302–309. 65 Michael, J. P. (2003). Quinoline, quinazoline and acridone alkaloids. Natural Product Reports 20 (5): 476–493. 66 Cho, S. H. et al. (2011). Recent advances in the transition metal-catalyzed twofold oxidative C–H bond activation strategy for C–C and C–N bond formation. Chemical Society Reviews 40 (10): 5068–5083. 67 Beletskaya, I. P. and Cheprakov, A. V. (2004). Copper in cross-coupling reactions: the post-Ullmann chemistry. Coordination Chemistry Reviews 248 (21–24): 2337–2364. 68 Nandwana, N. K. et al. (2015). Synthesis of novel azole-fused quinazolines via one-pot, sequential Ullmann-type coupling and intramolecular dehydrogenative C–N bonding. Organic and Biomolecular Chemistry 13 (10): 2947–2950.

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69 Reddy Kotla, S. K. et al. (2017). Palladium-catalyzed intramolecular cross-dehydrogenative coupling: synthesis of fused imidazo[1,2-a]pyrimidines and pyrazolo[1,5-a]pyrimidines. ACS Omega 2 (1): 11–19. 70 Tripathi, K. N., Ray, D., and Singh, R. P. (2017). Synthesis of pyrrole-annulated heterocycles through copper-catalyzed site-selective dehydrogenative cross-coupling. European Journal of Organic Chemistry (38): 5809–5813. 71 Sahoo, S. and Pal, S. (2021). Rapid access to benzimidazo[1,2-a]quinoline-fused isoxazoles via Pd(II)-catalyzed intramolecular cross dehydrogenative coupling: Synthetic versatility and photophysical studies. Journal of Organic Chemistry 86: 4081–4097. 72 Shinde, V. N. et al. (2018). Synthesis of imidazopyridine-fused indoles via one-pot sequential Knoevenagel condensation and cross dehydrogenative coupling. Organic and Biomolecular Chemistry 16 (33): 6123–6132. 73 Dabiri, M. et al. (2019). Palladium catalyzed cross-dehydrogenative coupling/annulation reaction: A practical and efficient approach to hydroxyisoindolo[1,2-b]quinazolinone. European Journal of Organic Chemistry 2019 (18): 2933–2940. 74 Chen, Y. et al. (2021). Fe-catalyzed intramolecular B–H/C–H dehydrogenative coupling: synthesis of carborane-fused nitrogen heterocycles. Organic Letters 23 (11): 4163–4167.

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13 C–H Functionalization of Saturated Heterocycles Beyond the C2 Position Amalia-Sofia Piticari, Natalia Larionova, and James A. Bull Department of Chemistry, Imperial College London, Wood Lane, London, UK

13.1  Introduction Saturated heterocycles present extremely valuable substructures in medicinal chemistry [1]. In particular, five- and sixmembered ring nitrogen and oxygen heterocycles are prevalent in marketed drugs, [1, 2] and four-membered ring systems such as azetidines and oxetanes are becoming increasingly of interest to access new medicinally attractive chemical space [3]. These heterocycles present numerous well-defined exit vectors to elaborate a hit compound in 3-dimensions for the development of required selectivity and potency in a drug discovery program. Consequently, there are vast numbers of synthetic methods available for the preparation of new heterocycle derivatives. C–H Functionalization on saturated heterocycles presents a conceptually highly attractive approach for their elaboration to explore the available carbon exit vectors [4, 5]. Numerous methods have been developed to exploit the relatively weak C–H bonds adjacent to the heteroatom. Examples include deprotonation [6], carbene insertion [7], and radical generation (recently notably with photoredox catalysis [8]), as well as employing N-linked directing groups (DGs) for C-H functionalization at these activated positions [9]. On the other hand, methods for C–H functionalization at unactivated positions remote to the heterocycle have emerged later and have required alternative strategies [10]. This chapter will describe the nature and the development of such methods, focusing on those methods that use transition metal catalysis for C–H functionalization and form a discrete carbon-transition metal bond. This chapter aims to explore the scope and application of these approaches up to 2021. C–H functionalization on saturated heterocycles at positions remote to the heteroatom brings its own challenges, not least being the competing coordination of heteroatom groups on the ring, and interference of protecting groups, in addition to questions of stereo- and regioselectivity. Consequently, these have emerged later than methods applicable to carbocyclic derivatives. On saturated heterocycles, many approaches have used the strongly coordinating bidentate aminoquinoline DG first reported by Daugulis [11], and related derivatives [12]. These typically position a palladium(II) catalyst to effect C–H activation through a concerted metalation deprotonation mechanism and have the advantage of occupying coordination sites on palladium to prevent β-hydride elimination. Yu has successfully used monodentate DGs in combination with other ligands, based on pioneering studies from the Yu group [13]. These methods have been limited to palladium catalysis to date. N-Heterocycles have seen greater investigation with less work on oxygen heterocycles. This chapter will cover examples of C–H functionalization according to the position of the DG and the site of functionalization, focusing on N-heterocycles (Figure 13.1).

13.2  Heterocycle Functionalization with a C2 Directing Group 13.2.1  Carboxylic Acid-Linked C2 Directing Groups The first studies of C–H functionalization of N-heterocycles focused on proline derivatives. In 2014, Bull reported the first example of unactivated C(sp3)–H bonds in heterocycles being functionalized using palladium catalysis and a pre-installed DG (Figure 13.2) [14]. Starting from N-Cbz S–proline, the 8-aminoquinoline DG reported by Daugulis was installed at C2 to form aminoquinoline amide 1 [11]. Highly regio- and stereoselective C3 functionalization was achieved, with formation of Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

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13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

H n

N R

DG

H DG

n

C2 directing group C3-functionalization n = 0, 1 , 2

N R

DG

H H n

N R

C3 directing group C4 -functionalization and C5 -functionalization n = 1, 2

N DG

C4 directing group C3-functionalization

N directing group C4-functionalization n = 1 and bicycles

Figure 13.1  Chapter outlined based on the directing group location illustrated for N-heterocycles.

2,3-disubstituted pyrrolidines of general structure 2 as single cis-diastereomers. Moreover, complete retention of S–proline enantiomeric excess was demonstrated in the reaction with 4-iodotoluene. A high reaction concentration was necessary to achieve very good conversions, and the reaction was ultimately performed solvent-free. Conditions were optimized to allow the relatively low loadings of aryl iodide and AgOAc (1.8 equiv each) and using 5 mol% Pd(OAc)2. The reaction scope was tolerant of aryl iodides with various electronic properties. p-Electron-donating groups led to up to 91% yield, and an excellent yield was maintained in the presence of the electron withdrawing p-ethoxycarbonyl group. Aryl halides proved successful, as well as 2-naphthyl. An unfavorable steric effect was observed with 2-fluoroiodobenzene, requiring prolonged heating to achieve 44% yield. This was less apparent in the case of meta-substituents, with 3,5-disubstituted aryl iodides achieving up to 70% yield. Heteroaromatics such as thiophene and pyridine were also installed, moreover, a free benzylic alcohol, as well as an unprotected benzaldehyde could be directly employed to provide handles for further derivatisation. Under the same reaction conditions, C(sp3)–H alkenylation was demonstrated using (E)-2-iodovinylbenzene, with retention of alkene double bond geometry.

AQ (1.8 e quiv)

I (S)

H N

N

R

R Pd(OA c)2 (5 mol% ) AgOAc (1.8 equiv)

AQ

neat 110 ° C, 2 0 h

N Cbz O 1

N Cbz O 2 single cis stereoisomer F

R R AQ N Cbz O 91%a 88% 78% 68%b 85% 90%

R = Me F Cl Br OMe CO 2Et

AQ N Cbz O

AQ N Cbz O

73%

R = CF 3 NO 2 CN

76% 74% 59%

AQ N Cbz O 44%c

70%

CHO

OH

N

S AQ

87%

F

AQ N Cbz O

Cl

N Cbz O

NO2

AQ N Cbz O 54%

AQ N Cbz O 22%

AQ

AQ

N Cbz O

N Cbz O

29%

51%d

Figure 13.2  C(sp3) − H functionalization of N-Cbz proline with a C2 aminoquinoline amide (AQ) directing group a>98% ee b9% yield of the corresponding bis-pyrrolidine c 60 h reaction time d E/Z =95:5.

13.2  Heterocycle Functionalization with a C2 Directing Group

Similar to previous accounts [11, 15], the functionalization mechanism was proposed to involve a palladium(II)/ palladium(IV) manifold (Figure 13.3). With palladium coordinating to the DG, initial cyclopalladation takes place by concerted metalation-deprotonation (CMD) aided by acetate ligands. The resulting five-membered palladacycle 3 undergoes oxidative addition to afford a palladium(IV) complex 4. Subsequent reductive elimination and halide abstraction by silver, followed by palladium decomplexation regenerates the active palladium(II) species giving the 2,3-cis-disubstituted product. The observed stereoselectivity is supported by independently reported deuteration studies [16], proving preferential activation of the cis C–H bond with respect to the DG. Aminoquinoline removal from these products proved challenging under various conditions due to the hindered nature of the strong amide bond. However, when starting from amide 5 bearing the more electron-rich 5-methoxyaminoquinoline DG (5-OMe-AQ, previously introduced by Chen) [17], similar yields of C3 arylation were obtained (Figure 13.4). The DG was then readily removed by treatment with ceric(IV) ammonium nitrate (CAN) to afford primary amides 6a-c. Following Cbz deprotection, medicinally relevant fragments 7a-c could be generated. A subsequent publication by Maulide demonstrated the ring opening of the quinolinyl moiety by aromatic ring oxidation with ozone [18]. Under the ozonolytic conditions, followed by treatment with aqueous ammonia, deprotection of the aminoquinoline motif was shown on the arylated proline substrate 8. The corresponding free primary amide 9 could be directly isolated in an excellent 88% yield without C2 epimerisation (Figure 13.5), opening new opportunities for entry to valuable medicinal chemistry motifs directly from the products of aminoquinoline-directed C(sp3)–H functionalization. A concise optimization approach reported by Bull also demonstrated the compatibility of a range of five- and six-membered saturated N-heterocycles with the C3 functionalization reaction [19]. Compared to Cbz-protected pyrrolidines, the N-Boc protected derivatives were significantly less reactive affording lower conversions and requiring longer reaction PdII(OAc)2 Ar

N

N R

O

N

H

H N O O

Pd

N R

O

H N O

O

AcOH

AcOH

OAc

N R

Ar L PdII N N

Me O HO

O

N

reductive elimination AgI

N R

O

HO Me

O AgOAc

PdII N

HO

I Ar N R

PdIV N

N

Me

O PdII N

O 4 Ar

oxidative addition

C-H activation (cyclopalladation)

I

N R

O

N

R O

O

H

PdII

N

N

3 N R

O

CMD Figure 13.3  Proposed PdII/PdIV mechanistic cycle for C(3) arylation of proline with a C2 AQ directing group.

569

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13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

R

DG

R

R

(1.8 equ iv)

I ( S)

H N

N Cbz O

Pd(OAc)2 ( 5 mol%)

N

A gOAc (1.8 equiv) nea t, 110 ° C, 20 h

OMe

5 R

(S) (S)

NH2

(S) (S)

CAN (3 equiv)

DG

N Cbz O single cis stereoisomer >98% ee R= H Me F

MeCN/H 2O rt,4−5 h

75% 82% 75%

R

(S) (S)

H 2, Pd/C

N Cbz O

N H

6a-c

R= 7a H 7 b Me 7c F

(S) (S)

NH2 N Cbz O R= 6a H 6b Me 6c F

7 5% 7 9% 6 4%

NH2 O

99% 99% 99%

Figure 13.4  5-OMe-AQ removal and synthesis of medicinally relevant amide-containing fragments.

Me

Me i) O3, CH2Cl2, -78 °C ii) DMS, CH2Cl2, rt

AQ N Cbz O 8

iii ) NH 4 O H, THF, rt 88%

NH2 N Cbz O 9

Figure 13.5  AQ removal to the corresponding amide via an ozonolysis protocol demonstrated by Maulide.

times (up to 72 h) and higher catalyst and aryl iodide loadings (Figure 13.6). To date, there is not a good explanation for this remarkable difference in reactivity, though the proximity between the N-protecting group and the C2 DG could exert an influence of the overall ring geometry, and hence influence the energy of the cis-palladacycle and subsequent intermediates. N-Cbz piperidines showed a significant increase in reactivity compared to the five-membered ring derivatives, allowing C3 arylation to occur even in the presence of more challenging aryl iodides such as substituted pyridines, in up to quantitative yields. Moreover, complete conversion was achieved in 24 h in the presence of lower Pd(OAc)2 loadings and without requiring additional additives. As in the pyrrolidine series, N-Boc protection also led to decreased yields of piperidine arylation, however, the combination of Ag2CO3 base with pivalic acid additive and solvent-free conditions achieved an excellent functional group tolerance and expansion of the scope of aryl iodides to include nitrile and methyl ketone substituted aryl groups. In the same work, Bull reported the functionalization of THFs [19], related to earlier work from Babu [20], both using an aminoquinoline amide DG. At a similar time, Liu developed the C3 functionalization of N-pivaloyl prolines 10 [21], broadening the N-protecting group options (Figure 13.7). In contrast to the protocol from Bull, the reaction was carried out in toluene at a relatively high dilution (0.1 M). Under these conditions, the coupling partner loading was increased to five equivalents, whereas the use of an organic phosphate additive (dibenzylphosphate) in substoichiometric amounts improved the reaction yield to up to 93%. Reaction was achieved with para- and meta-substituted aryl iodides, as well as with heteroaryl iodides (thiophene, pyridine). Arylation was also achieved with the less reactive aryl bromides, in up to 36% yield. As well as alkenylation with iodovinylbenzene to give 11, the reaction conditions could be adapted to achieve alkylation with 2-bromoacetate to give 12 in a modest yield. This protocol also enabled the expedient synthesis of a monoamine reuptake inhibitor in two steps (13, Figure 13.8). This consisted of proline C3 arylation with 3,4-dichloroiodobenzene, followed by basic hydrolysis of the aminoquinoline amide and pivaloyl deprotection under acidic conditions to give the corresponding amino acid TFA salt 14.

13.2  Heterocycle Functionalization with a C2 Directing Group Ar

I (3 equiv), Ag2CO3 (1 equiv)

n

N PG

N Boc

O

Cl

AQ N Boc

O

53%

AQ

PivOH (30 mol%) PhMe (0.3 M), 110 °C, 72 h

OMe

AQ

Ar

Pd(OAc)2 (10 mol%)

AQ

Cl

N

AQ N Boc

O

59%

n

AQ N Boc

O

41%

O

N PG

O

n

PG

Conditions modifications

1

Boc

see reaction scheme

2

Cbz

2

Boc

AgOAc (2 equiv), Pd(OAc)2 (5 mol%), no additive, 24 h Pd(OAc)2 (5 mol%), no solvent, 24 h

38% CN

OMe

AQ

N Cbz

Cl

N Cbz

O

98%

AQ

N

N Cbz

O

90%

Cl

COMe

AQ

AQ

N Boc

O

98%

N Boc

O

46%

64%

AQ O

S

N Boc

AQ O

73%

Figure 13.6  Optimized conditions and selected reaction scope for the C3 functionalization of pyrrolidines and piperidines with a C2 AQ directing group. Pyrrolidine products obtained as single enantiomers starting from enantiopure S-proline-derived AQ amide.

Ar

X (5 e quiv), AgOAc (2 eq uiv)

(S)

Ar

Pd(OA c)2 (10 mol% )

AQ

AQ

(Bn O)2PO2H (20 mol%)

N

N

Ph Me (0.1 M), 11 0 °C, 24 h

O O

Ar X: I

O O

10 I

I

I

S

N

R R R = Me 89% Br 81% CO 2Me 75%

R = Me 93% tBu 75% F 78% CO2Et 76%

86%

43%

I AQ Br R R= H Me F

36%a 35%a 31%a

alkenylation

N Piv O 11 36% EtOOC

Br COOEt alkylation

AQ N Piv O 12 34%b

Figure 13.7  Selected reaction scope for the C3 functionalization of N–Piv pyrrolidines with a C2 AQ directing group. a48 h reaction time. b1-AdCOOH (20 mol%), Ag2CO3 (2 equiv), DCE (0.1 M).

571

572

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

Cl I

Cl

Cl

(5 equ iv)

Cl

AgOAc (2 eq uiv) Pd(OAc)2 (10 mol%)

AQ

(S)

AQ

(BnO)2P O2H (20 mol%)

N

N

PhMe (0.1 M), 110 ° C, 2 4 h

O

68%

O

Cl

10

OH

ii. TFA/H 2O (4:1, 0.3 M), reflux, 2 h

O

O

Cl

i. NaOH (30 equiv) EtOH (0.2 M), 100 °C, 12 h

N H

76%

13

TFA

O

14

Figure 13.8  Preparation of a monoamine reuptake inhibitor by arylation followed by AQ and pivaloyl deprotection.

As a potential tool for the late-stage modification of peptides, the aminoquinoline-directed arylation at the C3 position of proline and pipecolinic acid fragments contained in di- and tripeptides such as 15 has also been demonstrated [22]. Affording high syn selectivity and proceeding with retention of configuration at all stereogenic centers, the reaction was compatible with a range of aryl iodides (Figure 13.9A), including an example of piperidine moiety functionalization with 1,3-dimethyl-5-iodouracil in 89% yield. Additionally, the aminoquinoline auxiliary could be hydrolysed to the corresponding carboxylic acid 16 without peptide degradation in order to allow peptide diversification from the C-terminus (Figure 13.9B). Wu illustrated the aminoquinoline amide directed C3 arylation of enantiopure piperidine substrates 17 derived from commercially available S-pipecolinic acid [23]. For the first time, the reaction scope featured an example of a free phenol moiety being installed in up to 72% yield upon addition of 2,6-diethoxybenzoic acid additive. Arylation with 3-iodobenzonitrile proceeded in a comparable yield and allowed preparation of a potential drug precursor 18. Aminoquinoline hydrolysis to acid 19, followed by selenoate formation (20), radical decarboxylation and installation of an N-nPr group led to the isolation of neuroleptic molecule 21 used in the treatment of schizophrenia (Figure 13.10) [24]. Also in 2016, Yu demonstrated the regio- and stereoselective C3 functionalization of six-membered N-heterocycles 22 using a monodentate directing group (Figure 13.11) [25]. A commercially available N-heterocyclic carbene ligand (NHC) was employed to enhance σ-donation to the metal center, promoting the first example of C(sp3)–H activation by a Pd(II)/NHC complex. By tuning the steric features of the NHC ligand with adamantyl substituents (L1), N-TFA piperidines could be arylated with common p-substituted aryl iodides in excellent yields, whereas decreasing the steric hindrance on the NHC ligand to include tBu substituents (L2) improved the functionalization yields for meta-OMe,

A. Arylation of proline and pipecolinic acid-containing dipeptides

n

Me

AQ

N O NHBoc

Ar I (2 equ iv) AgOA c (2 e quiv) P d(OAc)2 (5 mol%)

Ar n

PhMe, 110 ° C, 1 6 h

Me

O

Ar:

Me

n=1

80%

O2N

n=0 n=1

57% 71%

n=0

69%

AQ

N O NHBoc

O

15 B. AQ deprotection and diversification from C-terminus Me

AQ

N O NHBoc

1. Boc 2O (15 equiv) DMAP (3 equiv) MeCN, 70 °C, 2 h 2 . LiOH, H O

2 2

O

THF/H 2O (3 :1) 0 ° C to rt, 16 h 67% (over 2 steps)

Br

Me

N O O NHBoc 16

OH

Me

Gly-OMe HCl EDC, N-methyl morpholine, HOBt CH 2Cl2, 0 ° C to rt, 30 h 65%

H N

N O NHBoc

COOMe

O

Figure 13.9  A. C3 arylation of proline and pipecolinic acid moieties in peptides; B. Peptide elongation from C-terminus after AQ removal.

13.2  Heterocycle Functionalization with a C2 Directing Group

Figure 13.10  AQ-directed C3 arylation of S-pipecolinic acid derivative using 3-iodobenzonitrile. Synthesis of a dopaminergic autoreceptor agonist by aminoquinoline removal and decarboxylation.

ortho-OMe, and ortho-NHAc substituted aryl iodides, which proved challenging substrates in aminoquinoline directed approaches. Interestingly, the benzaldehyde moiety, as well as an alkyl phosphate substituted aryl group were both tolerated under these functionalization conditions, whereas the more strongly coordinating pyridinyl iodides were not found to be compatible with this NHC-enabled approach. Mechanistic investigations confirmed a palladium(II)/ palladium(IV) manifold in operation, with the Pd(II)/NHC complex promoting β-C–H activation in the absence of aryl iodide. One-pot removal of the DG by labilization of the amide by methoxycarbonyl protection under controlled basic conditions, followed by nucleophilic attack by MeO – or EtS – helped unveil either ester 23 or thioester 24, respectively (Figure 13.12). Wu expanded the scope of piperidine C3 functionalization to include alkoxylation and acyloxylation, with the combination of solvent and oxidant being crucial in determining the outcome (Figure 13.13). Related to reports on the alkoxylation of unactivated methylene bonds [26], exclusive O-alkylation to 26 was achieved in the presence of 25 as oxidant and ethylene glycol as solvent. Interestingly, employing benzyl alcohol as solvent did not form the corresponding O-benzylated product, Ar

N TFA

I (3 equiv), [A g] base

Ar

Pd(TFA)2 (10 mol%)

AQ DG

L1 or L2 (20 mol%) He xaflu orobenzene , 100 °C, 24 h

O

N TFA O

AQ DG

DG DG

=

H N F

OMe

AQ DG O

98%a

AcHN

MeO

N TFA

F CF3 F

OMe

N TFA

F

AQ DG

N TFA

O

92%b

AQ DG O

83%b L1 N

N TFA

CHO

AQ DG O

70%b

N TFA

AQ DG O

53%b

PO(OEt)2

N TFA

AQ DG O

73%b

L2 N

Cl-

N

N Cl-

Figure 13.11  NHC ligand mediated C(3) functionalization of N-TFA protected piperidines with a C2 monodentate directing group. Products obtained as racemic mixtures of cis-diastereoisomers. aUsing L1, Ar-I (2 equiv) and AgOAc (3.0 equiv). bUsing L2, Ar-I (3 equiv) and Ag2CO3 (2.0 equiv).

573

574

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

Me c) MeO Na

Me

N TFA

H N O

MeOH, rt, 10 min

a) LiHMDS THF, 0 °C, 10 min

F F

F

N TFA O 23

OMe

Me

b) MeOCOCl c) EtS H

CF3

LiHMDS, 0 ° C, 10 min

F

N TFA 24 O

SEt

Figure 13.12  Removal of the C2 monodentate directing group.

but instead steered the reactivity towards acyloxylation in up to 73% yield, with the resulting product 27 enabling facile entry to the 3-hydroxylated piperidine on LiAlH4 reduction. DMP used in conjunction with MeOH as solvent gave highyielding methoxylation to 28, whereas acetoxylation to 29 could be promoted using PIDA in toluene. The use of alkyl halides as electrophiles in palladium-catalyzed C–H functionalization reactions has presented challenges such as nucleophilic substitution of iodine by carboxylate ligands and/or homocoupling. Chen reported the aminoquinoline-directed alkylation of unactivated β-C(sp3)–H bonds in α-aminoacids [27]. Using α-haloacetates as coupling partners, a range of aminoacids could be β-alkylated in a highly stereoselective fashion, including N-Cbz protected S-pipecolinic acid derivative 30 (Figure 13.14A). Two individual examples of directed C(3) fluorination of N-Cbz protected piperidines were reported by Xu and Ge (Figure 13.14B) [28, 29]. In Xu’s work N-fluorobenzenesulfonimide (NFSI) was used as both fluorine source, and oxidant together with Ag2O. Despite moderate product yields, the addition of PivOH is suggested to aid in preventing the competing C–N bond formation in the reductive elimination step by replacement of the N(SO2Ph)2 ligand on palladium. Ge’s work featured the use of a 2-(pyridin-2-yl)isopropyl (PIP) amide DG instead of aminoquinoline to prevent aromatic substitution of the auxiliary by strongly electrophilic fluorine reagents. Hence, Selectfluor could be used as fluorine source, whereas addition of Fe(OAc)2 was suggested to help facilitate palladium de-coordination from the final product after reductive elimination, increasing the fluorination yield to up to 82% for the six-membered cyclic aminoacid. High diastereoselectivity for the formation of cis-fluorinated piperidine 31 was also observed in this case. Interestingly, making use of the aminoquinoline directed strategy, Yang demonstrated the possibility of alkylating primary and secondary C(sp3)–H bonds with phosphonated alkyl iodides and applied it to the synthesis of γ-phosphono-α-amino

Oxidants:

( S)

N Cbz O 30

Pd(O Ac) 2 (10 mol%) oxidant (2 equi v)

AQ

sol vent, 110 °C 1 5-24 h

OCH3 I O

OR AQ

N Cbz

O single cis enantiomer I

AcO OAc I OAc O

O

AcO

I

O

25

DMP

PIDA

O O N Cbz O 26

AQ

O

O

OH

N Cbz O 27

OMe AQ

OAc

N Cbz O 28

AQ

O N Cbz O 29

Oxidant

25

25

DMP

PIDA

Solvent

HO(CH2)2OH

BnOH

MeOH

PhMe

Yield

57%

73%

75%

70%

AQ

Figure 13.13  AQ-directed C3 alkoxylation and acyloxylation as influenced by the choice of oxidant and solvent.

13.2  Heterocycle Functionalization with a C2 Directing Group

acids [30]. Whereas the substrate scope mostly featured linear amino acids, an S-pipecolinic derivative was compatible with the transformation, leading to high dr of the cis-functionalized piperidine 32 resembling a γ-phosphorylated unnatural amino acid (Figure 13.14C). In addition to the illustrated examples, β-alkynylation was reported on N-Cbz proline and pipecolic acid derivatives bearing a C2 aminoquinoline amide DG using 1-bromo-2-triisopropylsilylacetylene as coupling partner [31]. The C3 alkynylated heterocycles were obtained in good yields (50–70%) with exclusive cis diastereoselectivity, in contrast with linear aminoacids with non-bulky side-chains, for which mixture of cis and trans diastereomers were isolated. After TIPS removal, the alkynes underwent further manipulations, by Sonogashira coupling or copper(I)-catalyzed azide–alkyne cycloaddition. Exploiting the possibility of C–N bond formation after the reductive elimination step, Wu achieved a palladium-catalyzed protocol for the intramolecular amination of readily available aminoquinoline carboxamides to generate a series of natural-product-derived β-lactams [32]. Key to the observed reactivity was the tuning of the steric and electronic properties of the aryl iodide coupling partner, with bulky and electron-withdrawing pentafluoroiodobenene disfavoring the crosscoupling product. Under microwave irradiation, exclusive bond formation between the activated carbon position and the aminoquinoline amide nitrogen was observed, affording four-membered lactams. When applied to substrates containing ring units, cis fused β-lactam products could be obtained with high regio- and stereoselectivity. Starting from the S-proline 8-methoxyquinoline amide 5, cis-C3 intramolecular amination to give products of general structure 33 could be achieved in 86% yield (Figure 13.15). Removal of the pendant quinoline unit by ceric ammonium nitrate (CAN) oxidation followed by Cbz hydrogenolysis afforded unsubstituted diazabicyclic β-lactam 34 as a valuable intermediate in the formal synthesis of β-lactamase inhibitor MK-8712 developed by Merck [33]. A later study by Wu expanded the scope of cyclic substrates that can undergo cis-fused β-lactam formation in high yields (35–37), demonstrating DG and Cbz deprotection on each of them to the free diazabicyclic and/or diazatricyclic intermediates (38–40) [34]. The indoline substrate bearing a C2 aminoquinoline amide and the hydroxyproline derivatives were incompatible. In 2016 Schreiber identified a series of azetidines as potent anti-malarials targeting all three stages of the parasite lifecycle [35, 36]. C(sp3)–H functionalization was seen as an opportunity to minimise the number of synthetic steps towards the key building blocks of this class of compounds, whilst allowing further stereoselective elaboration of azetidine analogues. This prompted development of the C(3) arylation of commercially available enantiopure S-azetidine-2-carboxylic acid in 2017 [37]. Using the 8-aminoquinoline amide DG at C2, the use of an N-TFA protecting group was found to be essential to high reactivity (41, Figure 13.16). This gave the opportunity to hydrolyse the TFA group in the same pot, directly affording the free azetidine products. Using (BnO)2PO2H as an additive, a broad reaction scope was observed with

Figure 13.14  Directed C3 alkylation, fluorination and phosphorylation of N-Cbz protected pipecolinic acid derivatives. aRelative stereochemistry of the fluorination product assumed.

575

576

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

Pd(OAc)2 (10 mol%) AgOAc (1.2 equiv) C6H6I (6.8 equiv) microwave, 160 °C 1.5 h, 86%

CH3CN/H2O,

Figure 13.15  Top: Intramolecular amination of an S-proline derivative directed by 5-methoxy-quinoline towards the synthesis of β-lactamase inhibitor MK-8712. Bottom: synthesis of various diazabi- and tri-cyclic β-lactams by carboxamide-directed intramolecular C(sp3)–H functionalization.

respect to the aryl iodide, including both electron-rich and electron-poor substrates. meta-Substituted aryl iodides were well tolerated, with functionalization in the presence of 3-bromoiodobenzene affording 52–54% yield of desired cis-arylated compounds 42 and 43, the reaction towards 43 being carried out on a 10 g scale. Excellent yields (>70%) were obtained for the C3 functionalization of the homologous series of four-, five-, and six-membered N-heterocycles. 4-Iodobiphenyl was found to react efficiently as coupling partner, whereas heterocycles such as thiophene, indazole and pyridine could also be installed on the azetidine ring. A series of azetidine carboxylic acid building blocks were prepared in a stereodivergent deprotection of the AQ DG (Figure 13.17). Starting from the (2S,3R) azetidine 42 bearing the m-Br-aryl substituent, Boc protection of the aminoquinoline amide followed by LiOOH-mediated hydrolysis resulted in the corresponding carboxylic acid 44 with retention of stereochemistry. Alternatively, using NaOH at elevated temperatures achieved both hydrolysis and epimerisation to afford

13.2  Heterocycle Functionalization with a C2 Directing Group

AQ

Ar

AQ

I (3 equiv)

A gOAc (2 equi v) (S )

O

Ar

Pd (OAc)2 (10 mol%)

N 41 TFA

( S)

O

NH

(BnO)2PO2H (20 mol% )

DCE (1 M) , 110 °C, 24 h, N 2 the n NH3 /MeOH

AQ X

X = OMe H F O Cl (S) Br NH I CF3 AQ

X

72% 70% 58% 52% 57% 48% 52%

NH

65% X = Me 50% NO2 CO2Et 51%

AQ

AQ

( S)

Br ( S)

O

Br

O

( R)

NH 42 54%

O

NH 43 52%a Me

Me

Me

AQ

Homologous series:

( S)

O

AQ N H O 95%

NH 70%

AQ ( S)

NH 61%

AQ O

S

(S)

N H O 72%

Cl

AQ O

Me N N

NH

(S)

NH

80%

46%

O

AQ

AQ N (S)

O

NH 24%

3

Figure 13.16  Substrate scope for the one-pot C(sp )–H directed arylation-TFA deprotection of S-azetidine-2-carboxylic acid derivates. aReaction performed on 10 g scale using the R-azetidine-2-carboxylic acid starting material. TFA deprotection using K2CO3 in 9:1 MeOH/H2O.

(2R,3R) carboxylic acid 45. In a similar fashion, the other 2 possible carboxylic acid stereoisomers 46 and 47 could be derived from the (2R,3S) functionalized azetidine 43. In 2017, Schreiber also achieved the C3 functionalization of pyroglutamic acids (Figure 13.18) [38]. This class of compounds had previously been readily functionalized at C2 and C4, given the electronic bias and relative acidity of these positions [39]. The C2 carboxylic acid was used as a handle for the installation of the aminoquinoline DG. Under optimized conditions, C3 arylation occurred regioselectively and with complete retention of pyroglutamic acid enantiomeric excess, giving products of structure 48 as single cis diastereoisomers and single enantiomers. The use of dibenzylphosphate used as an additive significantly enhanced the reactivity, increasing the functionalization yield to over 80%, compared to only 9–10% in the absence of any additive and only 7% in the presence of the more commonly used pivalic acid (PivOH). The reaction could be conducted in cyclopentyl methyl ether (CPME), a solvent with a good safety profile, using relatively high concentrations and at lower temperatures (80°C) than previous reports. A broad reaction scope was demonstrated with respect to the aryl iodide, with excellent yields in the presence of electron-rich aromatics with either para or meta-substituents. The steric effects posed by the presence of an ortho-substituent could be overcome by increasing the Pd(OAc)2 loading, as in the case of 2-fluoroiodobenzene. Changing the N-protecting group to various substituted

577

578

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

i. Boc O, MeCN, 2 then DMA P

AQ Br

( R)

( S)

HO Br

(R) (S)

ii. LiOH, H O

2 2

NH 44

THF/MeOH 69%

O

NH 42

i. Boc 2O, MeCN, then NaOH, EtOH

HO

Br

( R) ( R)

110 ° C, 15 min

AQ Br

( S)

( R)

HO Br

( S) ( R)

ii. LiOH, H2O 2 THF/MeOH

O

i. Boc 2O, MeCN,

43

then NaOH, EtO H

O

NH 46

72%

NH

O

NH 45

81%

i. Boc 2O, MeCN, then DMA P

O

HO

Br

( S)

110 ° C, 15 min

( S)

O

NH 47

77%

Figure 13.17  AQ deprotection to generate C3-arylated azetidine 2-carboxylic acids with any stereochemistry of choice. Ar

I (3 equiv)

AgOAc (1.5 equiv) (S)

O

Ar

Pd (OAc)2 (5 or 10 mol% )

AQ

(BnO)2PO2H (20 mol% )

N O Cbz

CPME (1 M), 80 ° C, 8 h

AQ O

N Cbz O 48 single cis stereoisomer >99% ee

Ar I (aryl iodide scope):

N-aryl scope: Ar

I

I

O

R

N

83% 58% 59% 46%

70% 70% 53% 65% 71%

AQ

O I

O

I

F

O 69%a

OMe 56% Ar N

O

CO2Et

66%

62% Ar

I

I N Ts

O O

O B

N

O 59%

50%a

AQ O

N

Me

O

decreasing electron-rich character

R = Me Br NHBoc CO 2 Me NO 2

Ar =

O

R R = OMe Ph F CO2Et

Br AQ

CF3 63%

Figure 13.18  Selected reaction scope for the C3 functionalization of pyroglutamic acids with a C2 AQ directing group. a10 mol% Pd(OAc) used.

13.2  Heterocycle Functionalization with a C2 Directing Group

aromatics did not significantly affect the reaction yield and as a general trend, more electron-deficient arenes led to higher C(3) arylation yields. The methodology was applied to the synthesis of medicinally relevant building blocks, also showcasing aminoquinoline deprotection strategies (Figure 13.19). Ozonolysis followed by treatment with aqueous NH4OH allowed the isolation of cis-amide derivatives of pyroglutamic acid (49a-b). trans-Substituted amides (50a-b) could be generated in similar yields following this procedure after successful epimerisation of the aminoquinoline-protected pyrrolidine by treatment with a strong phosphazene base (P2-Et). On the other hand, treating the imide intermediate with LiOOH generated corresponding cis-carboxylic acids 51a-b. Interestingly, the presence of an N-phenyl group significantly prevented the product formation under these conditions. Direct access to trans-carboxylic acids 52a-b was enabled by a same-pot epimerisation/hydrolysis with LiOH at 75°C. More recently, Mykhailiuk studied the effect of pre-existing ring substituents such as alkyl and (het)aryl group on the directed C3 functionalization of S-proline [40]. Starting from either N-Cbz and/or N-TFA protected prolines, bulky alkyl substituents (such as cyclohexyl and cyclopentyl) at the 4-trans position with respect to the C2 DG significantly lowered the reaction conversion, even at elevated temperatures (>110°C). However, phosphoric acid additives such as BINOLPO2H or dibenzylphosphate enhanced the reactivity, affording up to 80% yield of C3 benzylated products (Figure 13.20A). Notably, for the cyclopentyl-substituted example, the starting material was employed as a 1:1 mixture of cis:trans-isomers with the reported lower yield (40%) being due to the exclusive arylation of the trans-isomer. Proline derivatives with a 5-trans-substituent reacted in 50–65% yield, with examples of cycloalkyls, as well as 4-chlorobenzyl and thiophene being tolerated (Figure 13.20B). The relatively small C5 cis-methyl substituent could also be employed, in a remarkable 88% yield. Five-membered saturated rings fused to proline at C4 and C5 reacted well, regardless of the stereoconfiguration of the fused system (Figure 13.20C). Any C3 substituent significantly prevented the arylation at this position, with a methyl group giving a modest 18% product yield and an ethyl group completely suppressing the reaction (Figure 13.20D). Similarly, a C2 ethyl group effectively inhibited the arylation. However, a C2 methyl group led to the unexpected formation of a triarylated compound in 85% yield, arising from mono-functionalization at C3, together with diarylation of the C2 methyl group (Figure 13.20E). Under the standard conditions six-, seven-, and even eight-membered saturated N-heterocycles bearing a C2 aminoquinoline auxiliary could be arylated in excellent yields of up to 92% for the largest ring size (Figure 13.21A). However, since an increase in ring size correlates with higher conformational flexibility, lower stereoselectivity for cis arylation was observed for seven- and eight-membered ring examples. Similar to pyrrolidines, six-membered N-Cbz analogues afford cis arylation, this selectivity being maintained in the case of 5,6-cyclohexane-fused and 4,5-benzene-fused piperidines, however, benzene-fused piperidines afford reduced yields of C3 functionalization due to the presence of a reactive benzylic position (Figure 13.21B). Seven-membered N-heterocycles could be functionalized with a range of p- and m-substituted

Me

Me i) O3, CH 2Cl2, -78 ° C

ii) DMS, CH2Cl2, -78 °C

ii) DMS, CH Cl , -78 ° C 2 2

OH

O

N O R R = Ph 51a trace H 51b 54%

Me

O

OH N R

O

R = Ph 52a 81% H 52b 79%

Me i) O3, CH 2Cl2, -7 8 °C

iii) LiOH, H 2O2, THF/H2O, r t

AQ

(S)

O

O

Chan-L am (57% ) P 2 Et THF, 80 °C

Me

AQ

(R)

O

N R

NH2 N O R R = Ph 49a 63% H 49b 69%

O

N R

LiOH MeOH, 75 °C

iii) NH 4OH, THF, rt

N N N P N P N N N P2 E t

Me

i) O3, CH 2Cl2, -7 8 ° C ii) DMS, CH2Cl2, -78 ° C iii) NH 4OH, THF, rt

O O

R = Ph 61% H 51%

NH2 N R

O

R = Ph 50a 70% H 50b 60%

Figure 13.19  Applications in the synthesis of medicinally relevant building blocks by aminoquinoline deprotection.

579

580

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position Ar

I (3 eq uiv)

AgOA c (2 equiv)

R

(S)

N PG

R

AQ

(B nO)2PO2H (20 mol%)

N

P hMe (1 M), 120 °C, 24 h

O

A. C(4) trans substituents:

PG

O

B. C(5) substituents:

AQ N PG

Ar

Pd(OAc)2 (10 mol% )

AQ

AQ

O

PG: Cbz (80%) TFA (78%)

AQ Me

N Cbz O

N TFA

AQ N Cbz O

O

88%

40%

55%

C. 4,5-disubstituted prolines (ring fused):

H AQ H N PG

O H

AQ

H N Cbz O

O

PG: Cbz (45%) TFA (82%)

S

18%

Cl

N Cbz O 65%

E. C(2) substituents:

Me AQ

N Cbz O

N Cbz O

AQ

50%

85%

D. C(3) substituents:

Me

AQ

AQ

AQ N Cbz O 0%

AQ

O N Ph Cbz Ph

O N Cbz Me

85%

0%

Figure 13.20  C3 arylation of proline derivatives with a C2 aminoquinoline amide directing group. A study of the effects of various pre-existing ring substituents.

aryl iodides including 3-iodo-N-Ac aniline and an example of diiodinated fluoren-9-one for which only one iodine atom selectively reacted (Figure 13.21C). Also notable is that certain geometrical and electronic factors were required for proline derivatives to undergo directed C3 arylation. The presence of C4 electron-withdrawing substituents such as fluorine, as well as the presence of oxygen inside the ring rendered the substrate unreactive as were substrates with locked conformations (Figure 13.22). This is indicative of some of the ongoing limitations in the field.

13.2.2  Applications of N-Heterocycle Functionalization with C2 Directing Groups These C–H functionalization methods have been applied in the preparation of specific target compounds in medicinal chemistry and life sciences programs in fewer steps and with reduced costs. Bicyclic azetidine BRD3914 and related structures were developed by Schreiber as efficient antimalarials as part of a diversity-oriented synthesis (DOS) programme [35, 36]. The stereoselective C(3)-directed functionalization of azetidines reduced the total synthetic steps from 14 to 7 (Figure 13.23) [37]. Starting from the C3 arylated (R,S)-disubstituted azetidine 53 confirmed by X-ray crystallography and obtained in only two steps from common feedstocks, a global Boc protection

13.2  Heterocycle Functionalization with a C2 Directing Group Ar I (3 equiv) AgOAc (2 equiv)

R n = 1-4 N PG

Ar

Pd(OAc)2 (10 mol%)

AQ

R

(BnO)2PO2H (20 mol%) PhMe (1 M), 120 °C, 24 h

O

A. Ring size scope: 5- to 8-membered rings

n = 1-4 N PG

AQ O

B. Functionalization of substituted 6-membered rings H AQ

AQ N Cbz

AQ N Cbz O

O

73%

AQ N Cbz O

N H Cbz O 60%

75%

40%

C. Functionsalization of 7-membered rings NHAc O

AQ

N Cbz O

N Cbz

O 92% cis/trans = 3:2

85% cis/trans = 2:1

AQ

AQ N Cbz O 67% cis/trans = 1.6:1

N Cbz O 53%

AQ I

Figure 13.21  C3 directed arylation on various N-heterocyclic ring sizes, including substituted six-membered rings.

Electron-withdrawing substituents: F

F

F

AQ

AQ N TFA O

N Cbz

F

N Cbz

O

O

AQ

AQ

N Cbz

O

O

Conformationally restricted substrates:

AQ N Cbz

O

AQ N PG

O

AQ N TFA O

AQ

AQ N TFA O

N TFA

O

PG = Cbz/TFA

Figure 13.22  Substrates incompatible with C3 arylation in the presence of a C2 aminoquinoline directing group.

was carried out in order to activate the amide. A LiOOH-mediated hydrolysis unveiled the C2 carboxylic acid functionality with stereochemistry retention, whereas Boc deprotection of the azetidine N-atom allowed the installation of a bifunctional linker by reductive amination (54). Fmoc removal and intramolecular amide formation gave the azetidine-fused eight-membered lactam. Finally, lactam reduction and urea formation with 4-methoxyphenyl isocyanate, followed by Heck alkynylation with phenylacetylene gave the target BRD3914. The flexibility to access different stereoisomers made stereochemical-based structure-activity relationship (SAR) studies possible. Later, Schreiber focused on a strategy to increase the number of under-represented chemical classes and features in DNA-encoded libraries (DEL), such as the presence of saturated small heterocycles with stereodefined substitution

581

582

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position i. HCl/dioxane

Br

Br

AQ ( S)

( R)

O

HO O

(S)

NH

(R )

N

72%

53

N H

ii.

O

Fmoc

Br HO

H NaBH(OAc)3

( S)

N

71%

Boc

( R)

54

absolute stereochemistry confirmed by X-ray

O

(CH2)4 HN Fmoc OMe

Br HO ( S)

( R)

Br O

N

SiliaBond  Piperazine then HATU 89%

H

(S)

O ( R)

N

O H N

i. Ru3(CO)12,TMDS then isocyanate ii. XPhos Pd G3 phenylacetylene 48%

NH

H (S)

NH

N (R)

N BRD3914

Fmoc 54

Figure 13.23  Synthesis of antimalarial BRD3914 in only five steps starting from a C3-arylated azetidine obtained via a stereoselective aminoquinoline directed C(sp3)–H functionalization.

patterns [41]. Recognising the potential of C–H functionalization to help install desirable structural features [37], along with the incompatibility of palladium-catalyzed methodologies with the presence of DNA, functionalization was performed prior to DNA attachment. Making use of the C(sp3)–H arylation chemistry developed for the synthesis of azetidines, both four- and five-membered 2,3-disubstituted N-heterocycles were synthesised in an initial off-DNA stage (Figure 13.24). Starting from commercially available enantiomerically pure R- or S- cyclic aminoacids, aminoquinoline was installed at C2, with the ring-amine TFA protected. Arylation with 1,4-diiodobenzene was performed in DCE at 110°C using dibenzylphosphate as an additive and was followed by same-pot TFA deprotection to furnish 55. The potential bispyrrolidine side-product was not observed and aminoquinoline deprotection to the corresponding carboxylic acids could be carried out in the manner described previously to afford the full matrix of all the possible stereoisomers around the vicinal C2-C3 centers for both the azetidine and pyrrolidine scaffolds. An N-hydroxysuccinimide (NHS) ester-containing spacer was installed on each scaffold to distance the densely functionalized core from the DNA headpiece attachment point (56, ent-56, trans-56 and ent-trans-56). After DNA attachment and Boc-deprotection, two rounds of split-pool synthesis were performed: firstly, N-capping reactions by reductive amination/sulfonylation and secondly, Suzuki couplings to functionalize the aryl iodide. With three sources of diversity arising from the stereochemistry of the scaffold itself, the nature of the N-capping building block and the nature of the Suzuki coupling partner, a total of 53,808 azetidine and 53,808 pyrrolidine compounds were generated. The library showed excellent DNA barcode validation and correctly identified compound-target interaction with carbonic anhydrase IX, as further validated by synthesis of the corresponding azetidine hits 57, ent-57, 58, ent-58, 59 and ent-59 containing the primary sulfonamide motifs. Moreover, pyrrole at BB1 was found to give an up to 60-fold increase in the potency of the (R,R)-azetidine sulfonamide derivative 57, whereas a three-fold increase was observed with Boc carbamate at BB1 for the (S,S)-azetidine ent-58. The results demonstrate the robustness of this synthetic strategy, which bypasses the requirement to develop novel DNA-compatible chemistry, as well as the potential of remote C(sp3)–H functionalization in accessing uncharted DEL chemical space. trans-3-Aryl substituted prolines can act as competitive antagonists for ionotropic glutamate receptors (iGluRs), with affinities for the relatively underexplored NMDA subtype [42]. However, accessing a variety of tool compounds for the study and discovery of novel subtype selectivity profiles has proven challenging. Bunch and collaborators have recently taken advantage of the emergent C(sp3)–H functionalization methodology, reporting the synthesis of 40 new 2,3-trans disubstituted proline scaffold analogues of general structure 60 and an SAR exploration [43]. Initially applying a similar methodology to that

13.2  Heterocycle Functionalization with a C2 Directing Group

AgOAc (2 equiv) Pd(OAc)2 (10 mol%) (BnO)2PO2H (20 mol%) DCE (1 M), 110 °C, 24 h then K2CO3 (3 equiv) MeOH:H2O

C 10 h

117 boronic acids (+1 blank well)

56 DNA-HP trans-56 ent-56 then de-Boc ent-trans-56 = all possible stereoisomers

ent

ent

Sources of diversity: scaffold, BB1, BB2 complete matrix of stereoisomers 107,616 compounds (2×4 ×114 ×118)

ent

Figure 13.24  Synthesis of DOS-DEL-1 library starting from the enantiopure four- and five-membered R-aminoacids, generating all possible stereoisomers around the C2-C3 vicinal centers. Similar route starting from the corresponding S-aminoacids to generate a total of 107,616 DEL compounds. Selected examples of azetidine off-DNA compounds synthesised to confirm on-DNA hits. NHS=N-Hydoxysuccinimide.

described by Bull [19], the scope of the AQ-directed C3-cis-arylation of N-Boc prolines was expanded to include mono-, di-, and trisubstituted aryl group, all bearing the 3ʹ-carboxylate vital for biological activity (Figure 13.25) [43]. Moreover, resembling Mykhailiuk’s report [40], directed C3 functionalization occurred in the presence of a C4 allyl substituent. Full epimerisation to establish the desired 2,3-trans stereochemistry could be achieved in the same step as the DG

583

584

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position Ar I (2 equiv) Ag2CO3 (1 equiv) Pd(OAc)2 (10 mol%)

(R) AQ

(R)

(R)

N Boc O 60 R1

Br CO 2Me

CO2Me

AQ

CO 2Me

AQ

N Boc O

AQ N Boc O

N Boc O

62%

48% Br

AQ

(R)

PivOH (30 mol%) PhMe (0.3 M), 110 °C, 72 h

N Boc O

Ar

R1 = Br 61% CO2Me 37%

Cl CO2Me

CO2Me

AQ

AQ

N Boc O

N Boc O

31%

37%a

Figure 13.25  Expanding the scope of directed C3 arylation of N-Boc R-proline. The arylated products were subjected to AQ deprotection and further manipulations to generate tool compounds for SAR exploration around a known iGluR antagonist. a PhMe (0.2 M) and 48 h reaction time. Deprotection example: Br

Br

Cl CO 2Me (R)

N Boc

O

AQ

CO2tBu

i) NaOH (10 equiv) EtOH,100 °C, 24 h

ii) TBTA (5 equiv) CH2Cl2 (0.5 M), rt, 24 h 31% (over 2 steps)

Br

Cl

(S )

OtBu

N O Boc 61

TFA, CH Cl 2 2 rt, 18 h then 1 N HCl 96%

Cl COOH (S)

OH N H O ⋅HCl 62

HCOOH (2 equiv),Ac2O(2 equiv), Et3 N (5 equiv) Pd(OAc)2 (10 mol%), Xantphos (3 mol%) tBuOH (2 equiv),PhMe (0.5 M), 80 °C, 18 h 63%

HOOC

HOOC

Cl CO2tBu

( S)

OtBu

N Boc O 63

Cl COOH

TFA, CH2Cl2 rt, 18 h then 1 N HCl 93%

(S)

OH N H O ⋅HCl 64

Figure 13.26  Example of successful aminoquinoline deprotection (with full epimerisation) on a sterically hindered substrate. The bromine aromatic substituent can be converted to -COOH. Final compounds isolated as HCl salts.

13.2  Heterocycle Functionalization with a C2 Directing Group

removal, by basic hydrolysis with NaOH (Figure 13.26). The free carboxylic acids at both the C2 and 3ʹ positions were protected as their tert-butyl esters (61) to allow their cleavage concomitantly with N-Boc deprotection (62). Additionally, arylbromide substituents could be exchanged for carboxylate (63) or even amine functionalities under specific conditions, increasing the chemical diversity of the library. Final deprotections under acidic conditions led to the isolation of the corresponding HCl salts (64) for use in pharmacological characterisation. Overall, the C–H arylation strategy allowed access to 31 SAR exploration structures out of the total of 40 reported. This SAR study demonstrated an increased target selectivity in the presence of 5ʹ aromatic substituents and helped identify novel antagonists with up to 34-fold preference for GluN1/GluN2A over GluN1/GluN2B-D NMDA receptors. Els‐Heindl and Geyer used C–H arylation to synthesise rigidified aminoacid building blocks for the construction of bioactive peptides [44]. Amongst the 20 analogues prepared, indoylated proline derivative 65 could be generated from N-Cbz S-proline in 54% yield (Figure 13.27). The protocol by Bull was followed [14] with increased equivalents of N-Boc 3-iodoindole, as well as maintaining a decreased temperature over a prolonged time to account for the sensitivity of indole to decomposition. Interestingly, 65 displayed the highest conformational restriction of all reported aminoacid analogues, with a characteristic ring puckering and a single rotamer around the C3–indole bond. With tools available for the restoration of the parent carboxylic acid after conducting a directed C–H functionalization, Baran, Yu, Schreiber and coworkers designed a strategy for converting this versatile functionality into C–C or C–B bonds [45]. Carboxylate-assisted C3 activation was combined with a decarboxylative cross-coupling (dCC), resulting in the formation of vicinally difunctionalized carbon frameworks, as well as an overall Cβ–H/Cα–C activation of the starting aminoacid (Figure 13.28). The predictable stereochemical outcome (cis C-H activation, followed by trans C–C coupling for the dCC) ensured stereocontrolled access to trans-2,3-substituted four-, five-, and six-membered heterocyclic scaffolds (67–69). Given the previously proven retention of ee in the C–H activation and aminoquinoline removal steps, [18, 21, 37, 46] as well as no observed ee erosion in the dCC step, products could be isolated in high enantiopurity (>96% ee) at the end of the sequence. S-Azetidine-2-carboxylic acid, S-proline, and S-pipecolinic acid derivatives 66, 1 and 30, respectively, successfully underwent the series of transformations to afford (R,S)-disubstituted heterocycles 67–69. With various aryls installed at C3, the carboxylic acid functionality after aminoquinoline removal was converted to a redox-active TCNHPI ester, which was used in Giese, Negishi, Suzuki, as well as borylation reactions. A wide range of decarboxylative coupling partners were tolerated such as cycloalkyl, aryl, alkenyl, and heteroaryl groups. Sequential installation of a phenyl and a methyl group at C3 and C2, respectively, provided a facile route to accessing the main scaffold 68a of a series of known CNS drugs targeting the sigma-1 receptor [47]. This modular sequential functionalization could also be used to simplify a previously known synthesis of leukotriene inhibitor BIRZ-227, reducing the number of steps by two while increasing the overall yield from 11% to 40% and maintaining dr and ee [48]. Other substrates successfully subjected to the Cβ–H/Cα–C activation strategy include O-heterocycles (tetrahydrofuran2-carboxylic acid), morpholine-2-carboxylic acid, as well as piperidine-3-carboxylic acid, the latter affording the product corresponding to the formal Cγ–H/Cβ–C activation [45].

I (5 equiv)

N Boc

NBoc

AgOAc (1.8 equiv)

AQ

(S )

N Cbz

Pd(OAc)2 (20 mol%) neat, 80 °C, 6d

O

N -Cbz L-proline

54%

(S)

QHNOC Cbz N

AQ

N Cbz O 65 single cis enantiomer

NBoc 65

Cγ

endo

pucker

χ1 = 160 ° χ2 = -100°

Figure 13.27  Employing C-H functionalization in the synthesis of a conformationally restricted C3 indoylated pyrrolidine. Suggested conformation shown on the right, with ring puckering and restricted rotation around the C-indole bond.

585

586

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

67-69

Figure 13.28  Cβ–H/Cα–C activation strategy of four-, five-, and six-membered N-heterocycles, consisting in AQ-directed C3 functionalization, AQ removal and decarboxylative cross-coupling (dCC) (yields corresponding to the final transformation only) General conditions for dCC reaction: [N] TCNHPI ester (0.1 mmol, 1 equivalent), boronic acid (0.3 mmol, 3 equivalents), NiCl2·glyme (10–50 mol%), ditBuBipy (20–60 mol%), THF:N,N-DMF=3:2, rt, 12 h. [S] TCNHPI ester (0.1 mmol, 1 equivalent), boronic acid (0.3 mmol, 3 equivalents), NiCl2·6H2O (20–50 mol%), bathophenantroline (22–60%), Et3N (1 mmol, 10 equivalents), dioxane: DMF=10:1, 75°C, 12 h. aNo ee reported for this example, as racemic compound not prepared.

13.3  Heterocycle Functionalization with C3 Directing Groups 13.3.1  Carboxylic Acid-Linked C3 Directing Groups The use of a C3 DG on five- and six-membered heterocycles provides unsymmetrical substrates, which can present additional selectivity questions. Carboxylic acid-linked DGs at C3 have, to date, led to selective functionalization at the less hindered C4 position.

13.3  Heterocycle Functionalization with C3 Directing Groups

In 2016, Yu reported the palladium-catalyzed C4 arylation of 3-piperidinecarboxamides which relied on palladium catalysis with an N-heterocyclic carbene (NHC) ligand (Figure 13.29) [25]. For piperidine and tetrahydropyran derivatives 70– 72 high C4 regioselectivity was obtained, which was proposed to be due to repulsion from the nitrogen lone pair preventing activation at C2. The reaction was not stereoselective, with a mixture of cis and trans-arylated products being formed apart from the example of N-TFA piperidine 71 bearing a cis methyl substituent at C2. Considering a preferred equatorial conformation of the DG in this case, the authors argue that palladium activation of the cis axial C4–H bond is prevented by its unfavorable 1,3-interaction with the C2 axial methyl group. In 2018, Bull developed the C4-arylation of pyrrolidines with an aminoquinoline amide DG at C3 (Figure 13.30) [46]. The reaction conditions were optimized to minimise competing C2-functionalization, which was seen as a minor side-product initially, and also to prevent epimerisation. The optimized method had the advantage of avoiding the use of silver salts and

4-MeC6H4-I (3 equiv) Pd(TFA)2 (10 mol%) Ligand (20 mol%)

X

p-Tol AFT

N

X

Ag2CO3 (2.0 equiv) C6F6 100 °C

DG

DG

DG

p-Tol TFA

70 66% cis/trans = 1:1

N

L3

p-Tol

O

DG

71 74% trans/cis = >20:1

t-Bu p-Tol

N + t-Bu Cl-

N

DG

F

H N

DG O

72 72% cis/trans = 3:2

F

F

CF3 F

Figure 13.29  Yu’s C4-Arylation of piperidine and tetrahydropyrans.

O

N PG

(Het)Ar

AQ N PG 73

PhCF3 (1 M) 110 °C, 18 h

MeO

R O

O AQ

AQ

N PG PG = Boc Cbz CO2Me TFA

64% 67% 57% 19%

R=

Me Br CF 3 NHBoc SMe CH2OH

O

R

N Boc

X N

AQ N Boc

55% 45% 24% 54% 55% 35%

R=

CO2Et NO2

32% 30%

O O AQ N Boc

X=

O

(Het)Ar - I (3 equiv) Pd(OAc)2 (5 mol%) K2CO3 (1 equiv) PivOH (1 equiv)

AQ

Ts 59% H 60%

O

O AQ

N Boc 63%

AQ N Boc 20%

Figure 13.30  Bull’s C4 selective arylation of pyrrolidines using a C3 aminoquinoline amide directing group.

587

588

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

was successful for a wide range of aryl iodides, including potentially sensitive functionalities such as a free benzyl alcohol and tetrahydrobenzofuran. Various N protecting groups were tolerated, with Boc leading to higher yields and facile product purification. Medicinally relevant functionalities and diversification handles could be tolerated, such as CF3, NHBoc, and SMe. Both NH and NTs indole could be installed in similarly high yields and alkenylation with (E)-styryl iodide was also possible with retention of double bond geometry. The products of general structure 73 were exclusively cis-isomers, but epimerisation could be promoted by heating with Cs2CO3 in toluene to generate selectively the trans-substituted derivatives. Using the enantiopure substrate gave retention of the ee in the arylation step and isolation of products as single cis-stereoisomers. Furthermore, the epimerisation protocol led to the enantioenriched trans-3,4-disubstituted pyrrolidines. The same conditions were compatible with piperidine substrates, also affording the cis-3,4-disubstitution pattern 74 (Figure 13.31) [46]. Minor trans-configured products (75) were observed, apart from when using sterically hindered o-substituted aryl iodides which led exclusively to cis-functionalized substrates in moderate yields. trans-Arylation was proven to be due to competing trans-palladacycle formation, given the increased flexibility of the substrate, rather than epimerisation. DG removal and subsequent manipulations unveiled free polar functionalities, demonstrating the value of this methodology in the synthesis of saturated heterocycles relevant to drug-discovery (Figure 13.32) [46]. Hydrolysis of the aminoquinoline amide under excess NaOH occurred with concomitant epimerisation, leading to the trans-carboxylic acid 76 which could be Boc deprotected to the corresponding TFA salt 77. Ozonolysis using Maulide’s protocol [18] provided the free amide 78. Alternatively, Boc-activation of the DG amide could facilitate further divergent transformations: hydrolysis to carboxylic acid 79, transamidation (80), methanolysis (81) and reduction to the primary alcohol (82). Bull used this method in a short formal enantiocontrolled synthesis of (–)-paroxetine [46, 49, 50], as well as the preparation of enantioenriched bromo- and iodo-paroxetine derivatives of (–)-paroxetine (Figure 13.33) [51]. Using enantioenriched commercially available N-Boc-(R)-nipecotic acid 83, the arylation with the corresponding fluoro-, bromo-, and iodo-substituted aryl iodides gave the highly enantioenriched cis-C4-arylated products 84–86, with the corresponding trans-isomers 87–89 also being accessed by DBU-promoted epimerisation. Notably, the following telescoped Boc-activation/LiAlH4 reduction en-route to the key enantioenriched alcohol intermediates 90–92 tolerated both bromo- and iodo-substituents. Finally, mesylation, followed by nucleophilic substitution with benzodioxol-5-ol and N-deprotection gave desired Br-paroxetine and I-paroxetine in 12% yield over 8 steps. These derivatives were applied in a study of the SERT (serotonin transporter) binding site complexed to the drug analogues by cryo-EM and X-ray crystallography, exploiting the anomalous scattering of bromine and iodine [51].

O AQ N PG PG = Boc or Cbz

(Het)Ar - I (3 equiv) Pd(OAc)2 (5 mol%) K2CO3 (1 equiv) PivOH (1 equiv)

AQ N Boc

R = 4-OMe 4-Me 4-F 4-Cl 3-CN 2-OMe

cis 44% 35% 42% 30% 25% 44%

O

Ar AQ

PhCF3 (1 M) 110 °C, 18 h

R O

Ar

trans 20% 21% 16% 14% 13% -

AQ

N PG

N PG

74

75

S

O

O

cis trans 41% 24% AQ

N Boc NH

R

cis trans R = 4-OMe 50% 19% 3-CO 2Et 25% -

O

O

AQ N Cbz

cis trans 47% 19% AQ

N Cbz

Figure 13.31  Bull’s C4 selective arylation of N-Boc and N-Cbz piperidines using a C3 aminoquinoline amide directing group.

13.3  Heterocycle Functionalization with C3 Directing Groups

O NaOH (10 equiv)

PMP

EtOH, 100 oC, 30 min 86%

O OH

N Boc 76

TFA (10 equiv) CH2Cl2, 25 °C, 22 h, 98%

O Ar

O NHQ

Boc2O (5 equiv) DMAP (0.2 equiv)

ii) NH4OH, THF 25 C, 20 h 49%

O Tol

O NH2

N Boc 78

PMP

N H2 TFA 77

BnNH 2 (1.5 equiv) PhMe, 60 oC, 24 h 69%

PMP

N Cbz 79

K2CO3 (2 equiv) MeOH 25 oC, 22 h 56%a

O NHBn

N Boc 80

OH N Boc 82

88% 86%

O OH

PMP

THF, 20 C, 30 min 76%

N PG

PG = Boc Cbz LiOH, H2O2 THF/H2O, 20 C, 1 h 92%

i) O3 ,CH2Cl2 -78 C, 10 min then DMS, 2 h

OH

Boc N LiAlH4 (4 equiv) Q

PMP

MeCN

N PG

PMP

PMP

OMe N Cbz 81

Figure 13.32  Divergent removal of AQ directing group.

X=F Br I

(-)-paroxetine 86% (HCI salt, 12% over 8 steps) 81% (HCI salt, 12% over 8 steps)

X=F Br I

90 79% 91 60% 92 71%

X=F Br I

87 95% 88 94% 89 91%

99.2% ee >98% ee >98% ee

Figure 13.33  Stereocontrolled synthesis of bromine and iodine analogies of antidepressant (−)-paroxetine from N-Boc-(R)-nipecotic acid.

589

590

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

13.3.2  Amine-Linked C3 Directing Groups DGs have been installed on saturated heterocycles through amine functionalities. In 2016 Maes demonstrated the Pd-catalyzed functionalization of piperidines at C5 using a C3 amine-linked picolinamide DG [52]. In this case, the formation of a five-membered palladacycle (93) dictates the regio and stereospecific γ-cis-arylation with respect to the amine (Figure 13.34). Solvent-free conditions, the addition of 25 mol% 2,6-dimethylbenzoic acid and increasing aryl iodide loading to up to six equivalents were key to improving reactivity. Heteroaryl iodides such as an N-protected 3-indoyl and a 2-CF3-substitued pyridinyl moiety could be installed at C5 in over 70% yields. An N-Boc protecting group was found to perform best, by more efficiently preventing undesired intramolecular coordination of the ring nitrogen to palladium compared to N-methylene-linked protecting groups (94). The picolinoyl moiety could be easily removed by basic hydrolysis with retention of dr to liberate the free amine for further derivatisation. Besides arylation, examples of γ-alkynylation directed by the picolinamide group have been reported by Balaraman on linear and carbocyclic amides, including an example of chiral C3-substituted Boc-protected piperidine (95) [53]. Using Pd(OAc)2 catalyst and (triisopropylsilyl)ethynyl bromide as coupling partner, the corresponding C5-alkynylated piperidine 96 could be obtained in 82% yield (Figure 13.34B). Picolinamide-directed olefination of piperidines and tetrahydropyrans with 1,1-dibromoalkenes was demonstrated by Maes with high regio- and cis-diastereoselectivity, managing to overcome the competing debromination of products to alkynes (Figure 13.34C) [54]. Interestingly, in the presence of CuI catalyst in the same pot, the bromo-alkenylated products (97) were shown to undergo intramolecular amidation with the picolinamide NH, generating bridged bicyclic normorphan scaffolds (98). Maulide expanded the applicability of the picolinamide DG in the C(sp3)–H functionalization of quinuclidine [55]. Commercially available 3-aminoquinuclidine 99 was used as a substrate for the regioselective C(8) arylation, which occurs on the adjacent bridge (Figure 13.35A). A number of electron-rich and electron-deficient para- and ortho- substituted aryl iodides were comparable, including successful implementation of the methodology in the synthesis of an estradiol-quinuclidine derivative with 100. Starting from enantiomerically pure (–)-p-methoxyphenyl arylated substrate 101 obtained by functionalizing (–)-3-aminoquinuclidine, the total synthesis of natural (–)-quinine could be achieved over 10 steps (Figure 13.35B). Moreover, an analogous synthetic route could be applied starting from the antipode quinuclidine, allowing the first total synthesis of unnatural (+)-quinine for which no biological activity studies were available at the time. Both natural (−)- and unnatural (+)-quinine as well as two C3 arylated analogues obtained via this methodology exhibited potential therapeutic applications as antimalarials. As the structural diversity generated by directed γ-functionalization methodologies relies on the availability of feedstocks with suitable functionalization handles for the installation of the DG, new protocols for accessing building blocks containing the picolinamide motif have attracted attention. Starting from commercially available 3-piperidone 102, an atom-economical route involving a 4-component Ugi reaction was developed by Polindara-García to access 3,3-disubstituted piperidines 103 bearing the picolinamide group (Figure 13.36) [56]. With the bidentate auxiliary now present at a congested quaternary center, γ-arylation proceeded in good to excellent yields under microwave irradiation, with significantly shorter reaction times required compared to previous conventional heating procedures. Moreover, the choice of carboxylic acid used in the Ugi adduct formation allowed flexibility with respect to the nature of the DG introduced, and 1-isoquinoline and 2-piperazine carboxamide (105 and 106, respectively) led to arylation yields comparable to the picolinyl-derived auxiliary 103, whereas 3-methylpiperidine led to a significant decrease in the arylation yield (107) (Figure 13.36A). Notably, no γ,γ-diarylation was observed with any DG. Finally, deprotection of the tBu group originating from the isocyanate component was demonstrated to the corresponding amide (108), which could then be further converted to the carboxylic acid (109) via nitrosylation with t-butyl nitrite, followed by hydrolysis. Deprotection of the picolinamide was achieved by zinc/HCl treatment, with the Boc-protected primary amine 110 isolated (Figure 13.36C). Transient DGs (TDGs) have also been employed as means to effect C–H functionalization on tetrahydropyran derivatives [57]. TDGs represent advantageous strategy for C–H functionalization since they avoid steps for the preinstallation and cleavage of a DG from the target product [58]. One of the common ways to introduce TDG is the reversible formation of an imine which can coordinate palladium(II). The Yu group demonstrated that a wide scope of alkyl amines could be heteroarylated with palladium-catalyst in presence of hydroxybenzaldehydes as TDG and additional 2-pyridone ligand L4 acting as acetate surrogate [57]. In this case, a six-membered palladium(II) chelate 111 formed with the transient imine species promoted γ-C(sp3)−H activation via a five-membered palladium cycle, providing the C5-arylated tetrahydro-2H-pyran3-amine derivative 112 in 51% yield as a single cis-isomer (Figure 13.37).

13.3  Heterocycle Functionalization with C3 Directing Groups

C-H activation with pd

undesired : heteroatom-Pd coordination

Pd(OAc)2 (10 mol%) Cul (20 mol%) K2CO3 (3 equiv) PivOK (0.2 equiv) 1,2-DCE (0.13 M) 120 °C, 24 h

Figure 13.34  A. C5-Arylation of N-Boc-3-(picolinoylamino)piperidines B. C5-alkynylation of of N-Boc-3-(picolinoylamino)piperidines. C. γ-Alkenylation and synthesis of bridged bicyclic scaffolds by orthogonal palladium-copper tandem catalysis.

591

592

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position H

2-picolinic acid H2N

DGHN H

N

H

Ar )

H N

N

DMF (0.3 M) 100 C, 16 h

99 A. Aryl iodide scope

H

R= H 4-CF3 4-O Me I 3,4,5-3OMe 4-Me 4-Cl 4-F 4-CO2Me 2-O Me

R

DGHN

2

H

90% 88% 94% 94% 84% 79% 43% 57% 49%

MeO

OMe

H

100 26%

O

N

DG

I

B. Conversion of arylated quinuclidine to (−)-quinine OMe O

N

N

8 steps

O Me

LiHMDS, thenTi(O-i-Pr), MsNHNH2

O

H N O

H

1.

MeO

N

N 101

2. LiAlH4

N OH N (-)-quinine 5.4% overall yield

Figure 13.35  A. C(sp3)-H arylation on quinuclidine using an amine-linked picolinamide directing group; B. Conversion of quinuclidine to (–)-quinine.

13.3.3  Alcohol-Linked C3 Directing Groups The possibility of promoting β-C–H functionalization using alcohol-linked DGs was recently demonstrated by Yu who employed a salicylaldehyde oxime auxiliary, installed by one-pot reaction of oxaziridine and dichlorosalicylaldehyde derivatives with the corresponding alcohol [59]. Similar to the transient directed activation, regioselectivity is explained by the formation of a six-membered palladium(II) chelate with the DG, which would undergo preferential formation of a [6,5] bicyclic palladacycle by metal insertion into the β-C–H bond. By contrast, a five-membered Pd chelate formed with pyruvic acid-derived DGs had previously been found to dictate [5,6]-fused palladacycle formation and activation of the γ-C–H bond, thus demonstrating flexibility in reversing site-selectivity in these types of functionalization reactions [60]. Addition of the 2-pyridone ligand L5 was crucial for reactivity and selectivity, having previously been demonstrated to lower the transition state energy for the activation of secondary and tertiary-C-H bonds [61], and here suggested to stabilise the corresponding [6,5]-bicyclic palladacycle intermediate. The protocol enabled arylation of azetidine, pyrrolidine, and piperidine substrates with ethyl-4-iodobenzoate (Figure 13.38). N-TFA azetidine bearing the DG at C3 led to a mixture of mono- and di- arylation in moderate yields. Also employing the DG at C3, cis-C4 arylated pyrrolidine could be isolated in high dr, whereas in the presence of DG at C4, C3 arylated piperidine was obtained in good yield, but modest diastereoselectivity. The same drop in diastereoselectivity was observed for five- and six-membered carbocycles. Removal of the DG by Pd/C-catalyzed hydrogenation was demonstrated on a complex substrate synthesised en route to the antihyperglycemic drug englitazone.

13.3  Heterocycle Functionalization with C3 Directing Groups O

R OH

R

InCl (2 mol%)

3 NH3 F3CCH2OH (0.3 M) O

N C

HN

O O

70 °C, 24 h

N Boc 102

Ar I (1.5 equiv) Pd(OAc)2 (10 mol%) Ag2CO3 (1.5 equiv) 2,6-diMeC6H3COOH (25 mol%) toluene, MW, 3 h, 110 °C

R Ar

N NH-tBu Boc 103

HN

O O

N NH-tBu Boc 104

A.Selected directing group scope N

HN

N

N

O O

HN

N O O

HN

N NH-tBu Boc 107 25%

N NH-tBu Boc 106 79%

N NH-tBu Boc 105 85%

O O

B.Selected aryliodide scope

N HN

N

Ts N

O 2N O O

N Br

HN

N NH-tBu Boc

O O

HN N

N NH-tBu Boc

95%

O O

NH-tBu N Boc

50%

75%

C.Deprotection of tBu and/or directing group

N

Ar

HN

N O O

a) BF3 CH3COOH (0.4 M) rt, 48 h 67%

Ar

HN

N O O

b) t BuONO (3.0 equiv) CH3COOH (0.33 M) MW, 75 °C, 1h 70%

Ar

HN

O O

N HN Boc

N NH 2 Boc

N OH Boc

104

108

109

N

Ar

HN

N HN Boc 104

O O

a) Zn (15 equiv), HCl (12 M) THF-H2O, rt, 1.5 h b) Boc2O , Et N (2.0 equiv) 3 CH2Cl2, rt, 18 h 70% (over 2 steps)

Ar

NHBoc O N HN Boc 110

Figure 13.36  Ugi adduct formation for synthesis of 3,3-disubstituted piperidines containing the picolinamide directing group, followed by subsequent γ-arylation. Yields representative of the arylation step.

593

594

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

NH2

O

N

CF3

Cl

Pd(OAc)2 (10 mol%), TDG (20 mol%), Ligand (50 mol%)

2 M HCl, THF

3 equiv AgTFA, HFIP, 10 equiv H2O, 150 C, 12 h

10 M NaOH, Boc2O 51%

N 112

via :

O Pd O H N

NHBoc

O

Cl

Cl

N

O

Cl TDG

F3 C N L4

OH

OH

O 111

Figure 13.37  C5-arylation of tetrahydropyran directed by a C3-transient directing group. CO 2Me DG

O n

H N TFA

Ar I (3 equiv) Pd(OAc) 2 (10 mol%) ligan d (40 mol%) AgTFA (1.5 equiv)

DG

Cl

Cl

O n

N TFA

HFIP, 100 C, 12 h n = 0: 45% (mono:di = 6.5:1), >20:1 dr 1: 42%, >20:1 dr 2: 61%, 2:1 dr

N

F3C

OH DG

NO 2 N H

O

L5

Figure 13.38  C3-arylation of aza-heterocycles.

13.4  Heterocycle Functionalization with a C4 Directing Group Functionalization of saturated heterocycles in the presence of a C4 DG has not been extensively studied, despite a few of isolated examples. In particular, positioning the DG at C4 on six-membered rings poses additional selectivity challenges, due to neighbouring pairs of equivalent methylene groups, in mono-/di-arylation as well as diastereoselectivity. The first single example of C4-directed C3-arylation was reported by Yu in 2012 on a tetrahydropyran substrate using the N-arylamide Yu-Wasa auxiliary 113, being the first example of C–H functionalization on any heterocycle (Figure 13.39A) [62]. The methodology was developed to achieve Pd(II)-catalyzed β-arylation of cyclic and acyclic compounds in the presence of a weakly coordinating DG, the key to promoting C–H activation being the combination between L6 ligand containing the 2,6-dialkoxypyridine motif and the electron deficient auxiliary. Later, Yu reported the alkynylation of C(sp3)–H bonds with TIPS-alkynyl bromides using the same N-arylamide DG 113 [63]. A palladium(0)/palladium(II) manifold was in operation in this case and no co-oxidant was required. The adamantane-substituted NHC ligand L7 was found to be most suitable based on similar electronic and steric grounds as before, in addition to providing the best stereoselectivity. The reaction scope again included tetrahydro-2H-pyran-4-carboxamide, which now afforded the C3-monoalkynylated product 114 as a single cis diastereomer in 61% yield (Figure 13.39B). Alternatively, C(sp3)–H arylation promoted by NHC ligands and directed by Yu’s monodentate N-arylamide 113 was achieved, through a palladium(II)/palladium(IV) mechanism [25]. N-TFA and N-Troc piperidines bearing the C4 DG could be arylated in 52–57% yields, albeit with low or no diastereoselectivity (Figure 13.39C). Low diastereoselectivity was seen on tetrahydropyran, whereas the saturated six-membered cyclic sulfone exhibited a higher cis selectivity, due to preferential reaction of the cis-axial C–H bond given the bulkiness of the sulfonyl moiety. Bull and coworkers recently reported the stereoselective mono-functionalization of unbiased N-Boc piperidines and tetrahydropyrans bearing a C4 DG [64] (Figure 13.40). Of the DGs trialed, aminoquinoline amide promoted the highest

13.4  Heterocycle Functionalization with a C4 Directing Group

A.

H DG

O

4-MeC6H4 I (3 equiv) Pd(TFA)2 (10 mol%) L6 (20 mol%) Ag2CO3 (2 equiv) K2HPO4 (1.2 equiv)

DG

O

hexane, 110 °C, 55%

O

p-Tol

H

H DG

O

Br (2 equiv) TIPS [Pd(allyl)Cl]2 (5 mol%) L7 (20 mol%) Cs2CO3(2 equiv), 85 °C, Et2O, N2, 61%

H

F

F

CF 3 F 113

cis/trans = 6:1 B.

F

H N

H

DG

H DG

O

N

114

cis only

O i-Bu

L6

TIPS 4-MeC6H4

C. DG X

H

N

p-Tol

57% cis/trans = 3:2

Ad N DG

100 °C, hexafluorobenzene

DG TFA

I (3 equiv)

Pd(TFA)2 (10 mol%) L8 (20 mol%) Ag2CO3 (2 equiv)

DG Troc

N

p-Tol

52% cis/trans = 1:1

X

O

p-Tol

L7

37% cis/trans = 1:1

DG O2 S

Ad

BF4

p-Tol DG

N

p-Tol

62% cis/trans = 7:1

t-Bu N

N t-Bu

Cl L8

Figure 13.39  A. β-Arylation of tetrahydropyran. B. β-Alkynylation of tetrahydropyran. C. C3-Arylation of saturated heterocycles bearing C4-DG.

reactivity. Room temperature conditions were sufficient for reaction to occur and to observe selective mono-cis-arylation in moderate yields in the presence of mesityl carboxylic acid additive (MesCOOH) and halogenated solvents. DoE (design of experiment) optimization enabled fine tuning the reaction conditions to achieve high selectivity for the cis diastereomer (>85:15) and good isolated yields of single diastereoisomers. The optimized protocol employed temperatures below 50°C to prevent overreaction, this being the first example of saturated heterocycle functionalization at an unactivated position that did not require temperatures in excess of 100°C. Electron-rich and electron-poor aryl iodides were tolerated, as well as heteroarenes and a vinyl iodide. Epimerization to the corresponding trans isomers (116) could be promoted in the same pot as the arylation, by the addition of DBU to the crude reaction mixture, followed by heating to 110°C, to directly access trans-arylated products as single diastereomers. Divergent DG removal enabled unveiling a range of polar functionalities (nitrile, amide, carboxylic acid and primary alcohol), providing access to screening fragments with a variety of binding elements and diversification points in maximum 4 synthetic steps from common feedstocks. Sheppard reported an example of an amine-linked DG to achieve C2 arylation [65]. Sheppard also modified the structure of the picolinamide DG and used elevated temperatures to achieve high yield and selectivity for the γ-arylation. Building on works that have primarily been conducted on unsubstituted scaffolds, recently extensive studies have been conducted on the C–H functionalization of glycosides [66, 67]. More details are presented in Chapter 16 of this book. In particular, Messaoudi addressed the challenge of achieving highly regio- and stereoselective C(sp3)−H functionalization at the anomeric position [66]. The picolinamide DG was installed at C3 (with the sugar numbering C4 with respect to the tetrahydropyran) and preferred an axial conformation in 117, hence dictating the activation of the axial anomeric C–H bond through a five-membered palladium-cycle (Figure 13.41). The final product 118 adopted the more favored 1C4 conformation in which the aryl group occupied the equatorial position. This method provides access to naturally occurring C–aryl glycosides of biological interest. The same group developed a powerful C3 trans-selective arylation of glycoside analogues with a C2 aminoquinoline amide DGs [68].

595

596

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

C, 24 h

Figure 13.40  C3 arylation of piperidines and tetrahydropyrans with a C4 AQ DG to generate either mono-cis or mono-trans products as single diastereoisomers and an overview of fragments synthesised by AQ removal .a Reaction conditions: Ar–I (3 equiv), Ag2CO3 (1.5 equiv), MesCOOH (15 mol%), PhCF3 (0.5 M), 50°C. b Each of the four possible alkenylation products were isolated: mono-cis (21%), mono-trans (20%), di-cis-cis (21%), and di-cis-trans (19%) alkenylated piperidines. Alkene (E)-geometry preserved in all cases.

A. Directed functionalization at the anomeric position AcO AcO

O HN

(Het)Ar I (3 equiv) Pd(OAc)2 (10 mol%) Ag2CO3 (3 equiv)

AcO

117

AcO

O

(O Ac)3 O

t-AmOH, 120 °C, 4 h

DG

via

NH

N

(Het)Ar DG

O

H

Pd II L N

DG 118

Figure 13.41  Highly regio- and stereoselective functionalization of glycosides at the anomeric position using a picolinamide directing group.

13.4  Heterocycle Functionalization with a C4 Directing Group

In 2020 Gaunt reported the regioselective palladium-catalyzed γ-C–H functionalization of tertiary alkylamines with boronic acids [69], whereby β-hydride elimination could be suppressed by employing N-acetyl tert-leucine as a ligand. A broad reaction scope was demonstrated with respect to the tertiary alkylamine, for instance piperidines bearing N(1) methyl or butyl groups could be grown by appending a phenyl group to the linear alkyl, reacting at the γ-C–H bond. On the other hand, using 4-(N,N-dimethyl)-methane amine-substituted tetrahydropyran 119 afforded the C3 arylated derivative 120 in 34% yield and 10:1 dr (Figure 13.42). Interestingly, the preferred conformation of the 5,6-trans-fused palladacycle intermediate led to predominant trans arylation, with a promising 64% ee. Gaunt has expanded C(sp3)–H functionalization reactions directed by native amine functional groups to other aliphatic substrates [70–74]. Overcoming the strongly coordinating nature of amines and the potential of bis(amine) metal complex formation, strategies based on the control of sterics and hydrogen bonding interactions successfully achieved regioselective activation of methylene C–H bonds. This included the amine-directed carbonylation of β-methylene bonds in the presence of potentially more reactive β-methyl C(sp3)–H bonds in α-tertiary amines such as 121 [70]. The selectivity in this case was argued to be driven by the steric bulk of the tertiary alkylamine motif which orientates palladium complex formation away from the quaternary center. The initial CO insertion step preceding the C–H activation leads to formation of a five-membered palladium-cycle instead of a four-membered intermediate [74]. Moreover, hydrogen bonding between the inserted carbonyl and a second palladium-coordinating amine NH (122) was proposed to lock the molecule geometry in a conformation dictating functionalization on the ring (Figure 13.43). When saturated tetrahydropyrans and N-Ts piperidines containing a methyl-substituted amine at C4 were employed, lactamisation at the adjacent C3 ring position was observed in high yields and syn selectivity (73–75%). C4-disubstituted six-membered thioethers were also tolerated, affording the corresponding syn lactam in 84% yield. A carbonylation example is also reported on an N-Ts piperidine bearing a C3 α-tertiary amine motif, in this case occurring with exclusive selectivity for the less sterically hindered C4 position.

Me Me

Pd(OAc)2 (10 mol% ) N-Ac-L-tLeu (25 mol%)

O

N

(HO)2B

H

Me

Ag2CO3 (2.5 equ iv) benzoquinone (2 equiv) NMP, 50 °C 3 4%

O

Me N

119

Me Me

Me O

Me

N O

120 anti/syn = 10:1 64% ee

via O Me Pd H N H Me O H

Figure 13.42  C3-Arylation of tetrahydropyran with a C4 pendant tertiary alkylamine group.

v ia

H3C H 3C PivO N H

Pd(OAc)2 (10 mol%), CO(1 atm) Xantphos (10 mol%)

X 121 X = O, NTs, S PivO

H3C N

O

AgOAc (3 equiv) Benzoquinone (2 equiv) PhMe, 80 °C

PivO

H 3C N

H

H3C PivO N

O

O

O

H

H

Pd N

X trisubstituted β-lactam

O

PivO

N

H3C N

H

R

H-bonding locks conformation

H O CH3

R = Me or Et

PivO

122

O O

H

N CH 3 O TIPS

H

O

N Ts

S

N Ts

75%

73%

84%

59%

from C(3) disubstituted piperidine sole C(4) functionalization product

Figure 13.43  Regioselective amine-directed carbonylation of saturated six-membered heterocycles to form β-lactams. Proposed restricted conformation in the intermediate leading to ring methylene functionalization.

597

598

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

13.5  Transannular Heterocycle Functionalization with N-linked Directing Groups In 2016, Sanford reported the nitrogen-directed transannular C–H functionalization of alicyclic amine cores, proceeding through a boat-like intermediate (123) [75]. To overcome the low population of the boat conformer, the test substrate of 3-azabicyclo[3.1.0]hexane 124 was carefully chosen to more easily adopt the boat-like geometry, and to offer cyclopropyl C–H bonds (Figure 13.44). An amide derived from p-CF3C6F4 aniline was designed to be appended to the ring nitrogen via a short alkyl group to provide a bidentate DG to facilitate the five-membered palladacycle formation. Transannular C–H arylation of model substrate 124 was carried out with various aryl iodides, including those bearing unprotected alcohol and aldehyde moieties. Good yields were observed in the presence of heteroaryl iodides with electron-withdrawing substituents and a phenylalanine derivative could also be installed. An example of C3 substituted 3-azabicyclo[3.1.0]hexane could be arylated at C4 in the presence of high excess (20 equiv) of aryl iodide to demonstrate late-stage functionalization of amitifadine (125–128). The removal of the fluoroimide coordinating group was achieved by reductive cleavage with samarium diiodide (SmI2), followed by N-pivaloyl protection of the free amine. With few modifications, the conditions were applied to piperidine example 129: higher temperatures were required to facilitate chair-boat isomerisation, and solvent-free conditions increased the yield (Figure 13.45). Further yield enhancement was based on the identification of a series of aminal side-products, some of which could be converged to the desired product by introducing a NaBH4 workup. Sanford later developed a second-generation catalyst system for the transannular functionalization, expanding to more challenging substrates [76]. The addition of 5 mol% pyridine- or quinoline-carboxylate ligands such as L9 prevented early reaction stalling by rescuing a proportion of catalyst that becomes reversibly deactivated. Arylation yields were significantly increased compared to the first-generation conditions, with most notable improvements seen on 6-oxo-azabicyclo[3.1.1]heptane 130, azabicyclo[3.2.1]octane 131 (undergoing diarylation), and vareniclidine 132 scaffolds (Figure 13.45). Reactions proceeded at lower temperature (100°C compared to 150°C) and in the presence of 3 equivalents of aryl iodide, rather than a large excess. Interestingly, a β-hydride elimination was observed when applying the conditions to a homotropane substrate, leading to a formal transannular C–H dehydrogenation (133). Employing high equivalents of coupling partner and more elevated temperatures (140°C) rendered the second-generation conditions applicable to the generation of 3β-arylated tropanes (134a-f). A.

[Pd] N R

H

[Pd]

H [Pd] N R

N R

Ar

I

N

Ar

R

123 B. H

NHC 7F7 N

Pd(OAc) (10 mol%) Ar I (1 or 2 equiv) CsOPiv(3 equiv)

Ar

NHC7F7 N

t-AmylOH, N2, 130 °C, 18 h

O

124

C7F 7 N [Pd] N

O

Aryl iodide scope

Amitifadine analogues CF 3

R F

R R = 4-OMe 4-Br 2-F 3-OH 4-CHO

75% 70% 68% 57% 86% CO2Me

CF 3 69%

N NHC 7F7

68%

O

N

R= N Boc

NHAc 63%

O

H 4-OMe 4-Br 3,5-diCF3

125 126 127 128

74% 51% Cl 35% 37%

Cl

59%

Figure 13.44  A. Conceptual approach for transannular C–H arylation of via a bicyclo[2.2.1]metallacycle intermediate B. Transannular C–H arylation of 3-azabicyclo[3.1.0]hexane core.

13.5  Transannular Heterocycle Functionalization with N-linked Directing Groups First-generation H

Ar I (30 equiv) Pd(OAc) 2(10 mol%) CsOPiv (3 equiv)

NHC7F 7 N 129

Second generation

Ar I (3 equiv) L9 (5 mol%) Pd(OAc) 2 (10 mol%) CsOPiv (3equiv) t-AmylOH 100 °C, 18 h

NHC7F7 N

O

NHC 7F7 N

t-AmylOH or neat 150 °C, 18 h

O

H

Ar

Ar

O

NHC 7F7 N

O

Selected scope (second generation) Ph

Ph

DG N

DG N

O

130 76%

90% Ph

DG N

DG N

N

N

Ph

O

PMP

132 81% (vareniclidine analogue)

N

DG

O

O

OMe

R

O

R = 3-OMe 4-Br 3,4-diOMe 3,5-diCF 3

134a 134b 134c 134d

Ar =

134e 42%

C6F 5

134f

Me

60% 46% 47% 44%

54%

O 131 64% N

133 50%

DG

N

O

OH L9 (5 mol%)

Figure 13.45  Scope of transannular C–H arylation of alicyclic amines using the 2nd generation catalyst system developed by Sanford. First-generation conditions shown for comparison.

Mechanistic investigations confirmed the role of the ligand in catalyst regeneration. Initial deuteration studies identified C−H activation as the turnover limiting step, however, similar KIE values (kH/kD) obtained with and without ligand (3.2–3.3) eliminated the possibility of ligand involvement in this step. Product inhibition was also discarded as a cause of low yield, whereas analysis of the black precipitate formed under first-generation catalytic conditions revealed palladium deactivation. The latter could be reversed by ligand addition, albeit not completely, suggesting an irreversible catalyst decomposition was also in operation. In 2019, Sanford provided more evidence on the mechanism of transannular arylation by isolating the key palladium intermediate complexes (Figure 13.46) [77]. It had previously been argued that bidentate coordination of palladium to both the ring heteroatom and the appended amide dictated the selective γ-activation despite the availability of the more acidic α position. To gain more insights on this, palladium(II) bidentate complexes 135 and 136 (derived from 3-azabicyclo[3.1.0] hexane and 2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine, respectively) were isolated in the presence of pyridine as a stabilizing ligand and their square-planar structures were confirmed by X-ray crystallography. Interestingly, 136 was isolated as a single isomer in which both Pd and the pivalate ligand thought to be involved in the CMD (concerted metalationdeprotonation) step were positioned in close proximity of the C4–H bond. 135 also exhibited a conformation compatible with γ-activation, but was separated from a 1:1 mixture with another isomer bearing the cyclopropane ring oriented away from palladium. Both 135 and 136 underwent transannular arylation with phenyl iodide in 98% and 72%, respectively. Isolation of the strained bicyclo[2.2.1] palladacycle precursor proved elusive, especially with DFT calculations suggesting a high thermodynamic penalty (>20 kcal/mol) for its formation. Instead, deuteration experiments on 135 and 136 showed high levels of H/D exchange at the γ position even in the absence of the pivalate ligand and at temperatures as low as 40°C, demonstrating the reversibility of the C–H activation step, as well as its occurrence prior to oxidative addition.

599

600

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

N II

PivO Pd

NC 7F7 O

N 135

PhI (3 equiv) CsOPiv (3 equiv) t-AmylOH, 100 °C, 18h

Ph

NC 7F7

then N2H4 EtOAc 25 °C, 10 min, 98%

N

O via

137

O H

Pd II NC 7F7

N PivO Pd H N

O

II

NC 7F7 O

136

PhI (3 equiv) CsOPiv (3 equiv) t-AmylOH, 100 °C,18 h

N C 7 F7 N

Ph

N

then N2H4 EtOAc 25 °C, 10 min, 72%

R

O

139

O

138

Figure 13.46  Transannular arylation of isolated square-planar palladium(II)-complexes 1-A and 1-B.

Recognizing the variety of 3-dimensional saturated heterocycles that can be generated, Sanford adapted the transannular arylation methodology to the synthesis of fragment-based drug discovery (FBDD) compounds [78]. Aiming to maintain a low molecular weight across the library, 3-azabicyclo[3.1.0] hexane 124 was selected, being subjected to γ-arylation with coupling partners that included heteroaromatics such as pyridines and quinolines, as well as free phenols (Figure 13.47). Microwaveassisted conditions led to a decrease in the reaction time from 18 h to less than 1 h, without significant drop in the arylation yield. The fluoroimide removal procedure was modified to use TPPA in place of the highly toxic HMPA for SmI2 reduction, and to isolate the free amines of general structure 140 (Figure 13.48). Alternatively, to prevent degradation of sensitive functionalities (such as pyridines) by SmI2, activation of the ring nitrogen was performed by treatment with neat acetyl chloride under microwave irradiation to give N-acetyl products (141). Fragment property analysis revealed appropriate physicochemical properties and rule-of-three compliancy, together with a high degree of 3-dimensionality for the compounds in the collection. Using Sanford’s first generation arylation conditions as a starting point, Dandapani aimed to expand the scope of heteroaryl iodides in this type of transannular functionalization [79]. A rapid medium-throughput ligand screening on the 3-azabicyclo[3.1.0] hexane model substrate 124, identified 6-methylpicolinic acid L10 as the ligand increasing the yield. The optimized conditions allowed the installation of heterocycles containing up to 3 heteroatoms, some of the new examples including pyrazine, quinazoline, pyrazole and thiazole rings (Figure 13.49). Additionally, the

H

NHC 7F7 N

O

Pd(OAc)2 (10 mol%) (Het)Ar-I (2-3 equiv) CsOPiv (3 equiv)

(Het)Ar NHC 7F7 N

t-AmylOH, N2, 180 C (MW), 30-50 min

O

124 R

R = H, 8 3% 4-F , 4 2 % 4-C F 3, 60 % 4-C l, 3 4% 4-M e , 79 % 4-E t , 7 1 % 4-O M e, 7 2% 4-O H, 1 2% 3-O H, 5 6%

N

49%

N

Cl

18%

N

42%

24% N

N

F

45%

N

65%

Figure 13.47  Transannular C–H arylation of 3-azabicyclo[3.1.0]hexane core for the synthesis of a fragment collection.

13.5  Transannular Heterocycle Functionalization with N-linked Directing Groups (Het)Ar NHC 7F7 N

SmI2, TPPA MeOH, NEt3 rt, 3 h

O

(Het)Ar

(Het)Ar = 4-Ph 4-F-Ph 4-CF3-Ph 4-Me-Ph 4-Et-Ph 3-OH-Ph 3-Pyr

AcCl neat 150 °C (MW), 3 h

(Het)Ar

34% 48% 44% 49% 39% 38% 0%

(Het)Ar =

NH

N N N P N O

140

O

141

TPPA

4-Ph 4-Cl-Ph 4-Pyr 3-Pyr 2-Pyr 2-F-5-Pyr 2-Cl-5-Pyr 2-Cl-3-Pyr 6-quinoline

25% 25% 0% 19% 19% 0% 19% 12% 23%

Figure 13.48  Removal of DG via reductive cleavage with SmI2 and acylative dealkylation.

(Het) Ar I (2-3 equiv) Pd( OAc)2 (30 mol%) ligand (10 mol %) CsOPiv (3 equiv)

H N

O N

t-AmylOH, air 1 30 ° C, 8-18 h

DG

124

NHC7F7

(Het)Ar

X N

one heteroatom

R

N

S 36%

60%

R

N

N N

N S

60% R= H Br 41% CO2Me 24%

N

N

28%

N N Me

N

N N

DG

Ph

N N

DG

N

O 43%

N 35%

N

N

N

O

R = H 40% CF3 41%

18%

N

CF3

N

56%

N

N N

DG

NC

N 56%

CO2H

L10

N

61%

N

S

DG

N

X = H 54% Me 59% two heteroatoms

DG

N

DG

Ph 142 24%

33%

57% DG removal

N

i. SmI2, DMPU MeOH, Et3N

N N

DG

ii. TsCl 52% over 2 steps

N

N N

Ts

143

Figure 13.49  Transannular C–H heteroarylation of the 3-azabicyclo[3.1.0]hexane core and of other alkylamines, including a spircocylic example. DG removal to obtain tosyl-protected amines.

601

602

13  C–H Functionalization of Saturated Heterocycles Beyond the C2 Position

method was applied on various bridged bicyclic amine cores, being even compatible with spirocyclic amine substrate 142 to give regioselective diarylation at the two corresponding C4 positions in the presence of iodobenzene. Significant efforts were then made to achieve DG removal. The SmI2 promoted alkyl cleavage developed by Sanford was modified to generate N-tosylated 143, with higher yields seen upon addition of N,N′-dimethylpropyleneurea (DMPU). Very recently, Sanford reported a strategy for transannular activation of alicyclic amines with formation of new bonds to halogens, oxygen, nitrogen, boron, and sulfur [80]. Compared to aryl iodides, alternative electrophiles that would promote formation of bonds other than C–C are kinetically more reactive oxidants and would increase the rate of α-functionalization, diminishing the γ-activation pathway. To prevent this issue, the authors opted to preassemble a reactive complex between the palladium(II) catalyst and the substrate (144, Figure 13.50). Subjecting the complex to NBS treatment resulted in formation of a single γ-brominated regio- and stereoisomer 144, which suggested palladium reaction at the most proximal Cγ–H bond, followed by C-Br bond formation with retention of configuration on treatment with NBS. Although a stochiometric amount of palladium was required, a wide variety of electrophiles were tolerated, such that borylations, thiolations, acetylations, and halogenations could be performed with high regiocontrol (Figure 13.51). This therefore constitutes a promising protocol for expedient late-stage γ-functionalization of alicyclic amines, since the only alternative routes to these complex structures involve multistep de novo syntheses

O

N DG

L C7F7 O PdII N N O

Pd(OAc)2 (1 equiv) DMSO (1 equiv)

Br N DG

NBS (1 equiv) 100 °C, 18 h

MeCN 100 °C, 1 h

144

145

Figure 13.50  2-Step one-pot procedure for transannular Cγ-bromination, including substrate pre-complexation to palladium.

SPh N DG BPin N DG

N DG B 2Pin2

O

S 2Ph 2

57% N N DG 38% I

O

O Ac

75%

N O Bz

NCI

Pd complex

53%

OAc I AcO Mes

F N DG

(PhO2S)2−N−F NCS

44% Cl

N DG 24%

N DG 50%

Figure 13.51  Expanded scope of coupling partners for the γ-functionalization of alicyclic amines.

References

13.6  Conclusions This chapter describes detailed recent studies on the C(sp3)–H functionalization of saturated N-heterocycles at unactivated positions beyond C2, i.e. remote from the heteroatom. These have been utilised to provide direct access to pharmaceutically relevant compounds that would otherwise require lengthy de-novo syntheses. Valuable and robust strategies that overcome the low reactivity of unactivated C–H methylene bonds are now available for the synthesis of four-, five-, and six-membered nitrogen heterocycles, as well as larger and bicyclic systems, with fewer methods also developed on oxygen heterocycles. To date, all examples are using palladium-catalysis and high stereocontrol is achieved on most substrate classes, with a pronounced preference for cis-functionalization seen due to formation of a thermodynamically preferred five-membered palladium-cycle intermediates. Defined substitution patterns can be prepared based on the position and the nature of the DG. The DG, typically bidentate DGs, have been studied at C2, C3, or C4, and linked through carboxylic acids, amines and alcohols, using commonly available feedstocks. Several of these methods have been applied in the syntheses of medicinally-relevant molecules, many providing shorter alternative routes to the isolation of lead candidates and marketed drug analogues. Several important challenges remain in the field. Its notable that all examples discussed in this chapter employ palladium catalysis, with relatively few examples of earth-abundant metals, such as iron, cobalt, or nickel being used to effect the functionalization of unactivated C(sp3)-H bonds in general to date. The majority of the C(sp3)–H functionalization protocols at unactivated heterocyclic positions still rely on temperatures in excess of 100°C, and there remains a general requirement for strongly coordinating groups. These can present difficulties in their removal, particularly on sterically hindered substrates. A few studies have achieved functionalization in the presence of weakly coordinating auxiliaries, as well as polar functionalities native to aliphatic feedstocks, however, additional specific substrate features are often required to influence regioselectivity. In this sense, further developments in C–H functionalization mediated by weak coordination, or through the use of TDGs, for example, would be advantageous to expediently generate molecular complexity without the need for installation or removal of directed groups. The range of bond formations achieved to date on these substrates is still relatively limited, with most work on arylation. The potential to achieve such transformations in a late-stage in the presence of other functionality, is a challenge across the field of C-H functionalization. Also importantly, there are no reports to date of enantioselective functionalization at positions remote from the heteroatom in saturated heterocycles; enantioselective desymmetrisation of symmetrical substrates would be of high value, for example, in medicinal chemistry. Nonetheless, the facile and selective functionalization methodologies described here on important pharmacophores open huge opportunities in drug discovery programs, by potentially accelerating access to analogues in hit optimization stages, and also enabling late-stage functionalization of complex scaffolds, with exciting potential for further developments.

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A steric tethering approach enables palladium-catalysed C–H activation of primary amino alcohols. Nature Chemistry 7 (12): 1009–1016. 72 a) McNally, A., Haffemayer, B., Collins, B. S. L., and Gaunt, M. J. (2014). Palladium-catalysed C–H activation of aliphatic amines to give strained nitrogen heterocycles. Nature 510 (7503): 129–133. b) Smalley, A.P., Cuthbertson, J.D., and Gaunt, M.J. (2017). Palladium-catalyzed enantioselective C–H activation of aliphatic amines using chiral anionic BINOLphosphoric acid ligands. Journal of the American Chemical Society 139 (4): 1412–1415. c) Rodrigalvarez, J., Reeve, L.A., Miró, J., and Gaunt, M.J. (2022). Pd(II)-catalyzed enantioselective C(sp3)–H arylation of cyclopropanes and cyclobutanes guided by tertiary alkylamines. Journal of the American Chemical Society 144 (9): 3939–3948. 73 He, C. and Gaunt, M. J. (2015). Ligand-enabled catalytic C–H arylation of aliphatic amines by a four-membered-ring cyclopalladation pathway. Angewandte Chemie - International Edition 54 (52): 15840–15844. 74 Willcox, D., Chappell, B. G. N., Hogg, K. F., Calleja, J., Smalley, A. P., and Gaunt, M. J. A. (2016). General catalytic β-C–H carbonylation of aliphatic amines to β-lactams. Science 354 (6314): 851–857. 75 Topczewski, J. J., Cabrera, P. J., Saper, N. I., and Sanford, M. S. (2016). Palladium-catalysed transannular C-H functionalization of alicyclic amines. Nature 531 (7593): 220–224. 76 Cabrera, P. J., Lee, M., and Sanford, M. S. (2018). Second-generation palladium catalyst system for transannular C-H functionalization of azabicycloalkanes. Journal of the American Chemical Society 140 (16): 5599–5606. 77 Aguilera, E. Y. and Sanford, M. S. (2019). Model complexes for the palladium-catalyzed transannular C–H functionalization of alicyclic amines. Organometallics 38 (1): 138–142. 78 Lee, M., Adams, A., Cox, P. B., and Sanford, M. S. (2019). Access to 3D alicyclic amine-containing fragments through transannular C–H arylation. Synlett 30 (4): 417–422. 79 Li, Z., Dechantsreiter, M., and Dandapani, S. (2020). Systematic investigation of the scope of transannular C-H heteroarylation of cyclic secondary amines for synthetic application in medicinal chemistry. The Journal of Organic Chemistry 85 (10): 6747–6760. 80 Sanford, M. and Aguilera, E. Y. (2021). Palladium-mediated Cγ−H functionalization of alicyclic amines. Angewandte Chemie International Edition 60 (20): 11227–11230.

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14 Asymmetric Functionalization of C–H Bonds in Heterocycles Olena Kuleshova and Laurean Ilies RIKEN Center for Sustainable Resource Science, 2–1 Hirosawa, Wako, Saitama, Japan

14.1

Introduction

As discussed throughout this book, heterocyclic compounds are unique scaffolds for drug discovery [1], and therefore valuable synthetic targets. Taking into account that more than 50% of the commercially available drugs are chiral molecules [2], it comes to no surprise that the enantioselective synthesis of chiral heterocyclic compounds has received much attention as a potential key enabler for drug discovery and production. While there has been much effort dedicated to the invention of a plethora of synthetic strategies, the creation of a chiral center through transition metal-catalyzed C–H bond activation [3] has the potential to maximize step- and atom-efficiency, while minimizing waste. Moreover, the C–H activation strategy enables late-stage functionalization of complex molecules [4] and introduction of chiral center(s) down-stream the synthetic route has advantages (e.g. minimizing racemization). However, enantioselective C–H activation is still in its infancy [5] and significant challenges still need to be addressed. For example, the typically harsh reaction conditions required for the C–H activation step are often incompatible with the fine energetic requirements in the enantioselectivity-determining step. Two reaction patterns have been explored to date: enantioselective C–H activation, where the selectivity is generated during the C–H activation step, and C–H activation followed by enantioselective functionalization, in which case the selectivity is generated in a different step than the C–H activation step. This classification assumes that mechanistic studies have been performed to reveal the enantioselectivity-determining step; in reality, the mechanistic aspects are ambiguous or speculative in many cases. Reactions where the selectivity is determined at the C–H cleavage step include C(sp3)–H activation, C(sp2)–H activation of metallocenes, and desymmetrization of prochiral substrates. The second type of enantioselective reactions include non-selective C–H activation followed by migratory insertion (typically selectivity-generating), and reactions where the selectivity-determining step is ambiguous (e.g. atropo-enantioselective reactions). The C–H activation step can be classified into inner-sphere C–H activation, where a transition metal cleaves the C–H bond to generate a C–metal bond, and more broadly defined C–H cleavage that proceeds through outer-sphere mechanisms such as carbene insertion and electron transfer. There are also examples where the reaction mechanism is unclear and the above classification becomes ambiguous. The present review will discuss mainly reactions that proceed through inner-sphere C–H activation mechanisms and other reactions such as carbene insertion will be just briefly mentioned. Reactions of acidic C–H bonds and reactions using a stoichiometric amount of a strong base are not covered here. According to the purpose of this book, only transition metal catalysis, and only compounds where the C–H bond of the heterocycle itself is functionalized, will be described.

14.2 Enantioselective C–H Activation 14.2.1 Activation of C(sp2)–H Bonds Attempts to activate a C–H bond in an enantioselective manner using a transition metal catalyst have been known since the 2000s. An early, pioneering report from the Murai group in 2004 [6] described a rhodium-catalyzed, pyridine-directed alkylation at 120°C to give an axially-chiral compound with low enantioselectivity. The next milestone in enantioselective Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

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14  Asymmetric Functionalization of C–H Bonds in Heterocycles

activation came from the Yu group, who in 2008 reported a palladium-catalyzed enantioselective C(sp2)–H and C(sp3)–H activation [7]. Although this report did not describe heterocyclic C–H bond activation, it set the stage for the dominance of palladium catalysis for enantioselective C–H activation, as described below. One year later, the Cramer group reported a palladium-catalyzed enantioselective C–H activation of arenes using a TADDOL-based phosphoramidite chiral ligand [8]. While mostly arene substrates were explored, one example of thiophene activation was also reported to proceed with high yield and enantioselectivity (Scheme 14.1, top). The authors proposed that the alkenyl triflate oxidatively adds a palladium(0) species, and, after ligand exchange with acetate that functions as a base to assist the C–H cleavage step, the key activation step takes place; the resulting palladacycle finally undergoes reductive elimination to give the tricyclic product. The exact role of the ligand in discriminating the two thiophene C–H site for achieving enantioselectivity was not detailed. The authors further expanded this strategy to the synthesis of dibenzazepinones, and again one example of a thiophene substrate was described (Scheme 14.1, bottom) [9]. A similar palladium/phosphoramidite chiral catalyst oxidatively added an aryl bromide, followed by intramolecular enantioselective C–H bond activation of a thiophene’s C–H bond to selectively generate an unconventional eight-membered palladacycle. The Cramer group also used chiral phosphordiamidite ligands for palladium-catalyzed cyclative C–H functionalization to produce isoindole congeners with high yield and enantioselectivity [10].

Scheme 14.1  Intramolecular enantioselective C–H functionalization of thiophene catalyzed by palladium/chiral phosphoramidite.

The Yu group reported a palladium-catalyzed enantioselective iodination of protected diarylmethylamines using an amino acid derivative as the chiral ligand (Scheme 14.2) [11]. Aryl substrates were mainly investigated, but one example of a heteroaromatic substrate, protected bis(thien-2-yl)methylamine, was reported to react with moderate yield and high enantioselectivity. The authors established the absolute stereochemistry only for the product of the iodination of bis(2tolyl)methylamine, and based a proposed model for stereoselectivity that in which the triflamide group weakly coordinates the palladium/N-benzylleucine catalyst.

14.2  Enantioselective C–H Activation

Yu, 2013

I 2 (3 equiv) Pd(OAc) 2 (10 mol%) Bz-Leu-OH (40 mol%)

NHTf H

H S

CsOAc (3 equiv) Na2CO3 (3 equiv) DMSO (15 equiv) tAmylOH, 30 °C

S

O H

H Pd

N

S

51% yield 99% ee CO2H

S

H

N OAc H

HN

O

Ph Bz-Leu-OH

Th S

O

S

CF3 OCs

O

O

NHTf H

I

Ph

Scheme 14.2  Enantioselective iodination of protected bis(thien-2-yl)methylamine catalyzed by palladium/chiral amino acid derivative.

14.2.2  Activation of C(sp3)–H Bonds The activation of a C–H bond at a prochiral C(sp3) site is a straightforward method to create a chiral center; however, the transition metal-catalyzed activation of a C(sp3)–H bond [12] is more challenging than that of a C(sp2)–H because of the lack of stabilizing interactions between the alkyl group and the metal catalyst. Pioneering work on enantioselective C(sp3)–H activation using a palladium catalyst and a chiral amino acid ligand was reported by Yu in 2008 [7]. They mainly investigated the enantioselective activation of aromatic substrates and demonstrated only one example of the desymmetrization of methyl groups with low enantioselectivity, highlighting the challenges associated with C(sp3)–H activation. Based on an initial study on palladium/chiral NHC-catalyzed enantioselective cyclative C(sp3)–H activation [13], the Kündig group investigated the cyclization of 6-membered heterocycles containing sulfur, oxygen, and nitrogen atoms (Scheme 14.3) [14]. The reactions required high temperatures, but proceeded with high yield and enantioselectivity. The Kündig, 2013 Br H

H S

N CO 2Me Pd/L

[Pd(η 3-cinnamyl)Cl]2 (2.5 mol%) ligand (5 mol%)

Pd N

O

*L

O

CsOPiv OMe

N H CO2Me 69% yield 87% ee

H

tBu O

*L

Pd S

NBoc

N H CO 2Me 93% yield* 95% ee

tBu

ligand

OH H S

N CO2Me

CO2Me

O

N I–

tBu

Pd O H H

S

N

92% yield 93% ee

N

H

tBu

N H CO2Me

Cs2CO3 (1.5 equiv) CsOPiv (1 equiv) mesitylene, 160 °C

L*

Br

S

H

H

NCbz

N H CO2Me 55% yield* 91% ee

*catalyst (10 mol%), 140 °C.

Scheme 14.3  Enantioselective cyclization of 6-membered heterocycles catalyzed by palladium/chiral NHC.

611

612

14  Asymmetric Functionalization of C–H Bonds in Heterocycles

authors investigated the reaction mechanism by experiment and calculation and proposed that the C–H activation step proceeds through a concerted metalation-deprotonation (CMD) mechanism, which is not turnover-limiting, but enantioselectivity-determining. Computational analysis suggested that the steric repulsion between the benzene ring of the substrate and the naphthyl group on the NHC ligand (replaced with an ortho-tolyl group in the computational model) destabilizes the transition state for the formation of the (S)-product. The Cramer group reported a similar reaction using triflates as the starting material, and a palladium catalyst in combination with a chiral phosphine ligand and a carboxylic acid additive [15]. Only one heterocyclic substrate was reported, a tetrahydropyran derivative that reacted with high yield and selectivity (Scheme 14.4). Cramer, 2012 [(η 3-cinnamyl)PdCp] (10 mol%) ligand (20 mol%) O

OTf H H N Tf

iPr O

H

N H acid (10 mol%) Na3PO 4 (1.2 equiv) Tf 75% yield cumene, 135 °C 97:3 e.r.

P CyO

OCy

iPr

ligand CO2H

O acid

Scheme 14.4  Enantioselective cyclization of a tetrahydropyran derivative catalyzed by palladium/chiral phosphine.

The Clot and Baudoin groups used a chiral binepine ligand for the palladium-catalyzed intramolecular reaction of an aryl bromide with the C–H bond of a six-member heterocycle to produce chiral fused cyclopentanes [16]. Two heterocyclic substrates were reported to react with high yield and high enantio- and diastereoselectivity (Scheme 14.5). Computational studies suggested that the (R,R) enantiomer was favored by stabilizing weak interactions between the phosphine and the base/substrate in the transition state. Clot, Baudoin, 2015 X NC

Br H

X Pd2dba3 (5 mol%) ligand (15 mol%) Cs2CO 3 (2 equiv) X DMSO, 100 °C

–

NC H

BF4

P

H oTol

H

X X = NBoc 97% yield 97.5:2.5 e.r. 80% yield X=O 95:5 e.r.

ligand

Scheme 14.5  Enantioselective cyclization of 6-membered heterocycles catalyzed by palladium/chiral binepine.

An intermolecular enantioselective arylation of heterocyclic thioamides was developed by the Yu group using palladium catalysis and a chiral phosphoric acid ligand (Scheme 14.6) [17]. A variety of three- to seven-membered cyclic thioamides could be arylated with aryl boronic acids in good yield and enantioselectivity. The reaction tolerated boronic acids bearing sensitive functionality such as chloride, bromide, aldehyde, ketone, ester, and nitrile. The thioamide group could be deprotected in two steps to produce the corresponding Boc-protected cyclic amines. The Glorius group reported the enantioselective arylation of similar heterocyclic thioamides with aryl iodides, by using a rhodium catalyst and a monodentate phosphonite ligand (Scheme 14.7) [18]. A variety of substrates such as tetrahydroquinolines, piperidines, piperazines, azetidines, pyrrolidines, and azepanes reacted well under these conditions.

14.2  Enantioselective C–H Activation

Yu, 2017 Ar

PhB(OH)2 (2 equiv) Pd2dba3 (5 mol%) H ligand (12 mol%) N

H

R

S

1,4-benzoquinone (1.2 equiv) KHCO3 (2 equiv) tAmylOH, 65 °C

R = 2,4,6-tris(iPr)C6H2

N R

R

S

R

O OH

N

N

Ph R

R S 86% yield 98:2 e.r.

Ph S

77% yield 94:6 e.r.

Br

N

N

N

71% yield 97:3 e.r.

P

Ar ligand (Ar = 9-anthracenyl)

94% yield 98:2 e.r. (gram scale)

S

H 3C

S

O

S

mono: 40%, 98:2 e.r. + di: 13%, 98:3 e.r. 62% yield (tr ans/cis>20:1) 95.5:4.5 e.r.

R

O

Ph

Ph

N

Ph

H N

R

S 50% yield 93:7 e.r.

R

O S 71% yield 97:3 e.r.

H

CH3

N R

S

47% yield 87.5:12.5 e.r.

Scheme 14.6  Enantioselective arylation of heterocyclic thioamides catalyzed by palladium/ chiral phosphoric acid.

Scheme 14.7  Enantioselective arylation of heterocyclic thioamides catalyzed by rhodium/chiral phosphonite.

The Shibata group reported the intermolecular enantioselective alkylation of γ-butyrolactams with activated alkenes in the presence of a cationic rhodium catalyst and a BINAP derivative (Scheme 14.8) [19]. Electron-deficient alkenes such as acrylates, vinyl sulfonates, vinyl phospohonates, and styrene derivatives reacted with good yield and enantioselectivity. The authors also demonstrated the removal of the pyridine directing group (DG) and applied the method for the enantioselective synthesis of pyrrolam A, a bicyclic lactam natural product. The Xu group reported that chiral bidentate boryl ligands in combination with an iridium catalyst enable regio- and enatioselective borylation of azacyclic compounds (Scheme 14.9) [20]. A variety of substrates, including three- to nine-membered azacycles,

613

614

14  Asymmetric Functionalization of C–H Bonds in Heterocycles

Shibata, 2015 N N

CO 2Et

CO2Et (4 equiv) H H [Ir(cod) 2]BF4 (10 mol%) ligand (10 mol%) dioxane, reflux

O

SO2Ph N

N

H

P(pTol)2 P(pTol)2

N

85% yield O 94% ee (1 gram scale)

ligand

P(O)(OEt) 2 N

H N

N

H

N

H

H N

N

N

O 70% yield 82% ee

C6F5

Ph

O

O 69% yield 94% ee

O 85% yield 82% ee

82% yield 76% ee

(8 equiv of alkene was used for these reactions)

Scheme 14.8  Enantioselective alkylation of γ-butyrolactams with activated alkenes catalyzed by palladium/chiral diphosphine.

fused bi- and tricyclic compounds and derivatives of natural products such as α-D-galactopyranose and estradiol were borylated with good yield and selectivity. The boroester group is a useful synthetic handle, and the authors demonstrated its transformation into a variety of organic groups with retention of stereochemistry. The authors proposed an active species having an iridium:ligand ratio of 1:1, and proposed a model for the transition state to rationalize the enantioselectivity and regioselectivity. Xu, 2020

N

B2pin2 (1.5 equiv) [IrCl(cod)]2 (0.5 mol%) L1-3 (1 mol%)

NEt 2

H

H O (1.16 g)

H

H Bpin

N

Ir O

Et 2N

N N

N

B

N

R2

Bpin B N N

N

R1 SiMe2

O

88% yield 81% ee (L2)

Scheme 14.9 

Ph N

H Bpin

N Et2N

61% yield 94% ee (L1) *B2pin2 (3 equiv)

O

iPr2N

86% yield 90% ee (L2)

Bpin

N O

86% yield 84% ee (L3)

Me H

O O

O

NEt2

Bpin O

TBSO

O

iPr 2N

84% yield 95% ee

H

Cl

O

Bpin

Bpin O

S

Ph Ph L1: R1 = R2 = Et L2: R1 = Cy; R2 = H L3: R1 = tBu; R2 = H

N

NEt2

Ph

Ph Ph

N

hexane, 70 °C

O

H N

iPr 2N 73% yield >95:5 d.r. (L2)

H

Bpin

N

O

Bpin O 62% yield 97:3 d.r. (L1)

NEt 2

14.3  C–H Activation Followed by Enantioselective Functionalization

Although our discussion focuses on functionalization based on inner-sphere C–H activation, enantioselective carbene insertion reactions deserve a mention because of their synthetic value, as typically high yields and selectivities are achieved for a variety of substrates in both intra- and intermolecular fashion. These reactions have been extensively reviewed elsewhere [21] and only one example is illustrated here. Davies reported [22] that a pyrrolidine derivative can be functionalized with a diazoacetate derivative in high yield, enantioselectivity, diastereoselectivity, and regioselectivity, in the presence of 2 mol% of a chiral prolinate dirodium complex at 50°C (Scheme 14.10).

Davies, 2003 H H

Boc N

OTBDPS

+ MeO2C

2,2-dimethylbutane, 50 °C N2

Br

(2 equiv)

MeO 2C

Rh2(S-DOSP)4 (2 mol%)

O

Br

Rh

H

Boc N

OTBDPS

85% yield 95% ee, >94% de

N O Rh SO 2Ar 4

Ar = C12 H25C6H4 Rh2(S-DOSP) 4

Scheme 14.10  An example of enantioselective carbene insertion into a pyrrolidine derivative catalyzed by a chiral prolinate dirodium complex.

14.3  C–H Activation Followed by Enantioselective Functionalization By contrast with the metal-catalyzed C–H activation at prochiral centers of heterocycles, chirality is generated at a step other than C–H cleavage in the case of C–H activation followed by enantioselective functionalization. In this subchapter, the enantioselective functionalization of C(sp2)–H bonds is divided into two categories: intramolecular and intermolecular reactions. The most investigated heterocyclic substrates for these reactions to date are indole and congeners. The C–H activation step is catalyzed by a variety of metals including rhodium, iridium, palladium, platinum, cobalt, nickel, scandium, and zirconium.

14.3.1  Intramolecular Coupling 14.3.1.1  Indoles and Pyrroles as Coupling Partners

The first highly enantioselective reaction involving arene C–H activation was reported in 2004 by Ellman and Bergman [23]. Fused aromatics were obtained from ketimines with high yield (up to 96%) and enantioselectivity, using Rh(I)/ BINOL-derived phosphoramidate as a catalyst and imine as a DG. Only one example of heterocycle functionalization was described: an N-alkylindole was transformed into a tricyclic compound in 90% yield and 70% ee (Scheme 14.11, the compound at the bottom right). Four years later, the authors reported a follow-up study on the reaction mechanism and also expanded the reaction scope [24]. The synthetic value of the reaction was demonstrated by the synthesis of a PKC inhibitor: the key reaction intermediate, a dihydropyrroloindole congener, was obtained after acidic hydrolysis in 61% yield and 90% ee, and then was converted to the PKC inhibitor in a few steps [25]. In 2015, the Shibata group reported an iridium-catalyzed enantioselective alkylation of N-substituted indoles (Scheme 14.12) [26]. The regioselective activation at the C2 position was controlled by the presence of an aroyl DG at the C3 site. Depending on the nature of alkene, different catalysts were utilized. Thus, for terminal alkenes ligand 1 (SEGPHOS) was effective, whereas for alkyl-substituted alkenes ligand 2 was superior. Interestingly, the reaction typically gave 5-exocyclized products, but the 6-endo-cyclized product formed for phenyl-substituted alkenes. The next milestone in enantioselective intramolecular alkylation of indoles and pyrroles was accomplished by the Cramer group (Scheme 14.13) [27]. The reaction proceeded under mild conditions and did not require a DG. The key factor

615

616

14  Asymmetric Functionalization of C–H Bonds in Heterocycles

Bergman, Ellman, 2004, 2006, 2008 RN

RN

R2 H

N

R2

[Rh(coe) 2Cl] 2 (10 mol%) ligand (10 mol%) toluene, 50–90 °C R

1

via

R2

N

R1

NR

H [Rh]

O

N

O

P NHR3 ligand

R1 H N

Examples: O

O

BnN

O

H

NHPh

N

N

N

OMe

OMe 90% yield, 70% ee

PKC inhibitor

61% yield, 90% ee

Scheme 14.11  Enantioselective intramolecular alkylation of indoles catalyzed by Rh(I)/BINOL-derived phosphoramidate.

Shibata, 2015 O

R1

Ar R2

xylene, 120 °C

R2

N

R1

Ar = 4-MeOC6H4

Ar

O [Ir] N

R2 R1

N

[Ir]

ligand 1

6-endo with ligand 2 98% yield, 84% ee O [Ir]

H R1

N

Ph H

ligand 2

O

PPh2

PR2

O

PPh2

PR2

O

N

or

R2 O

Ph

Ar

O

H

Ar

or

5-exo with ligand 1 8 examples: 61–98% yield, 33-98% ee Ar

R1

O

Ar

ligand 1 or 2 (10 mol%)

H

N

O

[Ir(cod)2]OTf (10 mol%)

R = 3,5-xylyl

Scheme 14.12  Ir(I)-catalyzed intramolecular enantioselective alkylation of indole derivatives at the C2 site.

to achieve high yield and selectivity was a newly-developed chiral carbene ligand having bulky flanking groups. endoCyclization was the predominant reaction pathway. In 2006, the Widenhoefer group reported the enantioselective hydroarylation of 2-(4-pentenyl)indoles to produce tetrahydrocarbazoles, catalyzed by a platinum/chiral diphosphine complex (Scheme 14.14) [28]. They found that the reaction enantioselectivity increases with the increasing size of the aryl groups on the phosphine, and with the increasing donicity/

14.3  C–H Activation Followed by Enantioselective Functionalization

R N

H n

Ni(cod) 2 (5 mol%) R ligand (5.5 mol%) R2 NaOtBu (25 mol%)

R2 N

R1

PhCF3, 60 °C

R1

n

Ar Ar Ar = 3,5-tBu-C6H3 ligand

23 examples 57–92% yield, up to 97.5:2.5 e.r.

MeO 2C

N

92% yield, 96:4 e.r.

N

OBn

84% yield, 97:3 e.r.

4

N

N

Examples:

N

Ar

Ar

Cramer, 2019

HCl

N

MeO2C

72% yield, 89:11 e.r.

Scheme 14.13  Directing-group-free alkylation of indoles and pyrroles catalyzed by Ni(0)/carbene.

Widenhoefer, 2006 H R2 R2

R1

N R

n

PtCl2 (10 mol%) ligand (10 mol%) 1 AgOTf (10 mol%) R methanol, 60 °C

R2 MeO MeO

R2 N R 12 examples 56-96% yield up to 90% ee

n

PAr 2 PAr 2

ligand Ar = 2,5-di-tBu-4-MeOC6H2

Scheme 14.14  Hydroarylation of 2-(4-pentenyl)indoles catalyzed by a platinum/chiral diphosphine complex.

polarity of the solvent. Thus, the optimal solvent was found to be methanol, and a chiral bulky diphosphine was used as the ligand to achieve up to 90% ee. The Oestreich group reported an enantioselective Fujiwara-Moritani cyclization of indoles or pyrrole derivatives, catalyzed by palladium(II) and PyOx or NicOx ligands, in the presence of benzoquinone or dioxygen as an oxidant (Scheme 14.15). [29, 30] A ligand having a nicotine core (NicOx) showed higher catalytic turnover compared with PyOx (73% vs 39%) due to the presence of the carboxyl group at C3, making these ligands more effective for oxidative C–C bond formation. Although the reaction enantioselectivity and yield were moderate, this type of annulation to create five-membered rings was unprecedented. Attempts to construct six-membered ring analogues resulted in either no conversion or no stereoinduction.

Oestreich, 2008 Pd(OAc)2 (10 mol%) PyOx or NicOx (30 mol%) 1,4-benzoquinone N

H

tAmylOH/AcOH, 80 °C

N

R

PyOx: 39% yield, 43% ee NicOx: 73% yield, 44% ee Oestreich, 2010 H N

Pd(OAc)2 (10 mol%) NicOx (30 mol%) O2

O

N N

iPr PyOx: R = H NicOx: R = CO2Me N

tAmylOH/AcOH, 80 °C indole: 38% yield, 51% ee pyrrole: 47% yield, 59% ee

Scheme 14.15  Palladium/PyOx or NicOx-catalyzed enantioselective Fujiwara-Moritani cyclization.

617

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14  Asymmetric Functionalization of C–H Bonds in Heterocycles

14.3.1.2  Imidazoles and Benzoimidazoles as Coupling Partners

The enantioselective cyclization of imidazole derivatives via C–H activation using a rhodium(I)/chiral biphosphine ligand catalytic system was reported by Bergman, Ellman, and coauthors [31]. The phosphine ligand depicted in Scheme 14.16 performed the best among twelve different phosphorus-containing ligands. Thus, it was speculated that an electron-rich phosphine ligand that may undergo partial dissociation from the catalytic site is important for high reactivity. Although the reaction proceeded at elevated temperature, good to high enantioselectivity was achieved (53–98% ee). Bergman, Ellman, 2009 R R1 R2

N

[Rh(coe)2Cl]2 (10 mol%) ligand (19 mol%) R1 H

THF, 135–175 °C

N

R2

R N

P

10 examples 71–92% yield 53–98% ee

N

P

tBu tBu ligand

Examples: Ph

N

N

N

N Ph 90% yield 95% ee

CF3

N

N

MeO

81% yield 71% ee

92% yield 81% ee

Scheme 14.16  Asymmetric intramolecular alkylation of imidazoles using a Rh(I)/chiral biphosphine ligand catalytic system.

In 2018, the Ye group reported a bimetallic nickel/aluminum-catalyzed intramolecular functionalization of imidazoles [32]. A TADDOL-based phosphine oxide ligand is able to bind two metals and the substrate simultaneously, and this property was used to control the enantioselective and exo-selective addition of the alkene. Bi- and polycyclic imidazoles were obtained in high yields (65–98%), with selectivity up to 99% ee (Scheme 14.17). Ye, 2018 N Ar

R1 Ni(cod)2 (5 mol%) ligand (5 mol%) R2 AlMe3 (20 mol%) toluene, 100 °C

H

N

R1 N Ar

Ni

Ar N Ar

N

R1 R2

Ar O

O

P

O

O H

O Ar

Ar 30 examples 65–98% yield, 80–99% ee Ar = 3,5-tBu2C6H3 ligand

R2

O P * Al O O

N

Scheme 14.17  Asymmetric exo-selective intramolecular functionalization of imidazoles using Ni−Al/chiral phosphine oxide.

The Hou group developed a synthesis of bicyclic imidazoles featuring β-all-carbon-substituted quaternary stereocenters in high yields (92−96%) and with high enantioselectivity (up to 97:3 e.r., Scheme 14.18) [33]. The coupling was catalyzed by a chiral half-sandwich scandium catalyst. 14.3.1.3  Pyridines and Pyridones as Coupling Partners

The development of methods to access enantiopure pyridines is still in its infancy. In 2019, the Shi group reported the first enantioselective intramolecular functionalization of pyridines at C3 and C4 sites (Scheme 14.19). [34] The driving force of the transformation is a bulky carbene ligand and a bulky MAD additive, which coordinates to pyridine’s nitrogen, thus pushing the alkene close to the nickel center and facilitating the formation of a η2-alkene nickel complex. Chiral partially saturated quinolines and isoquinolines were obtained in high yields (up to 99%) and selectivities (up to 99% ee) by this approach.

14.3  C–H Activation Followed by Enantioselective Functionalization

Scheme 14.18  Asymmetric exo-selective intramolecular coupling of imidazoles with 1,1-disubstituted alkenes. Shi, 2019

R2

Ni(cod)2 (5 mol%) ligand (5 mol%) MAD (1.2 equiv)

Py

R1 NaOt Bu (10 mol%) CPME, 80 °C

ligand R N

R1 R2

Py

34 examples up to 99% yield up to 99% ee

N R HCl

Ph

Ph

R=

Scheme 14.19  Enantioselective intramolecular functionalization of pyridines by Ni(0)/carbene catalysis.

The Cramer group described the synthesis of annulated pyridones via intramolecular alkylation at the C6 site [35]. The enantiomeric variant of this reaction was limited to two examples and there was poor selectivity (57% ee). Several years later, the same group published a comprehensive study [36]. They designed a chiral bulky N-heterocyclic carbene ligand that enabled synthesis of chiral annulated pyridones in excellent yields and selectivity, under mild reaction conditions (Scheme 14.20). Cramer, 2018

O

R1

O

R2

N

O

O

N

ligand

R1 R2 Ni(cod)2 (10 mol%) 20 examples 42–90% yield, up to 99:1 e.r. ligand (11 mol%) MAD (40 mol%) O

H

X

T = 40 °C

N H

R3

X T = 60 °C

N

R N

Ar

N R

Ar

R=

O R3 Ar = 3,5-xylyl 7 examples 51–91% yield, up to 99:1 e.r.

Scheme 14.20  Asymmetric synthesis of annulated pyridones catalyzed by Ni(0)/sterically hindered N-heterocyclic carbene.

14.3.2  Intermolecular Coupling 14.3.2.1  Directing-Group-Free C–H Functionalization

In 2013, the Hartwig group reported [37] a highly enantioselective C2 alkylation of heterocycles in the presence of an unprotected C3 site, without the requirement of a DG. They used [Ir(coe)2Cl]2 in combination with a chiral diphosphine ligand, and strained alkenes such as norbornene and norbornadiene as the coupling partner (Scheme 14.21). A large variety of

619

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14  Asymmetric Functionalization of C–H Bonds in Heterocycles

Hartwig, 2013

R X

H +

O

[Ir(coe)2Cl2] (1.5 mol%) ligand (3 mol%) R X

THF, 100 °C

H

P Ir Het P Cl

O

PAr 2

O

PAr 2

O

H

P Ir P Cl

ligand

Het Ar =

tBu OMe tBu

Examples: N H 61% yield, 93% ee

O 86% yield, 72% ee

Cl

S

98% yield, 97% ee

N H 90% yield, 96% ee

Scheme 14.21  Ir(I)-catalyzed intermolecular enantioselective hydroarylation of heteroarenes.

heteroarenes including pyrroles, furans, thiophenes, and indoles reacted with up to 98% yield and 99% ee. Mechanistic studies revealed that oxidative addition of the C–H bond to iridium(I) occurs quickly and unselectively, even at room temperature, and the turnover-limiting step is the insertion of the alkene into the Ir−C bond. The reaction scope was limited to strained alkenes. In 2014, the Hou group reported a comprehensive study on the enantioselective synthesis of alkylated pyridines (Scheme 14.22) [38]. The reaction was catalyzed by a cationic scandium alkyl complex bearing a Cp* ligand with a chiral binaphthyl backbone. To prevent unproductive coordination of the ligand to the substrate, a bulky substituent was introduced ortho to nitrogen, enabling the reaction to proceed in moderate to excellent yields (63–98%) with selectivities up to 98:2 e.r. The first report on enantioselective functionalization of pyridines using an ansa zirconocene complex was published in 1994 by the Jordan group [39], albeit with low yield and selectivity (64% yield, 58% ee).

Scheme 14.22  Scandium-catalyzed enantioselective addition of pyridines to alkenes.

In 2015, Sigman and coworkers reported an intermolecular enantioselective Heck reaction between indoles and trisubstituted alkenes (Scheme 14.23) [40]. Ligand optimization studies guided by computational analysis revealed that an increase of negative charge on the oxazoline’s nitrogen on the ligand correlates with higher enantioselectivity. Accordingly, a newly designed ligand bearing a fluorine atom gave the highest selectivity. The reaction could proceed via a Heck-type or Wacker-type mechanism; experimental evidence suggests that the Heck-type mechanism is more plausible.

14.3  C–H Activation Followed by Enantioselective Functionalization

Sigman, 2015 H

OH R1 +

N

R3

n

R2

Examples:

Pd(MeCN)2(OTs)2 (10 mol%) ligand (20 mol%) CuSO4 (7 mol%)

R2 R

n

DMF, 3A MS, O2, rt

N

Me

Me

O

O H

H

69% yield, 93:7 e.r.

O N 2-naphtyl ligand

N

N

N

F N

Me

O

H

R3

(CH2)2iPr

(CH2)2Ph

nBu

O

1

63% yield, 93:7 e.r.

72% yield, 92:8 e.r.

Scheme 14.23  Intermolecular enantioselective Heck reaction between indoles and trisubstituted alkenes.

14.3.2.2  Functionalization Assisted by a Directing Group at the C3 Site

The intermolecular enantioselective C–H functionalization of indoles was studied by the Yoshikai group (Scheme 14.24) [41]. The reaction was catalyzed by cobalt and a chiral phosphoramidite ligand, and an imine DG on indole was required. The reaction proceeded in moderate to good yields, and good enantioselectivity. However, the functional group tolerance was limited due to the use of a reactive Grignard reagent. Yoshikai, 2015 PMP N H + N Boc

R1

Co(acac)3 or CoBr 2 (10 mol%) ligand (20 mol%) Me3SiCH2MgCl (75 mol%) H+ Ar

CHO

THF, rt

R1

N Boc

O Ar

O

P N(iPr)2 ligand

Examples: R1 = H, Ar = 4-ClC6H4, 69% yield, 78% ee R1 = F, Ar = 4-MeOC6H4, 72% yield, 87% ee

Scheme 14.24  Cobalt-catalyzed intermolecular enantioselective C–H functionalization of indoles.

The enantioselective functionalization of furan and thiophene at the C3 position was reported by Nishimura and coworkers in 2016 [42]. The reaction was catalyzed by a hydroxoiridium/chiral diene complex and proceeded with high selectivity (Scheme 14.25). Nishimura, 2016 O

O

NHMes +

H X X = O, S

OBu

toluene, 70 °C

O

O

NMes

NMes X

[Ir] H

NHMes

[Ir(OH)ligand]2 (5 mol%)

X OBu X = O: 70% yield, 93% ee X = S: 77% yield, 96% ee F

F F

[Ir] H

F

X BuO

ligand

Scheme 14.25  Asymmetric alkylation of N-mesitylhetaryl-3-carboxamide.

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14  Asymmetric Functionalization of C–H Bonds in Heterocycles

A comprehensive study on thiophene alkylation was disclosed later by Bower and coworkers (Scheme 14.26) [43]. They designed diphosphite ligands that enabled the alkylation of aryl and heteroaryl anilides with high enantiomeric excess. An interesting feature of the ligand is its modular structure, having two units that can be modified separately to tailor the catalyst activity for any class of substrates. For example, ligand 1 was efficient for the alkylation of aryl anilides, but ligand 2 bearing a ferrocene unit was found to be optimal for the reaction of thiophene anilides. By using the optimized ligands, the alkylated products were obtained with high enantioselectivity, and the diastereoselective hydroarylation of complex molecules such as steroid derivatives also proceeded well. Mechanistic studies suggested that reductive elimination is the irreversible turnover-limiting step. Bower, 2018 iPr O

iPr

NH

+ H

[Ir(cod)2]OTf (10 mol%) O ligand 2 (5 mol%)

R2

dioxane, 100 °C

S R

NH R2

S

Examples: H iPr N

R1

O

R O

O R P O

O O P

1

R

Fe

R1

R

iPr

P O O

O O P O R

7 examples: 71–83% yield up to 98:2 e.r. branched:linear > 25:1

S Ph 77% yield 97.5:2.5 e.r. H N

O

S

R1 R

1

R = tBu ligand 1

R = mesityl ligand 2

78% yield 19:1 d.r.

O

Scheme 14.26  Enantioselective hydroheteroarylation of styrenes with thienyl anilide.

In 2013, the Cramer group disclosed a rhodium(I)-catalyzed annulation of aryl ketimines with a racemic mixture of allenes to prepare enantiopure indenylamines (Scheme 14.27) [44]. The C−H activation was governed by the ketimine DG and the acidity of the C−H bond, and therefore electron-deficient substrates were the most reactive. After the C–H activation step, coordination and migratory insertion of the allene may lead to eight stereoisomers. The authors succeeded in controlling the selectivity by making the isomerization of diastereomeric allyl rhodium intermediates occur faster than Cramer, 2013

N

+

Ph

via:

N

H

Ph

DYKAT

NH2

N

fast Bu

N

NH2 Pr

Pr Bu 62% yield, 99:1 e.r. 91% yield, 99:1 e.r. >20:1 E/ Z 15:1 E/ Z

H

N [Rh]

Ph

N

Bu toluene, 120 °C

C

Ph

NH2

[{Rh(cod)OH}2] (2.5 mol%) (R)-BINAP (6 mol%)

NH

[Rh]

N

N

Ph Bu

72% yield, 98:2 e.r.

Scheme 14.27  Synthesis of enantiopure indenylamines using dynamic kinetic transformation.

14.3  C–H Activation Followed by Enantioselective Functionalization

the subsequent addition across the imine moiety, and thus dynamic kinetic transformation (DYKAT) becomes feasible. Chiral (R)-BINAP was used as a chiral auxiliary. Three annulated pyridines were obtained by this method with good yield and excellent stereo- and diastereoselectivity. 14.3.2.3  Functionalization Assisted by a Directing Group at the N-1 Site

In 2018, the Ackerman group reported a Cp*Co(III)-catalyzed enantioselective alkylation at the C2 site of indoles under mild conditions, with tolerance of a range of substituents including hydroxyl and halides (Scheme 14.28) [45]. The high enantioselectivity was enabled by a newly designed chiral carboxylic acid, and the yield was improved by the use of the acid additive Amberlyst 15. The regioselectivity was controlled by the 5-methylpyridine DG on nitrogen. The authors studied the reaction mechanism by experiment and computation, and they concluded that the reaction proceeds via a reversible insertion/selective protonation mechanism. Higher selectivities were obtained for activated alkenes, but unactivated alkenes were also reactive with reduced selectivity. The synthetic utility of the method was demonstrated by the removal of the 5-methylpyridine group, without depreciation of the enantiomeric excess.

Scheme 14.28  Enantioselective alkylation at C2 site of 1-(5-methyl-pyridin-2-yl)indoles.

In 2020, the group of Matsunaga and Yoshino, the pioneers of Cp*Co(III)-catalyzed C–H activation, reported the 1,4-addition of indole to maleimides in the presence of Cp*Co(III) and a BINOL-derived chiral carboxylic acid (Scheme 14.29). [46] Mechanistic investigations suggested that the reaction proceeds via a reversible insertion/selective protodemetallation mechanism. In 2019, the C2 functionalization of indoles was expanded to 7-azabenzonorbornadienes as coupling partners (Scheme 14.30) [47]. A Cp*Rh(I) catalyst bearing a chiral binaphthyl backbone, developed by Cramer and coworkers in 2012 [48], Matsunaga, Yoshino, 2020 R

O H N Pym

N R1

+

[Cp*Co(CH3CN) 3](SbF6)2 (5 mol%) chiral acid (10 mol%) R tBuOK (12 mol%)

N

R N N

Co N

R1

O

R

N

O

N N

N

R1

R1

O Cp*

N

N O Pym 12 examples up to 99% yield, up to 82:18 e.r.

MS13X O TFE/DCM (4:1), 10 °C Pym = 5-methylpyrimidin-2-yl chiral acid O

O

Co Cp*

Ph CO2H chiral acid

Scheme 14.29  Enantioselective 1,4-addition of N-pyrimidylindoles to maleimides.

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14  Asymmetric Functionalization of C–H Bonds in Heterocycles

Zheng, Li, 2019 Ts N

R H + N Pym

catalyst (2.5 or 4 mol%) R AgSbF6 (10 or 16 mol%) Ag2SO 4 and/or AgOAc

TsHN

MeO

N Pym

Cl

62% yield, 95:5 e.r.

23 examples up to 95% yield, e.r. > 95:5 in most cases

N Pym

toluene or DCT, 60 °C

Examples: F

TsHN

TsHN

OMe

N Pym

OMe

73% yield, 95.5:4.5 e.r.

catalyst

Rh I

I

2

Scheme 14.30  Enantioselective addition of N-pyrimidylindoles to 7-azabenzonorbornadienes.

was used for this purpose. To suppress the competing reaction at the C3 site, AgSbF6 was used as a mild base. Through mechanistic studies it was revealed that AgSbF6 abstracts OAc from the Rh(III) species, thus suppressing the C(3)–H activation pathway. Under these conditions, the coupling products were obtained in excellent yields and selectivity. The Shibata group reported the alkylation of indoles with terminal alkenes catalyzed by cationic iridium and phosphine ligands [49]. The nature of the group on nitrogen determined the reaction outcome: when a benzoyl group was used, the branched alkylation product was predominant, but when an acetyl group was used, the linear isomer formed. Only one enantioselective reaction was shown, the alkylation of indole with styrene using a chiral phosphine ligand, which proceeded with moderate enantioselectivity (Scheme 14.31). Shibata, 2012

N Bz

H +

[Ir(cod) 2]BArF4 (10 mol%) ligand (10 mol%) Ph

dioxane, 100 °C

PPh2 PPh2

N Ph Bz 93% yield, 42% ee

ligand

Scheme 14.31  Ir(I)-catalyzed enantioselective hydroarylation of indole with styrene.

14.3.3  Atropo-enantioselective Synthesis of Heterobiaryls When the rotational barrier is high enough, the atropo-enantioselective construction of bis(hetero)aryl derivatives is possible [50]. We classify these reactions as “C–H activation followed by enantioselective functionalization”, but the selectivity-determining step is largely unclear and the mechanistic studies are complicated by the rotational flexibility of the reaction intermediates. The Gu group reported that a palladium/chiral phosphoramidite catalytic system is efficient for the atroposelective C−H cyclization of indole derivatives (Scheme 14.32) [51]. The reaction proceeded with high yield and enantioselectivity on gram scale, and the product was isolated by precipitation, without the need of column chromatography. Gu, 2017

O H N (1.00 g)

O I

PdCl2 (5 mol%) ligand (6 mol%) Cs2CO 3 (3 equiv) DCE, 65 °C

Ar Ar O P N O O Ar Ar O

O N 86% yield 96:4 e.r.

O

Ar =

N Ph

Ph ligand

Scheme 14.32  Atroposelective cyclization of indole derivatives catalyzed by palladium/ phosphoramidite.

14.3  C–H Activation Followed by Enantioselective Functionalization

The Shi group achieved the paladium-catalyzed intermolecular atropo-enantioselective alkynylation of various fivemembered heteroarenes, using a commercially available amino acid as a chiral auxiliary [52]. Transient introduction of a DG has been developed for the functionalization of weakly coordinating substrates [53], and this strategy allows control of enantioselectivity by in situ installing a catalytic amount of a chiral auxiliary [54]. Thus, a chiral amino acid reversibly converts the aldehyde group on the substrate to a strongly coordinating chiral imine group, which coordinates the palladium species and directs C–H cleavage in an atroposelective manner (Scheme 14.33). After oxidative addition of the bromoalkyne, reductive elimination and hydrolysis of the imine gives the product and regenerates the chiral amino acid auxiliary. The authors also expanded the strategy to allylation and alkenylation of similar substrates [55].

Shi, 2019 S

S

Br TIPS (3 equiv) Pd(OAc)2 (10 mol%) L-ter t-leucine (30 mol%)

CHO H

TIPS

AgTFA (2 equiv) AcOH/toluene, 55 °C

S

S 92% yield 93% ee

(1.2 g) H

S

H

S tBu

tBu

N H

CHO

N O

[Pd]

HO

S

O O

S

Examples: MeO CHO

CHO

TIPS

X X = S 84%, 92% ee X = O 82%, 71% ee

TIPS

X X = S 47%, 99% ee X = O 70%, 0% ee

MeO

CHO

TIPS

X X = S 97%, 99% ee X = O 86%, 0% ee

Scheme 14.33  Atroposelective alkynylation of 5-membered heteroarenes catalyzed by palladium/chiral amino acid.

The You group reported a chiral *SCpRh-catalyzed atropo-enantioselective oxidative C−H/C–H coupling of 1-arylisoquinoline derivatives with electron-rich heteroarenes in the presence of a chiral carboxylic acid and AgF as an oxidant (Scheme 14.34) [56]. A variety of thiophene, furan, and N-protected pyrrole derivatives and their benzene-fused congeners reacted well; the reactions of these heteroarenes were regioselective, except for benzofuran, which gave a 1:1 mixture of 2- and 3-isomers. The authors proposed that the rhodium(I) precatalyst is first oxidized to a chiral *SCp-Rh(III) species, which coordinates the isoquinoline group and enantioselectively cleaves the C–H via carboylate-assisted concerted metalation−deprotonation. Next, the heteroarene’s C–H is cleaved through electrophilic metalation, and subsequent reductive elimination, possibly induced by the oxidant, gives the product, and regenerates the active rhodium species. The atroposelective construction of biaryl derivatives through enantioselective cross-coupling of a heteroarene with an aryl nucleophile or electrophile is challenging, especially in an intermolecular fashion. An obvious requirement is that the chiral biaryl product must be stable against racemization under the C–H activation conditions. A pioneering study by Yamaguchi and Itami demonstrated the enantioselective coupling of thiophene derivatives with naphthyl boronic acids in the presence of a palladium/chiral bisoxazoline ligand (Scheme 14.35, top) [57a]. However, just two examples were presented, and the selectivity was moderate. One year later, the authors reported the same reaction with a different catalyst system [57b], but the enantioselectivity remained moderate. After an initial study by the Cramer group on an intramolecular synthesis of axially chiral dibenzazepinones by a palladium/TADDOL-derived phosphoramidite catalyst [58], the

625

626

14  Asymmetric Functionalization of C–H Bonds in Heterocycles

You, 2020 N

OMe N

[*SCpRh] (5 mol%) H *acid (20 mol%) AgF (3 equiv)

[*SCpRh]

85% yield 93% ee

(3 equiv)

Pri O

N

N

Rh

OMe

DMF, 60 °C

+ S

H

S

SCp

N

O

SCp Rh

Rh

CO2H

*acid

S

X

Scheme 14.34  Atroposelective oxidative C–H/C–H coupling of electron-rich heteroarenes catalyzed by chiral SCpRh.

Yamaguchi, Itami, 2012 Me

+ Me

S

Me

Pd (OAc)2 (10 mol%) ligand (10 mol%)

H H

TEMPO (4 equiv) iPrOH, 70 °C

Me B(OH)2 (4 equiv)

O

Me

S

H

63% yield, 41% ee 95% C4-selective

O

N N ligand

iPr

Me

iPr

Baudoin, Cramer, 2020 H Me N N N

Ph

+

OMe Br (1.5 equiv)

POPh2 PPh2 ligand

Pd(OAc)2 (10 mol%) ligand (20 mol%)

N Me Me N N N

OMe

OiPr Ph

71% yield 80:20 e.r. (90 °C)

Me N N

Ph

CN 97% yield 97:3 e.r.

OMe Me N Ph N N 93% yield, 95:5 e.r.

PivOH (30 mol%) Cs2CO 3 (1.5 equiv) MeOH, 80 °C

N N N Me Ph MeO OMe Me

Ph

N N N 76% yield >99.5:0.5 e.r. (2 equiv C-H)

Scheme 14.35  Palladium-catalyzed atroposelective arylation of heteroarenes.

Baudoin and Cramer groups developed an intermolecular atropo-enantioselective arylation of heteroarenes with aryl bromides, using a palladium catalyst and a chiral diphosphine ligand (Scheme 14.35, bottom). [59] Various 1,2,3-triazoles and pyrazoles reacted with naphthyl, aryl, and heteroaryl bromides in good yield and enantioselectivity. An atroposelective two-fold C–H arylation was also demonstrated, to construct two sterogenic axes with excellent selectivity. The authors speculate that the reductive elimination may be the selectivity-detemining step.

References

14.4  Conclusions and Perspectives Despite the relatively short history of enantioselective C–H functionalization, the potential of these reactions to enable straightforward access to complex chiral molecules has spawned a large body of research recently. Initial reports focused mainly on arenes and alkyl derivatives as the substrate [6, 7], but studies on enantioselective functionalization of heterocyclic compounds have steadily increased due to the importance of these compounds for drug discovery. The presence of heteroatoms can be challenging because they can coordinate unproductively with the active metal species. This is especially problematic for directed C–H activation, where heteroatoms may compete with the DG. Despite these challenges, a series of factors have contributed to the increase of reports on enantioselective C–H functionalization of heterocycles. These include recent developments of efficient catalytic systems for C–H activation of heterocyclic compounds, advances in C–H activation without the requirement of DGs [60], accumulated knowledge for the design of chiral ligands effective for C–H activation, and an increase in catalytic systems that activate a C–H bond under mild conditions [61] to avoid racemization. However, challenges still abound, as illustrated by the relatively few reaction patterns, especially for enantioselective C–H activation (Chapter 14.1). These challenges include the following. 1) The activation of C(sp2)–H bonds is the most studied, but for asymmetric functionalization the reaction patters are limited. Thus, development of more efficient functionalization at C(sp3)–H centers is desirable, because these compounds represent the bulk of chiral centers in natural and bioactive compounds. 2) Control of regioselectivity has heavily relied on the use of DGs, or on intramolecular reactions; site-selective intermolecular activation of substrates without DG assistance is a challenging, but imperative goal. The heteroatom often imparts regioselectivity, but it does so discriminatorily, typically at the ortho or alpha C–H sites. 3) Finally, currently the field is dominated by precious metals, especially palladium, ruthenium, iridium, etc. Because of economic and environmental concerns [62], Earth-abundant metals have received much attention for C–H activation recently [63], and it is expected that this trend will expand into enantioselective functionalization of heterocycles. It is our hope that this short review of the current state of the art will stimulate the efforts of the synthetic community to achieving truly useful asymmetric functionalization of heterocyclic compounds: intermolecular reactions of simple or complex heterocycles without DG assistance, high yield and enantioselectivity control, broad functional group tolerance, and high and controllable degree of regiocontrol; moreover, the catalysts may shift towards Earth-abundant metals, and enable reactions under mild conditions.

References 1 a) Bemis, G. W. and Murcko, M. A. (1996). The properties of known drugs. 1. Molecular frameworks. Journal of Medicinal Chemistry 39 (15): 2887–2893. b) Gibson, S., McGuire, R., Rees, D.C. (1996). Principal components describing biological activities and molecular diversity of heterocyclic aromatic ring fragments. Journal of Medicinal Chemistry 39 (20): 4065–4072; c) Lewell, X.Q., Jones, A.C., Bruce, C.L. et al. (2003). Drug rings database with web interface. A tool for identifying alternative chemical rings in lead discovery programs. Journal of Medicinal Chemistry 46 (15): 3257–3274; d) Ertl, P., Jelfs, S., Mühlbacher, J. et al. (2006). Quest for the rings. In silico exploration of ring universe to identify novel bioactive heteroaromatic scaffolds. Journal of Medicinal Chemistry 49 (15): 4568−4573; e) Taylor, R.D., MacCoss, M., Lawson, A.D.G. (2014). Rings in drugs. Journal of Medicinal Chemistry 57 (14): 5845−5859. 2 Sanganyado, E., Lu, Z., Fu, Q. et al. (2017). Chiral pharmaceuticals: A review on their environmental occurrence and fate processes. Water Research 124: 527–542. 3 a) Dyker, G. ed. (2005). Handbook of C–H Transformations. Wiley-VCH: Weinheim. b) Dixneuf, P.H. and Doucet, H. ed. (2016). Topics in Organometallic Chemistry: C–H Bond Activation and Catalytic Functionalization. Springer Berlin: Heidelberg; c) Yu, J.-Q. (2016). Catalytic Transformations via C–H Activation, In: Science of Synthesis. vol. 2. 37–62. Thieme: Stuttgart. 4 a) Godula, K. and Sames, D. (2006). C–H bond functionalization in complex organic synthesis. Science 312 (5770): 67–72. b) Yamaguchi, J., Yamaguchi, A.D., and Itami, K. (2012). C–H Bond functionalization: Emerging synthetic tools for natural products and pharmaceuticals. Angewandte Chemie International Edition 51 (36): 8960–9009; c) Wencel-Delord, J. and Glorius, F. (2013). C–H bond activation enables the rapid construction and late-stage diversification of functional molecules. Nature Chemistry 5: 369–375; d) Hartwig, J.F. (2016). Evolution of C–H bond functionalization from methane to methodology. Journal of the American Chemical Society 138 (1): 2−24.

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14  Asymmetric Functionalization of C–H Bonds in Heterocycles

5 a) Giri, R., Shi, B. F., Engle, K. M. et al. (2009). Transition metal-catalyzed C–H activation reactions: Diastereoselectivity and enantioselectivity. Chemical Society Reviews 38 (11): 3242–3272. b) Zheng, C. and You, S.L. (2014). Recent development of direct asymmetric functionalization of inert C–H bonds. RSC Advances 4 (12): 6173–6214; c) You, S. L. ed. (2015). Asymmetric Functionalization of C–H Bonds. Cambridge, UK: Royal Society of Chemistry; d) Newton, C.G., Wang, S.-G., Oliveira, C.C. et al. (2017). Catalytic enantioselective transformations involving C–H bond cleavage by transition metal complexes. Chemical Reviews 117 (13): 8908–8976; e) Loup, J., Dhawa, U., Pesciaioli, F. et al. (2019). Enantioselective C−H activation with earthabundant 3d transition metals. Angewandte Chemie International Edition 58 (37): 12803–12818; f) Wu, Q.-F., Chen, G., He, J. et al. (2019). Catalytic, enantioselective, C–H functionalization to form carbon-carbon bonds. 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F., Maugel, N., Zhang, Y. H. et al. (2008). PdII-catalyzed enantioselective activation of C(sp2)–H and C(sp3)–H bonds using monoprotected amino acids as chiral ligands. Angewandte Chemie International Edition 47 (26): 4882–4886. 8 Albicker, M. R. and Cramer, N. (2009). Enantioselective palladium-catalyzed direct arylations at ambient temperature: Access to indanes with quaternary stereocenters. Angewandte Chemie International Edition 48 (48): 9139–9142. 9 Saget, T. and Cramer, N. (2013). Enantioselective C–H arylation strategy for functionalized dibenzazepinones with quaternary stereocenters. Angewandte Chemie International Edition 52 (30): 7865–7868. 10 Grosheva, D. and Cramer, N. (2018). Enantioselective access to 1H-isoindoles with quaternary stereogenic centers by palladium(0)-catalyzed C−H functionalization. Angewandte Chemie International Edition 57 (41): 13644–13647. 11 Chu, L., Wang, X. C., Moore, C. E. et al. (2013). 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Angewandte Chemie International Edition 51 (9): 2238–2242. 16 Holstein, P. M., Vogler, M., Larini, P. et al. (2015). Efficient Pd0-catalyzed asymmetric activation of primary and secondary C–H bonds enabled by modular binepine ligands and carbonate bases. ACS Catalysis 5 (7): 4300–4308. 17 Jain, P., Verma, P., Xia, G. et al. (2017). Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides. Nature Chemistry 9: 140–144. 18 Greβies, S., Klauck, F. J. R., Kim, J. H. et al. (2018). Ligand-enabled enantioselective Csp3–H activation of tetrahydroquinolines and saturated aza-heterocycles by RhI. Angewandte Chemie International Edition 57 (31): 9950–9954. 19 Tahara, Y., Michino, M., Ito, M. et al. (2015). Enantioselective sp3 C–H alkylation of γ-butyrolactam by a chiral Ir(I) catalyst for the synthesis of 4-substituted γ-amino acids. Chemical Communications 51 (93): 16660–16663. 20 Chen, L., Yang, Y., Liu, L. et al. (2020). Iridium-catalyzed enantioselective α-C(sp3)–H borylation of azacycles. Journal of the American Chemical Society 142 (28): 12062–12068. 21 a) Davies, H. M. L. and Beckwith, R. E. J. (2003). Catalytic enantioselective C−H activation by means of metal−carbenoidinduced C−H insertion. Chemical Reviews 103 (8): 2861–2904. b) Davies, H.M.L. and Manning, J.R. (2008). Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion. Nature 451: 417–424; c) Doyle, M.P., Duffy, R., Ratnikov, M. et al. (2010). Catalytic carbene insertion into C−H bonds. Chemical Reviews 110 (2): 704–724. 22 Davies, H. M. L., Venkataramani, C., Hansen, T. et al. (2003). New strategic reactions for organic synthesis: Catalytic asymmetric C−H activation α to nitrogen as a surrogate for the Mannich reaction. Journal of the American Chemical Society 125 (21): 6462–6468.

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15 Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases Yong Liang1 and Stanislaw F. Wnuk2 1 2

Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, US Department of Chemistry and Biochemistry, Florida International University, Miami, FL, US

15.1  Introduction Transition metal-catalyzed cross-coupling reactions have contributed significantly to the development of new strategies for the formation of new carbon-carbon or carbon-heteroatom bonds. These coupling reactions have been applied extensively to the synthesis of purine and pyrimidine nucleoside analogues [1–4], which often possess potent biological activity and interesting physicochemical properties [5–9]. The direct C–H bond functionalization of purine and pyrimidine bases and the corresponding nucleosides has been summarized [10–16] and the C–H functionalization of sugar moieties has been reviewed as well [17]. This chapter is focused on the functionalization of pyrimidine and purine nucleosides by direct C–H bonds activation in nucleobases and is organized by the position of C–H bond in the heterocyclic rings. Transition metal-catalyzed direct C–H functionalization [18–22] has been also developed as a powerful alternative tool for the synthesis of organic molecules and pharmaceutical scaffolds [23–28]. These methodologies are utilized in the development for the formation of carbon-carbon and carbon-heteroatom bonds in nucleosides due to the advantages of: (a) high atom economy; (b) high functional group tolerance; (c) ease of handling; (d) relatively short synthetic routes; and (e) environmentally friendly processes avoiding the usage of toxic metals [10, 12, 13, 16, 29, 30]. Because these reactions require only one activated substrate (C–H activation) and sometimes do not require activation for either substrate (double C–H activation), they are atom efficient and avoid the preparation of often unstable activated substrates for traditional couplings. Major challenges associated with direct C–H functionalization of nucleosides include: (a) the need for developing regioselective activation of specific C–H bonds in nucleobases in the presence of other C–H bonds; (b) low chemoselectivity that often requires the protection of other sensitive functional groups present in nucleoside substrates; (c) the necessity of working at the high temperature needed to activate C–H bonds with intrinsic low activity; and (d) the need to overcome the instability of glycosylic bonds. The strategies for direct C–H bond functionalization of nucleoside heterocyclics can be divided into several categories based on: (a) position of functionalization C8 vs C6 vs C2 in purines or C6 vs C5 in pyrimidines; (b) the types of substrates coupled to nucleobases (e.g. aryl- or alkenyl halides, arenes, alkenes, or amines); (c) number of required C–H bond activations (one vs two coupling substrates); and (d) the kind of transition metal catalyst used. Palladium and copper are two of the most common transition metal catalysts used for C–H activation, but C–H functionalization of a nucleoside using nickel [31], rhodium [32, 33, 103], ruthenium [34–36, 108], and other metals [37–39] has been reported. There are also few examples of transition metal-free photo-catalyzed or radical-mediated functionalizations of nucleobases based on direct C–H activation [40, 41]. Direct C–H functionalization of pyrimidine nucleosides is still limited to uracil nucleoside substrates and, despite progress achieved in recent years, advances are still needed to improve strategies for the regioselective activation of the C5-H versus the C6-H bond. Available methodologies for functionalization at the C5 (Figure 15.1, path a) or C6 (Figure 15.1, path b) position involve cross-couplings between inactivated nucleobases with aryl/alkenyl halides or alkenes/ alkynes. Because such couplings often occur with limited regioselectivity, the thermal or photoinduced strategies developed employ coupling between 5- (or 6)-halo-modified uracil or uracil nucleosides with arenes, heteroarenes, alkenes, or even alkanes (which require selective C–H bond activation at the simple organic molecules instead of nucleobases for C5 (path c, Figure 15.1) or C6 modifications). Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

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15  Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases

In the purine nucleosides, C8-H functionalization has been studied the most extensively, although C6-H bond functionalization has been also well developed (Figure 15.2). The only example of C2-H functionalization was accomplished by the treatment of adenosine with cyclohexane carboxylic acid in the presence of an organic photocatalyst. The main approaches for the functionalization of the C8-H bond in nucleobases involve coupling with (hetero)aryl halides (Figure 15.2, path a) or cross-dehydrogenative couplings with inactivated alkene and alkane substrates (Figure 15.2, path b). Major approaches for the functionalization of the C6-H bond involve coupling with boronic or carboxylic acids or oxalate salts (Figure 15.2, path c) or cross-dehydrogenative radical couplings with alkanes (Figure 15.2, path d). O

O

HN

HN 3

O

HO

N

O

R

R-X or R-H

HO

Path b OH

C6-H

X

O

O

4

H

N

H

5 2 16

HN R-X or R-H

O OH

Path a C5-H

X

O

HO

O R

N

O

HO

R-H

O

X

HN N

O

Path c OH

X

OH

X

Figure 15.1  Strategies for direct C5-H and C6-H functionalization of uracil and uracil nucleosides.

R N

N N HO

N

Carboxylic or boronic acids, or oxalate salts

H N1

6 5 2 4 3

path c

N

O R-H OH

OH

C6-H functionalization

HO

N

7 8 9

O

HO

OH

R N

path a

N

O

R-H path b

path d OH

H

N

N

N

(Hetero)aryl halides

OH

OH

C8-H functionalization

Figure 15.2  Strategies for direct C–H functionalization of purines and purines nucleosides.

15.2  Direct Functionalization of the C5-H Bond in Uracil Nucleosides The C5-substituted pyrimidine nucleosides display a broad spectrum of antibacterial, antiviral, and anticancer activities, whereas C5-modified nucleotides are engaged in various molecular biology applications such as gene expression, mRNA fluorescence in situ hybridization (FISH) experiments, and mutation detection on arrays and microarrays. In 2020, the Covid-19 mRNA vaccine was approved for the prevention of pandemics that incorporates 1-methylpseudouridine instead of uridine to dampen innate immune sensing and to increase mRNA translation in vivo [42]. Synthetic mRNA tools often use pseudouridine and 5-methyl cytidine as substitutions for uridine and cytidine to avoid the immune response and cytotoxicity induced by introducing mRNA into cells. Moreover, 5-modified thymidine phosphate has also been employed for the synthesis of stable DNA-protein conjugates, as well as for the post-synthetic labeling of DNA [107]. Direct C–H functionalization of the pyrimidine nucleosides is still limited to the uridine derivatives. The main challenges that still need to be overcome are: (a) the shortage of efficient strategies for regioselective activation of the C5–H or C6–H bond of the uracil ring; and (b) the lack of the effective conditions that could apply to 2ʹ-deoxyuridine analogues. The C–H functionalization of pyrimidines has been recently reviewed [13–15]; therefore, this section will focus primarily yon the C–H functionalization of pyrimidine nucleoside substrates.

15.2.1  Cross-Dehydrogenative Alkenylation at the C5 Position The discovery of the potent antiviral activity of E-5-(2-bromovinyl)-2ʹ-deoxyuridine (BVDU) led to the exploration of synthetic strategies for the oxidative coupling of uracil nucleosides with alkenes based on direct C–H bonds activations.

15.2  Direct Functionalization of the C5-H Bond in Uracil Nucleosides

The new routes avoided the use of mercury that was central to Walker’s synthetic approach to BVDU involving the condensation of 5-mercurated 2ʹ-deoxyuridine with ethyl acrylate [43, 44]. The direct C–H activation also seems advantageous to other cross-coupling protocols between 5-halouracil nucleosides and organometallics [1]. Itahara employed the oxidative coupling of uracil nucleosides 1–3 with maleimides 4 for the synthesis of 5-substituted uridines of type 5–8 (Scheme 15.1) [45]. The yields for uridine and 2ʹ-deoxyuridine nucleosides were lower (4–22%) than those of the 1,3-dimethyluracil (DMU) substrate (~20–50%). It was proposed that the coupling of uridines with maleimides proceeds via palladation of C5 uracil base with palladium acetate, which requires the stoichiometric amount of AgOAc as a reoxidant.

O

O H

HN RO

N

O OR

N R1

+

R1 N O

HN

O

H

O

O

Pd(OAc) 2, AgOAc

RO

MeCN, reflux

O

N

O

O OR

R1 = H, Me

X

1 X = OAc, R = Ac 2 X = OH, R = H 3 X = H, R = H

5 6 7 8

4

X X X X

X

= OAc, R = Ac, R 1 = Me; 22% = OH, R = H, R 1 = H; 4% = H, R = H, R1 = H; 10% = H, R = H, R1 = Me; 11%

Scheme 15.1  Palladium-catalyzed oxidative coupling of (2ʹ-deoxy)uridine with maleimides.

In 1987, Hirota and coworkers reported the oxidative coupling of uridine 2, 2ʹ-deoxyuridine 3 and isopropylidene-protected uridine 9 with methyl acrylate 10 or styrene 11 using catalytic loading of Pd(OAc)2 in the presence of t-butyl perbenzoate 12 as the reoxidant to prepare 5-vinyl uridine analogues 13 (Scheme 15.2) [46]. Similar results were obtained with stoichiometric amounts of Pd(OAc)2 (1.2 equivalents) without the necessity of adding reoxidant 12. The couplings proceeded stereoselectively to give trans-isomers. The reaction conditions were compatible with unprotected and protected uridine substrates, but coupling of isopropylidene-protected uridine 9 with 10 produced 5-substituted uridine 13 in 74% yield with 5ʹ,6-cyclouridine byproduct 14 in 23% yield. The protection of N3-H in the pyrimidine base was not required. O HN 2

R O

O

N

O

+

2

R3

HN H

R3

10 R 3 = COOMe 11 R 3 = Ph

OR 1 X 1

O H

2 X = OH, R = R = H 3 X = R1 = R2 = H 9 X = R 1 = isopropylidene, R2 = H

Pd(OAc)2 , (PhCO3t Bu) 12 MeCN, rt

HO

O

O MeOOC

N

O

NH N

O O

+

OH X 13, 35-74%

O

O

O

14, 23%

Scheme 15.2  Palladium-catalyzed oxidative coupling of (2ʹ-deoxy)uridine with terminal alkenes.

Yun and Georg reported palladium-catalyzed cross-dehydrogenative coupling of isopropylidene-protected N3-methyl uridine 15 and silyl-protected 2ʹ-deoxyuridine 18 with t-butyl acrylate 16 in the presence of AgOAc/PivOH in DMF (60 oC/24 h) to give trans-5-alkenyl products 17 and 19 in good yields (Scheme 15.3) [47]. The coupling occurred with regio (C5) and stereoselectivity (E-isomer), although, 3-N-methyl protection at the uracil ring was necessary. The coupling was postulated to occur via the electrophilic palladation pathway [48] at the C5 position of the uracil ring followed by deprotonation with the pivalate anion to give the palladated intermediate. Coordination with the alkenes via transmetallation, and subsequent β-elimination provided 5-alkenyluridine derivatives [47].

633

634

15  Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases O Me HO

N

O

Me

N +

O O

O H

CO 2t Bu

H

Pd(OAc)2 , AgOAc

O

HO

N

O

PivOH, 60 oC, 24 h

16

O

CO2 tBu

N

O

O 17, 66%

15

O

O Me iPr

O

O

iPr Si O iPr

N

O

Si

O

Me

H N

iPr + H

CO2 tBu

Pd(OAc)2 , AgOAc PivOH, DMF 60 oC, 24 h

16 18

O

O

N

O

iPr Si

iPr

iPr

O

CO2 tBu

N

Si

O

iPr 19, 75%

Scheme 15.3  Palladium-catalyzed cross-dehydrogenative alkenylation of uracil nucleosides.

15.2.2  Direct C–H Arylation at the C5 Position Kim and coworkers developed direct arylation of 1-(tetrahydrofuran-2-yl)-3-benzyluracil 20 (a substrate bearing a glycosylic bond) with bromobenzene 21 in the presence of Pd(OAc)2, K2CO3, and PivOH at 100 oC for the synthesis of a 5-phenyluracil analogue 22 in 55% yield (Scheme 15.4) [49]. The formation of the corresponding 6-phenyl isomer was not observed. However, decomposition of 20 was observed at the elevated temperature (130 oC), a condition that provided 5-arylation of 1,3-dimethyluracil substrate in good yields [49]. O Bn

H

N

O

N O

20

21 Ph-Br 2.0 equiv, Pd(OAc)2 10 mol%, PPh3 20 mol%, PivOH 30 mol% K 2CO3 3 equiv, DMF , 100 oC, 12 h

O Bn

Ph

N

O

N O

22, 55%

Scheme 15.4  Palladium-catalyzed direct C5-H arylation of 1-(tetrahydrofuran-2-yl)-3-benzyluracil.

A further study reported by Kim and coworkers reveals the formation of C5-C5ʹ uracil nucleoside dimers (as well as C6-C6ʹ and C5-C6 uracil base dimers) during the palladium(II)-catalyzed oxidative homo-coupling of protected uridine nucleosides [50]. Thus, treatment of N1-tetrahydrofuranyl uracil 23 with AgOAc and Pd(TFA)2 in mesitylene at 120 oC gave the C5-C5ʹ dimer 24 in 52% yield in addition to the recovered 23 (28%, Scheme 15.5) [50]. It is interesting to note that two H-6 protons of 24 were observed as two singlets (1:1) at δ=8.26 and 8.36 p.p.m. in the 1H NMR spectrum (CDCl3) indicating the existence of a pair of rotational isomers attributed to hindered rotation around the C5–C5ʹ single bond. Analogously, treatment of N3-benzyl-2ʹ,3ʹ,5ʹ-tri-O-benzoyluridine 25 afforded the corresponding C5–C5ʹ dimer 26 in 43% yield. The H-6 proton of 26 was observed as singlet δ=8.42 p.p.m. (CDCl3), which implied the presence of only one rotational isomer due to the presence of bulky sugar moieties compared with 24, which existed as two restricted rotational isomers [50].

15.2  Direct Functionalization of the C5-H Bond in Uracil Nucleosides (a)

O Bn

O H

N

O

Bn Pd(TFA) 2 5 mol%, AgOAc 3 equiv

N

O

N

BzO

N

O

24, C5-C5' dimer, 52% O H

N

O

Bn

N

O

O Bn

5'

O

23 (b)

N

O

mesitylene, 120 oC, 4 h

O 5

Bn Pd(TFA)2 5 mol%, AgOAc 3 equiv

N

N

O

mesitylene, 120 oC, 12 h BzO

O

O 5

N

5'

N N

O

OBz OBz 25

Bn O

OBz

O

OBz OBz OBz OBz 26, C5-C5' dimer, 43%

Scheme 15.5  Synthesis of uracil dimers by direct C5-H functionalization.

15.2.3  Direct C–H Alkylation at the C5 Position Guo’s group developed a radical-promoted transition metal-free C5-H functionalization of pyrimidine nucleosides 27–30 with cycloalkanes that gave access to C5-cycloalkyl substituted nucleosides 31–34 (Scheme 15.6) [51]. It is noteworthy that coupling occurred in the presence of the free 5ʹ-hydroxyl group at the ribose moiety and that no protection of the N3 amino group in uracil was needed. Most importantly, coupling occurred regioselectively and only C5 substituted products were obtained for all of the tested nucleosides. Similar conditions were applied for the synthesis of C6-cycloalkyl or C6,C8dicycloalkyl substituted purine nucleosides (see Section 7.3 for detail) [51].

O

O H

HN R4 O

O O R1

N

Cycloalkane tBuOOtBu (2 eq.) 4 R O 140 o C, 24h

OR3 R2 27 28 29 30

R1 = R1 = R1 = R1 =

H, R2 = OAc, R 3 = R 4 = Ac H, R2 = OBz, R 3 = R 4 = Bz H, R2 = R3 = isopropylidene, R 4 = H OAc, R2 = H, R 3 = R 4 =Ac

HN O O R1

N

OR3 R2 31 32 33 34

R1 R1 R1 R1

= H, R 2 = OAc, R 3 = R4 = Ac; 79% = H, R 2 = OBz, R 3 = R4 = Bz; 77% = H, R 2 = R 3 =isopropylidene, R 4 = H; 83% = OAc, R 2 = H, R 3 = R4 =Ac; 78%

Scheme 15.6  Transition metal-free direct C5-H alkylation of pyrimidine nucleosides.

Direct C–H alkylation of iminoamido N-heterocycles, including 6-azauracil nucleosides 35–36 with trialkylsulfoxonium salt 37 as an alkylating agent, leads to C5-alkylated nucleosides 38–41 in high yields (Scheme 15.7) [52]. Based on deuterium-labeling experiments, a plausible mechanism that involves nucleophilic addition of sulfoxonium ylide I to the nucleoside substrate and subsequent E2 elimination of DMSO from intermediate II was proposed (Scheme 15.8). The released DMSO byproduct was successfully detected by GC-MS analysis of the crude reaction mixture. The feasibility of gram-scale reactions highlights its synthetic potential and the use of H2O and i-PrOH as environmentally friendly solvents and economical inorganic bases makes this protocol practical for the pharmaceutical industry.

635

636

15  Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases O

O Me

N

O

RO

Me

H N

N

O

+

O OR

R

S R

K 3 PO4 , i-PrOH 100 o C, 24 h

X R

O

RO

N

OR 38 39 40 41

35 X = OBn, R = Bn 36 X = H, R = Bn

N

O

37

X

R

N

X X X X

X

= OBn, R = Bn, R = Me; 91% = H, R = Bn, R = Me; 94% = H, R = Bn, R = Et; 72% = H, R = Bn, R = n-Pr; 60%

Scheme 15.7  Direct C5-alkylation of azauracil nucleosides with sulfur ylides.

O Me

H

N

O

N

O

O H 2C

N

Me

S

Me Me I

PG

Nucleophilic Addition

O

H

OH O

N N

O Me

S Me2 - DMSO

N

H 2O

PG

O E2 Elimination

H2O

N N

N

PG

II

H

O Me O

OH

Me

N N

N

PG

PG = sugar protection group

Scheme 15.8  Proposed mechanism for the C5-alkylation of azauracil nucleosides.

15.2.4  Miscellaneous Direct C–H Functionalizations The palladium-catalyzed regioselective C–H acetoxylation at the C5 position of uracil nucleosides with PhI(OAc)2 under reasonably mild conditions (60 oC, 3–5 h) has been developed (Scheme 15.9) [53]. The acyl-protected uridine 1 and silylprotected 2ʹ-deoxyuridine 42 were compatible with these conditions to give the corresponding 5-acetoxy products 43 and 44 in 55% and 25% yields, respectively. However, partial glycosidic bond cleavage under the acidic conditions was observed, which led to the isolation of 5-acetoxyuracil (16%). The reaction was proposed to proceed via oxidative electrophilic palladation at the electron-rich C5 position to give the 5-palladauracil intermediate followed by oxidation to give a palladium(IV) intermediate, which yielded 5-acetoxyluridine via the reductive elimination of palladium(II). O HN RO

O

N

X

1 X = OAc, R = Ac 42 X = H, R = TBS

OAc

HN Pd(OAc)2 , PhI(OAc) 2 AcOH, 100 o C, 2 h

O OR

O H

RO

O

N

O OR

X

43 X = OAc, R = Ac; 55% 44 X = H, R = TBS; 25%

Scheme 15.9  Pd-catalyzed direct C5-H acetoxylation of uracil nucleosides.

The 5-selenouracil derivatives were prepared by electrochemical dehydrogenative selenylation of uracils with 1,2-disubstituted diselenides using platinum as a cathode (3 mA). Unfortunately, 5-selenouridine was not accessible from uridine under similar conditions [54].

15.3  Direct Functionalization of C6-H Bond in Uracil

15.3  Direct Functionalization of C6-H Bond in Uracil Strategies for the regioselective activation of the C6-H bond in pyrimidine nucleosides with typical transition metalcatalyzed coupling methods are very limited. However, several bond constructions involving C6-H in the uracil derivatives have been reported and are discussed below. The key factor is the presence of two β-carbonyl groups at the C2 and C4 positions that increase the acidity of the C–H bond at the C6 position, thereby favoring proton abstraction in the presence of a base. As a result, the traditional lithiation of uracil nucleosides with lithium diisopropylamide (LDA) under low temperature selectively functionalizes C6-H bond in the pyrimidine nucleosides [55–57].

15.3.1  Stepwise C6-H Functionalization of Pyrimidine Nucleoside via Lithiation and Alkylation Most methods for the synthesis of C6-substituted uracil nucleosides are based on ring lithiation followed by treatment with the appropriate electrophiles. Thus, sequential lithiation of 2ʹ,3ʹ-O-isopropylideneuridine 9 with LDA in THF and electrophilic quenching with n-bromobutane was reported to give 6-n-butyl derivative 46 (60%, Scheme 15.10) [56]. The 5ʹ-hydroxyl group was proposed to participate in the stabilization of the 6-lithio derivative (e.g. 45), resulting in regioselective alkylation at C6. Treatment of 46 with trifluoroacetic acid gave 6-n-butyluridine [56].

O

O

HN HO

O

O

N N

O O

O

H

Li LDA THF, -78 oC

O

Li

N

O O

9

Li O

HN n-BuBr -78 to -40 oC

HO

O 45

O

N

n-Bu

O O

O 46

Scheme 15.10  Stepwise lithiation and alkylation of 2ʹ,3ʹ-O-isopropylideneuridine.

It was also reported that lithiation of the 5ʹ-O-TBDMS-2ʹ,3ʹ-O-isopropylideneuridine under similar conditions (5 equivalents of LDA in THF at −70°C) followed by addition of D2O resulted in the exclusive deuterium incorporation at the C6 position with 82% yield [55]. Moreover, treatment of the 5-substituted 2ʹ,3ʹ-O-isopropylidene-5ʹ-O-methoxymethyluridine with LDA (2.5 equivalents) at −70oC followed by the addition of diphenyl disulfide or iodine gave 6-phenylthio or 6-iodo uridine derivatives [57].

15.3.2  Direct C6-H Functionalization of the Uracil Base 15.3.2.1  Functionalization with Aryl Halides

Hocek and coworkers reported catalyst-dependent regioselective C–H arylations of 1,3-dimethyluracil (47, DMU, R=Me) with aryl halides. Thus, arylation of 47 in the presence of Pd(OAc)2 and Cs2CO3 mainly formed the 5-arylated uracil analogues 48, whereas coupling in the presence of palladium catalyst and CuI (3 equivalents) preferentially formed the 6-arylated derivatives 49 (Scheme 15.11, Method A) [58, 59]. Interestingly, copper-mediated arylation in the absence of palladium catalyst gave exclusively 6-aryluracils 49, albeit in lower yields (Method B). The experimental results indicated that different mechanisms are involved in these diverse arylation reactions [58, 59]. These couplings required a high temperature (160oC) and a long time (48 h) and were not applicable to the synthesis of unsubstituted uracils. These protocols were also applied to N-benzyl-protected uracil derivatives which after debenzylation afforded unprotected 5- or 6-aryled uracil derivatives [58, 59].

637

638

15  Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases O R

Ar

N

O

Method A: Ar-I, Pd(OAc)2 , CuI, P(perFPh) 3 Cs 2 CO 3, DMF, 160 o C, 50h

O Ar-I, Pd(OAc)2 , P(C 6F5 )3 Cs2 CO 3, DMF, 160 oC, 48 h

N

R

H

N

O

N

R

Method B: Ar-I, CuI, Cs 2CO3 DMF, 160 o C, 50h

H

R R = Me, MEM, PMB, Bn

48, 4-53%

47

O R O

N N

Ar

R 49, 6-73%

Scheme 15.11  Catalyst-controlled direct C5-H or C6-H arylation of uracils with aryl halides.

Direct arylation of DMU 47 with less reactive aryl bromides (including electron-deficient ones) in the presence of Pd(OAc)2, K2CO3, and PivOH (130 oC/12 h/DMF) gave predominantly C5 arylated products 48 in up to 79% yield along with a small amount of 6-arylated isomers 49 (up to 25%) [49]. Also, an efficient palladium-catalyzed C6-H functionalization of N1-(4-methoxybenzyl)-N3-methyluracil 50 with (hetero)aryl halides and boronic acids has been developed (Scheme 15.12) [60]. Utilization of the Pd(OAc)2/Xantphos catalytic system with a stoichiometric amount of CuI and DBU as the base was vital to provide 51 in good synthetic yields. O Me

O

N

O

N

H

Me

Ar-X Pd(OAc)2, CuI Xantphos, DBU DMF, 110 o C, 12 h

O

X = Br, I, B(OH)2

MeO

N N

Ar

MeO

50

51, 22-92%

Scheme 15.12  Palladium-catalyzed C6-H arylation of uracil with aryl halides and boronic acids.

The 6-aryl-5-(trifluoromethyl)-1,3-dimethyluracil (53) has been synthesized by sequential direct activations of C5-H and C6-H bonds (Scheme 15.13) [61]. Thus, treatment of 47 with electrophilic (Umemoto’s or Togni’s) or nucleophilic (Rupert’s) reagents in combination with a palladium or copper catalyst either failed or led to the formation of 5,5- or 5,6-dimeric products or 5-CF3 product in low yields. However, radical trifluoromethylation of 47 with sodium trifluoromethanesulfinate in the presence of t-butyl hydroperoxide provided 1,3-dimethyl-5-(trifluoromethyl)uracil 52 in 67% yield [61]. The subsequent direct arylation at C6-H of 52 with 4-iodotoluene in the presence of Pd(OAc)2 and CuI/CsF afforded desired 5,6-disubstituted uracils 53 in low yield (25%), probably because of the electron-withdrawing effect of the CF3 group at the C5 position. It is worth noting that the C6-H arylation was not applicable to other aryl halides and often was accompanied by cleavage of the CF3 group due to hydrolysis followed by decarboxylation, especially when Cs2CO3 was used as the base. O

O Me O

H

N N Me 47

Me NaSO2CF3 , tBuOOH DCM/H 2O (2.5:1), rt

O

O

CF3

N

Ar-I, Pd(OAc)2 N

H

Me

Ligand, Base 160 oC, 48 h

52, 67%

Me O

CF3

N N

Ar

Me 53, 5-25%

Scheme 15.13  Synthesis of 6-aryl-5-(trifluoromethyl)uracils by direct C5-H and C6-H activations.

15.3.2.2  Cross-Dehydrogenative Functionalization with Arenes

Do and Daugulis reported a highly regioselective CuI/phenantroline-catalyzed oxidative direct arylation of DMU 47 with arenes (e.g. 3-methylanisole 54) to give C6-arylated uracil 55 as a sole product in 61% yield (130oC, 48 h; Scheme 15.14) [62]. The protocol used iodine as an oxidant and required only a small excess of the arene (1.5–3.0 equivalents). This overall cross-dehydrogenative coupling (CDC) was believed to proceed by in situ iodination of 54 followed by copper-catalyzed direct arylation at the most acidic bond in the DMU substrate (C6-H).

15.3  Direct Functionalization of C6-H Bond in Uracil O

O Me

N

O

N

Me + H

CuI, Phenanthroline

H OMe

Me 47

Me

I 2, Pyridine, K 3 PO4 , 130 oC 1,2-dichlorobenzene, 2 days

N

O

Me N Me

OMe

55, 61%

54

Scheme 15.14  Sequential iodination and Cu-catalyzed direct C6-H arylation of DMU with arenes.

The palladium-catalyzed cross-coupling of DMU 47 with benzene or xylenes 56 in the presence of PivOH and AgOAc was found to produce 6-aryluracil analogue 57 as the major product (52–85%) along with 5-arylated counterpart 58 and uracil dimers as the byproducts (Scheme 15.15) [49, 50]. It is believed that the 6-arylation occurred via a concerted metalation-deprotonation (CMD) process involving Pd(II)(L)(OPiv) species I. Deprotonation at the more acidic hydrogen at C6 of the uracil ring followed by a subsequent arylation of uracil palladium intermediate with benzene via a second CMD process produced 57 after reductive elimination of palladium(0).

O Me

H

N

O

O + Ar

N

H

H

Pd(TFA)2 , PivOH

AgOAc, 110 oC, 20 h

Me O

Me

Me N +

N N

Ar

Ar

O

56

O

Me

57, 52-85%

58, 5-18%

Me N

Me N LPd

N

Me

47

O

O

O

H6 O more acidic than H 5

CMD Intermediate I

Scheme 15.15  Palladium-catalyzed direct C6-H arylation of uracils with arenes.

15.3.2.3  Functionalization with Aryl Boronic Acid

Recently, an efficient and regioselective C6 arylation of DMU 47 with arylboronic acids 59 in the presence of Pd(OAc)2 and 1,10-phenanthroline (90oC/16 h) has been also developed for the synthesis of C6-arylated uracil 60 (Scheme 15.16) [63]. However, the coupling was unsuccessful with unsubstituted uracil or 2ʹ,3ʹ,5ʹ-tri-O-acetyl-3-N-methyluridine or when the heteroaromatic boronic acids were employed [63].

O Me O

O

N

B(OH) 2 Pd(OAc)2 , 1,10-phenanthroline O2 , DMF, 90 oC, 16 h Ar=Ph, 3-OMePh o-tol, p-tol

+ Ar N Me 47

H

59

Me O

N N

Ar

Me 60, 70-82%

Scheme 15.16  Palladium-catalyzed direct C6-H arylation of uracils with boronic acids.

15.3.2.4  Intramolecular C6-H Functionalization of Uracil Derivatives

The intramolecular C6-H arylation of the uracil derivatives 61 having a substituent at the N1 position bearing aryl halides in the presence of TBAB and Pd(OAc)2 provided convenient access to the benzo[c]pyrimido[1,6-a]azepine scaffold 62 (Scheme 15.17) [64]. Other uracil analogues (e.g. thymine, 5-fluorouracil, or 5-ethyluracil) also gave the corresponding N1-C6 cyclization product in 59–78% yields. Majumdar’s group reported the synthesis of pyrrolo[3,2-d]pyrimidine derivatives of type 64 by the intramolecular dehydrogenative coupling of the 5-aminouracils 63 via the selective activation of uracil C6-H bond in the presence of Cu(OTf)2 (Scheme 15.18) [65]. However, this coupling between Csp2-H (in the uracil ring) and C -H (in the side chain) bonds was

639

640

15  Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases

Br

N

N

H

O

MeOOC

COOMe O Bn

N

Pd(OAc) 2, T BAB, KOAc

N

DMF, 120 oC, 30 min

Bn O

O

61

62, 78%

Scheme 15.17  Palladium-catalyzed intramolecular C6-H arylation of N1-substituted uracil.

R1

O R

N

N

O

O

H R2 H CN

N R

R1

O

63

K 2 CO 3, Cu(OTf)2 toluene, 110 o C, 4 h R, R 1 = Me, Et R 2 = Me, Et, i-Pr, allyl,

R

O

N

N

O

R2

N

CN

R

64, 62%-76%

Scheme 15.18  Intramolecular cross-dehydrogenative cyclization at C6 of the uracil ring.

not successful when R2 = H. The authors suggested that coupling most probably involved a single electron transfer (SET) processes and might require a more stable tertiary radical on the side chain to proceed. Maes and coworkers reported an iron-catalyzed intramolecular direct C6-H amination of 1,3-protected 5-(2-pyridyl) aminouracils 65 to the purine-type products 66 in the presence of oxygen (Scheme 15.19) [106]. Both electron-donating groups and electron-withdrawing groups at the pyridyl ring were well tolerated. However, the presence of a substituent at the α-position to nitrogen in pyridine inhibited the coupling due to steric hindrance. Dramatic suppression of the coupling with the addition of radical inhibitor (TEMPO) indicated that the direct intramolecular cyclization proceeded via the radical mechanism. O PMB O

H N

N N

H

PMB 65

R N

O FeCl2 4H 2O, O2 DMSO, 120 o C

PMB O

N

N N

N

R

PMB 66, up to 93%

Scheme 15.19  Iron-catalyzed intramolecular C6-H amination of 5-(2-pyridyl)aminouracils to purines.

Finally, as discussed above, treatment of 2ʹ,3ʹ-isopropylideneuridine 9 with methyl acrylate 10 in the presence of palladium acetate (1.2 eq.) provided 5ʹ,6-cyclouridine derivative 14 in 23% yield (see Scheme 15.2; section 2.1) [46] which could be considered as the overall direct C6-H functionalized of uridine derivative.

15.4  Inverted C–H Functionalization of Uracil Nucleosides 15.4.1  Inverted C5-H Functionalization of Uracil Nucleosides The lack of regioselectivity in the direct activation of uridine derivatives (C5-H versus C6-H) during cross-couplings with aryl halides, and the fact that protection of 3-N position in uracil base is usually required, can be overcome by switching the halide substituents from aryl halides to uracil ring and allowing the reaction of 5-halouridines with readily available arenes instead. Wnuk’s group found that the 5-iodouracil nucleosides 67–69 coupled with simple arenes or heteroarenes 70 in the presence of Pd2(dba)3 and TBAF in DMF under reasonably mild conditions (100oC/1–2 h) gave the 5-arylated

15.5  Direct C2-H Functionalization of Adenosine

uracil nucleosides 71 in high yields (Scheme 15.20, Method A) [66]. This TBAF-promoted protocol, which proceeded without the necessity of adding ligands and/or additives, worked efficiently with the natural uracil nucleosides and was compatible with the stability of the glycosylic bond for 2ʹ-deoxyuridine substrates (e.g. 69). The 5-(2-furyl, or 2-thienyl, or 2-pyrrolyl)uridine derivatives 71, which are important RNA and DNA fluorescent probes [68–70, 104], were synthesized in up to 98% yields without the necessity of using toxic organometallic substrates. The arylation proceeded also when TBAF was replaced with Cs2CO3 base with or without the presence of PivOH (Scheme 15.20, Method B) [66]. The analogous coupling of 5-iodocytidines with arenes failed to afford 5-arylated products. The fact that 3-N-methyl-5-iodouracil substrates, which lack the ability to tautomerize, did not undergo these couplings with arenes indicates that the C4-alkoxide of the enol form of uracil may participate in the intramolecular processes of hydrogen abstraction [66]. Zhang and coworkers also applied the inverted coupling strategy and developed the photo-induced direct arylation of 5-iodouridine 67 with (hetero)arenes in the presence of NaOAc for the synthesis of C5-arylated uridine derivatives (Scheme 15.20, Method C) [41]. Although the yields of 5-arylated products 71 were relatively low, the coupling proceeded with regioselectivity due to the presence of C5–I bond in the uracil ring under relatively mild conditions without a transition metal catalyst. O

O

RO

X

O

I

HN

HN N

+

O

X H

Method A: Pd2(dba)3 , T BAF, DMF , 100 oC, 1 h Method B: Pd(OAc) 2, Cs 2 CO 3, DMF, 100 o C, 1 h

RO

N

O

Method C: hv, NaOAc, MeCN/H 2O, rt 70 X = O, S, NH

OR X 67 X = OAc, R = Ac 68 X = OH, R = H 69 X = H, R = H

O

OR

X

71, 45-98%

Scheme 15.20  Cross-coupling of 5-halouracil nucleosides with arenes and heteroarenes.

15.4.2  Inverted C6-H Functionalization of Uracil The inverted coupling was also applied to the synthesis of 6-arylated uracils 74 by visible-light photo-catalyzed direct functionalization of 6-halouracils 72 with N-methylpyrrole 73 employing N,N-diisopropylethylamine (DIPEA) as an electron donor and rhodamine 6G as photoredox catalyst (Scheme 15.21) [40]. Alternatively, irradiation of the mixture of 6-chloro-2,4-dimethoxypyrimidine, various (hetero)arenes, rhodamine 6G (Rh6G), and N,N-diisopropylethylamine (sacrificial electron donor) with blue LEDs (455±15 nm) under nitrogen atmosphere gave also the coupling products. Hydrolysis of the methoxy groups of the C6-H arylated products gave uracils analogues of type 74 in almost quantitative yields [40].

Me O

N

+ N

Cl

N H

Rh-6G, DIPEA DMSO/H2 O 25 oC, 48 h

Me O

HN

N N

N

H3 C

H 3C O

NH O

Me

Me 72

CH 3

O

O

73

74, 22%

Rh-6G

Cl

CH3 CH 3

O

Scheme 15.21  Cross-coupling of 6-halouracils with (hetero)arenes.

15.5  Direct C2-H Functionalization of Adenosine The charge distribution in the purine ring features electron-deficient pyrimidyl and electron-rich imidazolyl rings, however, the π-electron clouds of both monocyclic systems in purines overlap. In general, site-selective direct C–H functionalization at the C2, C6, or C8 positions of purine nucleobases is still a challenging task [12–14, 71]. Contrary to the reasonably well developed direct C–H functionalization at C6 or C8 position of purines, direct C2-H derivatization is still a challenging task and the reported methods are very limited.

641

642

15  Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases

One of the examples for direct C2-H functionalization of purine nucleoside involves alkylation of adenosine 75 in the presence of an organic photocatalyst. Thus, treatment of 75 with cyclohexanecarboxylic acid and 1,2,3,5-tetrakis(carbazol9-yl)-4,6-dicyanobenzene (4-CzIPN) under the LED light provides the 2-cyclohexyl product 76 in 11% yield (Scheme 15.22) [72]. Although the authors did not elaborate further on the formation of product 76, it is noteworthy that this protocol has been successfully applied for the direct C6-H functionalization of purine nucleosides when used with purine substrates without the amino group at the C6 position (see section 15.6.1.3 for detail). NH 2 N N HO

NH 2 N

N N

H

N

TFA, DMSO, 4-CzIPN 3 h, 40 oC, 34 W blue LEDs

O

OH

Cy-COOH DMAP, DIC, 24 h HO

N N

N Cy

O

N

N

NC

CN N

OH

OH

75

OH 76, 11%

4-CzIPN

Scheme 15.22  Decarboxylative C2-H alkylation of adenosine with alkyl carboxylic acids.

15.6  Direct C6-H Functionalization of Purine Nucleoside 15.6.1  Direct C6-H Alkylation Biological and pharmaceutical activities of the C6-modified purines and purine nucleosides [73–75] have been a driving force behind development of the novel methods for their synthesis by direct activation of the C6-H bond that expediently increase their diversity. 15.6.1.1  With Cycloalkanes

Guo’s group developed a transition metal-free C6-H bond functionalization of purine nucleosides with cycloalkanes in the presence of di-tert-butyl peroxide (Scheme 15.23) [51, 76]. Thus, treatment of purine and 2-fluoropurine nucleosides 77 with various cycloalkanes for 2 hours gives only C6-monocycloalkyl purine derivatives 78–83 in good yields (up to 91%). This radical protocol has a general character and was applied to ribosyl, arabinosyl, or 2ʹ-deoxyribosyl purine nucleosides as well as pyrimidine nucleosides (see section 15.2.3). With an extended reaction time (24 h) and higher loading of di-tertbutyl peroxide (3 equivalent), the 6,8-dicycloalkyl purine derivatives are obtained in good yields [51] (see section 15.7.3 for C8-alkylation). This protocol represents an improvement as compared to the previous method [67], which was based on the coupling of purines with iodocycloalkyls in the presence of FeSO4 and tBuOOH under acidic conditions for the regioselective alkylation and acylation of 9-benzylpurines. R3

H N

N R2 R O

N

N

1

R2 1 R O

O Y OR1 77

N

N

R 3-H t-BuOOt-Bu (2 equiv), 140 o C, 2 h

N

N

O Y OR1 X

X 78 79 80 81 82 83

1

R =Ac, R 1=Ac, R 1=Bz, R 1=Bz, R 1=Ac, R 1=Ac,

X=OAc, Y=H, R 2=H, R3 =Cy; 91% X=OAc, Y=R 2=H, R3 =Adamantanyl; 80% X=OBz, Y=R 2=H, R3 =Cy; 89% X=OBz, Y=H, R 2=F, R 3=Cy; 78% X=H, Y=OAc, R 2=F, R 3=Cy; 75% X=Y=R2 =H, R3 =Cy; 80%

Scheme 15.23  Free radical C6-H cycloalkylation of purine with cycloalkane.

15.6  Direct C6-H Functionalization of Purine Nucleoside

15.6.1.2  With Boronic Acid

A photoredox-mediated Minisci C–H alkylation reaction of acetyl-protected purine nucleoside 84 with propyl boronic acid in the presence of tris(bipyridine)ruthenium(II) chloride as a photocatalyst and acetoxybenziodoxole (85, BI-OAc) as an oxidant in hexafluoroisopropanol (HFIP) provides C6-substituted nucleoside 86 in 60% yield (Scheme 15.24) [77]. It is noteworthy that the alkylation was selective at the C6 position and that the 6,8-dialkylated regioisomer is formed in 20:1) is obtained in para position, which may be due to the reduced steric hindrance between the substituents and the iodine atom. To remove the DG, they first activated the amide linked with a Boc group, which was followed by cleavage with LiOH, giving the final carboxylic acid in a yield of 81% (over 2 steps).

H R2 9

R1

O N H NPhth

Q

+

TIPSO

Pd(OAc)2 (5 mol%) Ag2 CO3 (3 equiv.)

O I

R1 TIPSO

TFA (2 equiv.) THF, 75 °C, 24 h

2, (2 equiv.)

10

O

R2 O

NPhth HN

TIPSO TIPSO

OTIPS O

TIPSO TIPSO

TIPSO

OTIPS O

HN Q 10a, (67%, dr = 5:1)

TIPSO TIPSO

OTIPS O

HN Q 10b, (71%, dr = 7:1)

tBu TIPSO TIPSO O

NPhth HN

Q 10e, (68%, dr > 20:1)

O

O

OTIPS O O

NPhth HN

Q 10f , (65%, dr = 6:1)

Me TIPSO NPhth

O

NPhth

NPhth

TIPSO

OTIPS O

TIPSO

O

NPhth 10c, (85%)

TIPSO TIPSO CF3

Q

HN

O

NPhth

HN 10d, (73%, dr > 20:1) Q

Q

OTIPS O

O

TIPSO TIPSO NO 2

HN

Q 10g, (72%, dr > 20:1)

Scheme 16.6  Palladium(II)-catalyzed synthesis of C-alkylglycolamino acids reported by Liu et al.

OTIPS O

Me F

NPhth

O

HN Q 10h, (78%, dr = 12:1)

16.3  Directed C-H Activation Approach

After experimental investigation, they proposed a mechanism for this methodology (Scheme 16.7). First, a cyclometallation leads to the formation of the palladacycle intermediate A. An oxidative addition with the 1-iodoglycal then generates the intermediate B, which undergoes a reductive elimination that leads to the complex C. The last dissociation step gives the desired product P and regenerates the initial palladium catalyst. The role of the TFA is unclear, but Liu and coworkers supposed that either it could act as a unique ligand to stabilize the palladium(II) intermediate A, or it could help in the oxidative addition step. R1

O

O

TIPSO

R2 O

Npthn HN

P

PhthN R2

N H

Q

H

Pd II

Q

Complexation and C-H palladation R2 R1 TIPSO

O

O Npthn C

O N PhthN

PdII N L

N Pd II N L A R2

Oxidative addition

Reductive elimination O

N N Pd IV L

I PhthN B

R2

R1 TIPSO

O I

O R1

Scheme 16.7  Mechanism proposed by Liu et al.

The same year, Ackermann and coworkers [18] independently developed a similar palladium-catalyzed Csp3-H glycosylation, but this approach permitted the production of C-aryl/alkylglycopeptides (Scheme 16.8). In this work, they used the assistance of a DG such as TAM derivative or 8-AQ. They employed different catalytic systems. The first involved the Pd(OAc)2 as the catalyst with 1-AdCO2H and Ag2CO3 in dioxane at 80°C (Scheme 16.8). These conditions were compatible with phenylalanine derivatives, which led to nine examples in moderate to excellent yields (51–95%) and high diastereoselective ratios (dr>20:1) in the presence of the TAM derivative DG. They used another catalytic system, using the Pd(OAc)2 with benzoquinone, AgTFA, and K2CO3 in dioxane at 60°C leading, in the presence of 8-AQ DG, to eight examples in yields of 52% to 93% and diastereoselective ratios of 4:1 to 10:1 (Scheme 16.8). In addition, diverse terminal peptides and peptide-natural product hybrids 13 were used in the presence of a Pd(TFA)2 as catalyst, with 1-AdCO2H, Ag2CO3 in dioxane at 80°C, which gave seven modified peptides 14 in moderate to good yields (32–80%, Scheme 16.9) [18]. These conditions were also compatible with internal peptides placed on the TAM DG, which led to five glycopeptides in 50% to 67% yields (Scheme 16.9). Finally, they applied this methodology to bio-compatible fluorescent probes, such as BODIPYs (boron difluoride group joined to a dipyrromethene group), which enabled them to obtain five unprecedented BODIPs labeled glycoamino acids 14e-g in good to excellent yields (57–97%, Scheme 16.9). Their publication described several mechanistic studies using DFT calculations. They supposed that the first step is the activation of the C–H bond; this is followed by the dissociation of acetic acid and the association of 1-iodoglycal, which leads to an intermediate that could be further stabilized by Ag2CO3. The cleavage of the C–I bond occurs with the help of the silver salt, forming the palladium(IV) complex intermediate. Then there is the reductive elimination, permitting formation of the C–C bond, and finally, a protonation step that leads to generation of the desired compound. In 2019, Nishimura and coworkers proposed an iridium-catalysed hydroarylation of glycals of type 16 through a directed C–H activation reaction of a pyridinyl compound 15 using [IrCl(cod)2], NaBArF4 and (S)-binap in toluene for 24 hours (Scheme 16.10) [21]. These conditions led in most cases to the β isomer 17. Similarly, the use of (R)-binap switched the

663

664

16  C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides O PhthN

R

N H R2

H

OTIPS O

TIPSO TIPSO

R1

I

11

OTIPS O

TIPSO TIPSO

O

R1

O

HN

TAMBn

NPhth

O

O

R 2 HN

12

OTIPS O

TIPSO NPhth

NPhth

O

TIPSO

Additives 1,4-dioxane 60-80 °C, 8-10 h

2, (2 equiv.)

NPhth

HN

TIPSO

+

Pd(OAc) 2 (10 mol%) [Ag]

O

O

Me TIPSO

HN

TAMBn

TIPSO TIPSO

R

NPhth O HN

TAMBn

O O 12a, (95%, dr > 20:1)

NPhth O HN

NPhth O

O Me TIPSO

HN

Q

12d, (74%, dr > 20:1)

12c, (86%, dr > 20:1)

TIPSO

OTIPS O

TIPSO TIPSO

N N N

H O 12b, (56%, dr > 20:1)

OTIPS O

TIPSO TIPSO

NPhth O

O

Q

HN

OTIPS O

TIPSO TIPSO

HN

Q

OEt 12e, (79%, at 100 °C)

12f, (52%)

F

NPhth O Q

NPhth

12g, (92%, dr = 10:1)

12h, (92%, dr = 6:1)

Scheme 16.8  Glycosylation with directing group reported by Ackermann et al.

O PhthN H

TIPSO TIPSO

OTIPS O

NPhth O HN

14a, (80%)

O

R1 N H

R +

TIPSO

R2 13

TIPSO TIPSO

TAMBn

I

OTIPS O

NPhth

TIPSO TIPSO

O HN

O

O

TAMBn

OTIPS O

NPhth O HN

14c, (32%)

TIPSO TIPSO

TAMBn

NPhth

O

O 14

OTIPS O

14d, (65%)

R2 HN

R

NPhth O Me

HN

Me N N N

MeO2C

Me

NHAc

Me

NBoc

R1 TIPSO

Ag2CO 3 (20 mol%) 1,4-dioxane, 80 °C, 16 h

2, (2 equiv.)

14b, (64%)

NH

Pd(TFA) 2 (10 mol%) 1-AdCO2H (30 mol%)

O

HN

OTIPS O

TIPSO NPhth O HN

14e, (84%) Me

NPhth O

O Me TIPSO 14f, (97%)

HN

TIPSO TIPSO

OTIPS O

NPhth O HN

TAMBn 14g, (72%)

Me N

Me

TAMBn

B

F F

TIPSO TIPSO

TAMBn

OTIPS O

NPhth O

14h, (67%)

HN

Me Me

N N N

N

N Me

B

N

N

F F MeO

OMe O

Me TIPSO TIPSO

Me

OMe

B

N

F F OMe

Scheme 16.9  Glycosylation of terminal peptides, hybrids and glycoaminoacids reported by Ackermann et al.

Me

O

Me NH

HN O

CO 2Me

Ph

16.3  Directed C-H Activation Approach

stereoselectivity to the α adducts 18. These conditions permitted the formation of several C-aryl glycosides in good to excellent yields (61–92%) and excellent diastereoselectivities (up to 98% de) in the majority of the cases, and allowed the possibility to reach both α and β configurations starting from the same precursor. No di-arylated products were observed, and diverse protected or non-protected glycals could be successfully engaged. Because glycals are precursors of the corresponding iodoglycals used in the previous studies, this route has the advantage of shortening the access to the corresponding C-aryl glycosides.

N

RO RO RO

+

H

15 (1.5 equiv) BnO

[IrCl(cod) 2] (5 mol% Ir) NaBArF4 (10 mol%)

O

(S)- or (R)-binap (6 mol%) toluene, 24 h

(t-Bu) 2Si O O HO

O BnO

R1O R2 O R3O

O RO

O O HO

with (R)-binap 60°C 18 R1 O R2 O R3 O

O Py

17c, (S)-binap (94%) 99:1 ( β:α ) (R)-binap (84%) 64:36 ( β:α)

O

Py

18a, R = Bn (78%) 2:98 (β :α) 18b, R = Ac (84%) 4:96 (β :α)

PMP

17b, (88%) 99:1 ( β :α)

OR

Py

with (S)-binap 80°C 17

O

O

or

Py

Py 17a, (74%) 99:1 (β :α) RO

Py O

RO RO RO

16

OBn

RO RO RO

Py

O Py

17d , R1 = R2 = H (68%) 80:20 ( β:α)

17e, R1 = R2 = Bn (82%) 98:2 ( β:α ) 17f, R1 = R2 = CH2OMe (92%) 99:1 ( β:α ) 17g, R1 = SiMe 2 t-Bu, R2 = H (61%) 99:1 ( β:α)

18c, R1 = SiMe2 t-Bu, R2 = H (83%) 28:72 ( β:α ) 18d, R1 = R2 = H (69%) 15:85 ( β :α)

Scheme 16.10  Iridium(I)-catalyzed hydroarylation of glycals 16 via C–H activation: impact of the absolute configuration of the ligand binap.

Several aromatic compounds were employed as shown in Scheme 16.11 and Scheme 16.12, leading to moderate to excellent yields (53–97%) and good diastereoselectivities (87–98% de).

N

PMP

H

+ R'

O O HO

O

[IrCl(cod) 2] (5 mol% Ir) NaBAr F4 (10 mol%)

PMP

(S)-binap (6 mol%) toluene, 80 °C, 24 h

O Py

19

15 (1.5 equiv)

O O HO 17

R'

> 99:1 (β :α)

R' PMP

O O HO

O

Py 17h, R' = Me, OMe, F, Br, Ph (66-87%)

PMP

O O HO

O

PMP S Py

17i, (77%)

O O HO

O

17j, X = O, NMe N (71%)

X

Scheme 16.11  Iridium(I)-catalyzed hydroarylation of glycal 19 in the presence of (S)-binap, varying the nature of the aryl.

665

666

16  C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides

N +

H R

AcO AcO AcO

15 (1.5 equiv) AcO AcO AcO

AcO AcO AcO

[IrCl(cod)2 ] (5 mol% Ir) NaBAr F4 (10 mol%)

O

Py

(R)-binap (6 mol%) toluene, 80 °C, 48 h

AcO AcO AcO Py

R 18e, R = Me, OMe, F, Br (67-97%) 4:96-2:98 (β:α)

AcO AcO AcO

O

R

18 > 99:1 ( β :α)

20 O

O

O X

Py

N S 18g, X = O, S (53-56%) 1:99 ( β :α)

18f, (67%) 7:93 (β:α)

Scheme 16.12  Iridium(I)-catalyzed hydroarylation of glycal 20 using (R)-binap, varying the nature of the aryl.

Nishimura and coworkers proposed a reasonable mechanism based on their previous work [22] (Scheme 16.13). By reaction between [IrCl(cod)2], NaBArF4, and the binap ligand, the in situ formation of the iridium(I) complex ([Ir(binap)]+[BArF4]-) undergoes complexation with the aryl-pyridine substrate to form A. An ortho C–H activation favored by the proximity of the metal affords the aryl(hydrido)iridiumIII B. Depending on the absolute configuration of the binap ligand, the insertion of glycal 1 into Ir-H bond evolves to either C or D, which lead respectively, after reductive elimination, to the β-aryl glycoside 2 and to the α-aryl glycoside 3. H Ir

III

O

(RO) n

N

14

2 OA C-H activation

H Ir

3

B

I

O

(RO)n

N H (RO)n

A

complexation insertion

O

H

N Ir

or

III

III

N

C

D

4

1

RE and

decomplexation

complexation 1 H

Ir = [Ir(binap*)] N

15

Ir

IrBAr F4 + NaCl

(RO) n

O N

F4

NaBAr binap* [IrCl(cod) 2 ]

17 or 18

Scheme 16.13  Proposed mechanism for the iridium(I)-catalyzed hydroarylation of glycals 16.

16.3  Directed C-H Activation Approach

16.3.b.1.b  Using Glycosyl Chloride Partners (4)

In 2019, Chen and colleages presented [23] an access to C-aryl glycosides from glycosyl chlorides 22 that used similar conditions to Ye’s work. They proposed two different conditions, which used either the cheap acetic acid co-ligand or the more expensive N-acetyl protected isoleucine (Ac-Ile-OH). The co-ligand appears to be crucial for observing a good reactivity, but its exact role is not clear. The corresponding C-aryl glycosides 23 were synthesized in excellent yields in most of the cases (Scheme 16.14).

Q O

HN

BnO +

H

BnO BnO

OBn O

R

22, (2 equiv)

BnO

QHN OBn O O

BnO

O

Bn

BnO

QHN OBn O O

BnO

O

OBn O

R BnO

23h, R = Me, Ph, OAc, F, Cl, Br; (62-87%) (B)

23c, R = Ph (92%) (A) 23e, R = OAc ( 78%) (B) 23f, R = CF 3 (27%) (A)

BnO

OBn O OBn

QHN

BnO O Bn

X

23i, X = NMe (91%) (B) 23j, X = O (77%) (B)

OBn O OBn

O Bn

Bn 23

O

R

QHN OBn O

OBn

R 23k, R = H, OMe; (68-92%) 12:1-1:2.6 (mono:di) (B)

O

C4

BnO

Bn

23a, R = Me ( 95%) (A) 23b, R = i-Pr ( 95%) (A)

QHN

1

O

Q HN O

BnO

QHN OBn O O

Bn

R

23g, R = F, Cl, I; (79-95%) (A)

BnO

25-110 °C, 6-12 h AcOH (2 equiv) (conditions A) Ac-Ile-OH (30 mol%) (conditions B)

Cl

21 BnO

Pd(OAc)2 (10 mol%) KOAc (1.5 equiv) toluene, Ar

O Bn

O X R

23m, X = NMe, R = H, (65%) (B) 23n, X = O, R = H, (63%) (B) 23o, X = S, R = Me, (92%) (B)

O

O

23l, (77%) (B) 1:1.2 (mono:di)

Scheme 16.14  Palladium(II)-catalyzed synthesis of C-aryl pyranosides varying the aryl moiety.

Chen and coworkers obtained a wide range of products bearing different benzamide parts (62–95%) (Scheme 16.14 and Scheme 16.15) or diversely protected pyranose 22 and furanose 26 moieties (Scheme 16.15 and Scheme 16.16), mainly as the mono-arylated form. Electron-withdrawing groups on benzamide substrates, such as CF3, led to lower yields. Heteroarenes such as furans, pyrroles, thiophenes, and indoles were also successfully coupled. The bidentate and the nonsubstituted N-amide atom characters of the DG were proved to be essential for the reactivity. Tri- and tetra-saccharide substrates were also used in these conditions. The authors proposed an application of their method to the mannosylation of repaglinide, an antidiabetic drug. Different amidoquinolyl-type DG, such as aryl acetamide or phenol derivatives, were successfully employed, which led to the corresponding aryl and heteroaryl substrates in moderate to excellent yields (42–95%, Figure 16.2). Finally, the aminoquinoline DG was cleaved on a few examples using Schwartz’s reagent or saponification conditions. Removal of the phenolic DG was also proposed using ethylamine in methanol at room temperature on one derivative, thereby furnishing the desired compound in a quantitative manner. Chen and coworkers take a mechanistic point of view and suggest that a species more reactive than starting 1-chloro mannoside 22 could be involved in the process. Due to both the stereoretention observed in most cases and the exclusive formation of the α product starting from a mixture of glycosyl chloride anomers, these results tend to prove the existence of an oxocarbenium ion C, which is formed from 22 due to the Lewis acidity of Pd(OAc)2 (Scheme 16.17). The attack on its less hindered side explains the observed stereoselectivity. The involved palladium complex A would be a 5,5- or 5,6- bicyclic structure (in green in Scheme 16.17), which favors a C–H activation process on the ortho position of the aryl ring. The mechanistic hypothesis is ascertained by the successful

667

R2 21

+

Pd(OAc) 2 (10 mol%) KOAc (1.5 equiv) toluene, Ar

O

1

(R O) 3

O

QHN OR2 O

O R1

OR2

i-Pr 24' 4C1

BnO

OBz O

OBn

BnO

O

BnO BnO

NHQ

O

O

O i-Pr 24'c, R = OBn (67%) 4.6:1 (a:b) 24'd, R = OAc a (52%)

O O

O O O

O

NHQ

R

24'b, (92%) i-Pr

24'a, (95%) i-Pr 10:1 (a:b) QHN

i-Pr OBn

O NHQ BnO

BnO

O

24 1C4

O

BnO

Q NH

or

(R O) 3

i-Pr

24a, R1 = Ac, R2 = R3 = Bn (87%) 24b, R1 = R2 = R3 = Ac (78%) 24c, R1 = R2 = R3 = All (93%) 24d,R1 = R2 = Bn, R3 = Ac (90%) 24e, R1 = R2 = Bn, R3 = TBDPS (95%) 24f, R1 = R2 = Bn, R3 = MOM (81%)

O

(R1O)3

1

O O BzO

Ph

2

O

O

25-110 °C, 6-12 h Ac-Ile-OH (30 mol%)

Cl 22

R 3O

R

R2

Q HN

NHQ

i-Pr

O

OAc i-Pr 24g, (91%)

24'e, (84%)

Scheme 16.15  Palladium(II)-catalyzed synthesis of C-aryl pyranosides varying the sugar.

Q O

HN

R3

H X

O

(R2O)3

+

R1

Cl

25 O

O

QHN

H

O

O

O

H

O

O

O i-Pr 27a, (93%)

(R2O)3

O

HN

O

NHQ

O

TBDPSO

OBn

O O

O

27

O

O O

I

O

R1

Q HN OBn

i-Pr 27d, (53%)

Scheme 16.16  Palladium(II)-catalyzed synthesis of C-aryl furanosides.

BnO BnO BnO

OBn O

Pd(OAc) 2 (2 mol%)

HO

+

Ph

Cl

22

BnO BnO BnO

Pd(OAc)2 OBn

OBn O

A OBn

BnO C α attack (favored)

O N II Pd

A

M eC

N

N

toluene, 25°C, 12 h

OA

BnO BnO BnO

OBn O Ph

O

(68%) no reaction without Pd

OBn O O

X

N N

IV

Pd

continued from scheme 4

Cl

L B R

22 KOAc (1.5 equiv) toluene, 110 °C, 2 h Ac-Ile-OH (30 mol%)

R O R

O

OBn

NHQ 27c, (79%)

27b, (67%)

Q O

X

25-110 °C, 6-12 h Ac-Ile-OH (30 mol%)

26

O

R3

Pd(OAc)2 (10 mol%) KOAc (1.5 equiv) toluene, Ar

Q HN

O

R 23h, R = OBn (91%)

Scheme 16.17  Proposed mechanism for the palladium(II)-catalyzed synthesis of C-aryl glycosides.

16.3  Directed C-H Activation Approach NHQ BnO OBn O OBn

O S

O

BnO

OBn O O

1 BnO

MeO O O

R2

Bn

O

OBn

BnO

O

O OBn O

Bn OMe 24n, di only (85%)

OBn

OBn BnO

BnO

2

BnO

O

NHQ

OAc

24m, (44%)

NHQ

O O

O

O

O

NHQ SBTO

O

O O

O

OBn BnO

24j, R = H, R = OMe (95%) 24k, R1 = CO 2Et, R2 = OEt (88%) 24l, R1 = H, R2 = F (42%)

24i, (52%) + C1-isomer (38%) NHQ

BnO

1

NHQ

O

R1

24h, (93%)

BnO

NHQ

BnO

O

OBn O O Bn

Bn

OBn O O

NHQ

BnO

O

O

O

O

O

MeO 24'f, mono only (69%)

27e, (83%)

27f, (80%)

Figure 16.2  Palladium(II)-catalyzed synthesis of C-aryl pyranosides and furanosides using different amidoquinolyl-DG in conditions A (using Ac-Ile-OH (30%) as additional ligand).

synthesis of the palladacycle A (Scheme 16.17) through reaction between Pd(OAc)2 with 2-methylbenzamide in acetonitrile, in addition to its successful reactivity in standard conditions for the formation of 23h from 22. One year later, the group of Chen and Liu used these conditions to propose the first total synthesis of a natural decamer-type C-glycopeptide hormone, Cam-HrTH-I [24]. The key step was the formation of a C2-α-mannosyltryptophan amino acid building block 29 that was ready-to-use in a peptide synthesis. This starting substrate was obtained via the previously developed palladium-catalyzed directed C–H glycosylation reactivity, which was applied on a tryptophan derivative using a mannosyl chloride partner 22. Investigation of different strategy to place the DG showed that the size of the palladacycle intermediate was crucial, and thus, installation on the N terminus position was the best option for reaching an excellent yield. Moreover, an isoquinoline-1-carboxylic acid-type DG was chosen thanks to a screening study. In this way, using the previously optimized C–H activation conditions, they formed the desired product 29 from the N-unprotected indole in an excellent yield and with an exclusive α selectivity (Scheme 16.18). After further post-functionalisation steps (including the removal of the DG), the authors engaged the obtained mannosyl amino acid in the peptide synthesis to reach the desired Cam-Hr-TH-I hormone in good yield and high purity. DFT calculations were performed in order to give mechanistic hypotheses. The C–H palladation seemed to proceed via a CMD pathway, as already postulated. However, whereas an oxocarbenium intermediate was classically assumed, the calculations tended to show that an oxidative addition could occur via a concerted three-membered cyclic transition state directly from the mannosyl chloride compound. Then, a concerted reductive elimination via a second three-membered cyclic transition state could form the desired product (Scheme 16.18). These calculations also allowed exclusion of the β-mannosylation pathway, which presents higher energy barriers. With this expertise, the group of Cheng and He applied the same conditions to the ortho-directed C–H glycosylation of different arenes (arylamines, carbazoles, indoles, and benzylamines) using either bidentate urea or amide DGs and either pyranose or furanose glycosyl chlorides 22 as partners (including one disaccharide example) (Scheme 16.19) [25]. As with the previously mentioned studies, the corresponding C-arylglycosides were obtained in good to excellent yields and excellent α selectivity. The switch from the 4C1 to the 1C4 sugar conformation was observed in the majority of the examples presented. Whereas several sugar protecting groups were tolerated, peracetylated derivatives were inactive. Cleavage conditions for all the engaged DGs were also proposed. Chen, He, and coworkers very recently demonstrated the huge versatility of their process by applying these conditions to the synthesis of C-vinyl-glycosides, which they accomplished by replacing the arene partner by an alkene 32 [26]. Due to an amide DG, they were able to perform the C–H activation of the γ position of allylamines 33 (Scheme 16.20) and the δ position of homoallyl amine substrates 34 (Scheme 16.21) in good to excellent yields, in addition to excellent regio- and stereoselectivity in favour of the α,cis-isomer (except for the ribosyl example, where the β-isomer was preponderant) (Scheme 16.20). The conditions were adapted depending on the substrate. The 4C1 or the 1C4 glycosyl conformation observed depends on the nature and steric hindrance of the alkene partner. In case of allylamines, a five-membered palladacycle was proposed that let the activation of the C–H bond in the γ position.

669

670

16  C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides

O

MeO 2 C N H

BnO

OBn O

+ BnO BnO

N

N H

OH H N

O

H N

N H

O

AQHi 1N

OBn N BnO H

22, (2 equiv)

28

Cam-HrTH-I = O

MeO2 C

110 °C, 12 h Ac-Ile-OH (30 mol%)

Cl

H N H

Pd(OAc)2 (10 mol%) KOAc (1.5 equiv) toluene, N2

OBn

29, (85%)

Key intermediate revealed by the DFT calculations

OH

O

O

O

O

N H

Cam-HrTH-I

BnO O

O

N

MeO NH2 H O O N

N H OH O

O

OMe O

NH2

N H

O

HO

H N

MeO MeO

N 3 Pd N Cl

HN

O

OH

OH N H

HO

Scheme 16.18  Palladium-catalyzed C–H glycosylation of tryptophan.

R' N n

H

Pd(OAc)2 (2-10 mol%) KOAc (1.5 equiv) toluene, N2

O O

(RO)3

R'' +

n

R

R' N (RO)3

O

60-110 °C, 6-12 h Ac-llE-OH (30 mol%)

Cl

O R''

n

22 (2 equiv)

30

n

31, α

R

Scope of amines and DG

HN

OBn O Bn

O

BnO N H

N

OBn O

N

O

BnO

N

Q

O

BnO

OMe

BnO N H

HN

N H

SMe BnO

O

BnO

Bn

Bn

31b, (81%)

31a, (94%)

HN

OBn O

N

O

BnO

O

31c, (>95%)

O

N BnO O O Bn OBn 31c, (57%)

Scope of sugars O

AllO HN

OAll O AllO

Q HN

O N H

Q

HN

OBn O

O All

N H

Q

O Bn

BnO OBn

31d, (90%)

O

TBDPSO

N H

31f, (85%)

Bn

O OBn O O Bn HN O

31i, (92%)

PA

O

N Bn

O

O OBn PA Bn HN

31j, (40%)

BnO

Bn

O OBn O O Bn HN O

31k, (57%)

O

Bn BnO O O O O AcO Ac OBn AcO OAc

31g, (93%) i 1QA

BnO

N H

HN

O

O

OBn OAc

Amide-linked auxiliary BnO

Q

O

BnO

31e, (69%)

O

O

BnO O Bn

O

O OBn i 1QA Bn NH

N

31l, (83%)

Scheme 16.19  Palladium-catalyzed C–H glycosylation of arenes using ureas and amides as DGs.

31h, (96%)

HN

N H

Q

16.3  Directed C-H Activation Approach i 1QA Pd(OAc) 2 (10-20 mol%) KOAc (1.5 equiv) 1,4-dioxane, Ar

O HN

(RO) 3

+

N

H

O n

Cl

Scope of alkenes OBn O

BnO BnO BnO

NHiQA

BnO

OBn O

NHiQA

O

OBn

33a, R = Et (85%) R 33b, R = iPr (71%) 33c, R = Cyp (82%) 33d, R = Ph (96%) 33e, R = pF-C6H5 (93%)

n

Bn

BnO

BnO NHiQA BnO

BnO

OBn O

33f, n = 1 (68%) 33g, n = 2 (79%)

Bn

33h, (78%)

AQiHN

O NHiQA

BnO

NHQiA

TBDPSO

AQiHN

O

O

BnO

O

OBn OAc 33i, (61%)

33, α

O

OBn

OBn

O

n

NHiQA

BnO

Scope of sugars BnO OBn

O

110 °C, 12 h Boc-Ava-OH or PivOH (RO)3 (30 mol%)

22 (2 equiv)

32

NHiQA

33j, (46%)

BnO

O

O OBn

BnO

33l, β (84%)

33k, (87%)

33m, (63%)

Scheme 16.20  Palladium-catalyzed C–H glycosylation of allylamines using ureas as directing groups.

In the case of homoallyl amine partners, a six-membered palladacycle intermediate was expected, leading to the C–H activation of the δ position (Scheme 16.21). The authors illustrated their hypothesis via deuteration experiments and showed a kinetic isotope effect of 6.0, revealing that the C–H palladation is the rate-limiting step in this reactivity. i 1QA O

N

+

O

(RO)3

H

n

Cl

22 (2 equiv)

32

OBn O

BnO NHiQA

O

Bn

33q, (77%) NHiQA Ph

NHiQA

O 33r, (67%)

33, α

O

Scope of sugars O O

n

NHiQA OBn O

OBn

33n, R = Me (>95%) R 33o, R = H (83%) 33p, R = Ph (>95%)

O

O

110 °C, 12 h Boc-Ava-OH or PivOH (RO)3 (30 mol%)

Scope of alkenes BnO BnO BnO

AQHiN

Pd(OAc)2 (10-20 mol%) KOAc (1.5 equiv) 1,4-dioxane, Ar

HN

TBDPSO

AQiHN BnO

O

BnO

O OBn

NHiQA

O OBn OBn 33s, (67%)

O

O

33t, β (81%)

BnO 33u, (54%)

Scheme 16.21  Palladium-catalyzed C–H glycosylation of homoallyl amines using ureas as directing groups.

671

672

16  C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides

Very recently, Liang and coworkers proposed a similar ortho-C–H reactivity, starting from the same glycosyl chlorides 22 and using an 8-aminoquinoline DG 21 through a nickel catalysis [27]. Their conditions, although considerably harsh (140°C), proved to be highly regioselective and stereoselective (for the α anomer in the majority of cases). Indeed, only mono-substituted 34 product was obtained. With regard to the scope of the reaction, the functional group tolerance (and their positions on the ring) was large on the benzamide part, but the successful glycosyl chlorides were limited. An experimental investigation of the mechanism showed an absence of free radical during the process. A reversibility of the C–H activation seemed to be the rate-determining step of the catalytic cycle. The authors proposed a mechanism following the same steps as Liu’s proposed mechanism (see Scheme 16.7), starting by the coordination of the nitrogen-containing DG to the nickel species, which can then C–H activate the close ortho C–H bond. After either an oxidative addition with the glycosyl chloride or an attack of the nickel complex onto the preformed oxacarbenium ion, a reductive elimination followed by a demetallization provides the desired product and regenerates the nickel species. Q

Q

HN

O

O +

H

PO

R

R1 HN R2

Q

O

R

O

34, ( α)

R

PO

HN S

O

O

Q O HN

O

O

O

R3

N O O

Cl

O

O

O O

O

R4 O O

34a, R1 = H (61%) 34b, R1 = Me (56%)

34h, R = Me (47%)

34o, (26%)

34i, R = t-Bu (37%)

1

34c, R = F (26%)

O

O

34j, R = OMe (52%)

34d, R2 = Me (42%) 34f, R 2 = Cl, Br, I (50-60%) 34g, R2 = F (60%, α / β : 5/1) HN

34l, R = F, Cl, Br, I (50-60%) 34m, R = CF 3 (44%) 34n, R = NO2 (51%)

Q

HN

O O

O

Q

HN

BnO

34r, R = Bn (37% β) 34s, R = CH=CH-CH 3 (27%, α / β : 1/5) 34t , R = TBDPS (49% β )

Q Ο O

Ο O

OR O

34p, R3 = Cl (51%) 34q, R4 = OMe (33%)

34k, R = Ph (51%)

34e, R2 = OMe (53%)

Scope of sugar

Q O O

O O

1,4-dioxane, Ar

0,1

HN O

140 °C, 16 h

HN

O O

0,1

KHCO3 (2 equiv)

22

21, (2 equiv) Scope of 1

Cl

Ni(dppf)Cl2 (5 mol%)

OBn OBn

34u, (21% α)

BnO

OBn OBn

OBn 34v, (19% α)

Scheme 16.22  Nickel-catalyzed C–H glycosylation.

Also very recently, the groups of Cheng [28] and Liang [29] simultaneously described a three-component palladiumcatalyzed stereoselective Catellani-type C–H glycosylation process. This reactivity promoted an ortho-alkylation of aryl iodide partners 35. Both developed conditions used a cooperative palladium/norbornene catalysis in the presence of a phosphorus ligand and a base (Scheme 16.23). This transformation proved to be very versatile for accessing a broad range of α-C-(hetero)aryl-glycosides 37 by changing the nature of the third reagent. Indeed, the developed methodologies

16.3  Directed C-H Activation Approach

involved a (hetero)aryl iodide, a glycosyl halide, and a third partner, which can be chosen depending on the substrate reached. In the presence of olefins, the (hetero)aryl iodide partner was transformed into an ortho-glycosylated cinnamyl compound. Diverse iodide substrates, as well as various alkenes, were successfully used by both groups, leading to α-Carylglycoside analogues in moderate to excellent yields with an exclusive α selectivity (Scheme 16.23). Cheng showed that dimannosylation became the majority product when para-substituted iodobenzenes were used. Through

R' I H

(R1O)3

+

R

R2

O

n

+

R'

Cl

36

22

35

R (R1O)3 37 : α/β : >20:1

R

R2

O

PdII

R2

(R1O)3

n

Cheng et al. 2020: Conditions: 1 (1 equiv.), 7 (1.5 equiv.), 2 (2 equiv.), Pd(OAc)2 (10 mol%), tri(2-furyl)phosphane (20 mol%),Cs2CO3 (3 equiv.), THF, 100 °C, N 2, 24h O R

O OMe

X

BnO OMe

BnO O

O BnO

OBn

OBn

OBn

37e, X = O (46%) 37f, X = S (38%)

O

R

OBn

37a, R = Me (85%) 37b, R = OMe (62%) 37c, R = F, Cl (48-62%) 37d, R = CF 3 (43%)

OMe

O

OBn

BnO

O NHPh R'

OR'

O

BnO

O

OBn

(2 equiv.)

O

BnO

OBn

OBn OBn

37m, R' = C(O)Et (57%) 37n, R' = CN (55%) 37o, R' = SO2Ph (61%) 37p, R' = 3,3-diOMe-C6H5 (40%)

37i, R' = Et (88%) 37j, R' = tBu (82%) 37k, R' = Bn (54%) 37l, R' = Cy (72%)

OBn 37g, R = Me (40%) di:mono = 5:1 37h, R = OMe (48%) di:mono = 9:1

Liang et al. 2020: Conditions: 1 (2 equiv.), 7 (2 equiv.), 2 (1 equiv.), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), Cs2CO3 (2.5 equiv.), 1.4-dioxane, 95 °C, N2, 13h N O O O R

OEt

OMe

OEt

OBn

BnO

OBn

OBn

BnO

O

OBn

BnO

OBn

O

n

(2 equiv.) CN

N O

OEt

MeO O

O O O

O

37q, R = Me (92%) 37r, R = OMe (89%) 37s, R = F (81%) 37t, R = CF 3 (55%)

O

O

MeO

O O

O

37u, (99%)

O

O O O

O

37v, (98%)

O

O O O

O

37w, 98%

O

O O O

O

37x, (76%)

Scheme 16.23  Catellani C–H glycosylation process for the synthesis of C-aryl-glycosides varying the aryl and the olefin moieties.

In terms of glycosyl chloride partners, the reaction tolerates both pyranose and furanose examples, as well as l-rhamnose, and d-glucose configurations, but the diastereoisometric ratio was moderate in the latter case (Scheme 16.24). Other ipso-terminations were then proposed by both groups. Cheng and coworkers showed that, in the presence of isopropanol instead of the olefin partner, the reaction evolves to the hydrogenated analogue in moderate to good yields (Scheme 16.24). The groups of Cheng and Liang also proposed the use of borylated partners to introduce a methyl or an aryl part. IpsoSonogashira analogues were obtained by Cheng and coworkers using alkyne reagents. This reactivity was applied on the synthesis of complex glycoside-estradiol conjugates 41k (Scheme 16.25). Finally, Liang’s group successfully used zinc cyanide to access the nitrile derivative 41l. It should be noticed that only minor modifications in conditions were used between these approaches. Via the method using isopropanol as third reagent, Cheng and coworkers proposed an access to an analogue of the drug dapagliflozine in 45% yield for the Catellani process. d-galactose,

673

674

16  C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides O OR I H

+

(R1O) 3

R2

O

n

Cl

O

22

38 Cheng et al.: O

n 39 : α /β : >20:1

O

O OBn

O

O O

OBn

O

O

O

OBn

BnO

OBn

O

39c, (32%), α / β = 1:12

O

O

O OEt

O BnO

OEt

OBn OBn

39f, (98%)

BnO

O OBn

MeO

OEt

OEt

OEt

O

OBn

O

O

O

O

OMe OMe

O

39e, (51%)

39d, (70%)

Liang et al.: O

OTBDPS

O O

OBn

39b, (43%)

39a, (98%)

OMe

OMe

OMe

O

O

O

O OMe

OMe

BnO

(R1O) 3

36

O

R2

O

OR

+

BnO

O

OBn OBn

OBn

OMe

OBn

39g, (98%)

39h, (63%), α / β = 5:2.2

39i, (15%), α / β = 10:1

O

OTBDPS

O

39j, (65%)

Scheme 16.24  Catellani C–H glycosylation process for the synthesis of C-aryl-glycosides varying the glycoside moiety.

The mechanism is supposed to proceed though the palladium-catalyzed formation of an oxocarbenium ion generated from the glycosyl chloride. This intermediate could then react through a SN1 pathway with an arylnorbornylpalladacycle C formed in the media through an oxidative addition to aryl iodide, followed by the migratory insertion of the norbornene part (complexe B) that permits the ortho C–H activation process (Scheme 16.26). A reductive elimination, followed by the extrusion of norbornene, completes the catalytic cycle. The preferential attack of the α face in most cases is explained by steric hindrances. 16.3.b.1.c  Intramolecular Anomeric C–H Arylation

An intramolecular C–H arylation of 2-bromophenyl glycosylcarboxamides 42 was explored by Messaoudi and coworkers in 2017 [30] (Scheme 16.27) using a palladium-catalyzed process. The peracetylated 2-deoxy glucoanalogue 42 evolved in the described conditions via the intramolecular selective anomeric C−H activation, which led to glucosylspirooxindole 43. This spiro compound was obtained in very good yield as a mixture of the two α and β isomers (d.r.=3:2). Contrary to this result, perbenzylated or protecting group-free analogues were completely unreactive in the same conditions. DFT calculations were performed in order to investigate the mechanistic pathway, which showed that the first step of the process was the oxidative addition of a palladium(0) species into the C–Br aryl bond, which led, after ligand exchange, to intermediate A (Scheme 16.27). The proximity of the palladium atom with the anomeric C–H bond then promoted a concerted metalation deprotonation (CMD) mechanism, forming a palladium C-enolate that was in equilibrium between the two diastereoisomers B and C. Finally, after a reductive elimination, 43 was obtained when a 2-deoxy starting substrate was used (R=H), whereas glucal 44 was observed when R=OAc. The formation of this latter compound was expected to follow a three-step process starting from a 1,2 palladium migration, followed by a reductive elimination and an elimination reaction (Scheme 16.27).

16.3  Directed C-H Activation Approach

I H R

+

Y

R2

(R 1O)3

O

n

(R 1O) 3

n 41 : α/β : >20:1

40 Me

R

Cheng et al.

H

H

H

OH

X=

R

Cl

22

35

O

O

BnO

OBn

Cheng and Liang et al. X = Me-B(OH) 2 or Ar-Bpin

O

41f, (52%)

Me Me

O

MeO2C BnO

O

OBn

H

TBSO Me O

O

O

O O

O

41j, (32%)

BnO

O

41i, (30%) Liang et al.

H TIPS

O

41h, (66%)

Cheng et al. R'

O

OBn OBn

41g, (36%)

O

O

OBn

BnO

OBn OBn

X=

O

41e, (72%)

F

Me

O

OBn OBn

41b, R = Me (68%) 41c, R = OMe (38%) 41d, R = F, CF3 (62-74%)

41a, (70%)

O

O

BnO

OBn OBn

OBn

H O

OBn

OBn

BnO

R2

O

X

+

OTBS H

X = Zn(CN) 2

Me CN

O

O OBn OBn

OBn 41k, (31%)

O O

O

41l, (48%)

Scheme 16.25  Diverse ipso-transformation using the Catellani C–H glycosylation methodology.

16.3.b.2  The Directing Group Attached to the Sugar Nucleus O DG

O

H

H

Csp 3-H

DG Csp 3-Csp 2

Another challenging tactic for synthesizing C-aryl glycosides is based on the design of a sugar architecture linked to a DG that can direct the Csp3-H functionalization selectively at the desired position. In this context, Messaoudi and coworkers reported for the first time the use of this approach to the anomeric Csp3-H arylation of glycosides 45 (Scheme 16.28) [31]. The authors showed that the rational design of glycoside substrates, by employing the picolinic amide as the DG combined with the use of Pd(OAc)2 (10 mol%) and Ag2CO3 (3 equivalents) in tAmOH at 120°C, led to the C-(hetero)aryl glycosides 46, with a precise control of the α-anomeric configuration. This glycosylation reaction tolerated different sugars and protecting groups such as acetate, benzoate, 4,6-benzylidene, and a benzyl group. However, the TBS-O-protected glycoside 46p

675

676

16  C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides O

(RO)n

4 oxidative addition

Pd II

3 C-H activation

C O

2

D

(RO) n

H

5 reductive elimination

Pd II

B

Pd IV L

(RO) n

O

insertion Pd II

E

H 6 extrusion Pd(II)I (RO)n

A

O

1

Pd II

oxidative addition

Pd(0)

H

F I

Scheme 16.26  Proposed mechanism for the Catellani C–H glycosylation.

AcO AcO AcO

O

O

Pd(OAc)2(10 mol%) PCy3 .HBF4 (20 mol%)

N Me

H

AcO AcO AcO

O

N Me

Cs2CO3 (3 equiv) PhMe,150 °C

Br

42

O

43, (78%), d.r. = 3/2

Mechanistic proposal

43

42

Pd(0)L2

1 OA R=H AcO AcO AcO C

AcO AcO AcO 44

AcO AcO AcO

O R O

3 RE

O

N Me

O N

O

RH

Pd

L Pd O

Me N

A AcO AcO AcO

O

O

R = OAc

O R Pd

O N

Me

2 CMD

B

Me

Scheme 16.27  Intramolecular C–H arylation of the position 1 of 2-deoxy-glucosylcarboxamide 9.

16.3  Directed C-H Activation Approach

Scheme 16.28  Anomeric Csp3-H glycosylation, conditions, scope, and limitations reported by Messaoudi et al.

showed poor reactivity under this procedure. This result may be explained by a switch of the conformation of the starting substrate from 4C1 to 1C4, which would be imposed by the bulky TBS groups [32]. This switch would induce an equatorial orientation of the DG that is not compatible with the formation of the palladacycle. Interestingly, the substrate bearing the DG in an equatorial position is not an effective glycoside partner. This approach is applicable to a wide range of commercially available aryl bromides and iodides, as well as other classes of synthetically useful substrates (Scheme 16.28). For example, C-aryl glycosyl amino acid building block 46h (which may be used in glycopeptide assembly) or the C-aryl glycosyl phenylazide 46d for CuAAC, as well as a fluorescent C-glycoside coumarin tag 46g, were prepared by this strategy in good to excellent yields (56%-93%). In addition, facile preparation of anthraquinone C-glycoside 46j (which is an analogue of the DNA binding drug) was also achieved in 71% yield. Finally, this reaction was used for the synthesis of two potentially bioactive C-glycosides 46e that are α-analogues of the dapagliflozin drug used to treat type 2 diabetes (Scheme 16.28). The authors suggested a mechanism to explain the α-selectivity based in the literature reports. The palladium preferentially approaches the more reactive axial anomeric C–H bond of the substrate (A) to generate a five-membered palladacycle (B) through the CMD mechanism (Scheme 16.29). This pathway will lead to the 1,3 diaxial complex (B), which may be involved in an oxidative addition in the presence of an aryl iodide to furnish the palladium(IV) complex (C). The reductive elimination step produces the desired C-aryl glycoside. The 1C4 conformation of α-arylated glycoside is dictated by the anomeric α-stereochemistry.

677

678

16  C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides

RO

1C

RO RO

4

Ar

O

HN

PdII(OAc)2

NH RO DG

O

4C 1

N

O A 2 AcOH

RO RO

Reductive elimination

O

O

N PdII

Ar O

O

RO RO

O OAg N H Ac AgI

axial CMD

RO RO Ag2CO3 AcOH O

O N

O II

Pd

N

PdIV N Ar

I

O H

N

O H

H O

B Ar-I Oxydative addition

C

  3

Scheme 16.29  Proposed mechanism for the anomeric Csp -H glycosylation.

AcO

HO O

O

AcONH DG

HONH2 NaOH (15 equiv)

or AcO

EtOH, 90 °C, 20 h O

AcONH DG

quantitative yield HO

or O

Cl

OEt

HONH2

Cl

OEt

quantitative yield dapagliflozin analog

Scheme 16.30  Removal of the directing group and protecting groups by Messaoudi et al.

One of the most important challenges in the directed C–H activation strategy is removing the DG at the end of the reaction without altering the final substrate. During this study, it was shown that the pyridyl amide DG cleanly removed from C-glycosides under basic conditions (sodium hydroxide in ethanol) (Scheme 16.30). It is of note that the acetate protecting groups were cleaved concomitantly under these conditions. The authors performed DFT calculations with the aim of getting further insights into this exclusive axial Csp3–H activation. They showed that when the DG is set in the axial position (Figure 16.3, green profile, left), the CMD pathway that gives rise to the α-configuration is slightly exergonic (-0.79 kcal/mol), and it presents a low barrier considering the reaction conditions (19.56 kcal/mol, 120°C). Contrastingly, the CMD-TS that would result in the ß-configuration of the palladium-complex (Figure 16.3, red profile, middle) presents a barrier of almost 70 kcal/mol while being highly reversible. In addition, in the case of the picolinic amide DG in the equatorial position (Figure 16.3, blue profile, right), the required energy is higher (28.95 kcal/mol) and the reaction is reversible, mainly due to the 1,3-steric hindrance.

References

Figure 16.3  DFT calculations reported by Messaoudi et al.

16.4  Conclusions and Perspectives This chapter highlights the recent progress achieved on Csp2–H and Csp3–H functionalization of sugars to access C-aryl glycosides. This new and sustainable approach has emerged as a powerful methodology, in comparison with traditional organometallic catalytic cross-couplings, that offers the advantage of reducing the generation of wastes from the time-consuming preparation of often unstable prefunctionalized substrates. In the span of approximately four years, these processes have become workhorses for the construction of an array of C–C bonds on the sugar nucleus. The protocols presented in this review show high efficiency as well as stereo- and regioselectivity, good functional group tolerance, and good scalabilities. Future developments in this field include the introduction of more abundant and less expensive metal-catalysts and general protocols for C(sp3)–H arylation. The continuation of efforts in this area, by avoiding the installation and removal of the DG (eg. using a transient DG strategy), will serve both to increase the impact of this rapidly growing field of research and to reach complex C-aryl glycosides of biological interest. In addition, the increase of the simplicity and versatility of reaction protocols will facilitate more routine adoption of these methods. Overall, we consider that many exciting applications will emerge by applying the C–H activation approach to synthesize rationally designed bioactive C-aryl glycosides.

References 1 (a) Pałasz, A., Cież, D., Trzewik, B. et al. (2019). In the search of glycoside-based molecules as antidiabetic agents. Topics in Current Chemistry 377 (19): 1–84. (b) Sadurní, A., Kehr, G., Ahlqvist, M.; et al. (2018) Fluorine-directed glycosylation enables the stereocontrolled synthesis of selective SGLT2 inhibitors for type II diabetes. Chemistry – A European Journal 24 (12): 2832–2836. 2 Woo, V. C. (2020). Cardiovascular effects of sodium-glucose cotransporter-2 inhibitors in adults with type 2 diabetes. Canadian Journal of Diabetics 44 (1): 61–67.

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3 (a) Davis, F. F. and Allen, F. W. (1957). Ribonucleic acids from yeast which contain a fifth nucleotide. Journal of Biological Chemitry 227 (2): 907–915. (b) Ge, J. and Yu, Y.-T. (2013). RNA pseudouridylation: new insights into an old modification. Trends in Biochemical Sciences 38 (4): 210–218. 4 Hofsteenge, J., Müller, D. R., de Beer, T. et al. (1994). New type of linkage between a carbohydrate and a protein: C-glycosylation of a specific tryptophan residue in human RNase Us. Biochemistry 33 (46): 13524–13530. 5 Ni, X., Schröder, M., Olieric, V. et al. (2021). Structural insights into plasticity and discovery of Remdesivir metabolite GS-441524 binding in SARS-CoV-2 macrodomain. ACS Medicinal Chemistry Letters 12 (4): 603–609. 6 Bililign, T., Griffith, B. R., and Thorson, J. S. (2005). Structure, activity, synthesis and biosynthesis of aryl-C-glycosides. Natural Product Reports 22 (6): 742–760. 7 Selected reviews: (a) Zhu, F., Yang, T., and Walczak, M. A. (2017). Glycosyl stille cross-coupling with anomeric nucleophiles – A general solution to a long-standing problem of stereocontrolled synthesis of C-glycosides. Synlett 28 (13): 1510–1516. (b) Yang, Y. and Yu, B. (2017). Recent advances in the chemical synthesis of C‐Glycosides. Chemical Reviews 117 (19): 12281– 12356. (c) Kitamura, K., Ando, Y., Matsumoto, T. et al. (2018). Total synthesis of aryl C‐glycoside natural products: Strategies and tactics. Chemical Reviews 118 (4): 1495–1598. (d) Bokor, É., Kun, S., Goyard, D. et al. (2017). C‑Glycopyranosyl arenes and hetarenes: Synthetic methods and bioactivity focused on antidiabetic potential. Chemical Reviews 117 (3): 1687−1764. (e) For a recent bock chapter on C-Glycosides, see: Babu, S. A., Padmavathi, R., Suwasia, S., et al. (2021). Recent Developments on the Synthesis of Functionalized Carbohydrate/Sugar Derivatives Involving the Transition Metal-Catalyzed C-H Activation / C-H Functionalization, Studies in Natural Products Chemistry (71): 311–399. Elsevier. 8 Xu, L.-Y., Fan, N. L., and Hu, X.-G. (2020). Recent development in the synthesis of C-glycosides involving glycosyl radicals. Organic & Biomolecular Chemistry 18 (27): 5095–5109. 9 (a) Zhu, F., Rourke, M.-J., Yang, T. et al. (2016). Highly stereospecific cross-coupling reactions of anomeric stannanes for the synthesis of C-aryl glycosides. Journal of the American Chemical Society 138 (37): 12049–12052. (b) Yi, D., Zhu, F., and Walczak, M. A. (2018). Glycosyl cross-coupling with diaryliodonium salts: Access to aryl C-glycosides of biomedical relevance. Organic Letters 20 (7): 1936–1940. (c) Koo, B. and McDonald, F. E. (2005). Synthesis of the branched C-glycoside substructure of altromycin B. Organic Letters 7 (17): 3621–3624. (d) Gunn, A., Jarowicki, K., Kocienski, P. et al. (2001). The Preparation of 1-tributylstannyl glycals from 1-phenylsulfonyl glycals via Ni(0)-catalysed coupling with tributylstannylmagnesium bromide. Synthesis 2001 (2): 331–338. (e) Khatri, H. R., Nguyen, H., Dunaway, J. K. et al. (2015). Total synthesis of antitumor antibiotic derhodinosylurdamycin A. Chemistry – A European Journal 21 (539): 13553 –13557. (f) Zhu, F., Rodriguez, J., Yang, T. et al. (2017). Glycosyl cross-coupling of anomeric nucleophiles: Scope, mechanism, and applications in the synthesis of aryl C-Glycosides. Journal of the American Chemical Society 139 (49): 17908–17922. (g) Yi, D., Zhu, F., and Walczak, M. A. (2018). Stereoretentive intramolecular glycosyl cross-coupling: Development, scope, and kinetic isotope effect study. Organic Letters 20 (15): 4627–4631. 10 (a) Gensch, T., James, M. J., Dalton, T. et al. (2018). Increasing catalyst efficiency in C−H activation catalysis. Angewandte Chemie International Edition 57 (9): 2296–2306. (b) Gong, L., Sun, H.-B., Deng, L.-F. et al. (2019) Ni-catalyzed Suzuki− Miyaura cross-coupling of α-oxovinylsulfones to prepare C-aryl glycals and acyclic vinyl ethers. Journal of the American Chemical Society 141 (19): 7680–7686. (c) Sasaki, M. and Fuwa, H. (2004). Total synthesis of polycyclic ether natural products based on Suzuki-Miyaura cross-coupling. Synlett 2004 (11): 1851–1874. (d) Pedzisa, L., Vaughn, I. W., and Pongdee, R. (2008). Suzuki–Miyaura cross-coupling of α-phosphoryloxy enol ethers with arylboronic acids. Tetrahedron Letters 49 (26): 4142–4144. 11 (a) Nicolas, L., Angibaud, P., Stansfield, I. et al. (2012). Diastereoselective metal-catalyzed synthesis of C-aryl and C-vinyl glycosides. Angewandte Chemie International Edition 51 (44): 11101–11104. (b) Adak, L., Kawamura, S., Toma, G. et al. (2017). Synthesis of aryl C-glycosides via iron-catalyzed cross coupling of halosugars: Stereoselective anomeric arylation of glycosyl radicals. Journal of the American Chemical Society 139 (31): 10693–10701. 12 Denmark, S. E., Regens, C. S., and Kobayashi, T. (2007). Total synthesis of papulacandin D. Journal of the American Chemical Society 129 (10): 2774–2776. 13 (a) Ousmer, M., Boucard, V., Lubin-Germain, N. et al. (2006). Gram‐scale preparation of a p‐(C‐glucopyranosyl)‐L‐phenylalanine derivative by a negishi cross‐coupling reaction. European Journal of Organic Chemistry 2006 (5): 1216–1221. (b) Gong, H., Sinisi, R., and Gagné, M. R. (2007). A room temperature Negishi cross-coupling approach to C-alkyl glycosides. Journal of the American Chemical Society 129 (7): 1908–1909. (c) Gong, H. and Gagné, M. R. (2008). Diastereoselective Ni-catalyzed Negishi cross-coupling approach to saturated, fully oxygenated C-alkyl and C-aryl glycosides. Journal of the American Chemical Society 130 (36): 12177–12183.

References

14 Selected recent reviews: (a) Rogge, T., Kaplaneris, N., Chatani, N. et al. (2021). C–H activation. Nature Reviews Methods Primers 43: 1–43. (b) Rej, S., Ano, Y., and Chatani, N. (2020). Bidentate directing groups: An efficient tool in C−H bond functionalization chemistry for the expedient construction of C−C bonds. Chemical Reviews 120 (3): 1788–1887. (c) He, J., Wasa, M., Chan, K. S. L. et al. (2017). Palladium-catalyzed transformations of alkyl C−H bonds. Chemical Reviews 117 (13): 8754–8786. (d) He, C., Whitehurst, W. G., and Gaunt, M. J. (2019). Palladium-catalyzed C(sp3)–H bond functionalization of aliphatic amines. Chem 5 (5): 1031–1058. (e) Trowbridge, A., Walton, S. M., and Gaunt, M. J. (2020). New strategies for the transition-metal catalyzed synthesis of aliphatic amines. Chemical Reviews 120 (5): 2613–2692. (f) Dalton, T., Faber, T., and Glorius, F. (2021). C–H activation: Toward sustainability and applications. ACS Central Science 7 (2): 245–261. 15 Anastas, P. and Eghbali, N. (2010). Green chemistry: Principles and practice. Chemical Society Reviews 39 (1): 301–312. 16 Ghouilem, J., de Robichon, M., Le Bideau, F., Ferry, A., and Messaoudi, S. (2021). Emerging organometallic methods for the synthesis of C-branched (hetero)aryl, alkenyl, and alkyl glycosides: C−H functionalization and dual photoredox approaches. Chemistry – A European Journal 27 (2): 491–511. 17 Liu, M., Niu, Y., Wu, Y.-F. et al. (2016). Ligand-controlled monoselective C-aryl glycoside synthesis via palladium-catalyzed C–H functionalization of N-quinolyl benzamides with 1-iodoglycals. Organic Letters 18 (8): 1836–1839. 18 Wu, J., Kaplaneris, N., and Ni, S. (2020). Late-stage C(sp2)–H and C(sp3)–H glycosylation of C-aryl/alkyl glycopeptides: Mechanistic insights and fluorescence labeling. Chemical Science 11 (25): 6521–6526. 19 de Robichon, M., Bordessa, A., Malinowski, M. et al. (2019). Access to C-aryl/alkenylglycosides by directed Pd-catalyzed C–H functionalisation of the anomeric position in glycal-type substrates. Chemical Communications 55 (78): 11806–11808. 20 Liu, Y., Wang, Y., Dai, W. et al. (2020). Palladium-catalysed C(sp3)-H glycosylation for the synthesis of C-alkyl glycoamino acids. Angewandte Chemie International Edition 59 (9): 3491–3494. 21 Sakamoto, K., Nagai, M., Ebe, Y. et al. (2019). Iridium-catalyzed direct hydroarylation of glycals via C–H activation: Ligand-controlled stereoselective synthesis of α- and β-C-glycosyl arenes. ACS Catalysis 9 (2): 1347–1352. 22 Ebe, Y., Onoda, M., Nishimura, T. et al. (2017). Iridium-catalyzed regio- and enantioselective hydroarylation of alkenyl ethers by olefin isomerization. Angewandte Chemie International Edition 56 (20): 5607–5611. 23 Wang, Q., An, S., and Deng, Z. (2019). Palladium-catalysed C−H glycosylation for synthesis of C-aryl glycosides. Nature Catalysis 2: 793–800. 24 Wang, Q., Fu, Y., Zhu, W. et al. (2021). Total synthesis of C-α-mannosyl tryptophan via palladium-catalyzed C–H glycosylation. CCS Chemistry 3 (6): 1729–1736. 25 Wang, Q., Zhu, W., Sun, Q. et al. (2020). Pd-catalyzed ortho-directed C—H glycosylation of arenes using N-linked bidentate auxiliaries. Chinese Journal of Chemistry 39 (3): 571–576. 26 Sun, Q., Zhang, H., Wang, Q. et al. (2021). Stereoselective synthesis of C-vinyl glycosides via palladium-catalyzed C–H glycosylation of alkenes. Angewandte Chemie International Edition 60 (36): 19620–19625. 27 Shi, W.-Y., Ding, Y.-N., Zheng, N. et al. (2021). Highly regioselective and stereoselective synthesis of C-aryl glycosides via nickel-catalyzed ortho-C–H glycosylation of 8-aminoquinoline benzamides. Chemical Communications 57 (71): 8945–8948. 28 Lv, W., Chen, Y., Wen, S. et al. (2020). Modular and stereoselective synthesis of C-aryl glycosides via Catellani reaction. Journal of the American Chemical Society 142 (35): 14864–14870. 29 Ding, Y.-N., Shi, W.-Y., Liu, C. et al. (2020). Palladium-catalyzed ortho-C–H glycosylation/ipso-alkenylation of aryl iodides. Journal of Organic Chemistry 85 (17): 11280–11296. 30 Probst, N., Grelier, G., Ghermani, N. et al. (2017). Intramolecular Pd-catalyzed anomeric C(sp3)–H activation of glycosyl carboxamides. Organic Letters 19 (19): 5038–5041. 31 Ghouilem, J., Tran, C., Grimblat, N. et al. (2021). Diastereoselective Pd-catalyzed anomeric C(sp3)–H activation: Synthesis of α-(hetero)aryl C-glycosides. ACS Catalysis 11 (3): 1818–1826. 32 Jensen, H. H., Pedersen, C. M., and Bols, M. (2007). Going to extremes: “super” armed glycosyl donors in glycosylation chemistry. Chemistry – A European Journal 13 (27): 7576–7582.

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17 Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals Harshita Shet1,2 and Anant R. Kapdi1 1

 Department of Chemistry, Institute of Chemical Technology, Nathalal Parekh Road, Matunga, Mumbai, India  Institute of Chemical Technology-Indian Oil Odisha Campus, IIT Kharagpur Extension Centre, Mouza Samantpuri, Bhubaneswar, Odisha, India

2

17.1  Introduction Late-stage C–H functionalization has emerged as a powerful tool for the synthesis of bio-active natural products and pharmaceuticals, creating a useful pathway towards drug discovery, investigation of pharmacological properties, and structure-activity relationships. This comes on the back of the extensive application of C–H bond activation towards the efficient functionalization of simple to complex heterocyclic core [1]. Development in this area has been driven by the introduction of methodologies involving C–H bond activation of complex molecular scaffolds that are effectively directed by the presence of transition metals such as ruthenium, rhodium, platinum, and palladium, with different coordinating ligands under mild reaction conditions and with controlled regioselectivity [2, 3]. However, in recent years, metal-free conditions have been found to be equally efficient with respect to enantioselective, visible-light-driven, and electrophilic functionalization [4]. The field of C–H functionalization, therefore, has grown rapidly over the last two decades with a number of very effective transformations that have been established for the functionalization of simple and complex molecular structures [5]. Though C–H functionalization has been notable, late-stage functionalization (LSF) is still limited to a narrow range of functional groups and substrates because reactions commonly rely upon the directing groups (DGs) present. The overall synthetic strategy for late-stage modification is complicated, given the complexity of the natural products and pharmaceutically important molecules comprising functional groups of similar reactivities. The challenge of selectively utilizing and functionalizing one specific functional group for the purpose of late-stage modification without affecting other groups could certainly prove to be a significantly powerful tool for synthesis of important scaffolds. The importance of the development of a LSF strategy could be envisaged from the fact that, in comparison to the generally employed cross-coupling processes that suffer from the pre-functionalization of the substrate (with several synthetic steps required), poor overall reactivity can be avoided and the number of synthetic steps can be better minimized. Such a strategy can also offer the unique possibility of developing structure–activity relationship studies, and it would certainly help simplify the overall route for the synthesis of many active pharmaceutical ingredients [6, 7]. Incorporation of a site-specific synthetic strategy for LSF would further help make the synthesis more attractive. (Scheme 17.1) [8] Keeping these points in mind, in addition to bringing out the powerful nature of the developed methodologies in literature for achieving the described goal, this book chapter will cover the methods involving the catalytic late-stage C–H functionalization strategy for the synthesis of natural products and pharmaceuticals.

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

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17  Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals

CO2H

O

H

O

NH

HN

Me

O

O O

N

O O OMe (+)-linoxepin CO2Et

N

OHC

HO

OH

YD-3

YC-1

O Diptoindonesin G

HO

M

HET

Cross-coupling

Me N

H N H Ibogamine

N

NBoc

Me

+ N OCOCF3 H N

(+/-)-aspidospermidine

O

(±)-dragmacidin D

Me

Me

N

N+

Me

Me O

OH Br-

Nigellidine hydobromide

Et

N H

H

H

OH

Br

N

H N

N

Complanadine A

NH

N H

N

X

HET

M

N H

CF3

SO2NH2 Celecoxib

R

N

HO

N

Cl

OH

N N Bn

C-H activation

HN

Gamendazole Cl

Me

H HET

N

OH

O

O N N Bn

(+/-)- rhazinilam

(+/-)-rhazinal

N

F3C

S

N Me

O N H

ClNH+

N

O

O N

Beclabuvir

Scheme 17.1  Transition metal-catalyzed C–H bond functionalization and cross-coupling.

17.2  Synthesis of (±)-Ibogamine Ibogamine, a member of iboga alkaloids, is an anti-convulsant, anti-addictive CNS stimulant alkaloid found in Crepe Jasmine (Tabernaemontana divaricata) and Tabernanthe iboga [9]. Ibogamine was first isolated in 1958 by Taylor and coworkers [9] from Tabernanthe iboga, and the structure was confirmed by spectral analysis. Ultraviolet absorption spectroscopy indicated the presence of indole-type moiety. The first total synthesis of (±)-ibogamine was described by Buchi and coworkers [10] in 1965 and this was later elaborated by Ban and coworkers [11] in 1969. In 1978, Trost and coworkers [12] reported the synthesis of ibogamine 02 via a palladium-catalyzed tandem C–H activation/reductive Heck sequence of unprotected indoles 01 at the C2 position in the presence of silver tetrafluoroborate (Scheme 17.2). The tryptamine precursor 01 was prepared in three steps as a major enantiomer (01, 7S). Subjecting the tryptamine precursor 01 to the C–H activation, followed by reduction using sodium borohydride, afforded the ibogamine alkaloid 02 in 40–45% yield. The formation of the product was confirmed by the comparison of infrared and mass spectra of the molecule obtained from natural origin.

17.4  Synthesis of Complanadine A

N

N H 01

N

PdCl2(MeCN)2 AgBF4,

H Me

NaBH4, 40-45% yield C-H/C-H coupling

H N H Me 02, Ibogamine

Scheme 17.2  Synthesis of (±)-Ibogamine, 02.

17.3  Synthesis of YD-3 and YC-1 (C–H Arylation of Indazoles) C3-arylated pyrazoles and indazoles are important structural motifs in pharmaceuticals and agrochemicals. Teng and coworkers [13] reported the antiplatelet effects and mechanisms of YD-3, which was synthesized based on the procedure described by Yoshina and Kuo [14]. It was observed that YD-3 can be used as the primary compound for the synthesis of a new class of thrombin receptor antagonists due to itsdistinct chemical structure compared to the existent thrombin receptor antagonist. It was also found that a non-PAR 1 thrombin receptor that intervenes in the major effects of thrombin in rabbit platelets is inhibited by YD-3. In the case of human platelets, YD-3 only functions significantly under the circumstances that the function of PAR 1 has been blocked or attenuated. Yamaguchi, Itami, and coworkers demonstrated palladium and copper-catalyzed C–H arylation of 1H- and 2H- indazoles with haloarenes for the synthesis of YD-3, which is a platelet anti-aggregating agent, and YC-1, which is an antitumor agent (Scheme 17.3) [15]. First, 03 (1-benzyl-2H-indazole) was synthesized by the benzylation of indazole that was further followed by the Pd/phenanthroline-catalyzed C–H/C–I coupling of 03 with 04 (ethyl 4-iodobenzoate) in the presence of Ag2CO3 (as an oxidant) and K3PO4 in dimethylacetamide solvent at 165 0C to form YD-3 (05) in 64% yield. Similarly, palladium/phenanthroline-catalyzed C–H/C–Br coupling of 03 with 06 (methyl 5-bromofuran-2-carboxylate), when performed in the presence of Ag2CO3 and K3PO4 in dimethylacetamide solvent at 165 0C followed by the reduction of the ester group using LiAlH4, afforded YC-1 (07) in 82% yield.

CO2Et

H N + N I Bn 03

PdCl2 (10 mol%) CO2Et phen(10 mol%) Ag2CO3, K3PO4 DMAc [64% yield] C-H/C-I coupling

04

N N Bn YD-3 (05) OH

H N + N Bn 03

Br O

1)PdCl2 (10 mol%) phen(10 mol%) CO2Me

06

O

Ag2CO3, K3PO4 DMAc 2) LiAlH4

N N Bn

[82% yield] YC-1 (07) C-H/C-Br coupling (2012, Yamaguchi and Itami)

Scheme 17.3  Synthesis of YD-3 and YC-1.

17.4  Synthesis of Complanadine A Complanadine A is a member of lycopodium alkaloid that was isolated from the club moss Lycopodium complanatum [16]. The complanadine A alkaloid is interesting because it is found to induce the neurotrophic factor secretion from 1321N1 cells and to enhance mRNA expression for a nerve growth factor (NGF) and NGF production in human glial cells [17]. The

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17  Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals

skeletal structure represents an unsymmetrical dimer of lycodine with a C2-C3ʹ linkage pattern, which creates an interesting challenge for synthesis [16]. In 2010, Sarpong and Fisher [18] reported the synthesis of Complanadine A 11 via iridium-catalyzed C–H functionalization of pyridine moiety 09. The triflate group 08 in precursor was removed under palladium-catalyzed reducing conditions to give pyridine 09 in 90% yield. Further iridium-catalyzed borylation of Bocprotected lycodine gave boronic ester 10 in 75% yield. The Suzuki-Miyaura cross-coupling of boronic ester 10 with the triflate precursor 08, followed by the Boc group cleavage, afforded complanadine A 11, in 42% yield (Scheme 17.4).

Me

Me N

OTf

N

Pd(OAc)2 dppf, NH4O 2CH 90% yield

NBoc

[Ir(COD)(OMe)]2 dtbpy, B2(pin)2 H

NBoc 09

08

THF, 80 oC 75% yield C-H activation

Me N Bpin

NBoc 10

Me N

1) 88, PdCl2(dppf) K3PO4, Et3SiH 2) 6N HCl 42% over 2 steps

NBoc

H N

N H

H

Complanadine A, 11

Me

Scheme 17.4  Synthesis of complanasine A, 11.

17.5  Synthesis of Diptoindonesin G (C–H Arylation of Benzofuran) Diptoindonesin G is a resveratrol (Rev) aneuploid that was isolated from the tree bark Hopea mengarawan [19] or Hopea chinensis. Diptoindonesin G is found to exhibit potent immunosuppressive activity, as well as anticancer activity [20]. These are known to belong to the oligostilbenoid class of compounds, with Syah and his coworkers [19] being the first to report the isolation and structural elucidation of diptoindonesin G 14 based on HRESIMS analysis, NMR analysis, IR spectroscopy, and UV spectroscopy. The authors also demonstrated that the synthesis of diptoindonesin G 14 proceeds via a radical mechanism pathway by the condensation between resveratrol and 3,5-dihydroxybenzoyl ester.

HO

OMe

O

HO Pd(OAc)2, PCy3.HBF4 PivOH, K2CO3,

Br + H

MeO

12

O

OMe

DMAc 83% yield C-H/C-Br coupling

OMe

O OMe O 13

MeO HO

OH

O

BBr3 CH2Cl2 93% yield

OH HO

Scheme 17.5  Synthesis of diptoindonesin G, 14.

O Diptoindonesin G, 14

17.6  Synthesis of Dragmacidin D (C–H Arylation of Indoles at the C3 Position)

In 2010, Kim and coworkers [21] reported the synthesis of diptoindonesin G 14 by the employment of palladium-catalyzed C–H arylation of benzofuran as a key step. The coupled product 13 was synthesized by subjecting the benzofuran derivative 12 at the C2 position with aryl bromide under palladium-catalyzed C–H arylation conditions (C–H/C–Br coupling), with pivalic acid used as a proton shuttle and potassium carbonate as the base in DMA solvent at 100oC. Following this, the deprotection of three methyl groups of the coupled product 13 using BBr3 afforded diptoindonesin G 14 in 93% yield (Scheme 17.4).

17.6  Synthesis of Dragmacidin D (C–H Arylation of Indoles at the C3 Position) Dragmacidin D 24 is a biologically important member of a family of heterocyclic bis(indole) marine natural products isolated from deep-water Caribbean sponges of the Spongosorites and Dragmicidon genera [22]. The characteristic structure of dragmacidin D represents a central pyrazinone moiety with flanking indole substituents, in addition to another indole substituent further expanded with an aminoimidazole unit by a stereogenic methine linker. The dragmacidin D natural product in isolation was found to exhibit potent inhibitory activity towards serine-threonine protein phosphatases (PP) and is therefore useful for the treatment of Parkinson’s, Huntington’s, and Alzheimer’s diseases [22]. In 2002, Stoltz and coworkers reported the first total synthesis of racemic dragmacidin D, in 17 steps, via a series of successive, temperature-controlled Suzuki-Miyaura cross-coupling reactions. The Stoltz group also proposed the configuration of natural (+)-dragmacidin D and ( ̶)-dragmacidin E to exhibit 6ʹ’’S and 5ʹ’’R, 6ʹ’’S, respectively, assuming common biogenesis [23]. Yamaguchi, Itami, and coworkers [24] reported the second total synthesis of dragmacidin D, in 15 steps (Scheme 17.6). Initially, iodoindole derivative, 15 (7-(benzyloxy)-4-iodo-1-tosyl-1H-indole) was prepared in three steps from commercially available 7-benzyloxyindole. Furthermore, Pd(OAc)2-catalyzed C–H/C–I coupling of iodoindole derivative with 3-triisopropylsilyloxy-substituted thiophene 16 was carried out in the presence of

(i-Pr)3SiO OBn

Ts N + H

[60% yield] OSi(i-Pr)3 C-H/C-I coupling

I 15

b) Bu 4NF, AcOH Raney Ni [77% yield]

a) Pd(OAc)2 P[OCH(CF3)2]3 Ag2CO3

S

O

S

16

c) Mg(OMe)2 d) MOM-Cl [2 steps-91% yield]

N

BnO 17

H

Ts

-O

Br

O

MOMO

N MOM

H

N H

O

N H

e) Pd(OAc)2 AgOAc

O

23

Scheme 17.6  Synthesis of dragmacidin D, 24.

N+ O-

MOMO NH HN

i) (Boc)guanidine, CF3CO 2H [51% yield]

HO

N

f) (CF3CO)2O

21

Br h) i-Pr2NEt3, Me3SiOTf NBS [73% yield]

N

MOMO

N MOM

N

H N

O

19

O

22

[2 steps- 57% yield] C-H/C-H coupling

N

N+

[50% yield] C-H/C-H coupling

g) CF2SO 3H, air

H

N MOM

18 H

H N

MOMO

N MOM 20

+ N OCOCF3

H N Br

N

N H

N H

O

(±)-dragmacidin D, 24

687

688

17  Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals

P[OCH(CF3)2]3 (20 mol %), Ag2CO3 (1.0 equiv) in 1,4-dioxane as the solvent at 140 oC to give the coupled product 17 in 60% yield. The triisopropylsilyl group from 17 was removed in a one-pot process by reacting with Bu4NF/AcOH followed by Raney nickel reduction, thus resulting in the simultaneous reduction of thiophene ring and debenzylation to give the corresponding methyl ketone derivative in 77% yield. The bis-MOM-protected indole 18 was obtained by the exchange of protecting group tosyl with methoxymethyl (MOM) in 91% yield. A Pd(OAc)2 catalyzed C–H/C–H coupling sequence was next to follow, involving the reaction between bis-MOM-protected indole 18 with pyrazineN-oxide 19 providing a regioselective coupled product 20 in 50% yield. The product 20 was further reacted with (CF3CO)2O, yielding the corresponding pyrazinone 21, which was subjected to oxidative C–H/C–H coupling reaction with 6-bromoindole 22 in the presence of CF3SO3H; this resulted in in the simultaneous removal of two MOM groups to afford the corresponding coupled product 23 in 57% yield. Treatment of 23 with i-Pr2NEt/Me3SiOTf, followed by the reaction with N-bromosuccinimide, gave α-bromoketone in 73% yield. The resultant product was treated with (Boc)guanidine and the deprotection of Boc group using CF3CO2H gave dragmacidin D 24 in 51% yield. The resultant dragmacidin D obtained was purified by reverse-phase preparative liquid chromatography and characterized by 1H and 13C NMR spectroscopy.

17.7  Synthesis of Celecoxib (C–H Arylation of Pyrazoles) Celecoxib 28 (CelebrexTM) is a non-steroidal anti-inflammatory drug and exerts its pharmacological effect as a selective cyclooxygenase (COX-2) inhibitor. Celecoxib is used to treat numerous medical conditions such as osteoarthritis, rheumatoid arthritis, menstrual symptoms, and acute pain [25, 26]. The commercial route for the synthesis of celecoxib includes the condensation reaction between 4-sulfamidophenylhydrazine and diketone intermediate [27]. In 2011, Gaulier and coworkers [28] demonstrated the palladium-catalyzed C–H arylation of pyrazole derivative 25 at the C2 position with aryl bromide 26 (C–H/C–I coupling), which afforded the coupled product 27 in 66% yield as a single regioisomer after column purification. The structure of the obtained product was confirmed using 1H NMR and performing NOESY experiments. The removal of the benzyl group from the coupled product 27 eventually afforded celecoxib 28 in 69% yield, with more than 95% purity (Scheme 17.7).

CF3 H

N

CF3

N I + Me

SO2NBn2 25

26

Pd(OAc)2, PBuAd2 PivOH, K2CO3

N

Me

DMAc, 140 oC, 50 h 66% yield C-H/C-I coupling

27 rt, 2 h 69% yield

N

SO2NBn2 H2SO4 CF3

Me

N

N

SO2NH2 Celecoxib, 28

Scheme 17.7  Synthesis of celecoxib, 28.

17.8  Synthesis of Aspidospermidine

17.8  Synthesis of Aspidospermidine The alkaloids that comprise indole structural motifs have gained substantial attention from the synthetic community since the 1960s, primarily due to the attractive framework with the possibility of providing multiple stereogenic centers. The aspidosperma family is the largest group among the various indole alkaloids [29], whereas aspidospermidine exhibits a unique pentacyclic skeleton with a series of four stereocenters. Many successful synthetic routes for the synthesis of aspidospermidine have been established, which include Fischer indole synthesis [30–32], intramolecular cyclization of an aniline-type intermediate [33, 34], and Pictet-Spengler rearrangement [35, 36]. Bach and coworkers [37] recently presented the synthesis of aspidospermidine 38 by palladium-catalyzed Catellani reaction (C–H/C–Br coupling) for obtaining indole 2-alkylation in the presence of indole 29, alkyl bromide 30 and norbornene at 70°C to form 31 in 65% yield. The reaction of 31 with lithiumhexamethyldisilazide (LiHMDS) was followed by quenching afforded lactam enolate, which, on further reaction with allylbromide, gave α-allyl-δ-lactam 32 in 87% yield. The sequential hydroboration-oxidation of 32 afforded 33 in 96% yield, which was then oxidized using Dess-Martin Periodinane (DMP) to form an aldehyde intermediate 34 in 87% yield. The aldehyde intermediate 34 obtained was further transformed to its hemiaminal 35 form using DIBAL-H, then transformed under mild acidic condition to tetracyclic intermediate 36 in a three-step sequence in 79% yield. The amino alcohol 36, on treatment with MsCl and t-BuOK, rapidly underwent intramolecular cyclization reaction to form 37. Finally, the aspidospermidine with 53% yield was obtained by reducing the imine group of 37 using NaBH4 (Scheme 17.8). The aspidospermidine 38 synthesid was, therefore, accomplished in nine steps with an overall yield of 15%. Based on the spectral, mechanistic, and kinetics studies, the catalytic cycle indicates that the key intermediate is an N-norbornene-type palladacycle, and the oxidative addition of alkyl bromide to the Pd(II) center functions as the rate-determining step.

H N 29 H + Et EtO2 C

CO 2Et PdCl2(MeCN)2 norbornene, K2CO3, DMA, H2O, 70 oC 65% yield C-H/C-Br coupling

Br 30

N O

LiHMDS, THF

N

Et

OH

Et NH

35

N H

CH2=CHCH2 Br -78 oC to rt 87% yield

31

Et

O 32

9-BBN, THF, 0 oC H2O2, NaOH 96% yield

1) HOCH2CH2NH2 NaBH4, EtOH, 0 oC

DMP

N

2) DIBAl-H CH2Cl2, -78 oC

Et

O 34

AcOH-THF-H2O (3:1:1)

O

NaHCO 3 CH2Cl2, rt 87% yield

N Et

O 33

HO

(79%, 3 steps) HO

N

N H

Et

1) MsCl, Et3 N, CH2Cl2 -20 oC 2) t-BuOK, THF -20 oC to rt

36

Scheme 17.8  Total synthesis of (±)-aspidospermidine, 38.

N

N 37

Et

N

Et

N H (+/-)-aspidospermidine, 38

689

690

17  Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals

17.9  Synthesis of Pipercyclobutanamide A The pipercyclobutanamide A 47 was first isolated from the fruits of the black pepper plant (Piper nigrum) in 2001 by Fujiwara and coworkers [38]. Later, in 2006, Tezuka and coworkers [39] demonstrated pipercyclobutanamide A to have selective inhibition towards the cytochrome P450 2D6 (CYP2D6) enzyme found in the liver (directly related to the metabolism and elimination of many drugs). Pipercyclobutanamide A, therefore, can bring about the reduced activity of the cytochrome P450 2D6 (CYP2D6) enzyme to improve the efficacy of drugs that could be rapidly eliminated by the enzyme in general. Structurally, the presence of four different substituents on the cyclobutane ring poses a significant synthetic challenge for obtaining pipercyclobutanamide A 47. In 2012, Baran and coworkers [40], chalked out the total synthesis of pipercyclobutanamide A 47, starting with the photochemical 4π-electrocyclization of the precursor, methylcoumalate 39, under reduced temperature, to afford the photopyrone 40 (Scheme 17.9). The unstable intermediate 40 formed was immediately hydrogenated and subsequently subjected to C–N coupling with 8-aminoquinoline in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as the coupling agent, thus affording the corresponding C–H arylation precursor 42 in 54% overall yield. Precursor 42 was next exposed to the palladium-catalyzed C–H/C–I coupling involving the part of 42 between the cyclobutene, with 1-iodo-3,4-methylenedioxybenzene A in the presence of pivalic acid (as a proton shuttle) in tertiary butanol (t-BuOH), to give monoarylated product 43 with 54% yield. The C–H arylation performed earlier was subsequently followed by the Pd-catalyzed C–H olefination reaction involving C–H/C–I coupling between styrenyl iodide B and product 43 in the presence of silver acetate (AgOAc) in PhMe to afford all-cis (referencing the 4 different substituents on the cyclobutene ring) cyclobutane product 44 in 59% yield. The reaction of 44 with sodium methoxide afforded the

O

O

O

O

hv

O

Pt/C, H2

O

HO

EDC OMe

OMe O

OMe 39

OH

N N

OMe

H O

O

45

[59% yield] C-H/C-I coupling

O N N

I

O

O C, KOt-Bu

O

N O

O

O

O 47, Pipercyclobutanamide A

Scheme 17.9  Synthesis of pipercyclobutanamide A, 47.

I B=

O O

N

80% yield

O O

O

46

O

A=

O

O

O

OMe H

43

(40-45%,3 steps) Piperidine, T3P

N

H

44

O

O

O

O O

B Pd(OAc)2 AgOAc

O

2) DIBAL-H

O

H

O

A Pd(OAc)2 Ag 2CO3

[54% yield] C-H/C-I coupling

O

1) NaOMe, 1 N NaOH

O

OMe

H

O O

H

N

42

41

O O

N

8-aminoquinoline

O

O 40

H

C= ArO

O P OAr

O N

17.11  Synthesis of (+)-Linoxepin

required stereochemistry. Hydrolysis of the ester group and cleavage of the DG was carried out by successive treatment with 1N NaOH and DIBAL-H to form the corresponding aldehyde 45. The coupling of the crude aldehyde 45 with piperidine in the presence of T3P afforded the amide 46 in 40–45% yield upon isolation after three steps. Finally, the pipercyclobutanamide A 47 was synthesized by the reaction of amide 46 with Ando phosphonate C in the presence of KOt-Bu in 80% yield (Scheme 17.9).

17.10  Synthesis of Nigellidine Hydrobromide Nigellidine is a natural alkaloid used for the treatment of various diseases and was first isolated from the seeds of Nigella sativa in 1995 [41]. In 2013, Yu and coworkers [42] demonstrated the total synthesis of nigellidine hydrobromide (53) in six steps with an 18% overall yield (Scheme 17.10). Initially, 48 (4-methoxy-6-methyl-(1H)-indazole) was treated with 2-tetrahydropyranyl (THP) for the protection of the secondary amine group of the indazole moiety, This was followed by Pd/ phenanthroline-catalyzed C–H/C–Br coupling with 4-bromoanisole in the presence of Cs2CO3 as the base in PhMe at 160 o C to afford the coupled product (50) in 54% yield. Product 50 was further subjected to deprotection of the THP group by using acetyl chloride in methanol solvent at 55 oC, and the resultant unprotected product underwent the stepwise N-alkylation with 1,4-dibromobutane in the presence of sodium hydride, resulting in the formation of precursor 52. Next, demethylation of precursor 52 was next carried out in the presence of BBr3 in dichloromethane at ambient temperature, which afforded nigellidine hydrobromide (53). In addition to confirming the synthesized nigellidine hydrobromide using general characterization techniques, the authors were successful in obtaining a single crystal X-ray analysis.

OMe Br OMe H

OMe H DHP

Me 48

N TsOH, DCM Me N H

49

OMe

Pd(OAc)2 (10 mol%) phen (30 mol%)

OMe

N Cs2CO3 N PhMe, 160 oC Me THP [54% yield] C-H/C-Br coupling

50

N N THP

AcCl 87% yield MeOH 55 oC OH

OH

Me

N

N

+Br

-

BBr 3 CH2Cl2, rt

Nigellidine hydobromide, 53 74% yield X-ray structure confirmation

Me

OMe 1) NaH, Br(CH2)4Br, DMF/DMSO 0 oC to rt OMe Br 2) CH3CN, N+ Me 110 oC N 81% yield 52

OMe OMe N N H 51

Scheme 17.10  Synthesis of Nigellidine hydrobromide, 53.

17.11  Synthesis of (+)-Linoxepin Linoxepin 59 was isolated from the aerial parts of Linum perenne L. by Schmidt and coworkers [43] in 2007. The timedependent density functional theory (TDDFT) quantum mechanical simulations and CD spectroscopy were used to reveal the R configuration at the C8 position of linoxepin, confirming the presence of the novel 2,8-dihydro-3H-benzo[e]

691

692

17  Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals

naphtho[1,8-be]oxepine ring system. Linoxepin was found to consist of an oxepine ring, in addition to a ring formed by an oxymethylene bridge between C3 of ring A and C6ʹ of ring D of the aryldihydronaphthalene skeleton [44]. Tietze and coworkers [45] described the total synthesis of Linoxepin 59 in ten steps using Pd-catalyzed Sonogashira reaction, followed by a domino carbopalladation/Heck reaction sequence of an allylsilane. In 2013, Lautens and coworkers [46] reported the asymmetric synthesis of (+)-linoxepin 59 in eight steps, using a modified version of Catellani reaction that was employed for the enantioselective and protection group-free synthesis of natural products. The start of the synthesis involves the formation of the key intermediate 57, which is obtained by a Catellani reaction that is facilitated by norbornene and involves a palladium-catalyzed ortho C–H alkylation between aryl iodide 55 with enantioselective iodolactone 54 (C–H/C–I coupling). In the same reaction pot, the addition of t-butylacrylate 56 and cesium carbonate base in DMF led to the simultaneous Heck alkenylation reaction to provide a decent yield of the desired intermediate 57. The key intermediate 57 formed was further oxidatively cleaved under Lemieux-Johnson conditions to an aldehyde, which underwent an intramolecular aldol condensation reaction using TiCl4 to afford 58 in 49% yield. (+)-Linoxepin 59 was eventually obtained in 74% yield under the palladium-catalyzed intramolecular Mizoroki-Heck conditions (Scheme 17.11).

O H

O O

54 O

O

H I

I +

O

OtBu

56

55

OtBu

Pd(OAc) 2 (10 mol%) PPh3 (22 mol%)

Br

OMe

O

H

Norbornene (5.0 equiv) Cs2CO3, DMF

O O

Br O OMe

O

57

C-H/C-I coupling

O

1) OsO4, NaIO4 2) TiCl4, Et3N

H

O

O

H

O

O

PdCl2, PPh3 O O OMe

O

Br o

CsOAc, DMF, 75 C 79% yield

59, (+)-linoxepin

O OMe 58

O

O

Scheme 17.11  Synthesis of (+)-Linoxepin, 59.

17.12  Synthesis of (±)-Rhazinal The rhazinilam-type alkaloid rhazinal was isolated from the stem extracts of a Malayan Kopsia species, Kopsia teoi, by Kam and coworkers [47] in 1998. Kam and coworkers also elucidated the structure of rhazinal based on spectral analysis. In 2009, Trauner and Bowie Jr. [48] reported the synthesis of rhazinal via Pd-catalyzed C–H functionalization strategy. Then, in 2013, Gu and coworkers [49] reported the total synthesis of (±)-rhazinal, 63 via palladium-catalyzed tandem Catellani-type ortho-arylation/intramolecular Heck reaction of iodopyrrole 60 moiety. The cyclized core fragment 62 was prepared by the palladium-catalyzed chemoselective Catellani reaction of iodopyrrole derivative 60 with 2-nitrobromobenzene 61 in the presence of norbornene to provide the desired product in 75% yield. Furthermore, the reduction of nitro and ester group, followed by cyclisation in an additional three steps, afforded (±)-rhazinal 63 in 80% yield (Scheme 17.11).

17.13  Synthesis of Podophyllotoxin (C–H Arylation)

H

CO 2tBu I

N

OHC

O 2N Me

60 +

CS2CO3 OHC dioxane, 85 C 75% yield C-H/C-Br coupling

Br

61

NO2

HN

3 steps

PdCl2, PPh3 CO2tBu

N

Me

O N OHC

62

(+/-)-rhazinal, 63

Scheme 17.12  Synthesis of (±)-rhazinal, 63.

17.13  Synthesis of Podophyllotoxin (C–H Arylation) Prototypical aryltetralin lignans derived from plants have found a wide range of use due to their potential antibacterial, antiviral, and antineoplastic properties. Podophyllotoxin is proven to be valuable in the area of cancer chemotherapy, as it is starting material for the synthesis of the type II topoisomerase targeting drugs teniposide (VM-26) and etoposide (VP-16), which are used for the treatment of testicular and lung cancer, leukemia, Kaposi’s sarcoma, and lymphoma [50]. Maimone and coworkers [51] in 2014, demonstrated the synthesis of podophyllotoxin 68 by the employment of the C–H activation strategy. As a part of the synthesis, authors obtained 2-methylthioaniline-containing amide 66 by the deprotonation of the starting material 64, using potassium hexamethyldisilazide at 0oC followed by the diastereoselective cycloaddition with monomethyl fumarate 65. The C–H arylation precursor 67 was next to be obtained, in 41% overall yield, as a single diastereomer by the addition of super hydride into the mixture, which resulted in the in situ reduction of the ester group and subsequent ketalization of the crude material obtained after a workup. Molecule 67 was next subjected to the palladium-catalyzed C–H arylation, with 5-iodo-1,2,3-trimethoxybenzene (C–H/C–I coupling) and stirring the product in TFA/THF/H2O mixture at ambient temperature, thus affording podophyllotoxin 68 in 43% yield and C4 epi in 33% yield (Scheme 17.13).

OH

O O 64

O

OK KHMDS, -78 oC

O

CO2Me

O

CO2Me

O

O

HS 66

HS

2) DMP, TsOH

O H 67

MeO

O O

HN

NHDG 65

DG=

1) LiEt3BH

O

OMe

HN HS

1) Pd(OAc) 2 2) TFA/H2O,THF

MeO I C-H/C-I coupling

OH

O

O

O O MeO

OMe OMe

68, (43%) + (33% 4-epi 68)

Scheme 17.13  Pd-catalyzed C–H arylation for the synthesis of podophyllotoxin, 68.

693

694

17  Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals

17.14  Synthesis of (±)-Rhazinilam Rhazinilam 76 alkaloid was first isolated from the Melodinus australis plant by Linde in 1965 [52]. Later, it was also isolated from other organisms, as well as from the shrub Rhazya stricta. The rhazinilam 76 alkaloid acts as a spindle poison and exhibits activity similar to that of taxol, colchicine, and vinblastine as a potent anticancer agent [52, 53]. Rhazinilam was also found to interfere with the dynamics of tubulin polymerization, hence making it useful for the development of anticancer agents. The classical method for the synthesis of rhazinilam was first demonstrated by Smith and coworkers [54] in 1973. Later, in 2005, Trauner and coworkers [55] demonstrated the concise synthesis of rhazinilam via an intramolecular palladiumcatalyzed C–H activation of an unactivated pyrrole. In 2014, Yao and coworkers [56] also reported the total synthesis of (±)-rhazinilam 76, using a palladium-catalyzed intramolecular regioselective C5-H alkenylation of pyrrole derivative 71. The pyrrole derivative 71 was synthesized via van Lausen reaction between phenyl acrylate 69 and TosMIC 70. Furthermore, alkyl pyrrole 73 was synthesized through reaction of 71 with iodoalkene 72 in the presence of NaH in DMF. The palladiumcatalyzed regioselective intramolecular C–H activation (C–H/C–I coupling) of 73 provided the precursor 74 in 56% yield in 4:7 ratio for the synthesis of 76. The configuration of 74 was confirmed by X-ray crystallographic analysis. Finally, the hydrogenation of precursor 74 using Wilkinson’s catalyst formed 75 in quantitative yield. A subsequent decarboxylation, hydrogenation, and macro-lactamization of 75 gave (±)-rhazinilam 76 in 62% yield (Scheme 17.14).

NO2 69 +

O

CO2Me

NaH, DMF

CN+

rt, 1 h

O

S

CO2Me

NaH, DMF, rt

O2N

70% over 2 steps

N H 71 +

CO2Me O2N H

N

CO2tBu

73

70 ButO2C

NH O N 76, (+/-)- rhazinilam

I 72

NO2 CO2Me

NO2 CO2Me (PPh3) 3RhCl (20 mol%)

1) H3PO4 100% 80 o C, 20 min 2) H2, Pd/C, rt, 1 h ButO2C 3) EDCl, DMAP, rt, 4 h 62% over 3 Steps

Pd(OAc)2 (10 mol%) C-H/C-H coupling AgOAc (2.0 equiv) DMF:DMSO (4:1) 80 oC, 15 h

N 75

H2, rt, 12 h quantitative

ButO2C

N 56% yield (7:4) (+/-)- 74

Scheme 17.14  Total synthesis of (±)-rhazinilam, 76.

17.15  Synthesis of Aeruginosins (sp3 C–H Alkenylation and Arylation) Aeruginosins are important marine natural products and include more than 20 congeners, among which 298A, 98A-C, and 101 display potent in vitro inhibition of various serine proteases, including trypsin and thrombin. Aeruginosins were isolated from cyanobacterial water blooms and sponges [57]. Murakami and coworkers [58] initially elucidated the structure of aeruginosin 298A, in which the configuration of the hydrophobic amino acid as l-leucine was found to be misassigned. Later, the groups of Bonjoch [59] and Wipf [60] independently reported the total synthesis of aeruginosin 298A and revealed a d-configuration of the leucine moiety. In 2015, Baudoin and coworkers [61] demonstrated a general and scalable synthetic procedure for the synthesis of aeruginosins via sp3 C–H activation reactions.

17.15  Synthesis of Aeruginosins (sp3 C–H Alkenylation and Arylation)

The initiation of the total synthesis involved the reaction between TBS-protected L-alanilol 78 with tert-butyldiphenylsilyl (TBDPS)-protected dibromocyclohexenol 77 to afford a 1:1 mixture of two diastereomers, which was followed by the protection of the amine group as trifluoroacetamide by the reaction with trifluoroacetic anhydride in the presence of pyridine to afford the desired diastereoisomer 79. Next, the authors performed the most crucial step of the synthesis, which involves the palladium-catalyzed intramolecular C–H alkenylation (C–H/C–Br coupling) of the precursor in the presence of pivallic acid and potassium carbonate base to afford 81 with 71% yield (Scheme 17.15.1).

Br + TBSO TBDPSO

NH2

TBDPSO

Me

Br

Br

DMF

78

77

H OTBS

N H

79 + Other diastereoisomer (1:1) TFAA, Pyridine

OTBS TBDPSO

H N O 81

CF3

Pd(PCy3)2 PivOK, K2CO3

Br

TBDPSO 71% yield C-H/C-Br coupling

H OTBS

N O

CF3

80

Scheme 17.15.1  Palladium-catalyzed intramolecular C–H alkenylation.

The rhodium-catalyzed diastereoselective hydrogenation of the trisubstituted alkene 81 was next to be carried out, which was followed by the treatment of the resultant molecule with 0.5% HCl in MeOH to afford alcohol 82. The alcohol 82 was further oxidized using Jones reagent, and a subsequent esterification of the corresponding acid group and removal of amine protecting group were achieved under the reductive condition to form amino ester 83 in 82% yield (Scheme 17.15.2).

H

OTBS TBDPSO

1) H2, Rh/C

H N O 81

CF3

2) 0.5 HCl/MeOH

H

OH

O

1) Jone's reagent TBDPSO

H N O 82

CF3

2) TMSCHN2 3) NaBH4

TBDPSO

H N H 83

OMe

Scheme 17.15.2  Synthesis of amino ester fragment 83.

Another important step of the total synthesis involved the reaction between benzyl-protected iodophenol 84 and precursor 83 under the palladium-catalyzed C–H activation (C–H/C–I coupling) conditions, which afforded the arylated product 85 in 78% yield. The product thus obtained was subjected to hydrolysis of the amide group to form acid. Therefore, the southern part of aerugniosin 87 wassynthesized by coupling of acid 86 with D-leucine methyl ester in 82% yield (Scheme 17.15.3). Hydrolysis of the ester group to the acid of fragment 87 was carried out using lithium hydroxide, which was then subjected to peptide coupling with 83 to afford 88 in 76% yield. The methyl ester group was then hydrolyzed using lithium hydroxide, followed by the coupling with L-argol moiety A, to give 89. Finally, cleavage of TBS group on the argol moiety using hydrochloric acid in methanol, followed by hydrogenolysis of benzyl and Cbz groups, afforded aeruginosin 298 A 90 in 73% yield (Scheme 17.15.4).

695

696

17  Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals

PIP

OBn

H N

H O 84

I + BnO

Pd(OAc)2 K2CO3, MeCN, 110 oC 78% yield C-H/C-I coupling

PIP

OBn

H N O

85

MeO2C Me

OBn O

Me

87

OBn

Me MeO2C

H2N PIP =

NOBF4

Me

H N

OBn

NH2

OBn

N

OBn

HO

PyBOP, DIPEA 82% yield

O

86

Scheme 17.15.3  Synthesis of southern part aerugniosins, 87.

Scheme 17.15.4  Synthesis of aeruginosin 298 A, 90.

17.16  Synthesis of Gamendazole Gamendazole 95, derived from lonidamine (LND) and consisting of an indazole carboxylic acid framework, finds application as a drug for male contraception. Gamendazole is known to induce reversible germ cell exfoliation present in the seminiferous epithelium by disrupting the testis-specific atypical adherens junction. The previously reported method for synthesis of gamendazole involved nine steps [62, 63]. In 2015, Guillaumet and coworkers [64] synthesized gamendazole in three steps via a palladium-catalyzed regioselective C3- oxidative alkenylation of indazoles. The precursor 93 in 87% yield was prepared by the treatment of commercially available indazole 91 with 2,4-dichloro-1-(chloromethyl)benzene. Precursor 73 was then

17.17  Synthesis of Beclabuvir (BMS-791325)

subjected to palladium-catalyzed regioselective C3 oxidative alkenylation (C–H/C–H coupling), with methyl acrylate in the presence of silver carbonate and acetic acid in 1,4-dioxane solvent at 120 oC, to give olefinated compound 94 in 69% yield. Finally, the hydrolysis of ester group in 94 using LiOH·H2O mixture provided gamendazole 95 in 91% yield (Scheme 17.16). H

N N H K2CO 3 (1.5 equiv)

F3C 91 +

N F3C

Cl

N

Cl Cl 93 (87%)

Cl

H

+

NMP, 200 oC, MW, 20 min

Cl 92

N

N

F3C

Cl

Cl (11%) CO2H

CO2Me CO 2Me

Pd(OAc)2 (5.0 mol%) Ag2CO3/ Argon AcOH/ Ac2O, 18 h 1,4-dioxane, 120 oC 69% yield C-H/C-H coupling

N

N

THF, MeOH

N

F3C

Cl 94

Cl

F3C

LiOH, H2O TA, 4 h 91% yield

N Cl Cl Gamendazole, 95

Scheme 17.16  Total synthesis of gamendazole, 95.

17.17  Synthesis of Beclabuvir (BMS-791325) Beclabuvir, abbreviated as BCV and known by research name BMS-791325, has been studied for clinical trials as BristolMyers Squibb’s HCV NS5B inhibitor, an antiviral drug used for the treatment of hepatitis C virus. Beclabuvir 98 represents the seven-membered ring in the center of the active pharmaceutical ingredient that can be formed by metal-catalyzed intramolecular arylation of indole containing aryl bromide moiety. A. J. DelMonte and coworkers [65] reported palladium catalyzed intramolecular C–H arylation of indole containing aryl bromide ethyl ester 96, following the hydrolysis of the ester moiety and isolating it in the form of monopotassium salt 97 in 85% yield. Further coupling of monopotassium salt 97 with bridged piperazine formed beclabuvir 98 (Scheme 17.17).

EtO2C Me

O O O S N N H Me

N

O

OMe Br H

KO2C

1) Pd(OAc) 2, PCy3.HBF4 O O O KHCO3, Me S o N N DMAc:Toluene, 120 C, 4h H Me 2) KOH, MTBE/H2O

0.5 N

3) HCl 4) EtOH, KOEt, DMAc 96

Me 1) HOB1 hydrate, EDAC Me

NH+

97

C-H arylation

NH2+Cl-

DIPEA, CH3CN 20-25 oC, 12 h 2) EtOH, HCl, MTBE

Me

NH+

Cl- O N

O O O S N N H Me

Beclabuvir, 98

Scheme 17.17  Synthesis of beclabuvir, 98.

N

NMe2

697

698

17  Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals

17.18  Conclusions This book chapter highlights the powerful nature of the C–H bond functionalization strategy to construct complex synthetic targets, such as natural products and pharmaceutical drugs that could be commonly produced using cross-coupling reactions. One of the many advantages this strategy would provide over the coupling processes would be to curtail the requirement of initial functionalization steps needed in cross-coupling reactions. This book chapter discusses a total of 15 natural products and pharmaceutical drugs, allowing the applicability of the developed late-stage C–H bond functionalization methodology to be fully understood. In spite of the rapid development taking place in this area of research, the number of bio-active molecules synthesized is much smaller than the number of those prepared using cross-couplings. Besides increasing the efforts to develop more complex bio-active molecules, a conscious effort should be made to improve the appeal of the synthetic strategy, in terms of the reagents as well as higher reactivity. Commercial success of a few such methodologies would certainly boost the case for the late-stage C–H bond functionalization-based strategy to be applied more readily in the future.

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701

703

18 Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products François Richard, Elias Selmi-Higashi, and Stellios Arseniyadis Queen Mary University of London, Department of Chemistry, Mile End Road, London, UK

The development of new bioactive molecules, notably in the agrochemical and pharmaceutical industries, strongly relies on the screening of chemical libraries of small molecules. The chemical synthesis of these potential new candidates is a time-consuming and inevitable step. Among the available strategies, the diversification of well-known bioactive molecules or de novo syntheses of their analogues are classical approaches to identify new lead compounds. A representative example of this strategy is camptothecin, a natural product with antitumoral properties, whose synthesis enabled the development of numerous marketed chemotherapeutic medications including topotecan, irinotecan, belotecan, and exatecan. These topoisomerase I inhibitors addressed the low-solubility issue of the natural camptothecin and concomitantly increased its selectivity, therefore reducing its adverse effects. With the aim to speed up the generation of such chemical libraries, late-stage functionalization (LSF) has emerged as a method of choice. Indeed, these transformations aim to consider inert C–H bonds as strategic sites to selectively install a new functional group of interest. These methods feature high site- and chemoselectivity, high group and structural complexity tolerance, and mild reaction conditions. Several LSF methods have highlighted their compatibility and selectivity on the camptothecin skeleton, generating analogues in a single step from the bioactive natural product and therefore demonstrating the potential of LSF in drug discovery (Scheme 18.1).

Scheme 18.1  C–H functionalization of camptothecin and marketed analogues.

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

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18  Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products

18.1  C–H Methylation and Alkylation The introduction of a methyl group in a drug candidate can have a tremendous impact on the biological activity of a given molecule. Solubility and selectivity can be boosted through methylation. Indeed, a methyl group can decrease the desolvatation energy from an aqueous to a lipophilic environment required to transfer the drug into a protein cavity. This so called "magic methyl effect" is of primary importance in drug development as it can favor binding and lower the IC50 value of a candidate. Additionally, the simple installation of a methyl group can induce a significant change in conformation, which can sometimes be beneficial [1]. A stunning example is the methylation of the dual antagonist of orexin-1 and orexin-2 receptors developed by Merck for the treatment of insomnia. The addition of a methyl group at the 2-position of the central piperidine ring resulted in a 480-fold boost in potency (Figure 18.1). The magic methyl effect triggered the synthetic community to develop late-stage C–H methylation reactions. In 2014, Tudge and DiRocco reported a photocatalytic methylation of aromatic N-heterocycles (Scheme 18.2) [2] Their high-throughput experimentation approach identified several sets of conditions relying on the use of iridium-based photocatalysts, blue light irradiation, and tert-butylperacetate as the methylating agent. The mild generation of an alkyl radical intermediate enabled the functionalization of various pharmaceuticals such as fasudil, camptothecin, voriconazole, loratadine, and bustinib, although bis-methylation was also frequently observed. The method was eventually extended to the installation of ethyl and cyclopropyl groups using tert-amylperacetate or biscyclopropanecarbonyl peroxide, respectively. More recently, the White group reported a late-stage C–H methylation of N- and O-containing heterocycles (Scheme 18.3) [3]. The sequential approach relied on a manganese-catalyzed C–H hydroxylation followed by hydroxyl activation to form a reactive iminium or oxonium intermediate by action of a fluoride source (DAST) or a Lewis acid (BF3·Et2O). The reactive intermediate was then trapped by trimethylaluminium to afford the methylated analogue. The method featured extremely good functional group tolerance as well as a great chemo- and regioselectivity. It was finally applied to the functionalization of several pharmaceuticals such as cromakalim, indoprofen, fenspiride, pozanicline, citalopram, diclofensine, and tedizolid, as well as natural products (e.g. ambroxide). Subsequently, the groups of Ackermann and Johansson developed a C−H methylation protocol designed to diversify pharmaceutical candidates (Scheme 18.4) [4]. Metal-catalyzed C–H functionalization reactions traditionally required the installation of a directing group (DG) that needed to be removed afterward, an approach incompatible with the concept of LSF. To circumvent this issue, the two groups took advantage of the chelation offered by the functional groups already available on the bioactive molecules. A multiparameter optimization was undertaken to unveil the highly electrophilic Cp*Co(PhH)(PF6)2 as a catalyst and trimethylboroxine as the methylating agent of choice in the presence of potassium carbonate and silver carbonate. Mechanistically, the transformation is believed to start with the complexation of the catalyst to an inherent functional group to enable the following C–H activation step. This is followed by a transmetallation with the boron-based methylating reagent to afford a cobalt(III) complex that undergoes reductive elimination and reoxidation of the catalyst. The synthetic utility of the method was illustrated in the synthesis of a myriad of bioactive molecules including ivacaftor, apremiplast, rupacarib, and strychnine. More recently, Pilarski and coworkers reported a sustainable rhodium-catalyzed C–H methylation reaction [5]. Due to the mechanical action of ball milling, the reaction was performed without any solvent using potassium methyltrifluoroborate as the source of methyl groups (Scheme 18.5). The mechanochemical methylation of etoricoxib, a known non-steroidal anti-inflammatory drug, showed the compatibility of the method for late-stage C–H functionalization. The methylated analogue was obtained in 60% yield and with high regioselectivity. Stahl and coworkers reported a powerful and mild nickel-catalyzed C(sp3)–H methylation [6]. This photocatalytic method relies on the homolytic cleavage of di-tert-butyl peroxide followed by β-scission or H-atom transfer for the

N N

N

N

O

O

O

N N

F

vs N

N

N

IC50 = 96 nM

Figure 18.1  Boost in potency for the methylated candidate.

O

Me

IC50 = 0.2 nM

N

F

18.2  C–H Arylation and Olefination

C–H methylation O H

+

O

N

O O S

Conditions A-D

O

Me

450 nm

Me

NH

N

Me

N

N

O

N

H/Me

N N HO

N N

N

N

O Me

HO

Me

O

from Camptothecinb

from Fasudil a 43%

from Voriconazole c 37% mono / 21% bis

77%

C–H alkylation O

O H+ N

O

O

Me

or

O

Me

Conditions A-B

O

450 nm

O

or N

N

or H O O S

NH N

4

Cl

N 2

O O or H

N N Me from Fasudild 56%

O

N CN

N

HN

O

N

Cl

Cl

O

from Loratadine d 10% mono C 2 / 21% mono C4 / 13% bis

from Bosutinib d 57%

a Conditions A: AcOH:ACN (1:1) (0.1M), [Ir(dF-CF -ppy)2(dtbpy)]PF (2 mol%). b Conditions B: TFA/ACN (1:1) [0.1M], 3 6 [Ir(ppy)2(dtbpy)]PF6 (2 mol%). c Conditions C: TFA:ACN (1:1) (0.1M), [Ir(dF-CF3-ppy)2(dtbpy)]PF6 (2 mol%). d Conditions D:

AcOH/ACN (1:1) [0.1M], TFA (1 equiv.), [Ir(ppy)2(dtbpy)]PF6 (2 mol%).

Scheme 18.2  Photocatalytic methylation of N-heterocyclic bioactive compounds.

generation of a key methyl radical. Afterward, the nickel catalyst assists the radical-radical coupling to create the new C– CH3 bond. This transformation was applied to the methylation of the acyl-protected sitagliptin, a marketed anti-diabetic drug (Scheme 18.6). Remarkably, the methylated analogue was obtained in 61% yield.

18.2  C–H Arylation and Olefination The LSF of bioactive molecules has also been extended to the installation other groups of interest such as aromatic rings and olefins.

705

706

18  Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products

(S,S)-Mn(CF3 PDP) H 2O 2, AcOH, MeCN, –36 ºC then DAST or BF3 ·Et 2O

H

Me

then AlMe3, CH 2Cl2

X

X

X

N

Me

N

O

X

Methylation

CF3

F3C

(S,S)-Mn(CF3PDP)

Me

N

NH

N

OMe

O

NCMe

N

Me

OAc

NCMe

Mn

N

C–H hydroxylation

CF3

N

N

X= -N or -O

OR F- or Lewis acid activation

(SbF6) 2

F3C

O

O

O

from cromakalim acetate

from indoprofen methyl ester

from fenspiride

51%

33%

24%

N

N

O

O Me

SO2 Ph

Me

N

O

Me

N

N Ns

OMe F

from nosyl-pozanicline

from citalopram

from sulfonyl-diclofensine

34%

34%

23%

Me O

O

H

O AcO

N

N Me

N N N N

F

from ambroxide

from tedizolid acetate

32%

40%

Scheme 18.3  Manganese-catalyzed C–H methylation of saturated N- and O-heterocycles.

In 2010, Baran and coworkers revisited the Minisci reaction to achieve a late-stage C–H arylation [7]. In this case, the silver(I)-catalyzed process enabled the direct C–H arylation of nitrogen-based heterocycles after carbon-boron cleavage of a boronic acid to generate an aryl radical. The functional group tolerance of this operationally simple and easily scalable procedure was benchmarked through the direct arylation of quinine in 40% yield (Scheme 18.7). Later, Sanford and coworkers reported a palladium-catalyzed transannular arylation of cyclic amines, which culminated with the synthesis of arylated analogues of vareniciline and cytosine (Scheme 18.8) [8]. These agonists of nicotinic acetylcholine receptors are currently used as nicotine addiction treatments. Remarkably, the reactions yielded only single diastereoisomers, installing the new aryl group in the axial position of the ring. This transformation requires the presence of a fluoroamide-DG, that can be removed through SmI2-mediated reductive cleavage. Through a series of successive reports, the Yu lab reported the direct and remote C–H olefination and arylation of aromatic and heteroaromatic rings. These studies all showcased the potential of these reactions in the LSF of camptothecin,

18.2  C–H Arylation and Olefination

H

H FG

FG

CoIIIXCp*

Me 3B3O3 Cp*Co(PhH)(PF6)2 Ag 2CO3, K2CO3

[Ox]

Me

CoI—Cp*

FG

FG

MeTHF, 100 ºC

C–H activation

reductive elimination FG

CoIIIXCp*

H

X HX FG

transmetallation

CoIIIXCp*

Co IIICp* Me

X B(OR)2

O

O NH

O

Me

N O

Me

H N Me

O

H

H N

O

H

O S O

N

H

Me B(OR)2

NH

O

N H

F

O

from apremilast

from strychnine

from rucaparib

23%

28%

39%

Scheme 18.4  Cobalt-catalyzed methylation of pharmaceuticals.

[Cp*RhCl2]2 AgSbF6 MeBF3K, Ag2 CO3

SO2Me Cl

Cl

Teflon TM vessel Stainless steel ball (15mm) MM, 36Hz, 30min 60%

N H

SO2 Me

N

N Me

N

Etoricoxib

Scheme 18.5  Mechanochemical C–H methylation of etoricoxib.

O H N

N

O

CF3

HN

N N

+

F

F3C

F Sitagliptin acyl

O

O

NiCl2 •dme 2,6-di-t ert -butylpyridine Ir[dF(CF3 )ppy]2 tBubpyPF6 0.3 M, TFE, visible light, rt 61%

F

Scheme 18.6  Photocatalytic nickel-catalyzed methylation of sitaglptin acyl.

O Me N

N

O

CF3

HN

N N

F

F3C

F F

707

708

18  Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products

N

H

N AgNO3 TFA, K2S2 O8

OH B(OH) 2

MeO

+ N

OH

MeO

CH2 Cl2 :H 2O (1:1), rt

PhO

H

H

N

40%

OPh

Quinine

Scheme 18.7  Ag-mediated C2-arylation of quinine.

H

R +

O

N

R

Pd(OAc) 2

I

CsOPiv t-amylOH, 150 ºC, air

NHC 7F7

O

N

NHC 7F7 R2 R1

O

N

O

N

NHC 7F7

N

R3

NHC7 F7

O

O

N

NHC7 F7

N

N

N

N

from cytisine

from varenicline

25%

45%

R1 = R1 = R1 = R1 =

from varenicline

H, R2 = OMe, R3 = H (40%) H, R2 = CH 3, R3 = H (42%) CF3 , R 2 = H, R 3 = CF3 (36%) H, R2 = CH 3, R3 = CH 3 (43%)

Scheme 18.8  Diversification of varenicline and cytisine by palladium-catalyzed arylation.

the antileukaemic and antitumoral alkaloid presented earlier. Through various sets of conditions, Yu and coworkers displayed a powerful reaction manifold for the selective and late-stage C–H functionalization of this natural alkaloid. They first reported the palladium-catalyzed C12–H olefination of camptothecin. This non-directed approach relied on the use of a 2-hydroxypyridine ligand to enhance the selectivity of the transformation at the most electron-rich position, C12 (Scheme 18.9) [9]. Remarkably, no other regioisomer was obtained and the camptothecin analogue was isolated in 46% yield.

H

H 9

H

N

10 11

12

CO2Et

O

O HO

N

Pd(OAc)2 , Ligand

N

H

H

AgOAc, HFIP, 100 ºC, 24 h 46% F3C

CF3 N

Ligand

Scheme 18.9  C12-olefination of camptothecin.

OH

N O

CO2 Et

O

Campthothecin

12

O

HO

O

18.2  C–H Arylation and Olefination

In a following report, the group attempted to reach a more remote position on the quinoline ring. Through the coordination of the nitrogen ring to a U-shaped template and the presence of a remote cyano directing-group, the C–H activation reaction was directed into the less accessible C9-position of camptothecin (Scheme 18.10) [10]. CO2 Et

CO2Et

H H N

Template

O

Pd(OAc)2 , Ac-Gly-OH

N H

N H

49%

O

O

N

AgOAc, HFIP, 80 °C, 43 h

O HO

H

O HO

O

Campthothecin MeO

O

O

N N

OMe

Pd

F

N Et

N

LPdII

N

Scheme 18.10  C9-olefination of camptothecin.

In 2020, access to the C10-position of camptothecin was finally made possible. The concomitant use of the same type of template and norbornene 2-methyl ester as a transient mediator enabled the site-selective C–H arylation of camptothecin (Scheme 18.11). However, subsequent addition of DMAP in toluene was required to cleave the coordination bond between the template and the product [11]. I CO2Me

H H N

Template, NBE-CO2 Me Pd(OAc) 2, Ac-Gly-OH

O

N O

H HO

AgOAc, Ag2 CO3 , HFIP, 80 ºC, 43 h then DMAP, toluene, 80 ºC

O

47%

H N

MeO2 C

O

N H

O HO

O

Campthothecin F3 C

O

F3 C

O

N N

Pd

N

F

N Me

NC PdIIL

Scheme 18.11  C10-olefination of camptothecin.

Imidazoles are a well-known class of antifungal agents in the agrochemical industry. These heterocycles are known to interfere in the biosynthesis of ergosterol, an essential component of the fungal cell membrane. In 2019, Soulé and coworkers undertook the development of a palladium-catalyzed late-stage C–H arylation of imidazoles [12]. The

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18  Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products

C5-selective transformation was developed on bifonazole, climbazole, and ketoconazole (Scheme 18.12). Using Pd(OAc)2 as a catalyst in the presence of potassium acetate in dimethylacetamide, this highly regioselective method enabled the production of 19 arylated-analogues of bifonazole, six analogues of climbazole, and five analogues of ketoconazole. Pd(OAc)2

R

N H

N

Br

+

N

DMA, 150 ºC

Cl

Ph

R

N

KOAc

O

O Ph N

O O

R

N

R

N

N

N

Cl

O

N

R

N

Cl

N

O from climbazole 6 examples, 14-72%

from bifonazole 19 examples, 28-90%

from ketoconazole 5 examples, 12-68%

Scheme 18.12  Diversification of imidazole containing antifungal agents by palladium-catalyzed arylation.

Thiophene and furan rings are also frequently encountered in bioactive compounds. As a result, these building blocks of interest constitute a structure of choice to develop new LSF transformations. In this context, the group of Carrow reported the highly site-selective C–H alkenylation of thiophenes and furans [13]. The method took advantage of a thioether ligand that enhanced the rate of reaction at the more electron-rich C2-position (Scheme 18.13). Analogues of duloxetine, a treatment for major depressive disorder, and furosemide, a loop diuretic, were prepared in good yields (56% and 86%) using this method.

X H

+

Pd(OAc)2 , Ligand Benzoquinone AcOH, 60 °C

X

CO2 tBu

CO2 tBu Ligand

X = O, S

S

X = O, S

Me2N

O Boc N

HO t Bu O C 2

O S

from duloxetine 56%

O

HN

CO2t Bu

O S NH2 O Cl

from furosemide 86%

Scheme 18.13  Late-stage olefination of thiophene and furan-containing pharmaceuticals.

Following this report, Dong and coworkers developed a palladium-catalyzed difunctionalization of thiophene rings [14]. Relying on a palladium/norbornene-mediated catalysis, they proposed that the palladation first occurred at the most electron rich C5-position. This was followed by insertion of norbornene, resulting in subsequent arylation at the C4-position.

18.3  Formation of Other C−C Bonds

Norbornene exclusion would eventually result in a C5-palladation that would be followed by olefination. These conditions were applied to duloxetine and clopidrogel (Scheme 18.14). Acrylate and benzoate installation occurred in 57% yield for duloxetine and in 48% yield for clopidrogel.

S

Pd(OAc)2 , AsPh3 AgOAc, Benzoquinone, AcOH EtOAc, 65 °C

I H +

CO 2Me

+

S

CO2 Me NBE

H

CO2 tBu CO2 Me

O N H

Me

CO2 tBu O

S

CO2 Me

CO2 Me

MeO2 C MeO 2C

N S

Cl

BocN from duloxetine 56%

from clopidogrel 47%

Scheme 18.14  Difunctionalization of bioactive thiophenes.

18.3  Formation of Other C−C Bonds The LSF of molecules of biological interest has also been developed beyond the scope of simple alkyl, alkenes, and aromatic rings. A handful of reports have described the addition of further functionalized building blocks onto complex molecules. Beckwith and Davies reported a pioneering study on rhodium(II)-catalyzed C−H insertion into complex alkaloids (Scheme 18.15) [15]. The study showcased a robust site-selective method, tolerant of basic amines recurrent in this class of natural products. Brucine was selected as the starting point of the study. Interestingly, the choice of catalyst could greatly modulate the outcome of the reaction in term of selectivity. Indeed, the use of Rh2(Oct)4 resulted in the formation of a azaylide that undergoes [1,2]-Stevens rearrangement, whereas the C−H insertion products could be obtained selectively when using Rh2(TPA)4 and Rh2(S-BTPCP)4, respectively. This functionalization of complex alkaloids proved the utility of the dirhodium(II)-catalyzed process in the LSF and was further exemplified in the functionalization of securinine. As mentioned earlier, Minisci-type reactions represent an excellent synthetic tool for the formation of C–C bonds on N-containing heteroaromatics. This transformation has gained more attention recently due to the emergence of photoredox catalysis as it enabled the mild generation of reactive radical species. This selective transformation appeared to be perfectly compatible with late-stage considerations and was therefore applied in several studies. A remarkable example can be found in the recent report by Chen and coworkers in which the hydroxybenziodoxolemediated generation of an alkoxy radical followed by a 1,5-HAT enabled the formation of a remote carbon center radical. The latter acted as a coupling partner in a ruthenium(II)-catalyzed Minisci reaction [16]. As a result, the desired heterocycle was functionalized with a carbon chain containing a remote hydroxy group. Late-stage applications included the derivatisation of camptothecin, the antiviral famciclovir, and the fungicide quinoxyfen (Scheme 18.16). Fu and Shang reported a Minisci-type aminoalkylation of N-heteroaromatic compounds. Their approach relied on the concomitant use of an iridium-photocatalyst and a phosphoric acid. This co-catalytic system enables the generation of an alpha amino carboxylate radical form of N-(acyloxy)phtalimide that is converted into an alpha-amino radical upon decarboxylation. This reactive species adds to the aromatic ring to generate a radical cation, which is then further oxidized by the photocatalyst to yield the desired product. The aminoalkylation of fasudil and famciclovir was performed in good yields, showcasing the suitability of the method for late-stage C–H functionalization (Scheme 18.17).

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18  Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products

Br CO2Me N

Rh 2(Oct) 4 MeO

74%

H N H

MeO

O

O Br

N MeO

H N H

MeO

Br

+

Rh2 (TPA)4

O N2

O

MeO

50%

CO2Me

H

CO2 Me N H N H

MeO

O

O Br MeO2C H

Rh2 (S-BTPCP) 4

N

39%

MeO

H N H

MeO

O

Scheme 18.15  Rhodium-catalyzed selective C–H bond functionalization of brucine.

PFBI-OH Ru(bpy) 3Cl2 N

+ H

H OH

R

N

HFIP, CFL, 30 °C, 24 h fluorescent light irradiation O I

F

O

PFBI-OH

OH

R

OH

F

F F

F

HO N

O N

N

N O HO

Cl

OH

H2N

N

O

OAc

N

OAc

Cl

N

OH

O

2

from camptothecin

from famciclovir

from quinoxyfen

58%

53%

67%

Scheme 18.16  Photocatalytic Minisci-type installation of butanol derivatives.

Bpin

O

18.3 Formation of Other C−C Bonds

Ir[dF(CF3 )ppy] 2(dtbbpy)PF6

O N

+

N

H

O

PG NH

O

O

(+/-) BINOL-P(O)OH

PG

N

NH

Blue LEDs, DMA, rt, 3 h

R

R

NHBoc

HN N

NHBoc S

O O

t

BuO

N

N

N

NHBoc

OAc

N

N

H2N

OAc

from fasudil

from famciclovir

56%

53%

Scheme 18.17  Minisci-type aminoalkylation of fasudil and famciclovir.

Later, Phipps and coworkers developed an asymmetric version of this transformation using a chiral phosphoric acid. Mechanistic studies suggested that the addition of the aminoalkyl radical was reversible and that deprotonation of the resulting intermediate was the enantiodetermining step. This enantioselective aminoalkylation showed good substrate compatibility as showcased by the aminoalkylations of metyrapyrone and etofibrate, which proceeded in good yields (70– 86%) and high ees (93–95% ee, Scheme 18.18) [17].

O PhthN

H N

O

R

O

(R)-TCYP

N H

Blue LEDs 1,4-dioxane rt, 14 h

N

Ac NHAc

N

O HO

N

Ac N H

N+

H

H P

O-

HO

OH

P

N H OOH

O O

O

O

O

N

H O

Cl

O

R

R

R

Ir[dF(CF3)ppy]2(dtbbpy)PF6

NHAc

N NHAc

from metyrapone

from etofibrate

70% (95% ee)

86% (93% ee)

Scheme 18.18  Enantioselective photocatalyzed-aminoalkylation of metyrapone and etofibrate.

In 2016, Krksa and DiRocco reported their effort to perform C–H hydroxymethylation of N-heterocyclic-based pharmaceuticals through a photocatalyzed Minisci reaction (Scheme 18.19) [18]. This unique group can modulate the solubility and the log P of a compound, but can also act as a binding site. The reaction relied on an iridium-based photocatalyst and the use of benzoyl peroxide and methanol in an acidic medium. The marketed vasodilator fasudil, the diuretic torsemide, and the antifungal voriconazole were functionalized in satisfying yields (20-60%).

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18  Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products

N

Ir[dF(CF3 )ppy]2 (dtbpy)PF6 Benzoyl peroxide

CH 3OH

+

N

Blue LEDs TFA, rt, 16 h

H

NH

O N O S

N

O

HO

OH

N N HO

N NH HN H S O O N

N

OH

N

N OH F

F

F

from fasudil

from torsemide

from voriconazole

60%

20%

44%

Scheme 18.19  Photocatalyzed hydroxymethylation of N-heterocyclic pharmaceuticals.

18.4  C–H Hydroxylation Late-stage C–H hydroxylation is a powerful method when it comes to the diversification of N-containing heterocycles. When the C−H hydroxylation takes place alpha to the nitrogen center, a hemiaminal is generated that can be further engaged in other synthetic transformations such as arylations and alkylations. Strategies for direct C(sp3)−H hydroxylation are limited due to the potential over-oxidation of the resulting hydroxyl or even elimination to the corresponding olefin when high temperatures or harsh conditions are used [19, 20]. In 2021, Zhao and coworkers reported a copper-catalyzed late-stage C(sp3)−H functionalization of N-heterocycles under mild reaction conditions using commercially available PyBOX type ligands (Scheme 18.20) [21]. The method was shown to be compatible with a broad range of functional groups including alkenes and secondary alcohols. This copper(I) acetatecatalyzed transformation was used for the LSF of various drugs including nitrofurantoin, indoprofen methyl ester, the tedizolid precursor, and a proline-based dipeptide natural product. CuOAc, Ligand NFSI R

H

+

CH3CN, 30-35 °C

ROH

N R

Ligand O

L1: R = Ph N L2: R = Bn R

O

O O

N N OCH3

OR N R

O

N N

R

O

O HN

R

O

from nitrofurantoin 51%a

NO 2

N

F

OH Br

OAc OH from tedizolid precursor 72%a, 5:1 d.r

O

NH

O

N O O

O

N Ns OH

from indoprofen methyl ester 73%b

OH-PA 61%c, 10:1 d.r

Conditions: a Ligand L1, ROH (0.6 mmol); b Ligand L1, temperature : 35 °C; c Ligand L2, temperature : 30 °C

Scheme 18.20  Copper-catalyzed C−H hydroxylation of N-heterocyclic substrates.

18.5  C–H Amination

Subsequently, Yu and coworkers developed a C−H hydroxylation protocol for the late-stage modification of drugs and peptides [22]. They designed a new palladium(II) catalyst bearing a bidentate pyridine-pyridone ligand that enables C−H hydroxylation on various complex scaffolds bearing a carboxylic acid moiety. The fine-tuned pyridine-pyridone ligand allows a key binding switch for the transformation. The first C−H activation step proceeds with the L,X coordinated ligand and is followed by tautomerisation into an L,L coordinating mode for the subsequent O2 activation step. The tautomerization was supported both by computational analysis and infrared spectroscopy (IR). The method was eventually applied to the LSF of the clonixin, a nonsteroidal anti-inflammatory drug (Scheme 18.21).

N Cl

N H

Pd(OAc)2 , Ligand, BQ

H O

OH

N Cl

KOAc, DMF, O2 (1 atm), 110 °C 65%

N H

O

OH O

OH

N H N

Ligand

Clonixin

Scheme 18.21  Palladium-catalyzed C−H hydroxylation of clonixin.

18.5  C–H Amination Methodologies that directly install an amino functional group into C−H bonds of complex scaffolds are desirable due to the potent effects of such groups on the chemical and biological properties of molecules. Nevertheless, the direct and selective intermolecular C−H amination remains a challenging task as it requires excellent site selectivity and functionalgroup tolerance while maintaining a high reactivity. In 2018, White and coworkers reported an efficient strategy for the late-stage C−H amination of bioactive molecules and natural products that showed good compatibility with tertiary amine and heterocycles [23]. This intermolecular benzylic C(sp3)–H amination method catalyzed by a manganese perchlorophthalocyanine catalyst [Mn(III)(ClPc)] used an iminoiodinane as the nitrogen source. Remarkably, both Brønsted and Lewis acids (HBF4·Et2O or BF3·Et2O) could be used to complex the basic tertiary amines present in the substrate. An electrophilic metallonitrene intermediate was proposed to be involved in a stepwise mechanism in which the cleavage of the C–H bond to form the benzylic radical is the rate-determining step. The method was evaluated on the late-stage C–H amination of citalopram, a common antidepressant drug, and provided the benzylic amino product as a single diastereomer in 71% yield (Scheme 18.22).

Scheme 18.22  Copper-catalyzed C–H hydroxylation of the drug citalopram.

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18  Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products

18.6  C–H Trifluoromethylation The incorporation of a trifluoromethyl group into a drug molecule often improves its pharmacokinetic properties, including "Absorption, Distribution, Metabolism, and Excretion” (ADME). This approach is therefore widely used in modern medicine and agrochemistry [24]. Recently, considerable attention has been given to the development of efficient trifluoromethylation methods that do not require any prefunctionalization of the targeted substrates. Strategies for aromatic C(sp2)–H trifluoromethylations commonly rely on Minisci-type pathways which have become widely used in a variety of examples [25]. Although methodologies for aliphatic C(sp3)–H bond functionalization are mostly limited to allylic [26] and benzylic systems [27], C–H activation of strong aliphatic bonds still require a DG [28]. In 2020, MacMillan and coworkers reported a C(sp3)–H trifluoromethylation method using Togni’s reagent. The strategy relies on the merger of light-driven, decatungstate-catalyzed hydrogen atom transfer (HAT) and copper catalysis. Remarkably, this aliphatic C–H trifluoromethylation showed excellent compatibility for a wide range of drugs and natural products. For example, nicotine was converted to the corresponding trifluoromethylated analogue in a single step (40% yield, 67% selectivity, Scheme 18.23). For this example, the authors reported that the dominant selectivity observed was for the strong, electron-neutral C–H bonds over the α-ammonium heterobenzylic position due to the high degree of polarity mismatch [29].

F3 C

H N N

+

CF3

I O O

H2 SO4 , NaDT, CuCl2 H2 O:MeCN (9:1) rt, 390 nm Kessil Lamp

Nicotine

40%

N N 1.5:1 d.r.

4O O 4 Na+ W O W O OO O OO O OO W O W O O W O OO O W OO O W O W O O O O O W O OW O O NaDT

Scheme 18.23  Metallaphotoredox-catalyzed trifluoromethylation of nicotine.

18.7  C–H Difluoromethylation Just like the trifluoromethyl group, the difluoromethyl group (CHF2) has also attracted considerable attention in the medicinal chemistry community. Difluoromethylated heteroarenes are recognized as valuable targets for drug discovery as the difluoromethyl group provides additional hydrogen bonding interactions and modulates the lipophilicity of the compound. Several examples of complex molecules bearing a difluoromethylated heteroarene have been developed such as thiazopyr (herbicide), fluxapyroxad (fungicide), and deracoxib (an anti-inflammatory drug) [30]. Over the years, LSF strategies have been attempted for the direct C–H difluoromethylation of heteroaromatics [31]. For example, Qing and coworkers recently reported a copper-mediated C−H oxidative difluoromethylation for the LSF of biologically relevant compounds. Based on their experimental results and mechanistic investigations, the authors proposed the following mechanism (Scheme 18.24). The difluoromethyl reagent, TMSCHF2, is first converted to CuCHF2 and Cu(CHF2)2 upon treatment with t-BuOK and CuCN. The C–H bond of the heteroarene is then deprotonated with t-BuOK, followed by the transmetallation that delivers intermediate I. Finally, the heteroaromatic [CuCHF2] complex is oxidized by 9,10-phenanthrenequinone (PQ) [32] and a reductive elimination eventually affords the desired difluoromethylated product. This methodology was successfully applied to the late stage difluoromethylation of the natural products neosalvianen and thiabendazole (fungicide and parasiticide) in 85% and 82% yields, respectively. In 2018, Tautermann and coworkers presented a method to introduce a difluoromethyl group through LSF using Baran’s diversinates [33]. This strategy addressed some limitations of the previous conditions (Scheme 18.25) [34]. For this reaction, zinc difluoromethanesulfinate ([CHF2SO2]2Zn or “DFMS”) was used as a difluoromethyl source, with Fe(acac)3 as the catalyst. The authors showed that the regioselectivity could be predicted using computational methods and eventually validated experimentally. Finally, they demonstrated that these LSF reactions led to new analogues with improved in vitro DMPK parameters. Despite the recent achievements in difluoromethylation reactions, methodologies for the introduction of CHF18F into druglike compounds remains scarce. Positron emission tomography (PET) is a functional imaging technique that use radioactive compounds to visualize changes within the human body [35]. Fluorine-18 is a commonly used isotope in the development of

18.7  C–H Difluoromethylation

X Y

R

Z

H

+

CuCN, PQ, t -BuOK

TMSCHF2

X Y

R

Z

NMP, rt CuCN

CHF2

t-BuOK Cu(CHF2) 2-

CuCHF2

PQ

t-BuOK X Y

R

CuI CHF 2

Z I

CHF 2 N

O

N

S

N Bn

O

N

CHF 2

from neosalvianen

from thiabendazole

85%

82%

Scheme 18.24  C–H Difluoromethylation of drug and natural product. Zn(SO 2R)2 Fe(acac) 3, TBHP, TFA

R N

O

S

H N O

F

H

N N N

R N

DCM/H 2O

O

N CHF2

O

O

F

H N

S

Cl

O

N N N F

Analog 1 38%

CHF 2

N CHF2 O

Analog 2 32% N H N

H 2N O

CHF2

N

O

NH

NH F

F3 C

O

Cl

Analog 3 28%

Scheme 18.25  Late-stage difluoromethylation of drug-like molecules.

new radiotracers. Recently, Genicot and coworkers reported a new method for the direct C–H 18F-difluoromethylation of complex N-heteroaromatic compounds through a photoredox flow reaction using an iridium-based photocatalyst and a newly labeled CHF18F reagent [36]. The strategy is simple and straightforward. Additionally, the photo-flow conditions enable very

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18  Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products

short reaction times (2 min). Most importantly, the method was applied in the late-stage labeling of drugs such as acyclovir (a well-known antiviral) (Scheme 18.26). The study was also extended to the functionalization of caffeine derivatives such as pentoxifylline (a hemorrheologic agent) and theophylline (used in the treatment of respiratory diseases). Additionally, the method was used for the synthesis of a moxonidine analogue, a licensed antihypertensive. OH N

N H 2N

N +

H

S

N

N

OH

O O S

fac-Ir(ppy) 3 DMSO, blue LED, 35 °C

F

H2 N

18 F

O

N

N

O

O

N

F O

70 ± 7%

O N

N

N

OH

Acyclovir

18 F

O N

18 F

N

F

N O

N

OMe

H N

18 F

N

F

N 18 F

H N Cl

N

OH

H N N

F

Scheme 18.26 

from Pentoxifylline

from Theophylline

Moxonidine analogue

30 ± 5%

42 ± 6%

65 ± 4%

18

F-Difluoromethyl labeling of N-heterocyclic drugs.

18.8  C–H Fluorination Several C–F bond-forming methods have been developed over the years due to the importance of this element in the pharmaceutical and agrochemical industries [37]. Among the various strategies used, fluorination via C–H activation has appeared as a powerful and straightforward method. In 2021, Doyle and coworkers reported a C(sp3)–H fluorination under photoredox conditions using N-acyloxyphtalimide as the methyl radical precursor (Scheme 18.27) [38]. The transformation features the formation of a carbocation via sequential hydrogen atom transfer (HAT), then oxidative radical-polar crossover followed by a fluoride nucleophilic addition from a triethylamine trihydrofluoride reagent. The method was applied in the late-stage fluorination of complex scaffolds including the natural pesticide rotenone. O H O H

OMe

H O

O

OMe

O Rotenone

O +

H O

Et 3N 3HF

O

Ir(p-F-ppy)3

O N O

t -BuCN, blue LEDs 33%

F

OMe

H O

OMe

O 4.5:1 dr

Scheme 18.27  Late-stage C(sp3)–H fluorination of rotenone pesticide.

18.9  C–H Silylation The incorporation of a silyl moiety through C–H functionalization represents an area of great importance as organosilicons are high value intermediates that can be converted to a wide range of products through oxidation, halogenation or palladium-catalyzed cross-coupling reactions. Nevertheless, the metal-silyl complexes are not very reactive in the context of

18.10  C–H Phosphorylation

C−H functionalization and most of the reported methods require high temperatures, a large excess of the C–H partner [39], or the need of a DG [40]. In 2015, Hartwig and coworkers reported a method to introduce silyl groups on various complex pharmaceuticals using [Ir(cod)(OMe)]2 and 2,4,7-trimethylphenanthroline (Scheme 18.28) [41]. Hence, the pyridine ring of the antidepressant mirtazapine was functionalized in a moderate 46% yield, whereas the thiophene rings in ketotifen, duloxetine and clopidogrel were silylated at their 2-position in excellent yields ranging from 75 to 88%. Furthermore, this strategy showed a high level of regioselectivity and good functional group tolerance.

[Ir(cod)OMe] 2, cyclohexene R

+ X

H

THF, 80-100 °C

HSiMe(OSiMe3 )2

R X

Ligand

Si

[Si] =SiMe(OSiMe3 )2 N

N

O [Si]

[Si]

S N

HN S

[Si]

N

MeO2 C O

Cl

N

[Si] S

N

N

from mirtazapine 46%

from ketotifen 75%

from duloxetine 86%

from clopidogrel 88%

Scheme 18.28  C−H Silylation of pharmaceutical compounds.

18.10  C–H Phosphorylation Phosphorus-containing derivatives often display some broad applications. For example, phosphine oxides are used in the field of medicine, the food industry, and even as flame-retardants in epoxy resins. Besides, phosphine-containing ligands are commonly used in metal-catalyzed cross-coupling reactions. Hence, the development of new phosphorylation methods for LSF of complex scaffolds has become an area of great interest. Numerous phosphorylation methodologies have been developed over the years using P-centered radicals, but usually suffer from poor site-selectivity and require harsh conditions [42]. In 2020, Liang and coworkers reported a visible light-mediated installation of a phosphoryl group using RuCl3 as a photocatalyst [43]. The wide functional group tolerance of the reaction was demonstrated in the phosphoroylation of pentoxifyllinein (Scheme 18.29).

O

O N

N O

N

N

H

+

O H P Ph Ph

RuCl3 3H 2O NaOAc, K2S2 O8, AgNO3 H 2O: MeCN (4:1) rt, blue LED 45%

Pentoxifylline

Scheme 18.29  Late-stage C–H phosphorylation of pentoxifylline drug.

O

O N

N O

N

N

O P Ph Ph

719

720

18  Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products

18.11  C–H Deuteration and Tritiation The elucidation of the mode of action of a bioactive substance constitutes an important part of a drug discovery program. In this context, the use of an isotopic label has become an important tool for the evaluation of the pharmacokinetic properties of a bioactive ingredient. The radiolabeled active molecule has a specific signal that can be detected in in vivo and in vitro studies and its structure remained substantially unaltered from its unlabeled analogue. Hence, the late-stage introduction of a radioisotope into a drug candidate clearly appears as an essential strategy in drug development. Lately, significant efforts have been made regarding the C–H deuteration and tritiaton of pharmaceuticals. Chirik and coworkers have been investigating the late-stage C(sp2)–H labelling of pharmaceuticals with earth-abundant metals such iron and cobalt [44, 45]. An important report featured the use of bis(arylimidazol-2-ylidene)pyridine iron bis(dinitrogen) complex as a catalyst in the presence of 2H2. The hydrogen isotope exchange occurred on a variety of substrates on which the functionalization at an electron-poor and sterically accessible site was favored. This trend was observed in the functionalization of varenicline, papaverine, loratadine, and suvorexant. On the orexin receptor antagonist MK-6096, the 2H was preferentially incorporated on the benzene ring, probably directed by the adjacent pyrimidine ring (Scheme 18.30).

iPr

N

N

H

catalyst X

N

N

1 atm 2 H 2 45 °C, THF, 24 h

N

N

iPr N

N iPr

Cl

>98%

N

N catalyst

70%

N

MeO

>98%

N

Fe

N

2H incorporation

MeO

>98%

HN

iPr

N

N

42%

OMe N

OMe O from papaverine

from varenicline

36%

35%

50%

N >98%

N

from loratadine

38%

F O

O

O

O

N

N

from MK-6096

Cl

N

N

N

38%

N

N

N

O

from suvorexant

Scheme 18.30  Iron-catalyzed deuteration of pharmaceuticals.

The iron catalyst was then used for the tritiation of commercially available pharmaceuticals and compared to the most commonly used Crabtree’s iridium catalyst for hydrogen isotope exchange [46]. The study was carried out using 25 mol% of catalyst under a subatmospheric pressure of 3H2 (0.15 atm). The resulting labeled pharmaceuticals exhibited high enough specific activities for pharmacokinetics study (ADME). The two approaches appeared to be complementary: the

18.11  C–H Deuteration and Tritiation

reaction was sterically driven when the iron-catalyst was used, but was directed by the adjacent heteroaromatic to a proximal C–H bond when Crabtree’s catalyst was used (Scheme 18.31). Deuteration and tritiation of C(sp3)-H bond can also be achieved through iridium-based photoredox catalysis. In their study, Macmillan and coworkers functionalized a large variety of alkyl amine containing pharmaceuticals at their alpha-amino position [47]. Mechanistically, an alpha amino alkyl radical is generated by the photo excited iridiumcatalyst; at the same time, a thiol catalyst undergoes exchange with D2O or T2O to give a deuterated or tritiated thiol that traps the alpha amino alkyl radical via hydrogen atom transfer. The method relies on 2% of the iridium photocatalyst and 30% of the thiol HAT catalyst, alongside Li2CO3 as a base and D2O or T2O in NMP under blue LED irradiation. The deuteration method appeared suitable for the functionalization of piperidines and piperazines and tolerated a wide range of functional groups. Remarkably, the stereogenic centers in diltiazem and levofloxacin remain unaltered during the process. It is also worth mentioning that alpha acyclic amine moieties are also functionalized in this reaction (Scheme 18.32). Tritiation of cloperastine, fenspiride, levofloxacin, and imatinib followed the same trend. By simply increasing the catalyst loading, tritium incorporation of these pharmaceuticals resulted in high specific activity sufficient for use in a ligandbinding study (Scheme 18.33).

N 3 H incorporation

Using Fe catalyst

Using Crabtree’s catalyst

F N

N

O

O

N

F N

(trace)

N

O

N

O

N

N

(trace)

from MK-6096 57 Ci mmol-1

O Cl

N

N

from MK-6096 16.9 Ci mmol-1

N

N

N

O

from suvorexant 15.2 Ci mmol-1

N

O (trace) (trace)

Cl

N

N

N

N

N

N

O

from suvorexant 15.3 Ci mmol-1

Scheme 18.31  Comparison of iron-catalyzed and iridium-catalyzed tritiation of pharmaceuticals.

721

Scheme 18.32  Photoredox-catalyzed C−H deuteration of alkyl amine-containing pharmaceuticals.

Scheme 18.33  Photoredox-catalyzed C−H tritiation of alkyl amine-containing pharmaceuticals.

References

18.12  Conclusions As mentioned in the opening of this chapter, the development of new bioactive molecules, notably in the agrochemical and pharmaceutical industries, strongly relies on the screening of chemical libraries of small molecules. As such, late-stage C−H functionalization constitutes a particularly attractive approach as it allows a rapid and highly straightforward entry into a plethora of new compounds starting from readily available non-pre-functionalized compounds. The concept of latestage C−H functionalization has matured and is now routinely used to incorporate a variety of functional groups in a selective fashion for the generation of chemical libraries.

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727

Index Note: Page numbers in italics refer to Figures; those in bold to Tables.

a

acceptorless dehydrogenative coupling 545 acetolysis 3 2’,3’,5’-tri-O-acetyl-3-N-methyluridine 639 acetoxybenziodoxole(BI-OAc) 643 5-acetoxyuracil 636 5-acetoxyluridine 636 N-acetyl protected isoleucine (Ac-Ile-OH) 667, 668, 670 Ac-Leu-OH 26, 412 Ac-Val-OH 76, 77, 133, 409 activation of C(sp2)-H bonds 609 activation of C(sp3)-H Bonds 611 N-(acyloxy)phtalimide 711, 718 1-AdCO2H 295, 663, 664 1,4-addition of indole 623 Aeruginosins 694 Jones reagent 695 sp3 C-H alkenylation and arylation 694 agostic interaction/ bonding/ bonds 4, 35, 36 AgTFA 129, 131, 132, 142, 159, 160, 167, 329, 594, 625, 663 aglycone core 657 alkenylation 326, 365, 374, 381, 468, 498 alkenylation of imidazole 131 alkenylation of pyrazole 131 benzannulation 132 alkenylation of isoxazole 133 alkoxycarbonyl alkylation 488 (alkynyl)(aryl)copper(III) intermediate 419 alkynylation 134, 330, 498 β-alkynylation of tetrahydropyran 594 alkynylation using gem-dihaloalkenes 135 alkynylation with haloalkynes 134 alkynylation with terminal alkynes 135 alkynylcuprates 647

alkylation 136, 320, 358, 370, 378, 471, 486, 575 alkylation of imidazole 139 alkylation of pyrazole 141 allenylation 498 α-C-arylglycoside analogues 673 amberlyst 15, 623 amidoquinoline 659, 662 amination 143 amination/amidation 474 direct alkynylation of 4-chromenone by iridium(III)-catalysis 477 direct C-H amination of 4-chromenone with azides 474 manganese-catalyzed C-H amidation of chromenones with sulfonyl azide 476 rhodium(III)-catalyzed C5-amidation of chromenone using dioxazolone 476 α-amino acids 543, 662 amino alkylation 493 amino-NHC nickel-aluminium system 381 aminoquinoline 567, 569, 572, 573, 574, 577, 579, 581, 582, 584, 585, 659, 667 8-aminoquinoline (AQ) 237, 337, 424, 471, 557, 558, 567, 575, 661, 672, 690 aminoquinoline amide 337, 567, 568, 570, 572, 575, 576, 580, 587, 588, 595 3-aminoquinuclidine 591 (–)-3-aminoquinclidine 591 5-aminouracil 639 amitifadine analogues 598 ammonium persulfate 643, 644 ammoxidation catalysts 32 anagostic 36 annualtion/cyclization 442 coumestrol 444 flemichapparin C 443, 444, 448, 450

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

728

Index

Hermann-Beller catalyst  442 annulation of indoles  232 benzocarbazole scaffolds  232 C3-acetoxylation of indoles  238 cis-hydrobenzo[b]oxepine scaffolds  235 fluorinated isocryptolepine analogs  233 phenanthridine and benzocarbazole  232 anomeric C(sp3)-H glycosylation  677, 678 α-anomeric configuration  675 ansa-scandocene  30 ansa zirconocene complex  620 anti-HCV activity  518 AQ deprotection and diversification from C-terminus  572 aquayamycin  658 arylation  333, 361, 371, 380, 438, 509 aryl/heteroaryl alkylation  489 arylation of isoxazole  126 β-arylation of tetrahydropyran  594 arylnorbornylpalladacycle  674 arylstannanes  646 arylation of pyrazole  123 Au/Ag dual catalytic process  125 davephos  124 sylphos  124 6-aryl-5-(trifluoromethyl)-1,3-dimethyluracil  638 6-aryluracil  637, 639 (E)-5-(arylvinyl)triazole  649 Aspidospermidine  684, 689 Fischer indole synthesis  689 hemiaminal  689, 714 Pictet-Spengler rearrangement  689 asymmetric alkylation of  N-mesitylhetaryl-3-carboxamide  621 atorvastatin  61, 62 atropo-enantioselective synthesis of heterobiaryls  624 aza-Baylis-Hillman type CDC reaction  544 7-azabenzonorbornadienes  623, 624 azacycles  613, 614 azanickelacyclopropane  394 6-azauracil  635 azetidine  567, 575, 576, 577, 580, 581, 582, 583, 592, 612

b 

B(C6F5)3  359 beclabuvir (BMS-791325)  684, 697 belotecan  703 benziodoxolone-based hypervalent iodine reagent  77, 213 benzo[c]pyrimido[1,6-a]azepine  639 1H-benzo[d][1,2,3]triazole  420 benzotriazoles  649 8-benzotriazolyltubercidin  649 4,6-benzylidene  675 N3-benzyl-2’,3’,5’-tri-O-benzoyluridine  634

(R)-BINAP  622, 623, 663, 665, 666 (S)-BINAP  224, 663, 665 BINAP derivative  613 [1,1’-biphenyl]-2-yldicyclohexylphosphane  440 2,2-bipyridine/2,2’-bipyridine  110, 220, 221, 334, 346, 347, 370, 441, 494, 508, 529, 531 2,2’-bipyrimidine  401 2,2’-biquinoline  370 1,3-bis(arylethynyl)-imidazo[1,5-a]pyridine  502 1,2-bis(dicyclohexylphosphino)ethane (dcype)  110, 113, 114, 118, 128, 336 1,2-bis((2S, 5S)-2,5-diphenylphosphalano)ethane ((S,S)Ph-BPE)  417 1,2-bis(diphenylphosphino)benzene(dppbz)  126, 134 1,1’-bis-(diphenylphosphino)ferrocene (dppf)  112, 127, 128, 199, 686 1,2-bis(diphenylphosphino)ethane (dppe)  21, 39, 95, 112, 114, 128, 138, 139, 328, 349, 416 bis(2-dimethylaminoethyl)ether (BDMAE)  419, 420 bis(heteroaryl)methanes  489 bisimidazo diselenide aryl-copper(III) species  526 bis(thien-2-yl)methylamine  610, 611 bis(trimethylsilyl)diazomethane  320, 321 3,3-bithiophene/3,3’-bithiophene  98, 550 Boc-Ava-OH  671 BODIPYs (boron difluoride group joined to a dipyrromethene group)/ boron-dipyrromethene  79, 521, 663 σ-bond metathesis (SBM)  8,12, 13, 18, 19, 26, 28, 29, 30, 32, 35, 37, 80, 417 borylation  19, 141, 229, 377, 382 B2Pin2/ B(Pin)-B(Pin)  20, 101, 142, 230, 377, 378, 382, 425, 602, 614 BRD3914  580, 581, 582 2-bromophenyl glycosylcarboxamides  674 2-(2-bromophenoxy) pyridine  371 5-(2-bromophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazines  422 (BVDU)  632, 633 Buchwald-Hartwig amination  287, 422 γ-butyrolactams  613, 614 Bz-Leu-OH  611 BzONRR  341

c 

carbazole  168, 227, 235, 322, 669 C-aryl/alkenylglycosides  661, 665, 667, 668, 669, 673, 674, 675, 679 C-alkylglycoamino acids  662 C2-α-mannosyl-tryptophan  669 C4 acylation  165 C2 alkenylation of indoles  204 alkylidenecyclopropanes (ACPs)  209 Co-pyphos  205

Index

indolyl-tehthered spiro[cyclobutene-1,1-indenes]  208 potassium vinyltrifluoroborate  208 C2 alkenylation of oxazole and thiazole  127 P^N bidentate ligand (PhMezole-Phos)  128 C4 alkenylation  161 1H-indole-3-carboxaldehydes/ indole-3carboxaldehydes  161, 169 C4 alkenylation of oxazole  131 C5 alkenylation of oxazole and thiazole  127 C7 alkenylation  176 C4 alkylation  156 (1H, 1H-perfluoroalkyl)mesityliodonium triflates  156 α-carbonyl sulfoxonium ylides  157 C5-alkylation of Azauracil nucleoside  636 C7 alkylation  175 C3 alkynylations of indoles  213 β-hydroxide elimination  214 thiocarbamate DG methodology  217 C4 alkynylation  163 C7 alkynylation  177 C2 alkylation of indoles  221 Iboga alkaloids  224 (R)-SDP  223 (S)-DM-SEGPHOS  223 (S)-DTBM-SEFPHOS  223 C2 alkylation of oxazole and thiazole  136 trans-2-decylcyclopropyl iodide  136 C5 alkylation of oxazole and thiazole  139 C4 amidation  169 indole-3-carboxaldehydes/1H- indole-3carboxaldehydes  161, 169 C7 amination/amidation  183 C7 amination/amidation of indolines  287 1-adamantanecarboxylic acid  295 azidoformates  289 Buchwald-Hartwig amination reactions  287 Curtius rearrangement  289 doxorubicin  290 N-nosyloxycarbamate  287 pyrroloindolidione  293, 294 Ullmann-Goldberg reaction  287 C3 allylations of indoles  217 aminophosphine ligand  217 d-(+)-camphor-sulfonic acid  221 Grignard reactions  219 C4 allylation  163 C4 annulation reactions  165 benzo-fused oxindoles  165, 167 4H-oxepino[2,3,4,5-def]carbazoles  168 3-(1H-indol-3-yl)-3-oxopropanenitriles  168 C4 arylation  159 C5 arylation  171 diaryliodonium triflate salts  171

C6 arylation  174 C7 arylation  176 C2 arylation of imidazole  118 C5 arylation of imidazole  119 C2 arylation of oxazole and thiazole  110 C4 arylation of oxazole and thiazole  117 C5 arylation of oxazole and thiazole  115 cam-HrTH-I  669, 670 camptothecin  703–706, 708, 709, 711, 712 CAN  569 canagliflozin, invokana  657, 658 carbon-boron bond formation  425 carbon-carbon bond formation/ C-C bond formation  320, 393, 486, 546 C-arylglycosides  657, 659, 661 C-aryl glycosyl amino acid  677 C-aryl glycosyl phenylazide  677 C2 functionalization of indoles  195, 207, 208, 623 carbon-halogen bond formation  427 carbon nanotubes supported palladium(II) nanoparticlecatalyzed C-H activation  258 carbonylation  503 C-2 carbonylation of indole  238 carbon-silicon bond formation/C-Si bond formation  425, 535 cassialoin  658 Catellani reaction/strategy  417, 421, 673, 689, 692 Catellani-type C-H glycosylation  672, 673, 674, 675, 676 cationic rhodium(I)-catalysis  384 C-B bond formation  300, 557 Chan-Lam-type coupling  303 CdCl2•TMEDA  350 C-H acetoxylation  636 C-H activation: formation of C-CF3  716 decatungstate-catalyzed hydrogen atom transfer  716 C-H activation: formation of C-CHF2  716 acyclovir  718 C-H oxidative difluoromethylation  716 deracoxib  716 fluxapyroxad  716 hydrogen atom transfer (HAT)  716, 718, 721 moxonidine analogue  718 neosalvianen  716, 717 positron emission tomography (PET)  716 theophylline  718 thiabendazole  716, 717 thiazopyr  716 TMSCHF2  716 zinc difluoromethanesulfinate  716 C-H activation: formation of C-F bond  718 rotenone  718 C-H activation: formation of C-P bond  719 C-H activation: formation of C-Si bond  718

729

730

Index

duloxetine  710, 711, 719 ketotifen  719 mirtazapine  719 C-H activation in actinide complexes  28 alcoholysis  28 interligand proton transfer  28 C-H amination  715 citalopram  704, 706, 715 manganese perchlorophthalocyanine catalyst [Mn(III)(ClPC)]  715 metallonitrene intermediate  715 C-H arylation and olefination  705 bifonazole  710 climbazole  710 ergosterol  709 fluoroamide-DG  706 furosemide  710 2-hydroxy-pyridone  708 ketoconazole  710 (S, S)-Mn(CF3PDP)  706 norbornene 2-methyl ester (NBE-CO2Me)  709 palladium-catalyzed transannular arylation  706 SmI2-mediated reductive cleavage  706 vareniciline  706 C-H deuteration and tritiation  720 bis(arylimidazole-2-ylidene)pyridine iron bis(dinitrogen)  720 Crabtree’s iridium catalyst  720 cloperastine  721, 722 diltiazem  721, 722 fenspiride  721, 722 imatinib  721, 722 ioratadine  720 levofloxacin  721, 722 orexin receptor antagonist  720 papaverine  720 suvorexant  720 varenicline  720 β-C-H elimination  410 C-H hydroxylation  714 bidentate pyridine-pyridone ligand  715 clonixin  715 copper-catalyzed late-stage C(sp3-H) functionalization  714 indoprofen methyl ester  714 L, L coordinating mode  715 L, X coordinated ligand  715 nitrofurantoin  714 PyBOX  714 C-H methylation and alkylation  704 apremiplast  704 biscyclopropanecarbonyl peroxide  704 bustinib  704

citalopram  704 cromakalim  704 DAST  704, 706 diclofensine  704, 706 etoricoxib  704, 707 fasudil  704, 705, 711, 713, 714 fenspiride  704, 706, 721, 722 IC50 value  704 indoprofen  704 iridium-based photocatalysts  704 ivacaftor  704 loratadine  704, 705, 720 magic methyl effect  704 oxerin-1, 704 oxerin-2, 704 pozanicline  704 rupacarib  704 sitagliptin  705 strychnine  704, 707 tedizolid  704, 714 trimethylboroxine  704 voriconazole  713, 714 C-H alkenylation of furans  86 dehydrogenative Heck reactions (DHRs)  87, 98 (±)-TMS-SEGPHOS ligand  87, 88 C-H alkenylation of pyrroles  74 4,5-diazafluoren-9-one (DAF)  76, 77 switchable oxidative Heck reaction  75 trans-configurated poly(arylenevinylene)s  74 C-H alkenylation of thiophene  98 C-H bond alkylation of indolines at the C7-Position  268 C7-alkylated indolic scaffolds  268 diazomalonates  269 ethyl glyoxalate  273, 286 Hofmann-Martius rearrangement  278 Meldrum’s diazoester  269 C-H alkylation of furans  88 lignocellulosic biomass  88 C-H alkylation of pyrroles  69 bis(phosphanylamino)triazine ligands  72 copper-catalyzed Friedel-Crafts alkylation  70 hydrogen-autotransfer β-alkylation  72 hydrotrispyrazolylborate ligand  73 isatins  70, 71 PYBOXDIPH-Zn(II) complex  69 pyridine 2,6-bis(5’,5’-diphenyloxazoline)-metal complexes  69 C-H bond alkynylation of indolines at the C7-Position  265 (triisopropylsilyl)acetylene  266 C-H alkynylation of furans  89 C-H alkynylation of pyrroles  77 schizophrenia drug  78 C-H alkynylation of thiophene  98

Index

C-H amidation of pyrroles  81 acridinium dye  81 hydrotris(3,4,5-tribromo-pyrazolyl)borate) (TpBr3)  82 C-H bond allylation of indolines at the C7-Position  279 aza-Michael reaction  279 Friedel -Crafts allylation reactions  279 Tsuji-Trost reaction  279 C-H amidation of thiophene  102 APE 1 inhibitor  102 tubulin polymerisation inhibitor  102 zyprexa  102 C-H bond arylation of indolines at C7-position  252 C-H arylation of furans  84 biomass-derived furanic building blocks  85 PEPPSI  85, 87, 93 C-H arylation of pyrroles  63 cobalt-porphyrin catalysed direct C-H arylation  65 copper(I)-catalyzed homolytic dediazoniation  65 2-(dicyclohexylphosphino)-biphenyl ligand  64 Meerwein-type radical C2 arylation  65 palladium-catalyzed desulfitative arylation  65 sequential oxidative C2 arylation  66 tetrakis-4-anisylporphrinatodianion (tap)  66 TMG  69 C-H arylations of thiophene  91 abnormal NHC palladium(II) dimer  91 DAF ligand  97 raloxifene precursor estrogen receptor modulator  93 reductive/oxidative Heck coupling  97 C-H bond acylation of Indolines at the C7 Position  282 C-H bond alkenylation (olefination) of indolines at the C7-Position  260 C7 alkenylation of N-acetylated indolines  262 carbazole  261, 265 N-fluoro-2,4,6-trimethylpyridinium triflate [F+]  261 quinoxalinone  265 C-H bond alkylations  415 C-H bond alkynylations  418 C-H bond (hetero) arylations  393 C-H bond carboxylations  419 C-H bond olefinations  406 C-H bond perfluoroalkylation of heteroarenes  418 C-H borylation of furans  89 C-H borylation of pyrroles  80 9-borabicyclo[3.3.1]nonane dimer [(9-BBN)2]  80 catecholborane (catBH)  80 fused 4,5-borazaropyrrolo[1,2-a]quinolone derivatives  80 Suzuki coupling  80 C-H borylation of thiophene  100 1,3-bis-(2,6-diisopropylphenyl)imidazole-2-ylidene) (IPr)  100 C7 carbonylation  182 C4 chalcogenation  170

1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4diium ditetrafluoroborate (Selectfluor)  420 C-H bond cyanation of indolines at the C7-position  298 N-cyano-N-phenyl-para-methylbenzenesulfonamide (NCTS)  298 C-H bond halogenation of indolines at the C7-position  306 mesityl(trifluoroethyl)iodonium triflate  308 para-toluenesulfonic acid, (p-TSA)  308 Pd@MIL-88B-NH2(Cr)  306 Pd@MIL-88B-NH2(Fe)  306 celecoxib  26, 684, 688 C-H arylation of pyrazoles  688 cyclooxygenase  688 complanadine A  378, 684, 685, 686 Lycopodium complanatum  685 C-glycopeptide hormone  669 C-glycoside metabolite GS-441524  657 C-glycosylation reaction  657 C-(hetero)aryl glycosides  675 C-H glycosylation  669, 670, 671–676 chilenamine  549 C2 heteroarylation  201 benzo[b]thiophene 1,1-dioxides  201 Bpym  202 Cy-DHTP  202 POPd  202 C3 heteroarylation  203 C-halogen bond formation  349 chalcogenation reactions  155 chelation-assisted C2 arylation of indoles  197 N-methoxy-1H-indole-1-carboxamides  198 C3 arylation of indoles  200 dinuclear palladium phosphinous acid complexes  200 meta-(indol-3-yl)phenol framework  201 palladium-dihydroxyterphenylphosphine (DHTP)  200 chiral bidentate boryl ligands  613 6-chloro-2,4-dimethoxypyrimidine  641 (2-chlorophenyl) quinolin-4-ylamine  372, 373 (3-chloropyridin-2-yl) pyridin-4-ylamine  372, 373 chromenes  435, 478 2H-chromene-ones  437 alkenylation  437 palladium-catalyzed direct C3-H olefination  437 2H-chromenes  435 C-H functionalization of 2H-chromene derivatives  435 ruthenium(II)-catalyzed oxidative annulation  435, 436 4H-chromene  459 C2 and C3-arylation of 4H-chromene  462 4H-chromenones (chromones)  462 cobalt(II)-catalyzed direct alkynylation of acrylamides  463

731

732

Index

cinnoline  394 citric acid  661 Cl3CCH2OC(O)NHOTs (TrocNH-OTs)  423 clopidogrel  61, 62, 711, 719 C-mannosyl tryptophan  657, 658 (C5Me5)Sc(CH2C6H4NMe2-o)2  359 (C5Me5)Y(CH2C6H4NMe2-o)2  359 C7-nitration of indolines  296 C-N bond formation/ carbon-nitrogen bond formation  420, 532 C-nucleoside pseudouridine  657 C-S bond formation/ carbon-sulfur bond formation  303, 424 C-Se bond formation  525 C2-selective functionalization  358 C3-selective functionalization  370 C5 selenylation  173 diaryl diselenides  173 C-H silylation of furans  89 1,5-cyclooctadiene (cod)  89 2-ethylhexanoate (2-EH)  90 pincer Ru(II) catalyst  89 tert-butylethylene (TBE)  90, 426 C-H silylation of pyrroles  82 (S,S)-iPr-BPE ligand  82 2,4,7-trimethylphenanthroline ligand  82 C-H silylation of thiophene  100 C-O bond formation/ carbon-oxygen bond formation  300, 424 cobalt catalysis  328 cobalt(II)-catalyzed oxidative C-H/C-H coupling of benzo-fuzed azoles  337 cobalt-catalyzed C-H and C-O coupling of quinoline-N-oxides  386 concerted metalation deprotonation  (CMD)  2,5, 6, 9, 91, 196, 443, 397, 409, 419, 516, 569, 612, 639, 669, 673, 677 copper(I)-benzimidazole  548 copper carbene  320 copper catalysis  320, 326, 333, 347 C(sp2)-H metalation of benzo-fused azoles using copper catalysis  333 copper(I)-tert-butoxide  340 copper(II)-mediated oxidative coupling  342 copper catalyzed C-H benzylation and allylation  320 copper-catalyzed cascade two-fold C-N bond formation  342 copper-catalyzed dehydrogenative C-H/C-H cross-coupling of benzothiazoles  320 copper-catalyzed oxidative amination of benzoxazoles  340 copper-mediated oxidative C(sp3)-H/C(sp2)-H coupling of carboxamide-pyridine-N-oxides  334 CuCl-catalyzed C2-alkenylation of benzoxazoles  326 direct C2-thiolation of benzothiazoles  348

NHC-CuI  347 oxidative C2-arylation of indoles with benzo-fused oxazoles  334 oxidative copper-catalyzed phosphonation of benzo-fused azoles  344 tandem ring-opening/annulation of aziridines with benzimidazoles  342 thiolation of benzoxazoles  347 CoCp*(CO)I2  264, 387 copper-catalyzed microwave-assisted C2 alkylation  360 copper(II)-catalyzed alkynylation of arenes and heteroarenes  418 copper(I) catalyzed azide-alkyne cycloaddition  575 copper-catalyzed cascade bis-heteroannulation  424 copper-catalyzed C-H bond ortho-ethynylation of pyridazine and pyrimidine  419 copper/phenanthroline-based catalytic system  393 couplings by using glycal partners  662 C-P Bond Formation  303, 344, 533 Cp*Rh(η4-C6Me6)  20, 382 Cp2Ni  362 Cp2ZrL  358 CpRu(PPh3)2Cl  366 CRF1 receptor  382 cross-dehydrogenative coupling (CDC)  96, 98, 217, 255, 462, 463, 464, 465, 466, 492, 495, 499, 508, 535, 543, 544, 547, 548, 549, 551, 557, 560, 632, 633, 638 cross-dehydrogenative radical coupling  632 C3-selective C-H activation  463 electron-transfer mediators (ETMs)  465 FePc (iron pthalocyanine)  466 carbonylation of flavones  466 copper(II)-catalyzed selenylation  467 C4-selective functionalization  378 C4-H selective functionalization  449 palladium(II) catalyzed oxidative-Heck type reaction of coumarin  449 tandem alkenylation/decarboxylation  451, 453 chromeno[3,4-c]pyridines  454 rhodium-catalyzed redox-neutral [4+2] annulation  454 internal electrophilic substitution (IES)-type pathway  454 C5-selective C-H activation  468 C5- selective functionalization  456 iridium(III)-catalyzed C5-alkenylation  456 C6-selective C-H activation  478 C6-selective C-H oxidative alkenylation of chromenone  478 C8-selective functionalization  382 CsOPiv  66, 68, 196, 226, 405, 406, 407, 452, 463, 550, 598, 599, 600, 601, 611, 708 C3-sulfenylation of indoles  238 CuAAC  677 cumene  612 Cummins/Wolczanski complex  34

Index

Cu(OAc)2-catalyzed electrophilic amination of quinoline-N-oxides  368 8-cuprioadenine  647 cyanation  503 N6-cycloalkylpurines  648 C8 cyclopalladation  384 cyclopentyl methyl ether (CPME)  379, 401, 577, 578, 619 cyJohnPhos/2-(dicyclohexylphosphino)-biphenyl ligand (cyJohnPhos)  128, 196, 519, 520 Cy3PAuCl  361, 362, 397 cyclometalation  10, 11, 13, 259 5’-O,8-cyclopurine nucleosides  649 5’,6-cyclouridine  633 CzIPN/4-CzIPN/ dicyanobenzene  69, 642, 643, 644

d 

DABCO  424, 425, 529, 530 dapagliflozin analogue  661, 678 dapagliflozin drug (FORXIGA)  657, 658, 662, 673, 677 dcpe  114, 128, 328 DDQ (2,3-dicyano-5,6-dichlorobenzoquinone)  140, 218, 257, 258, 261, 262, 263, 265, 269, 270, 274, 277, 283, 284, 290, 299, 300, 303, 308, 395, 543, 544, 545 7-deazaadenosine  649 7-deazapurine  643 decarboxylative coupling  127, 491, 494, 585 dehydrogenative annulation  236, 545, 546, 551, 553, 554, 556 dehydrogenative aromatization  201 dehydrogenative C-N bond formation  550 dehydrogenative cross-coupling  4, 26, 91, 98, 115, 118, 119, 263, 339 dehydrogenation-tautomerisation reactions  203 De-nova cyclization, 194 de novo synthese  602, 703 2’-deoxy-2’-fluoroadenosine  647 2’-deoxyadenosine  646 2-deoxy-glucosylcarboxamide  676 2’-deoxyguanosine  647 2’-deoxyinosine  647 2’-deoxyuridine nucleoside  632, 633, 641 Dess-Martin Periodinane, (DMP)  574, 689, 693 Dewar-Chatt-Duncanson model  41 diaryliodonium salts  64, 65, 195, 232 4,5-diazafluorenone (DAF) ligand  76, 97, 132, 133 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)  112, 159, 268, 529, 588, 595, 638 dcypt  110, 111, 113 diazoacetate derivative  615 diazoacetonitrile  497 diazonaphthoquinones  199 dibenzazepinones  610, 625

DIC  642 5-(5,6-dicyanophenyl)-2-p-tolylpyrimidine  422 1,4-di-(8-adenosinyl)benzene  646 dibenzylphosphate  570, 577, 579, 582 2,6-diethoxybenzoic acid  572 difluorinated isocoumarins  650 α,α-difluoromethylene alkynes  650 di(3,5-difluoromethylphenyl)phosphinoethane (dArFpe)  416 dihydropyrroloindole  615 N,N-diisopropylethylamine (DIPEA)  79, 209, 583, 641, 696, 697 2,4-dimethoxy-5-bromopyrimidine  417, 422 dimethoxymethylsilane (DMMS)  417 N,N-dimethylacetamide (DMA)  71, 74, 87, 110, 112, 114, 115, 116, 117, 119, 120, 121–128, 130–132, 133, 138, 195–197, 200, 205, 221, 237, 283, 324, 339, 372, 380, 400, 414, 445, 446, 462, 490, 509, 510, 511, 513, 514, 517, 518, 519, 523, 528, 687, 689, 710, 713 dimethylacetamide (DMAc)  63, 85, 86, 92, 95, 196, 205, 335, 371, 380, 500, 513, 610, 685, 686, 688, 697 6,6’-dimethyl-2,2’-bipyridine  423 2,2-dimethylbutane  615 1,3-dimethyl-5-(trifluoromethyl)uracil  638 Dimethylfuroguaiacin  61, 62 2,9-dimethylphenanthroline-ligated manganese catalyst  403 2,9-dimethyl-1,10-phenanthroline  334 1,3-dimethyluracil(DMU)  633, 634, 637, 638 1,3-dipolar cycloaddition reactions  364, 365 4,7-diphenyl-1,10-phenanthroline/ bathophenanthroline  221, 408, 517 diphenyl disulphide  637 diptoindonesin G  684, 686 C-H arylation of benzofuran  686 Hopea mengarawan/ Hopea chinensis  686 resveratrol aneuploid  686 direct C2 arylation  195 directed C(sp2)-C(sp2) bond formation  659 directed C(sp2)-C(sp3) bond formation  662 directed functionalization at the anomeric position  596 directing-group-free C-H functionalization  619 dirhodium(II)-catalyzed process  711 di-tert-butyl peroxide (DTBP)  345, 349, 493, 535, 642, 648, 649, 704 divaplon  546 DMAP  211, 531, 532, 572, 578, 589, 642, 644, 694, 709 DMPU  118, 123, 222, 364, 394, 601 domino palladium-catalyzed Heck-cross coupling  418 DPEphos  129, 134, 135, 328, 398, 502 [(dtbpy)Ir(H)(Cl)(SiEt3)]2  370 dppp  96, 129, 137, 324, 408 Dragmacidin D  687 (+)-dragmacidin D  687

733

734

Index

(–)-dragmacidin E  687 biogenesis  687 C-H arylation of indoles at the C3 position  687 DIBAL-H  689, 690, 691 Dragmicidon  687 Spongosorites  687 methoxymethyl (MOM)  688 reverse-phase preparative liquid chromatography  688 serine-threonine protein phosphatases (PP)  687 dtbpy  135, 141, 142, 230, 331, 377, 382, 403, 425, 426, 492, 494, 495, 686 dynamic kinetic transformation (DYKAT)  623

e 

EDC  572, 690, 694 electrophilic aromatic substitution (SEAr)  6, 306, 364, 445, 511 electrophilic auration of arenes  6 electrophilic metalation  75, 251, 437, 548, 550, 554, 625 empagliflozin, jardiance  657, 658 enantioselective CDC reactions  543 enantioselective C-H activation  379, 478, 609, 610, 627 enantioselective 1,4-dearomatization of heteroarenes  379 endogenic C-glycosides  658 englitazone  592 eosin-Y  258 epibatidine  357 ertugliflozin, steglatro  658 esomeprazole  357 ethylenebis(tetrahydroindenyl) (L)  358 estradiol  614 5-ethyluracil  639 etofibrate  713 exatecan  703 2D EXSY  256

f 

fabI Inhibitor  375 fairlamb’s protocol  648 famciclovir  711, 712, 713 fasiplon  546 FBDD  600 fludioxonil  61, 62 flufuran  61 fluoro alkylation  486 2-fluoro-2’-deoxyadenosine  647 fluorescence in situ hybridisation (FISH)  632 5-fluorouracil  526, 639 fragments synthesised by divergent AQ removal  596 Friedel-Crafts acylation  38, 155, 219, 282, 503 Friedel-Crafts reactions  24, 268, 357, 543 Fujiwara-Moritani reaction  4, 5, 617 furopelargone B  61, 62 5-(2-furyl)uridine  641

g 

α-D-galactopyranose  614 Gamendazole  696 lonidamine (LND)  696 Gd[N(SiMe3)2]3  369 gefitinib  410, 412 gilvocarcin E  658 gilvocarcin M  658 gilvocarcin V  658 glucosylspirooxindole  674 glycochemistry  658 glycosylation of terminal peptides, hybrids and glycoaminoacids  664 glycosylation with directing group  664 gold(I)-catalysis  396 gold-catalyzed annulation  414 GS-441524 anti-SARS-CoV-2  658 GSK812397  546

h 

1,5-HAT  711 HATU  582 8-haloguanine nucleoside  647 5-halouracil  633, 641 5-halouridines  640 Heck reaction  75, 97, 201, 239, 382, 417, 620, 692 2-(hetero)aryl N-heteroarenes  363 heteroarylation  201, 473, 509 heterocyclic functionalization with C2 directing group  567 carboxylic acid linked  567 N-heterocycle functionalization  580 heterocyclic functionalization with C3 directing group  580 carboxylic acid linked  585 amine linked  588 alcohol linked  592 heterocyclic functionalization with C4 directing group  592 homolytic aromatic substitutions (HAS)  252 [HPAd2nBu]I  404 HPRBF4  364 hydroarylation of 2-(4-pentenyl)indoles  616, 617 hydroarylation reaction  129, 139, 469

i 

(±)-ibogamine  684, 685 Tabernaemontana divaricata  684 Tabernanthe iboga  684 IMes  113, 139, 140, 201, 223, 224, 328, 370, 381, 382, 383, 396, 501 imidazoles and bezoimidazoles  618 imidazo[1,2-a]pyridine  233, 485–535, 551–552, 555 imidazo [1,5-a] pyridines  327, 328, 331, 485, 500–502, 555

Index

imidazo[1,5-a]quinolone  485, 486 indazoloquinolines  329, 330 indeno[2,1-c]chromene-6,7-dione  453, 549, 552 indenylamines  622 indoloquinolines  169, 380 inner-sphere C-H activation mechanisms  609, 615 inosine  647, 648 intermolecular C3-H functionalization  445 4-hydroxy-2H-chromen-2-one  445 spiropentadiene chromanones  446, 449 tri(2-furyl)phosphine, (TFP)  447 oxidative annulation of 4-hydroxycoumarins  448, 450 intermolecular coupling  504, 619 intermolecular enantioselective hydroarylation of heteroarenes  620 intramolecular enantioselective alkylation of indole derivatives  616 5-iodocytidines  641 1-iodoglycals  659 iodopyridines  648 6-iodouridine  637 ionotropic glutamate receptors(iGluRs)  582 ipragliflozin astellas  658 (IPr)AuCl  415 i PrOH  68, 626 ipso-Sonogashira analogues  673 iron Catalysis  337, 342, 348, 402, 503 C-H amination of benzoxazoles  342 Fe3O4-nano catalyzed thiolation of benzothiazoles  348 iron-catalyzed arylation of benzothiazoles  337 Ir(I)-catalyzed enantioselective hydroarylation of indole with styrene  624 [Ir(cod)(m-OMe)]2  377, 382 [Ir(coe)2Cl]2  88, 619 [IrCl(cod)]2  377, 378, 456, 614, 663 [IrCp*Cl2]2  159, 160, 161, 165, 169, 181, 209, 261, 263, 270, 288, 290, 363, 384, 402, 469, 473–475, 477 Ir4(CO)12  371 [Ir(OMe)(cod)]2  81, 101, 425–427 iridium-catalyzed activation of pyridine C-H bond  370 iridium-catalyzed amidation of quinoline-N-oxides  386 iridium-catalyzed borylation at C5-position  378 iridium-catalyzed borylation of pyridine  377 iridium-catalyzed C-H/C-H cross-coupling between heteroarenes  402 iridium(I)-catalyzed hydroarylation of glycals  665, 666 iridium-3,4,7- trimethylphenanthroline  82, 425, 427, 719 irinotecan  703 isoniazid  357 3-isopropylidene  645 2’,3’-O-isopropylideneinosine  648 2’,3’-O-isopropylideneuridine  637,640

5’-O-TBDMS-2’,3’-O-isopropylideneuridine  637 isopropyl trifluoroborate  643 isoquinoline-1-carboxamides  368

k 

kinetic isotope effect (KIE)  3, 4, 27, 258, 301, 445, 559, 671, Knoevenagel condensation  557, 559

l 

β-lactamase inhibitor  575 Lamellarins  61, 62, 66 Langlois reagent  486 late-stage functionalization (LSF)  82, 96, 406, 597, 683, 703 lennoxamine  549 LiHMDS  199, 201, 202, 222, 276, 277, 574, 591, 689 ligand-free copper-catalyzed direct alkenylation of electrondeficient heteroarenes  367 (+)-linoxepin  684, 691, 692 Lemieux-Johnson conditions  692 Linum perenne L.  691 Mizoroki-Heck conditions  692 LiTMP  349, 350 lithium diisopropylamide (LDA)  637 L-proline  343, 346, 363, 659, 660 L-tert-leucine  625

m 

MAD ((2,6-tBu-4-Me-C6H2-O)2AlMe)  378, 408, 619 MAD additive  618 manganese-catalyzed C-H bond arylation of pyrimidine  403 manganese-mediated reaction  345 Mannich type alkylations  155 (4-MeOC6H4)3P  418 Mannich type reaction CDC reaction  544 β-mannosylation pathway  669 Maulide’s protocol  588 5-mercurated-2’-deoxyuridine  633 2-methylbenzamide  669 1-methyl cyclohexyl radical  644 5-methyl cytidine  632 3-N-methyl-5-iodouracil  641 3-methyl-2-isopropyl-2-(phenylthio)acetic acid  412 1-methylpseudouridine  632 MesCOOH  291, 293, 595, 596 mesitylene  117, 133, 256, 305, 610, 611, 634, 635 5-methoxyaminoquinoline  569 N1-(4-methoxybenzyl)-N3-methyluracil  638 6-methylpicolinic acid  600 5-methylpyridine  623 5-methylpyrimidin-2-yl  623 minisci C-H alkylation  643 minisci-type reactions  9, 14, 393 MK-8712  575

735

736

Index

MLC mechanism  19 monodentate phosphonite ligand  612 Morita-Baylis-Hillman adducts  163, 281 MS13X  623 mutation detection  632

n 

Na2WO4.2H2O  427 N-acetyl-2-methylindoline  253 1-naphthyltrimethylammonium triflate  337 N-alkylindole  196, 615 naphthyl boronic acids  625 naphthyridinones  375 natural C-glycosides  658 NBE-CO2Me  399, 709 N-Cbz S-proline  567, 585 N-cyano-N-phenylp-toluenesulfonamide (NCTS)  231 nebularine-N1-oxide  645 Negishi cross-coupling  363 neuroleptic molecule  572 N-fluorobenzenesulfonimide (NFSI)  574 (NHC)AuOH  420 N-heterocyclic carbene (NHC)  9, 38, 85, 322, 340, 370, 509 N-heterocyclic carbene ligand  373, 378, 379, 420, 572, 586, 619 N-hydroxysuccinimide (NHS)  582 NiBr2•diglyme/[diglyme(NiBr2)]  113, 135, 322, 331, 334, 335 nickel-based chain-walking mechanism  407 nickel catalysis  321, 326, 330, 334 C5-selective C-H alkenylation of imidazo [1,5-a] pyridines  327 C-H/C-Br cross coupling  330 Ni/dcpye-catalyzed C-H/C-O coupling  326 Ni(IMes)[P(OEt)3]Br2  322 Ni(IPr*OMe)[P(OEt)3]Br2  322 regioselective C7-alkenylation of triazolopyridines  327 nickel-catalyzed C-H glycosylation  672 nickel-catalyzed direct C-H arylation of pyridine  361 nickel-catalyzed E-selective alkenylation of pyridine-N-oxides  366 nickel-catalyzed hydrosilylation of a carbon-carbon double bond  426 Ni(cod)2  113, 114, 118, 128, 129, 131, 134, 139, 140, 223, 224, 230, 323, 327, 328, 336, 362, 366, 367, 379, 394, 395, 407, 427, 501, 617–619 NicOx  617 Ni(dppf)2Cl2  672 Nieuwland catalyst  32 Nigellidine Hydrobromide  691 Nigella sativa  691 N-iminopyridinium ylides as substrates  365 3-nitropyridine  646 N1, N1-diisopropyl-N2-(quinoxalin-6-yl) oxalamide  421

N-dimethyl carbamoyl/N,N-dimethyl carbamoyl  74, 201, 205, 215, 271, 283 2D NOESY/NOESY  256, 688 non-chelation assisted C2 arylation of indoles  195 chloropyrazines  195 diaryliodonium salts  195 SEM-protected indoles  195 potasssium aryltrifluoroborate salts  195 NMDA  174, 582, 585 N-methylmorpholine oxide  495 norbornene  31, 71, 142, 221, 224, 359, 417, 422, 427, 619, 674, 689, 692, 711 N-phthaloyl phenylalanine  662 N-pivaloyl-directed C7-arylation  258 N-pivaloylindoles  177, 183 N-pivaloyl proline  570 N-(2-pyridyl)sulfonyl group  74, 205 Nugent’s ammine-imido equilibrium  33 N-(2-(pyridine-2-yl)propan-2-yl) pyridazine-4-carboxamide  424 N-pyrimidyl benzimidazole  345 N-TFA piperidine  572, 586

o 

O-benzoylhydroxylamine  340 O-benzoyl hydroxylmorpholine  421, 422 olefin dismutation  33 olefin disproportionation  33 organofluorescent nucleoside (RONs)  646 organotrifluoroborates  80, 643 orientin  658 ortho-iodobenzoyloxy radical  643 outer-sphere mechanisms  609 oxazetidines ring system  225 oxerine  357 oxetane  567 oxidative cross-coupling reaction  7, 91, 261, 366, 556 oxidatively added transition state (OATS)  13 oxidative hydrogen migration (OHM)  13, 18, 23 oxocarbenium ion  667, 674

p 

palbociclib  546 5-palladauracil  636 palladium-catalyzed atroposelective arylation of heteroaenes  626 palladacycle intermediate  182, 197, 257, 287, 549, 550, 592, 595, 659, 663, 669, 671 palladium catalysis  322 π-allylpalladium complex  328 base free benzylic C(sp3)-H activation  323 NHC-Pd(II)-Im complex  337 palladium-catalyzed arylation of benzoxazoles  337

Index

palladium-catalyzed C2-alkenylation of benzoxazoles  328 palladium-catalyzed decarboxylative arylation of benzothiazole  337 phosphonation of benzoxazoles and benzothiazoles  346 palladium-catalyzed aminocarbonylation  661 palladium(II)-catalyzed arylation/  alkenylation of C2-amidoglycals  661 palladium(II)-catalyzed C-H functionalization  546 palladium-catalyzed C-H glycosylation of allylamines  671 palladium-catalyzed C-H glycosylation of homoallyl amines  671 palladium(II)-catalyzed direct oxidative Suzuki-Miyaura cross-coupling reactions  252 P(C6F5)3  638 palladium(0)-catalyzed atrope-enantioselective C-H bond arylation of heteroarenes  398 palladium(II)-catalyzed C-H cross-coupling  363 palladium(II)-catalyzed ortho-alkylation of  (±) preclamol  374 pyridine-N-oxides  359, 366 palladium(II)-catalyzed regioselective oxidative C-H/C-H cross-coupling  364 palladium-catalyzed C2-alkenylation with acrylates  366 palladium-catalyzed C3-H alkenylation of pyridines  376 palladium-catalyzed C-H bond amination of pyrimidine  422 palladium(II)-catalyzed C2-arylation of 4H-chromenones  462 palladium-catalyzed C-H bond arylation  404 palladium-catalyzed C-H bond arylation of pyridazine-based 1,2,4-triazoles  405 palladium-catalyzed C-H bond (hetero)arylation  406 palladium-catalyzed C-H functionalization reaction  359, 574 palladium-catalyzed C-H bond olefination of unfunctionalized pyrazine  409 palladium-catalyzed C-H bond olefination of unfunctionalized pyrimidine  408, 409 palladium-catalyzed C-H/C-H cross-coupling between heteroarenes  400 palladium-catalyzed direct arylation using ligand free conditions  372 palladium-catalyzed direct oxidative C-H/C-H cross-coupling  410 palladium-catalyzed dual C-H activation of isoquinoline and quinoline-N-oxides  368 palladium-catalyzed C-H/C-H homodimerization of azines  401 palladium-catalyzed regioselective C8 arylation of quinoline-N-oxides  384 palladium-catalyzed regioselective direct arylation of pyridine-N-oxides  363 palladium-catalyzed sequential Heck/C-H bond arylation of 7-bromoquinoxaline  398 palladium(II)-catalyzed synthesis of  C-alkylglycoamino acids  662

C-aryl furanosides  668 C-aryl pyranosides  667, 668, 669 C-aryl glycosides  660, 661 palladium-catalyzed tandem intermolecular, intramolecular dual C-H bond functionalization  406 palladium/chiral bisoxazoline ligand  625 palladium/PyOx or NicOx-catalyzed,  enantioselective Fujiwara-Moritani  cyclization  617 palladium/triphenylphosphine/pivalic acid catalytic system  396 palladium(II)-catalyzed pyrimidine formation  556 palladium-nanoparticles (PdNPs)  646 palmanine  549 [Pd(π-allyl)Cl]2  110, 337, 338 Pd(cod)Cl2  196, 661 Pd2(dba)3  181, 397, 612, 613 [Pd/dppp]  359 Pd(MeCN)2Cl2/ PdCl2(MeCN)2  67, 71, 111, 202, 221, 227, 324, 369, 325, 685, 689 [Pd(phen)2](PF6)2  122, 337 Pd(0)/PR3-catalyzed arylation  380 Pd(piperidine)2(DMF)2  646 Pd(TFA)2  68, 129, 131, 196, 199, 201, 202, 203, 238, 283, 284, 285, 329, 410, 411, 412, 438, 452, 463, 534, 573, 575, 587, 594, 634, 635, 639, 663, 664 2-(4-pentenyl)indoles  616 peri-borylation  425 permethylscandocene  30 9,10-phenanthrenequinone (PQ)  14 phenanthroline-catalyzed oxidative direct arylation  638 1,10-phenanthroline/ phenanthroline  40, 85, 86, 222, 323, 329, 330, 333, 348, 350, 371, 410–412, 418, 438, 514, 515, 526, 531, 639 phenazine  396 phenyl cinnamate  327 2-phenylimidazo[1,2-a]pyrimidine  398, 399, 514 phenyliodine diacetate (PIDA)/ PhI(OAc)2, 125, 171, 238, 239, 261, 270, 271, 286, 287, 295, 300, 301, 636 6-phenylthiouridine  637 5-phenyluracil  634 Phillips triolefin process  33 PhMezole-Phos  128, 129, 328 phthalazine  394, 492 phosphordiamidite ligands  610 photo-catalytic reactions  545 photocatalyzed Minisci reaction  713 photochemical rearrangements  365 Ph2Zn  394 picolinamide directed γ-alkenylation  590 picolinamide directed γ-alkylation  590 picolinamide directed γ-arylation  590 2-picoline  358

737

738

Index

2-picolinic acid  591 picolinic amide  675, 678 2-picolylamine  405 pipercyclobutanamide A  690, 691 ando phosphonate  690 CYP2D6  690 methylcoumalate  690 photopyrone  690 Piper nigrum  690 T3P  690, 691 PKC inhibitor  615 pinacolborane  80, 100, 229 PIP  419, 424 2-piperazine carboxamide  592 pioglitazone  357 PivOH  68, 92, 98, 100, 112, 116, 117, 120, 121, 123, 126, 130, 133, 136, 140–141, 158–161, 171, 184–185, 196, 209–211, 214, 216, 219, 226, 233, 264–265, 288, 291, 335, 337, 339, 363, 380, 381, 397–401, 405, 409, 437, 438, 442–444, 449, 452, 453, 460–461, 463–464, 466, 472–473, 500–501, 510, 512–513, 519–520, 571, 574, 575, 577, 584, 587, 588, 610, 626, 633, 634, 638, 639, 649, 671, 686, 688 pivaloyl DG/N-pivaloyl DG  176, 184, 198, 263 PivOK  416, 519, 590, 695 PMDETA  418 podophyllotoxin  693 C-H arylation  693 VM-26 and VP-16  693 post-Shilov electrophilic activation  8 potassium peroxodisulfate  9 post-synthetic labelling of DNA  632 post translational modification of proteins  Potassium organotrifluoroborate  80, 269, 643 (PTM)  657 P(perFPh)3  638 proline directed olefination  591 propyl boronic acid  643 propylene ammoxidation  32 pseudouridine  658 purine  203, 631, 632, 635, 640–650 PyOx  617 pyrazine  5, 100, 361–362, 394–395, 397, 400, 402, 403, 406–410, 412–414, 419, 421, 428 pyrazoles  123, 124–126, 132–133, 141–142, 626, 685, 688 pyridazine  379, 393, 394, 400, 404–405, 417, 419, 420, 424 pyrimidine  18, 197, 198, 223, 225, 226, 260, 267, 270, 273, 277, 285, 286, 289, 291, 295, 296, 300, 308, 309, 329, 393, 394, 395, 398, 400, 403, 404, 408, 409, 410, 412, 418, 419, 422, 424, 426, 556, 631, 632, 635, 637, 642, 643, 648 pyridine-N-oxides as substrates  363 5-(2-pyridyl)aminouracil  640 pyridone/2-pyridone  265, 333, 335, 435, 592, 619 pyroglutamic acid  577,579

pyrolinate dirodium complex  615 pyrrolam A  613 pyrrolo[3,2-d]pyrimidine  639 5-(2-pyrrolyl)uridine  641

q 

quinazoline  394, 395, 405, 406, 407, 410, 414, 415, 421, 550, 551, 554, 600 quinolones, and isoquinolines  357, 387, 618 quinoline-2-carboxamides  368 quinolone  265, 426, 709 quinuclidine  591 quinine  357, 591, 706, 708 quinoxaline  394, 395, 396, 397, 398, 399–402, 410, 414, 415, 418–427, 492 quinoxyfen  711, 712

r 

rac-BINAP  269, 270, 360 reductive Heck sequence  684 regioselective C-H bond alkenylation/methylation of 2,4-dimethoxy-5-iodopyrimidine  417 regio- and enantioselective nickel(0)-catalyzed endoselective C-H cyclization of pyridines  379 repaglinide  667 (±)-rhazinal  692 Kopisa teoi  692 (±)-rhazinilam  75, 694 Melodinus australis  694 Rhazya stricta  694 van Lausen reaction  694 Rh(I)/BINOL-derived phosphoramidate  615 [RhCl(CO)2]2  362, 395, 396 [RhCl(cod)]2  212, 359, 416 [RhCl(coe)2]2  340, 359, 395 [Rh(coe)2Cl]2  139, 178, 196, 278, 616, 618 [RhCp*Cl2]2  73, 157, 158, 163, 164, 165, 167, 168, 169, 171, 172, 176, 177, 180, 184, 209, 210, 225, 227, 231, 235, 236, 237, 260, 264, 266, 268, 270, 272–275, 279, 280–282, 290, 292–294, 299, 300, 301, 306, 307, 308, 371, 374, 375, 385, 387, 410, 412–414, 468, 474 Rh2(Oct)4  490, 711, 712 Rh2(S-BTPCP)4  711, 712 Rh2(S-DOSP)4  615 Rh2(TPA)4  423, 711, 712 rhodamine 6G(Rh6G)  641 Rhodium Catalysis  325 [Rh(cod)OAc]2  325 C2-thiolation of benzothiazoles and benzoxazoles  349 rhodium(I)-catalyzed arylation of benzo-fused azoles  340 rhodium-catalyzed pyrimidine-directed C5-olefination of benzimidazoles  329

Index

Rh-NHC-catalyzed double C(sp2)-H hydroarylation of 2,2’-bipyridines  370 rhodium (NHC)-catalyzed C8 selective arylation of quinolines  382 rhodium(I)-catalyzed alkylation of pyridines and quinolines  359 rhodium-catalyzed cascade oxidative olefination/cyclization of secondary amide-functionalized pyrazine  412 rhodium-catalyzed C-H bond alkylation of amidefunctionalized pyrazine  412 rhodium-catalyzed C-H bond amidation of 2,4,6-trimethoxypyrimidine  423 rhodium-catalyzed C-H bond olefination of amidefunctionalized pyrimidine  412 rhodium(I)-catalyzed strategy for direct arylation of pyridines and quinolines  361 rhodium(III)-catalyzed C3 selective oxidative alkenylation of pyridines and quinolines  375 rhodium(III)-catalyzed C8-alkylation of quinoline-N-oxides  386 rhodium(III)-catalyzed hydroarylation  375 rhodium(III)-catalyzed intermolecular oxidative alkenylation/cyclization of picolinamides  375 rhodium(III)-catalyzed oxidative annulation of picolinamides  376 rhodium(III)-catalyzed oxidative annulation of pyridines  374 rhodium-catalyzed C3/5 methylation of pyridines  370 rhodium-catalyzed iodination of quinoline-N-oxides  386 rhodium-catalyzed regioselective C8-H acylmethylation of quinoline-N-oxides  386 ribovarin  649 rollover cyclometalation  370, 557 Rosenmund-von Braun  230 Ru(bpy)3Cl2  82, 490, 643, 712 [RuCl2(p-cymene)]2  77, 78, 197, 227, 259, 260, 281, 282, 288, 414, 436, 452, 456, 457, 470, 475, 476, 499, 500, 515 RuH2(CO)(PPh3)3  25, 370, 378, 402, 403 rupert’s reagent  638 RuPhos  110, 328, 329 ruthenium(II)-catalyzed Minisci reaction  711 ruthenium-mediated regio- and stereoselective alkenylation reaction of pyridine  365

s 

Sandmeyer reactions  230 sangivamycin  649 saponification  667 S-azetidine-2-carboxylic acid  575, 577, 585 schizophrenia  78, 265, 572 Scandium catalyzed enantioselective addition of pyridines to alkenes  620 Schrock-type olefin metathesis  17 Schwartz’s reagent  667

SCpRh  625, 626 SEGPHOS  225, 615 5-selenouracil  636 5-selenouridine  636 serotonin transporter (SERT)  588 sequential and multi-arylation of 1,3-azoles  121 one-pot sequential triarylation of 1,3-azoles  122 Shilov reaction  7 ambiphilic metal-ligand activation (AMLA)  8,9 showdomycin  658 σ-complex assisted metathesis (σ-CAM)  13 silabond piperazine  582 silver catalysis  348 silver(I)-catalyzed thiolation of benzoxazoles  348 silver-catalyzed C-H bond fluorination of 2-aminopyrazines  428 silver-mediated reaction  345 phosphorylation of benzothiazoles  345 silver pivalate  550 silylation  142, 185 single-electron transfer (SET)  95, 222, 296, 298, 305, 326, 345, 446, 486, 493, 496, 497, 503, 504, 505, 506, 507, 508, 514, 640, 717 site-directed C-H activation  24 tetramethylpiperidide (TMP)  24 (+)-lithospermic acid  26 site-specific phenylation of pyridine  361 sodium trifluoromethanesulfinate  638 Sonogashira cross-coupling reaction  265, 575, 647, 692 S-Phos  380 sterically tunable transition metal catalysts  109 S-pipecolinic acid  572, 573, 574, 585 S-proline 8 methoxyquinoline amide  575 [1,2]-Stevens rearrangement  711 Stille cross-coupling reaction  254 styryl pivalate  327 sulfonyl/carbonyl/cyano alkylation  496 Sunitinib  61, 62 Suprofen  61, 62 Suzuki coupling type product  198 Suzuki-Miyaura C-C bond forming reactions  258 Suzuki Miyaura cross-coupling/ Suzuki Miyaura coupling  19, 64, 252, 382, 523, 647, 685, 687 synthesis of heteroarene-fused cyclooctatetraene  553 synthesis of large-sized molecules: COTs  549

t 

TADDOL-based phosphine oxide ligand  618 TADDOL-derived phosphoramidite catalyst  625 TADDOL-based phosphoramidite chiral ligand  610 triazolyldimethylmethyl-amine (TAM)/TAM derivative  660, 663 TBA  14, 15, 19 TBAB  112, 118, 128, 203, 373, 499, 556, 558, 639, 640 TBAC  372

739

740

Index

TBAF  110, 196, 267, 640, 641 TBAI  365, 424 TBAP  238 tBuOOtBu  635, 648 TCNHPI ester  585, 586 TEMPO  98, 117, 121, 223, 261, 270, 305, 514, 626, 640, 645 Tenoxicam  61, 62 tert-alkyl oxalate salt  644 t-amylCOOH  88, 99 t-amylOH/tAmOH  26, 113, 118, 130, 176, 202, 207, 468, 575, 598, 599, 600, 601, 611, 613, 617, 675, 708 tert-amylperacetate  704 tert-butyldimethylsilyl  645 t-butylethylene (TBE)  14, 15, 18, 90, 426 tert-butyl hydroperoxide (TBHP)  102, 137, 219, 221, 261, 285, 286, 344, 441, 486, 487, 493, 494, 557, 560, 638, 649, 717 tert-butyl nitrite (TBN)  229, 297 tert-butylperacetate  704 t-butylperbenzoate  633 2,4,6-tri-tert-butylphenol (TTBP)  649 6-n-butyluridine  637 tertiary 1-methyl cyclohexyl radical  644 1-(tetrahydrofuran-2-yl)-3-benzyluracil  634 2,3,5,6-tetrafluoropyridine  380 5,6,7,8-tetrahydroisoquinolines  379 5,6,7,8-tetrahydroquinolines  379 3,4,7,8-tetramethyl-1,10-phenanthroline  349, 425, 426 2,2,6,6-tetramethylpiperidine (TMP)  89 5-(2-thienyl)uridine  641 thiolation  142 thiophene activation  610 thoracyclobutanes  29 thymidine phosphate  632 thymine  639 Tiaprofenic acid  61, 62 TIPS  213, 419, 420, 456, 477, 575, 662 TIPS-alkynyl bromide  595 TIPS-ethynylbenziodoxolone (TIPS-EBX)  78, 79, 89, 98, 163, 177, 212, 266, 268, 386 tetramethylethylenediamine (TMEDA)  201, 220, 269, 403 tmpMgCl•BF3•LiCl  362, 363 (±)-TMS-SEGPHOS  87, 88 tofogliflozin, apleway  658 Togni’s reagent  486, 716 topoisomerase I inhibitors  703 topotecan  703 torsemide  713, 714 Tosylmethylation  496 TosMIC  496, 497, 694 toyocamycin  649 TPPA  600 traditional C-glycosylation  659 transannular C-H heteroarylation  601

1,2,3-triazoles  626 transition metal-free photo-catalysed  functionalization  631 transition metal-free redical-mediated functionalization  631 tricyclopentylphosphine(PCyp3)  129, 131, 362, 366 2,4,7-trimethylphenanthroline  82, 427, 719 2-(trimethylsilyl)ethoxymethyl (SEM) switch strategy  122 trialkylsulfoxonium salt  635 trastuzumab  546 (triphos)ReH5  15 (triphos)WH6  15 triruthenium dodecacarbonyl ([Ru3(CO)12])  86, 88, 283, 367, 368 tris(bipyridine)ruthenium(II) chloride  643 tris(dimethylphosphinoethyl)phosphine (pp3)  39 tris(2-furyl)phosphine  418 tubercidin  649

u 

Ullman  342, 550, 551 Ullmann/Negishi type cross-coupling reactions  252 umemoto’s reagent  638

v 

vanadium(IV)-catalysis  495 vareniclidine  598 Vaska’s complex  9, 10, 11 Vilsmeier-Haack Reaction  155, 219 5-vinyl uridine  633 visible-light photo-catalyzed direct functionalization  641 vitexin  658

w

Wacker-Tsuji type oxidation  554 Wheland intermediate  4, 5, 6, 511 Wilkinson’s hydrogenation catalyst/ Wilkinson’s catalyst  15, 694

x 

X-phos/2-dicyclohexylphosphino-2’,4’,6’triisopropylbiphenyl  113, 203, 204, 343, 582 xantphos  134, 221, 276, 277, 328, 331, 524, 584, 597, 638 xylyBINAP  385

y 

YD-3 and YC-1  685 C-H arylation of indazoles  685 palladium/phenanthroline catalyzed coupling  685, 691 Y[N(SiMe3)2]3  369

z 

Zinquin ethyl ester  386 zirconocene architectures  30 Zn(tmp)2  341, 342 ZnCl2•TMEDA  40, 349