C-H Activation for Asymmetric Synthesis 3527810846, 9783527810840

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C–H Activation for Asymmetric Synthesis

C–H Activation for Asymmetric Synthesis Edited by Françoise Colobert Joanna Wencel-Delord

Editors

University of Strasbourg Lab d’Innovation Moléculaire et Applications, UMR 7042 25 rue Becquerel 67087 Strasbourg France

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Dr. Joanna Wencel-Delord

Library of Congress Card No.:

University of Strasbourg Lab d’Innovation Moléculaire et Applications, UMR 7042 25 rue Becquerel 67087 Strasbourg France

applied for

Prof. Françoise Colobert

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A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at . © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Print ISBN: 978-3-527-34340-9 ePDF ISBN: 978-3-527-81084-0 ePub ISBN: 978-3-527-81086-4 oBook ISBN: 978-3-527-81085-7 Typesetting SPi Global, Chennai, India Printing and Binding

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v

Contents Foreword xi

Part I

Asymmetric Activation of C(sp3 )—H Bonds

1

Part I.A C(sp3 )—H Bond Insertion by Metal Carbenoids and Nitrenoids 2 1

Stereoselective C—C Bond-Forming Reactions Through C(sp3 )—H Bond Insertion of Metal Carbenoids 3 Aoife M. Buckley, Thomas A. Brouder, Alan Ford, and Anita R. Maguire

1.1 1.2 1.3 1.4 1.4.1 1.4.1.1 1.4.2 1.4.2.1 1.4.2.2 1.4.2.3 1.4.3 1.5 1.5.1 1.5.1.1 1.5.1.2 1.5.2 1.5.2.1 1.5.2.2 1.5.2.3 1.5.2.4 1.5.3 1.5.3.1 1.5.3.2

Introduction 3 Diazo Compounds 4 Mechanistic Understanding 5 Catalysts 7 Copper 7 Bisoxazoline and Schiff Base 7 Rhodium 8 Rhodium(II) Carboxylates 9 Rhodium(II) Carboxamidates 10 Ortho-metalated Complexes 11 Iridium and Ruthenium 11 Intramolecular C(sp3 )—H Bond Insertion 11 Chemoselectivity 13 Catalyst Effects 13 Substrate Effects 14 Regioselectivity 16 Formation of Three-Membered Rings 17 Formation of Four-Membered Rings 18 Formation of Five-Membered Rings 20 Formation of Six-Membered Rings 20 Diastereoselectivity 23 Substrate Effects 23 Catalyst Effects 25

vi

Contents

1.5.4 1.6 1.6.1 1.6.1.1 1.6.1.2 1.6.1.3 1.6.2 1.6.2.1 1.6.2.2 1.6.2.3 1.6.3 1.6.3.1 1.6.3.2 1.6.4 1.7

Enantioselectivity 25 Intermolecular C(sp3 )—H Bond Insertion 30 Chemoselectivity 30 Diazo Compounds 32 Catalyst Effects 34 Substrate Functional Groups 35 Regioselectivity 36 Substrate Effects 36 Catalyst Effects 38 Diazo Compound Effects 39 Diastereoselectivity 39 Substrate Effects 39 Catalyst Effects 42 Enantioselectivity 43 Conclusion 45 References 45

2

Stereoselective C—N Bond-Forming Reactions Through C(sp3 )—H Bond Insertion of Metal Nitrenoids 51 Philippe Dauban, Romain Rey-Rodriguez, and Ali Nasrallah

2.1 2.2 2.2.1 2.2.2 2.3

Introduction 51 Historical Background 52 Seminal Studies in Catalytic C(sp3 )–H Amination 52 Mechanistic and Stereochemical Issues 56 Catalytic Stereoselective C(sp3 )–H Amination Reactions with Iminoiodinanes 60 Catalytic Intermolecular Enantioselective Reactions (Chirality Only on the Metal Complex) 60 Catalytic Intramolecular Enantioselective Reactions 63 Catalytic Intermolecular Diastereoselective Reactions (Chirality on the Metal Complex and the Nitrene Precursor) 66 Catalytic Stereoselective C(sp3 )–H Amination Reactions with Azides 67 Transition Metal-Catalyzed C(sp3 )–H Amination Reactions 67 Enzymatic C(sp3 )–H Amination Reactions 68 Catalytic Stereoselective C(sp3 )–H Amination Reactions with N-(Sulfonyloxy)carbamates 70 Conclusion 72 References 72

2.3.1 2.3.2 2.3.3 2.4 2.4.1 2.4.2 2.5 2.6

Part I.B C(sp3 )–H Activation as Stereodiscriminant Step 77 3

Enantioselective Intra- and Intermolecular Couplings 79 Qiaoqiao Teng and Wei-Liang Duan

3.1

Introduction 79

Contents

3.2 3.2.1 3.2.2 3.3 3.3.1 3.3.2 3.3.3 3.4

Enantioselective Intramolecular Couplings of Aliphatic Substrates 79 C–C Coupling 79 C–X Coupling 89 Enantioselective Intermolecular Couplings of Aliphatic Substrates 90 Pd Catalysis 91 Rh Catalysis 102 Ir Catalysis 102 Conclusion 104 References 105

4

Substrate-Controlled Transformation: Diastereoselective Functionalization 107 Sheng-Yi Yan, Bin Liu, and Bing-Feng Shi

4.1 4.2

Introduction 107 Diastereoselective Functionalizations of N-Phthaloyl-α-Amino Acids 108 Diastereoselective β-C(sp3 )–H Functionalizations of N-Phthaloyl-α-Amino Acids 108 Bidentate Directing Group 108 Monodentate Directing Group 114 Diastereoselective γ-C(sp3 )–H Functionalization of α-Amino Acid Derivatives 114 Diastereoselective C–H Activation Controlled by Chiral Auxiliary 116 Diastereoselective C(sp3 )–H Functionalization of Conformationally Restricted Cyclic Substrates 121 Summary and Conclusions 127 References 128

4.2.1 4.2.1.1 4.2.1.2 4.2.2 4.3 4.4 4.5

Part II Stereoselective Synthesis Implying Activation of C(sp2 )—H Bonds 131 5

Planar Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step 133 Qing Gu and Shu-Li You

5.1 5.2 5.3 5.3.1 5.3.2 5.3.3 5.3.4 5.4

Introduction 133 Diastereoselective Synthesis of Planar Chiral Ferrocenes 134 Enantioselective Synthesis of Planar Chiral Ferrocenes 134 Pd(II)-Catalyzed Direct C—H Bond Functionalization 134 Pd(0)-Catalyzed Direct C—H Bond Functionalization 140 Ir/Rh-Catalyzed Direct C—H Bond Functionalization 144 Au/Pt-Catalyzed Direct C—H Bond Functionalization 146 Conclusion 147 References 148

vii

viii

Contents

6

Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step 151 Quentin Dherbassy, Joanna Wencel-Delord, and Françoise Colobert

6.1 6.2 6.2.1 6.2.2 6.2.3 6.2.4 6.2.5 6.3

Introduction 151 Asymmetric Coupling of Two Arenes by Oxidative Dimerization 152 Copper-Catalyzed Reactions 153 Vanadium-Catalyzed Reactions 154 Iron-Catalyzed Reactions 155 Application in the Synthesis of Natural Products 155 Conclusion 156 Stereoselective C–H Functionalization of Prochiral or Racemic Biaryls 158 Asymmetric C–H Alkylation of Naphthylpyridines 158 Diastereoselective C–H Functionalization Using a Chiral Directing Group 159 Sulfinyl as Chiral Directing Group 159 Phosphates as Chiral Directing Group 162 Enantioselective C–H Functionalization of Racemic Biaryl 163 Stereoselective C–H Functionalization Using a Transient Chiral Directing Group 165 Conclusion 167 Atroposelective Cross-Coupling of Two Moieties 167 Pd-Catalyzed C–H Arylation of Thiophene Derivatives 167 Pd-Catalyzed C–H Arylation of Biaryl Sulfoxides 169 Rh-Catalyzed C–H Arylation of Diazonaphthoquinones 171 Conclusion 172 General Conclusion 172 References 172

6.3.1 6.3.2 6.3.2.1 6.3.2.2 6.3.3 6.3.4 6.3.5 6.4 6.4.1 6.4.2 6.4.3 6.4.4 6.5

7

Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization and Kinetic Resolution 175 Soufyan Jerhaoui, Françoise Colobert, and Joanna Wencel-Delord

7.1

Synthesis of C-Stereogenic Molecules via C(sp2 )–H Functionalization 175 Desymmetrization 175 Kinetic Resolution 182 Synthesis of P-Central Chiral Molecules via C(sp2 )–H Functionalization 183 Synthesis of Chiral Organosilicon Molecules via C(sp2 )–H Functionalization 187 Synthesis of S-Chiral Molecules via C(sp2 )–H Functionalization 189 Conclusions 190 References 191

7.1.1 7.1.2 7.2 7.3 7.4 7.5

Contents

8

Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization of Metallacyclic Intermediate 193 Xiaohong Chen, Xue Gong, Bo Wang, and Guoyong Song

8.1 8.2 8.2.1 8.2.2 8.2.3 8.2.4 8.3 8.3.1 8.3.2 8.3.3 8.4

Introduction 193 Intramolecular Couplings 194 Palladium and Nickel Catalysis 194 Rhodium Catalysis 196 Iridium Catalysis 200 Enantioselective Hydroacylation 203 Intermolecular Couplings 210 Rhodium Catalysis 210 Iridium Catalysis 219 Other Metal Catalysis 226 Conclusion 231 Acknowledgments 231 References 231

9

Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation 239 Parthasarathy Gandeepan and Lutz Ackermann

9.1 9.2 9.2.1 9.2.2 9.3 9.4 9.4.1 9.4.2 9.5 9.5.1 9.5.2 9.6

Introduction 239 C–H Activation with Alkenes 241 Nondirected C–H Alkenylation 241 Directed C–H Alkenylation 244 C–H Activation with Alkenyl (Pseudo)halides 250 Hydroarylation 252 Hydroarylation of Alkynes 252 Hydroarylation of Allenes 257 Hydroacylation 261 Hydroacylation of Alkynes 261 Hydroacylation of Allenes 263 Conclusion 264 References 265 Index 275

ix

xi

Foreword The ability of metals to cleave and functionalize strong C—H bonds was discovered in the late nineteenth century. Since then, major conceptual and methodological breakthrough has been accomplished using transition metal catalysts, and the interest for this field has exponentially grown from the beginning of the current century. Nowadays, a wide variety of catalytic methods are available to activate and functionalize different types of C—H bonds in a highly chemo- and site-selective manner. Whereas these aspects are still progressing, stereoselectivity has gained increasing momentum and is currently lying at the forefront of the field. This book, written by specialists of the topic, presents stereoselective C–H functionalization with a broad coverage, from outer-sphere to inner-sphere C—H bond activation and from the control of olefin geometry to the induction of point, planar, and axial chirality. Moreover, methods wherein asymmetry is introduced either during the C–H activation or in a different elementary step are discussed. Another striking feature appearing in the enclosed chapters is the diversity of stereogenic elements that can now be constructed by C–H activation methods: single or multiple stereogenic centers, metallocenes with planar chirality, and biaryl stereogenic axes are all accessible through stereoselective C–H functionalization. Moreover, the span of enantioselective reactions has greatly expanded in recent years and now includes almost all facets: desymmetrization of enantiotopic aryl or alkyl groups; classic, parallel, or dynamic kinetic resolution; activation of enantiotopic secondary C—H bonds; atropselective cross-coupling; functionalization of pro-atropisomeric systems; etc. These reactions are increasingly applied to the synthesis of complex molecules such as active pharmaceutical ingredients and natural products, and numerous examples are provided along the chapters. One can easily predict that stereoselective C—H bond functionalization, which employs readily available precursors, will become a major tool to make chiral molecules for a variety of applications, including at the industrial scale. This book will therefore constitute an invaluable support to guide both academic and industrial researchers through these developments. 21 December 2018

Olivier Baudoin University of Basel, Switzerland

1

Part I Asymmetric Activation of C(sp3 )—H Bonds

2

Part I.A C(sp3 )—H Bond Insertion by Metal Carbenoids and Nitrenoids

3

1 Stereoselective C—C Bond-Forming Reactions Through C(sp3 )—H Bond Insertion of Metal Carbenoids Aoife M. Buckley 1 , Thomas A. Brouder 1 , Alan Ford 1 , and Anita R. Maguire 2 1 University College Cork, School of Chemistry, Analytical and Biological Chemistry Research Facility, College Road, T12K8AF Cork, Ireland 2 University College Cork, School of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, College Road, T12K8AF Cork, Ireland

1.1 Introduction The selective and efficient construction of complex molecules is one of the most challenging goals in organic synthesis. To access such intriguing molecules, innovative methodologies in bond formation are required compared to traditional functional group transformations. It is for this reason that selective functionalization of the ubiquitous but inert C—H bond is of great interest to the chemical community [1–4]. A challenging aspect in organic chemistry for decades has been the stereoselective carbon–carbon bond formation by activation of a C(sp3 )—H bond in the synthesis of pharmaceuticals, natural products, and other industrially relevant targets. A powerful approach to achieve such useful C–H functionalization is via C(sp3 )–H insertion by metal carbenoids [5–8]. Generation of the metal carbenoid can occur through a number of precursors such as diazo compounds, ylide derivatives, hydrazones, and, more recently, triazoles. In this chapter, we will exclusively discuss metal carbenoids derived from α-diazocarbonyl compounds. In order to take advantage of metal carbenoid-induced C–H insertion, one must consider the reactivity of the electrophilic metal carbenoid. The synthetic utility of the free carbenes is limited by low selectivity in most reactions. In contrast, when nitrogen extrusion is facilitated by a transition metal, the resulting metal carbenoid retains the reaction scope of a free carbene while allowing highly selective transformations to occur (Figure 1.1). Historically, copper was used as the transition metal source, but few examples of efficient and selective C–H insertion were reported. The key development in C–H insertion was the discovery by the Teyssié group that dirhodium(II) carboxylates catalyzed the intermolecular C–H insertion reaction of ethyl diazoacetate with alkanes [9]. Following this, Wenkert et al. [10] and Taber and Petty [11] highlighted the potential of intramolecular C–H insertion reactions of α-diazocarbonyl compounds to lead to cyclopentanone derivatives. Importantly, it was demonstrated that C–H insertion takes place with retention of C–H Activation for Asymmetric Synthesis, First Edition. Edited by Françoise Colobert and Joanna Wencel-Delord. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.

4

1 Stereoselective C–H Insertions of Carbenoids

Figure 1.1 Nitrogen extrusion from α-diazocarbonyl compounds in the presence of a transition metal (TM) allows for more selective C—C bond formation through C(sp3 )–H insertion.

O

O R

X N2

TM

R

X

New C C bond H

R

1

1

R

configuration at the reacting C—H bond [12]. These early studies triggered four decades of intensive development of selective C–H insertion. This chapter will explore how the complex relationship between the catalyst and the substrate affects the chemo-, regio-, diastereo-, and enantioselectivity of C—C bond formation through C(sp3 )—H bond insertion by metal carbenoids.

1.2 Diazo Compounds Diazoalkanes such as diazomethane and diazoethane are challenging to synthesize, inherently unstable, and even explosive in their pure form. Analogs such as phenyldiazomethane exhibit increased stability due to conjugation with the aromatic ring, but still cannot be stored for long periods of time. The presence of a carbonyl group adjacent to the diazo group confers much greater stability, and several diazocarbonyl compounds are stable enough to be stored, and some are commercially available (Figure 1.2). The reactivity and selectivity of metal carbenoids are affected by the substituents that flank the metal carbene. Diazo carbene precursors are generally classified into three groups according to the nature of their substituents (Figure 1.3). The terms “acceptor” and “donor” refer to electron-withdrawing and electron-donating character principally through resonance effects. Due to the buildup of positive charge on the carbene carbon during the formation of the carbenoid, ideal substituents will act to stabilize this buildup of positive Diazoalkanes N2

Aryldiazomethanes N2

>

Diazoketones

>

N2

R

> O

Diazoacetates N2

RO

>

R1

Aryldiazoacetates

Vinyldiazoacetates Diazoacetoacetates

N2

RO

∼

RO

O

O

N2 R1

N2

R

>

O

O

OR1

Diazomalonates N2

RO

>

O

O

OR1

O

Figure 1.2 Relative reactivity of diazo compounds.

EWG

EWG=

EWG=

N2 H

CO2R, COR, NO2, PO(OR)2, SO2R

1 Acceptor substitued

EWG=

N2 EWG

EWG

CO2R, COR, NO2,SO2R, CN

2 Acceptor/acceptor substituted

Figure 1.3 Types of diazo compounds.

CO2R, COR

N2 EWG

EDG 3

Donor/acceptor substitued

EDG= aryl, vinyl, alkynyl, heteroaryl

1.3 Mechanistic Understanding

charge without altering its reactivity. Acceptor groups do little to stabilize the electrophilic carbene center. This leads to limited site selectivity; therefore these compounds are better suited to intramolecular C(sp3 )–H insertion than intermolecular C(sp3 )–H insertion. Conversely, the presence of an electron-donating group confers a degree of stability to the metal carbenoid. Aryldiazoacetate derivatives are the most commonly used donor/acceptor-substituted α-diazocarbonyl precursors for intermolecular C–H insertion.

1.3 Mechanistic Understanding The mechanism of transition metal C–H insertion has been thoroughly investigated by several research teams [13–17], and a simplified catalytic cycle is shown in Figure 1.4. The metal ligated catalyst (MLn ) coordinates with the diazo compound leading to nitrogen extrusion and formation of a metal carbenoid. This metal carbenoid then undergoes C–H insertion to form the new carbon–carbon bond. For C–H insertion reactions to be synthetically useful, high chemo-, regio-, diastereo-, and enantioselectivity are necessary. To be able to achieve such control, a more detailed understanding of the mechanism is required. Several hypotheses on the mechanism have been proposed for the rhodium-catalyzed C–H insertion [13, 18–20]. Doyle suggested a three-centered concerted mechanism, which was advanced by Nakamura’s theoretical studies [15]; however intermolecular density functional theory (DFT) computational studies carried out by Davies have disputed this hypothesis in certain cases [17]. Initially, the metal carbenoid intermediate (Figure 1.5) is generated through (i) the σ-bonding from the carbene carbon to the metal atom and (ii) the π-backdonation from the filled metal d-orbitals to the carbene carbon that possesses a vacant p-orbital. This vacant 2p orbital leads to the formation of a highly electrophilic metal carbenoid [21]. The ligands coordinated to the metal can alter the electrophilicity of the metal carbenoid. A more reactive carbenoid is observed when electron-withdrawing ligands are present on the metal due to reduced backbonding to the vacant Metal carbenoid R LnM

N2

C

H C R1

R N2

MLn

C R1

Diazo compound

H R C C R1 C(sp3)–H insertion product

Figure 1.4 Simplified catalytic cycle of C(sp3 )–H insertion via metal carbenoid formation.

5

6

1 Stereoselective C–H Insertions of Carbenoids

π

Figure 1.5 Bonding in a metal carbenoid.

R R

σ

LnM

C

LnM

R1

R1

π

carbene p-orbital. Alternatively, a less reactive carbenoid is generated with the use of electron-donating groups. There is a balance that needs to be struck between reactivity and selectivity of the carbenoid. Once the carbenoid is formed, it undergoes C–H insertion through the overlap of the empty p-orbital of the metal carbenoid with the σ-orbital of the C—H bond. This involves two steps: (i) hydride transfer and (ii) carbon–carbon bond formation. It is believed that these steps can occur in an asynchronous concerted three-centered transition state (TS-I; Scheme 1.1) or with considerable hydride transfer character, which is likely to be followed by rapid carbon–carbon bond formation (Scheme 1.2) [17]. H CO2Me (HCO2)4Rh2

CO2Me δ– δ+ H L4Rh2 C1 δ+ C2 Ph

C2

MeO2C

δ–

C1 Ph

Ph

H C1 C2

Rh2(O2CH)4

TS-I

Scheme 1.1 Less activated C(sp3 )—H bonds proceed via an asynchronous concerted three-centered transition state. L

O

L

O

O

Rh

Rh

O

O

O

H

O O

C4 δ–

CO2Me

L4Rh2

C3 Ph

CO2Me δ–

δ+ C3

Ph

L

H

δ+ C4

TS-II

L Metal carbenoid represented with dirhodium carboxylate paddlewheel MeO2C Ph

CO2Me

H C3

L4Rh2

C4

C3

H C4

Rh2(O2CH)4

Ph

Scheme 1.2 More activated C(sp3 )—H bonds proceed with a hydride transfer characteristic and a more asynchronous mechanism.

1.4 Catalysts

Computational studies by Davies and coworkers suggest that reactions of donor/acceptor carbenoids with less activated C—H bonds (e.g. cyclopentane) more closely resemble to the concerted asynchronous mechanism, while more activated C—H bonds (e.g. cyclopentadiene) show an appreciable degree of hydride transfer in a somewhat earlier transition state (TS-II; Scheme 1.2). For a donor/acceptor-substituted α-diazocarbonyl compound, C–H insertion is believed to be the rate-limiting step as a higher activation energy is calculated for C–H insertion over nitrogen extrusion [15]; however, DFT calculations have shown for acceptor-substituted diazo compounds that the nitrogen extrusion is the rate-limiting step for secondary C–H insertion [17]. Although these computational studies have modeled intermolecular experiments, the same hypothesis has been applied to the understanding of intramolecular C–H insertion reactions. While rhodium(II) catalysts have been the most widely researched transition metal complexes for C–H insertion, in recent years, attention has also turned to the prospect of efficient and selective catalysts from other metals including copper, iridium, ruthenium, iron, and gold, for which a similar C–H insertion mechanistic pathway is anticipated [22].

1.4 Catalysts Efficient and selective C–H insertion requires a carbenoid intermediate of appropriate reactivity and electrophilicity. Judicious choice of metal–ligand combination is essential to strike the right balance between reactivity and selectivity. While carbenoids can be generated with a number of transition metals, some like the coinage metals (gold, silver) are too reactive, thus rendering selectivity difficult to achieve [23]. Others such as ruthenium are too stable to undergo C–H insertion. Typically, copper and rhodium are the transition metals of choice for C–H insertion reactions. 1.4.1

Copper

Before the advent of dirhodium tetraacetate, virtually all of the early literature relating to metal-catalyzed carbenoid reactions reports the use of copper complexes [24–26]. Synthetic utility of these copper-based catalysts was limited to geometrically rigid systems, and yields were moderate at best [24]. Since the first reported copper-catalyzed enantioselective C–H insertion reactions by Sulikowski and coworker [27], this area of metal catalysis has seen renewed interest. 1.4.1.1

Bisoxazoline and Schiff Base

The most widely studied copper-based ligands are the C 2 -symmetric bisoxazolines. The success of such ligands can be attributed to the symmetry about the C 2 axis, which reduces the number of possible transition states for a given reaction. In addition, they also possess a conformationally constrained metal chelate

7

8

1 Stereoselective C–H Insertions of Carbenoids

O

O

R1 R1

O O

O

N

O

N

N N

N

N

N R

R

11 R1 Me Et H Me H Me Me

R 4 i-Pr 5 i-Pr 6 t-Bu 7 t-Bu 8 Ph 9 Ph 10 Bn

12

O

O

Ph

Ph

N

O

O

N

N

Cl

N

N

N

Cl

Cl

Cl

N

Ph

Ph

R

R

R

13

16

14 i-Pr 15 Ph

Figure 1.6 A selection of commercially available bisoxazoline ligands (4–15) and a Schiff base ligand (16).

structure where the stereocenter that affects enantiocontrol resides on the carbon adjacent to the metal-coordinating nitrogen of the oxazoline ring, thereby directly influencing the stereochemical outcome of the reaction. Much of the extensive range of bisoxazoline ligands synthesized to date has been covered by Desimoni et al. [28]; a selection of the most commonly used and commercially available ligands is presented in Figure 1.6. The ligands are usually reacted in situ with a copper source such as copper chloride or copper triflate. Bisoxazoline complexes have been employed in both intraand intermolecular C–H insertion with enantioinduction of up to 98% ee being achieved in the synthesis of cyclopentanones 18 and thiopyrans 19 (Scheme 1.3) [29, 30]. O SO2Ph

17a R1 = (CH2)3Ph R2 = Ph

Ph

N2

Cu–bisoxazoline–NaBARF R1

18

R2 S O

O 17a,b

Up to 89% ee

O

Cu–bisoxazoline–NaBARF 17b R1 = OMe R2 = (CH2)4Ph

O O

O S

OMe Ph 19 Up to 98% ee

Scheme 1.3 Cyclopentanone and thiopyran formation using a copper-bisoxazoline catalytic system.

A further example of copper-catalyzed asymmetric C–H insertion involves the C 2 -symmetric Schiff base copper complex 16, which has shown moderate success in the enantioselective synthesis of d-threo-methylphenidate [31]. 1.4.2

Rhodium

Since the introduction of dirhodium tetraacetate in the early 1980s [9], rhodium has been the transition metal of choice for a wide range of carbene-mediated transformations and specifically for asymmetric C–H insertion due to its superior selectivity and efficiency compared with other metals. Key to the success

1.4 Catalysts

of dirhodium complexes is their highly symmetrical paddlewheel conformation [32]. Within this framework, the dirhodium-bridged cage forms a “lantern” structure. Only one of the two rhodium atoms serves as a binding site for the diazo-generated carbene. The second rhodium atom acts as an electron sink, thereby increasing electrophilicity of the carbene and facilitating cleavage of the rhodium carbene bond upon reaction completion. 1.4.2.1

Rhodium(II) Carboxylates

Following the success of rhodium tetraacetate, a wide range of rhodium(II) carboxylates were investigated. Rhodium carboxylates are particularly effective in carbene transfer reactions due to their electron-deficient character. Since the first use of a chiral rhodium(II) catalyst, Rh2 (S-BSP)4 (20), by McKervey and coworkers [33], the design and synthesis of novel rhodium(II) carboxylate catalysts has been the subject of intensive research. Only a limited number of chiral templates have produced consistently high enantioselectivities, and a selection of these will be discussed here. Davies has reported excellent results with chiral dirhodium tetraprolinates and donor/acceptor-substituted carbenoids at −78 ∘ C [34]. The tetraprolinates were shown to have enhanced enantioselectivity in nonpolar solvents, thought to be the result of solvent-induced orientation of the prolinate ligands, leading to a complex with overall D2 symmetry [34, 35]. This led to the development of hydrocarbon-soluble Rh2 (S-TBSP)4 (21) and Rh2 (S-DOSP)4 (22) catalysts (Figure 1.7). Rh2 (S-DOSP)4 in particular has been a valuable asset in achieving high enantioinduction in the challenging field of intermolecular C–H insertion [36]. A second generation of more finely tuned catalysts included Rh2 (S-biTISP)4 (24) and Rh2 (S-biDOSP)4 (25), which possess a rigid bridge structure locked in a D2 -symmetric conformation [37]. A further class of catalysts was developed with cyclopropanecarboxylate ligands (26–28), which have shown excellent selectivity and asymmetric induction in intermolecular C–H insertion [38, 39]. Hashimoto and Ikegami developed rhodium(II) carboxylate catalysts built around N-phthaloyl-(S)-amino acid templates, the most successful of which has been Rh2 (S-PTTL)4 (31), and later a second generation of catalysts that extended the phthalimide moiety by an additional benzene ring [40, 41]. Davies

Ar ArO2S

ArO2S N

N O Rh

O Rh

Ph

N SO2Ar

Ph

O OO O Rh Rh

O

O

Rh

Rh

Ar 20 21 22 23

Ph 4-t-BuC6H4 4-(C12H25)C6H4 2-Naphthyl

Rh2(S-BSP)4 Rh2(S-TBSP)4 Rh2(S-DOSP)4 Rh2(S-NSP)4

Ar Ar 24 2,4,6-tri-iPrC6H2 Rh2(S-biTISP)4 25 4-(C12H25)C6H4 Rh2(S-biDOSP)4

26 C6H5 Rh2(R-TPCP)4 27 p-BrC6H4 Rh2(R-BTPCP)4 28 p-PhC6H4 Rh2(R-BPCP)4

Figure 1.7 Commonly used prolinate- and cyclopropane-derived rhodium(II) carboxylate catalysts.

9

10

1 Stereoselective C–H Insertions of Carbenoids X O

29 30 31 32 33 34 35

O

R

N

O Rh

O

R O

Rh

R Me i-Pr t-Bu Bn Ph CEt3 Adamantyl

Rh2(S-PTA)4 Rh2(S-PTV)4 Rh2(S-PTTL)4 Rh2(S-PTPA)4 Rh2(S-PTPG)4 Rh2(S-PTTEA)4 Rh2(S-PTAD)4

O Rh

X

O R

N O Rh

O

O Rh

R 36 Me Rh2(S-BPTA)4 37 t-Bu Rh2(S-BPTTL)4

X N

X

O Rh

R 38 t-Bu 39 t-Bu 40 Adamantyl

O

X F Rh2(S-TFPTTL)4 Cl Rh2(S-TCPTTL)4 Cl Rh2(S-TCPTAD)4

Figure 1.8 Commonly used phthaloyl-derived rhodium(II) carboxylate catalysts.

has reported high levels of asymmetric induction using the phthaloyl catalyst with the adamantylglycine-derived Rh2 (S-PTAD)4 (35) [42]. Recently a third generation of phthaloyl catalysts has been introduced, Rh2 (S-TFPTTL)4 (38) and Rh2 (S-TCPTTL)4 (39), incorporating halogens on the phthalimide ring. These have shown excellent enantioselectivity and reactivity, high turnovers, and low catalyst loadings [43–46] (Figure 1.8). 1.4.2.2

Rhodium(II) Carboxamidates

First described by Dennis et al. [47], chiral rhodium(II) carboxamidates are constructed from lactams derived from amino acids and possess four carboxamidate ligands around the dirhodium core with two oxygen and two nitrogen donor atoms. Four different isomers are possible due to the unsymmetrical bonding of the carboxamidate ligands to the rhodium core. The most dominant isomer formed after ligand exchange with rhodium acetate is the 2,2-cis configuration (85%) [48]. In general, rhodium(II) carboxamidates are less reactive toward α-diazocarbonyl compounds than rhodium(II) carboxylates; thus higher selectivity is possible. This is especially true for acceptor-substituted carbenoids derived from α-diazoesters and α-diazoacetamides. A wide range of carboxamide catalysts have been described by Doyle and coworkers, including the complexes 41–48 shown in Figure 1.9. These catalysts have proven very effective in cyclizations of specific substrate types. X O Rh

N Rh

X H 41 CH2 CO2Me 42 O 43 NCOCH3 44 NCOCH2Ph

Rh2(5S-MEPY)4 Rh2(4S-MEOX)4 Rh2(4S-MACIM)4 Rh2(4S-MPPIM)4

CO2R O Rh

N Rh

45 46 47 48

Figure 1.9 Commonly used rhodium(II) carboxamidate catalysts.

R Me i-Bu Bn l-Menthyl

Rh2(5S-MEAZ)4 Rh2(4S-IBAZ)4 Rh2(4S-BNAZ)4 Rh2(4S,R-MenthAZ)4

1.5 Intramolecular C(sp3 )—H Bond Insertion

Z Z

PR2 R2P Rh O O

O

Rh O

F3C CF3

49 50 51 52 53 54 55

R Ph Me p-MeC6H4 m-MeC6H4 3,5-Me2C6H4 p-t-BuC6H4 p-FC6H4

Z H H p-CH3 m-CH3 3,5-CH3 p-t-Bu p-F

Figure 1.10 Ortho-metalated rhodium(II) catalysts utilized in C–H insertion.

1.4.2.3

Ortho-metalated Complexes

Unusually these dirhodium catalysts, which were first reported by Cotton et al. [49], do not derive chirality from stereogenic ligands but instead possess backbone chirality. They are made up of two ortho-metalated arylphosphines and two carboxylate ligands arranged in a cis confirmation (Figure 1.10). They have had reasonable success in the cyclizations of α-diazoketones via C–H insertion (up to 74% ee) [50]. 1.4.3

Iridium and Ruthenium

In 2009, Suematsu and Katsuki described the first example of iridium-catalyzed asymmetric C–H insertion with excellent enantioselectivities of up to 97% ee using complex 57 [51]. Iridium bisoxazoline 58 [52] and iridium porphyrin complex 59 [53, 54] have also found use in intermolecular C–H insertion allowing excellent yields and enantioselectivities (up to 99% ee) to be achieved (Figure 1.11). Ruthenium complexes 61–64 have been used to catalyze intramolecular C–H insertion of alkyl diazomethanes with excellent diastereoselectivity. Few examples of ruthenium-catalyzed enantioselective C–H insertion reactions are reported, but Che and coworkers have published an intermolecular C(sp3 )–H insertion catalyzed by 60, delivering a chiral product with 92% ee [55]. This group has also shown that diastereoselective synthesis of β-lactams can be carried out via [RuCl2 (p-cymene)]2 -catalyzed cyclization of α-diazoacetamides in good to excellent yields and asymmetric induction of up to 55% ee has been achieved with the use of pyridine bisoxazoline 15 together with this catalyst [56].

1.5 Intramolecular C(sp3 )—H Bond Insertion Intramolecular C–H insertion was not regarded as an efficient transformation until Wenkert et al. [10] and Taber and Petty [11] almost simultaneously, but

11

12

1 Stereoselective C–H Insertions of Carbenoids

Me

N

Ir

N

Me

Me

O

O L O R R

O N

Cl

N Ir Cl OH2

58

L = 4-CH3C6H4 56 R = H 57 R = Ph

Z

Y N N

L1 N M

Y

Y

X

X X

X N

CO N Ru

N

N

Z

L2 N

Y

Z X

X X

Y

Y

X Y

Y Z 59 M = Ir, L1 = Me, L2 = EtOH, 60 M = Ru, L1 + L2 = N

N

61 X=Y=H, Z=Me 62 X=Z= Me, Y=H 63 X=Y=Z=F 64 X=Cl, Y=Z=H

[Ru(TTP)(CO)] [Ru(TMP)(CO)] [Ru(F20-TPP)(CO)] [Ru(TDCPP)(CO)]

Figure 1.11 Iridium and ruthenium catalysts utilized in C–H insertion.

independently, reported the rhodium-catalyzed cyclization of α-diazoketones, 65 and 67, respectively, in the early 1980s. This work, which was preceded by the use of dirhodium tetracarboxylates in intermolecular C–H insertion by Teyssié, allowed intramolecular C–H insertion to emerge as a powerful synthetic pathway for the construction of five-membered rings. Taber recognized the potential for asymmetric induction in this transformation by introducing chiral auxiliaries to the α-diazoketone precursors [57], followed by McKervey and coworkers who reported the first use of chiral dirhodium catalysts in asymmetric intramolecular C–H insertion to provide cyclopentanone 70 with a modest 12% ee (Scheme 1.4) [33].

1.5 Intramolecular C(sp3 )—H Bond Insertion O O

Rh2(OAc)4 N2

H AcO

AcO

H

OAc

N2

H

H

OAc

65

O CO2Me

H

DME

66

O

O

Rh2(OAc)4

O SO2Ph

CO2Me

CH2Cl2

N2

Rh2(BSP)4

SO2Ph

CH2Cl2

R R 67

68

70 12% ee

69

Scheme 1.4 Seminal work in intramolecular C–H insertion by Wenkert, Taber, and McKervey.

Since these seminal reports, the field of metal-catalyzed asymmetric intramolecular insertion into C—H bonds has seen major advances and become a reliable methodology for C—C bond formation. For clarity, this chapter will be organized in terms of chemo-, regio-, stereo-, and enantioselectivity with rhodium-catalyzed C–H insertion dominating the literature in this field. 1.5.1

Chemoselectivity

1.5.1.1

Catalyst Effects

The preference of carbenoids to undergo C–H insertion over other carbenebased transformations is of great interest to synthetic chemists. In rhodiumcatalyzed carbene-mediated transformations, selectivity for C–H insertion has been found to be dependent on the catalyst, specifically the electronic properties of the ligands. This was demonstrated by Padwa, Doyle, and coworkers in a series of intramolecular competition experiments [58, 59]. The α-diazoketone 71 has the potential to undergo cyclopropanation or C(sp3 )–H insertion; it was found that C–H insertion was the only reaction pathway observed when using the highly electrophilic carbenoid derived from Rh2 (pfb)4 (74). In contrast, the more electron-rich carbenoid derived from Rh2 (cap)4 (75) led to a switch in chemoselectivity, favoring cyclopropanation completely. The electronic properties of Rh2 (OAc)4 (76) fall somewhere between the other two catalysts, so very little chemoselectivity was observed (Figure 1.12 and Scheme 1.5). CH3

CF2CF2CF3 O

O

Rh

Rh

74 Rh2(pfb)4

O

N

Rh

Rh

75 Rh2(cap)4

Figure 1.12 Achiral rhodium catalysts.

O

O

Rh

Rh

76 Rh2(OAc)4

13

14

1 Stereoselective C–H Insertions of Carbenoids

Rh2L4 H

+

CH2Cl2

N2

O

O 71

72

73 C−H insertion

Cyclopropanation Entry

Catalyst

Ratio 72 : 73

1

Rh2(pfb)4

0 : 100

2

Rh2(OAc)4

44 : 56

3

Rh2(cap)4

100 : 0

Scheme 1.5 Ligand-dependent chemoselectivity between cyclopropanation and C–H insertion.

Another example of ligand-dependent chemoselectivity was observed when α-diazoacetamide 77, which possesses sites for C–H insertion and aromatic addition, was subjected to rhodium catalysis. In this experiment, C–H insertion was the preferred reaction pathway when using Rh2 (cap)4 , while Rh2 (pfb)4 produces mainly the aromatic addition product. No insertion into the tert-butyl group was observed (Scheme 1.6). Although only two examples are shown here, an extensive series of these competition experiments were conducted, which highlighted reactivity trends based on catalyst selection (Figures 1.13 and 1.14) [60]. H

Ph

t-Bu Rh2L4

N

N2 O

N

CH2Cl2

t-Bu

+

O

77

N

t-Bu

O

78

79

Aromatic addition Entry

Catalyst

Ratio 78 : 79

1

Rh2(pfb)4

95 : 5

2

Rh2(OAc)4

68 : 32

3

Rh2(cap)4

3 : 97

C−H insertion

Scheme 1.6 Ligand-dependent chemoselectivity between aromatic addition and C–H insertion.

1.5.1.2

Substrate Effects

Another factor that impacts selectivity for C–H insertion over other reaction pathways is the substitution pattern of the α-diazocarbonyl substrate. Typically acceptor-substituted compounds (bearing only one electron withdrawing group

1.5 Intramolecular C(sp3 )—H Bond Insertion

R

H

>

R

R >

H

>

~ −

R

Formal aryl C−H insertion

H H

R 3° Aliphatic C−H insertion

Cyclopropanation

Aromatic addition

2° C−H insertion

Figure 1.13 Reactivity trends for highly electrophilic carbenoids such as those derived from Rh2 (pfb)4 .

H

>

R >

R

R >

H

Formal aryl C−H insertion

H

>

H

R Cyclopropanation

R

3° Aliphatic C−H insertion

2° C−H insertion

Aromatic addition

Figure 1.14 Reactivity trends for more electron-rich carbenoids such as those derived from Rh2 (cap)4 .

[EWG] α to the diazo moiety) lead to more reactive carbenoid intermediates. This may allow homocoupling to compete as a side reaction. This homocoupling side reaction is strongly disfavored for less reactive acceptor/acceptor or donor/acceptor α-diazocarbonyl compounds (Scheme 1.7). O

O Rh/Cu

H

R

R R

N2 Acceptor substituted α-diazocarbonyl

O Homocoupling

R = alkyl, aryl, OR, NR1R2

Scheme 1.7 Homocoupling may occur between acceptor-substituted α-diazocarbonyl compounds.

Interestingly, Padwa and Moody showed that if a hydroxyl group is present within the substrate, O–H insertion will dominate over any other carbenoid-mediated transformation, regardless of the dirhodium catalyst employed (Scheme 1.8). While yields varied, O–H insertion was the sole product obtained with no evidence for cyclopropanation, aromatic addition, or aliphatic or aromatic C–H insertion [61]. Wee and coworkers designed a study made up of 11 α-diazoanilides 82 with varying N-substituents to investigate alkyl vs. aryl C–H insertion (Scheme 1.9). In all cases, alkyl C–H insertion was the only pathway observed (e.g. 83). In contrast, when the α-diazoester moiety was changed to a phenylsulfone or a methyl ketone, formal aromatic C–H insertion was observed exclusively (one

15

16

1 Stereoselective C–H Insertions of Carbenoids

O

R

O Rh(II)

MeO

O

OH N2

O

R

80a R = Ph 80b R = HC CH2 80c R = C CH

CO2Me

81a–c

Scheme 1.8 O–H insertion is the dominant carbenoid-mediated reaction pathway when a hydroxy group is present in a molecule. Ph

MeO2C N R = Ph, R1= CO2Me

O R

O

R1

N N2

OMe

83

Rh2(OAc)4

SO2Ph MeO OMe

R = Bu, R1= SO2Ph

O N

82

Bu 84

Scheme 1.9 Alkyl vs. aryl C–H insertion depending on the electronic properties of the group α to the diazo moiety.

example, 84). This can be rationalized as the more electron-withdrawing acetyl or phenylsulfonyl group leads to a more electrophilic carbenoid when compared with an ester-derived carbenoid [62]. It should be noted that while this reaction pathway is frequently referred to as “aromatic C–H insertion,” strictly speaking it should not be, as the mechanism is aromatic substitution rather than C–H insertion. It has also been shown that the electronic properties of the aryl ring play a role in the chemoselectivity of a carbenoid reaction, with the strongly electronwithdrawing nitro substituent disfavoring aromatic addition and promoting C–H insertion as the dominant reaction pathway (Scheme 1.10) [59]. 1.5.2

Regioselectivity

Following Taber’s investigations [11, 12, 63], it was well established that intramolecular C–H insertion occurs to preferentially form five-membered ring compounds. This fact has been exploited to construct cyclopentanones, dihydrofurans, γ-lactones, and γ-lactams among other five-membered carboand heterocyclic ring systems.

1.5 Intramolecular C(sp3 )—H Bond Insertion Ar

t-Bu N N2

N

t-Bu +

R

O

R

N

O

85

85 a b

t-Bu

N

+

O

O

86

Entry 1 2

t-Bu

Ar

Rh2(OAc)4

87

R OMe NO2

88

Ratio 86 : 87 : 88 76 : 24 : 0 8 : 77 : 15

Scheme 1.10 Electronic properties of the aryl ring play a role in chemoselectivity.

Although 1,5 C–H insertion is the favored reaction pathway due to entropic factors, steric or electronic factors can override this preference to form larger or smaller ring sizes. In general, 1,4 C–H insertion can occur if the C—H bond is activated by a neighboring heteroatom, usually nitrogen or oxygen, while 1,6 C–H insertion has been observed for more structurally rigid systems. Even 1,3 C–H insertion has been reported for β-tosyl α-diazocarbonyl compounds. 1.5.2.1

Formation of Three-Membered Rings

While three-membered rings can be constructed through C–H insertion in geometrically rigid structures, only one example of three-membered ring formation in a freely rotating system has been reported to date. Wang and coworkers found that α-diazocarbonyl compounds with a β-tosyl functionality undergo C–H insertion to give a cyclopropane ring with excellent diastereoselectivity (Scheme 1.11) [64]. When the reaction is performed under strict oxygen-free conditions to prevent formation of oxidation product 91, 1,3 C–H insertion is the major reaction pathway observed in all but one case. Interestingly, α-diazocarbonyl compound 89e has the potential to undergo 1,3 C–H insertion or 1,5 C–H insertion. Using Rh2 (OAc)4 as the catalyst, an equal distribution of insertion products is observed, but if a catalyst with more electron-withdrawing ligands such as Rh2 (tfa)4 is employed, 1,3 C–H insertion is favored. This study demonstrates the dramatic effect of neighboring groups and catalyst selection on regioselectivity. At the time of writing, 1,3 C–H insertion has only been reported with achiral catalysts. Ts

O R1

+

O

R

R1

Benzene

N2 89a 89b 89c 89d 89e

Ts

Ts

Rh2(OAc)4

R

R = CH3, R1 = OEt R = CH3CH2, R1 = OEt R = CH3, R1 = CH3 R = CH3, R1 = Ph R = CH3(CH2)2, R1 = OEt

R

1

COR 90a–e

O 91a–e

Scheme 1.11 1,3 C–H insertion is possible in freely rotating α-diazocarbonyl compounds with a β-tosyl functionality.

17

18

1 Stereoselective C–H Insertions of Carbenoids

1.5.2.2

Formation of Four-Membered Rings

The most common four-membered rings formed through C–H insertion are β-lactones and β-lactams. The selective synthesis of these structural motifs is of great interest as they are found in many and biologically active compounds. The main barrier to the formation of four-membered rings from C–H insertion reactions is the preference for 1,5 C–H insertion when both sites of insertion are available. It is thus necessary to restrict access to the δ-C–H insertion site either electronically or sterically in order to force 1,4-insertion. Attempts to synthesize β-lactones have been challenging, as γ-lactones are almost always the exclusive reaction products in C–H insertion reactions of α-diazoacetates. A notable exception to this trend was reported by Doyle when he showed the cyclization of alkyl phenyldiazoacetates, which produce β-lactones as the major reaction product (Scheme 1.12). In the examples shown here, Rh2 (S-DOSP)4 is employed to produce β-lactones 93 and 95 in good yields and modest enantioselectivity with only trace amounts of the γ-lactone product detected [65]. O

N2 O

Rh2(S-DOSP)4

92

Pentane, ∆

O 93 78%, 41% ee

O

Rh2(S-DOSP)4

O

Pentane, ∆

O

O

N2

O

94

95 69%, 63% ee

Scheme 1.12 β-Lactone synthesis from alkyl phenyldiazoacetates.

This regioselectivity can be suppressed when a highly activated γ C—H bond is available for insertion. In Scheme 1.13, no β-lactone is formed; instead the γ-lactone 98 is formed in 94% yield and excellent enantioselectivity. O

O

N2 O

Ph O

96

O

Rh2(4S-MAEZ)4

+

Ph

O

Ph

97

98

0%

94%, 90% ee

Scheme 1.13 β-Lactone synthesis is suppressed when a highly activated γ C—H bond is available.

This work has been expanded further by Davies and coworkers [46] and Bach and coworker [66] to show that it is not only the substitution at the ester site that influences the regioselectivity but also the substitution on the α-aryl ring. Both groups observed that an ortho substituent on the aryldiazoacetate promoted 1,4-insertion, while Davies reported that the ortho substituent is essential to achieve any β-lactone product when performing methyl C–H insertion and enantioselectivity is enhanced in the presence of a methoxy group on the aryl ring (Scheme 1.14).

1.5 Intramolecular C(sp3 )—H Bond Insertion

O

N2 R

Rh2(S-TCPTAD)4

O X

O

O

R

CH2Cl2, 40 °C

X

99

100

Entry 1 2 3

99 a b c

R H H OMe

X H Br I

%Yield 100 — 53 67

%ee 100 — 61 92

Scheme 1.14 Ortho-substitution on the aryl ring is essential for β-lactone synthesis when inserting into a methyl C—H bond.

The β-lactam ring is arguably one of the most pharmaceutically important heterocycles in modern medicine due to its presence in the essential broad-spectrum antibiotics such as penicillins and cephalosporins. Intramolecular C–H insertion of α-diazoacetamides can be exploited to generate β-lactams as the amide nitrogen activates the adjacent C—H bond toward insertion by a carbenoid. The first report of β-lactam formation through C–H insertion came from Corey and Felix [67], but the first enantioselective β-lactam synthesis by C–H insertion was published by Doyle et al. [68]. In this report, the efficiency of β-lactam formation was dependent on the substituents on the N-alkyl chain of the α-diazoacetamide precursor, never reaching over 25% yield with any chiral catalyst and moderate enantioselectivity of up to 80% ee in the case of 103a using Rh2 (4S-MEOX)4 (Scheme 1.15). R

N

Rh2(4S-MEOX)4

R

N

+

R

+

N

R

N

CH2Cl2

O

O

N2 101

102

Entry

101

R

1 2 3

a b c

Et i-Pr OEt

%Yield 102 91 82 100

%ee 101 71 69 78

O

O 103 %Yield 103 9 18 0

%ee 103 80 65 —

104 %Yield 104 0 0 0

%ee 104 — — —

Scheme 1.15 First report of enantioselective β-lactam synthesis.

Due to the preference of freely rotating alkyldiazoacetamides to undergo 1,5 C–H insertion, Doyle investigated enantioselective synthesis of β-lactams using more conformationally constrained α-diazoacetylazacycloalkanes. While no success was reported with pyrrolidine-, piperidine-, or morpholine-derived α-diazoacetamides, the azacycloheptane and azacyclooctane analogs displayed excellent regioselectivity with >99 : 1, β:γ lactam formation, excellent yields,

19

20

1 Stereoselective C–H Insertions of Carbenoids

O

O Rh2(4S-MEOX)4

N

N

O

+

N CH2Cl2

N2

H

105

H

106

107

>99%, 98% ee

Scheme 1.16 β-Lactam synthesis from an azacyclooctane-derived α-diazoacetamide.

and very high enantioselectivities (Scheme 1.16) [69]. More examples of chiral β-lactam generation through C–H insertion exist, but all show a high dependence on the substitution pattern of the α-diazoacetamide as well as catalyst sensitivity [70]. 1.5.2.3

Formation of Five-Membered Rings

The early studies by Taber and coworkers [11, 57, 63] and Doyle et al. [71] have demonstrated that a carbene will insert into a tertiary C—H bond over a secondary C—H bond and primary C–H insertion is the least favorable. This is because a buildup of positive charge occurs on the carbon at the insertion site; therefore a substitution pattern that can better stabilize the positive charge will promote the insertion process (Scheme 1.17). This selectivity can also be influenced by the electronic properties of the catalyst [19]. 1° O

O

O

O

O Rh2L4 O

O

O O

+

Benzene

N2

2° 108

Entry 1 2 3

Catalyst Rh2(pfb)4 Rh2(OAc)4 Rh2(cap)4

109

110

2° Insertion

1° Insertion

Ratio 109 : 110 34 : 66 75 : 25 92 : 8

Scheme 1.17 The preference for insertion to occur into 1∘ vs. 2∘ bonds can be influenced by the ligands on a catalyst.

1.5.2.4

Formation of Six-Membered Rings

The formation of six-membered rings through C–H insertion has been shown to be strongly dependent on the nature of the α-diazocarbonyl precursor. It was found that by activating the C–H insertion site with an adjacent heteroatom, six-membered rings could be constructed. Expanding on earlier work by McKervey and Ye [72], Hashimoto and coworkers have reported the chemo-, stereo-, and enantioselective synthesis of six-membered oxygen-containing heterocycles through 1,6 C–H insertion [73]. The tetrahydropyran 112 was synthesized

1.5 Intramolecular C(sp3 )—H Bond Insertion

CO 2Me O

CO2Me

Rh2(S-PTTL)4

N2

+

CO2Me

O

O 111

112

113

Up to 80% yield, >99 : 1 cis 95% ee

Not formed

Scheme 1.18 Diastereo- and enantioselective synthesis of a tetrahydropyran through 1,6 C–H insertion.

in up to 95% ee and complete cis diastereoselectivity using Rh2 (S-PTTL)4 (Scheme 1.18). When the reaction was carried out in diethyl ether at −60 ∘ C, there was no evidence for the competing β-hydride elimination product 113. α-Heteroatom activation is not always necessary to induce 1,6 C–H insertion as has been demonstrated by Novikov and coworkers [74, 75], Taber et al. [76], and Du Bois and coworkers [77] in the synthesis of six-membered cyclic sulfones, sultones, and cyclohexanones. Novikov and Taber have studied the effects on regioselectivity of varying substitution patterns on the α-diazocarbonyl substrate. Novikov and coworkers looked at changing the substitution on the carbon adjacent to the sulfone moiety and at the insertion site. Substitution α to the sulfone favored 1,5 C–H insertion, while a longer chain length promoted thiopyran formation through 1,6 C–H insertion (Scheme 1.19) [75].

R

O

O S

CO2Et Rh2(OAc)4

R1

N2

CH2Cl2

R

O

O

O S

CO2Et

R1

R +

O S

CO2Et

R1

R2

R2

R2

114 Entry 1 2 3

115 114 a b c

Substituents R = H, R1 = H, R2 = Me R = H, R1 = H, R2 = H R = Me, R1 = Me, R2 = Me

116 %Yield 115 65 2 5

%Yield 116 9 25 75

Scheme 1.19 Varying chain length and substitution α to the sulfone affects 1,5 vs. 1,6 C–H insertion.

Regioselective sultone formation has also been achieved by Du Bois and coworkers (Scheme 1.20). The strong preference for 1,6 C–H insertion was attributed to the similarity of the bond angles in the acyclic sulfonate and the cyclic sultone. The formation of a five-membered γ-sultone is inhibited as 1,5 C–H insertion would require an unfavorable C—S—O bond distortion [77].

21

22

1 Stereoselective C–H Insertions of Carbenoids

O R

O

O S

O

O Rh2(OAc)4 OEt

N2

O

O CO2Et

S

CH2Cl2 R

117

118

Scheme 1.20 Regioselective sultone formation.

The Taber group have synthesized cyclohexanones from α-diazo-β-aryl ketones with excellent regioselectivity by choosing electron-withdrawing aryl substituents α to the diazo moiety and electron donating substituents at the insertion site. The formation of a six-membered ring was in contrast to Taber’s seminal work in the area. He rationalized this by illustrating how the electronic properties of donor/acceptor carbenoid, such as one derived from structure 119, influences the selectivity for a different C—H bond than a carbenoid derived from an α-diazo-β-keto ester. Cyclohexanone 120 was synthesized in 99 : 1 selectivity over the corresponding cyclopentanone 121 (Scheme 1.21).

O

Br

Rh2(esp)4

N2

Br

O

Br

O

+

OMe OMe

119

120 : 121 99 : 1

OMe

Scheme 1.21 Regioselective cyclohexanone formation.

Du Bois and coworker have also reported stereoselective cyclohexanone formation as one of the key steps in their synthesis of the poison tetrodotoxin. The dirhodium catalyst employed for this transformation was Rh2 (HNCOCPh3 )4 [78]. Maguire and coworkers have demonstrated the regioselective synthesis of cis thiopyran 124 with excellent enantioselectivity [30]. Interestingly this transformation is performed using a chiral copper-bisoxazoline catalyst complex. Surprisingly, when rhodium catalysts were applied to the similar substrate 122a, the maximum asymmetric induction that could be achieved was 50% ee using Rh2 (S-PTTL)4 . This could be increased to 90% ee when the ester moiety was replaced by a menthyl chiral auxiliary (Scheme 1.22) [79]. The reaction solvent has also been shown to influence the competition between 1,6 C–H insertion and β-hydride elimination. It has been reported that less polar solvents such as cyclohexane shift the reaction pathway toward 1,6 C–H insertion, while acetonitrile and tetrahydrofuran completely favor the β-hydride elimination process (Scheme 1.23) [80].

1.5 Intramolecular C(sp3 )—H Bond Insertion O

O CO2Et

S

L*9 CuCl, NaBARF

S

R1

CH2Cl2

R N2

122a 1 R = Me, R = OEt

123

O O

O

Rh2L4

S

OMe

CH2Cl2, ∆ 122b R1 = Ph, R = OMe

122a-b

O O

O

Ph 124

Scheme 1.22 Thiopyran synthesis in up to 98% ee can be achieved with copper-bisoxazoline catalytic system. Enantioselectivities are lower when rhodium catalysts are applied to similar α-diazocarbonyl substrates. CO2Me O

CO2Me

Rh2(OAc)4

N2

CO2Me

+

Solvent

O

Ph

O

Ph

Ph 125

126

Entry 1 2 3 4 5 6 7

Solvent Cyclohexane Benzene Toluene Dichloromethane Dimethoxyethane Tetrahydrofuran Acetonitrile

127

Ratio 126 : 127 70 : 30 54 : 46 59 : 41 23 : 77 13 : 87 0 : 100 0 : 100

Scheme 1.23 Solvent variation influences competition between 1,6 C–H insertion and β-hydride elimination.

1.5.3

Diastereoselectivity

1.5.3.1

Substrate Effects

Early studies by Taber and Ruckle [63, 81] and Doyle et al. [71] of Rh2 (OAc)4 catalyzed cyclizations of disubstituted α-diazocarbonyl compounds noted the preferential formation of trans cyclopentanones and γ-lactones (Scheme 1.24). O

O EWG

X

Rh2(OAc)4

EWG

X

N2 R 128a X = CH2, EWG = CO2R 128b X = O, EWG = COR

R 129a,b

Scheme 1.24 Preferential formation of trans cyclopentanones and γ-lactones as noted by Taber and Doyle.

In the C–H insertion reaction of 130, the favored formation of trans products can be explained on the basis of a chair-like transition state (TS-III; Scheme 1.25), with insertion occurring into the C—HA bond to give the trans diastereomer

23

24

1 Stereoselective C–H Insertions of Carbenoids

R1

HB

HA

N2

R

R CO2Me

O

CO2Me HB MLn HA O R1

CO2Me R1

R

O TS-III

130

131

Scheme 1.25 Synthesis of trans cyclopentanones proceeds through a proposed chair-like transition state.

Ph

Ph

Rh2L4

N2 CO2Me

CO2Me

132

H H

CO2Me Rh

Ph

H

Me

Ph

133

Ph

H

CO2Me Rh

H Me

H

133a

Ph H

CO2Me Me Rh H

Ph

Ph CO2Me

H

CO2Me 133b

Ph H H

CO2Me Me Rh H

Ph CO2Me 133c

CO2Me 133d

Favored stereoisomer

Figure 1.15 Four possible transition states of the carbenoid derived from α-diazocarbonyl compound 132 and the corresponding stereoisomers of cyclopentanone 133.

of cyclopentanone 131. Insertion into C—HB bond to give the cis diastereomer would require R1 in the less favorable axial position in the transition state [81]. Taber expanded this work by developing a computational model for predicting the diastereoselectivity of intramolecular C–H insertion reactions of α-diazoesters based on the cyclization of 132 (Figure 1.15) [18]. The relative transition state stabilities of the four possible transition states that would each lead to a different diastereomer of cyclopentanone 133 were analyzed. This model was then applied to α-diazo β-keto esters and accurately predicted the dominant stereoisomer formed. This study, together with another in-depth theoretical study by Nakamura and coworker [16], showed that the trans conformation is preferred in the cyclizations of α-diazoesters and α-diazo-β-keto esters due to the alkyl group at the insertion site occupying the equatorial position in the transition state. In contrast, the cis transition state suffers from 1,3-diaxial repulsion. The Nakamura calculations highlighted that a vinyl or phenyl group at the insertion site theoretically made the trans transition state less stable, but only trans products are observed experimentally.

1.5 Intramolecular C(sp3 )—H Bond Insertion

1.5.3.2

Catalyst Effects

Doyle later reported excellent cis diastereoselectivity and high enantioinduction in the synthesis of bicyclic lactone 135 using the chiral rhodium catalyst Rh2 (4S-MACIM)4 , while Rh2 (5S-MEOX)4 gave poor diastereocontrol when applied to the same system (Scheme 1.26) [82]. These examples are just some of the many reactions performed that highlighted the significant catalyst influence on the conformation of the reacting metal carbene and the resulting stereoselectivity [83–86]. H O

Rh2L4

N2

134

O O

CH2Cl2

O

Entry

H O +

O

H

H

135a

135b

Rh2L4

%Yield 135a

%ee 135a

%Yield 135b

%ee 135b

1

Rh2(OAc)4

40

—

60

—

2

Rh2(4S-MEOX)4

55

96

45

95

3

Rh2(5S-MEPY)4

86

>99

14

93

4

Rh2(4S-MACIM)4

99

97

1

65

Scheme 1.26 Ligands on the carboxamidate catalysts affect diastereocontrol.

1.5.4

Enantioselectivity

Recognizing the potential for asymmetric induction in intramolecular C–H insertion, Taber employed chiral auxiliaries to preferentially direct insertion into one face of the carbene. This was followed by the introduction of chiral ligands on the dirhodium scaffold leading to the first report of catalytic asymmetric C–H insertion of α-diazocarbonyl compounds by the McKervey group. To date, numerous studies have been reported investigating the influence of various chiral ligands and also substrate structure on the enantioselectivity of intramolecular C–H insertion reactions [1, 5, 6, 8]. Symmetry is a major factor in chiral catalysis as it reduces the number of transition states available during the stereodifferentiating step. The dirhodium paddlewheel structure achieves high symmetry through four identical ligands of low symmetry that surround a highly symmetric dirhodium core. Taking rhodium carboxylates as an example, the O–Rh–O plane can be viewed as a disc with an upper and a lower face, arbitrarily α and β (Figure 1.16). To induce asymmetry in a C–H insertion reaction, the ligands attached to the rhodium need to restrict the space above or below the O–Rh–O plane so that only one enantiotopic transition state is favored during the reaction, leading primarily to one enantiomer. Depending on the orientation of these ligands toward the upper face or lower face of the O–Rh–O plane, dirhodium carboxylates can adopt multiple conformations. The symmetry of the complex is also affected by the inherent symmetry of the ligand. If ligands are C 1 symmetric, the most effective conformations for

25

26

1 Stereoselective C–H Insertions of Carbenoids

α R

O O O

R

α O

Rh

R

O O

Rh O

O

Figure 1.16 Viewing O–Rh–O plane as a disc with an α and β face.

R

β

β

α,α,β,β

α,β,α,β

α,α,α,α

α,α,α,β

A

B

C

D

Blocking group

Figure 1.17 Four possible conformations of C 1 -symmetric ligands.

asymmetric catalysis are structures A (giving overall C 2 symmetry to the complex) and B (giving overall D2 symmetry to the complex) as both faces of the plane are equivalent (Figure 1.17) [32]. Strong experimental evidence has also emerged for Rh2 (S-PTTL)4 and related catalysts (29–40) engaging in asymmetric cyclopropanation when ligands are in conformation C, the “all up” or crown conformation even though it had previously been dismissed as unable to catalyze reactions enantioselectively [87, 88]. While difficult to model experimentally, the catalyst ligands are thought to have more flexibility than once thought; this ligand flexibility is borne out by reports that describe enhancement of enantioselectivity with a change in solvent to a nonpolar solvent such as hexane or pentane [35]. If the carboxylate ligands possess C 2 symmetry, the overall symmetry of the catalyst can reach up to D4 , which is the optimal symmetry for these chiral dirhodium complexes as both faces of the O–Rh–O plane are equivalent (conformation E). D2 symmetry can be achieved with two bridged C 2 -symmetric ligands, such as bridged prolinates, providing a more rigid analog of the α,β,α,β conformation adopted by C 1 -symmetric ligands (conformation F) (Figure 1.18). The structures of chiral rhodium carboxamidates are more rigid in comparison and are limited to complexes of C 2 symmetry due to their preferred cis (2,2) Figure 1.18 Possible conformations of C 2 -symmetric ligands.

E

F

Entry 1

Rh2L4 136

%Yield 135a 99

%ee 135a 97

%Yield 135b 1

%ee 135b —

2 3 4

137 138 139

80 97 98

72 >99 74

20 3 2

13 >99 33

O

O N

Ph O

N

N

H CO2Me

O

Ph

O

N

H CO2Me

N

N PhO2S

O

O

N

H CO2Me

N

N PhO2S

O

N

H CO2Me

Rh Rh

Rh Rh

Rh Rh

Rh Rh

136 Rh2(4S,2′S,3′S-MCPIM)4

137 Rh2(4S,2′R,3′R-MCPIM)4

138 Rh2(4S,2′S,-BSPIM)4

139 Rh2(4S,2′R,-BSPIM)4

Figure 1.19 Different diastereomers of catalyst ligands lead to differing enantioselectivities.

28

1 Stereoselective C–H Insertions of Carbenoids

conformation. They adopt the α,α,β,β conformation A. Although electron-dense carboxamidate ligands are less reactive than carboxylate ligands, they can be more selective in carbenoid-mediated reactions. To explore the effect of changing the ligand orientation in space, two sets of diastereomeric catalysts, 136/137 and 138/139, were used to cyclize the α-diazoacetate 134 (Scheme 1.26). Catalysts 136 and 138 led to excellent enantioselectivities, but there is a drop-off in asymmetric induction when the other isomers of the catalysts (137, 139) are used. The different orientations of the ligands of different isomers lead to a conformation that is either “matched” or “mismatched” with the substrate structure [89] (Figure 1.19). Bisoxazoline ligands have become some of the most widely used ligands in asymmetric catalysis due to the C 2 -symmetric complexes that result when the ligands are coordinated to a metal such as copper. This C 2 symmetry results in equivalent structures upon rotation of the catalyst by 180∘ , meaning a reduction in the number of possible transition states and substrate approach trajectories during the reaction [90]. While catalyst symmetry is an important element in producing C–H insertion products with good enantiocontrol, so too is the electronic and steric nature of the ligands. Ligand-dependent enantioselectivity has been demonstrated in copper-bisoxazoline systems in studies reported by the Maguire group. Substrate 140 is just one example in a recent report of copper-catalyzed C–H insertion of α-diazocarbonyl compounds that were cyclized with five different commercially available bisoxazoline ligands. A wide variation in enantioselectivity was observed between the different ligands employed; the best asymmetric induction (87%) was achieved with the indane-derived bisoxazoline ligand (Scheme 1.27) [91]. O

O

O O S

Ph

L*, CuCl2, NaBARF

O O S

CH2Cl2

N2

OMe

OMe

Ph

140

141 O

O

L*

O

O N

% ee 141

N

N Ph

Ph

45

O

O

Ph

N Bn

Bn

77

O

O N

N Ph

Ph

52

Ph

O

O N

N

N

N

t-Bu

t-Bu

61

87

Scheme 1.27 Ligand-dependent enantioselectivity in copper-bisoxazoline-catalyzed C–H insertion.

In addition to catalyst effects on enantioselectivity, the substitution pattern of the α-diazocarbonyl substrate also has an important role to play. The Maguire group has also demonstrated how variation of both the substituent at the insertion site and the α-diazo substituent can have a dramatic effect on enantiocontrol of copper-catalyzed asymmetric C–H insertion. To investigate substitution at the insertion site, a series of α-diazocarbonyl compounds were prepared and cyclized in the presence of a catalytic

1.5 Intramolecular C(sp3 )—H Bond Insertion

system made up of a bisoxazoline ligand, CuCl2 , and an additive, sodium tetrakis(3,5-bis-(trifluoromethyl)phenyl)borate (NaBARF). It was found that, depending on the bisoxazoline ligand employed, variation of the electronic and steric properties at the insertion site could have a profound effect on enantioselectivity. In one example shown here (Scheme 1.28) using the diphenyl bisoxazoline ligand 13, there was no enantioinduction with a methyl group at the insertion site, but moderate enantioinduction could be achieved with a phenyl group. This enantioselectivity dropped off again with a benzyl group. These experiments showed how substituents at the insertion site are very influential on the enantioselectivity of the reaction with a phenyl group proving optimal in this instance [29]. O R

L* 13 CuCl, NaBARF

SO2Ph

O SO2Ph

CH2Cl2

N2

R

142

Entry 1 2 3

143

142 a b c

R Me Ph Bn

%Yield 143 75 82 46

%ee 143 0 58 0

Scheme 1.28 Varying the substitution pattern at the insertion site affects enantioselectivity.

Altering the substitution pattern α to the diazo moiety was also investigated. Initially various electron-withdrawing groups (sulfone, ester, ketone, phosphine oxide, and phosphonate) were examined for their impact on enantioselectivity (Scheme 1.29, Entries 1–5). The sulfone functionality is by far O Ph

R

O

L* CuCl2, NaBARF

R

CH2Cl2

N2

Ph

144a–g

145a–g

Entry

144

L*

R

%Yield 145

1

a

13

SO2Ph

53

%ee 145 89

2 3 4 5 6 7 8

b c d e f a g

13 13 13 13 9 9 9

CO2CH(i-Pr)2 COPh PO(Ph)2 PO(OMe)2 SO2Me SO2Ph SO21-Np

89 19 8 77 49 69 54

65 62 53 32 8 50 81

Scheme 1.29 Varying the electron-withdrawing group α to the diazo moiety affects enantioselectivity.

29

30

1 Stereoselective C–H Insertions of Carbenoids

the superior electron-withdrawing group at the α-diazo site. The decreasing electron-withdrawing character of the other groups leads to reduced selectivity and longer reaction times [91, 92]. The steric and electronic impact at the α-diazo motif was also investigated with a series of alkyl and aryl sulfonyl substituents. A selection of results here (Scheme 1.29, Entries 6–8) highlights how the enantioselectivity increases with increasing steric bulk adjacent to the diazo. It was noted in this study that electronic effects had very little impact on the asymmetric induction [91]. In addition, different levels of asymmetric induction are observed when using two different ligands with the same substrate (Scheme 1.29, Entries 1 and 7). In this instance, the diphenyl bisoxazoline ligand affords excellent enantioselectivity in the cyclopentanone product, once again highlighting that when good enantiocontrol is desired as a key component of a chemical transformation, choosing the optimal catalyst and substrate structure for enantioselective C–H insertion requires careful consideration. Nonetheless, intramolecular C–H insertion has proven itself useful as a key step in the synthesis of numerous pharmaceutically relevant molecules, a few of which are noted here (Figure 1.20) [93–96].

1.6 Intermolecular C(sp3 )—H Bond Insertion An intermolecular C–H insertion reaction consists of three components: a diazo compound, a substrate that may contain a range of functional groups, and a transition metal catalyst (Figure 1.21). This methodology has facilitated insertion into allylic, benzylic, and C(sp3 )—H bonds α to a heteroatom, as well as simple alkane substrates [97, 98]. The selectivity of intermolecular C–H insertion reactions is controlled by steric and electronic factors, with the ability to stabilize the buildup of positive charge during the transition state being key to its synthetic utility (Schemes 1.1 and 1.2). Intermolecular rhodium(II)-catalyzed reactions using acceptor/acceptor and acceptor-carbenoid complexes show limited selectivity due to the inability to stabilize the highly electrophilic carbenoid being generated. In order to achieve high levels of intermolecular selectivity at the desired C(sp3 )–H site on the substrate, a donor/acceptor metal carbenoid is most useful, as the donor group assists in the stabilization of the electron-deficient carbenoid [99]. Most research to date conducted in intermolecular C—C bond formation through C(sp3 )—H bond insertion by metal carbenoids is with the use of rhodium(II) catalysts. Accordingly, the reactivity and selectivity discussed in this section is primarily based on rhodium(II) catalysts unless otherwise stated. 1.6.1

Chemoselectivity

When carrying out an intramolecular C(sp3 )–H insertion, factors affecting chemoselectivity can be broken down into three sections: (i) diazo compounds, (ii) catalyst effects, and (iii) substrate functional groups.

O

O

O

O

O

NH2 HCl

HO2C

O OMe

Cl

OMe

OMe 63% Yield, 93% ee with Rh2(4R-MPPIM)4

Cl 81% Yield, 95% ee with Rh2(4S-MPPIM)4

A Enterolactone O

O2N

B (R)-(−)-Baclofen

O CO2Me

N

OMe

O 74% Yield, 88% ee with Rh2(S-BPTTL)4

CO2Me

HN

O

OMe

C (R)-(−)-Rolipram

CO2Me Br

Na2CO3 OH

OTIPS O 80% Yield, 84% ee with Rh2(S-PTTEA)4

O (−)-epi-Conocarpan

MeOH

OH O D (+)-Conocarpan

Figure 1.20 A selection of natural products that can be synthesized with high enantioselectivity using C–H insertion as a key step with the new C—C bond highlighted in light gray.

32

1 Stereoselective C–H Insertions of Carbenoids

New C C bond formation

EDG

Transition metal catalyst

H

N2 EWG

R

Donor/acceptor diazo compound

R

R

EDG EWG

R

H

R

R

C(sp3)–H insertion product

Substrate

Figure 1.21 Intermolecular C–H insertion reaction between a donor/acceptor diazo compound and a substrate using a transition metal catalyst to form a new carbon–carbon bond.

1.6.1.1

Diazo Compounds

The need for a donor/acceptor-substituted diazo compound in intermolecular rhodium(II) catalytic systems to preferentially undergo C(sp3 )—H bond insertion over cyclopropanation is demonstrated using cyclohexene (146) and 1,4-cyclohexadiene (150) (Schemes 1.30 and 1.31) [100]. Moderately activated C−H site by neighboring π-systems

C–H insertion ROOC

COOR N2 1

R

146

Cyclopropanation

R1

Catalyst

COOR R1

CH2Cl2, temp

147a–f

148a–f

Competing site for cyclopropanation

149a–f

Entry

147

R

R1

Catalyst

Ratio 148 : 149

%ee 148

1 2 3 4 5 6 7

a b c f f f f

Et DBMPa Me Me Me Me Me

H H COOMe Ph Ph Ph Ph

Rh2(OAc)4 Rh2(OAc)4 Rh2(OAc)4 Rh2(OAc)4 Rh2(2S-MEPY)4 Rh2(S-PTPA)4 Rh2(4S-DOSP)4

20 : 80 67 : 33 38 : 62 75 : 25 93 : 7 50 : 50 80 : 20

— — — — 45 53 75

a

DBMP = 2,6-di-t-butyl-4-methylphenyl.

Scheme 1.30 Competing C–H insertion and cyclopropanation of cyclohexene.

When cyclohexene is reacted with an acceptor substituted diazo compound, ethyl diazoacetate (147a), catalyzed by rhodium(II) acetate, cyclopropanation predominates over C–H insertion (80 : 20 ratio 149a : 148a (Scheme 1.30, Entry 1), and more noticeably when 1,4-cyclohexadiene is subjected to the same conditions, only the cyclopropanation product (152a) is isolated (Scheme 1.31,

1.6 Intermolecular C(sp3 )—H Bond Insertion Highly activated C−H site by two neighboring π-systems

C–H insertion R

ROOC COOR N2 1

R

150

Cyclopropanation

1

Catalyst

COOR R1

CH2Cl2, temp

147a–f

151a–f

Competing site for cyclopropanation

152a–f

O OCHiPr2

153

Entry 147

R

R1

Catalyst

Temperature

(°C)

Ratio % ee 151 : 152 151

1

a

Et

H

Rh2(OAc)4

25

98 : 2

—

f

6

f

Me

Ph

Rh2(2S-MEPY)4

25

>98 : 2

4

7

f

Me

Ph

Rh2(S-PTPA)4

25

>98 : 2

40

8

f

Me

Ph

Rh2(4S-DOSP)4

25

>98 : 2

65

9

f

Me

Ph

Ir(III)-salen (57)

0

>95 : 5

94

10

f

Me

Ph

Ir(III)-porphyrin (59)

−40

>99 : —c

95

11

f

Me

Ph

Ir(III)-bis(oxz) (58)

rt

>99 : —c

97

a

—

—

b

2,2-Dimethylbutane was the reaction solvent used. Isolated yield. product was not observed in reaction mixture. dNo C–H insertion product was observed but only the 1,2-hydride shift alkene (153). cCyclopropanation

Scheme 1.31 Competing C–H insertion and cyclopropanation of 1,4-cyclohexadiene.

Entry 1). Improvements in C–H insertion selectivity can be obtained by the use of a bulky ester, 2,6-di-t-butyl-4-methylphenyl (DBMP), ester (147b), where cyclopropanation is suppressed to an extent (Scheme 1.30, Entry 2). If an acceptor/acceptor-substituted diazo compound, such as dimethyl malonate 147c is used (Scheme 1.30, Entry 3 and Scheme 1.31, Entry 2), poor selectivity for C–H insertion is also achieved. Recently, it has been shown that the use of an α-alkyl-α-diazoester (147d) with 1,4-cyclohexadiene gives the corresponding C–H insertion product with modest yields and good enantioselectivity (Scheme 1.31, Entry 3) [101]. However, when the α-alkyl substituent is changed to ethyl (147e), no C–H insertion product is observed, and only the 1,2-hydride shift product (153) is isolated (Scheme 1.31, Entry 4). Achiral copper catalysts were also tested, but resulted only in high levels of cyclopropanation. Substrate design showed that the donor/acceptor substituted diazo compound 147f delivers selectively 151 regardless of the catalyst used (Scheme 1.31, Entries 5–11). A second example of a donor/acceptor-substituted diazo compound is vinyldiazoacetate (154), which undergoes selective C–H insertion into cyclohexane

33

34

1 Stereoselective C–H Insertions of Carbenoids

155

A

Ph

CO2Me

156 50% 83% ee

Rh2(S-DOSP)4

C–H activation/ cope rearrangment

C–H insertion TBSO

OTBS CO2Me

Ph

+

Me

B

N2

157 Rh2(S-DOSP)4, 2,2-DMB, 23 °C

Me

Me

Ph

Ph

CO2Me

154

CO2Me

TBSO

Ratio 1:1

158 >98% de 88% ee

159 >98% de 89% ee

Heat or microwave

Me

C–H activation/ cope rearrangment

Cyclopropanation

Me

Me

+

160

C

Rh2(S-DOSP)4

H H

Ph

H

Ph

CO2Me MeO2C

161 98% ee

Ratio 1:1

162 98% ee

Scheme 1.32 Donor/acceptor diazo compound, vinyldiazoacetate, undergoes a range of competing reaction pathways.

(155) using Rh2 (S-DOSP)4 , with moderate yield (50%) and high levels of enantioselectivity (83% ee) (A, Scheme 1.32) [36]. However, vinyldiazoacetates are relatively unstable, and their use has been limited due to spontaneous [1,5]-cyclization to yield pyrazoles [102]. In certain Rh2 (S-DOSP)4 catalyzed intermolecular C–H insertion reactions where acyclic or cyclic substrates containing allylic C(sp3 )—H bonds were investigated, vinyldiazoacetate (154) undergoes highly diastereoselective and enantioselective C–H insertion (158), cyclopropanation (161), and C–H activation/Cope rearrangement (159 and 162), with poor chemoselectivity for C–H insertion observed overall (B and C, Scheme 1.32) [36, 103, 104]. 1.6.1.2

Catalyst Effects

When cyclohexene and the methyl phenyldiazoacetate (147f) are reacted with a range of rhodium(II) catalysts, moderate to high selectivity toward allylic C(sp3 )–H insertion over cyclopropanation is observed at the moderately activated secondary site (Scheme 1.30, Entries 4–7). The highest level

1.6 Intermolecular C(sp3 )—H Bond Insertion

of chemoselectivity is observed with a rhodium(II) carboxamidate catalyst, Rh2 (2S-MEPY)4 , although with the lowest level of enantioselectivity (45% ee) (Scheme 1.30, Entry 5). These catalysts display varying steric and electronic properties, with a combination of both factors proposed to influence selectivity at the moderately activated cyclic C(sp3 )–H site. Similarly, chiral iridium complexes can be used to carry out the same intermolecular C–H insertion reaction with 1,4-cyclohexadiene (150) (Scheme 1.31, Entries 9–11) [51–53]. Insertion into the C(sp3 )—H bond predominates over cyclopropanation, regardless of the ligands. At low temperatures (Entries 9 and 10), high yields and enantioselectivity are observed. The iridium(III)-bis(oxazolinyl)phenyl catalyst (58) appears to be more advantageous, with good yields and the highest level of enantioselectivity even at room temperature (Scheme 1.31, Entry 11). The chemoselectivity for C–H insertion over cyclopropanation of an allylic substrate can be controlled by the catalyst [38, 105]. Rh2 (esp)4 is found to favor cyclopropanation in the reaction between trans-anethole (163) and aryldiazoacetate (164), with Rh2 (R-DOSP)4 achieving moderate levels of C–H insertion (Scheme 1.33, Entries 1 and 2). Interestingly, when using a more sterically congested catalyst system such as Rh2 (TPA)4 or Rh2 (R-BPCP)4 , C–H insertion is predominantly observed (Scheme 1.33, Entries 3 and 4). C–H insertion

Cyclopropanation

C6H4(p-Br) CO2Me

N2 MeO2C

CO2Me C6H4(p-Br)

C6H4(p-Br)

164 Catalyst, DCM, reflux O

163

+

O

O

165

Entry

Catalyst

1

Rh2(esp)2

2

Rh2(R-DOSP)4

166 Ratio 165 : 166

% ee 165

1 : >15

—

5:1

76

3

Rh2(TPA)4

>15 : 1

—

4

Rh2(R-BPCP)4

16 : 1

88

Scheme 1.33 Intermolecular chemoselectivity varies in certain cases with more sterically congested rhodium(II) catalysts.

1.6.1.3

Substrate Functional Groups

The chemoselectivity in allylic systems is influenced by steric effects. Monosubstituted and 1,1-disubstituted alkene substrates lead preferentially to cyclopropanation, while enhanced steric demand in trisubstituted alkenes favors C–H

35

36

1 Stereoselective C–H Insertions of Carbenoids

insertion [105, 106]. Electronic effects of the aryl ring on substituted trans styrene substrates can also have an effect on the product distribution between insertion and cyclopropanation. Electron-poor alkenes are highly selective toward C–H insertion, while electron-rich alkenes predominantly undergo cyclopropanation. Another factor that may have to be taken into consideration on the substrate undergoing C–H insertion is the presence of a heteroatom. The Lewis base nature of compounds such as ethers, sulfides, amines, and carbonyl compounds means they are prone to ylide formation and subsequent rearrangement, which is very common with alkyl and aryldiazoacetates. It has been shown that tetrahydrofuran (167) can undergo selective C(sp3 )–H insertion α to oxygen (168a and 168b) in moderate yields using rhodium and copper (Scheme 1.34, Entries 1–3) [107, 108]. The preference for C(sp3 )–H insertion in this reaction is also observed with the use of iridium-based chiral catalysts at low temperatures (Scheme 1.34, Entries 4–7) [51, 53]. Donor/acceptor diazo compound

O

CO2Me O

CO2Me +

O

Ar

Ar

Catalyst, temp 167

168a

Entry Diazo

Catalyst

Temperature (°C)

168b

Yield Ratio %ee %ee (%) 168a : 168b 168a 168b

1

147f

Rh2(S-DOSP)4

−50

67

2.8 : 1

97

—

2

147f

Cu(OTf)2 · L* 9

Reflux

48a

1.7 : 1

59

40

3

147f

88

46

−50

59a 75

3.5 : 1

147f

Cu(OTf)2 · immobilised L* 9 Ir(III)-salen (56)

Reflux

4

13 : 1

95

—

5

147f

Ir(III)-porphyrin (59)

−40

82

1 : 10

—

90

6

164

Ir(III)-salen (56)

−50

76

>20 : 1

93

—

7

164

Ir(III)-porphyrin (59)

−40

96

1 : >20

—

97

aConversion

to C–H insertion product observed.

Scheme 1.34 Intermolecular C–H insertion of THF.

Further examples of substrates containing heteroatoms include allyl ethers and silyl allyl ethers, where both the cyclopropanation and C–H insertion product are formed, in contrast with allyl acetate in which only the cyclopropanation product is formed [109]. Examples of C–H insertion α to a protected nitrogen are also known (Figure 1.23 and Scheme 1.39). 1.6.2

Regioselectivity

1.6.2.1

Substrate Effects

There are three types of sites for C(sp3 )–H insertion: primary, secondary, and tertiary (Figure 1.22a). The favorability of a site toward intermolecular functionalization is dependent on the ability to stabilize the buildup of positive charge during the transition state, which is more easily achievable at a tertiary site, rather

1.6 Intermolecular C(sp3 )—H Bond Insertion

iv.

i. 0.66

28000 R H

H R1

R

1°

R H

2°

R1 R2

ii. 2700

O

v. >

>>

0.078

3° iii. 1700

(a)

Boc N

vi.

1.0 0.011

(b)

Figure 1.22 (a) Primary, secondary, and tertiary C(sp3 )–H site. (b) Relative rates of C–H insertion using aryldiazoacetate.

than a secondary site, and less so for a primary site. However, from the perspective of accessibility, reactions at the least sterically hindered primary site are often favored over a secondary or tertiary site. Insertion at secondary C(sp3 )–H sites is commonly seen as a compromise between electronic stabilization and steric effects [110]. Davies and coworkers investigated the factors affecting intermolecular C–H insertion regioselectivity using rhodium(II) catalysts [20]. This work highlighted how electronic and steric effects play an important role in intermolecular C–H insertion compared with intramolecular C–H insertion, where five- or six-membered ring formation dominates regioselectivity. The reactivity of C(sp3 )—H bonds were compared with the C—H bonds in cyclohexane, which was given a relative reactivity of 1 (Figure 1.22b). 1,4-Cyclohexadiene (Figure 1.22b, i) is found to be 28 000 times more reactive toward C–H insertion, with C–H sites α to a heteroatom such as oxygen and nitrogen, 2700 and 1700 times more reactive, respectively (Figure 1.22b, ii and iii). Electronic effects have a major impact on C–H insertion in the first three cases (Figure 1.22b, i–iii); however in the second three cases (Figure 1.22b, iv–vi), steric effects can be seen to play a role. While insertion at a tertiary bond would be more electronically favored over a secondary bond, in practice, 2-methylbutane (v) and 2,3-dimethylbutane (vi) are found to undergo C–H insertion 10 and 100 times more slowly, respectively, than cyclohexane. Similarly, C(sp3 )–H insertion at relatively activated benzylic and acyclic allylic positions is also favored. Insertion at a primary C(sp3 )—H bond is challenging except in cases where it is activated, for example, being α to a nitrogen or oxygen. It is interesting to note here that C—H bonds β to oxygen have been shown not to undergo C–H insertion, possibly due to inductively destabilizing the buildup of positive charge during the transition state (Scheme 1.35) [107].

O

O 169

Rh2(S-DOSP)4 (1 mol%)

N2

X

CO2Me

(p-Br)C6H4 164

hexane, rt, 2 h

Scheme 1.35 C–H insertion favored at sites α to oxygen but not β.

C6H4(p-Br) O

O 170

CO2Me

37

38

1 Stereoselective C–H Insertions of Carbenoids 68% AcO

TBSO Sterically deactivated benzylic 2° site α to heteroatom

(a)

94% AcO

X

N Boc 171

54% (b)

(c)

TBSO 5%

(f)

41%

23% OMe

OMe AcO

TMSO

(g)

35%

AcO

TMSO

(e)

OAc 92%

(d)

39%

(h)

75%

Figure 1.23 Steric factors affecting C–H insertion and varying effect of different alcohol protecting groups on intermolecular C–H insertion with aryldiazoacetate.

The reactivity patterns that would be anticipated by electronic effects are frequently moderated by steric effects. For instance, a secondary benzylic site α to a heteroatom (171) is a very favorable site for insertion; however, the presence of a Boc protecting group sterically blocks the electronically favored secondary position, and C–H insertion occurs at the primary position (Figure 1.23) [111]. An overview of how protecting groups affect C–H insertion electronically is illustrated by the reactions of protected alcohols [109]. The electron-rich TBS group is able to stabilize the buildup of positive charge, and as a result, high yielding C–H insertion at a secondary site α to the oxygen is observed (Figure 1.23a). With an electron-withdrawing acetate protecting group, the α position is deactivated, and minimal C–H insertion is observed at this site, with C–H insertion occurring predominantly at the alternative allylic position (Figure 1.23b). C–H insertion across a range of protected alcohols can be seen to occur at the most electron-rich site (Figure 1.23). 1.6.2.2

Catalyst Effects

It has been shown that site selectivity for the primary C—H bond with benzylic, methoxy, and allylic C—H bonds can be enhanced by the use of a catalyst with sterically demanding ligands, Rh2 (R-BPCP)4 , in place of the widely employed catalyst, Rh2 (R-DOSP)4 (Scheme 1.36) [38]. 4-Isopentyltoluene (172) contains a primary and a secondary benzylic site that undergo C–H insertion at a comparable extent with aryldiazoacetate 164 using Rh2 (R-DOSP)4 or Rh2 (S-PTAD)4 (Scheme 1.36, Entries 1 and 2). When the sterically demanding catalyst Rh2 (R-BPCP)4 is used on the same substrate, regioselectivity predominantly shifts to the primary site (>20 : 1) (Scheme 1.36, Entry 3). The same high levels of regioselectivity and enantioselectivity are observed with a range of aromatic substrates. It is interesting to note here that no reaction is observed at the tertiary C–H site of 4-isopentyltoluene (172). The selectivity of Rh2 (R-BPCP)4 toward primary C–H insertion also applies to allylic substrates [38]. Rh2 (R-DOSP)4 favored functionalization at the tertiary position, which electronically stabilizes the buildup of positive charge, while

1.6 Intermolecular C(sp3 )—H Bond Insertion

(p-Br)C6H4 CO2Me

1° 2°

N2 1° C–H insertion MeO2C

164

C6H4(p-Br)

Catalyst, DMB, reflux

172

173 CO2Me

(p-Br)C6H4

2° C–H insertion 174 Entry 1 2 3 a

Catalyst Rh2(R-DOSP)4 Rh2(S-PTAD)4 Rh2(R-BPCP)4

Ratio 173 : 174 1 : 1.7 1.1 : 1 >20 : 1

%Yielda 173 70 73 90

%ee 173 77 70 94

The yields of Entries 1 and 2 are the combined yields of 173 and 174.

Scheme 1.36 Impact of rhodium(II) carboxylate ligands on regioselectivity of C–H insertion.

Rh2 (R-BPCP)4 showed a strong bias for insertion at the easily accessible primary position. Even though it has been demonstrated that regioselective C–H insertion at secondary and tertiary sites can be achieved using Rh2 (R-DOSP)4 and primary sites can be functionalized using Rh2 (R-BPCP)4 , the rationale to explain these results is not yet fully understood. The bulky nature of the ligands on rhodium(II) catalysts facilitating the intermolecular insertion at primary C–H sites is not the only contributing factor as a new sterically demanding triarylcyclopropanecarboxylate catalyst, Rh2 [R-3,5-di(p-t BuC6 H4 )TPCP]4 , can exclusively access a secondary position in simple alkane substrates with high diastereoselectivity and enantioselectivity, instead of the least sterically hindered primary position available for insertion [98]. 1.6.2.3

Diazo Compound Effects

Changing from the methyl aryldiazoacetate to the 2,2,2-trichloroethyl (TCE) aryldiazoacetate ester affords higher regio- and enantioselectivity in certain cases [112]. A higher level of regioselectivity is observed at the primary position over the secondary benzylic position in 4-ethyltoluene (175) when the trichloroethyl ester is used as the coupling partner instead of the methyl ester with Rh2 (R-BPCP)4 (Scheme 1.37). 1.6.3 1.6.3.1

Diastereoselectivity Substrate Effects

Controlling diastereoselectivity is one of the most challenging aspects in intermolecular C(sp3 )–H insertion as it is strongly substrate and catalyst dependent. The mechanism of C(sp3 )–H insertion has been examined in recent

39

40

1 Stereoselective C–H Insertions of Carbenoids

2°

1°

RO2C

175

RO2C

N2 164

C6H4(p-Br)

Ar

1° C–H insertion H

176 Ar CO2R

Rh2(R-BPCP)4, DCM, reflux

H 2° C–H insertion 177

Entry 1 2

R Me CH2CCl3

176 : 177 5:1 13 : 1

%Yield 176 74 75

%ee 176 92 99

Scheme 1.37 2,2,2-Trichloroethyl aryldiazoacetate achieves higher regio- and enantioselectivity over methyl aryldiazoacetate.

computational studies; it is assumed that relatively activated C(sp3 )—H bonds approach perpendicular to the metal carbenoid. It is believed that during this approach, the substrate substituents are orientated in the least sterically hindered manner. The directional approach taken by the substrate substituents to the metal carbenoid is determined by the steric environment of the catalyst. The hypothesised D2 symmetrical Rh2 (S-DOSP)4 consists of a dirhodium paddlewheel (represented by a disc) and its respective ligands in an α-β-α-β arrangement (represented by a wedge) (Figure 1.24) [110]. The ester group on the metal carbenoid is sterically demanding as it is perpendicular to the plane of the metal carbenoid, and as a result the smallest substituent (S) is positioned between the ester and the rhodium catalyst ligand, the less sterically crowded position. The largest substituent (L) positions itself the furthest away from the rhodium(II) catalyst paddlewheel and the catalyst ligands, pointing upward, with the second most sterically demanding substituent (M) pointing away from the catalyst ligands but toward the dirhodium paddlewheel as a result. This model can therefore be used in an attempt to predict the stereochemical outcome of intermolecular C–H insertion reactions. A large body of experimental research in intermolecular C–H insertion supports the above rationale of diastereocontrol (Figure 1.24) [110]. For example, when the medium and small substituents are methylene and hydrogen, respectively, the differentiation is small, and as a result, poor diastereoselectivity is observed (Figure 1.24a). However, high diastereocontrol is observed in cases where the difference in size is large (Figure 1.24b). A similar result can be observed when tetrahydrofuran is compared with N-Boc pyrrolidine. On the tetrahydrofuran group, there is little difference between the –CH2 – and the –O– substituents, yielding moderate diastereocontrol (Figure 1.24c); however, with the N-Boc pyrrolidine ring, there is a significant size differentiation between the N-Boc protecting group and the –CH2 –, affording high levels of stereocontrol (Figure 1.24d). Modest diastereocontrol is observed when using indane (Figure 1.24e); however, when the ring was changed to tetrahydronaphthalene,

1.6 Intermolecular C(sp3 )—H Bond Insertion

H

N2 MeO2C

O

R1

Relative size: L = large M = medium S = small

L

S M

R1= Ph, C6H4(p-Br)

L

O

H S M

Rh2(DOSP)4

Rh2(S-DOSP)4

H H

H

C6H4(p-Br)

Me

H

C6H4(p-Br)

TBSO

CO2Me

(a)

O

H CO2Me

H CO2Me

(b)

56% 56 : 44 dr 92% ee

(c)

94% 97: 3 dr 62% ee

H C6H4(p-Br) H CO2Me

(e) 62% 80 : 20 dr 85% ee

Ph

(f) 43% 57:43 dr 89% ee

CO2Me

72% 96 : 4 dr 94% ee H

C6H4(p-Br)

H CO2Me

Ph H

(d)

67% 74 : 26 dr 97% ee H

H N Boc

MeO

C6H4(p-Br)

H CO2Me

(g) 72% 79 : 21 dr 94% ee

Figure 1.24 Predicting diastereocontrol by differentiating between the relative size of substituents. Source: Davies and Morton [110]. Reproduced with permission of John Wiley & Sons.

poor diastereocontrol resulted (Figure 1.24f ). The change between a five- and six-membered ring in these specific cases leads to decreased diastereocontrol, but the presence of an electron-donating group improves diastereocontrol (Figure 1.24g). Another good example of substituent-dependent diastereocontrol, and how it can be controlled in a predictable manner, is seen in Scheme 1.38 [113]. When R = H, cyclopropanation dominates over C–H insertion; however, 15% yield of the C–H insertion product was isolated with poor diastereocontrol (52 : 48 dr) and 93% ee (Scheme 1.38, Entry 1). The poor stereocontrol observed is attributable to the marginal differentiation between the medium and large substituent observed during the substrate approach to the metal carbenoid. When 1-(trimethylsilyl)cyclohexene is used, an increase in diastereoselectivity is observed due to the more sterically demanding TMS group, with the catalyst able to favor one substrate approach over the other (Scheme 1.38, Entry 2). In order to achieve high levels of diastereoselectivity, the extremely bulky tert-butyldiphenylsilyl (R = TBDPS) substituent is required, affording the expected product with 94 : 6 dr, a yield of 64%, and 95% ee (Scheme 1.38, Entry 3).

41

42

1 Stereoselective C–H Insertions of Carbenoids

N2 MeO2C

C6H4(p-Br)

MeO2C

H

C6H4(p-Br)

H

MeO2C

C6H4(p-Br)

H

164

H

R Rh2(S-DOSP)4 2,2-DMB 23 °C

178

Entry 1 2 3

R H TMS TBDPS

R

R

179a %Yield 179a 15 48 64

179b dr 179a : 179b 52 : 48 70 : 30 94 : 6

%ee 179a 93 88 95

Scheme 1.38 High levels of diastereocontrol with increased steric hindrance.

1.6.3.2

Catalyst Effects

The catalyst can be seen to have a major impact on diastereocontrol, for example, as with N-Boc piperidine [31]. In an attempt to increase the diastereoselectivity of C–H insertion into the N-Boc protected piperidine ring, the reaction was examined with a number of catalysts. A chiral carboxamidate catalyst, Rh2 (5R-MEPY), exhibited the highest degree of diastereoselectivity (97 : 3 dr) with a modest enantioselectivity of 69% ee (Scheme 1.39, Entry 5). The Rh2 (S-DOSP)4 catalyst that produces a high level of diastereoselectivity for the pyrrolidine ring (96 : 4 dr) (Figure 1.24d) gave poor selectivity when reacted with piperidine (50 : 50 dr) (Scheme 1.39, Entry 1). Another rhodium(II) carboxylate catalyst examined, Rh2 (S-biDOSP)4 , induced higher diastereoselectivity (71 : 29 dr), but the major diastereomer 181a shows a moderate enantiopurity of 86% ee (Scheme 1.39). A copper Schiff base catalyst (Scheme 1.39, Entry 6) performed

Boc N

N2 Ph

MeO2C 180

Catalyst

CO2Me

CO2Me

NBoc

NBoc

147f 181a Entry 1 2 3 4 5 6

Catalyst Rh2(S-DOSP)4 Rh2(S-biDOSP)4 Rh2(4S-MPPIM)4 Rh2(4S-IBAZ)4 Rh2(5R-MEPY)4 (CuOTf)2 · L* 16

dr 181a : 181b 50 : 50 71 : 29 55 : 45 93 : 7 97 : 3 70 : 30

181b %ee 181a 25 86 16 26 69 18

Scheme 1.39 Catalyst effect on six-membered N-Boc protected piperidine.

1.6 Intermolecular C(sp3 )—H Bond Insertion

43

poorly on the same system, generating only moderate diastereocontrol (70 : 30) and poor enantioselectivity (18% ee). 1.6.4

Enantioselectivity

Intermolecular C(sp3 )–H insertion of metal carbenoids derived from aryldiazoacetates has been shown to be a highly enantioselective process, specifically with the use of chiral rhodium(II) catalysts and, in recent times, iridium(III) complexes. Even though there are challenges in controlling chemo-, regio-, and diastereoselectivity, moderate to high levels of enantiopurity can generally be achieved. Many examples of enantiocontrol at primary, secondary, and tertiary C(sp3 )—H bonds have been observed while achieving moderate to high yields (Figure 1.25a–f ) [36, 38, 42, 112–115]. The substrates for which high levels of enantiopurity can be achieved range from the simple cyclohexane to more challenging C–H positions, e.g. allylic or α to a heteroatom. Since the recent development of the TCE aryldiazoacetates, further improvements in yields and enantioselectivity of reactions at methyl ether groups have also been achieved with C–H insertion occurring at the primary position α to the oxygen (Figure 1.25g,h) [38]. While enantioselectivity with chiral rhodium(II) catalysts can sometimes be improved at lower temperature and in hydrocarbon solvents, it is interesting to take note of the chemo- and regioselective outcome by various catalysts on the reaction. In Scheme 1.36, the highest level of enantiopurity was obtained for the formation of 173 when catalyst favoring insertion at the primary C—H bond is used. Similarly, the greatest ee (88%) in the formation of 165 is seen while using Rh2 (R-BPCP)4 (Scheme 1.33), which is the most selective for C–H insertion over

Ph

Ph H

H N

CO2Me

CO2Me H

H

Ph

CO2Me

CO2Me

C6H4(p-Br)

80% (a) 95% ee

72% (b) 94% ee

58% (c) 91% ee

75% (d) 97% ee

Ph Ph

CO2Me C6H4(p-Br)

33% (e) 85:15 dr 96% ee

C6H4(p-Cl) H CO2Me

64% (f) 95% ee

Cl3CCH2O2C (p-Br)H4C6

83% (g) 91% ee

H

Cl3CCH2O2C O (t-Bu)H4C6

61% (h) 99%ee

Figure 1.25 Examples of high enantiopure yielding C–H insertion products using rhodium catalysts. New C—C bond highlighted in light gray.

H

O

OH MeO

CO2Me

MeO

H HO

TBSO Rh2(S-DOSP)4

N2

OMe

OMe

CO2Me

OH

OTBS S-184 43% 91% ee

MeO

(+)-Imperanene 186 O

TBSO OMe

MeO

CO2Me

OTBS 182

MeO O

H

183

HO

TBSO

Rh2(R-DOSP)4 OMe

OMe

Scheme 1.40 Synthesis of enantiopure (−)-α-conidendrin and (+)-imperanene.

OTBS

OH

R-184 44% 92% ee

(–)-α-Conidendrin 185

References

cyclopropanation. A highly chemo- and regioselective catalyst is important at times for optimal enantiopurity levels. There are few examples of vinyldiazoacetates producing high levels of enantioselectivity during intermolecular C(sp3 )–H insertion. However one of the key applications concerns the synthesis of chiral ligands for dirhodium(II) carboxylate catalysts. An adamantane tertiary site undergoes C–H insertion with methyl vinyldiazoacetate furnishing the rhodium(II) catalyst precursor with 91% ee (Figure 1.25c). This enabled the synthesis of Rh2 (S-PTAD)4 (35) [116]. The versatility of vinyldiazoacetates in enantioselective synthesis is also palpable in accessing (−)-α-conidendrin (185) and (+)-imperanene (186; Scheme 1.40) [117]. Rh2 (R-DOSP)4 was used to access one enantiomer (91% ee) via C–H insertion on an electron-rich benzylic primary C–H site, while Rh2 (S-DOSP)4 was used to synthesize the opposite enantiomer (92% ee). This highlights the importance of the availability of both enantiomers of the catalyst in accessing natural products (Scheme 1.40). Other examples of natural product synthesis that have taken advantage of the high enantioselectivity of intermolecular C–H insertion using both enantiomers of Rh2 (DOSP)4 catalysts include the antidepressant agent venlafaxine [118] and the antisickling agent (+)-cetiedil [119].

1.7 Conclusion Overall, carbenoid-mediated C–H insertion is a very powerful transformation enabling functionalization of an unactivated C—H bond under mild, neutral conditions. Catalyst developments over the past three decades have enabled regio-, diastereo-, and enantioselectivity in both intra- and intermolecular processes. While the most successful catalysts to date are derived from rhodium and copper, iridium catalysts also show promise. C–H insertion remains an active area of research and further developments are anticipated.

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14: 817. Natori, Y., Ito, M., Anada, M. et al. (2015). Tetrahedron Lett. 56: 4324. Fu, L., Wang, H., and Davies, H.M.L. (2014). Org. Lett. 16: 3036. Dennis, A.M., Korp, J.D., Bernal, I. et al. (1983). Inorg. Chem. 22: 1522. Timmons, D.J. and Doyle, M.P. (2005). Chiral dirhodium(II) catalysts and their applications. In: Multiple Bonds Between Metal Atoms (ed. F.A. Cotton, C.A. Murillo and R.A. Walton), 591–632. Cotton, F.A., Barcelo, F., Lahuerta, P. et al. (1988). Inorg. Chem. 27: 1010. Estevan, F., Herbst, K., Lahuerta, P. et al. (2001). Organometallics 20: 950. Suematsu, H. and Katsuki, T. (2009). J. Am. Chem. Soc. 131: 14218. Owens, C.P., Varela-Alvarez, A., Boyarskikh, V. et al. (2013). Chem. Sci. 4: 2590. Wang, J.-C., Xu, Z.-J., Guo, Z. et al. (2012). Chem. Commun. 48: 4299. Wang, J.-C., Zhang, Y., Xu, Z.-J. et al. (2013). ACS Catal. 3: 1144. Chan, K.-H., Guan, X., Lo, V.K.-Y., and Che, C.-M. (2014). Angew. Chem. Int. Ed. 53: 2982. Choi, M.K.-W., Yu, W.-Y., and Che, C.-M. (2005). Org. Lett. 7: 1081. Taber, D.F. and Raman, K. (1983). J. Am. Chem. Soc. 105: 5935. Padwa, A., Austin, D.J., Hornbuckle, S.F. et al. (1992). J. Am. Chem. Soc. 114: 1874. Padwa, A., Austin, D.J., Price, A.T. et al. (1993). J. Am. Chem. Soc. 115: 8669. Padwa, A. and Austin, D.J. (1994). Angew. Chem. Int. Ed. 33: 1797. Cox, G.G., Moody, C.J., Austin, D.J., and Padwa, A. (1993). Tetrahedron 49: 5109. Wee, A.G.H., Liu, B., and Zhang, L. (1992). J. Org. Chem. 57: 4404. Taber, D.F. and Ruckle, R.E. (1986). J. Am. Chem. Soc. 108: 7686. Shi, W., Zhang, B., Zhang, J. et al. (2005). Org. Lett. 7: 3103. Doyle, M.P. and May, E.J. (2001). Synlett 0967. Wamser, M. and Bach, T. (2014). Synlett 25: 1081. Corey, E.J. and Felix, A.M. (1965). J. Am. Chem. Soc. 87: 2518. Doyle, M.P., Protopopova, M.N., Winchester, W.R., and Daniel, K.L. (1992). Tetrahedron Lett. 33: 7819. Doyle, M.P. and Kalinin, A.V. (1995). Synlett 1075. Ring, A., Ford, A., and Maguire, A.R. (2016). Tetrahedron Lett. 57: 5399. Doyle, M.P., Bagheri, V., Pearson, M.M., and Edwards, J.D. (1989). Tetrahedron Lett. 30: 7001. McKervey, M.A. and Ye, T. (1992). J. Chem. Soc., Chem. Commun. 823. Ito, M., Kondo, Y., Nambu, H. et al. (2015). Tetrahedron Lett. 56: 1397. John, J.P. and Novikov, A.V. (2007). Org. Lett. 9: 61.

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75 Jungong, C.S., John, J.P., and Novikov, A.V. (2009). Tetrahedron Lett. 50:

1954. 76 Taber, D.F., Paquette, C.M., Gu, P., and Tian, W. (2013). J. Org. Chem. 78: 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97

98 99 100 101 102 103 104 105

9772. Wolckenhauer, S.A., Devlin, A.S., and Du Bois, J. (2007). Org. Lett. 9: 4363. Hinman, A. and Du Bois, J. (2003). J. Am. Chem. Soc. 125: 11510. Jungong, C.S. and Novikov, A.V. (2013). Tetrahedron: Asymmetry 24: 151. Rosales, A., Rodríguez-García, I., López-Sánchez, C. et al. (2011). Tetrahedron 67: 3071. Taber, D.F. and Ruckle, R.E. (1985). Tetrahedron Lett. 26: 3059. Doyle, M.P., Dyatkin, A.B., Roos, G.H.P. et al. (1994). J. Am. Chem. Soc. 116: 4507. Doyle, M.P., Zhou, Q.-L., Dyatkin, A.B., and Ruppar, D.A. (1995). Tetrahedron Lett. 36: 7579. Müller, P. and Polleux, P. (1994). Helv. Chim. Acta 77: 645. Doyle, M.P., Dyatkin, A.B., Protopopova, M.N. et al. (1995). Recl. Trav. Chim. Pays-Bas 114: 163. Doyle, M.P., Kalinin, A.V., and Ene, D.G. (1996). J. Am. Chem. Soc. 118: 8837. DeAngelis, A., Dmitrenko, O., Yap, G.P.A., and Fox, J.M. (2009). J. Am. Chem. Soc. 131: 7230. Lindsay, V.N.G., Lin, W., and Charette, A.B. (2009). J. Am. Chem. Soc. 131: 16383. Doyle, M.P., Morgan, J.P., Fettinger, J.C. et al. (2005). J. Org. Chem. 70: 5291. Rasappan, R., Laventine, D., and Reiser, O. (2008). Coord. Chem. Rev. 252: 702. Shiely, A.E., Slattery, C.N., Ford, A. et al. (2017). Org. Biomol. Chem. 15: 2609. Slattery, C.N. and Maguire, A.R. (2013). Tetrahedron Lett. 54: 2799. Bode, J.W., Doyle, M.P., Protopopova, M.N., and Zhou, Q.-L. (1996). J. Org. Chem. 61: 9146. Doyle, M.P. and Hu, W. (2002). Chirality 14: 169. Anada, M., Mita, O., Watanabe, H. et al. (1999). Synlett 1775. Natori, Y., Tsutsui, H., Sato, N. et al. (2009). J. Org. Chem. 74: 4418. Wu, W.-T., Yang, Z.-P., and You, S.-L. (2015). Asymmetric C–H Bond Insertion Reactions. In: Asymmetric Functionalization of C—H Bonds (ed. S.-L. You), 1. The Royal Society of Chemistry. Liao, K., Negretti, S., Musaev, D.G. et al. (2016). Nature 533: 230. Davies, H.M.L. and Denton, J.R. (2009). Chem. Soc. Rev. 38: 3061. Müller, P. and Tohill, S. (2000). Tetrahedron 56: 1725. Goto, T., Onozuka, T., Kosaka, Y. et al. (2012). Heterocycles 86: 1647. Davies, H.M.L., Huby, N.J.S., Cantrell, W.R., and Olive, J.L. (1993). J. Am. Chem. Soc. 115: 9468. Davies, H.M.L., Beckwith, R.E.J. (2004). J. Org. Chem. 69: 9241. (https://pubs.acs.org/doi/10.1021/jo048429m) Davies, H.M.L. and Walji, A.M. (2005). Angew. Chem. Int. Ed. 44: 1733. Davies, H.M.L., Coleman, M.G., and Ventura, D.L. (2007). Org. Lett. 9: 4971.

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65: 3052. 107 Davies, H.M.L. and Yang, J. (2003). Adv. Synth. Catal. 345: 1133. 108 Fraile, J.M., García, J.I., Mayoral, J.A., and Roldán, M. (2007). Org. Lett. 9:

731. 109 Davies, H.M.L., Beckwith, R.E.J., Antoulinakis, E.G., and Jin, Q. (2003). J.

Org. Chem. 68: 6126. 110 Davies, H.M.L. and Morton, D. (2011). Chem. Soc. Rev. 40: 1857. 111 Davies, H.M.L. and Venkataramani, C. (2002). Angew. Chem. Int. Ed. 41:

2197. 112 Guptill, D.M. and Davies, H.M.L. (2014). J. Am. Chem. Soc. 136: 17718. 113 Davies, H.M.L., Ren, P., and Jin, Q. (2001). Org. Lett. 3: 3587. 114 Davies, H.M.L., Hansen, T., Hopper, D.W., and Panaro, S.A. (1999). J. Am.

Chem. Soc. 121: 6509. 115 Davies, H.M.L., Stafford, D.G., Hansen, T. et al. (2000). Tetrahedron Lett. 41: 116 117 118 119

2035. Reddy, R.P. and Davies, H.M.L. (2006). Org. Lett. 8: 5013. Davies, H.M.L. and Jin, Q. (2003). Tetrahedron: Asymmetry 14: 941. Davies, H.M.L. and Ni, A. (2006). Chem. Commun. 3110. Davies, H.M.L., Walji, A.M., and Townsend, R.J. (2002). Tetrahedron Lett. 43: 4981.

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2 Stereoselective C—N Bond-Forming Reactions Through C(sp3 )—H Bond Insertion of Metal Nitrenoids Philippe Dauban, Romain Rey-Rodriguez, and Ali Nasrallah Université Paris-Sud, Université Paris-Saclay, Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France

2.1 Introduction The grafting of a nitrogen group onto a molecular backbone is a chemical operation that finds application in several scientific domains. The presence of a nitrogenous function indeed confers to the product the ability to interact with other surrounding molecules or macromolecules through a network of hydrogen bonds and/or electrostatic interactions. It also modulates its physicochemical properties by changing its polarity and solubility. There are myriad examples of amine derivatives that highlight the key value of nitrogen in science. Figure 2.1 displays some of them and showcases that chiral amines can be found in natural products (the neurotoxic natural amino acid (−)-dysiherbaine of marine origin), pharmaceuticals (the antidiabetic drug sitagliptin), agrochemicals (the herbicide indaziflam), ligands (the privileged chiral BOX ligands), or organometallic species (Ugi’s amine). The ubiquity of nitrogen, thus, has been a source of inspiration for the organic chemists to design efficient synthetic methods for the formation of C—N bonds [1–3]. Catalytic C–H amination reaction has recently emerged as a new synthetic tool for the synthesis of amines [4–12]. By comparison with other modern amination methods such as reductive amination or cross-coupling reactions, the direct conversion of a C—H to a C—N bond is a step- and atom-economical process. Given the high number of C—H bonds in organic products, it can lead to the formation of several regioisomeric amines providing that suitable conditions should be found for the chemo- and stereoselective functionalization of specific sites. The scope of catalytic C–H amination reaction, in addition, is complementary to that provided by other C—N bond-forming processes. It, thus, provides an access to a new molecular space of utmost interest in the context of late-stage C–H functionalization [13–15]. Significant achievements in catalytic C–H amination have been reported through the application of nitrene transfers as highlighted in numerous reviews and book chapters [16–31]. Nitrenes are neutral monovalent nitrogen species that behave as two-electron oxidants with a high capacity to undergo insertion C–H Activation for Asymmetric Synthesis, First Edition. Edited by Françoise Colobert and Joanna Wencel-Delord. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.

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2 Stereoselective C—N Bond-Forming Reactions

NH HO

F CO2H

H O

F

NH2 O

NH2 CO2H

O

H (–)-Dysiherbaine F N HN

N

H3 C

CH3

N

N F

N Sitagliptin

N CF3

CH3 N

O

O N

NH2

R

N R

Fe

NMe2

BOX ligand

Indaziflam

Ugi’s amine

Figure 2.1 Chiral amines in chemical and life sciences.

reactions into C—H or C=C bonds, allowing the introduction of nitrogen groups according to click-type reactions. To this end, the ability of transition metal complexes to promote these nitrene additions was crucial to optimize their efficiency and selectivity. Various catalytic inter- and intramolecular C–H amination reactions, thus, have been described since the first example of metal-catalyzed nitrene transfers reported 50 years ago. These almost lead to the functionalization of C(sp3 )—H bonds, thereby paving the way to the design of catalytic stereoselective processes. The last twenty years witnessed significant progress in asymmetric nitrene C(sp3 )–H insertions that mainly rely on the use of iminoiodinanes, azides, and N-sulfonyloxycarbamates as nitrene precursors [32–35]. This chapter will give an overview of the main results obtained in this area according to the nature of the nitrene source, with an emphasis on the reactions for which an asymmetric version has been further successfully developed.

2.2 Historical Background 2.2.1

Seminal Studies in Catalytic C(sp3 )–H Amination

The ability of transition metals to mediate the insertion of nitrenes into C(sp3 )—H bonds was first demonstrated 50 years ago. A couple of articles revealed the capacity of copper and zinc to react with azides or haloamines and, then, promote the amination of simple alkanes, though with very limited synthetic application [36–38]. Much more relevant were the seminal results published by the groups of Breslow [39, 40] and Mansuy [41, 42] in the 1980s. They both showcased the capacity of iron and manganese porphyrins to catalyze the amidation of hydrocarbons such as cyclohexane, heptane, or adamantane, the latter being converted to a single regioisomer (Scheme 2.1a). Importantly, these C(sp3 )–H amination reactions rely on the use of the hypervalent iodine reagent PhI = NTs 1. The latter belongs to the family of iminoiodinanes of general formula PhI = NR that can be prepared from various sulfonamides by

2.2 Historical Background

reaction with PhI(OAc)2 under basic conditions [43]. According to this protocol, Breslow and Gellman were able to prepare the iminoiodinane 2 that could be converted to the corresponding cyclic sulfonamide 3 in 77% yield in the presence of the iron porphyrin Fe(TPP)Cl (Scheme 2.1b). This result, notably, could be further improved by using the commercially available Rh2 (OAc)4 . H

NHTs Mn(TDCPP)(CF3SO3) X

X

PhI = NTs 1 X

(a) H N S O O

H O O 5 mol% IPh S Metal complex N

N

X

N M

N

X

N X

X

X

CH3CN, rt 2

(b)

Metal complex Fe(TPP)Cl: 77% Rh2(OAc)4: 86%

3

M = Mn - X = Cl: Mn(TDCPP) M = Fe - X = H: Fe(TPP)

Scheme 2.1 Seminal studies in catalytic C(sp3 )–H amination with iminoiodinanes. (a) Mn-Porphyrin catalyzed intermolecular amination of adamantane. (b) Catalytic intramolecular benzylic C(sp3 )–H amination.

These seminal studies were an invaluable source of inspiration to design efficient protocols for catalytic nitrene addition reactions. Thus, the use of the preformed iminoiodinane PhI = NTs and its nitro analogue PhI = NNs as nitrene precursors was further explored by the groups of Evans [44] and Müller [45] for the development of, respectively, copper- and rhodium-catalyzed alkene aziridination. The work from the Müller’s group, particularly, highlighted again the unique ability of dirhodium(II) tetracarboxylate complexes to catalyze nitrene C(sp3 )–H insertion, a general transformation that was studied more in details by the same group in a subsequent article (vide infra) [46]. However, more significant progress with the aim to develop synthetically useful C(sp3 )–H amination reactions was made by the group of Du Bois who managed to design a practical expedient procedure for the formation of metallanitrenes. The latter involves the in situ generation of iminoiodinanes from various nitrogen functions, such as carbamates 4 [47] or sulfamates 6 [48], by simple reaction with the commercially available PhI(OAc)2 in the presence of MgO. This protocol that avoids the troublesome preparation of iminoiodinanes has led to the discovery of highly efficient intramolecular C(sp3 )–H amination reactions catalyzed by readily available Rh2 (OCOR)4 complexes. These transformations afford the oxazolidinones 5 and oxathiazinanes 7, which can be considered as precursors of 1,2and 1,3-amino alcohols, respectively (Scheme 2.2). However, the ability of cyclic sulfamates to undergo regiocontrolled nucleophilic additions should be pointed out as it provides many other versatile opportunities in synthesis [49, 50].

53

54

2 Stereoselective C—N Bond-Forming Reactions

H R1

O R2 4 H

O

5 mol% Rh2(OAc)4

NH2

O

PhI(OAc)2 O O MgO S NH2 O

or Rh2(tpa)4 R

O

X

N

HN

R1

2 mol% Rh2(OAc)4 or Rh2(oct)4

R2 6

R1 R2 7

CPh3

Rh2(OAc)4:

O

O

Rh

Rh

Rh2(tpa)4:

O

O

Rh

Rh

44–86% 9 examples of oxazolidinones

R2 5 O O S HN O

IPh

X: CO, SO2

O

R1

60–91% 10 examples of oxathiazinanes

C7H15

Rh2(oct)4:

O

O

Rh

Rh

Scheme 2.2 Rhodium-catalyzed intramolecular C(sp3 )–H amination of carbamates and sulfamates.

The scope and the efficiency of these catalytic intramolecular processes were greatly improved by the design of the highly robust and active dirhodium(II) complex Rh2 (esp)2 8, the ligands of which derive from an α,α,α′ ,α′ -tetrasubstituted dicarboxylic acid [51]. The bidentate nature of the ligand combined with the m-xylene tether provides an optimal geometry to the complex that proves to be kinetically stable under the oxidizing reaction conditions. Complex 8, thus, has enabled to extend the scope of the intramolecular C(sp3 )–H amination reaction that can be performed with catalyst loading as low as 1 mol% starting from ureas and guanidines [52], sulfamides [53], and O-(sulfamoyl)-hydroxylamines [54]. More importantly, the Rh2 (esp)2 complex 8 has led to the development of efficient conditions for the intermolecular C(sp3 )–H amination reaction. Good conversions were often achieved only in the presence of an excess of substrate because of the high reactivity of the metallanitrene species. This limitation was overcome by using complex 8 in the presence of the more soluble iodine(III) oxidant PhI(OCOt-Bu)2 or by using the carboxylic acid PhMe2 CCOOH as an additive. Importantly, the chemoselectivity of the reaction that can often be tuned by the ligands of the dirhodium(II) complex was found here to depend on the nitrene source. Thus, the intermolecular C(sp3 )–H amination reaction occurs either at a secondary benzylic position with the sulfamate TcesNH2 9 [55] or at a tertiary center with the sulfamate DfsNH2 10 (Scheme 2.3) [56]. In parallel to the studies of Du Bois, and inspired again by the previous reports of Breslow and Mansuy, the group of Che has also described relevant practical conditions for C(sp3 )–H amination reactions catalyzed by the electron-deficient perfluorinated Mn- and Ru-porphyrins 11 and 12. Catalytic inter- [57] and intramolecular [58] processes have thus been developed by using an iminoiodinane generated from a combination of PhI(OAc)2 and a sulfonamide or a sulfamate. The conversion for the intramolecular reaction, moreover, was improved by adding the inorganic base Al2 O3 (Scheme 2.4). The same group has then reported the application of these conditions to the amidation of various hydrocarbons in the presence of simple ruthenium complexes [59].

2.2 Historical Background

H H R1 2

R

R1 R

X NHDfs 2

R3

R

PhI(OAc)2 PhMe2CCO2H

1 equiv

Me Me O O O Rh O Me O Rh O O Me O

Rh2(esp)2 8:

R1

O O S NH2

Cl Cl

45–70% Eight examples

R3

TcesNH2 9: Me Me

50–74% Eight examples

2

1 mol% Rh2(esp)2 8 1.2 equiv DfsNH2 10

H R1

NHTces

2 equiv PhI(OCOt-Bu)2

X 1 equiv

R2

2 mol% Rh2(esp)2 8 1 equiv TcesNH2 9

O Cl

DfsNH2 10:

F O

Me

S

NH2

O O F

Me

Scheme 2.3 Rhodium-catalyzed intermolecular C(sp3 )–H amination with sulfamates. 1 mol% Mn(TPFPP)Cl 11

H R2 R3 R1

PhI(OAc)2 + RSO2NH2

NHSO2R

R = p-Tol, p-NO2C6H4, Me Conversion: 36–94% Yields based on conversion: 72–92% 7 examples O O S H2N O R1

1.5 mol% Ru(TPFPP)(CO) 12 R3

R2

PhI(OAc)2 + Al2O3 56–88% 14 examples

F

R2 R3 R1 F

F

F

F

F

F

F F

O O S HN O

F F

R3 R2

F F

F

F

F F

F

R1

F

N L N M N N

F

M = Mn - L = Cl: Mn(TPFPP)Cl 11 M = Ru - L = CO: Ru(TPFPP)(CO) 12

Scheme 2.4 Mn- and Ru-porphyrin-catalyzed C(sp3 )–H amination.

It should be mentioned that several efficient C(sp3 )–H amination reactions with preformed or in situ generated iminoiodinanes have been described in the presence of copper scorpionate [60] or silver complexes [61–66], as well as with iron [67] and manganese phtalocyanines [68], to name but a few. However, contrary to the aforementioned examples, a catalytic asymmetric process based on a chiral version of one of these complexes remains to be found. Most of the progress in catalytic C(sp3 )–H amination has been made with the use of iodine(III) oxidants, as highlighted by many beautiful synthetic applications [69]. However, remarkable achievements have also been reported with other nitrene precursors. Thus, the capacity to uncover synthetically useful nitrene insertions from azides was demonstrated more than 30 years after the seminal

55

56

2 Stereoselective C—N Bond-Forming Reactions

study of Kwart and Kahn [36]. The group of Katsuki, to this end, has contributed significantly with the design of the Lewis acidic ruthenium(salen) complex 13 that has proved to catalyze intermolecular nitrene C(sp3 )–H insertions with tosylazide, though with moderate efficiency (Scheme 2.5) [70]. Nevertheless, such results have paved the way to develop a catalytic asymmetric process of broad scope (vide infra). Cobalt porphyrins [71–74] and iron complexes [75] have also been shown to catalyze the intramolecular C(sp3 )–H amination starting from alkyl, sulfonyl, and sulfamoylazides, although non-enantioselectively. * 2 mol% (R,R)-Ru(salen)(CO) 13

NHTs

N CO N Ru O O Ph Ph

36% 57% ee

TsN3

*

NHTs

17% 80% ee

(R,R)-Ru(salen)(CO) 13

Scheme 2.5 Ru(salen)-catalyzed C(sp3 )–H amination with azides.

Azides are atom-efficient nitrene precursors because the only by-product released in the process is dinitrogen that is more acceptable than the iodobenzene moiety generated with iminoiodinanes. In such a context of sustainable chemistry, the use of haloamines offers relevant opportunities. However, these nitrene sources have received moderate attention so far, probably because of the poor stereoselectivity observed in the reactions involving these reagents (Scheme 2.6) [76–78]. 5 mol% Cu(CH3CN)4PF6 5 mol% L

NHTs *

Ligand L N

Cl TsN Na

NO2

O2N N

66% 28% ee

NO2

NO2

Scheme 2.6 Copper-catalyzed C(sp3 )–H amination with chloramine-T.

By comparison, N-(sulfonyloxy)carbamates have been found to be efficient sources of metallanitrenes following their reaction with dirhodium(II) tetracarboxylate complex in the presence of K2 CO3 [79]. Intra- and intermolecular C(sp3 )–H amination reactions have been described by the group of Lebel, respectively, from carbamates 14 and 15. It is noteworthy that the scope of these transformations is complementary to that of the reactions based on iodine(III) oxidants (Scheme 2.7). 2.2.2

Mechanistic and Stereochemical Issues

The mechanism of catalytic C(sp3 )–H amination reactions has been extensively investigated since the seminal work of Müller on the dirhodium(II)-catalyzed

2.2 Historical Background H N

O

H R1

O R2 14

R

R2

O

6 mol% Rh2(tpa)4

HN

3 equiv K2CO3

R1 R2

6 mol% Rh2(tpa)4

H 1

OTs

R3

5 equiv

41–92% O 10 examples of oxazolidinones

NHTroc

1 equiv TrocNH-OTs 15 3 equiv K2CO3

R1

R2

R3

35–85% 16 examples

TrocNH-OTs 15: Cl3C

O

O N H

OTs

Scheme 2.7 Rhodium(II)-catalyzed C(sp3 )–H amination with N-(sulfonyloxy)carbamates.

process [46]. The transformations depicted in the previous schemes, particularly, have been the purpose of detailed studies performed, respectively, by the groups of Du Bois [55, 80–82], Che [83, 84], Katsuki [85], and Lebel [79]. The results described in these articles allow for drawing a general mechanism for the C(sp3 )–H insertion of nitrenes (Scheme 2.8). R NH2 + PhIL2

Concerted asynchronous C–H insertion pathway

OSO2R1

H H N R

M: Rh(II), Ru(II) MLn

R N or R N3 or R N

R1

H

IPh

TS PhI or

N2

or R1SO3H

R2

or

H H R N MLn Metallanitrene 16

R1

R2

MLn H N H R R2 R1 Stepwise hydrogen atom abstraction/ fast radical recombination pathway

MLn H N R H R2 R1

Scheme 2.8 General mechanism for the catalytic C(sp3 )–H amination reactions.

Catalytic C(sp3 )–H amination reactions all involve the metallanitrene species 16 (also referred to “metal-nitrenoid species” or “imido metal complex”) as the key intermediate. The latter has been characterized by the group of Che with a ruthenium porphyrin either as a mono- or bis-imido complex [83] or detected by desorption electrospray ionization mass spectrometry with a rhodium complex [82]. These metallanitrene species are formed by reaction of the metal complex with iminoiodinanes, azides, or N-(sulfonyloxy)carbamates that generates iodobenzene, dinitrogen, or a sulfonic acid, respectively, as a by-product. It should be mentioned that, in the case of the rhodium catalysis, the in situ generation of the iminoiodinane would be the rate-limiting step [80] and the subsequent generation of 16 might also proceed through two consecutive proton-coupled electron transfer [86]. Several physical organic experiments including Hammett studies, the reactions with cyclopropyl radical clocks or stereochemical probes, and the measurement

57

58

2 Stereoselective C—N Bond-Forming Reactions

of kinetic isotope effects have enabled the elucidation of the nature of the nitrene C(sp3 )–H insertion step. These experimental data led to the conclusion that the direct amination of the C—H bond can proceed via either a concerted asynchronous pathway or a stepwise radical process. The latter involves a first step of hydrogen atom abstraction followed by the sometimes extremely fast recombination of the radical intermediates. Whereas the concerted pathway is now generally accepted to describe the intramolecular C(sp3 )–H amination, as corroborated by DFT calculations [87–89], recent studies suggest that the intermolecular process would be best described by the stepwise mechanism [56, 90]. With respect to their scope, catalytic C(sp3 )–H amination reactions often take place at electron-rich positions such as secondary benzylic and allylic sites, and methylene groups in α-position to ethers, because the electron-deficient metallanitrene species is sensitive to steric effects. However, secondary unactivated sites can also be functionalized by application of intramolecular additions. Such a regioselectivity in favor of a CH2 group is appropriate to design catalytic stereoselective processes. To this end, the Scheme 2.8 clearly indicates that the chirality must be included in the metallanitrene species to discriminate two stereotopic C—H bonds in the nitrene insertion step. The next chapters will demonstrate that this issue has been addressed by introducing a chiral auxiliary either on the metal catalyst or the nitrene precursor. Although the latter option implies the use of chiral amides in stoichiometric amounts, this solution has led to remarkable achievements in catalytic stereoselective C—N bond-forming reactions. It is worth pointing out that the selectivity in nitrene C(sp3 )–H insertions can also be controlled by the stereochemistry of the substrate. Several reviews have already summarized the main results in this domain [18, 29, 31], and the following paragraphs will give a summary of the most important contributions. The studies of Müller and coworkers [46] and Du Bois and coworkers [47, 48, 56] have clearly highlighted that inter- and intramolecular C(sp3 )–H amination reactions also enable the functionalization of tertiary centers. Importantly, in the course of their mechanistic investigations, both groups have demonstrated the stereospecificity of the reaction starting from stereodefined tertiary site-containing substrates, an observation that is in line with a concerted asynchronous C–H insertion pathway. Accordingly, the catalytic amination of enantiopure tertiary C(sp3 )—H bonds occurs stereospecifically with retention of configuration, thereby giving access to optically pure tertiary amines in a single step (Scheme 2.9). Conformational factors allow to perform intramolecular C(sp3 )–H amination reactions with high levels of diastereocontrol. Particularly, sulfamates can be converted to substituted six-membered rings with excellent 1,2-trans and 1,3-cis selectivities (Scheme 2.10) [91]. These results have been rationalized by the preferred nitrene insertion into the equatorial C(sp3 )—H bond because unfavorable torsional effects would develop in the resulting oxathiazinane following reaction at the axial C(sp3 )—H bond. In addition, the reaction would proceed through a chairlike transition state in which the substituents would be in a pseudo-equatorial layout to minimize gauche interactions.

2.2 Historical Background

O O S NH2 2 mol% Rh2(OAc)4 O

H TBDPSO

PivO

TBDPSO

PhI(OAc)2, MgO 85%

CO2Et

Me

O O S HN O

PivO

1 mol% Rh2(esp)2 8 1.2 equiv DfsNH2 10

Me

Me

PhI(OAc)2 PhMe2CCO2H 68%

H

CO2Et

Me

NHDfs

Scheme 2.9 Stereospecific C(sp3 )–H amination of tertiary centers.

Me N TsN

O O S H2N O

2 mol% Rh2(oct)4 PhI(OAc)2 MgO

Me Me

Me N TsN

O O S N O

H

Rh

84% 20 : 1 dr Me

H R2

N

3

R

R1

Me

S

H

O

O O Favored Rh

O O S H2N O

4 mol% Rh2(oct)4

O O H S N O

PhI(OAc)2 Ph MgO TMS

Ph

H 62% 20 : 1 dr

R2

3

R

N H H

S

O O R Disfavored

S

N

O

O R2

3

R

1

TMS

O

H

H

O R1

H

Scheme 2.10 Diastereoselective intramolecular C(sp3 )–H amination of sulfamates.

Moderate to excellent acyclic stereocontrol has been also reported for the intermolecular functionalization of secondary benzylic positions, providing that the latter is substituted at the α-position by a stereogenic center [90]. Syn products, thus, are preferentially obtained as a result of a favored conformation where the reacting C(sp3 )—H bond and the electron-withdrawing substituent are antiperiplanar because of steric repulsions, as are the aromatic and methyl groups for steric reasons (Scheme 2.11). H

NHTces X

MeO

Me

1 mol% Rh2(esp)2 TcesNH2 PhI(OAc)2

X MeO

X = Br: X = PO(OEt)2: X = SO2Ph: X = NO2: X = CO2Me: X = CN: X = CH2OAc:

Me 89%; >19 : 1 dr 65%; >19 : 1 dr 56%; >19 : 1 dr 63%; 91: 9 dr 82%; 82/18 dr 86%; 80/20 dr 70%; 60/40 dr

Electrostatic [Rh2] repulsion NTces Me H H X H Minimized steric hindrance OMe

Scheme 2.11 Diastereoselective intermolecular C(sp3 )–H amination of benzylic methylene groups.

59

60

2 Stereoselective C—N Bond-Forming Reactions

2.3 Catalytic Stereoselective C(sp3 )–H Amination Reactions with Iminoiodinanes 2.3.1 Catalytic Intermolecular Enantioselective Reactions (Chirality Only on the Metal Complex) The first examples of asymmetric induction in catalytic C(sp3 )–H amination reactions were reported in the seminal study of Müller and coworkers [46]. The reaction of indan in the presence of the chiral dirhodium(II) complexes Rh2 (R-bnp)4 17 or Rh2 (S-ptpa)4 18 led to the expected enantioenriched benzylic amines albeit with low to moderate enantiocontrol (Scheme 2.12). With the aim to improve the enantiomeric excess of 31% obtained with Rh2 (R-bnp)4 , substitution of the 3-3′ position of the BINOL backbone could be envisaged according to the excellent results recorded with the corresponding phosphoric acids in asymmetric catalysis [92]. However, such substituted BINOL derivatives are too sterically hindered to be installed on the dirhodium core. By contrast, the amino acid of complex 18 could offer the possibility to modify either the side chain or the nitrogen protecting group to increase the ees, an opportunity that has been investigated successfully by several groups (vide infra).

PhI = NNs 20 equiv

O

NHNs

5 mol% Rh2L*4 *

N O O P O O Rh Rh Rh2(R-bnp)4 17 71%; 31% ee

O

H

O Rh

Ph O Rh

Rh2(S-ptpa)4 18 77%; 7% ee

Scheme 2.12 Seminal study in rhodium(II)-catalyzed asymmetric C(sp3 )–H amination reaction.

Based on their long expertise in the design of chiral dirhodium(II) complexes derived from protected amino acids [93, 94], Hashimoto and coworkers have screened various N-phthaloyl and N-benzene-fused-phthaloyl-(S)-amino acids, thus, demonstrating that the per-halogenated ligands confer the capacity to induce good to excellent enantiocontrol to the resulting rhodium complex. The per-chlorinated complex Rh2 (S-tcpttl)4 19 that derives from tert-leucine proved to be the most efficient catalyst for the amination of secondary benzylic sites [95] and silylketene acetals [96], while the perfluorinated analogue Rh2 (S-tfpttl)4 20 was optimal in the reaction with silyl enol ethers (Scheme 2.13) [97]. It is worth mentioning that the last two sets of reactions should only be considered as formal nitrene C–H insertions as they rather involve a catalytic alkene aziridination of the enol moiety followed by a ring opening. However, they proceed efficiently from substrates used in stoichiometric amounts or so, giving access to enantiopure phenylglycine derivatives, likely to be converted to chiral oxazolidinones, and α-amino ketones that are useful intermediates in

2.3 Catalytic Stereoselective C(sp3 )–H Amination Reactions with Iminoiodinanes

H H

2 mol% Rh2(S-tcpttl)4 19

Ar R 5 equiv

1 equiv PhI = Np-Ns

Ar

OMe 1.2 equiv

OSiR3 R1

3 mol% Rh2(S-tcpttl)4 20

F O

Cl N

Cl O

Rh

Rh2(S-tcpttl)4 19

R2 NHo-Ns

F

p-Ns:

80–98% 47–95% ee 13 examples of α-amino ketones

SO2

O N

F

Rh

O R1

R2 No-Ns

F

O

48–98% 80–99% ee OMe 11 examples NHo-Ns of phenylglycine derivatives

OSiR3 R1

H

O

O

Ar

OMe No-Ns

1.05 equiv PhI = No-Ns then TFA

Cl

R

52–88% 33–84% ee 5 examples of benzylic amines

OSiEt3 Ar

1 equiv PhI = No-Ns

R2 1 equiv

Cl

Ar

1 mol% Rh2(S-tcpttl)4 19

OSiEt3

H NHp-Ns

O

H NO2

O

O

Rh

Rh

o-Ns:

SO2 NO2

Rh2(S-tfpttl)4 20

Scheme 2.13 Catalytic asymmetric nitrene additions with per-halogenated rhodium(II) complexes.

synthesis. In the context of sustainable chemistry, it should be pointed out that the Rh2 (S-tfpttl)4 catalyst can be immobilized on a polymer, thereby allowing its recycling in the asymmetric amination of silyl enol ethers [98]. The amination of silyl enol ethers is specific to the (Z)-isomers. Acyclic (E)-derivatives did not react under these conditions, whereas a cyclic (E)-enol ether underwent a catalytic allylic C(sp3 )–H amination. The use of the Rh2 (S-tcpttl)4 19 complex, thus, led to the formation of the enantioenriched allylic amine that, after hydrolysis, afforded a β-amino ketone in good yield and ee (Scheme 2.14) [99]. This rare example of catalytic asymmetric intermolecular OSiEt3

1 equiv

2 mol% Rh2(S-tcpttl)4 19 1.2 equiv PhI = Np-Ns

OSiEt3

O 10% HCl

NHp-Ns

NHp-Ns 79% 72% ee

Scheme 2.14 Catalytic asymmetric intermolecular allylic amination of a cyclic enol ether.

61

62

2 Stereoselective C—N Bond-Forming Reactions

allylic C(sp3 )–H amination is a relevant example of a switch in chemoselectivity controlled by the substrate. The scope of the catalytic benzylic C(sp3 )–H amination reaction has been extended with the design of the bulkier complex Rh2 (S-tcptad)4 21 that results from the replacement of the tert-butyl side chain of the Rh2 (S-tcpttl)4 complex 19 by an adamantyl group [100]. Higher yields in the 62–94% range and enantioselectivities of up to 94% were obtained from various indans, indanones, and their higher cyclic homologues in the presence of 21 (Scheme 2.15). However, as a major limitation, the reaction requires an excess of substrate to secure good conversion. H H

X

R

n

PhI(OAc)2 p-NsNH2 MgO

5 equiv n = 0,1 X : CH2, C = O

Cl

H NHp-Ns

2 mol% Rh2(S-tcptad)4 21

X

R

Cl O

Cl

n

N

Cl O

65–95% 62–94% ee Seven examples of benzylic amines

H

O

O

Rh

Rh

Rh2(S-tcptad)4 21

Scheme 2.15 Catalytic asymmetric intermolecular benzylic amination with Rh2 (S-tcptad)4 21.

The design of an efficient catalytic enantioselective intermolecular amination reaction of broad scope is still an issue to address. A possible solution could arise from the design of chiral analogues of the highly active Rh2 (esp)2 complex 8, but this approach has not proved conclusive so far. The best results reported up to now have been obtained through the design of the elegant supramolecular rhodium(II) complex 22 (Scheme 2.16) [101]. The latter includes two lactam binding sites that can interact with substrates bearing two complementary hydrogen bond donor and acceptor, such as 3-benzylquinolones. The coordination through the two expected hydrogen bonds allows for discriminating the NHTces 2 mol% 22 N H

1. 5 equiv PhI(OAc)2 X 1 equiv TcesNH2

O

N H

X

O

15–52% er 74/26 to 87/13 Five examples of benzylic amines

2 equiv Me Me H

O OO O

O NH

Me

Me

Rh Rh O

O Rh O Rh O NTces H

HN O O

OO O

Me Me

O

H

Me Me

H 22

NH

HN O

OMe H

Scheme 2.16 Catalytic asymmetric intermolecular amination with the supramolecular complex 22.

2.3 Catalytic Stereoselective C(sp3 )–H Amination Reactions with Iminoiodinanes

two enantiotopic benzylic C(sp3 )—H bonds. The enantiomeric ratios, which were found to increase with lower concentrations, are moderate to good; however, such a supramolecular approach remains specific in scope. Chiral Mn- and Ru-porphyrins derived from complexes 11 and 12 have been tailored by the group of Che to induce enantiocontrol in intermolecular C(sp3 )–H amination reaction in the presence of the preformed PhI = NTs 1 or using the one-pot procedure for the in situ generation of the iminoiodinane [102]. Starting from a stoichiometric amount of various benzylic substrates, the yields are in the 78–91% range; however these are based on conversion that remains low, while the enantiomeric excesses do not exceed 56% (Scheme 2.17). 1.3 mol% Ru(Por*)(CO) 24

H H

NHTs

Ar * R 2 equiv PhI = NTs 1 Conversion: 14–32% Yields based on conversion: 78–91% 3–47% ee Six examples of benzylic amines

Ar R 1 equiv

1 mol% Mn(Por*)(OH) 23

H H

N L N M N N

NHMs

R Ar 1 equiv

Ar * R PhI(OAc)2 MeSO2NH2 Conversion: 21–26% Yields based on conversion: 84–92% 46–56% ee Three examples of benzylic amines

M = Mn - L = OH: Mn(Por*)(OH) 23 M = Ru - L = CO: Ru(Por*)(CO) 24

Scheme 2.17 Catalytic asymmetric intermolecular amination with chiral porphyrins 23 and 24.

Porphyrin ligands are somewhat sophisticated and, therefore, costly to prepare. By comparison, the salen ligands appear more flexible and versatile with the aim to search for an efficient asymmetric nitrene C(sp3 )–H insertion. Surprisingly, this approach has been rarely investigated in combination with iodine(III) oxidants so far. The group of Katsuki, nevertheless, has documented the use of the tetrabromo-Mn(salen) complex 25 in the enantioselective intermolecular C(sp3 )–H amination with the preformed PhI = NTs 1 [103]. In addition to benzylic sites, this catalyst enables the functionalization of secondary allylic positions with acceptable enantiocontrol but, remarkably, with complete chemoselectivity (Scheme 2.18). 2.3.2

Catalytic Intramolecular Enantioselective Reactions

The catalytic intramolecular C(sp3 )–H amination reaction mediated by iodine(III) oxidants has been reported from various nitrogen functions. However, the related enantioselective processes have been successfully developed mostly from sulfamates so far, because these are more efficient nitrene precursors

63

64

2 Stereoselective C—N Bond-Forming Reactions

H H

NHTs

R Ar ~6 mol% 2.3 equiv Mn(salen) 25 H

1 equiv PhI = NTs 1

H

n

Ar * R

44–71% 77–89% ee Three examples of benzylic amines

N

N Mn+

42–44% 41–67% ee Two examples of allylic amines

Br

NHTs n

2.3 equiv

O

PF6–

Br

O

Br

Br

Mn(III)(3,3′,5,5′-tetrabromo-salen) 25

Scheme 2.18 Catalytic asymmetric intermolecular amination with Mn(salen) 25.

than sulfonamides, carbamates, ureas, or guanidines. Surprisingly, the use of chiral dirhodium(II) tetracarboxylates such as Rh2 (S-nttl)4 26 or Rh2 (S-tfpttl)4 20 has met a limited success in this context as the enantiomeric ratios are at best in the 3 : 1 range (Scheme 2.19) [104–106]. O S O NH2

O Cl Ph

3.5 mol% Rh2(S-nttl)4 26

O S O NH

O

PhI(OAc)2 MgO

Cl

* Ph

O

68% 52% ee

N O

2 mol% O S O Rh2(S-tfpttl)4 20 O PhI(OAc)2 MgO

H O N S O

H2N

O

98% 48% ee

H

O

O

Rh

Rh

Rh2(S-nttl)4 26

Scheme 2.19 Rhodium-catalyzed asymmetric intramolecular amination of sulfamates.

More significant achievements have been made with the cleverly designed rhodium(II) carboxamidate Rh2 (S-nap)4 27 that allows for performing the catalytic asymmetric intramolecular C(sp3 )–H amination of sulfamates with high levels of efficiency and enantiocontrol [107]. A relevant feature of 27 is its finely adjusted electrophilic character that makes Rh2 (S-nap)4 a rare example of a dirhodium(II) tetracarboxamidate complex able to mediate catalytic nitrene transfer under oxidizing conditions. The reaction proceeds at secondary benzylic sites of various aromatic and heterocyclic compounds with yields of up to 98% O O S H2N O

H 2 mol% Rh2(S-nap)4 27

Ar O O S R H2N O

PhI = O

O O S N O

Ar O O H S R N O

45–98% 56–99% ee Eight examples of benzylic amines 48–55% 82–84% ee Two examples of allylic amines

Ts H

N O

N

Rh

Rh

Rh2(S-nap)4 27

Scheme 2.20 Asymmetric intramolecular benzylic and allylic amination with Rh2 (S-nap)4 27.

2.3 Catalytic Stereoselective C(sp3 )–H Amination Reactions with Iminoiodinanes

and enantiomeric excesses of up to 99% (Scheme 2.20). More importantly, this new catalyst mediates the chemoselective functionalization of allylic substrates, leading to enantioenriched allylic amines but only starting from (Z)-alkenes. The comparison of the results obtained with the classical Rh2 (OAc)4 clearly showcases the influence of the ligands on the chemoselectivity of allylic nitrene C(sp3 )–H insertions. Moreover, the nitrogen protecting group strongly but inexplicably influences the catalytic performance [29]. Concomitant with the study on chiral dirhodium(II) complexes, the chiral Ru-porphyrin 24 and a neutral Mn(Cl) analogue of the Mn(salen) 25 were shown to catalyze the intramolecular benzylic C(sp3 )–H amination with sulfamates, though with lower efficiency and enantioselectivity (ees of up to 88% and 79%, respectively) [58, 108, 109]. But it is worth mentioning that five-membered rings can be easily obtained from various arylethanol-derived sulfamates using these two catalysts. More significant results, however, have been reported by the group of Blakey with the neutral Ru(II)(pybox)Br2 complex 28 in the presence of AgOTf [110]. This additive is indeed crucial to generate a cationic ruthenium(II) complex that proved to be more reactive than the parent complex 28. In parallel to the study of Du Bois with the Rh2 (S-nap)4 complex 27, Blakey and coworkers have developed efficient conditions for the intramolecular benzylic and allylic amination that afford the expected products in good to excellent yields of up to 92% and with high levels of enantiocontrol (Scheme 2.21). The scope of the chemoselective allylic C(sp3 )–H amination, in addition, is complementary to that described by Du Bois as an (E)-alkene is more reactive under these conditions than the corresponding (Z)-isomer. However, the low yield of 14% obtained from n-hexylsulfamate clearly demonstrates the limitation of catalytic asymmetric intramolecular amination reactions that, still, poorly apply to unactivated C(sp3 )—H bonds. O O S H2N O

H

Ar

Ar O O S H2N O 5 mol% Ru(pybox)Br2 28

Me

Me

O O 5 mol% AgOTf S PhI(OCOt-Bu)2 Me H2N O MgO

75–92% 80–92% ee Seven examples of benzylic amines O O H S N O 60% 89% ee O

O O H S Me N O

O O S H2N O Me

O O S N O

H Me

O O S N O

O

Br N

N

Ru

N Br

42% 50% ee Ru(pybox)Br2 28 14% -

Scheme 2.21 Asymmetric intramolecular benzylic and allylic amination with Ru(II)(pybox)Br2 28.

65

66

2 Stereoselective C—N Bond-Forming Reactions

2.3.3 Catalytic Intermolecular Diastereoselective Reactions (Chirality on the Metal Complex and the Nitrene Precursor) The catalytic asymmetric intermolecular C(sp3 )–H amination reactions are generally of limited scope and often suffer from low conversion that compels to work with an excess of substrate to obtain good yields. Nevertheless, these limitations have been overcome with the discovery of sulfonimidamides 29 as highly efficient chiral nitrene sources. These reagents are the aza analogues of sulfonamides in which one of the S=O bond has been replaced by an S = NTs function, thereby making the sulfur center chiral. Excellent diastereocontrol in catalytic nitrenoid C(sp3 )–H insertion reactions was then reported by combining the optically pure sulfonimidamide (S)-29 with the chiral rhodium complex Rh2 (S-nta)4 30. This matched pair of reagents has led to uncover a rhodium-catalyzed stereoselective C(sp3 )–H amination of benzylic and allylic substrates used as the limiting component [111–113]. The corresponding (R)-benzylic and allylic amines were isolated with yields of up to 99% and diastereomeric ratios of up to >20 : 1 (Scheme 2.22), the other (S)-enantiomer being also efficiently obtained using the other matched pair of reagents. Benzylic C–H amination 3 mol% H H Rh 2(S-nta) 4 30 Ar

R

1.2 equiv (S)-S*NH2 29 1.4 equiv PhI(OCOt-Bu)2

1 equiv

H NHS* Ar

51–99% dr: 93 : 7 to >20 : 1 18 examples of (R)-benzylic amines

R

Allylic C–H amination R2 H H R1

R3 1 equiv

3 mol% Rh 2(S-nta) 4 30

1.2 equiv (S)-S*NH2 29 1.4 equiv PhI(OCOt-Bu)2

R2 H NHS* R1

O

O

S

NH2 N O S O

(S)-S*NH2 29:

66–90% dr: 3 : 1 to 97 : 3 8 examples of cyclic or acyclic (R)-allylic amines

R3

N O

H

Me

O

O

Rh

Rh

Rh 2(S-nta)4 30

Scheme 2.22 Stereoselective intermolecular benzylic and allylic amination with sulfonimidamides.

The reaction can be applied with equal levels of efficiency and selectivity to more complex substrates such as diphenyl derivatives, enol ethers, or terpenes [113, 114]. In each case, a single compound was isolated, and the course of the

2.4 Catalytic Stereoselective C(sp3 )–H Amination Reactions with Azides Benzylic C–H amination of diphenyl derivatives F NHS* NHS* 96% dr: >20 : 1 Regioisomeric ratio: 9 : 1

MeO

99% dr: >20 : 1

Allylic C–H amination of enol ethers

Allylic C–H amination of terpenes

52–92% dr: 5 : 1 to >20 : 1

OR

Four examples of (R)-allylic amines n = 0,1,2 R = CO2allyl, Tf

NHS*

n

NHS* 91% dr: 39 : 1

NHS* 73% dr: 49 : 1

NHS* O

Cl3C

O

89% dr: >20 : 1

Figure 2.2 Stereoselective intermolecular amination of complex substrates with sulfonimidamides.

C(sp3 )–H functionalization was rationalized by a combination of steric, conformational, and electronic factors (Figure 2.2). The matched combination of the (S)-reagent 29 with the (S)-rhodium catalyst 30 has been recently applied to the catalytic stereoselective C(sp3 )–H amination of benzylic iodine(III) oxidants. The reaction delivers a functionalized iodo compound that can be subsequently engaged in one-pot palladium-catalyzed cross-couplings. This tandem process, therefore, has led to produce a library of more than 30 complex enantiopure benzylic amines (Scheme 2.23) [115]. H H (AcO)2I

Ar1

1.1 equiv

3 mol% Rh2(S-nta)4 30 1 equiv (S)-S*NH2 29

H NHS* I

Ar1

H NHS*

Pd-catalyzed cross-couplings R

Ar1

43–87% dr: >98 : 2 34 examples of (R)-benzylic amines

Scheme 2.23 Tandem catalytic intermolecular benzylic C–H amination cross-coupling reactions.

2.4 Catalytic Stereoselective C(sp3 )–H Amination Reactions with Azides 2.4.1

Transition Metal-Catalyzed C(sp3 )–H Amination Reactions

Mechanistic investigations of the ruthenium(salen)-catalyzed nitrene C(sp3 )–H insertion reactions depicted in Scheme 2.5 have enabled the design of an efficient catalytic asymmetric C(sp3 )–H amination with azides. The low turnover number observed with complex 13 was supposed to arise from its inactivation following an intramolecular C(sp2 )–H amination promoted by the Ru(salen)-azide

67

68

2 Stereoselective C—N Bond-Forming Reactions

complex. This undesirable reaction was supposed to proceed at a meta-C—H bond of one of the aromatic rings located at the C2′′ position of the BINOL moiety. Accordingly, the group of Katsuki has conceived two strategies to avoid this side reaction and improve the catalytic activity of Ru(salen) complexes. First, the introduction of a bulky tert-butyldiphenylsilyl group at the para position of the C2′′ -phenyl rings has allowed the preparation of the iridium(III) (salen) complex 31 that has proved to be the best catalyst for the intramolecular C(sp3 )–H amination of sulfonyl azides [116]. A variety of 2-ethylbenzenesulfonyl azides, thus, was efficiently converted to the corresponding five-membered benzosultams in excellent yields of up to 96% and high enantiomeric excesses of up to 93% (Scheme 2.24). Interestingly, the length of the 2-alkyl side chain strongly influences the regiochemical course of the reaction. The latter, for example, occurs exclusively at the homobenzylic position starting from the n-propyl analogue. This switch in regioselectivity would be the consequence of the subtle combination of steric and stereoelectronic effects.

R

O O 3 mol% S N3 (R,R)-Ir(salen) 31

O O S 71–99% NH 86–93% ee * Nine examples of benzosultams

R

Toluene or AcOEt

R

R O O 3 mol% S N3 (R,R)-Ir(salen) 31 Toluene or AcOEt R

O O S NH * +

93% α/β: 1 : >20 O O 99% ee S NH *

N L N Ir O O Ar Ar

(R,R)-Ir(salen) 31 Ar:

Ph

Si t-Bu Ph

Scheme 2.24 Ir(salen)-catalyzed intramolecular C(sp3 )–H amination of benzenesulfonyl azides.

The second strategy envisaged by the group of Katsuki was to introduce halogen substituents on the C2′′ -phenyl rings. Accordingly, a 2,6-difluorophenyl group was optimal to design a Ru(salen)-catalyzed enantio- and regioselective intermolecular C(sp3 )–H amination of large scope using 2-trimethylsilylethane sulfonyl azide as the nitrene source [85]. Several N-(Ses)-benzylic and N-allylic amines, thus, were isolated in good to excellent yields, and enantiomeric excesses generally greater than 90% (Scheme 2.25). Importantly, the reaction mostly takes place at ethyl substituents, thereby allowing the discrimination of a benzylic or allylic ethyl group against a propyl group or a longer chain, probably because of hyperconjugative effects. Another relevant feature of the reaction is the use of the easily cleavable Ses protecting group, which gives the opportunity to isolate the free amines by simple reaction with a fluoride anion source. 2.4.2

Enzymatic C(sp3 )–H Amination Reactions

Catalytic C–H amination is a truly synthetic method that has been discovered, thanks to the creativity of chemists. Many oxidases are indeed known in nature

2.4 Catalytic Stereoselective C(sp3 )–H Amination Reactions with Azides Benzylic C–H amination 4 mol% Ru(salen)CO 32

H H Ar

R

1 equiv SesN3

1.3 equiv

Allylic C–H amination

H NHSes

4 mol% Ru(salen)CO 32

H H R

1 equiv SesN3 1.3 equiv

N CO N Ru O O Ar Ar

R Ar 73–99% 79–99% ee 11 examples of benzylic amines H NHSes R 51–99% 46–94% ee 7 examples of allylic amines

(R,R)-Ru(salen) 32 Ar: F

SesN3: F

Si

O O S N3

Scheme 2.25 Ru(salen)-catalyzed asymmetric intermolecular C(sp3 )–H amination with SesN3 .

to catalyze the regio- and stereoselective C–H hydroxylation of alkanes. By contrast, no natural enzyme able to mediate the direction amination of C—H bonds has been described so far. Nevertheless, several groups have recently managed to engineer cytochrome P450 to produce modified enzymes that are able to catalyze C(sp3 )–H amination reactions. These studies have taken inspiration from the seminal work of Breslow on the intramolecular amination of N-(arenesulfonyl)iminoiodinanes catalyzed by a Fe(III)-containing P450 enzyme [117]. The groups of Arnold [118] and Fasan [119], thus, have demonstrated that intramolecular benzylic amination of arenesulfonyl azides can be performed with turnover numbers in the 390 range using carefully mutated P450 enzymes. Strikingly, this chemistry can be carried out in cellulo on a 50 mg scale, the resulting benzosultam being isolated in 69% yield and 87% ee (Scheme 2.26a). However, the scope of these asymmetric reactions remains limited to a couple of examples. O O S N3

0.1 mol% Fe2+-P411BM3CIS-T438S

O O S 58% NH 87% ee *

NaDPH or Na2S2O4 KPi buffer (pH 8.0) (a)

O

O S O N3

(b)

0.33 mol% Ir(Me)-CYP119 C317G, T213G, V254L 100 mM Na-Pi 100 mM NaCl (pH 6.0)

O

O S O NH

*

84% 80% ee

Scheme 2.26 Enzymatic asymmetric intramolecular C(sp3 )–H amination of azides. (a) Fe(II)-containing P411 variant-catalyzed intramolecular C–H amination. (b) Ir-containing CYP119 variant-catalyzed intramolecular C–H amination.

Key to the success of the enzymatic intramolecular amination of sulfonyl azides was the introduction of a reduced Fe(II) center into the porphyrin. Significant

69

70

2 Stereoselective C—N Bond-Forming Reactions

progress was then made by designing a new CYP119 mutant containing an iridium porphyrin cofactor Ir(Me)-PIX. The asymmetric intramolecular C(sp3 )–H amination of azides proceeds with yields of up 98% in the presence of Ir(Me)-PIX CYP 119 mutant and with a broader substrate scope that was extended to sulfamates (Scheme 2.26b) [120]. In a recent and more impressive study, directed mutagenesis of selected residues located in the heme domain of an evolved variant has led to discover a highly active biocatalyst that has allowed to perform asymmetric intermolecular benzylic C(sp3 )–H amination reactions with high turnover numbers of up to 1300 in the presence of tosylazide. Various benzylic amines can thus be isolated with high levels of enantioselectivity in the presence of the cytochrome P411CHA (Scheme 2.27) [121]. Importantly, the protein not only provides the appropriate chiral environment for achieving excellent enantiocontrol, but it also promotes the reactivity of the iron cofactor that was found inactive when tested alone. Though the scope of the reaction is limited to secondary electron-rich benzylic sites, this study should definitely be a source of inspiration for the design of more efficient biocatalysts complementary to chemical catalysts in terms of scope. H H

0.12 mol% Fe2+-P411CHA

R Ar 1 equiv

2 equiv TsN3 KPi buffer (pH 8.0)

6−86% 87 to >99% ee 14 examples of benzylic amines

H NHTs Ar

R

Scheme 2.27 Enzymatic asymmetric intermolecular C(sp3 )–H amination with tosylazide.

2.5 Catalytic Stereoselective C(sp3 )–H Amination Reactions with N-(Sulfonyloxy)carbamates The bulky complex Rh2 (S-tcptad)4 21, which was designed by the group of Davies for the catalytic intermolecular benzylic nitrene C(sp3 )–H insertion (Scheme 2.15), was also shown to catalyze the intramolecular C(sp3 )–H amination of N-(sulfonyloxy)carbamates [100]. The reaction proceeds with enantiomeric excesses in the 43–82% range for benzylic, allylic, and unactivated methylene groups, but the scope remains limited to four examples (Scheme 2.28). It is noteworthy that the intramolecular C(sp3 )–H amination provides enantioenriched oxazolidinones, which are not accessible using the iodine(III) Cl

R

H N

O O

2 mol% Rh2(S-tcptad)4 21

O

HN

OTs K2CO3

R

62−75% 43−82% ee O Four examples

Cl O

Cl N

Cl O

O Rh

H

O Rh

Rh2(S-tcptad)4 21

Scheme 2.28 Enantioselective intramolecular C(sp3 )–H amination with N-(tosyloxy)carbamates.

2.5 Catalytic Stereoselective C(sp3 )–H Amination Reactions with N-(Sulfonyloxy)carbamates

oxidant chemistry. However, the rhodium complex 21 as well as others such as Rh2 (S-nttl)4 26 did not prove relevant to mediate the intermolecular addition of N-(sulfonyloxy)carbamate-derived nitrenes as the enantiomeric ratio is at best of 2.57 : 1 [122]. Using the matched-pair approach previously described with iodine(III) oxidants, diastereoselective intermolecular C(sp3 )–H amination reactions have been reported in the presence of chiral N-(sulfonyloxy)carbamates derived from the Troc-reagent 15. The tosyloxy derivative 33, thus, reacts with substituted (E)-alkenes in the presence of the Rh2 (S-Br-nttl)4 complex 34 to afford allylic amines with very good diastereocontrol (Scheme 2.29) [123].

R2

5 mol% Rh2(S-Br-nttl)4 34

H H

R1

R3 1 equiv

R2 HN

1.5 equiv K2CO3 R1 1.2 equiv Ph O OTs Cl3C O N H 33

Br

Ph

O

CCl3

O

N R3 56−69% dr: 4 : 1 to 11 : 1 Four examples allylic amines

O

O H

O O Rh Rh

Rh2(S-Br-nttl)4 34

Scheme 2.29 Stereoselective intermolecular allylic C(sp3 )–H amination with tosyloxy reagent 33.

It should be mentioned that application of these reaction conditions to terminal alkenes or (Z)-alkenes exclusively affords the corresponding aziridines. The diastereoselective intermolecular C(sp3 )–H amination reaction was then extended to benzylic and propargylic substrates following the development of the more sustainable mesyloxy reagent 35 that releases the biodegradable potassium methanesulfonate as the only by-product. After purification by flash chromatography or recrystallization, benzylic and propargylic amines were isolated with very high levels of diastereocontrol (Scheme 2.30) [124]. This chemistry can be performed on a gram scale using a catalyst loading as low as 0.3 mol%; then the chiral auxiliary can be recovered following simple methanolysis. Ph

O O

58−93% CCl3 dr: 7.4 : 1 to >99 : 1 17 examples benzylic amines

O

Ph

H H HN Ar

R

2 mol% Rh2(S-Br-nttl)4 34

1 equiv H H R Ar 1 equiv

3 equiv K2CO3 1.2 equiv Ph O OMs Cl3C O N H Ar 35

Ar

R

HN

O R

CCl3

50−62% dr: 52 : 1 to >99 : 1 2 examples propargylic amines

Scheme 2.30 Stereoselective intermolecular allylic C(sp3 )–H amination with mesyloxy reagent 35.

71

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2 Stereoselective C—N Bond-Forming Reactions

2.6 Conclusion Significant progress has been made since the pioneering studies reported by Müller in 1997, in the stereoselective C—N bond-forming reactions through C–H amination of metal-bound nitrenes generated from iodine(III) oxidants, azides, or N-(sulfonyloxy)carbamates. These transformations involve the direct C(sp3 )–H insertion of a metallic nitrene that proceeds via either a concerted asynchronous pathway or a stepwise radical process. Inter- and intramolecular enantioselective reactions have been reported following the design of chiral transition metal complexes. Mainly rhodium but also ruthenium and manganese complexes have proved to be the metals of choice to this end. Catalytic intermolecular diastereoselective processes have been also described by combining a chiral dirhodium complex with a chiral nitrene source. These have significantly extended the scope and efficiency of C(sp3 )–H amination reactions as they enable the functionalization of substrates used as the limiting component. All these synthetic methods now are reliable tools for the organic chemists that provide a rapid access to a large variety of enantiopure benzylic and allylic amines. Challenging issues in catalytic asymmetric C(sp3 )–H amination, nevertheless, still need to be addressed. While electron-rich benzylic and allylic C(sp3 )—H bonds can be converted to C—N bonds, the asymmetric intramolecular amination of unactivated C(sp3 )—H bonds has not been reported so far. More fundamentally, the search for an efficient transition metal-catalyzed asymmetric intermolecular process remains a great challenge for the synthetic chemists. In the context of sustainable chemistry, the development of such protocols that will be based on the use of the more abundant hence less expensive first row transition metals is highly desirable.

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77

Part I.B C(sp3 )–H Activation as Stereodiscriminant Step

79

3 Enantioselective Intra- and Intermolecular Couplings Qiaoqiao Teng 1 and Wei-Liang Duan 2 1 Changzhou University, School of Petrochemical Engineering, 1, Gehu Road, Changzhou, Jiangsu 213164, P.R. China 2 Yangzhou University, College of Chemistry and Chemical Engineering, 180, Siwangting Road, Yangzhou, Jiangsu 225002, P.R. China

3.1 Introduction C(sp3 )–H activation [1] assisted by transition metal catalysts in an asymmetric manner [2] could also be realized via the so-called inner-sphere mechanism, in which a direct metal and C—H bond interaction is involved. The activated C unit in the organometallic intermediate then undergoes reductive elimination reaction with the other moiety on the same metal to form the chiral product. The other moiety is mainly carbon derivatives and has been recently extended to heteroatoms such as Si, B, N, and F, giving rise to enantioenriched products constructed by C–C, C–Si, C–B, C–N, and C–F couplings. Overall, the C–X formation could occur intra- and intermolecularly, which will be discussed separately in Sections 3.2 and 3.3.

3.2 Enantioselective Intramolecular Couplings of Aliphatic Substrates 3.2.1

C–C Coupling

To the best of our knowledge, the intramolecular coupling reactions reported to date to form C—C bonds involving a C(sp3 )–H activation as the stereodiscriminant step are all catalyzed by Pd complexes through a Pd(0)/Pd(II) mechanism (Scheme 3.1). The catalytic cycle begins with oxidative addition of a Pd(0) complex to the carbon (pseudo)halide bond, followed by salt metathesis with a metal carboxylate, which is generated in situ via deprotonation of the released carboxylic acid with an inorganic base. The resulting carboxylato-coordinated Pd(II) species subsequently activates the C—H bond via a typical concerted metalation–deprotonation (CMD) process [3]. A stereocenter is thus generated, and upon final reductive elimination, the enantioenriched coupling product forms. C–H Activation for Asymmetric Synthesis, First Edition. Edited by Françoise Colobert and Joanna Wencel-Delord. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.

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3 Enantioselective Intra- and Intermolecular Couplings

C

C

C *

X C H

LnPd0

LnPdII

X LnPdII

C

C *

H C

C O

O R

R

OH

R*

R O

OM

HB

MB

O

*LnPdII C

H C

or

O

MX

O

LnPdII C

H C

Scheme 3.1 General mechanism of palladium(0)-catalyzed asymmetric intramolecular coupling of aliphatic substrates.

This methodology was first disclosed by Kündig when they attempted to make chiral fused indolines 3 from N-cycloalkyl-substituted carbamate 1 [4]. A well-defined palladium-(S,S)-NHC complex [PdI(η3 -cinnamyl)(L1*)] (2) together with pivalic acid and Cs2 CO3 was initially used. Under this condition, the C—H bond on the methylene group is selectively activated. The N-cyclohexyl is thus desymmetrized, and with subsequent C–C coupling cyclization, fused indoline 3a was obtained in a good yield of 89%. Remarkably, the (S,S)-NHC auxiliary ligand dictates only the trans fusion with the (S,R)-enantiomer generated in an excess of 95%. The pivalic acid is essential to the high yield in accordance with the above mechanism. The naphthyl substituents in the NHC ligand provide extra sterical protection to the metal center, making it robust at 140 ∘ C or even higher temperature with more challenging substrates. DFT calculation, kinetic isotope effect, and stoichiometric experiments indicated that the halide/carboxylate ligand exchange is the rate-limiting step; the CMD is relatively faster and determines the stereoselectivity in this process [5]. Later, the authors simplified the system by generating the Pd-(S,S)-NHC catalyst in situ and found it almost equally efficient. In addition, the enantioselectivity could be delicately inversed when the corresponding (R,R)-NHC⋅HI was used in a follow-up study (Scheme 3.2). These optimal conditions were thus used to extend the substrate scope. First, it was found that aryl bromide gives the best results than other aryl (pseudo)halide for this system. Second, ethyl carbamate induces the best activity to the reactant (3b). However, for availability concern, the methyl ester analogues were kept

3.2 Enantioselective Intramolecular Couplings of Aliphatic Substrates

N

N

N H CO2Me

Xylene, 140 °C, 24 h

CO2Me 1a

(S,S)-L1•HI

H

[PdCl(η3-cinnamyl)]2 L1•HI Cs2CO3, CsCO2tBu

Br

(S,R)-3a, 84%, 95% eea

N

N

(R,R)-L1•HI

I

H

I

H N H CO2Et

H

F N H COiPr

3b, 92%, 94% eeb

H

3d, 81%, 92% eea

N H CO2Me

3g, 94%, 95% eea

3h, 86%, 90% eea

N N H CO2Me

H N H CO2Me

3e, 92%, 93% eeb 3f, 77%, 80% eea

H

X

S

H N H CO2Me

3c, 68%, 94% eeb

N H CO2Me

N

H

H N H CO2Me

X = Br, 3i, n.d.a Cl, 3j, 13%, 10% eea

N H CO2Me 3k, n.d.a

N

N H CO2Me 3l, n.d.b

Reaction condition: carbamate (1 equiv), 2.5–5 mol% [Pd(η3-cinnamyl)Cl]2, 5–10 mol% NHC•HI, cesium pivalate (1 equiv), cesium carbonate (1.5 equiv), xylene or mesitylene, 140 or 160 °C. a(S,S)NHC•HI; b(R,R)-NHC•HI.

Scheme 3.2 Chiral Pd-NHC-catalyzed asymmetric synthesis of fused indolines 3 from carbamates 1.

being used for other scope examination. Such reaction shows generally good tolerance toward various functional substituents or heteroatoms incorporated in the aryl and the aliphatic parts with compounds 3d–3f selected as representatives. It has also been successfully extended to cycloheptyl-fused indoline (3g) as well as simple 2-methyl-substituted indoline (3h) by C–H activation of a methyl group instead. The reaction is, however, not suitable for substrates with bromo/chloro-substituted aniline precursors, N-cyclopentane, and 2-aminopyridine (3i–3l). When the substrate contains unsymmetrical N-alkanes such as an isobutyl group, the C–H activation could occur under extreme conditions at four sites (Scheme 3.3). Activation of the tertiary methine C–H is less likely considering Br [Pd]/L N CO2Me 4a

N

*

+

CO2Me 5a, methine

* + N CO2Me 6a, α-methyl

* + * N CO2Me

7a, methylene

Scheme 3.3 Potential products in the C(Ar)–C(sp3 ) coupling reaction of 4a.

N * CO2Me 8a, β-methyl

81

82

3 Enantioselective Intra- and Intermolecular Couplings

Table 3.1 Regiodivergent synthesis of 2-substituted indolines 6 and 2,3-disubstituted indolines 7. Br N CO2Me

R1

[PdCl(η3-cinnamyl)]2 L1•HI Cs2CO3, tBuCO2Cs Xylene, 140 °C, 24 h

4

H R1 R1 N H CO2Me

N H CO2Me

6

7

Entry

Starting material

R1

L1 ·HI

6 (yield, ee [%])

7 (yield, ee [%])

1

4a

Me

(S ,S )

(R )-6a (59, 68)

(R ,S )-7a (35, >99)

2

4b

Ph

(S ,S )

(R )-6b (49, 95)

(R ,S )-7b (44, 98)

3

4c

4-OMe-Ph

(R ,R )

(S )-6c (50, 93)

(S ,R )-7c (49, 99)

4

4d

2-OMe-Ph

(R ,R )

(S )-6d (60, 66)

(S ,R )-7d (38, 99)

5

4e

2-Furyl

(R ,R )

(S )-6e (45, 97)

(S ,R )-7e (42, 98)

6

4f

(CH 2 )2 OTBS

(S ,S )

(R )-6f (68, 30)

(R ,S )-7f (21, >99)

the ring strain of the resultant four-membered azacycle 5a; formation of this product is indeed not observed. The activation of β-methyl C–H to form tetrahydroquinoline 8a is also challenging due to the necessity of forming a seven-membered palladacyclic intermediate according to the mechanism (Scheme 3.1). Only the two indoline products 6a and 7a were experimentally obtained as they are both stable five-membered rings formed via six-membered palladacyclic intermediates (Table 3.1) [6]. Using the same catalytic system as above, the 2-substituted indoline 6 was generally obtained in higher yield compared with the 2,3-disubstituted indolines 7 in line with the better acidity and sterical availability of the methyl C–H in 4. The reactivity of methylene C–H is electronically enhanced when an (hetero)aryl R1 is adjacent, thus resulting in a lower discrimination between the two products (Entries 2, 3, and 5), while ortho substitution on the aryl ring expectedly deactivates it due to steric hindrance (Entry 4). Notably the generally inferior activity of the methylene C–H leads to a better stereocontrol during the CMD, and enantiopure 7 is obtained in most cases. Besides chiral NHCs, phosphorous-derived ligands have proven to be as good chiral auxiliaries also for the C(sp3 )–H activation and cyclization. Due to their ready availability, more relevant studies have been carried out in the last few years, and a wide array of industrially useful, enantioenriched cyclized products have been obtained.

3.2 Enantioselective Intramolecular Couplings of Aliphatic Substrates

For example, similar indolines have been prepared by Kagan and coworkers [7] and Cramer and coworkers [8] using chiral phosphine ligands derived from phospholanes as chiral space inducers and carboxylic acids as hydrogen abstractor upon deprotonation by inorganic base (Entries 1–6, Table 3.2). Notably, the chiral environment for asymmetric C–H activation could also be created by the chiral carboxylic acids. Theoretically, such chiral induction should be more effective as this ligand is closer to the reactive site and participates directly in the subsequent stereodiscriminant CMD process. Such strategy has been attempted with chiral Boc-valine amino acid [7] or a tetralinecarboxylic acid together with IPr ligand [8a] but with limited success. The readily available binol-derived phosphoric acids (BPAs), however, show promising results. A preliminary study was first conducted by Duan and coworkers [9], in which the simplest BPA1 was used in combination with an achiral phosphine L5 ligated Pd complex, giving the indoline 3a and 3h in moderate yields and enantiomer excess (Entries 7 and 8). Later, this system was modified by Baudoin and coworkers, a detailed optimization study allowed to determine a protocol permitting the generation of 3h in 86% yield and 92% ee (Entry 10) [10]. All these reactions require high temperature to overcome the energy barrier required for the C(sp3 )–H activation. The phosphine ligands display activity and stereoselectivity in a wide range. In general, they induce better reactivity and stereoselectivity to N-isopropyl substrates than the chiral NHC ligand L1 but behave poorer in the activation of methylene protons. For instance, the PCy3 /BPA2 has been successfully applied in the formation of 3p with a quaternary stereocenter by activating more sterically crowded methyl C–H protons. In contrast, the methylene C–H of the isobutyl group is even not reactive at all with L2/pivalic acid or PCy3 /BPA2, and the reactions selectively afforded the 2-ethyl-substituted indoline 6a (Entries 3 and 12). Indanes were synthesized by Baudoin and coworkers by cyclization reaction of substrate type 9 using chiral phosphine ligands [11]. Cmethyl –H activation of isopropyl substrate afforded product comprising cis-(CN, Me)-isomer 10 as the major product together with a noticeable amount of trans-(CN, Me)-diastereomer 11. In contrast, Cmethylene –H activation of those cycloalkane rings is diastereoselective to the former cis product (Scheme 3.4). The binepine ligand family outperforms the other phosphine ligands in such reactions without the necessity of adding carboxylic acid in addition to an inorganic carbonate base. The same group later found that the corresponding phosphonium tetrafluoroborates can be directly used as precursors using the basic reaction conditions; thus need for handling of air-sensitive binepines is avoided. Accordingly, a series of modulated binepines to be used for a broader range of substrates was prepared (Scheme 3.4, selected examples). Remarkably, even the substrate bearing the cyclopentyl motif has been successfully fused to the indane with a contra-thermodynamic trans ring junction (10i). For selected substrates, the reaction temperature could be lowered to 90 ∘ C, which represents a significant improvement compared to other discussed C(Ar)–C(sp3 ) coupling reactions. Expanded ring products were later obtained by Cramer and coworkers via delicate use of a cyclopropyl ring connected to the aryl bromide in substrates 12–14 (Scheme 3.5) [12]. The cyclopropyl C–H displays an enhanced acidity and

83

84

3 Enantioselective Intra- and Intermolecular Couplings

Table 3.2 Selected examples of Pd(0)/phosphine/acid-catalyzed asymmetric synthesis of indolines. X [Pd], PR3, acid N Y

Base, ∆

N * Y

X = Br, OTf; Y = COOMe, Tf

Acid

Ligand

Entry 1a

P

P

Yield, ee (%)

(R,S)-3a

60, 46

(S)-3h

97, 93

(S)-6a

65, 23

O

2a

OH

3a

Product

L2, Kagan i

Pr

4

P

b i

PrO

OiPr

H COOH

N H Tf

i

Pr

(S,R)-3m

66, 95

(R)-3n

55, 88

(R)-3o

96, 71

O

5b

N

L3, Cramer

O

P

6c

N Tf

OH HBF4 L4·HBF4, Cramer

7d PCy2

(S,R)-3a

39, 67

(S)-3h

47, 50

3b

n.d.

(S)-3h

86, 92

O O P O OH

8d L5

N Tf

BPA1, Duan CF3

9e

CF3

10e PCy3e 11e

O

O P O OH CF3

CO2Me N

(S)-3p

83, 84

CO2Me e

12

BPA2, Baudoin CF3

(S)-6a

31, 46

Reaction condition: aAryl bromide (1 equiv), 5 mol% Pd(OAc)2, 10 mol% L2, pivalic acid (0.5 equiv), Cs2CO3 (1.4 equiv), xylene, 140 °C, 2 h; bAryl triflate (1 equiv), 5 mol% [Pd(Cp)(η3-cinnamyl)], 12 mol% L3, 9H-anthene-9-carboxylic acid (0.05 equiv), Na3PO4 (1.2 equiv), xylene, 135 °C, 12 h; cAryl bromide (1 equiv), 5 mol% Pd(dba)2, 12 mol% L4·HBF4, pivalic acid (0.3 equiv), Cs2CO3 (1.5 equiv), mesitylene, 130 °C, 12 h; dAryl bromide (1 equiv), 5 mol% Pd(OAc)2, 10 mol% L3, BPA1 (0.1 equiv), Cs2CO3 (1.5 equiv), xylene, 130 °C, 12 h; eAryl bromide (1 equiv), 5 mol% Pd(PCy3)2, BPA2 (0.1 equiv), Cs2CO3 (3 equiv), DME, 4Å powdered MS, 120 °C, 24 h.

3.2 Enantioselective Intramolecular Couplings of Aliphatic Substrates Pd(OAc)2 or Pd2(dba)3 L, K2CO3 or Cs2CO3

Br

DMSO, 90–150 °C NC

i NC Pr

i

Pr

i NC Pr trans

cis

11

10

9

L

Product 10 (yield [%], dr, ee [%]) N S

P tBu i

NC Pr

F

10a (79, 22:1, 60)

L6

i

NC Pr 10b (90, 23:1, 64)

NC Pr 10c (95, 29:1, 80)

10d (75, 31:1, 80)

H

BF4 H P

10a (96, 89:1, 92) MeO

i NC Pr

Fe

10e (84, 99: 1, 90)

L7•HBF4

10f (80, 96)

H NC Cy 10f (46, 76)

H

H NC C7H13 10g (76, 60)

NBoc

H BF4 H P Ar

i NC Pr

i

H NC

H 10g (20, 84)

H NC

NBoc Ar = Ph, L8•HBF4 o-Tol, L9•HBF4

10h (97, 95)

10i (61, 56)

Scheme 3.4 Chiral Pd(0)-phosphine-catalyzed asymmetric synthesis of indanes.

allows its Cmethylene –H to be activated and subsequently coupled to the aryl ring via a seven- or even eight-membered palladacycles (vide infra). The resulting tetrahydroquinolines and dihydro-(iso)quinolones are obtained with a fused cyclopropane, all of which are important subunits found in natural products and synthetic drugs. Moreover, the cyclopropane provides further possibility of structure modifications via ring-expansion and ring-opening reactions. A taddol phosphoramidite ligand L10 turns out to be a versatile ligand for all the three substrates type [13]. Products 15–17 with various aryl, cyclopropyl, and N-substituents were obtained in good to excellent yields and enantiomer excesses. Similar system has also been applied with success in the synthesis of the drug candidate BMS-791325 by building up its cyclopropyl-fused azacycle core via this C(Ar)–C(sp3 ) coupling reaction [12b]. Its preparation was thus dramatically simplified demonstrating the synthetic utility of the current method. Moreover, this preliminary result indicates a potential extension of substrate scope to form more challenging seven-membered azacycles. Surprisingly, the reaction is tolerant to phenyl and benzyl substituents on the cyclopropane ring, although the C(sp2 )—H bonds are believed to be more

85

86

3 Enantioselective Intra- and Intermolecular Couplings

Pd(dba)2, L10 RCO2H, Cs2CO3

Br R1

O O

Solvent, 110–130 °C

O P N O

L10

15–17

12–14

R1

R2 N Tf

R1

R2 N R3

R2

R1

O

X

R1 N O

R3

15a, R1 = Me, R2 = H, 98%, 92% ee 15b, R1 = Ph, R2 = H, 89%, 94% ee 15c, R1 = Me, R2 = 3,5-F2, 89%, 86% ee

16a, R1 = Me, R2 = H, R3 = Me, 90%, 95% ee 16b, R1 = Bn, R2 = H, R3 = Me, 97%, 94% ee 16c, R1 = Me, R2 = 4-Me, R3 = Me, 94%, 93% ee 16d, R1 = Me, R2 = H, R3 = PMB, 99%, 95% ee 17a, R1 = (CH2)3Ph, R2 = H, R3 = Me, X = CH, 93%, 87% ee 17b, R1 = CO2Et, R2 = H, R3 = Me, X = CH, 99%, 83% ee 17c, R1 = (CH2)3Ph, R2 = H, R3 = PMB, X = CH, 98%, 89% ee 17d, R1 = H, R2 = H, R3 = PMB, X = CH, 70%, 85% ee 17e, R1 = (CH2)3Ph, R2 = H, R3 = PMB, X = N, 99%, 93% ee

Scheme 3.5 Chiral Pd(0)-phosphine-catalyzed asymmetric synthesis of six-membered azacycles.

reactive. In contrast the protocol is not compatible with an unsubstituted cyclopropyl ring as the Cmethine –H will be preferentially activated, giving rise to spirocyclic compounds as the major products. Such bias is significantly suppressed in the reaction with 14 so that the expected dihydroisoquinolone 17d could be obtained. Secondary amines/amides are neither amenable to such reaction possibly due to an unfavorable interference of the coordinative NH donor. However, the corresponding cyclized products have been accessed by removing the suitable protecting group on the tertiary nitrogen atom in 15–17. The C(sp2 ) coupling partner is not necessarily a bromo-arene ring but also has been extended to cyclic alkenyl bromide using simple Pd–phosphine catalyst by Charette group (Scheme 3.6) [14]. The asymmetric version of this direct alkenylation reaction was realized using binol-derived phosphoramidite L11 or a biphosphine monoxide. A cyclopropyl-fused azacycle 19 was prepared with comparable activity and selectivity. Lately, Cramer has further extended the partner scope to trifluoroacetimidoyl chloride (Scheme 3.7) [15]. Highly sterical hindered chiral alkoxy diazaphospholidine was found as the best phosphorous ligand to promote the bicyclic imine formation in high yields and excellent enantiomeric excesses. In contrast to PPh3 ,

3.2 Enantioselective Intramolecular Couplings of Aliphatic Substrates

Pd(dba)2, L11 2H, K2CO3

Br N

*

tBuCO

CO2Et

* CO2Et N

Toluene, 110 °C, 16 h

O

O 19 (88%, 90% ee)

18 L11: O

P N

O

Scheme 3.6 Chiral Pd(0)-phosphoramidite-catalyzed cyclopropyl C(sp3 )–H alkenylation.

R1 R2 N

R2

R1

Pd(allyl)Cp, L12 CsOAc

Cl RF

Toluene, 110 °C, 1–6 h

R2 R2

RF

N

20

21 L12: N tBu

P

N

OMe

tBu

Ph(H2C)3 Me Me

N

CF3

21a (81%, 96% ee)

Me Me

N

CF3

21b (73%, 97% ee)

N

CF3

21d (22%, 92% ee)

Me Me

N

CF3

21c (90%, 95% ee)

Ph(H2C)3

Ph(H2C)3

Ph(H2C)3

O

CF3

Me Me

N

F F 21e (93%, 97% ee)

N

nC7F15

21f (86%, 94% ee)

Scheme 3.7 Chiral Pd(0)-diazaphospholidine-catalyzed synthesis of 3-azabicyclo[3.1.0]-hexenes.

this special ligand successfully suppresses the CAr –H activation in the R1 group and grants this catalytic transformation decent tolerance with imidoyl chlorides bearing alkyl, aryl, and heteroatom-containing groups (21a–c). Moreover, it allows incorporation of perfluoroalkyl chains into the pharmaceutically important 3-azabicyclo[3.1.0]hexenes, which have been demonstrated as precursors

87

88

3 Enantioselective Intra- and Intermolecular Couplings

O R1

N

Pd(dba)2, L14 AdCO2H, Cs2CO3

O R1

Cl

N

Toluene, 110 °C

Toluene, 70 °C

R2

22, 23 O

O Ar

R1 N R2

25

O

O

R2

H

Ar

Pd(dba)2, L13 AdCO2H, Cs2CO3

Ar O P R O Ar

24

O tBu

Et N

O tBu

N

O tBu

N

N

Ph Ph Naphth Ph-4-CN 24a 24b 24c 24d (74%, 96% ee) (99%, 97% ee) (96%, 99% ee) (99%, 99% ee)

L13 (Ar = 3,5-tBu2-4OMe-Ph, R = N(CH2)4) Mes N L14 (Ar = 3,5-tBu2H Ph, R = Ph)

O

O

O PMB

N

N

Mes

NC

H H 25a 25b (99%, 86% ee) (99%, 85% ee)

O

H 25c (99%, 90% ee)

N Et

25d (75%, 58% ee)

Scheme 3.8 Chiral Pd(0)-phosphine-catalyzed asymmetric synthesis of β- and γ-lactams.

to heavily substituted pyrrolidines. The cyclization is not as efficient for imidoyl chloride without R2 substituents (21d). In 2014 and 2015, Cramer and coworkers disclosed the synthesis of chiral lactams via asymmetric C(sp3 )–H activation/cyclization (Scheme 3.8) [16]. Chloroacetamide was used as the substrate, of which a benzylic/cyclopropyl C–H on the N-substituent is stereoselectively activated and coupled to the α-C atom. This discovery represents a major breakthrough, which has expanded the aforementioned methodology boundaries from C(sp2 )–C(sp3 ) to C(sp3 )–C(sp3 ) bond formation. The challenges here rise mainly from the rare oxidative addition of the C(sp3 )–Cl to the Pd(0) center, the subsequent reductive elimination to form (strained) C(sp3 )–C(sp3 ) linkage, and the competitive electrophilic substitution of C–Cl with the carboxylate base. They have been overcome by using highly modular taddol phosphoramidite/phosphonite ligand family in combination with sterically hindered adamantly carboxylic acid. Both reactions are suitable for a wide range of tertiary acetamides. Better efficiency was achieved with bulky R1 substituent as that helps to prearrange the benzylic/cyclopropyl proton to the favorable position for activation/cyclization. The competition reaction of activating CPh –H present in the R1 and R2 substituents is again negligible in most cases. Formation of the ring-constrained β-lactam requires higher temperature than that of the γ-lactam. Of note, when both benzylic and cyclopropyl proton are present, the activation/cyclization sequence takes place selectively at the cyclopropyl C–H (25a, 25b). The cyclopropane has been preliminarily replaced by two methyl groups forming 25d, albeit with low yield and efficiency at this stage.

3.2 Enantioselective Intramolecular Couplings of Aliphatic Substrates

R

R

N

H Me

X O

Ar

Pd(OAc)2, L15 PhI(OAc)2, Ac2O or I2, AgOAc

R

N

O

Me

27a 88%, 93% ee

Ar L15

O

BnO Me

O 27b 54%, 90% ee

N

N

N

OH

Me

27

N

P

O O

26

O

O

X

EtOAc, 70–90 °C

Me

O

R

N

N O

27c 87%, 86% ee

Me

O

NC

Me

27d 91%, 91% ee

Scheme 3.9 Chiral Pd(II)-phosphoric acid-catalyzed C(sp3 )–H amination.

3.2.2

C—X Coupling

Few examples of C(sp3 )—N and C(sp3 )—Si bond formation have been disclosed by Gaunt and coworkers [17], Takai and coworkers [18], and Hartwig and coworker [19]. These challenging C(sp3 )–H functionalization occurs when secondary amines or hydrosilane are used as directing groups (DGs). The newly generated bonds in the arising cyclic aziridines and organosilicons are reactive toward further functionalizations with concurrent ring-opening process and thus serve as attractive precursors to industrially important chiral molecules that are otherwise difficult to access. The C(sp3 )–N coupling was catalyzed by Pd(II) complexes with 3,3′ -diaryl-binol phosphoric acid L15 as an asymmetric inductor (Scheme 3.9). The α-methyl C–H of an ester or amide group is selectively activated and subsequently coupled to the secondary amine forming the highly ring-constrained aziridines. A detailed kinetic study and computational investigation disclosed that such C(sp3 )–H amination occurs via a Pd(II)/Pd(IV)-catalytic process (Scheme 3.10) [20]. The amine first coordinates to the Pd(II) to direct the methyl C(sp3 )–H in proximity to the metal center. The C(sp3 )—H bond is subsequently broken in a similar CMD way assisted by the deprotonated 3,3′ -diaryl-binol phosphoric acid ligand. The resulting four-membered metallacycle undergoes oxidative addition with an external oxidant, subsequent amine deprotonation by the acetato ligand, and a final reductive elimination reaction to afford the three-membered aziridines. The chiral organosilicon compounds 31–33 were synthesized via dehydrogenative silylation of C(sp3 )—H bonds, which were catalyzed by Rh(I) complexes with chiral diphosphine ligands in the presence of a hydrogen acceptor (Scheme 3.11). Compound 31 was obtained with a tertiary carbon stereocenter through Cmethyl –H activation/cyclization of hydrosilane 28. When a dihydrosilane 29 was used instead, a sequential twofold Cmethyl –H activation/cyclization was also feasible, leading to the formation of 32 bearing a tetraorganosilicon stereocenter.

89

90

3 Enantioselective Intra- and Intermolecular Couplings

R R

HOAc

R N

X O

R

H

X

Me

O

O PdII O

H

OPO3R2*

Me Ar O

PdII(OAc)2 R

HN

O

R N

P

R

O X

OH O

Ar

R O HN * Pd II O

X O

Me

PhI(OAc)2 R X O

*

N

R O O

R

IV O

Pd

O

X O

PhI

R OAc HN IV OAc * Pd O O

HOAc

Scheme 3.10 Plausible mechanism of palladium(II)-catalyzed asymmetric intramolecular C(sp3 )–H aminations.

The stereoselectivity was significantly enhanced when an alternative cyclopropyl Cmethylene –H was involved in such reaction. The hydrosilyl ether was generated in situ and used without isolation via a Ru-catalyzed dehydrogenative coupling of cyclopropylmethanols 30 with diethylsilane. Ligands screening showed that diphosphines having electron-rich biaryl backbone is generally much more reactive. This is in accordance with the proposed mechanism in which the C(sp3 )–H is activated via oxidative addition to the Rh(I) center; thus a more electron-donating ancillary will be favored by making the Rh(I) center more electron rich (Scheme 3.12).

3.3 Enantioselective Intermolecular Couplings of Aliphatic Substrates Intermolecular coupling reaction via transition metal-catalyzed C–H functionalization is relatively more difficult to realize as it involves sequential asymmetric activation of a C(sp3 )—H bond in one molecule and a related fragment in an independent coupling partner. Great efforts initiated by Yu group have been invested to this area, and to date a decent amount of protocols have been established as highly effective methodologies to construct practically useful molecules. In all these reported processes, a directing donor group in the C(sp3 )–H-containing substrate is essential for an efficient activation to form a

3.3 Enantioselective Intermolecular Couplings of Aliphatic Substrates t

OMe

Bu OMe

[RhCl(cod)]2, L16 3,3-Me2-1-butene H

Si Me Me

*

1,4-Dioxane 50 °C, 24 h

28

Si Me Me

[RhCl(cod)]2, L17 3,3-Me2-1-butene

t

R O Si Et Et

30

PPh2

THF, 50 °C, 24 h

O

OMe

O

tBu

P P

L17

R O Si Et Et

R = Ph, 33a (71%, 87% ee) 2-Naphth, 33b (78%, 90% ee) 3-OMe-Ph, 33c (89%, 91% ee)

tBu

O

L16

PPh2

[RhCl(cod)]2, L18 cyclohexene

H

C6H6 or THF 50 °C, 12 h

2

2

Bu

32 (75%, 40% ee)

RuCl2(PPh3)3 Et2SiH2 OH

OMe

* Si

1,4-Dioxane 100 °C, 24 h

29

R

Bu Bu

t

OMe

31 (83%, 37% ee)

H Si H

t

P P

MeO MeO

2

tBu

O

OMe t

Bu

2

L18

Scheme 3.11 Chiral Rh(I)-diphosphine-catalyzed C(sp3 )–H silylation.

stable five-membered metallacycle intermediate. The stereoselectivity, on the other hand, is at the same time induced by an external chiral auxiliary ligand. In general, the efficiency and stereoselectivity of the reactions arise from a proper combination of all the three reaction components, i.e. substrates (DG), chiral ligands, and metal centers. The discussion here will be divided into three sections primarily based on the different transition metal that was used. In all but two exceptions, direct C—C bonds were formed as results. 3.3.1

Pd Catalysis

The reported reactions were most commonly catalyzed by palladium complexes that can be categorized into two mechanistic scenarios (Scheme 3.13). Both catalytic cycles begin with a directed C—H bond cleavage reaction facilitated by a basic Pd(II) complex, during which a stereocenter is generated. The resultant organometallic species further react in two different ways dependent

91

92

3 Enantioselective Intra- and Intermolecular Couplings

* Si Me Me

H Si Me Me

I

Rh H

iPr

Rh

H Rh III Si H Me Me

III

H Si Me Me

t

Bu

H

i

Pr H

I

Rh Si Me Me

Rh Si Me Me

III

t

Bu

tBu

Scheme 3.12 Proposed mechanism of Rh(I)-catalyzed asymmetric intramolecular Csp3 –H silylation.

on the coupling partners. Boron compounds will participate in transmetalation/reductive elimination reaction to give the coupled product, the catalytic cycle of which is subsequently closed by reoxidation with an external oxidant (left, Pd(II)/Pd(0)). Aryl halide, on the other hand, oxidatively adds to the intermediate and upon reductive elimination affords the coupled compound (right, Pd(II)/Pd(IV)). The first example employing the Pd(II)/Pd(0) way was reported by Yu and coworkers early in 2008, when they attempted asymmetric mono-butylation of the two enantiotopic methyl groups in substrate 34 to generate chiral product 35 (Scheme 3.14) [21]. The connected pyridine acts as the DG through precoordination to the metal center and thus brings the methyl C–H in proximity for activation. Chiral environment is presumably crafted by cyclopropyl amino acid L19 with both the NH and the carboxylate moieties coordinating to the Pd center in a bidentate manner. Remarkably, both the N-Boc and the α-Ph substituents are important in restricting the amino acid coordination conformation, which in turn affects the chiral C–H activation/C–C coupling to one enantiomer in excess. Benzoquinone (BQ) was added to accelerate the C–H activation and reductive elimination process, and Ag2 O plays the role of the oxidant. Although the product 35 was obtained only in 38% yield and 37% ee in this preliminary study, there is a vast potential for further improvement considering the diversity and ready availability of chiral amino acids. Therefore, this example formally opens new avenues for the

3.3 Enantioselective Intermolecular Couplings of Aliphatic Substrates

[O]

DG * C C

LnPdIIX2 LnPd0

DG * C C

DG C H Ln GD Ln

II

Pd

GD

C

*

HX

Y

IV

Pd

X C

C

C

*

Ln

II

Pd

GD

X C

*

M X

Y C

M C

Scheme 3.13 General mechanism of Pd(II)-catalyzed asymmetric intermolecular coupling of aliphatic substrates. DG: directing group.

Bu

N

B(OH)2

Pd(OAc)2, L19 Ag2O, BQ tamylOH,

100 °C, 6 h

34

Bu N

*

35 (38%, 37% ee) L19:

Ph

CO2H NHBoc

Scheme 3.14 The first example of Pd(II)/Pd(0)-catalyzed asymmetric intermolecular coupling.

potential application of chiral amino acid and their congeners in the asymmetric C(sp3 )–H activation/transformations. A follow-up study by the same group employed the N-arylamide-directed cyclopropane (36) Cmethylene –H activation/organoboron cross-coupling as the model reaction to investigate the detailed development of a versatile chiral amino acid ligand (Scheme 3.15) [22]. Base was added to accelerate the C—H bond cleavage at a milder condition. The mono-N-protected amino acid (MPAA) ligand L20 featuring a bulky and electron-deficient carbamate protector and an aryl side chain outperforms the others among a wide range of amino acids. The reaction allows Ccyclopropane to be coupled with arenes, olefins, and alkanes in significantly improved efficiency and enantioselectivity (39a–39d). The asymmetric activation of less reactive cyclobutane Cmethylene –H and acyclic Cmethyl –H in substrates 37 and 38 needs fine-tuning of the amino acid ligand [23]. Derivatization to mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) series was found beneficial owing to their increased Lewis basicity,

93

94

3 Enantioselective Intra- and Intermolecular Couplings F F

CN

N H

F

O R1

F

Pd(OAc)2, L Ag2CO3, BQ, base

R2 Bpin

O R1

Solvent, 40–70 °C

or R2–BF3K

*

F

*

R2

Product (yield, ee [%]) O

F

Me

O Me

CCl3 O

O L21 Ar = 4-F-Ph

Et

O N H

Ar

Bu

N H

Ph

Boc

N H

O L22

H N

OMe

Me

*

Ar

Ph-4-NHAc

40a (75, 92)

Et

N H

40b (57, 93)

O

Ar

N H

F

39c (49, 62)

39d (70, 91)

PhthN N H

Ar

Ph

Bu

O

Et

O i

Me

39b (60, 82)

F

O

n

O

N H

Ar

Ph

Ar Ar H N OMe

N H

Ar

39a (81, 91)

L20

Boc

N H

F COOH

N H

O

F F

39–41

Ligand

Pr n Pr

CN

N H

36–38

n

F

O

Ar

Ph 40c (61, 92)

N H

Ar

Ph 40d (68, 81)

O N H

Ar

Ph 41a (32, 29)

t

Bu Me

*

N H

Ar

Ph-4-OMe 41b (61, 80)

Scheme 3.15 N-arylamide-directed C(sp3 )–H functionalization with organoboron reagents.

which would result in a stronger coordination to the Pd(II) center rigidifying the transition state and thus enhancing the stereoselection. The highest yields and enantiomeric excesses of cyclobutane transformation were eventually achieved with 2,6-(4-F-Ph)2 -phenylalanine O-methylhydroxamic acid ligand L21, while L22 with an isobutyl side chain is more effective for the enantioselective activation of acyclic Cmethyl —H bonds. These two reactions are thus far limited to arylation but with good functional group tolerance on the aryl rings. In addition, a bulkier α-substituent R1 is seemingly conducive for the arylation and allows the preparation of products with highly sterically congested quaternary stereocenters (40c, 41b). The resulting compounds 39–41 are valuable precursors to the respective chiral carboxylic acid upon hydrolysis. When the organoboron reagent was replaced with bis(pinacolato)diboron, the cycloalkane Cmethylene –H and isopropyl Cmethyl –H were activated and transformed to form C—Bpin bonds instead [24]. Acetyl-protected aminomethyl oxazolines (APAO) capable of bidentate chelation to Pd(II) center were developed as the best catalysts in this borylation reaction. However, the different substrates are sensitive to the catalyst structure with the best match displayed in Scheme 3.16. In contrast to the aforementioned reactions, α-substituent R1 is not necessarily required in this case. The resulting chiral boronate esters were demonstrated to serve as precursors to introduce functions such as OH and halide groups with

3.3 Enantioselective Intermolecular Couplings of Aliphatic Substrates F

O R1

F

CN

N H

F

F

Pd(OTf)2(CH3CN)4, L O2, K2HPO4

B2Pin2

O R1

CH3CN/DCE/H2O 80 °C

F

*

F

CN

N H BPin

*

43

42

Ac

Ac

O

N H

F F

N

N Ph

L23

Ac

O

N H

L24

O

N

N H

O N H

BPin 43a (32%, 95% ee)

Ar

Et

O

N H

Ar

N

Ph L26 (Ar = 4-CF3-Ph)

L25

O Ar

Ac

O

N H

O Ar

Me

N H BPin

*

BPin 43b (78%, 96% ee) 43c (75%, 99% ee)

N H BPin

Ar

43d (54%, 66% ee)

Scheme 3.16 Pd(II)/Pd(0)-catalyzed asymmetric C(sp3 )–H borylation.

enantiomeric ratio retention. Moreover, they are important coupling partners in the well-known Suzuki–Miyaura reactions. Besides, these chiral boronic ester derivatives could also be used as original coupling partners in other C–H functionalization reactions delivering even more complex scaffolds (see Scheme 3.15). The amide substrates scope was lately extended to sulfonamide, of which the γ-C(sp3 )–H was functionalized by using the APAO ligands (Scheme 3.17) [25]. Arylation and vinylation requires fine-tuning of the APAO ligand at the oxazoline R1

Me NHTf

+

Ar Bpin or Vinyl Bpin

Pd(OAc)2, L Ag2CO3, BQ, Na2CO3 AmylOH/THF/H2O 70–80 °C

44 Ligand

Ac

N H

R1

t

R2 NHTf 45

Product (yield, ee [%]) CO2Me OMe

NBoc

O N

NHTf Ph

L27

CO2Me

NHTf

45a (64, 97)

NHTf 45c (58, 96)

45b (60, 96)

NHTf 45d (45, 96)

Ph Ac

N H

O

Ph

Ph

Ar NHTf

N

Ph L28 (Ar = 4-F-Ph)

45e (56, 99)

NHTf

NHTf

45f (58, 98)

NHTf

45g (65, 99)

CO2Me Ac

N H

CO2Me

O N

L29

TBSO NHTf 45i (32, 96)

45h (54, 98)

NHTf 45j (34, 98)

MeO2C

NHTf 45k (34, 94)

NHTf 45l (19, 99)

Scheme 3.17 Pd(II)/Pd(0)-catalyzed asymmetric γ-functionalization of Tf-protected amines.

95

96

3 Enantioselective Intra- and Intermolecular Couplings

rings. The γ-C(sp3 )–H functionalizations lead to desymmetrization of the prochiral carbon in 44a–44h, furnishing aryl/vinyl-functionalized chiral sulfonamides with various substituents in moderate yields with excellent enantioselectivity. However, no corresponding product was observed using bromophenyl boronic acid pinacol ester, probably due to a competitive arylation reaction via Ar—Br bond activation (Pd(II)/Pd(IV), vide infra). The combination of unsymmetric amines 44i–44l with the APAO ligand L29, on the other hand, affords the cross-coupled product by kinetic resolution in relatively lower yields. Remarkably, the catalytic system is sufficiently selective in differentiating the terminal C–H of ethyl from methyl and propyl groups (45i, 45j) and is compatible with amino alcohol/acid-derived substrates (45k, 45l). The Tf group of 45 could be conveniently removed to yield the respective free amine, or they could undergo intramolecular C(sp2 )–N coupling to afford tetrahydroquinolines, both of which showed no loss of optical activity. Installing a C—C bond asymmetrically at the α-position of an amine is a long-standing challenge but an attractive strategy to construct enantioenriched N-compounds. Yu group thus continued their exploration of C(sp3 )–H activation/organoboron cross-coupling, aiming at the α-functionalization of amines [26]. A less common thionyl DG is connected to the nitrogen atom in this case (Scheme 3.18). While the aforementioned amino acid did not lead to any coupled product, the BPAs showed promising activity and stereoselectivity Ar′

N Ar

+

Pd2(dba)3, L30 BQ, KHCO3

R B(OH)2

65–85 °C Ar = 2,4,6-iPr3-Ph

S

Ar

46

Ar

O

N Ar

47a (87%, 96% ee)

O OH

Ar′ L30 (Ar′ = 9-anthracenyl)

Ph

Ph S

P

S 47

N

O

R

N

tamylOH,

Ph

N Ar

S

47b (62%, 91% ee)

N

Ph S

47c (54%, 97% ee)

Ar

S

47d (40%, 96% ee)

Ph Ph

N Ar

S

47e (86%, 96% ee)

3N

Ar

Ph-4-COCH3

N S

47f (53%, 84% ee)

Ar

S 47g (79%, 94% ee)

Me

N Ar

S

47h (47%, 75% ee)

Scheme 3.18 Pd(II)/Pd(0)-catalyzed asymmetric α-functionalization of amines.

3.3 Enantioselective Intermolecular Couplings of Aliphatic Substrates

in the proposed reaction. The easy modification of BPAs also allowed ligand optimization study, with L30 established as the most effective one. This protocol allows convenient α-arylation of aza-heterocycles with fourto seven-membered rings in good efficiency and excellent enantioselectivity (47a–47d). The reported α-lithiation followed by cross-coupling with aryl halides represented another well-established way of making chiral amines [27]. It is, however, limited to the α-arylation of pyrrolidines and piperidines, highlighting the significance of the current system. Moreover, the C(sp3 )–H arylation is somewhat regioselective in this protocol, when unsymmetrical N-substituents are present (47e, 47f). The DG was shown to be removable furnishing the secondary amine with complete preservation of the enantiomeric excess. The first example of intermolecular C(sp3 )–H activation/arylation with aryl halide through the Pd(II)/Pd(IV) cycle was also disclosed by Yu and coworkers using mono N-protected chiral amino acid [28]. The substrate was cyclopropanes with a weakly coordinating sulfonamide DG (Scheme 3.19). Amino acid L31 was found as the best chirality inductor with a Boc protecting group and an isopropyl side chain. In this case, Ag2 CO3 was added to scavenge the iodido ligand in the palladacyclic intermediates as well as to promote the oxidative addition and reductive elimination processes. The reaction is suitable for both unsubstituted and alkyl/aryl-substituted cyclopropanes with regioselective activation of the cyclopropyl Cmethylene —H bond. Functional groups on the aryl iodide were well tolerated under the reaction conditions. Substrates with the more common carboxamide groups were used in the following studies to direct transformation of acyclic C(sp3 )—H bonds. The distinct

NHTf R1

+ Ar

I

Pd(OAc)2, L31 Ag2CO3, NaTFA tBuOH,

Ar

*

NHTf

*

80 °C, 18 h

R1

48

49 Me

iPr

Boc

N H

CO2H

L31

NHTf

NHTf

49a (83%, 98% ee)

49b (83%, 99% ee) Me

Cl

Me F F

NHTf

NHTf NHTf 49c (87%, 99% ee)

Bn 49d (91%, 98% ee)

F 49e (99%, 99% ee)

Scheme 3.19 The first example of Pd(II)/Pd(IV)-catalyzed asymmetric C(sp3 )–H arylation.

97

98

3 Enantioselective Intra- and Intermolecular Couplings

N H

α

R1

Ar

O

β

N

or γ R2

PdCl2(CH3CN)2 L32 or 33, Cs2CO3

+ Ar

I

α N β H

R3

N

N H

R1

Q

or

Xylene, 140 °C, 12 h or neat, 110 °C, 24 h

O

O

Ar

O N H

R2

R3

N

52, 53

50, 51 OMe O O P O NH2

N H L32

Q

52a (97%, 80% ee)

O O P O OH

L33/BPA1

F

N H

52b (74%, 71% ee)

N H

52c (43%, 72% ee)

O

N

53a (97, 90% ee)

N H Br

Q

OMe

O N H

O

Q

OMe

CF3

Ph

S

O

O

O Ph N

53b (97, 92% ee)

N H

N

53c (97, 93% ee)

Scheme 3.20 Pd(II)/Pd(IV)-phosphoric acid/amide-catalyzed asymmetric β- and γ-Cbenzylic –H arylation.

β-arylation was first achieved by Duan group [29] using phosphoric acid/amides (Scheme 3.20). The substrates 50 used here contain an additional quinoline moiety that together with the carboxamide enables bidentate coordination to the Pd center to direct C(sp3 )–H functionalization. Kinetic studies indicated that the C—H bond cleavage is the rate-limiting step, and the phosphoric amides showed superior acceleration effect than that of the well-established pivalic acid. Thus, the employment of chiral phosphoric amides here not only omits the necessity of adding an additional chiral source for enantiocontrol, but it also assists the C–H cleavage more effectively to give relatively higher yields. He and Chen subsequently disclosed a similar combination of chiral phosphoric acid (L33) with picolinamide-type substrates 51 to direct γ-arylation under milder condition and with enhanced efficiency and stereoselectivity (53) [30]. In fact, these two examples are the very first reports of introducing phosphoric acid/amides to asymmetric C–H activation. However, both these two systems are only suitable for the arylation of benzylic C–H, while the stereocontrol for more prevalent aliphatic methylene is poor. The substrate scope was extended to aliphatic Cmethylene –H by Yu and coworkers when they inversed the situation by using substrates with a mono-coordination site (54) but bidentate ligands of acetyl-protected aminoethyl quinoline (APAQ) [31]. DFT calculation revealed that the distinct six-membered palladacycle formed via bis-chelation of the APAQ ligand L34 generated a beneficial chiral

3.3 Enantioselective Intermolecular Couplings of Aliphatic Substrates F β R1

F

O

+ Ar

F

N H

α

Pd(OAc)2, L34 Ag2CO3

CF3 I

Ar

N H

R1 β

HFIP, 80 °C 36 h

F

54

N Ac

ArF

55

O ArF

N H

55a (89%, 90% ee)

Et t

Bu

N H t

L34

O

O N H

O

ArF

O N H

55b (61%, 88% ee)

Bu

ArF

N H

55c (72%, 88% ee)

ArF

55d (81%, 90% ee)

Scheme 3.21 Pd(II)/Pd(IV)-catalyzed asymmetric β-Caliphatic –H arylation. β PhthN

O

α

R1

N H 56, 57

+ R2

I

R2 O

Condition a/b/c/d

N R1 H 58, 59 *

PhthN

O Ac

Ac

O

N H

or

N Ph

L35

N H

O

Ph

N L36

Ph

ArF O2N

58a (68%, 96% ee)

N H

N H

O Ph

NTs 58d (60%, 84% ee)

ArF

58e (60%, 88% ee)

N H

MeO2C

58f (43%, 88% ee)

O F

PhthN

O

F

N H

L37

O N

Ph

OMe

F 59a (66%, 94% ee)

PhthN

N H

OMe

58c (60%, 96% ee)

ArF

ArF

58h (60%, 89% ee) O

O N H

OMe

CF3 59b (75%, 92% ee)

N H

TIPS

58g (57%, 86% ee)

PhthN

ArF

O N H

O N H

F

F

ArF

N H

S

O

O N H

ArF

58b (72%, 98% ee)

O ArF

O

O N H

Ph

59c (72%, 89% ee)

PhthN

N H

OMe

O O 59d (70%, 90% ee)

Condition a: PdCl2(CH3CN)2, NaTFA, L35, Ag2CO3, toluene, 60 °C 72 h; b: Pd(OAc)2, L36, Ag2CO3, toluene, 50 °C, 72 h; c: PdCl2(CH3CN)2, NaOAc, L36, Ag2CO3, toluene, 50 °C, 48 h; d: Pd(OAc)2, L37, AgOAc, HFIP, 35 °C, 72 h.

Scheme 3.22 Pd(II)/Pd(IV)-catalyzed asymmetric β-Cmethyl –H functionalization to generate α-chiral centers.

environment for the regio- and stereoselective β-C–H activation/coupling. The products were prepared in constantly high selectivity (Scheme 3.21). When the monodentate substrates are isobutyric acid derivatives, its β-Cmethyl –H functionalization would provide convenient access to enantioenriched carboxylic acid with α-chiral centers. This was realized by Yu and coworkers employing the bidentate aminomethyl oxazoline ligands L35–L37 (Scheme 3.22) [32]. The acetyl-protected ligands L35 and L36 were efficient for the formation of tertiary carbon stereocenters (58), and the coupling partner is not only limited to aryl iodide (58a–58d) but also alkenyl (58e–58g) and alkynyl iodide (58h). The more challenging quaternary carbon stereocenter generation

99

100

3 Enantioselective Intra- and Intermolecular Couplings O R1

O Ar

OH

O

+

Ar

I

Pd(OAc)2, L38 Ag2CO3, Na2CO3

R1 O

Ar

60, 61 MeO2C

OH NPhth

N H

MeO2C

Br

O

62a (80%, 94% ee)

O

Ac OH

62b (81%, 88% ee)

O

Me

S

63a (65%, 72% ee)

OH

OH

62c (65%, 90% ee)

O

MeO2C

O

O

Me

OH NPhth

OH

Me 62e (76%, 90% ee)

NMe2

L38

62, 63

OH

MeO2C

Ac

Me

HFIP, 80 °C 16–24 h

OH Me NPhth

OH

62d (76%, 96% ee)

O OH NPhth

Me

O OH NPhth

Br 63b (65%, 84% ee)

63c (65%, 84% ee)

Scheme 3.23 Pd(II)/Pd(IV)-catalyzed asymmetric β-C(sp3 )–H arylation of carboxylic acids.

requires modification of both the N-substituent R1 in the substrate and the N-protecting group in the ligand. Eventually, the N-methoxy amide of N-phthaloyl-2-aminobutyric acid was successfully coupled to various aryl iodides using an ortho-difluorobenzoyl-protected aminomethyl oxazoline ligands L37. Remarkably, the rising products 58 and 59 still have one remaining methyl group, and an additional β-Cmethyl –H functionalization has been proven feasible by the authors to introduce aryl, alkenyl, alkynyl, and boryl groups with full conservation of the enantiomeric excess. This further widens the possible α-carboxylic acid product scope that can be obtained through the current recipe. Lately, Yu has realized the direct β-C(sp3 )–H arylation of free carboxylic acids by employing an ethylenediamine-derived chiral ligand (Scheme 3.23) [33]. The monoprotected aminoethyl amine (MPAAM) was applicable to the formation of both cyclopropanecarboxylic acid and 2-aminoisobutyric acid. α-Substitution is not necessary for the former affording respective product in comparable yields and stereoselectivity. The utility of this transformation was successfully demonstrated in the structural modification of itanapraced, which is a promising drug candidate for neurological disorders. As has been highlighted, a proper DG is often essential for the intermolecular C(sp3 )–H functionalization. However, their stoichiometric and covalent installation and removal limits the applicability especially when other functional groups present in the molecule are incompatible with the reaction conditions. While researchers are searching for new ligand families to realize functionalization of substrates without exogenous DGs, such as the above free carboxylic acid, Yu group has come up with an idea of using transient state DG, which forms when the catalytic cycle starts and dissociates when the catalytic cycle ends.

3.3 Enantioselective Intermolecular Couplings of Aliphatic Substrates O R1

+

Ar

Pd(OAc)2, L-tert-leucine AgTFA, H2O, AcOH

I

HFIP, 100 °C, 24 h

t

via:

O

Bu

Ar

R2

Pd O R2 OAc

R2

64

O

N

R1

65 O

O

CO2Me

F3C

F3C

Me 65a (62%, 96% ee)

Me 65b (88%, 96% ee)

Cl

O

O F

F

MeO2C

Me 65c (71%, 92% ee)

OBn 65d (54%, 96% ee)

Scheme 3.24 Pd(II)/Pd(IV)-catalyzed asymmetric Cbenzylic –H arylation via a transient imino acid directing group.

Yu group designed the usage of amino acid to aid the benzylic C(sp3 )–H arylation of 64 (Scheme 3.24) [34]. An imino acid was transiently formed from reaction with an aldehyde group in the substrate. It worked as a bidentate DG and, at the same time, a chiral auxiliary for the benzylic C(sp3 )–H arylation. More importantly, the chiral amino acid could be easily dissociated from the coupled product to react with another substrate molecule so that only a catalytic amount is needed. Notably, there are two more competitive reactions that could possibly happen during the consequential imine formation, imino acid coordination, and C–H activation. One is amino acid coordination to the Pd center, and the other is the imine decomposition before coordination and activation, both of which will lead to the erosion of reaction efficiency. The former requires suitable modification of the stereoelectronic properties of the amino acid with L-tert-leucine outperforming. The latter was resolved by adding water, which would reduce the concentration of the imine intermediate and prevent decomposition during reaction. In a recent study compound 64 was reacted with N-fluoro-2,4,6-trimethylpyridinium salt under similar conditions, and a mixture of acetoxylated 66 and fluorinated aldehyde products 67 were obtained (Scheme 3.25) [35]. Interestingly, these two products have opposite absolute configurations, with the minor product of the fluorinated one 67 showing the same configuration to that of the arylated product in the above study. The authors proposed that 67 forms via the classic inner-sphere reductive elimination, while the inversion of stereochemistry in 66 is a result of SN 2-type pathway, which is preferred under such conditions. The subsequent employment of alternative amino amide managed to switch the preference to afford 67 as the major product. Based on computational analysis, this is due to a more pronounced energy barrier decrease for the inner-sphere C(sp3 )–F reductive elimination. By using this ligand together with an electron-deficient carboxylic acid (C6 F5 COOH), a series of fluorinated aldehydes were obtained in moderate to good yields with high ee values. Generally, the C(sp3 )–F reductive elimination is easier for electron-deficient aldehydes, while those bearing electron-donating groups show limited success at this stage.

101

102

3 Enantioselective Intra- and Intermolecular Couplings via:

O

R1

BF4 +

Pd(OAc)2, L NBu4PF6, RCOOH

+

N F

R2

OAc R2

via:

O

64

R2 O

O i

F Me 67a (61%, 91% ee)

Bu

F

Pd

Pd

O

O

O OAc

F NEt2 O O

C6F5

L40

67 F3C

t

N

R1

F O

L39

66

Benzene 70 °C, 24 h

Bu N

R1 O

t

O O

O2N

Pr F

F

N

F Me

Me 67b (52%, 92% ee)

F3C

67c (38%, 99% ee)

67d (36%, 86% ee)

Scheme 3.25 Pd(II)/Pd(IV)-catalyzed asymmetric Cbenzylic –H fluoronation via a transient imino amide directing group.

3.3.2

Rh Catalysis

To the best of our knowledge, there is only one example of rhodium-catalyzed C(sp3 )–H functionalization reported to date. In this study, Glorius and coworkers utilized chiral NHC–Rh complexes to arylate benzylic C–H, which was directed by a quinoline group (Scheme 3.26) [36]. Elementary reactions probed by NMR spectroscopy suggested that the real catalyst is a Rh(I) complex that is coordinated by a bidentate C2 ligand generated in situ by deprotonation of the NCHN and ortho methyl groups on the N-aryl substituent of the NHC precursor. Such chelating mode is beneficial for both the subsequent oxidative addition and stereoselective C—H bond cleavage by electronically enriching the Rh(I) center and conformationally rigidifying the chiral environment, respectively. Different from the aforementioned Pd(II)/Pd(IV) route, this catalyst preferentially underwent oxidative addition to aryl bromides prior to quinoline coordination and C—H bond cleavage. With subsequent reductive elimination, the important chiral triarylmethanes were prepared in moderate to good yields and selectivity.

3.3.3

Ir Catalysis

The iridium-catalyzed asymmetric C(sp3 )–H activation was developed by Shibata and coworkers (Scheme 3.27) [37]. They used a chiral tolBINAP L42 to assist the enantioselective alkylation of the α-methylene C–H of 2-(alkylamino)pyridine/quinolones or N-(2-pyridyl)-γ-butyrolactams with alkenes. One example of alkenylation was also realized by reaction with alkyne (72f). By doing so, enantioenriched amines and γ-butyrolactams were obtained by subsequent deprotection of the directing pyridine/quinolones groups in the

3.3 Enantioselective Intermolecular Couplings of Aliphatic Substrates Ar1 N

Ar1 RhCl(PPh3)3, L NaOtBu Br Dioxane, 80 °C, 12 h

+ Ar2

68

Ar2

N

N Cl

F 69

N 69

N R* I PPh3 Rh PPh3

L41 OMe

Ar2 Br

Ar

t Bu

N

OMe

N

N

PPh3

PPh3

PPh3 IIIAr 2 Rh * Br C

PPh3 IIIAr 2 Ar 1 * Rh C * N

69a (75%, 78% ee)

69b (71%, 78% ee)

C

C

C *

C

PPh3 IIIAr 2

Rh

NaBr, HOtBu NaOtBu

N

F

68

F

N

N

Ar1

Br 69c (64%, 80% ee)

69d (78%, 68% ee)

Scheme 3.26 Rh(I)/Rh(III)-catalyzed asymmetric Cbenzylic –H arylation. N

N

[Ir(cod)2]BF4, L42

+

N

R1

O

DME or dioxane 75–100 °C, 48–96 h

PTol2 PTol2

O

70, 71

L42

72, 73

Ph

N

N

72a (76, 88% ee)

Ph N H

72e (69, 83% ee)

C4H9

N H 72f (32, 89% ee)

N H

72c (75, 99% ee) N

Ph

N

N H

72b (84, 87% ee) C4H9 N

CO2Et

N

N H

N H

N

R1 N *

Ph

72d (72, 98% ee) N

O 73a (85, 82% ee)

CO2Et N

N O

73b (87, 91% ee)

Scheme 3.27 Ir(I)/Ir(III)-catalyzed asymmetric α-functionalizations of amines and γ-butyrolactams.

resulting products 72 and 73. The γ-butyrolactams were further converted to the 4-substituted chiral γ-amino acids via ring-opening hydrolysis processes. Similarly to the mechanism proposed for the Rh-catalyzed dehydrogenative silylation (vide supra), the C—H bond here is activated via oxidative addition to the Ir(I) metal center, which omits the requisite of a base. The resultant

103

104

3 Enantioselective Intra- and Intermolecular Couplings

72a

H

70a

*IrI

Ph N

*IrI

III

N

*Ir N H

N H

*

*Ir III H

N Ph

N H

Scheme 3.28 Proposed mechanism of Ir(I)/Ir(III)-catalyzed asymmetric α-functionalizations of amines.

hydrido-iridium species underwent a formal hydroiridation addition to the alkenes/alkynes followed by reductive elimination to deliver the coupled product and the active iridium catalyst (Scheme 3.28).

3.4 Conclusion In conclusion, the stereodiscriminant C(sp3 )–H activation reported so far was either realized by deprotonation process with a basic transition metal (Pd, Rh) complex or oxidative addition to an electron-rich metal center (Rh, Ir) after precoordination of the “directing group.”1 Diverse ligand families of chiral phosphines, NHCs, amino acid, phosphoric acid, and their derivatives have been demonstrated as efficient asymmetric auxiliaries. Subsequent coupling reaction with an array of partners intra- and intermolecularly has provided convenient tools to access enantioenriched molecules of high interest. Most reactions are scalable to gram level without obvious loss of efficiency and stereoselectivity, which is important to practical production. Considering the enormous interests in developing efficient C(sp3 )–H functionalization in modern organic chemistry for the sake of atom and step economy and the importance of chirality in nature, the asymmetric C(sp3 )–H activation is expected to be widely expanded in the near future. 1 The directing group here has a broader definition referring to any coordinated unit that can bring the C(sp3 )-H in proximity to the metal center. For instance, the C unit in the intermediate resultant from intramolecular oxidative addition of the Pd(0) to the carbon (pseudo)halide in Scheme 3.1 counts.

References

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17 18 19 20 21 22 23 24 25 26 27

28 29 30 31 32 33 34 35 36 37

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4 Substrate-Controlled Transformation: Diastereoselective Functionalization Sheng-Yi Yan, Bin Liu, and Bing-Feng Shi Zhejiang University, Department of Chemistry, 38 Zheda Rd., Hangzhou 310027, China

4.1 Introduction Over the past decades, transition metal-catalyzed direct C(sp3 )–H functionalization assisted by a mono- or bidentate auxiliary group has been quickly developed [1]. Nevertheless, stereoselective functionalization of a prochiral C(sp3 )—H bond has not been well established probably because of the absence of suitable ligands or chiral auxiliaries [2]. Recently, a few Pd-catalyzed substrate-controlled stereoselective C(sp3 )–H functionalizations have been realized [1, 2]. Generally, three major strategies are adopted: (i) linking a directing group to chiral substrate, (ii) incorporating a chiral auxiliary into the substrate, and (iii) using a conformationally restricted cyclic substrate to impose a diastereoselective functionalization. Generally, category (iii) could be included in category (i). However considering that there are some unique features and special applications of the diastereoselective functionalization of cyclic substrates, we prefer to discuss this category separately. Guided by these strategies, highly diastereoselective C(sp3 )–H functionalization of amino acid derivatives bearing a mono- or bidentate auxiliary has been disclosed by several laboratories [3, 4]. Also diastereoselective functionalization of prochiral C(sp3 )–H with the help of chiral auxiliary has been achieved [5]. Finally highly diastereoselective γ- or δ-C(sp3 )–H functionalizations of some conformationally restricted cyclic substrates are described [6]. The present chapter aims to describe the recent advances in Pd-catalyzed substrate-controlled diastereoselective C(sp3 )–H functionalization reactions. The examples in each section are organized according to three different strategies adopted. Each section is further divided into subsections according to different directing groups used.

C–H Activation for Asymmetric Synthesis, First Edition. Edited by Françoise Colobert and Joanna Wencel-Delord. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.

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4.2 Diastereoselective Functionalizations of N-Phthaloyl-𝛂-Amino Acids 4.2.1 Diastereoselective 𝛃-C(sp3 )–H Functionalizations of N-Phthaloyl-𝛂-Amino Acids Unnatural amino acids are extensively applied in drug discovery, protein engineering, peptidomimetics, and glycopeptide synthesis, and thus numerous methods have been developed for their synthesis [7]. Traditional strategies for their preparation involve the synthesis of racemates followed by resolution, asymmetric synthesis using chiral auxiliaries, asymmetric hydrogenation, and biological approaches [8]. From the viewpoint of atom and step economy, transition metal-catalyzed diastereoselective C(sp3 )–H functionalization of optically active starting materials such as α-amino acids is rather appealing [3]. 4.2.1.1

Bidentate Directing Group

In 2006, Corey and coworkers reported a pioneering work on the Pd-catalyzed acetoxylation and arylation of N-phthaloyl-α-amino acids with the assistance of 8-aminoquinoline (AQ) auxiliary [4, 9]. The reaction occurred selectively at the β-carbon and the newly formed C—C or C—OAc bond adopted an anti position relative to NPhth group. They proposed that the observed stereochemistry of the β-functionalization can be rationalized by an in situ formation of the sterically more favored trans-palladacycle intermediate. Although this seminal work pioneered the tremendous efforts on the direct C–H functionalization of α-amino acids, the stereochemical integrity of the resulting products and the removal of the AQ group have not been reported. In 2012, Daugulis and coworkers investigated the diastereoselective β-C(sp3 )–H arylation and acetoxylation of N-phthaloyl-α-amino acids bearing an AQ auxiliary [10]. The AQ group can be removed by treatment of the arylated product 2 with BF3 ⋅Et2 O in MeOH to give the corresponding methyl ester (Scheme 4.1a). Consistent with Corey’s observation, the arylation and acetoxylation of methylene occurs with high diastereoselectivity in favor of the anti diastereomers (Scheme 4.1a,b). In order to identify the origin of diastereoselectivity, they conducted several mechanistic studies. They proposed that the diastereoselectivity is induced during the C–H activation step or, less likely, during the reductive elimination step. Since the protonation of intermediate B likely occurs with retention of configuration [11], and in H/D exchange experiment the major deuterium incorporation adopted S configuration, it can be assumed that the intermediate B has a trans arrangement of the phthaloyl and phenyl groups and that the diastereoselectivity of the arylation is established at the palladation step. Oxidative addition to give a PdIV intermediate C is followed by a reductive elimination that proceeds with retention of configuration (Scheme 4.1c). The diastereoselective C(sp3 )–H arylation was elegantly applied to the total synthesis of celogentin by Chen and coworkers. In this seminal work, the Pd-catalyzed diastereoselective arylation of valine derivative 4 was used as the key step, and a single diastereoisomer 6 was obtained in 85% yield on a 4 g scale (Scheme 4.2) [12].

4.2 Diastereoselective Functionalizations of N-Phthaloyl-α-Amino Acids NPhth H N

R H

N

Pd(OAc)2 (5–11 mol%) ArI, AgOAc,

Q

(a) NPhth H N Q H O 1a

Ph

(b)

O N H

N

BF3·Et2O

NPhth OMe

R

Q MeOH, 110 °C 60 °C, 72–96 h Ar O Ar O Phth = phthaloyl 2, Six examples R = iPr, Ar = p-OMePh 77–95%, dr = 13 : 1 to > 50 : 1 58%, 86% ee

O 1

NPhth H N

R

NPhth H N Q OAc O 3, 53%; crude dr = 8 : 1

Pd(OAc)2 (11 mol%) PhI(OAc)2, Ac2O

Ph

70 °C, 12 h

H

DS

O Ph

NPhth 1a

Pd(OAc)2 CD3CO2D

N H

N

Pd(OAc)2 –HOAc

O

Ph NPhth β-d –1a

N

O O

O

H

–HOAc Ph N NPhth C–H activation Pd OAc L A

N N

Pd L B

H

Ar Ph NPhth

Base +1a, –I

CD3CO2D

N

N H 2a

N

NPhth H Ph

ArI OA

NPhth

Pd L

N

O

I Ph Ar

RE

C

(c)

Ar Ph

N N

Pd I L D

NPhth

Scheme 4.1 (a) Pd(II)-catalyzed diastereoselective β-C(sp3 )–H arylation of N-phthaloyl-α-amino acids. (b) β-C(sp3 )–H acetoxylation of phenylglycine. (c) Mechanistic considerations. OA = oxidative addition, RE = reductive elimination. CO2Bu-t H

CO2Bu-t

O N H NPhth

+ N

4 (2.0 equiv)

Pd(OAc)2 (20 mol%) TsN AgOAc (1.5 equiv)

NHBoc I

t-BuOH, 110 °C, 36h 85%

N Ts 5 (1.0 equiv)

NH

O N H NPhth

N

6, Single diastereoisomer (4 g scale)

O O

NHBoc

OHN HN O HN O

N H

O NH

N HN

O NH2

N NH N

O HN NH

COOH Celogentin C

Scheme 4.2 Palladium(II)-catalyzed diastereoselective arylation of valine derivative as a key step in the total synthesis of celogentin C.

In 2013, the Chen and Shi groups independently reported the Pd-catalyzed diastereoselective alkylation of unactivated methylene C(sp3 )—H bonds of aminoquinolyl aliphatic carboxamides with α-haloacetates and methyl iodide (Scheme 4.3) [13]. This protocol enables the streamlined synthesis of various natural and unnatural amino acids in a diastereoselective manner. However, the

109

110

4 Substrate-Controlled Transformation: Diastereoselective Functionalization

O PhthN R′

O PhthN R′

Q

N H H 7

N PdII N

H

O PhthN

via

+ X Alkyl

R′

Conditions

H

X Alkyl = X

CO2R or MeI

H 8

Q N H Alkyl

Chen's conditions: Pd(OAc)2 (10 mol%), Ag2CO3 (2 equiv), (BnO)2PO2H (20 mol%), t-AmylOH, Ar, 110 °C, 6–24 h. 84–90% yield; dr = ∼ 3 : 1 to > 15 : 1 Shi's conditions: Pd(OAc)2 (10 mol%), Ag2CO3 (0.8 equiv), (BnO)2PO2H (30 mol%), DCE/t-BuOH (2 : 1), 90 °C, 9–12 h. 44–99% yield; dr > 50 : 1

Scheme 4.3 Pd-catalyzed AQ-directed diastereoselective alkylation of β-C(sp3 )—H bonds of amino acids with α-haloacetates and methyl iodide.

NPhth NHQ

R1 H

Pd(OAc)2 (10 mol%) Ag2CO3 (1.5 equiv) 4-ClC6H4SO2NH2 (0.3 equiv) + Alkyl

O 9

Alkyl

NaOCN (2.0 equiv) 1,4-dioxane, 80 °C, N2, 20 h

NPhth NHQ Alkyl O 10

I:

I

I

89% dr ∼ 8 : 1 I

I

R1

83% dr ∼ 10 : 1

84% dr 9 : 1

Ph 72% dr ∼10 : 1

I

I

I

( )5

I

I

36% dr ∼ 10 : 1

Ph CN I ( )5 Ph 55% dr ∼ 9 : 1

I

80% dr ∼ 10 : 1

CF3 ( )2 81% dr ∼ 12 : 1

OTBDPS ( )2 75% dr ∼ 15 : 1

( )16

I

Cy

Cl ( )5 83% dr ∼ 10 : 1 I

81% dr ∼ 12 : 1 O CO2Me NHCbz I I ( )3 ( )4 O I 71% 45% 86% dr ∼ 10 : 1 dr ∼ 12 : 1 dr ∼ 10 : 1 TIPS I I

79% dr ∼ 10 : 1

I

( )4 75% dr ∼ 12 : 1

56% dr ∼ 12 : 1

Scheme 4.4 Sulfonamide-promoted Pd(II)-catalyzed alkylation of β-C(sp3 )—H bonds of amino acids with various alkyl iodide.

scope with respect to the alkylation reagents was limited to two classes of very reactive alkylating agents that do not contain β-hydrogen atoms. To overcome this limitation, Shi and coworkers reported a sulfonamidepromoted palladium(II)-catalyzed alkylation of unactivated β-methylene C(sp3 )—H bonds of α-amino acid derivatives (Scheme 4.4) [14]. The reaction tolerates a variety of functional groups and proceeds efficiently with high diastereoselectivity. Notably, this reaction tolerates alkyl iodides containing eliminable 𝛽-hydrogen atoms. Furthermore, this protocol enabled the synthesis

4.2 Diastereoselective Functionalizations of N-Phthaloyl-α-Amino Acids

12 mol% Pd(OAc)2 Oxone (2.5 equiv) Ac2O (6.0 equiv)

NPhth H R N Q H O

MECN/DCE = 2 : 1 N2, 85 °C, 14 h

11 (a)

R

NPhth H N

NH2 Q Deprotection

12 51–86% yield dr = 1.7 : 1 to >20 : 1

(b)

O PhthN

N Pd

R AcO

OH

OH O 13, anti-βhAA R = 3,4-diMePh, 67% R = Ph, 77%

OAc O

O PhthN

R

N

vs. N

L

R

Pd

N

AcO

C–O coupling via intermolecular SN2 attack by OAc

Intramolecular C–OAc RE

R = Aromatic rings bearing EWGs or less sterically bulky groups

R = Aromatic rings bearing EDGs or sterically bulky groups

Scheme 4.5 (a) Pd-catalyzed acetoxylation of α-amino acid derivatives. (b) The possible origin of the diastereoselectivity in C–H acetoxylation.

of various β, β-hetero-dialkyl- and β-alkyl-β-aryl-α-amino acids via sequential C(sp3 )–H functionalizations. In 2015, Shi and coworkers reported a practical procedure for the stereoselective synthesis of anti-β-hydroxy-α-amino acids (anti-βhAAs) through palladium-catalyzed β-acetoxylation of N-phthaloyl-α-amino acids directed by AQ auxiliary (Scheme 4.5) [15]. They observed that the diastereoselectivities were strongly influenced by electronic effects and steric properties of the side chain of α-amino acids. To explain this phenomenon, a competition of intramolecular C—OAc bond reductive elimination from PdIV intermediates vs. intermolecular attack by an external nucleophile (AcO− ) in an SN 2-type process was proposed. More recently Shi group developed a PdII -catalyzed intermolecular silylation of primary and secondary C—H bonds of α-amino acids (Scheme 4.6) [16]. This method provides divergent and stereoselective access to a variety of optical pure β-silyl-α-amino acids. Shortly after, Pd(OAc)2 -catalyzed stereoselective alkoxycarbonylation of methylene C(sp3 )—H bonds with alkyl chloroformates through a Pd(II)/Pd(IV) catalytic cycle was also reported by the same group [17]. A stable palladacycle intermediate 18 was prepared. Moreover 18 may be not only directly converted into the desired product but also may be used as well-defined catalyst in a catalytic coupling (Scheme 4.7). The α-amino-β-lactam motif is a versatile chiral building block in organic synthesis and is present in both penicillin and cephalosporin scaffolds. In 2013, Shi and coworkers reported a palladium(II)-catalyzed sequential C(sp3 )–H monoarylation/amidation to synthesize of α-amino-β-lactams from alanine derivatives stereoselectively [18]. The N,N-bidentate PIP (2-(pyridin-2-yl)isopropyl) amide directing group was found to be effective both in controlling selectivity for the monoarylation step and in enhancing

111

112

4 Substrate-Controlled Transformation: Diastereoselective Functionalization

H

O Q

N H NPhth 14, R = Ar, alkyl R

(Me3Si)2 Pd(OAc)2 (15 mol%) 1.5 equiv DMBQ

TMS O

0.5 equiv Ag2CO3 1,4-Dioxane, 125 °C

R = H 15a, 70%, dr > 20 : 1 R = OMe 15b, 75%, dr > 20 : 1 TMS O R = NHAc 15c, 58%, dr > 20 : 1 Q N R = Me 15d, 71%, dr > 20 : 1 H NPhth R = Et 15e, 71%, dr > 20 : 1 R = Cl 15f, 53%, dr > 20 : 1 R = CF3 15g, 35%, dr > 20 : 1

R

TMS O AcHN

N H NPhth

Cl 15i, 61%, dr > 20 : 1

N H NPhth 15

R

TMS O MeO

N H NPhth

MeO

Q

15h, 72%, dr > 20 : 1

TMS O Q

Q

TMS O

N H NPhth

Q

Q

N H NPhth

MeO 15j, 36%, dr > 20 : 1

15k, 43%, dr = 3 : 1

Scheme 4.6 Diastereoselective Pd-catalyzed intermolecular silylation of secondary C—H bonds of α-amino acids.

H R1

O N H NPhth

Q + ClCO R 2

Pd(OAc)2 (10 mol%) 2.0 equiv Ag2CO3 1.0 equiv I2, toluene Air, 120 °C,16 h

(a) 16

Q

R1

N H NPhth 17, R1 = aryl, alkyl

O PhthN

ClCO2Et

Ph

Standard conditions

Ph MeCN 18 H Ph

(c)

PhthN Ph

Cl N PdIV N CO2R Via Ph

CO2Et O N PdII N

(b)

O

CO2R O

17a, 40%

O

N H NPhth 16a

N H NPhth

Q

10 mol% 18 ClCO2Et Standard conditions

Q + PhthN

N Q O

19, 0%

CO2Et O Ph

N H NPhth

Q

17a, 70%

Scheme 4.7 (a) Pd-catalyzed alkoxycarbonylation of β-methylene C(sp3 )—H bonds. (b) Stoichiometric reactivity of palladacycle 18. (c) Catalytic reactivity of palladacycle 18.

reactivity at the amination step (Scheme 4.8) [19]. Using the same directing group, Shi group described a diastereoselective Pd(II)-catalyzed fluorination of unactivated methylene C(sp3 )—H bonds of α-amino acid derivatives using Selectfluor (Scheme 4.9) [20a]. A range of substrates containing both aliphatic and benzylic C(sp3 )—H bonds were compatible with this protocol, leading to an array of β-fluorinated α-amino acids. A palladacycle intermediate INT-A was prepared and isolated. Moreover the stoichiometric fluorination takes place

®

4.2 Diastereoselective Functionalizations of N-Phthaloyl-α-Amino Acids

O PhthN

N H

H

Pd(OAc)2 (10 mol%) CuF2 (1.5 equiv) DMPU (5.0 equiv) PhthN

N PIP

H 19 + Ar–I

Acetone (0.2 M) N2,100 °C, 24 h

Pd(OAc)2 (10 mol%) NaIO3 (2.0 equiv) Ac2O (1.0 equiv)

O N H

Ar

PIP

PhthN N

MeCN, N2, 70 °C, 24 h

H

20 35–82% yield

O

Ar

PIP

21 46–86% yield dr up to > 30 : 1

Scheme 4.8 Stereoselective synthesis of α-amino-β-lactams through palladium-catalyzed sequential C(sp3 )–H functionalization.

H

O N H NPhth

R

H

PIP N H NPhth 23, 32–73% yield O

O

1 equiv Pd(OAc)2 PIP 10 equiv i-PrCN, DCM N H NPhth 25 °C, overnight

PhthN

(b)

O 2 equiv pyridine PhthN

N Pd L

Ph

87% yield

22a

O

R

Selectfluor

22

(a) Ph

F

Pd(II) (6–10 mol%)

PIP

DCM, rt, 5 h 84% yield

INT-A (L = i-PrCN)

Charactered by 1H NMR and 13C NMR 1.05 equiv selectfluor d3-MeCN, rt, 5–10 min F Ph

O N H NPhth

NH4Cl, Na2S

PIP

rt, 10 min 86% yield

23a

PhthN Ph F

N Pd Ph L L = Pyridine confirmed by X-ray diffraction

78% yield

O N L Pd L BF4

INT-C (L = d3-MeCN) observed by 1H NMR and 19F NMR 23a

2 AcOH PhthN Ph

Pd(OAc)2

Decomplexation

22a

C–H activation

O

O PhthN

N L Pd F L BF4

N Pd L INT-A (L = i-PrCN)

Ph

INT-C (L = i-PrCN) Direct RE (with rettention of configuration at β-carbon) O PhthN N Pd Ph F L BF 4

(c)

N

Oxidation N F N N

Cl 2BF4

Cl 2BF4

INT-B (L = i-PrCN)

Scheme 4.9 (a) Fluorination of unactivated methylene C(sp3 )–H of α-amino acid with Selectfluor; a single diastereoisomer was isolated. (b) Synthesis and stoichiometric reaction of INT-A. (c) Proposed mechanism.

113

114

4 Substrate-Controlled Transformation: Diastereoselective Functionalization

H

O

R1 R2 24

N H

PIP

Pd(OAc)2 (10 mol%) Selectfluor (2.5 equiv)

F R1

O N H

PIP

R2 Fe(OAc)2 (0.75 equiv), Ag2CO3 (2.0 equiv) MeCN, DCE, 150 °C, air 25, 53–85% yield dr = 5 : 1 to > 19 : 1

Scheme 4.10 Palladium-catalyzed diastereoselective fluorination of aliphatic amides.

rapidly under very mild condition. INT-A was proved to be a viable precatalyst for C–H fluorination, and a putative catalytic cycle is proposed. Later, a highly diastereoselective fluorination of aliphatic amides via a palladium-catalyzed bidentate ligand-directed C—H bond functionalization is reported by Ge and coworkers (Scheme 4.10) [20b]. 4.2.1.2

Monodentate Directing Group

In 2014, Yu and coworkers found that palladium-catalyzed β-C(sp3 )–H arylation of alanine N-4-(CF3 )C6 F4 amide can be promoted by pyridine and quinoline derivatives: the former promotes exclusive monoarylation, whereas the latter activates the catalyst to achieve sequential diarylation. The reactions proceed with excellent diastereoselectivity; both configurations at the new β-stereogenic center can be constructed by simply choosing the order of aryl group installation (Scheme 4.11) [21]. They have successfully characterized the C–H insertion intermediates (29 and 30) by single-crystal X-ray diffraction, and both intermediates are able to catalyze the arylation. Accordingly these intermediates are viable precatalysts for primary and secondary C(sp3 )–H arylation, respectively. Later, they developed a pyridine-type ligand-promoted diastereoselective arylation of primary and methylene β-C(sp3 )–H of α-amino acid with the help of N-methoxyamide auxiliary [22]. 2-Picoline promotes the monoselective arylation of primary C(sp3 )—H bonds, while 2,6-lutidine enables the subsequent one-pot arylation of secondary C(sp3 )—H bonds in one pot (Scheme 4.12). Then Yu and coworkers demonstrated that a palladium-catalyzed β-C(sp3 )–H fluorination of both primary and methylene C(sp3 )—H bonds was accelerated by quinoline ligand L3 (Scheme 4.13) [23]. Mechanistic studies shown that the stereogenic center was built during the C(sp3 )–H activation step and was controlled by the favorability of a trans-substituted five-membered palladacycle intermediate. 4.2.2 Diastereoselective 𝛄-C(sp3 )–H Functionalization of 𝛂-Amino Acid Derivatives In 2013, Carretero reported a Pd-catalyzed γ-arylation of the readily available N-(2-pyridyl)sulfonamide derivatives of simple amino acid methyl esters. This strategy has been also applied for remote C(sp3 )–H arylation of dipeptide derivatives (Scheme 4.14) [24]. In 2016, the Carretero group further reported the Pd-catalyzed γ-selective C(sp3 )–H carbonylation/cyclization of N-SO2 Py-protected aliphatic amines,

4.2 Diastereoselective Functionalizations of N-Phthaloyl-α-Amino Acids NPhth H

10 mol % Pd(TFA)2 20 mol % L1

CONHArF

TFA, Ar1–I Ag2CO3, DCE 100 °C, 20 h

H 26, ArF = 4-(CF3)C6F4

10 mol % Pd(TFA)2 20 mol % L2

NPhth Ar1

CONHArF

NPhth Ar1

TFA, Ar2–I Ag2CO3, DCE 100 °C, 20 h

H 27

CONHArF Ar2

28, 60–68% yield dr = 16 : 1 to > 20 : 1

(a)

PhthN NPhth H

+

CONHArF

N

H 26

PhthN

Me

Pd(TFA)2 (1.5 equiv)

+

CONHArF H

N

O

L2 (2 equiv)

27a

O N ArF O Pd

Ph

CsF (2 equiv) DCE, 60 °C, 12 h

Me

N Ar F N

Me Intermediate 29 (X-ray) 72% with CsF 60% with Ag2CO3

L1 (2 equiv)

NPhth Ph

N Pd

Base (2 equiv) DCE, 100 °C, 20 h

Me

O

Me

Pd(TFA)2 (1 equiv)

Me

N

N O

Me

Me Me

(b)

Intermediate 30 (X-ray), 75%

NPhth H

CONHArF H

10 mol% Intermediate 29 TFA, Ph-I Ag2CO3, DCE 100 °C, 20 h

26

(c)

NPhth

10 mol% Intermediate 30

NPhth CONHArF H

CONHArF

TFA, p-Tol-I Ag2CO3, DCE 100 °C, 20 h Me 28a, 60%, dr > 20 : 1

27a

Scheme 4.11 (a) Palladium-catalyzed diastereoselective one-pot diarylation of alanine derivative. (b) Synthesis of primary and secondary C(sp3 )–H activation intermediates. (c) Catalytic reactivity of intermediates in C(sp3 )–H arylation reactions. NPhth H

Pd(OAc)2 (10 mol%)

Pd(OAc)2 (10 mol%)

2-Picoline (20 mol%) 2,6-Lutidine (20 mol%)

CONHOMe H 31

Ar1–I, AgOAc, HFIP

Ar2–I, AgOAc

75 °C, 24 h

NaPO4·H2O, 75 °C

NPhth Ar1

CONHOMe Ar2 32, 47–71% yield dr > 20 : 1

Scheme 4.12 Ligand promoted heterodiarylation of alanine substrate.

R HH

NPhth NHAr O

33, Ar = 4-(CF3)C6F4

Selectfluor (1.5 equiv) Pd(TFA)2 (10 mol%) L3 (10 mol%) Ag2CO3 (2,0 equiv) 1,4-Dioxane (0.067 M) 115 °C, air, 15 h

R F H

Me

NPhth NHAr O

34, 25–79% yield dr > 20 : 1

Me

Me

N

O

L3

Scheme 4.13 Pd(II)/L3-catalyzed stereoselective C(sp3 )–H fluorination of amino acid.

Me

115

116

4 Substrate-Controlled Transformation: Diastereoselective Functionalization

N

S O O PySO2

O

H N

H 35

Pd(OAc)2 (10 mol%) 2.5 equiv ArI, AgOAc OMe 1M HFIP, 4 h, 140 °C

N H

Pd(OAc)2 (10 mol%) OMe 2.5 equiv ArI, AgOAc O

PyO2S

H N

O OMe

p-Tol p-Tol 37, 18%

36, 70%, dr ≥ 20 :1

HN

H

OMe + PyO2S

p-Tol

H

O PyO2S

PyO2S

O

H N

O

H N

OMe

N H

O

1M HFIP, 150 °C p-Tol

38

39, 60%

Scheme 4.14 Palladium-catalyzed γ-arylation C(sp3 )–H of α-amino acid derivatives and dipeptides.

PyO2S

Pd(OAc)2 (10 mol%) Mo(CO)6 (0.33 equiv) CO2Me BQ (2.0 equiv)

H N

H

H 40

AgOAc (1.5 equiv) HFIP, 110 °C, 18 h

PyO2S N O

CO2Me +

trans-41, 75%

PyO2S N O

CO2Me

cis-41, 13%

Scheme 4.15 Palladium-catalyzed γ-C(sp3 )–H carbonylative cyclization of α-amino acid derivatives and short peptides.

leading to γ-lactams. When the procedure was applied to α-amino acid derivatives, a good trans diastereoselectivity was observed. This can be explained by a remarkable preference for C–H activation of the pro-S methyl group of α-amino acid derivatives. More importantly, this carbonylation protocol also allows late-stage modifications of more complex, functional compounds such as dipeptides or tripeptides (Scheme 4.15) [25].

4.3 Diastereoselective C–H Activation Controlled by Chiral Auxiliary In 2005, Yu and coworkers reported a seminal work on the palladium-catalyzed C–H iodination with moderate to excellent diastereoselectivity. Temporary installation of a chiral oxazoline auxiliary provides high stereocontrol during C–H insertion/functionalization step (Table 4.1) [5a]. Later, they reported a diastereoselective C(sp3 )–H acetoxylation reaction using the same strategy [5b]. Moderate diastereoselectivity were achieved in the acetoxylation of chiral oxazoline substrates (Table 4.2). The origin of diastereoselectivity is rationalized by the following transition state: the chiral oxazoline induces high stereoselectivity during C—H bond activation in conjunction with the resulting bicyclic conformation via the steric repulsion model depicted in Scheme 4.16. When the R1 is larger than Me, transition state 46 will be favored over 47 as a result of a larger steric repulsion

4.3 Diastereoselective C–H Activation Controlled by Chiral Auxiliary

Table 4.1 Palladium-catalyzed asymmetric iodination of unactivated C(sp3 )—H bonds. H N

R1

t-Bu

O

I

Pd(OAc)2 (10 mol%) I2, PhI(OAc)2

N

R1

DCM, 24 °C, 24–36 h

42 Entry

Product

Yield

dr

Entry

83

91: 9

3

Product

I 1

I N

t-Bu

t-Bu

O 43 Yield

dr

Ph N

t-Bu

b

99 :1

65c

99 :1

98

t-Bu

O

O 43a

43c

I 2

a

N

4

93 : 7

62

N

TBSO

t-Bu

I

O 43b a

b

t-Bu

O 43d

c

50 °C, 48 h. 13 h. 96 h.

Table 4.2 Palladium-catalyzed stereoselective acetoxylation of unactivated C(sp3 )—H bonds. H N

R1

OAc

Pd(OAc)2 (5 mol%)

O

Lauroyl peroxide R2

N

R1

Ac2O, O2, 50 °C, 48 h

44 Entry

Product

Yield

45 de (%)

Entry

Product

OAc 1

49

82

4

t-Bu

N

TBSO

O

66

N

38

5

t-Bu

N

MeO2C

73

24

67

18

t-Bu

O 45e

45b OAc

O

62

OAc

O

3

43 t-Bu

45d

OAc Cl

de (%)

O

45a

2

Yield

OAc

N

t-Bu

R2

O

N

N O O 45c

OAc t-Bu

38

12

6

N

Et

i-Pr

O 45f

between R1 and R2 . In this situation, the conformation of 46 controls the stereochemistry of C–H insertion and hence the overall stereochemical outcome of the C–H functionalization sequence. They also identified a trinuclear C–H insertion intermediate 48 by 1 H NMR and X-ray crystallography. Using novel chiral directing groups, Ferreira group reported the palladiumcatalyzed diastereoselective C–H acetoxylation and olefination in 2012 [26]. The chiral directing group can be covalently attached to substrates reversibly, and

117

118

4 Substrate-Controlled Transformation: Diastereoselective Functionalization

Large groups in anti position

O R1

Large groups in syn position

R2 N M

O

H

RL

O Pd O

H

N

H

Favored

Disfavored

46

47

(S)

O Pd O O O

R2 N M

R1

H t-Bu N Pd O O

O

RL

(S) New chiral center

O

t-Bu

(S) Chiral auxiliary

48

Scheme 4.16 Proposed diastereoselective model and intermediates.

N O

N H

N Ph

Then dppe Toluene/DCM, 23 °C

49

O

N AcO

H

+

N

O N

N Ph OAc

H

AcOH/Ac2O, 55 °C, 24 h

51, 13%

N

N O

N AcO H

+ N

Ph OAc

Ph HH

52

53

54

43%, dr = 10 :1

13%

CO2Me

N

Pd(OAc)2 (10 mol%) O

N H

O

N AcO

N

Ph

N

O

N AcO

Ph

Pd(OAc)2 (10 mol%) PhI(OAc)2 (1.5 equiv)

N

N

50, 69%, dr >10 :1

N

H

N

Pd(OAc)2 (50 mol%) PhI(OAc)2 (1.8 equiv) AcOH/Ac2O, 85 °C, 24 h

N Ph

H4[PMo11VO40] 32H2O (1 mol%) Cu(OAc)2 (1.1 equiv) TFE, 110 °C, air

N Ph

MeO2C 52

O

N H H

55, 43%, dr > 10 :1

Scheme 4.17 Palladium-catalyzed diastereoselective C–H acetoxylation and olefination.

4.3 Diastereoselective C–H Activation Controlled by Chiral Auxiliary

H

O O

NH

Ar2

Pd(OPiv)2 (10 mol%) Ag2CO3 (1.5 equiv) (BnO)2PO2H (1.0 equiv)

I + 1

Ar

N

NaOPiv (2.0 equiv) HFIP/DMSO, 90 °C, 12 h

Bn

Ar1 O Ar2

O

NH

*

N

56

Bn

57 Br

OMe

O

O

O O

NH

Bn

Bn

Bn 57a, 59% (dr = 90 : 10)

N

Br

N

N

O

NH

O

NH

57b, 66% (dr = 88 :12)

57c, 50% (dr = 88 :12)

Scheme 4.18 Palladium-catalyzed diastereoselective β-C(sp3 )–H arylation of amide derivatives.

when linked, it can induce a directed functionalization at remote C(sp2 )–H and C(sp3 )—H bonds with high site specificity and diastereoselectivity (Scheme 4.17). In 2015, the Shi group found that amino oxazoline facilitated Pd-catalyzed arylation of β-methylene C(sp3 )–H of amides. When a chiral center was introduced to the oxazoline directing group, the arylation could be realized with good diastereoselectivity (Scheme 4.18) [27]. By applying oxazoline carboxylate as the directing group, Shi and coworkers reported a palladium-catalyzed arylation of unactivated γ-methylene C(sp3 )–H and remote δ-C—H bonds. However, only low diastereoselectivity was achieved when chiral auxiliaries were used (Scheme 4.19) [28]. In 2015, through embedding Ile-NH2 directing group into the substrate, Hong and coworkers developed a Pd(II)-catalyzed highly diastereoselective arylation β-methylene C(sp3 )—H bond of cyclopropanes (Scheme 4.20) [29]. Through applying (S)-2-(p-tolylsulfinyl)aniline (APS) as the auxiliary group, Colobert, Wencel-Delord, and coworkers reported a palladium-catalyzed diastereoselective functionalization of β-methylene Csp3 —H bond of cyclopropane and cyclobutane carboxylic acid derivatives in 2016. Both arylation and Ac H

Ar–I (3 equiv) Pd(OAc)2 (10 ml%) Ag2CO3 (2 equiv)

O N H

O N R

R = iPr, 58a R = Bn, 58b

1-AdCO2H (0.5 equiv) DCE, N2, 110 °C, 24 h

O N H

O N

59a, 72% (dr = 1.4 : 1) 59b, 60% (dr = 1.5 : 1)

Scheme 4.19 Preliminary studies of the Pd-catalyzed diastereoselective arylation of γ-methylene C(sp3 )—H bonds.

R

119

120

4 Substrate-Controlled Transformation: Diastereoselective Functionalization

Pd(OAc)2 (10 mol%) K2CO3 (2.0 equiv)

O O

N H

+

Ar — I

O

0.5 M 100 °C, 24 h

NH2

H

O

N H

tAmylOH

NH2

Ar

60

61, 20 examples, 28–78% dr = 4.9 : 1 – 71.5 : 1

Scheme 4.20 Pd-catalyzed C(sp3 )–H arylation of cyclopropane derivatives.

O

H

+

Pd(OAc)2 (5 mol%) AgOAc (2.2 equiv) NaTFA (0.5 equiv)

Ar–I

O

NH 1.2 equiv

APS

HFIP/H2O 9 : 1 80 °C

S O

H

+

APS

63b

63a

Pd(OAc)2 (5 mol%) AgOAc (2.2 equiv) NaTFA (0.5 equiv) I

( )n O

CO2Et (3.0 equiv)

CH2CO2Et

67a, 34%

Alk b

68a, 46%

APS

APS

dr = 70 : 30

dr = 60 : 40 O CH2CO2Et

+

O APS

a O

CH2CO2Et

( )n Alk

APS

HFIP/H2O 9 : 1 80 °C

64, 65, or 66

O

Ar APS

16 examples, dr = 60 : 40 – 80 : 20

( )n

O

O

+

APS

62

O

Ar

CH2CO2Et

67b, 24%

68b, 21%

APS

APS O

CO2Et NH

S O

69, 13% dr = 90 : 10

Scheme 4.21 Pd-catalyzed diastereoselective arylation and alkylation of small cycloalkanes.

more challenging alkylation reactions have been investigated, and moderate to good diastereoselectivity is observed (Scheme 4.21) [30]. In 2017, He group used the same chiral auxiliary APS for palladium-catalyzed β-C–H arylation of alkyl carboxamides. The β-methylene C–H arylation with ortho-substituted aryl iodides was realized in moderate diastereoselectivity (Scheme 4.22) [31]. Shortly after, Colobert, Wencel-Delord, and coworkers reported the use of this stereogenic bicoordinating directing group APS bearing a sulfoxide as a source of chirality to the direct arylation of very challenging linear alkanes to occur with good to high stereoinduction (dr up to 9 : 1) (Scheme 4.23a) [32]. Moreover the method is compatible with a large panel of iodoarene coupling partners, as even sterically demanding ortho-substituted Ar–I could be used under standard protocol. Subsequently, they demonstrated that the sulfoxide auxiliary is recyclable; it might be not only efficiently removed but also

4.4 Diastereoselective C(sp3 )-H Functionalization of Conformationally

H

Ar–I (3 equiv) Pd(OAc)2 (10 mol%) Ag2CO3 (2.5 equiv)

O

R1

N H

R2

O

S

Ar R1

N H

R2

PivOH (1 equiv) HFIP, 110 °C, Ar, 24 h

TSOA

O TSOA

71 12 examples, 18–80%, dr = 1.1 : 1 – 3 : 1

70

Scheme 4.22 Pd-catalyzed APS-directed β-C(sp3 )–H arylation.

H H

R

O

Ph

1

+

N H O

S

pTol

I

R

Pd(OAc)2 (5 mol%)

1

AgOAc (2.2 equiv)

O

Toluene/HFIP (4 : 1) 80 °C, 16 h

N H

Ph

O 72 7

S

pTol

73 Up to 95% yield and 9 : 1 dr

(a)

H H H

Pd(OAc)2 (5 mol%) AgOAc (2.2 equiv) Toluene/HFIP (4 : 1) 80 °C, 16 h

O N H O

S

MeO H H

O APS

APS

NO2

NO2

NO2 I 1 equiv

75 78% yield; 7.5 : 2.5 dr

I 3.5 equiv

(b) H H Ph

O

Pd(OAc)2 (5 mol%) AgOAc (2.2 equiv)

N H O

(c)

72

S

pTol

O

OMe

pTol

74

AgOAc (2.2 equiv) 130 °C, 24 h

Toluene/HFIP (4 : 1) 80 °C, 16 h

OAc O Ph

N H O

S

pTol

76, 91%, 7 : 3 dr

Scheme 4.23 Pd-catalyzed APS-directed β-C(sp3 )–H arylation and acetoxylation.

recovered in excellent yield from the reaction mixture with no alteration of its optical purity. Finally, it is demonstrated also that due to high reactivity of the system, sequential biarylation might be achieved, allowing expedient synthesis of chiral compounds difficult to access otherwise (Scheme 4.23b). Noteworthy, they report also an unprecedented acetoxylation of the aliphatic substrates at methylene position (Scheme 4.23c) [32].

4.4 Diastereoselective C(sp3 )–H Functionalization of Conformationally Restricted Cyclic Substrates In the frame of the synthesis of teleocidin B-4 core 82, the Sames group found that by treatment of racemic 77 with a stoichiometric amount of PdCl2 a 6 : 1 diastereomeric mixture of palladacycles 78 and 79 was obtained in 65% yield, respectively

121

122

4 Substrate-Controlled Transformation: Diastereoselective Functionalization OMe

OMe OMe

OMe OMe

PdCl2, NaOAc

N

N Pd

HOAc, 70 °C O Me 77

OMe +

N Pd

O Me

78 OMe

OMe

O Me

79 OMe

1. CO (40 atm), MeOH 2. SiO2, CHCl3

+ NH

65% for three steps dr = 6 : 1 (80 : 81)

NH

O 80

N

O 81

O 82 Teleocidin B-4 core

Scheme 4.24 Construction of teleocidin B-4 core 82.

[33]. They rationalized that the observed diastereoselectivity is controlled by the remote chiral center of 77. In the preferred conformation, the bulky isopropyl group assumes a pseudo-equatorial position, bringing the methyl group anti to it also into a pseudo-equatorial position and in close proximity to palladium. Subsequent treatment of resulting palladacycles 78 and 79 with CO in methanol followed by acidic hydrolysis furnished lactams 80 and 81 (Scheme 4.24). In 2011, Chen and coworkers reported picolinamide-directed arylation and alkenylation of the γ-C(sp3 )—H bonds of a variety of aliphatic substrates under mild conditions [34]. Excellent regio- and stereoselectivity with a broad range of substrates were demonstrated (Scheme 4.25). In 2012, Baran and coworkers reported the total synthesis of piperaborenine (94). Sequential diastereoselective arylation of cyclobutyl carboxamides was the key step for its success (Scheme 4.26) [35]. In 2015, the same synthetic strategy was applied to the construction the cyclobutane cores of scopariusicides A and B by Pu and coworkers [36]. Subsequently, Maimone reported a short total synthesis of podophyllotoxin via Pd(II)-catalyzed high diastereoselective arylation cyclohexyl C(sp3 )—H bonds using the same directing group [37]. In 2014, Wang group developed a Pd-catalyzed C(sp3 )—H bond arylation of 3-pinanamine 95 [38]. The stereoselective arylation reaction took place exclusively at the methylene C(sp3 )—H bond pointing to the amino group (Scheme 4.27). They reasoned that the remarkable selectivity is derived from the strain-induced proximity of the δ-methylene C(sp3 )—H bond to the PA directing group. In 2014, Bull group described a protocol for Pd(II)-catalyzed functionalization of unactivated C(sp3 )–H at 3-position of proline derivatives (Scheme 4.28) [39]. This reaction directly affords cis-2,3-disubstituted pyrrolidines as single stereoisomers. Then the same group reported a palladium-catalyzed stereoselective C(sp3 )–H arylation of unactivated 3-positions of five- and six-membered N- and O-heterocycles bearing the aminoquinoline directing group (Scheme 4.29) [40]. Excellent cis selectivity was achieved in all cases except for the tetrahydropyran

4.4 Diastereoselective C(sp3 )-H Functionalization of Conformationally

(THP) substrate where minor trans products were formed through a different palladacyclic intermediate C in which palladation occurred in equatorial position. They propose that this is a result of both cis and trans palladacycles being formed, leading to the two diastereoisomers. By contrast, for the tetrahydrofuran (THF) and pyrrolidine substrates, the corresponding trans-5,5-palladacycle would likely be significantly higher in energy; hence only cis diastereoisomers are observed in these cases. Johnson group accomplished the total synthesis of indole diterpenoid paspaline 104 using the diastereoselective C(sp3 )–H acetoxylation to construct the C12b quaternary center in 2015 (Scheme 4.30) [41]. In 2016, Reisman and coworkers reported the first enantioselective total synthesis of (+)-psiguadial B. A key intermediate 106 was obtained as a single enantiomer by C(sp3 )–H alkenylation of a chiral cyclobutane amide 105 (Scheme 4.31) [42]. In 2006, using picolinoyl as the directing group, Zhang and coworkers reported the Boc-l-Ile-OH-promoted regio- and stereoselective C(sp3 )–H (hetero)arylation of rimantadinyl methylenes (Scheme 4.32) [6]. The high stereoselectivity was controlled by the substrate rather than by the mono-N-protected amino acid (MPAA) ligand. In 2016, Maes and coworkers reported a Pd-catalyzed C(sp3 )–H arylation of 1-Boc-3-(picolinoylamino)piperidine with iodo-(hetero)arenes (Scheme 4.33) [43]. This new approach permits efficient access to cis-3,5-disubstituted

OMe H NHPA

or

H H

H 83

H

1-Iodo-4-methoxybenzene Pd(OAc)2 (10 mol%)

NHPA

or

NHPA

NHPA

Ag2CO3 (1.0 equiv) tBuOH or TFE

H

84

85

22% (50 °C, 40 h) 95% (80 °C, 24 h)

(a)

OMe

86

71% (50 °C, 40 h) 78% (80 °C, 24 h)

I (1.5 equiv) CO2Me H

NHPA 87

CO2Me

(b)

NHPA

Pd(OAc)2 (0.1 equiv) AgOAc (1.5 equiv) BQ (± 0.1 equiv) tBuOH, 110 °C, 20 h CO2Me

NHPA

NHPA

88b

88c

19% (+BQ)

CO2Me

H

59% (–BQ) 69% (+BQ)

O PA =

88a

N

37% (–BQ) 46% (+BQ) CO2Me NHPA 88d 27% (+BQ)

CO2Me NHPA 88e 12% (+BQ)

Scheme 4.25 Palladium-catalyzed stereoselective γ-C(sp3 )–H arylation and alkenylation of cycle substrates.

123

124

4 Substrate-Controlled Transformation: Diastereoselective Functionalization

MeS O

H

I

+

OMe

HN

PivOH (1.0 equiv) HFIP, 90 °C

OMe

H

MeS

Pd(OAc)2 (15 mol%) Ag2CO3 (1.5 equiv)

OMe HN

Pd(OAc)2 (15 mol%) Ag2CO3 (1.0 equiv) t-BuOH, 75 °C

OMe

OMe

OMe CO2Me

OMe

91, 52%

MeS

H

LiOt-Bu

OMe CO2Me

90

O

OMe

H

CO2Me 89

HN

O

OMe

I

92, 79%,dr > 10 : 1

OMe (2.0 equiv)

MeS HN

O

OMe

MeO

OMe CO2Me

MeO

OMe

93, 46%

O N

O

OMe

MeO

OMe

MeO

OMe

N O

94, Piperaborenine B

Scheme 4.26 Palladium-catalyzed sequential diastereoselective arylation of cyclobutyl carboxamides of 2-(methylthio)aniline derivative.

N

Pd(OAc)2 (10 mol%)

H

H

HN

Me

H Me

Me 95

O

+

Ar

X

Ag2CO3 (1.0 equiv) Toluene, 130 °C, 24 h

Ar

H

HN

Me Me

X = I, Br (1.1 equiv)

PA

H Me

96 15 examples, 47–85%

Scheme 4.27 Pd-catalyzed C(sp3 )–H arylation of 3-pinanamine.

piperidines in a direct, regiospecific, and stereospecific fashion from 1-Boc-3-aminopiperidine, which is readily available. In 2016, Kazmaier and coworkers reported a palladium-catalyzed stereoselective β-arylation of phenylalanine-, proline-, and pipecolinic acid-containing peptides, and only cis products were obtained (Scheme 4.34) [44]. In 2016, Sanford reported a transannular C—H bond arylation of alicyclic amines at sites remote to nitrogen (Scheme 4.35) [45]. This reaction uses the boat conformation to achieve the palladium-catalyzed amine-directed C—H bond arylation of various alicyclic amine scaffolds. The selectivity was

4.4 Diastereoselective C(sp3 )-H Functionalization of Conformationally

H

(Het)Ar–I (1.8 equiv) Pd(OAc)2 (5 mol%)

N H N

AgOAc (1.8 equiv) Neat, 110 °C, 20 h, Ar

N Cbz O

N

(Het)Ar H N N Cbz O

97

98 27 examples, 28–91%

Scheme 4.28 Pd-catalyzed C(sp3 )–H arylation of proline derivatives.

H

(Het)Ar–I Pd cat, base

H N Q

( )n

( )n

X O

(Het)Ar H N Q

X O

X = O, Ncbz, NBoc; n = 1, 2

100, 38–98 yield

99

(a)

N Q=

syn H H N

O

AcOH

Pd(OAc)2

[Pd] N Q

O

Q

anti O

O

O

O

A, Axial

101

N Q

O O

[Pd]

[Pd] N Q

C, Equatorial

B, Equatorial

(b)

Scheme 4.29 (a) Pd-catalyzed stereoselective arylation of saturated heterocycles. (b) Viable conformations of the palladacyclic intermediate formed from THP carboxamide 101.

OBn N Me

Me

H Me

Pd(OAc)2 (15 mol%) PhI(OAc)2 OTBS

H

O H

H

Me Me

AcOH:Ac2O (1:1) 100 °C

OBn N Me AcO 12b Me

Me OTBS H

O H

H

Me Me

103, 79%, dr > 20 : 1

102 H

Me

Me OH

N H

Me

H

O H

H

Me Me

104, Paspaline

Scheme 4.30 Palladium(II)-catalyzed diastereoselective acetoxylation 97 for the synthesis of paspaline.

125

126

4 Substrate-Controlled Transformation: Diastereoselective Functionalization

O

Me Me

O

+

N H

N

Me Me

NH

TBME, 90 °C

I

H

O

Pd(OAc)2 (15 mol%) Ag2CO3

O

N O O

105

106, 72% Me MeH CHO H Me

O

H

OH CHO

Ph

OH

107, (+)-Psiguadial B

Scheme 4.31 Palladium(II)-catalyzed AQ-directed diastereoselective alkenylation of cyclobutane amide for the synthesis of psiguadial B.

H H H

NHPyC R H H +

H I

PdCl2(MeCN)2 (10 mol%) Boc-L-ILeu-OH (2.0 equiv)

Substrates

(a) H

NHPyC H H

NHPyC H H

113 (S, 99% ee)

NHPyC R Ar S H

109

Single diastereomer

(R)

(R,S,S)

(S)

(S,R,R) H

10 mol% PdCl2(MeCN)2 4-Chloroiodobenzene

H

NHPyC

NHPyC

Cl

H

+ H

Ag2CO3 (1.5 equiv) Boc-D-ILeu-OH (2.0 equiv) Toluene,100 °C

110

H H

S

Ag2CO3 (1.5 equiv) Toluene,100 °C

108

H

Ar

Ar

H

10 mol% PdCl2(MeCN)2 4-Chloroiodobenzene Ag2CO3 (1.5 equiv) Boc-D-ILeu-OH (2.0 equiv) Toluene,100 °C

Cl 112 (not observed)

111 , 78%

H

Cl

NHPyC H

H

(X-ray) Cl

114 (S, 99% ee)

(b)

Scheme 4.32 (a) Pd-catalyzed stereoselective arylation of adamantine scaffold. PyC = pyridinyl-2-ylcarbonyl group. (b) Control experiments.

4.5 Summary and Conclusions

H

(Het)ArI Pd(OAc)2 (10 mol%) 2,6-Dimethylbenzoic acid

NHPA N Boc

(Het)Ar

NHPA N Boc

Ag2CO3 (1.0 equiv) neat, 120 °C, 24 h

115

116 16 examples, 60–95%

Scheme 4.33 Pd-catalyzed stereoselective C-(sp3 )–H arylation of 1-Boc-3-amino piperidine. H

H N

BocHN

Ar H N

N O

O

Q

Pd(OAc)2 (5 mol%) Ar–I (2 equiv) AgOAc (2 equiv) Toluene,110 °C, 16 h

O

BocHN

117

H N

H N

N

Q

O

O O 118, 60–68% yield

Scheme 4.34 Pd-catalyzed diastereoselective β-C(sp3 )–H arylation of tripeptide. F

CF3

F F

H HN N

F

Aryl–I (1–2 equiv) Pd(OAc)2 (10 mol%) CsOPiv (3 equiv) t-AmylOH, 130 °C,18 h C7F7

O 119

N

Aryl NHC7F7 N

O

O 120, 57–88% yield

Pd N

121

Scheme 4.35 Pd-catalyzed transannular C–H arylation of 3-azabicyclo[3.1.0]hexane core.

achieved through intermediate 121 that presents a bidentate coordination of a sp3 -hybridized nitrogen of an alicyclic amine along with the nitrogen atom in fluoroamide.

4.5 Summary and Conclusions Recently, due to the powerful activity of palladium, substrate-controlled stereoselective C(sp3 )–H functionalization reactions have been extensively investigated to construct stereogenic centers. In these cases, the prochiral C—H bonds at the carbon atom are selectively cleaved on a metal center under the influence of an existing chiral center. However, there are also some challenges to be addressed: firstly, the types of transformation are still limited to functionalizations, such as arylation, alkylation, alkenylation, and fluorination. It would be desirable to

127

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4 Substrate-Controlled Transformation: Diastereoselective Functionalization

develop more reaction types. Secondly, in terms of diastereoselective functionalizations of α-amino acid derivatives, previous approaches are limited to the use of phthaloyl as protecting group. Synthetically more useful protecting group, such as Boc, Cbz, etc., would be more interested.

References 1 For selected reviews of direct C(sp3 )–H activation, see: (a) Chen, X., Engle,

2

3 4

5

6 7 8

K.M., Wang, D.-H., and Yu, J.-Q. (2009). Angew. Chem. Int. Ed. 48: 5094. (b) Daugulis, O., Do, H.-Q., and Shabashov, D. (2009). Acc. Chem. Res. 42: 1074. (c) Jazzar, R., Hitce, J., Renaudat, A. et al. (2010). Chem. Eur. J. 16: 2654. (d) Lyons, T.W. and Sanford, M.S. (2010). Chem. Rev. 110: 1147. (e) Baudoin, O. (2011). Chem. Soc. Rev. 40: 4902. (f ) Li, H., Li, B.-J., and Shi, Z.-J. (2011). Catal. Sci. Technol. 1: 191. (g) Rouquet, G. and Chatani, N. (2013). Angew. Chem. Int. Ed. 52: 11726. (h) Zhang, B., Guan, H.-X., Liu, B., and Shi, B.-F. (2014). Chin. J. Org. Chem. 34: 1487. (i) Daugulis, O., Roane, J., and Tran, L.D. (2015). Acc. Chem. Res. 48: 1053. (j) Rit, R.K., Ramu Yadav, M., Ghosh, K., and Sahoo, A.K. (2015). Tetrahedron 71: 4450. (k) Lu, X., Xiao, B., Shang, R., and Liu, L. (2016). Chin. Chem. Lett. 27: 305. (l) He, G., Wang, B., Nack, W.A., and Chen, G. (2016). Acc. Chem. Res. 49: 635. (m) Hartwig, J.F. and Larsen, M.A. (2016). ACS Cent. Sci. 2: 281. (n) He, J., Wasa, M., Chan, K.S.L. et al. (2017). Chem. Rev. 117: 8754. (o) Xu, Y. and Dong, G. (2018). Chem. Sci. 9: 1424. For selected reviews of asymmetric C–H activation, see: (a) Giri, R., Shi, B.-F., Engle, K.M. et al. (2009). Chem. Soc. Rev. 38: 3242. (b) Peng, H.M., Dai, L.-X., and You, S.-L. (2010). Angew. Chem. Int. Ed. 49: 5826. (c) Yang, L. and Huang, H. (2012). Catal. Sci. Technol. 2: 1099. (d) Wencel-Delord, J. and Colobert, F. (2013). Chem. Eur. J. 19: 14010. (e) Zheng, C. and You, S.-L. (2014). RSC Adv. 4: 6173. (f ) Newton, C.G., Wang, S.-G., Oliveira, C.C., and Cramer, N. (2017). Chem. Rev. 117: 8908. (g) Saint-Denis, T.G., Zhu, R.-Y., Chen, G. et al. (2018). Science 359: 759. Noisier, A.F.M. and Brimble, M.A. (2014). Chem. Rev. 114: 8775. For seminal examples of diastereoselective C(sp3 )–H functionalization of N-phthaloyl-α-amino acids, see: Reddy, B.V.S., Reddy, L.R., and Corey, E.J. (2006). Org. Lett. 8: 3391. For early examples, see: (a)Giri, R., Chen, X., and Yu, J.-Q. (2005). Angew. Chem. Int. Ed. 44: 2112. (b) Giri, R., Liang, J., Lei, J.-G. et al. (2005). Angew. Chem. Int. Ed. 44: 7420. For typical examples, see: Fan, Z.-L., Shu, S.-Q., Ni, J.-B. et al. (2016). ACS Catal. 6: 769. Bhat, S.V., Nagasampagi, B.A., and Sivakumar, M. (eds.) (2005). Chemistry of Natural Products, 317. Berlin: Springer. For selected reviews, see: (a) Nájera, C. and Sansano, J.M. (2007). Chem. Rev. 107: 4584. (b) Makino, K. and Hamada, Y. (2005). J. Synth. Org. Chem. Jpn. 63: 1198.

References

9 For the pioneering use of 8-aminoquinoline auxiliary, see: Zaitsev, V.G.,

Shabashov, D., and Daugulis, O. (2005). J. Am. Chem. Soc. 127: 13154. 10 Tran, L.D. and Daugulis, O. (2012). Angew. Chem. Int. Ed. 51: 5188. 11 (a) Fryzuk, M.D. and Bosnich, B. (1979). J. Am. Chem. Soc. 101: 3043.

12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

(b) Labinger, J.A., Hart, D.W., Seibert, W.E. III, and Schwartz, J. (1975). J. Am. Chem. Soc. 97: 3851. Feng, Y. and Chen, G. (2010). Angew. Chem. Int. Ed. 49: 958. (a) Zhang, S.-Y., Li, Q., He, G. et al. (2013). J. Am. Chem. Soc. 135: 12135. (b) Chen, K., Hu, F., Zhang, S.-Q., and Shi, B.-F. (2013). Chem. Sci. 4: 3906. Chen, K. and Shi, B.-F. (2014). Angew. Chem. Int. Ed. 53: 11950. Chen, K., Zhang, S.-Q., Jiang, H.-Z. et al. (2015). Chem. Eur. J. 21: 3264. Liu, Y.-J., Liu, Y.-H., Zhang, Z.-Z. et al. (2016). Angew. Chem. Int. Ed. 128: 14063. Liao, G., Yin, X.-S., Chen, K. et al. (2016). Nat. Commun. 7: 12901. Zhang, Q., Chen, K., Rao, W.-H. et al. (2013). Angew. Chem. Int. Ed. 52: 13588. For the development of PIP auxiliary, see: Chen, F.-J., Zhao, S., Hu, F. et al. (2013). Chem. Sci. 4: 4187. (a) Zhang, Q., Yin, X.-S., Chen, K. et al. (2015). J. Am. Chem. Soc. 137: 8219. (b) Miao, J.-M., Yang, K., Kurek, M., and Ge, H.-B. (2015). Org. Lett. 17: 3738. He, J., Li, S.-H., Deng, Y.-Q. et al. (2014). Science 343: 1216. Chen, G., Shigenari, T., Jain, P. et al. (2015). J. Am. Chem. Soc. 137: 3338. Zhu, R.-Y., Tanaka, K., Li, G.-C. et al. (2015). J. Am. Chem. Soc. 137: 7067. Rodríguez, N., Romero-Revilla, J.A., Fernández-Ibáˇnez, M.A., and Carretero, J.C. (2013). Chem. Sci. 4: 175. Hernando, E., Villalva, J., Martínez, A.M. et al. (2016). ACS Catal. 6: 6868. Stache, E.E., Seizert, C.A., and Ferreira, E.M. (2012). Chem. Sci. 3: 1623. Chen, K., Li, Z.-W., Shen, P.-X. et al. (2015). Chem. Eur. J. 21: 7389. Ling, P.-X., Fang, S.-L., Yin, X.-S. et al. (2015). Chem. Eur. J. 21: 17503. Kim, J., Sim, M., Kim, N., and Hong, S. (2015). Chem. Sci. 6: 3611. (a) Jerhaoui, S., Chahdoura, F., Rose, C. et al. (2016). Chem. Eur. J. 22: 17397. (b) Jerhaoui, S., Poutrel, P., Djukic, J.-P. et al. (2018). Org. Chem. Front. 5: 409. Mu, D.-L., Gao, F., Chen, G., and He, G. (2017). ACS Catal. 7: 1880. Jerhaoui, S., Djukic, J.-P., Wencel-Delord, J., and Colobert, F. (2017). Chem. Eur. J. 23: 15594. Dangel, B.D., Godula, K., Youn, S.W. et al. (2002). J. Am. Chem. Soc. 124: 11856. He, G. and Chen, G. (2011). Angew. Chem. Int. Ed. 50: 5192. Gutekunst, W.R. and Baran, P.S. (2011). J. Am. Chem. Soc. 133: 19076. Zhou, M., Li, X.-R., Tang, J.-W. et al. (2015). Org. Lett. 17: 6062. Ting, C.P. and Maimone, T.J. (2014). Angew. Chem. Int. Ed. 53: 3115. Cui, W., Chen, S., Wu, J.-Q. et al. (2014). Org. Lett. 16: 4288. Affron, D.P., Davis, O.A., and Bull, J.A. (2014). Org. Lett. 16: 4956. Affron, D.P. and Bull, J.A. (2016). Eur. J. Org. Chem. 2016: 139. Sharpe, R.J. and Johnson, J.S. (2015). J. Am. Chem. Soc. 137: 4968. Chapman, L.M., Beck, J.C., Wu, L., and Reisman, S.E. (2016). J. Am. Chem. Soc. 138: 9803.

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4 Substrate-Controlled Transformation: Diastereoselective Functionalization

43 Steijvoort, B.F.V., Kaval, N., Kulago, A.A., and Maes, B.U.W. (2016). ACS

Catal. 6: 4486. 44 Mondal, B., Roy, B., and Kazmaier, U. (2016). J. Org. Chem. 81: 11646. 45 Topczewski, J.J., Cabrera, P.J., Saper, N.I., and Sanford, M.S. (2016). Nature

531: 220.

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Part II Stereoselective Synthesis Implying Activation of C(sp2 )—H Bonds

133

5 Planar Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step Qing Gu and Shu-Li You State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China

5.1 Introduction Planar chirality is used to describe a chiral molecule lacking an asymmetric carbon atom but possessing two non-coplanar and dissymmetric rings [1]. It commonly exists in di- or multi-substituted metallocenes and certain substituted paracyclophanes. For instance, ferrocene-based planar chirality appears when two or more different substituents are introduced on one of the cyclopentadienyl (Cp) rings to remove the plane of symmetry of the parent substance. Since the serendipitous discovery of a sandwich-type structure of ferrocene in the early 1950s, planar chiral ferrocenyl compounds have been extensively investigated especially as chiral ligands or catalysts [2]. As a result, intense attention has been paid to the efficient introduction of planar chirality on the backbone of ferrocenes [3]. The most commonly used strategies involve diastereoselective directed ortho metalation (DoM), enantioselective DoM, chiral resolution, and desymmetrical reactions [4]. However, these methods often rely on the utilization of stoichiometric amounts of preinstalled chiral auxiliaries or chiral bases. Additionally, the practicality of these processes is hampered by the requirement of air-sensitive organometallic reagents, the poor compatibility of these reaction conditions with functional groups, and the low atom economy in some cases. In view of the atom and step economy, transition metal-catalyzed asymmetric direct C—H bond functionalization is certainly the most convenient and powerful method for the installation of planar chirality on ferrocene scaffold. The main challenge restricting the development of this field concerns the need to selectively discriminate inert enantiotopic C—H bonds under generally relatively harsh reaction conditions. Nevertheless, a number of important advances on this topic have been achieved using a transitional metal-catalyzed asymmetric C—H bond functionalization strategy [5]. In this chapter, we will summarize the relevant research progress starting from diastereoselective C—H bond activation of ferrocenes by using chiral auxiliary, followed by the development of chiral catalysts to realize chiral recognition of two enantiotopic C—H bonds of ferrocene.

C–H Activation for Asymmetric Synthesis, First Edition. Edited by Françoise Colobert and Joanna Wencel-Delord. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.

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5 Planar Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

5.2 Diastereoselective Synthesis of Planar Chiral Ferrocenes The development of diastereoselective C—H bond functionalization relies on the choice of an appropriate chiral auxiliary, which is responsible for a high stereocontrol during the C–H activation event. In 2007, You reported a diastereoselective synthesis of planar chiral ferrocene (S,Rp )-2 by using enantiopure ferrocenyl oxazoline (S)-1 with a simple arene (Scheme 5.1a) [6]. Of further note, (S,Rp )-2 was also easily obtained by refluxing the palladium dimer I in benzene. In 2012, Shibata and coworkers described a Rh-catalyzed diastereoselective C—H bond amidation with isocyanates using the same chiral oxazoline directing group, generating the desired amidation products (3) as a single diastereoisomer in moderate yields (Scheme 5.1b) [7]. O Fe H

N

i

Pr

(2) K2CO3 (2.3 equiv) benzene/reflux 24% yield

(S)-1

O

(1) Pd(OAc)2 (1 equiv) CH2Cl2/reflux

Fe

Ph N

i

Pr

K2CO3 (2.3 equiv) benzene/reflux 69% yield

i

Fe (S)-1

(b)

i

Pr +

RNCO

N

i

Pr

O

I

(a)

H N

Fe Pd O

2 (S,Rp)-2

O

O

[RhCp*(OAc)2(H2O) (5 mol%) HBF4•OEt2 (10 mol%) THF, 75 °C

O

Pr

N

O NHR

Fe (S,Sp)-3 24–69% yield

Scheme 5.1 Diastereoselective C–H arylation and amidation reactions by using chiral oxazoline as a directing group. (a) Cross-coupling reaction; (b) amidation reaction.

5.3 Enantioselective Synthesis of Planar Chiral Ferrocenes 5.3.1

Pd(II)-Catalyzed Direct C—H Bond Functionalization

Compared with the diastereoselective synthesis of planar chiral ferrocene induced by a chiral auxiliary, a more attractive alternative to introduce planar chirality implies the use of chiral catalyst. A seminal work in this subject was first reported by Siegel and Schmalz [8]. It is remarkable that cyclization products 5 were efficiently obtained with significant enantioselectivity by asymmetric carbene insertion into the ortho C—H bond of ferrocene with CuOTf/ bis-oxazoline (L1) as the catalyst (Scheme 5.2). They examined two substrates (4), and in both cases the desired products (5) were obtained with rather impressive enantioselectivities. The precedent work regarding enantioselective palladation of dimethylaminomethylferrocene promoted by a stoichiometric amount of chiral amino

5.3 Enantioselective Synthesis of Planar Chiral Ferrocenes

R R Fe

H

n

O N2

CuOTf (5 mol%) (S,S)-L1 (5.1 mol%) CH2Cl2, 40 °C

Me O

R R n

Fe

O

N

O N

Ph (S,S)-L1

5 5a: R = H, n = 1, 72% yield, 78% ee 5b: R = Me, n = 0, 89% yield, 62% ee

4

Me

Ph

Scheme 5.2 Cu-catalyzed enantioselective insertion of carbenoid into C—H bond of ferrocene.

acid was reported by the group of Sokolov, affording optically active planar chiral ferrocenylpalladium chloride dimer in high yield [9]. However it is less practical since the preparation of the optically active palladium(II) complex in advance and a stoichiometric amount of ligand are required. A major breakthrough concerning asymmetric C—H bond activation under palladium catalysis to generate central chirality was first reported by the Yu group employing monoprotected amino acid (MPAA) as the chiral ligand. It opened a new door to the field of the catalytic asymmetric C–H functionalization reactions [10]. Inspired by these pioneering studies, in 2013 the You group realized an asymmetric synthesis of planar chiral ferrocenes by the Pd-catalyzed cross-coupling reaction of dialkylaminomethylferrocene with arylboronic acids [11]. Employing commercially available Boc-l-Val-OH as the chiral ligand with air as the sole oxidant makes this method potentially practical. The reaction proceeds smoothly to afford the arylative products (7) in good yields and excellent enantioselectivity (Scheme 5.3). Unfortunately the reaction with aliphatic boronic acid works much less efficient. NMe2 H Fe 6a

+

ArB(OH)2

Pd(OAc)2 (10 mol%) Boc-L-Val-OH (20 mol%) K2CO3 (1 equiv) TBAB (0.25 equiv) DMA, 60 °C, air

NMe2 Me O

Ar Fe 7

Me

OH NHBoc

Boc-L-Val-OH

33–81% yield, 94–99% ee

Scheme 5.3 Pd-catalyzed asymmetric C—H bond arylation of ferrocenes with arylboronic acids.

A plausible catalytic cycle was proposed in Figure 5.1. The C—H bond of ferrocene 6a is selectively cleaved via concerted metalation–deprotonation (CMD) mechanism to generate cyclic Pd(II) A with the MPAA playing the role of the internal base in the enantioselectivity-determining step [12a]. Subsequently, A is transformed to the intermediate B by transmetalation with phenyl boronic acid, and finally reductive elimination of B delivers the desired product (Sa )-7a. The release of Pd(0) species and subsequent oxidation by air to Pd(II) species complete the catalytic cycle (Figure 5.1). A μ-carboxylato (MPAA) bridged dimer was also recently suggested as the catalytically active species in this catalytic C–H functionalization reaction of ferrocenes [12b].

135

136

5 Planar Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

Pd(OAc)2 NMe2

NMe2

L = Boc-L-Val-OH

Ph Fe

H

LnPd(0)

+

Air

LnPd(II)

Fe

7a

6a

Reductive elimination

C–H activation O

Pr Me Me N

O H

Me2N LnPd Ph

i

H

Fe

N

Pd O

tBuO

B

Fe

A Transmetalation PhB(OH)2

Figure 5.1 Plausible catalytic cycle of Pd-catalyzed asymmetric C—H bond arylation.

Almost at the same time, an asymmetric oxidative Heck reaction for the efficient synthesis of planar chiral ferrocenes was disclosed by Cui, Wu, and their coworkers by employing Boc-l-Phen-OH as an optimal ligand [13]. Olefins such as acrylates, substituted styrenes, vinylcyclohexane, and acrylamide are all suitable substrates, providing the alkenylated products (8) in good yields and excellent ee (Scheme 5.4a). Soon after, You and coworkers reported the Pd(II)-catalyzed asymmetric annulation of N,N-disubstituted aminomethylferrocenes with diarylethynes (Scheme 5.4b) [14]. This reaction is based on a previous racemic report by Cui, Wu, and coworkers [15]. Starting from the product (Sp )-9 obtained via this method, P,N-bidentate ligand (Sp )-L2 could be readily synthesized via DoM and electrophilic trapping with Ph2 PCl. The preliminary examination of (Sp )-L2 in Pd(0)-catalyzed asymmetric allylic alkylation showed that the alkylation product 11 was obtained in promising enantioselectivity (44% ee) (Scheme 5.4b). The asymmetric oxidative cross-coupling reaction of two arenes via double C–H activation pathway is undoubtedly the most expedient and straightforward method to synthesize chiral biaryls given its high atom economy during the coupling procedure. However the strategy of a twofold C—H bond activation was mainly reported in a racemic manner since the enantioselective activation of inert C—H bond of both substrates has not been well addressed. In 2016, You and coworkers achieved an asymmetric oxidative cross-coupling reaction

5.3 Enantioselective Synthesis of Planar Chiral Ferrocenes NMe2 R

+

Fe

NMe2

Pd(OAc)2 (5 mol%) Boc-L-Phe-OH (10 mol%)

H

K2CO3 (0.3 equiv), TBAB (0.5 equiv) DMF, 60 °C, air

6a

(a)

COOH

R Fe

NHBoc

8a 65–98% yield, 91–99% ee

Boc-L-Phe-OH

Ph NMe2 H +

Fe

Ph

Ph

Br 6b

Ph

Pd(OAc)2 (10 mol%) Boc-L-Phe-OH (20 mol%)

Ph

K2CO3 (1.0 equiv), TBAB (0.25 equiv), DMA, 80 °C, air, 48 h

NMe2

Fe Br

n

BuLi, Ph2PCl THF, –78 °C 43% yield, 97% ee

9, 42% yield, 96% ee Ph OAc Ph

Ph (rac)-10

[Pd(C3H5)Cl]2 (2 mol%) (Sp)-L2 (6 mol%) (MeO2C)2CH2, NaH THF, rt

Ph MeO2C

CO2Me Ph

Ph

Ph (S)-11 95% yield, 44% ee

NMe2 (Sp)-L2

Fe

(b)

PPh2

Scheme 5.4 Enantioselective synthesis of planar chiral ferrocenes via Pd(II)-catalyzed oxidative Heck and annulation reactions. (a) Oxidative Heck reaction; (b) oxidative annulation reaction and its application. NMe2

Pd(OAc)2 (10 mol%) Boc-L-Ile-OH (20 mol%)

R

H +

Fe

X R1

6

12

H

K2CO3 (1.5 equiv) BQ (0.1 equiv), H2O (4.0 equiv) DMA, air, 80 °C

R

NMe2 COOH

X Fe R1 13 36–86% yield, 95–99% ee

NHBoc Boc-L-Ile-OH

Scheme 5.5 An enantioselective oxidative C–H/C–H cross-coupling reaction.

by using Pd(OAc)2 and Boc-l-Ile-OH as the catalytic system [16]. Planar chiral ferrocenes (13) were constructed in high yields with exclusive regioselectivity and nearly perfect enantioselectivity directly from dimethylaminomethylferrocenes (6) and electron-rich heteroarenes (12) (Scheme 5.5). It is worth noting that this atom-economical reaction proceeds using oxygen from air as a green oxidant and without significant excess of either coupling partner. A plausible catalytic cycle of this twofold C—H bond activation reaction is similar to that of cross-coupling reaction of ferrocene with arylboronic acid. The only difference is that the arylation of intermediate A goes through electrophilic substitution with benzofuran rather than transmetalation with arylboronic acid (Figure 5.2). Apart from arylation and oxidative Heck and annulation reaction, the development of other types of reactions is less explored. In 2014, Cui, Wu, and coworkers reported a novel catalytic enantioselective C–H acylation reaction by using Pd(OAc)2 and Ac-l-Phe-OH as the catalytic system [17]. Diaryldiketones are well

137

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5 Planar Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

Pd(OAc)2 NMe2

NMe2

L = Boc-L-Ile-OH O Fe

H

LnPd(0)

+

LnPd(II)

Air

Fe

13a

6a

Reductive elimination

The first C–H activation Me

Me2N

O

Me

N

LnPd

LnPd

Fe

Fe B

A The second C–H activation H O

Figure 5.2 Plausible catalytic cycle of Pd-catalyzed asymmetric twofold C—H bond functionalization reaction. NMe2 H

O Fe

Ar

+ Ar

O 6a

NMe2

O

Pd(OAc)2 (10 mol%) Ac-L-Phe-OH (20 mol%)

COOH

Ar

K2CO3 (1.0 equiv), TBAB (0.5 equiv) TBHP (3.0 equiv), THF, 80 °C, 12 h

Fe

14 35–85% yield, 56–98% ee

NHAc Ac-L-Phe-OH

Scheme 5.6 Catalytic enantioselective C–H acylation of ferrocenes.

amenable to the acylation reaction, affording various planar chiral ferrocenes in satisfactory yields and enantioselectivity (Scheme 5.6). During the investigation of the reaction mechanism, they have found that the radical scavenger TEMPO could inhibit the reaction. Thus, a radical pathway was proposed. In the proposed reaction pathway, a cyclopalladated intermediate A is formed via selective C—H bond activation. Then, Pd(III) or Pd(IV) intermediate B is generated by the reaction of A with benzoyl radical, resulting from the reaction of diphenyldiketone with tert-butyl hydroperoxide. Finally, reductive elimination of the highly reactive species B delivers the desired product with regeneration of Pd(II) species to complete the catalytic cycle (Figure 5.3). C–H functionalization by using a transient directing group has been demonstrated to be a promising strategy, which avoids pre-installation and

5.3 Enantioselective Synthesis of Planar Chiral Ferrocenes

NMe2

O

NMe2

L = Ac-L-Phe-OH

Ph Fe

LnPd(II)

Fe

14a

6a

Reductive elimination

C–H activation O

PhOC

Me2 N

R

Me Me N

O H

Ln Pd

H

N

Pd O

Fe

Fe

Me

A

B

O

Ph

tBuOCOPh

•

tBuO•

Ph

O

Ph

O

PhCOOH

•OH

tBuOOH

Figure 5.3 Proposed reaction mechanism of catalytic enantioselective C–H acylation.

late removal of the directing group. In 2018, Jin, Xu, and coworkers reported an enantioselective Pd-catalyzed C–H arylation of ferrocenyl ketones by employing substoichiometric amount of l-tert-leucine as a chiral transient directing group [18]. In most cases, direct C–H arylation of ferrocenyl ketones with various (hetero)aryl iodides proceeded smoothly to give the arylative products in moderate to good yields with excellent enantioselectivities (Scheme 5.7). By utilizing this method, novel planar chiral mono-phosphine ligands were successfully synthesized in a concise manner. O Fe H R 15

R 1

Pd(OAc)2 (10 mol%) (60 mol%)

O

L-tert-leucine

+ ArI

Ag2CO3 (0.5 equiv), PivOH (2.0 equiv) NaHCO3 (0.5 equiv), HFIP, 130 °C

Fe Ar

R

via

R

R1

Fe

tBu

N

O HO

16 40–75% yield, 92–98% ee

Scheme 5.7 C–H arylation of ferrocenyl ketones enabled by a chiral transient directing group.

139

140

5 Planar Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

5.3.2

Pd(0)-Catalyzed Direct C—H Bond Functionalization

As described in Section 5.3.1, Pd(II)-catalyzed asymmetric C—H bond activation has become an important tool to build up planar chiral ferrocene derivatives. However, high catalyst loading (5–10 mol%) and external oxidant are often needed in this process. Pd(0)-initiated intramolecular asymmetric C–H arylation under oxidant-free reaction conditions was developed by the You group for the highly efficient synthesis of planar chiral ferrocenes (Scheme 5.8) [19]. The catalyst utilized here is derived from commercially available Pd(OAc)2 and BINAP. Compared with previous oxidative C–H arylation, such an overall redox-neutral process (Pd0 /PdII catalysis) does not require an external stoichiometric oxidant, thus addressing potential problems of overoxidation of substrates or a ligand. Remarkably when the catalyst loading was reduced to 0.5 mol%, the arylative product was obtained in a quantitative yield and excellent ee (99% yield, 96% ee). Simultaneously, Gu, Kang, and coworkers reported a similar intramolecular arylation reaction of aryl iodide incorporated into the ferrocene scaffold [20]. Besides ferrocenes, ruthenocene derivatives are also suitable substrates, and the corresponding planar chiral ruthenocenes could be synthesized in high enantioselectivity with good functional group tolerance. In addition, chiral BINOL-derived phosphoric acid was efficiently used by Duan, Ye, and coworkers to induce asymmetry in the Pd(0)-catalyzed C–H arylation of ferrocenes, albeit with moderate enantioselectivity in some cases [21]. R1 O

O X R2 R2

M R2 17

R2 R2

R

Conditions R2 R2

M R2 18

R2 R2

1

You

Gu

M = Fe, X = Br Pd(OAc)2 (2.5 mol%) (R)-BINAP (5 mol%) Cs2CO3 (1.5 equiv) Pivalic acid (0.3 equiv) p-Xylene, 60 or 80 °C

M = Fe, Ru, X = I Pd(OAc)2 (5 mol%) (R)-BINAP (6.5 mol%) Cs2CO3 (2.0 equiv) Toluene, 100 °C

82–99% yield 98–99% ee

80–97% yield 91–99% ee

Scheme 5.8 Pd(0)-catalyzed enantioselective intramolecular C–H arylation.

This new methodology developed by You was applied to the straightforward synthesis of planar chiral P,N-ligand, in which the planar chirality was previously introduced by DoM strategy [22]. To access a planar chiral ligand, the arylative product 18a was subjected to oximation, reduction (dr = 1 : 1), and reductive amination, affording the tertiary amine (S,Rp )-21 in 36% yield over three steps. Finally, the desired P,N-ligand (S,Rp )-22, which has shown excellent chiral induction in Pd-catalyzed asymmetric allylic alkylation and amination reaction [22], was obtained by the amine-directed lithiation and subsequent trapping with Ph2 PCl in 68% yield (Scheme 5.9). Interestingly, starting from C 2 -symmetric planar chiral ferrocene ent-18i, Guiry and coworkers readily prepared a novel family of planar chiral ferrocenyl diols 23, which were demonstrated as suitable catalysts in an asymmetric hetero-Diels–Alder reaction (Scheme 5.10) [23]. By utilizing an amide linker in the substrate 24, the Gu group realized an enantioselective synthesis of planar chiral quinilinoferrocenes by employing

5.3 Enantioselective Synthesis of Planar Chiral Ferrocenes

OH N

O NH2OH•HCl AcONa, EtOH 65 °C

Fe

NH2 Zn, HOAc

(Rp)-18a 97% ee

Fe

50 °C

Fe

20 dr = 1 : 1

(Z) and (E)-19

N ZnCl2, CH3OH NaBH3CN

N

(1) tBuLi, Et2O, 0 °C

HCHO (aq)

PPh2

(2) PPh2Cl, 0 °C to rt

Fe

Fe

(S,Rp)-22 68% yield

(S,Rp)-21 36% yield over three steps

Scheme 5.9 Efficient synthesis of planar chiral P,N-ligand (S,Rp )-22. Ar Fe O

Ar-M

Fe

OH

OH

O Ar

Ar = 3,5-(CF3)2C6H3 23

ent-18i

TBSO

NO2 + N

O

(1) 23 (20 mol%) Toluene, –78 °C, 40 h (2) AcCl, CH2Cl2-toluene –78 °C, 30 min

NO2 O O 61% yield, 59% ee

Scheme 5.10 Efficient synthesis of diol 23 and its application in asymmetric hetero-Diels–Alder reaction.

(R,Sa )-O-PINAP as the chiral ligand [24]. Soon after, asymmetric synthesis of these scaffolds was also reported by Liu, Zhao, and coworkers. This second protocol based on the use of a TADDOL-derived phosphoramidite ligand L3 showed improved efficiency, delivering the expected planar chiral products 25 in excellent yields and high optical purity (Scheme 5.11) [25]. This strategy provides a concise way to synthesize ferrocenes bearing a lactam skeleton. Chiral ferrocene derivatives containing a pyridine core are effective nucleophilic catalysts or Lewis base catalysts, showing powerful catalytic ability in numerous asymmetric reactions. You and coworkers developed a highly efficient synthesis of planar chiral ferrocenylpyridine derivatives via Pd-catalyzed

141

142

5 Planar Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step R3

R3 Conditions

Fe

Fe

O X H

R1

O N

R1 R2

R2

N

25

24 Me

Liu and Zhao

Gu

O N N PPh2 (R,Sa)-O-PINAP

Ph Ph O Et Me O P N Me O Et O Ph Ph

Pd(OAc)2 (5 mol%) (R,Sa)-O-PINAP (15 mol%) Cs2CO3 (2.5 equiv) Toluene, 120 °C, 12 h 50–98% yield 28–67% ee

Pd2dba3 (5 mol%) (R,R)-L3 (10 mol%) PivOH (30 mol%) Cs2CO3 (1.5 equiv) Toluene, 80 °C, 8 h

(R,R)-L3

70–91% yield 82–96% ee

Scheme 5.11 Enantioselective intramolecular C–H arylation of N-(2-haloaryl) ferrocenecarboxamides. O

H

Fe

R2

26

O

Br N R1

Fe

K2CO3 (1.5 equiv) Pivalic acid (0.3 equiv) p-Xylene, 80 °C

R1

N

Pd(OAc)2 (2.5 mol%) (R)-BINAP (5.0 mol%) R2

DMDO DCM, –10 °C

27

97% yield

83–99% yield, 96–99% ee O SiCl4 (1.1 equiv) 28 (10 mol%)

O Ph

Ph 29

DIPEA (1.1 equiv) DCM, –78 °C

Ph

N+ O

OSiCl3 Ph

Cl 30 95% yield, 66% ee

Et

Fe Et Et

Et Et

28

Scheme 5.12 Highly enantioselective synthesis of planar chiral ferrocenylpyridine derivatives and their application in asymmetric opening of meso epoxide.

intramolecular C–H arylation reaction (Scheme 5.12) [26]. In the presence of 2.5 mol% of Pd(OAc)2 and 5.0 mol% of (R)-BINAP, substrates with varied electronic effect or bearing bulky substituents were smoothly converted into the expected compounds. Furthermore, the pyridine N-oxide (28) bearing a pentaethyl Cp ring prepared by oxidation of 27 was tested as the catalyst in the asymmetric opening of meso epoxide, delivering the desired product 30 in 95% yield and 66% ee. This new method provides a convenient synthetic tool for further design and synthesis of planar chiral ferrocenyl pyridine catalysts. In order to clarify the excellent enantioselectivity obtained in the asymmetric C–H arylation reaction, computational investigations were conducted to show the origin of the excellent enantioselectivity. The CMD mechanism was applied to explain the chiral induction. Density functional theory (DFT) calculations found

5.3 Enantioselective Synthesis of Planar Chiral Ferrocenes

that the Gibbs free energy of the transition state (TS-CMD-S) leading to the planar chiral ferrocenes in S configuration is higher than that of the transition state (TS-CMD-R), leading to R product by 8.8 kcal/mol. This is due to the fact that significant steric interaction between the ferrocene moiety and one phenyl group of (R)-BINAP in quadrant II is observed in TS-CMD-S while such an unfavorable effect could be effectively avoided in TS-CMD-R where the ferrocene moiety is located in an open quadrant. Therefore, the biased interaction of the chiral ligand and the ferrocenyl moiety of substrates in the two diastereomeric transition states induce excellent stereochemical control during the C–H arylation step (Figure 5.4).

Fe 2

Pd C

N C1

C

Fe H

B(Pd–C1) = 2.269 B(Pd–H1) = 2.357 B(C1–H1) = 1.366 B(O2–H1) = 1.277 B(Pd–O1) = 2.851

Side view

Pd 2

C N

1

H

O2

O2

O1

1

1

O

1

B(Pd–C1) = 2.270 B(Pd–H1) = 2.417 B(C1–H1) = 1.407 B(O2–H1) = 1.235 B(Pd–O1) = 2.785

Side view

Fe

Steric repulsion

2

P

Fe

1

2

Pd C

C

Pd

P1

2

P1

1

C

H1 O

P N

N

2

C

1

H

O

1

O

2

O

D(P1–P2–C2–(C1–H1)) = 4.3

D(P2–P1–C2–(C1–H1)) = 28.6

Front view

(a) Shield Steric repulsion

Open

Shield

Open O Fe

Pd H

Pd

N

N

O

O H

O

(b)

Front view

O

Fe

Open

2

1

O

TS-CMD-S 8.8

O

H

Shield

Open

H

O

Shield

TS-CMD-R 0.0

Figure 5.4 (a) The structures of the two transition states TS-CMD-R and TS-CMD-S. (b) The quadrant analysis of the two transition states. The unsubstituted Cp ring of ferrocene moiety is omitted in the front views for the sake of clarity. The bond distances are in angstrom. The dihedral angles are in degree. The relative Gibbs free energies are in kcal/mol. Source: Gao et al. 2015 [26]. Reprinted with permission of American Chemical Society.

143

144

5 Planar Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

Intramolecular asymmetric C–H alkenylation reaction is clearly more challenging. The only exceptional example has been disclosed by the Cramer group. TADDOL-derived phosphoramidite was employed as an efficient ligand for this Pd(0)-catalyzed reaction [27]. Recently, the You group developed an intramolecular C–H alkenylation for the expedient synthesis of planar chiral ferrocenes [28]. Substrates bearing either an electron-donating or electron-withdrawing substituent on the Cp ring were well tolerated, giving rise to planar chiral ferrocenes in high yields and excellent enantioselectivity. Planar chiral ruthenocene could also be synthesized under the optimized conditions. Notably, the enantioselective and diastereoselective synthesis of planar chiral ferrocenes was firstly realized by cascade C–H arylation and alkenylation, furnishing the desired product in good level of yields, dr, and excellent enantioselectivity (Scheme 5.13). O

M

O H Br H

Pd(OAc)2 (2.5 mol%) (R)-BINAP (5 mol%) Cs2CO3 (1.5 equiv) Pivalic acid (0.3 equiv) Water (15 μl) p-Xylene

Br

O 31 M = Fe, Ru

M R O

R

32 59–99% yield, 94–99% ee

Scheme 5.13 Highly enantioselective synthesis of planar chiral ferrocenes via Pd(0)-catalyzed C–H alkenylation.

Pd-catalyzed isocyanide (RNC) insertion, known as imidoylation, is a powerful approach in the synthesis of various imine derivatives. In 2018, Zhu, Luo, and coworkers developed a Pd-catalyzed imidoylation, followed by enantioselective desymmetric C(sp2 )—H bond activation reaction by using SPINOL-derived phosphoramidite ligand (L4), affording various planar chiral pyridoferrocenes in high yields with good to excellent enantioselectivities (Scheme 5.14) [29]. CN

Fe H 33

R2 R1 +

R1

Pd(OAc)2 (5 mol%) L4 (10 mol%) ArI

Cs2CO3 (1.2 equiv), PivOH (0.6 equiv) Toluene, 75 °C

Fe

R2

N Ar 34

Me O P N O Me L4

Up to 99% yield, 99% ee

Scheme 5.14 Enantioselective synthesis of planar chiral pyridoferrocenes via Pd(0)-catalyzed imidoylative cyclization reactions.

5.3.3

Ir/Rh-Catalyzed Direct C—H Bond Functionalization

Compared with Pd-catalyzed asymmetric C—H bond functionalization, the development of rhodium or iridium catalytic systems has progressed slowly,

5.3 Enantioselective Synthesis of Planar Chiral Ferrocenes

especially for the introduction of planar chirality. Shibata and Shizuno reported Ir/chiral diene-catalyzed asymmetric C–H alkylation of ferrocenes using an isoquinolin-2-yl group as the directing group, which could suppress the secondary alkylation [30]. Several alkenes including allylbenzene, oct-1-ene, methyl methacrylate, and norbornene could proceed well in good yields and moderate to good enantioselectivities (Scheme 5.15). A preliminary mechanistic investigation showed that the pathway of C—H bond cleavage and the insertion of alkene are likely reversible. R

N Fe

Me

[Ir(coe)2Cl]2 (5 mol%) L5 (20 mol%)

H R

+

N

NaBArF (20 mol%) Toluene, 110 °C

R

OMe

N

+ Fe

Fe 34

33

Me

p-Tol

Me L5

35

Scheme 5.15 Ir-catalyzed enantioselective C–H alkylation of ferrocene.

Given the fundamental importance of silicon-containing compounds, the development of enantioselective C–H silylation to access planar chiral ferrocenes bearing the silole unit is highly desirable. In 2015, three groups independently reported rhodium-catalyzed asymmetric intramolecular C–H silylation for the construction of planar chiral benzosiloloferrocenes (Scheme 5.16) [31]. In the case of Shibata’s work [31a], the chiral diene ligand L6 was applied to the dehydrogenative coupling reaction, leading to the corresponding products in R R1

R X H H

R1 Conditions

M

M

R2

R2

37

36

Murai and Takai

He

Shibata [Rh(COE)2Cl]2 (10 mol%) L6 (24 mol%) 3,3-Dimethyl-1-butene (10 equiv) Toluene, 135 °C, 2–24 h M = Fe, X = Si, Ge 40–75% yield 5–86% ee

[Rh(COD)Cl]2 (5 mol%) (S)-L7 (10 mol%) Toluene, rt-45 °C, 48 h M = Fe, Ru X = Si 41–98% yield 77–94% ee

OMe

O O

Me

Ph L6

[Rh(COD)Cl]2 (2.5 mol%) (R)-DTBM-Segphos (7.5 mol%) DCE, 30–50 °C, 24–48 h M = Fe, Ru, X = Si 56–93% yield 77–93% ee O

O Me

X R2

O PAr2 PAr2

O (S)-L7: Ar = 3,5-(TMS)2C6H3

O

PAr2 PAr2

O (R)-DTBM-Segphos: Ar = 3,5-(tBu)2-4-OMeC6H2

Scheme 5.16 Rh-catalyzed intramolecular asymmetric C–H silylation.

145

146

5 Planar Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

moderate to good yields and enantioselectivity. Almost at the same time, He and coworkers [31b], Murai, Takai, and coworkers [31c] have respectively found that the chiral bisphosphine ligands could perform well in the dehydrogenative silylation with satisfactory yields and chiral induction after systematic exploration of chiral ligands. The process is compatible with quite mild reaction conditions and oxidants and therefore offers a practical and environmentally friendly route to functionalized planar chiral metallocenes. In 2014, the Pd-catalyzed annulation reaction of ferrocenecarboxamides with internal alkynes was realized by the group of Wang [32]. The non-requirement for ligand leaves a formidable challenge for realizing the chiral version of this reaction. With Rh catalysis, the You group developed an annulation reaction of N-methoxyferrocenecarboxamides with internal alkynes without external oxidant. Notably, asymmetric annulation of the reaction was initially demonstrated by using chiral Cp*Rh complex (Ra )-Rh1, affording the desired product 39 in 37% yield and 46% ee (Scheme 5.17) [33a]. Similarly, the N-ferrocenyl amide 41 was obtained in 26% yield and 40% ee in the amidation of ferrocenylpyridine with dioxazolone using (Ra )-Rh1 as a catalyst [33b]. These strategies provided the proof of concept for asymmetric synthesis and left the room for improvement in both yield and enantioselectivity. O

Fe

H

Ph

NHOMe +

O (Ra)-Rh1 (5 mol%) (BzO)2 (5 mol%) NaOAc (0.6 equiv) Et3N (1.0 equiv) TFE, 60 °C, 50 h

Me 38

Fe Me

NH Ph OMe

39 37% yield, 46% ee Rh

O N Fe

H 40

O

+ Ph

O N

(Ra)-Rh1 (5 mol%) (BzO)2 (5 mol%) AgNTf2 (0.1 equiv) NaOAc (0.2 equiv) DCE, 60 °C

Fe

N NHCOPh

OMe (Ra)-Rh1

41 26% yield, 40% ee

Scheme 5.17 Rh(III)-catalyzed asymmetric annulation and amidation reactions.

5.3.4

Au/Pt-Catalyzed Direct C—H Bond Functionalization

Gold-catalyzed intramolecular cycloisomerization has emerged as a powerful tool for the synthesis of phenanthrenes and helicenes. However, the enantioselective version of the cycloisomerization reaction has rarely been explored. Urbano and Carreño developed an asymmetric cycloisomerization process to synthesize aromatic tricyclic ferrocenes by enantioselective Au(I)-catalyzed C—H bond activation [34]. Substituents regardless of varied electronic properties and location on the phenyl ring could be tolerated well, showing good reactivity and satisfactory chiral induction. This represents the first example of a synthesis of planar chiral ferrocenes using gold catalysis. Shortly after, Shibata and coworkers have developed the cycloisomerization reaction to access planar chiral

5.4 Conclusion

R

R Conditions H

Fe

Fe 42

43

Urbano and Carreño

Shibata

(R)-DTBM-Segphos (AuCl)2 (10 mol%)

PtCl2(cod) (10 mol%) (S,S)-Ph-BPE (10 mol%) AgBF4 (20 mol%) DCE, rt, 15–24 h 62–97% yield 18–96% ee

AgSbF6 (20 mol%) Toluene, 0 °C, 3–15 h 74–92% yield 68–93% ee O O

PAr2

O

PAr2

O (R)-DTBM-Segphos: Ar = 3,5-(tBu)2-4-MeOC6H2

Ph Ph P

P

Ph

Ph (S,S)-Ph-BPE

Scheme 5.18 Enantioselective synthesis of planar chiral ferrocenes via Au/Pt-catalyzed cycloisomerization.

ferrocenes using Pt/(S,S)-Ph-BPE as the catalytic system (Scheme 5.18). Though these methods employed precious metals (Au or Pt) as the catalyst, these planar chiral ferrocenyl scaffolds cannot be easily constructed by other strategies [35].

5.4 Conclusion This chapter summarizes recent achievements in asymmetric C—H bond functionalization of ferrocenes by transitional metal catalysis, providing a variety of planar chiral ferrocene derivatives. Numerous catalytic systems have been disclosed using Pd(II)-catalyzed reactions. Indeed Pd(II) bearing various chiral ligands is able to discriminate enantiotopic C—H bond, thus affording planar chiral five-membered palladacycle intermediates. Remarkably this metallacyclic intermediates react with various downstream partners. In addition the redox-neutral process of Pd(0)-initiated intramolecular asymmetric C—H bond functionalization is a highly efficient approach to provide ferrocene derivatives with extremely high ee, which could be easily transformed to chiral ligands (P,N-ligand, ferrocenyl diol) or catalyst (pyridine N-oxide). Moreover asymmetric syntheses of structurally diverse planar chiral ferrocenes via Ir-, Rh-, Au-, and Pt-catalyzed C—H bond functionalization have also been described.

147

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5 Planar Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

The C–H activation-based protocols offer impressive advantages over traditional approaches for the synthesis of functionalized planar chiral ferrocenes in terms of both step and atom economy. While these achievements are notable, the progress in this field is still in its infancy. For example, enantioselective C–H functionalization of ferrocenes leading to a carbon–heteroatom bond formation (C—P, C—N, C—S bond, etc.) has been rarely explored. The catalytic activity is not sufficiently high for practical application purposes, especially in the case of Pd(II)-catalyzed intermolecular reactions. In addition, the need for the preinstallation of a directing group in the C–H functionalization reaction clearly diminishes the efficiency of the overall transformation. Accordingly further investigations on asymmetric C–H functionalization of ferrocenes bearing a synthetically useful directing group are highly desirable. Overall, development of diverse and efficient method for the synthesis of planar ferrocenes by asymmetric C–H functionalization continues to be the pursuit of the chemists in this field.

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S.-L. et al. (2003). Acc. Chem. Res. 36: 659–667. (c) Fu, G.C. (2004). Acc. Chem. Res. 37: 542–547. 3 For books and review, see: (a) Hayashi, T. and Togni, A. (eds.) (1995). Ferrocenes. Weinheim: VCH. (b) Togni, A. and Haltermann, R.L. (eds.) (1998). Metallocenes. Weinheim: VCH. (c) Štˇepniˇcka, P. (ed.) (2008). Ferrocenes. Chichester: Wiley. (d) Dai, L.-X. and Hou, X.-L. (eds.) (2010). Chiral Ferrocenes in Asymmetric Catalysis. Wiley. (e) Schaarschmidt, D. and Lang, H.S. (2013). Organometallics 32: 5668–5704. 4 Selected examples: (a) Battelle, L.F., Bau, R., Gokel, G.W. et al. (1973). J. Am. Chem. Soc. 95: 482–486. (b) Rebière, F., Riant, O., Ricard, L., and Kagan, H.B. (1993). Angew. Chem. Int. Ed. Engl. 32: 568–570. (c) Richards, C.J., Damalidis, T., Hibbs, D.E., and Hursthouse, M.B. (1995). Synlett 74–76. (d) Tsukazaki, M., Tinkl, M., Roglans, A. et al. (1996). J. Am. Chem. Soc. 118: 685–686. (e) Enders, D., Peters, R., Lochtman, R., and Raabe, G. (1999). Angew. Chem. Int. Ed. 38: 2421–2423. (f ) Laufer, R.S., Veith, U., Taylor, N.J., and Snieckus, V. (2000). Org. Lett. 2: 629–631. (g) Bolm, C., Kesselgruber, M., Muñiz, K., and Raabe, G. (2000). Organometallics 19: 1648–1651. (h) Bolm, C., Kesselgruber, M., and Raabe, G. (2002). Organometallics 21: 707–710. (i) Genet, C., Canipa, S.J., O’Brein, P., and Taylor, S. (2006). J. Am. Chem. Soc. 128: 9336–9337. For a review on kinetic resolution: (j) Alba, A.-N. R. and Rios, R. (2009). Molecules 14: 4747–4757; (k) Mercier, A., Yeo, W.C., Chou, J. et al. (2009). Chem. Commun. 5227–5229. (l) Mercier, A., Urbaneja, X., Yeo, W.C. et al. (2010). Chem. Eur. J. 16: 6285–6299. (m) Ogasawara, M., Arae, S., Watanabe, S. et al. (2013). Chem. Eur. J. 19: 4151–4154. 5 (a) Wang, Y., Zhang, A., Liu, L. et al. (2015). Chin. J. Org. Chem. 35: 1399–1406. (b) Arae, S. and Ogasawara, M. (2015). Tetrahedron Lett. 6:

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10

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6 Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step Quentin Dherbassy, Joanna Wencel-Delord, and Françoise Colobert Université de Strasbourg/Université de haute Alsace, Laboratoire d’Innovation Moléculaire et Applications (UMR CNRS 7042), Ecole de Chimie, Polymères et Matériaux (ECPM), ECPM, 25 Rue Becquerel, Strasbourg 67087, France

6.1 Introduction Axial chirality has been recognized as an important factor governing the biological activities of many natural products [1]. Figure 6.1 displays few atropisomeric scaffolds – vancomycin, korupensamin, (−)-steganacin, and myricanol – that are only selected examples of the well-known biologically active compounds exhibiting such chirality (Figure 6.1). Moreover axial chirality is also the fundamental feature of ligands in asymmetric catalysis. Indeed, BINOL, BIPHEMP, and SEGPHOS are undeniably privileged chiral inductors [2]. Besides, several modern materials [3] like liquid crystals or molecular machines also exhibit chiral biaryl architectures. Regarding each family of axially chiral compounds, their unique features may be attributed to their atropisomerism (or axial chirality), i.e. restricted rotation around the biaryl linkage. These axially chiral scaffolds have established themselves as attractive structures not only because of their prevalence in asymmetric catalysis but also due to their expanding importance in pharmaceutical industries [4]. Indeed, an analysis of 1900 small drug molecules from the US Food and Drug Administration (FDA) DrugBank reveals that approximately 15% of FDA-approved scaffolds contain one or more atropisomeric axis and additional 10% of molecules are “proatropisomeric,” meaning that simple modification of a molecule in proximity of an axis would render it chiral. Even more markedly, the prevalence of atropisomeric compounds has been expanding drastically since 2011, and over the last six years, almost one out of three FDA-approved small molecules contains an axial chirality element, and an additional 16% are proatropisomeric. Consequently the past decade has witnessed significant advances in the field of atropisomeric synthesis of biaryls [1a, 5]. Recent strategies to access such compounds imply either (i) the stereoselective construction of biaryl linkages or (ii) the access to chiral biaryls via construction of an aromatic ring. In addition, (iii) the stereoselective transformation of prochiral or racemic biaryls C–H Activation for Asymmetric Synthesis, First Edition. Edited by Françoise Colobert and Joanna Wencel-Delord. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.

152

6 Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step HO HO O HO NH2

H O

O

O

O

O

O

OH

O

OAc

MeO HO O HN HO2C HO

O N H

Cl H N

Cl O O

N H

OH H N O

N H

H N

MeO HO

O

HO MeO

O NH2

(+)-aR,11S-myricanol

OMe (–)-aR-steganacin

OH OH Vancomycin Liquid crystal

AllylO

O

MeO

OPMB CO2H

Molecular machine

O PPh2 Me PPh2 Me

OEt OEt Liquid crystal

BINAP

PPh2 PPh2

BIPHEMP

O O

PPh2 PPh2

O SEGPHOS

Figure 6.1 Axially chiral compounds.

and (iv) the methods relying on a central-to-axial chirality transfer have been reported recently. Among these different approaches, the asymmetric transition metal catalysis occupies a central position, as it is arguably the more general approach furnishing an almost unlimited diversity of atropisomeric scaffolds. In particular, the atroposelective metal-catalyzed C–H functionalization has become a powerful strategy to access the chiral biaryls. Accordingly, the catalytic atroposelective construction of axially chiral biaryls through C–H functionalization can be reached based on two complementary synthetic routes involving either the coupling of two aryl counterparts or the functionalization of prochiral or racemic biaryl precursors. This chapter describes recent atropostereoselective C–H transformations; it would be divided into three parts: (i) asymmetric coupling of two arenes by oxidative dimerization, (ii) stereoselective functionalization of prochiral or racemic biaryls, and (iii) atropisomeric cross-coupling of two aryl moieties.

6.2 Asymmetric Coupling of Two Arenes by Oxidative Dimerization Regarding the importance of axially chiral biaryl ligands in asymmetric catalysis, a high number of methods to access these important skeletons have been developed. Interestingly, the first method corresponding to a formal C–H activation pathway was inspired by the biosynthesis of natural products and relates to the asymmetric oxidative couplings of phenols. Over the last decade, several efficient Cu-, V-, and Fe-based chiral catalytic systems performing homocouplings of naphthols have been reported at the end of the twentieth and early twenty-first centuries offering a very elegant strategy for the synthesis of biologically active atropisomeric skeletons.

6.2 Asymmetric Coupling of Two Arenes by Oxidative Dimerization

6.2.1

Copper-Catalyzed Reactions

The first copper-catalyzed asymmetric oxidative biaryl coupling reaction was reported in 1993 by Smrˇcina, Koˇcovský, and coworkers [6] in the presence of sparteine as chiral ligand. The desired binaphthol was obtained in modest 41% yield with 32% enantiomeric excess (ee) (Scheme 6.1a). The use of sodium salt of 2-naphtols as substrate was necessary to avoid the formation of HCl; AgCl is used as a stoichiometric oxidant to regenerate the copper(II) species. Subsequently, a particular attention has been paid to the development of aerobic transformations compatible with the use of air or O2 as terminal, green, and widespread oxidants (Scheme 6.1b). This clear improvement was first achieved by CO2Na ONa ONa

CO2H

CuCl2 (10 mol%) (–)-sparteine (20 mol%) AgCl (1.1 equiv)

OH OH

MeOH, rt, 72h 41% yield, 32% ee

(a)

CO2Me CO2Me OH

Cu source

OH OH

Chiral diamine ligand L

CO2Me

(b)

Palmisano and Sisti:

Nakajima and Koga:

Kozlowski:

CuCl (10 mol%) L1 (11 mol%) O2, DCM, reflux 78% yield, 70% ee

CuI (10 mol%) L2 (10 mol%) O2, DCE, 40 °C 85% yield, 93% ee

N H

L1:

N Ph

H N

L2:

Cu(OTf)2·C6H6 (10 mol%) L3 (10 mol%) O2, DCM/CH3CN: 2/1, 40 °C 90% yield, 65% ee

L3:

NH

Et

N

N

Ha:

Prim:

Sekar:

CuCl (9 mol%) L4 (10 mol%) O2, DCM, 0 °C 95% yield, 94% ee

CuI (9 mol%) L5 (10 mol%) O2, DCE, 40 °C 50% yield, 61% ee

CuCl (2.5 mol%) L6 (10 mol%) TEMPO (5 mol%) O2, DCM, 25 °C 90% yield, 97% ee

L4:

NHR NH2

Fe

L5:

N R = 3-pentyl

HN

Ph Me

Scheme 6.1 Copper-catalyzed oxidative coupling of phenols.

L6:

NH2 NH2

153

154

6 Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

Nakajima, Koga, and coworkers [7] who developed the homocoupling of various 2-naphthol derivatives with a catalytic amount of CuCl and O2 as oxidant using a chiral diamine derived from l-proline. ee up to 73% was obtained when using 2-naphthol bearing an ester moiety at the C3 position, suggesting a bidentate chelated copper intermediate in which both the hydroxyl group and the ester moiety are coordinated to the Cu center. Inspired by this seminal report and taking into consideration the crucial role of the ester moiety at the C3 position, several groups reported the use of various chiral ligands to achieve this oxidative homocoupling as summarized in Scheme 6.1b [8]. 6.2.2

Vanadium-Catalyzed Reactions

In parallel, vanadium-catalyzed aerobic oxidative coupling of biaryls has been developed in the last decade. Remarkably the use of chiraloxovanadium complexes brings a great advantage over the Cu-based system as now the presence of hydrogen instead of a coordinating moiety at the C3 position is tolerated. The use of oxovanadium(IV) complexes ligated with chiral tridentate Schiff base obtained from functionalized salicylaldehydes and amino acids was reported independently by Chen and coworkers [9] and Uang and coworkers [10] (Scheme 6.2a). More recently, Luo, Gong, and coworkers [11] designed a new generation of H8-BINOL-based bimetallic oxovanadium complexes. Good chemical yields, R1 R1

R2 R2

R2

OH OH

OH R1

(a) synthesis of binaphtol derivatives iBu X O N V O O Me H

N V O O O V N

O

Chen: X = iPr

Uang: X = Bn

Catalyst 10 mol% O2 CCl4, rt Yield up to 95% ee up to 59%

Catalyst 2 mol% TMSCl 2 mol% O2 CHCl3, rt Yield up to 91% ee up to 51%

Bn O

O O O O

N V O O O OH

O

iBu

O

Luo and Gong:

Chu and Uang:

Catalyst 10 mol% O2 CCl4, 0 °C Yield up to 98% ee up to 98%

Catalyst 5 mol% O2 CHCl3, rt Yield up to 96% ee up to 73%

(b) synthesis of biphenol derivatives tBu

O

O O V O N tBu

N V O O O

O

Sasai: Catalyst 5 mol% Air CH2Cl2, rt to 30 °C Yield up to 99% ee up to 93%

tBu

O2N

tBu

N V O O MeO O

Scheme 6.2 Vanadium-catalyzed oxidative coupling of phenols.

Kozlowski:

O

Catalyst 20 mol% AcOH O2 Chlorobenzene, 0 °C Yield up to 98% ee up to 89%

6.2 Asymmetric Coupling of Two Arenes by Oxidative Dimerization

excellent enantioselectivities, and high tolerance for substituents at R2 (OMe, Br, OtBu, Oallyl) are the additional advantages of this catalytic system. Other mono- and dinuclear oxovanadium complexes based on the BINOL skeleton and operating either under O2 or air atmosphere have also been reported, respectively, by Chu and Uang [12] and Sasai and coworkers [13], delivering the binaphthol products in excellent yields and stereoselectivities (Scheme 6.2). Recently, Kozlowski and coworkers disclosed the first example of the asymmetric oxidative coupling of simple phenols and 2-hydroxycarbazoles. This unique reactivity was reached in the presence of a more active, monomeric vanadium oxidative catalyst (Scheme 6.2b) [14]. 6.2.3

Iron-Catalyzed Reactions

The group of Katzuki put much effort toward the development of ecologically sustainable asymmetric oxidative biaryl couplings using iron-based catalyst. Following this ambition the authors designed a highly efficient asymmetric aerobic oxidative coupling of 2-naphthol derivatives catalyzed by a chiral dinuclear Fe(III)(salen) complex (Scheme 6.3). Importantly the reaction is compatible with 2-naphthols bearing in the C3 position a substituent other than an ester group or a hydrogen. This class of substrates was not tackled by either copper or vanadium complexes. In particular naphthols with a methyl, phenyl, 2-naphthyl, alkynyl, and even bromo substituents in position 3 could be converted into the corresponding binaphthols in excellent yields and ee [15]. R2 R2 3

R

R1 OH

Catalyst 4 mol% Toluene, air 60 °C

R1

R3 R3

OH OH

R2

R1

Ph H N

Ph H N Fe

O O Ph Ph

Yield up to 94% ee up to 97%

2

HO

Scheme 6.3 Iron-catalyzed oxidative coupling of phenols.

An original example of a Fe-catalyzed diastereoselective oxidative homocoupling was discovered by Zhou, Li, and coworkers [16]. The authors used a chiral sulfoxide moiety as both an ortho-directing group and a chiral inductor to promote the directed ortho metalation (DoM) of aryl sulfoxides followed by an iron-catalyzed C–C coupling. This radical coupling straightforwardly furnished axially chiral bis-sulfoxides with high stereoinduction (Scheme 6.4). 6.2.4

Application in the Synthesis of Natural Products

Regarding the presence of biphenols and binaphthol derivatives in many natural products, the asymmetric coupling of two arenes by oxidative dimerization

155

156

6 Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step (S) tBu S O

(1) LDA, THF, –78 °C MeO

S

tBu (2) FeCl , THF 3

O

MeO MeO

tBu S O O S tBu

MeO MeO

Li

Cl

O S tBu (S)

76% yield, > 95 : 5 dr

Proposed stereodiscriminant intermediate

Scheme 6.4 Diastereoselective oxidative homocoupling of sulfinyl arene.

represents a straightforward strategy to obtain such complex, high value added scaffolds. A key contribution to this field was done by Kozlowski who designed the asymmetric total synthesis of nigerone [17] and more recently the first enantioselective total synthesis of (S)-bisoranjidiol [18]. Both retrosynthetic pathways are based on the asymmetric oxidative biaryl coupling of a substituted 2-naphtol, for the first time, at the hindered C8 position. The Cu-catalyzed coupling in the presence of L2 (see Scheme 6.1) proceeded smoothly, providing important steric hindrance around the newly generated Ar–Ar linkage, thus delivering the expected binaphthol with 92% ee and in 62% yield (Scheme 6.4). The following selective para-quinone formation and regioselective tandem Diels–Alder/aromatization sequence were performed furnishing (S)-bisoranjidiol (Scheme 6.5). Moreover cyclophane natural products bearing an axially chiral biphenol moiety can be accessed via an intramolecular oxidative coupling. In this case stereogenic tethers prefixing the two aryl units were installed on the substrate, and accordingly the atropisomerism of the Ar–Ar bond formation results from a central-to-axial chirality transfer. Such an original approach was elegantly illustrated by the synthesis of hexahydroxydiphenoyl (HHDP) group, a motif component of ellagitannins, exemplified by (−)-corilagin as reported by Yamada. Indeed, a CuCl2 ⋅n-BuNH2 -mediated intramolecular oxidative coupling of bis(4-O-benzylgallate) containing a chiral l-(+)-tartaric acid-based auxiliary allowed the synthesis of HHDP moiety with excellent stereoselectivity (Scheme 6.6) [19]. 6.2.5

Conclusion

Since the first example of asymmetric oxidative biaryl coupling by Smrˇcina and Koˇcovský in 2009, significant progress has been achieved allowing the maturation of this methodology till the state of a well-established and valuable synthetic pathway for the synthesis of natural products. Several catalytic complexes based mainly on copper, vanadium, and iron showed their efficiency in this homocoupling reaction of 2-phenol and naphthol derivatives, and excellent levels of stereoselectivity could be reached using either temporarily installed chiral auxiliaries or polydentating N,N and N,O ligands.

6.2 Asymmetric Coupling of Two Arenes by Oxidative Dimerization O Br

CO2Me CO2Me

Enantioselective biaryl coupling 92% ee

OH

OH

OMe

Oxidation O O

OBn OBn

OMe

OH

OBn

Br

CO2Me

O

Diels Alder/ aromatization

OH O Me OH O O OH Me OH O (S)-Bisoranjidiol 12 steps 4% overall yield

Scheme 6.5 Synthesis of enantioenriched (S)-bisoranjidiol. BnO HO

OH OH

O O O O MeO MeO

OBn Intramolecular OH oxidative coupling 99% de

BnO

OH OH

HO

O O O O

BnO

OBn

OBnOBn OBn

BnO

OH

MeO MeO

HHDP

HO HO

OH OH

OH OH OH

O O O OO O OH

Scheme 6.6 Synthesis of enantiopure hexahydroxydiphenoyl.

OBn

O HO O OH

OH O

OH (–)-Corilagin

OH

157

158

6 Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

6.3 Stereoselective C–H Functionalization of Prochiral or Racemic Biaryls Due to the versatility of catalytic systems prompting to promote C(sp2 )–H activation and favorable formation of five- and six-membered metallacyclic intermediates resulting from the C–H metalation event, the possibility of introducing an additional ortho substituent on biaryls bearing a directing group has appeared as an interesting approach toward hindered biaryl scaffolds. Besides, chiral induction during the metalation event gives promise of generation of a metallacyclic intermediate in an atroposelective manner, and thus the atropopure products could potentially be accessed. Besides, regarding low rotational barrier of biaryls bearing only two substituents around the Ar–Ar axis, in situ racemization takes place thus allowing the overall process to follow a dynamic kinetic resolution (DKR) scenario [20]. Accordingly, this unique strategy enabling conversion of a racemic mixture of atropenantiomers into atropisomerically pure, highly substituted biaryl product – in theory, quantitative yields – is arguably the most economical route to access axially chiral biaryls. 6.3.1

Asymmetric C–H Alkylation of Naphthylpyridines

The pioneering work in this field has been reported in 2000 by Murai. In this seminal report Murai introduced the concept of the control of axial chirality via C–H activation. The working hypothesis surmised that if a naphthylpyridine substrate is used, a coordination of a metal by N atom would lead to a direct metalation at ortho position and formation of a five- membered metallacyclic intermediate. Subsequent functionalization would result in the introduction of an additional substituent around the biaryl axis and thus configurationally stable product might be expected (Scheme 6.7) [21]. In addition, if a chiral C–H activation catalyst is used, the induction of the axial chirality should take place during the metalation step, providing atropisomerically enriched

H N

+

Low inversion barrier

[RhCl(coe)2]2, 5 mol% L7: (R),(S)-PPFOMe, 30 mol%

*

Toluene, 120 °C, 20h

N

37% yield 49% ee

Restricted rotation

L7:

Fe

OMe PPh2

(R),(S)-PPFOMe

Scheme 6.7 Asymmetric Rh-catalyzed C–H alkylation of naphthylpyridine.

6.3 Stereoselective C–H Functionalization of Prochiral or Racemic Biaryls

metallacyclic intermediate. Following this working plan in the presence of a RhI precatalyst and a monodentate ferrocene-based phosphine ligand L7 (L7: (R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl methyl ether), the stereoselective C–H functionalization has been achieved with moderate yield and ee (up to 49%). Although somehow limited efficiency of this transformation, this early report is both a proof of concept and a nice illustration of a synthetic value of the asymmetric C(sp2 )–H activation. 6.3.2 Diastereoselective C–H Functionalization Using a Chiral Directing Group 6.3.2.1

Sulfinyl as Chiral Directing Group

Following a similar idea of accessing axially chiral biaryls via stereoselective functionalization of biaryls at the ortho position of the Ar–Ar linkage, our research group initiated a new research project devoted to the atropodiastereoselective C–H activation of biaryl substrates bearing a sulfoxide moiety as both directing group (DG) and chiral auxiliary. Indeed a rotationally unstable biaryl substrate bearing a sulfinyl group as chiral coordinating anchor in one ortho position could undergo a direct C–H cleavage with chiral discrimination generating preferentially one atropodiastereomeric metallacycle intermediate that is then functionalized, retaining the already fixed chirality. A DKR could be envisaged, and the formation of the desired atropoenriched biaryls in high yields might be expected. An additional key advantage of this strategy relies on the traceless character of the chiral sulfoxide DG which can be readily removed from the atropoenriched products with retention of the axial stereoenrichement by means of sulfoxide/lithium exchange followed by electrophilic trapping with a myriad of electrophiles. Accordingly, this synthetic route provides a unique strategy to access a panel of highly substituted axially stereoenriched skeletons. Following this general concept we explored the C–H acetoxylation, iodination, and oxidative Heck reactions, and we obtained the targeted triand tetra-substituted biaryls with excellent yields and atroposelectivities (Scheme 6.8) [22]. The majority of the biarylsulfoxide substrates are axially chiral molecules, atropostable at room temperature, used as a mixture of two atropisomers. Our direct functionalization reaction allows their conversion at room temperature into the highly atropoenriched compounds, generally isolated in excellent yields. These results clearly suggest that this transformation implies either dynamic kinetic asymmetric transformation (DYKAT) or dynamic kinetic resolution (DKR). Indeed, if the steric hindrance around the biaryl axis of the substrate is sufficiently high to prevent the atropo-epimerization of the substrate, atropisomers A and B would react with Pd(OAc)2 to generate the corresponding atropo-stereogenic palladacyclic intermediates Int-A and Int-B allowing the rapid atropo-epimerization toward the more stable palladacycle Int-A with palladation on the opposite side of the bulky pTol substituent of the sulfoxide moiety suggesting a DYKAT scenario (Scheme 6.9). As the steric hindrance of such an intermediate is reduced when the palladation occurs in the opposite side to the pTol substituent of the sulfoxide moiety; the disfavored palladacycle Int-B

159

160

6 Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

Pd(OAc)2 (10 mol%), (NH4)2S2O8 (2 equiv)

OAc

H2O (2 equiv), HFIP/AcOH (1 : 1), 25 °C

O S pTol H

1

R R2

Uncontrolled axial chirality

O S

R1

pTol

R2

56–96% yield 66 : 34 to > 98 : 2 dr

Pd(OAc)2 (10 mol%), NIS/NBS (1.3 equiv)

O S

R1

I/Br

HFIP/AcOH (1 : 1), 25 °C

pTol

R2

82–98% yield 63 : 37 to > 98 : 2 dr

Pd(OAc)2 (10 mol%), AgOAc (2 equiv) CH2 = CHR, HFIP 80 °C,

O S

R1

R

R2

pTol

41–98% yield 62 : 38 to > 98 : 2 dr

Scheme 6.8 Diastereoselective C–H acetoxylation, iodination, bromination, and oxidative Heck reactions of biarylsulfoxides. # O S pTol H

R1 R2

Pd(OAc)2

R2

k1A

O S pTol FG

R1

O

R1

S Pd

k3 A

R2

OAc A

C-SaS high yield up to >98 : 2 dr

Int-A k2A

Dynamic kinetic resolution

TSepi

kepi

O S pTol Pd OAc

R1 R2

Dynamic kinetic asymmetric transformation

k2 B # O

R1 R2

S H

Pd(OAc)2

pTol B

R1 R2

k1

S Pd

X k3 B

O

R1 R2

S H

OAc Int-B

B

O

Disfavored metallacyclic intermediate

Scheme 6.9 Mechanistic proposal of the C–H acetoxylation of biarylsulfoxides.

D

pTol

6.3 Stereoselective C–H Functionalization of Prochiral or Racemic Biaryls

undergoes rapid atropo-epimerization. We surmise that this rotation around the Ar—Ar bond is enhanced by the formation of the pallada-bridged cyclic species, enlarging the angle between two aromatic units and thus lowering the rotation barrier of this intermediate compared to the corresponding substrate. The rate of this atropo-epimerization is expected to be significantly faster than the reductive elimination from the disfavored metallacyclic intermediate, hence allowing an excellent stereocontrol during the overall transformation. Alternatively, if the substrates are less sterically demanding, a slow atropo-epimerization of the starting material cannot be excluded. Consequently, the excellent atroposelection observed in these C–H functionalization reactions could result from either DKR (epimerization of the starting material) or DYKAT (epimerization of the palladacyclic intermediate) (Scheme 6.9). Thanks to the convenient and versatile post-modifications of the atropopure biaryl products, this method is truly synthetically useful. Indeed the sulfoxide auxiliary could be easily cleaved in the presence of a lithium base affording the aryl-lithium intermediate that is configurationally stable at low temperature and subsequent electrophilic trapping could occur without any loss of the axial purity thus giving an access to a modular family of variously substituted atropopure biaryl scaffolds (Scheme 6.10).

R2 R1

O S pTol H

C–H functionalization R2 R1

O S

R

pTol

R= CH=CH2, OAc, X

(2) Trapping with El

R2 R1

(1) Sulfoxide lithium exchange

El R

El= CHO, OH, X, CO2H, NR2, PR2, R, . . . .

Scheme 6.10 Post-modifications of the atropopure biarylsulfoxides.

Regarding the excellent atroposelection generated during our asymmetric C–H activation and the traceless character of the sulfoxide directing group, we applied this synthetic route to the synthesis of a steganone derivative. Firstly, the sulfoxide biaryl substrate was prepared via a quantitative Suzuki coupling using commercially available boronic acid. In the key atroposelective step, an oxidative Heck reaction allowed the introduction of the acrylate substituent at the strategic ortho position. Although this direct functionalization occurred with 95 : 5

161

162

6 Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

atropodiastereoselectivity, the optically pure compound was isolated via simple crystallization with 92% yield. Subsequent functional group manipulations allowed interconversion of the acrylate moiety into the protected alcohol, and the final sulfoxide/lithium exchange followed by an electrophilic trapping furnished the desired enantioatropopure aldehyde. Accordingly, our C–H activation-based protocol enables an expedient synthesis of the expected molecule in only 10 steps, in an exceptional overall yield of 42% and with an enantiomeric excess above 99% (Scheme 6.11) [23]. O

O

O

O Atropodiastereoselective C–H activation

SO*pTol H

MeO MeO

SO*pTol CO2Me

MeO MeO

OMe

OMe

Uncontrolled axial chirality

Configurationally stable key intermediate

O

O O

O O

MeO

(aR)

MeO

O O

OMe (–)-Steganone

CHO MeO

OTBDMS

MeO OMe 10 steps 42% overall yield Complete stereocontrol

Scheme 6.11 Retrosynthesis of enantiopure steganone derivative.

6.3.2.2

Phosphates as Chiral Directing Group

In 2015, Yang reported a closely related diastereoselective C–H activation/DKR protocol using a chiral menthyl-substituted P(O)R1 R2 -DG to control the atroposelective outcome of the C–H activation event in the synthesis of axially chiral phosphates (Scheme 6.12) [24]. Accordingly, oxidative Heck reaction, acetoxylation, and iodination of the biaryl precursors were achieved with excellent stereoinduction. Interestingly, in the case of the olefination reaction, addition of an amino acid ligand to the reaction mixture was requested to

6.3 Stereoselective C–H Functionalization of Prochiral or Racemic Biaryls

R2 R1

O P Ph OMen(-) H

Cond. A Cond. B Cond. C

R2 R1

O P Ph OMen(-) FG FG : CH=CHR OAc, I

31–73% yield; > 95 : 5 dr

Cond. A : CH2=CHR, Pd(OAc)2, 10 mol%, Ac-Gly-OH, 20 mol%, Cu(OAc)2, 20 mol%, Ag2CO3, 1 equiv, TFE, 100 °C Cond. B : Pd(OAc)2, 10 mol%, PhI(OAc)2, 3 equiv TFE, 100 °C, 16 h Cond. C : Pd(TFA)2, 10 mol% NIS, 1.5 equiv AcOH/TFE, 100 °C, 16 h

Scheme 6.12 Diastereoselective C–H acetoxylation, iodination, and oxidative Heck reactions of biarylphosphates.

obtain optimal results. However, the axially chiral phosphates are generated with rather moderate efficiency (yields ranging from 31% to 73%). Moreover the harsh reaction conditions (temperature of 100 ∘ C) required, might suggest that epimerization of the starting material and/or palladacyclic intermediates is less efficient compared with the related sulfoxide-directed protocol.

6.3.3

Enantioselective C–H Functionalization of Racemic Biaryl

Concomitantly to our work on the atropodiastereoselective C–H functionalization, You reported an enantioselective transformation. The asymmetric oxidative olefination of 1-(naphthalen-1-yl)isoquinolone was achieved using Cramer’s [25] axially chiral CpRh-derived catalyst (Scheme 6.13) [26]. Good enantioselectivity (up to 86%) was obtained using only 5 mol% of the chiral inductor at 80 ∘ C. Subsequently a second generation of the chiral CpRh complexes bearing the 1,1′ -spirobiindane scaffold was designed and exhibited improved reactivity in the same coupling, delivering the expected cycloannulated compounds at room temperature and with enantioselectivity up to 96% [27]. The improved chiral induction arises from the architecture of the 1,1′ -spirobiindane scaffold with methoxy groups at the 6,6′ -positions pointing in the direction of the Rh center. As this transformation is limited to rather specific isoquinoline derivatives and targeting more useful ligands, You reported a palladium-catalyzed atropoenantioselective C–H iodination of racemic naphthyl isoquinoline N-oxide. In this Pd-catalyzed transformation the chiral induction was achieved using mono-N-protected amino acid ligand L8 (MPAA) (Scheme 6.14) [28]. The reaction proceeds through kinetic resolution and the enantioselectivities reached for the iodinated products are moderate from 60% to 83%. The authors proposed a Pd(II)–Pd(IV) catalytic cycle; initially MPAA-assisted C—H bond

163

164

6 Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step R1

R1 N

N +

Ar

Ar

H R2 Ar = 2-naphtyl

R2 OMe

Conditions: Rhcat, 5 mol%, (BzO)2, 5 mol%, Cu(OAc)2, 20 mol% Ag2CO3, 1 equiv., MeOH, 80 °C, Yield up to 99%, ee up to 82%

Rh OMe Cramer’s CpRh-derived catalyst

OMe Conditions: Rhcat, 5 mol%, (BzO)2, 5 mol%, Cu(OAc)2, 20 mol% Ag2CO3, 1 equiv., MeOH, 25 °C, Yield19–97%, ee 86–96%

Rh OMe

1,1′-Spirobiindane-derived CpRh catalyst

Scheme 6.13 Rhodium-catalyzed atropoenantioselective oxidative olefination of racemic 1-(naphthalen-1-yl)isoquinolone.

R1

R1

N

Pd(OAc)2, 10 mol% (S)-L8, 20 mol%

O H

NIS, 1.5 equiv MeCN, 70 °C

R2

L8:

HO

O Yield 33–73% ee 23–93%

R2 +

R1

R2 O

N

N

O I Yield 20–60% ee 60–83%

H N O

Scheme 6.14 Palladium-catalyzed atropoenantioselective C–H iodination of racemic naphthylisoquinoline N-oxide.

6.3 Stereoselective C–H Functionalization of Prochiral or Racemic Biaryls

cleavage occurs via concerted metalation-deprotonation mechanisms (CMD), followed by oxidation of the Pd(II) species by NIS. Also benefiting from the unique potential of MPAA in Pd-catalyzed asymmetric C–H activation, Yang reported an atropoenantioselective version of the C–H olefination of racemic diphenylphosphinobiphenyl (Scheme 6.15) [29]. Excellent yields and ee values were obtained for the synthesis of variously substituted axially chiral phosphine–olefin hybrid moieties. The diphenylphosphine oxide acts not only as directing group but is also important to demonstrate the synthetic utility of this method toward new chiral axis in biaryl phosphine–olefin hybrid ligands.

R2 R1

O PPh2 + H

R

Pd(OAc)2 (5 mol%) Boc-L-Val-OH (10 mol%) AgOAc (3 equiv) CF3CH2OH:DME = 1 : 1 60 °C

R2 R1

O PPh2 R

O O O

OH

N H

Boc-L-Val-OH Yield up to 99% ee up to 96%

Scheme 6.15 Palladium-catalyzed atropoenantioselective oxidative olefination of racemic diphenylphosphinobiphenyl.

6.3.4 Stereoselective C–H Functionalization Using a Transient Chiral Directing Group Compared to the diastereomeric approach, an elegant way to introduce the chirality relies on the use of a transient chiral directing group. In the ideal case, the transient auxiliary could be used in catalytic amount and would obviate additional steps needed to install and remove the covalently bonded chiral source. Such an original transformation is similar to the enantioselective approach with the use of a catalytic amount of the chiral inductor. Following this idea [30], Shi et al. described the atroposelective synthesis of biaryl compounds through a palladium-catalyzed C–H olefination using tert-leucine L9 as a catalytic transient directing group, thus enabling the in situ formation of the imine. With n-butyl acrylate or p-fluorostyrene as coupling partners, this strategy provides efficient access to highly functionalized biaryl compounds with excellent yields and enantioselectivities (Scheme 6.16) [31]. The authors proposed the following scenario (Scheme 6.17): the chiral amino acid reacts reversibly with the racemic biaryl substrate to give the imines Im-A and Im-B, allowing the rapid atropo-epimerization toward the more stable imine Im-B, thus affording an axially stereoenriched palladacycle intermediate C that undergoes a typical Heck reaction affording the enantioenriched biaryl together with the recovery of the chiral aminoacid and Pd(0), which is reoxidized in the catalytic cycle. In general low sterically demanding substrates proceeded through a DKR pathway giving the chiral biaryls in good to excellent yields and excellent enantioselectivities. In the case of highly sterically demanding substituents in position 6

165

166

6 Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

t-Bu

CO2H

L9: R2 R1

CHO H

NH2 20 mol%

R

+

R = CO2n-Bu p-FC6H5 rac

R2

CHO

R1

Pd(OAc)2 10 mol% HFIP/HOAc (4 : 1) BQ 0.1 equiv 60 °C, 48 h, O2

R

Yield 44–98% ee 97% to >99%

Scheme 6.16 Palladium-catalyzed atropostereoselective oxidative olefination through in situ formation of a chiral imine. Dynamic kinetic asymmetric transformation

H 2O R2 R1

CHO H

H

R2

t-Bu

CO2H

R1

NH2

rac

HN

t-Bu

HO Im-A

O

Pd(0)

R2 R1

R1

R H 2O aR

R2

HN

R1

t-Bu

HO Im-B

O

Pd(OAc)2

R

H

R2

CHO

#

H

N R t-Bu Pd O

H

R2

O

R1

N Pd O C

t-Bu O

Scheme 6.17 Mechanistic proposal of the C–H olefination of racemic biaryl using a catalytic transient chiral directing group.

and 2′ of the substrates, a kinetic resolution pathway occurred with excellent enantioselectivities. Following this highly efficient strategy, the same research group designed a closely related method targeting the C–H alkynylation of biaryl compound in view of the stereocontrolled formal synthesis of (+)-isoschizandrin and (+)-steganone [32]. Aiming the C–H alkynylation, tert-leucine turned out to be the optimal chiral inductor, while potassium dihydric phosphate was fundamental to buffer the reaction medium (sufficient acidity of the medium is required for the recycling of the amino acids). Consistent with their previous observation, a DKR scenario operates for low sterically demanding substrates, while a KR is observed when biaryls bearing bulkier substituents are used (Scheme 6.18). The efficiency of this strategy was validated through the synthesis of two natural products, (+)-isoschizandrin and (+)-steganone, demonstrating that the method is compatible with electron-rich substrates. Besides, a perfect site selectivity was witnessed in the case of (+)-steganone formal synthesis where potentially two C—H bonds can be activated (Scheme 6.19).

6.4 Atroposelective Cross-Coupling of Two Moieties

t-Bu

SiR3

R2 R1

CHO H

+

Br rac

CO2H

L9:

NH2 30 mol%

Pd(OAc)2 10 mol% AgOAc 2 equiv KH2PO4 2 equiv AcOH, N2, 60 °C, 48 h

R2

CHO

R1

R

Yield 44–99% ee 94–99%

Scheme 6.18 Palladium-catalyzed atropostereoselective C–H alkynylation through in situ formation of a chiral imine.

6.3.5

Conclusion

Without any doubt the synthesis of axially chiral biaryls through C–H functionalization of a flexible biaryl substrate can be considered as one of the most efficient strategies. Enantioselective or diastereoselective approaches together with the elegant use of a transient chiral directing group allowed the obtention of highly valuable biaryls either in the field of natural biologically active products or for asymmetric catalysis.

6.4 Atroposelective Cross-Coupling of Two Moieties 6.4.1

Pd-Catalyzed C–H Arylation of Thiophene Derivatives

The construction of atropisomeric scaffolds through the direct coupling of two bulky moieties (the bulkiness is required to ensure a high rotational barrier) is commonly recognized as extremely challenging, even via standard cross-coupling protocols such as Suzuki coupling [1a, 5]. Consequently only three examples of atroposelective direct arylation have been reported up to now. The scarcity of stereoselective Ar—Ar bond formation via C–H functionalization can be explained by the antagonism between the steric hindrance of both coupling partners necessary for ensuring atropostability of the Ar–Ar linkage newly formed (generally three substituents are required ortho to the Ar–Ar axis to efficiently prevent the rotation) and the drastic reaction conditions necessary to promote such a Ar—Ar bond-forming event. Recently Itami reported the pioneering example in this direction while describing the direct arylation of thiophene derivatives with naphthylboronic acids using a catalytic system based on Pd and 2,2′ -bis(oxazoline) ligand BOX L10 (Scheme 6.20) [33]. Such a C 2 -symmetric bisoxazoline ligand turns out to be crucial to enhance aromatic C–H arylation of sterically demanding thiophene congeners. Noteworthy, the induction of chirality of this transformation is quite unique and might stem either from a selective transmetallation step or an enantio-controlled C—C bond formation during the reductive elimination. Disappointingly but not surprisingly, clear antagonism between efficiency and stereoselectivity of this transformation is observed. High bulkiness of the arylating boronic acid is required to reach a satisfying level of stereocontrol, which

167

OMe

OMe

MeO

OMe

MeO

MeO MeO

CHO H

MeO

OMe

MeO OMe C OMe TIPS H

MeO MeO MeO

MeO

MeO MeO

CHO

Me

MeO

OMe rac

OMe

OMe

OMe

MeO

CHO H

O

MeO

MeO

MeO

OMe MeO

O CO2Me

O

O O

Scheme 6.19 Synthesis of enantiopure (+)-isoschizandrin and (+)-steganone.

MeO

O

CO2Me

TIPS O

O rac

(+)-Isoschizandrin

OMe

OMe MeO

Me Me

MeO

OMe Six steps, three purifications 68% overall yield complete stereocontrol

MeO

OH

MeO MeO

O Seven steps, 32% overall yield 96% ee

O

O O (+)-Steganone

6.4 Atroposelective Cross-Coupling of Two Moieties

H Me

R

+ B(OH)2 4 equiv

1 equiv

O N

Pd(OAc)2 10 mol% BOX or SOX, 10 mol%

R

S

Me

TEMPO, 1 equiv or Fe-Pc 5 mol%, O2 nPrOH or DMAc, 70 °C

O N

BOX L10

Me

S

61%, er 80.5 : 19.5

BOX: R = Me, 63% yield, 41% ee R = iPr, 27% yield, 72 % ee

O pTol S O N

Me

iPr

SOX L11

SOX: R = iPr, 61% yield, 61% ee

Scheme 6.20 Construction of axially chiral heterobiaryls via asymmetric C–H arylation.

concomitantly drastically decreases the overall yield. Pursuing this research project a second-generation catalytic system has been developed by Itami, Yamaguchi, and coworkers [34]. The bisoxazoline ligand was therefore replaced by a sulfoxide–oxazoline SOX L11 chiral inductor, and a catalytic amount of iron-phthalocyanine (FePc) was employed as oxidant. Such aerobic catalytic system enables to improve the yield of the atropisomeric arylation reaction while slightly decreasing the chiral induction. 6.4.2

Pd-Catalyzed C–H Arylation of Biaryl Sulfoxides

Targeting original atropisomeric ligands, our group was interested in the conception of optically pure scaffolds containing two contiguous atropisomeric axes, the first one being controlled using atroposelective functionalization of a biaryl precursor (see Section 6.3.2.1) and the second one being generated through the challenging atroposelective C–H arylation process. Such triaryl scaffolds should exhibit a unique tridimensional structure, thus becoming an appealing platform to construct unprecedented chiral ligands. Our working hypothesis surmised that if the biarylsulfoxide substrates previously used in oxidative Heck reaction, acetoxylation, and halogenation (see Section 6.3.2.1), bearing an additional substituent in meta position of the biaryl axis, undergo the atroposelective C–H arylation with an ortho-substituted aryl iodide, the newly generated terphenyl scaffold should exhibit two consecutive atropisomeric axes. Following this working plan, the expected ortho-orientated terphenyls were constructed in good yields and with excellent stereoselectivities. Remarkably the stereoinduction for both chiral axes is achieved in a single transformation (Scheme 6.21) [35]. A fine optimization study was necessary to discover the best reaction conditions promoting such a challenging transformation: Pd(TFA)2 with N-heterocyclic carbene ligand is essential to favor C–H cleavage event, whereas Ag2 CO3 and AgTFA are crucial additives to complete the catalytic cycle. Reaction also needs molecular sieves and HFIP is used as medium. The unique character of this transformation arises from the fact that both chirality elements are perfectly controlled in a single step. To explain the

169

170

6 Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

Pd(TFA)2 (10–25 mol%) IPr-HCl (20–50 mol%) Ag2CO3 (2.3 equiv.) AgTFA (1 equiv.)

R1 I S H O

R2

pTol

R3

+

R1 SOpTol

4 Å MS, HFIP, 85 °C, 4 h

R4

R4

R2 R3

Yield 16–72% ee 88% to >96%

Scheme 6.21 Synthesis of terphenyls with two axial chiralities.

high stereoselectivity observed, we proposed the following scenario: firstly, the stereoselectivity of Ar1 –Ar2 axis is induced during the C–H activation step as shown by the isolation of the atropisomerically pure palladacyclic intermediate B and the rapid racemization of the substrate under the reaction conditions. The interactions between the chiral auxiliary and the NHC ligand (L) are minimized (pTol moiety above the plane vs. NHC ligand underneath the plane) in palladacycle B compared with A, and the transformation implies DKR. Secondly, the chirality of the Ar1 –Ar3 linkage is controlled by the favored oxidative addition of the Ar–I coupling partner from a sterically less hindered face of the metallacyclic intermediate, i.e. minimizing the steric hindrance between the SOpTol moiety and the ortho substituent of the Ar–I. Finally, the reductive elimination from such a sterically less congested Pd(IV) intermediate seems also enhanced (Scheme 6.22).

Ar2 H O

S O

S H O ( S,S) a

O (aR,S)

Irreversible C–H activation X Pd O

Ar1

Me S O

S A

Disfavored L syn to the biaryl crowded face

Ar3

Pd

L

O

O

Me SOpTol

O

Pd

L X Favored L anti to the biaryl crowded face B

I

S O O

Pd X L X C Me

Me O

S O Pd X L X D

Favored Disfavored Me-group anti to the Me-group syn to the biaryl crowded face biaryl crowded face

Scheme 6.22 Mechanistic proposal of the C–H arylation of biarylsulfoxides.

The key application of these terphenyls with two chiral axes concerns their use as chiral ligands. X-ray crystal structures showed their unusual “open clam shell” geometry, which seems highly appealing for stereogenic ligand design. Accordingly, by means of functional group modifications, the diphosphine BiaxPhos was prepared and revealed excellent reactivity and enantioselectivity

6.4 Atroposelective Cross-Coupling of Two Moieties

in Rh-catalyzed benchmark hydrogenation of the trisubstituted methyl (Z)-α-acetamidocinnamate. Besides a S/N-Biax ligand was synthesized and showed its potential in 1,2-addition of Et2 Zn to benzaldehyde delivering the expected product in high yield and good enantiomeric ratio (er) of 93 : 7 (Scheme 6.23). Me Me SOpTol

1. tBuLi (5 equiv) –94 °C, Et2O, 20 min 2. ClPPh2 (4 equiv) –94 to –78 °C, PhMe

OMe Br

Me CO2Me

Me PPh 2

NHAc

Biaxphos /Rh(cod)2OTf (1.5 mol%) EtOH, 25 °C, 2 h

Ph

OMe 54% yield

PPh2

CO2Me NHAc Ph conv. > 99% er = 99.5 : 0.5

BiaxPhos

Me SOpTol Me

(1) H2NNH2 (50 equiv) THF/EtOH 1 : 1, 0-25 °C, 1h

(2) TsCl (1.05 equiv) pyridine (2.2 equiv) NPhth CHCl3, 25 °C, 2 h

O

ZnEt2 (2 equiv) S/N-Biax (5 mol%) PhMe, 25 °C 15 h

Me O

SOpTol Me O

Ph

H

OH

MeO2C

NHTs

82% yield er = 93 : 7

62% yield S/N-Biax

Scheme 6.23 Synthesis of atropopure terphenyl ligands and their application in asymmetric catalysis.

6.4.3

Rh-Catalyzed C–H Arylation of Diazonaphthoquinones

The third example of intermolecular atroposelective direct arylation was reported in 2017 by Antonchick, Waldmann, and coworkers [36] although it is not strictly speaking a biaryl coupling: indeed they designed a new chiral JasCp to enable the synthesis of axially chiral biaryls by direct Rh-catalyzed C–H arylation (Scheme 6.24). Highly reactive diazonaphthoquinones are used as coupling partners with benzamides providing, after rearomatization, two ortho substituents adjacent to the aryl–aryl bonds formed in the resulting biaryl compounds, yet ensuring the configurational stability of the axial chirality. Remarkably tetrasubstituted biaryls are built up in high yields and er, rendering this strategy truly useful to synthesize such rare scaffolds. JasCp: 4-BrC6H4 CO2Me R2

N H R1

O

OMe +

R2

Rh 4-FC H 6 4

N2

O

CO2Me

5 mol% (BzO)2 5 mol%

R1

CONHOMe OH

25 °C, dioxane, 48H CO2Me Yield up to 93% er up to 95.5 : 4.5

Scheme 6.24 Axially chiral biaryls by C–H functionalization with diazonaphthoquinones.

171

172

6 Axial Chirality via C(sp2 )–H Activation Involved in Stereodiscriminant Step

Moreover the presence of halides on the aromatic moieties is tolerated allowing post-functionalizations. 6.4.4

Conclusion

The cross-coupling of two hindered aryl moieties has been recognized as extremely challenging as the conditions must be compatible with the atropostability of the product. For these reasons, very few examples have been disclosed. Future progress in this field of research should be focused on expanding the variety of coupling partners as well as increasing the catalytic efficiency to couple highly sterically demanding substrates.

6.5 General Conclusion Over the past decade, asymmetric synthesis has been recognized as an important tool to build up enantiopure molecules. Among key chiral molecules, an important place is given to atropisomeric ligands as privileged chiral inductors [2]. Moreover there is an expanding interest for axially chiral molecules in pharmaceutical industries, as shown particularly by their presence in recent FDA-approved biologically active molecules. Such importance of axially chiral motifs has stimulated the development of new synthetic strategies allowing their synthesis. In particular over few years expanding attention is focused on designing asymmetric C–H activation-based protocols that might be used to build up axially chiral skeletons. Following this general goal, several distinct C–H activation-based strategies have been proposed, including (i) the oxidative homocoupling of two aryl moieties, (ii) the atroposelective C–H functionalization of biaryls with uncontrolled axial chirality, and (iii) the atroposelective Ar—Ar bond formation. Arguably the most impressive progress in this field comes from the employment of DKR of racemic biaryls to access optically pure compounds. Accordingly, an array of axially chiral compounds and particularly the precursors of atropisomeric ligands may now be obtained in a straightforward manner and in excellent optical purity using simple starting materials.

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Chem. Rev. 111: 563–639. (b) LaPlante, S.R., Fader, D.L., Fandrick, K.R. et al. (2011). J. Med. Chem. 54: 7005–7022. (c) Smyth, J.E., Butler, N.M., and Keller, P.A.A. (2015). Nat. Prod. Rep. 32: 1562–1583. 2 (a) Li, Y.-M., Kwong, F.-Y., Yu, W.-Y., and Chan, A.S.C. (2007). Coord. Chem. Rev. 251: 2119–2144. (b) Ohkuma, T. and Kurono, N. (2011). BINAP. In: Privileged Chiral Ligands and Catalysts (ed. Q.-L. Zhou), 1–53. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA.

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5

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8

9 10 11 12 13 14 15

16 17 18 19 20 21 22

53–60. (b) Toenjes, S.T. and Gustafson, J.L. (2018). Future Med. Chem. 10: 409–422. For recent reviews on the synthesis of axially chiral biaryls see: (a)Kozlowski, M.C., Morgan, B.J., and Linton, E.C. (2009). Chem. Soc. Rev. 38: 3193–3207. (b) Bringmann, G., Price Mortimer, A.J., Keller, P.A. et al. (2005). Angew. Chem. Int. Ed. 44: 5384–5427. (c) Baudoin, O. (2005). Eur. J. Org. Chem. 2005: 4223–4229; (d) Wencel-Delord, J., Panossian, A., Leroux, F.R., and Colobert, F. (2015). Chem. Soc. Rev. 44: 3418–3430. Smrˇcina, M., Poláková, J., Vyskoˇcil, S., and Koˇcovský, P. (1993). J. Organomet. Chem. 58: 4534–4538. (a) Nakajima, M., Kanayama, K., Miyoshi, I., and Hashimoto, S.-I. (1995). Tetrahedron Lett. 36: 9519–9520. (b) Nakajima, M., Miyoshi, I., Kanayama, K. et al. (1999). J. Organomet. Chem. 64: 2264–2271. (a) Caselli, A., Giovenzana, G.B., Palmisano, G. et al. (2003). Tetrahedron: Asymmetry 14: 1451–1454. (b) Kim, K.H., Lee, D.-W., Lee, Y.-S. et al. (2004). Tetrahedron 60: 9037–9042. (c) Grach, G., Pieters, G., Dinut, A. et al. (2011). Organometallics 30: 4074–4086. (d) Alamsetti, S.K., Poonguzhali, E., Ganapathy, D., and Sekar, G. (2013). Adv. Synth. Catal. 355: 2803–2808. Hon, S.-W., Li, C.-H., Kuo, J.-H. et al. (2001). Org. Lett. 3: 869–872. Chu, C.-Y., Hwang, D.-R., Wang, S.-K., and Uang, B.-J. (2011). Chem. Commun. 980–981. Guo, Q.-X., Wu, Z.-J., Luo, Z.-B. et al. (2007). J. Am. Chem. Soc. 129: 13927–13938. Chu, C.-Y. and Uang, B.-J. (2003). Tetrahedron: Asymmetry 14: 53–55. Somei, H., Asano, Y., Yoshida, T. et al. (2004). Tetrahedron Lett. 45: 1841–1844. Kang, H., Lee, Y.E., Reddy, P.V.G. et al. (2017). Org. Lett. 19: 5505–5508. (a) Egami, H. and Katsuki, T. (2009). J. Am. Chem. Soc. 131: 6082–6083. (b) Egami, H. and Katsuki, T. (2010). J. Am. Chem. Soc. 132: 13633–13635. (c) Matsumoto, K., Egami, H., Oguma, T., and Katsuki, T. (2012). Chem. Commun. 48: 5823–5825. Chen, Q.-A., Dong, X., Chen, M.-W. et al. (2010). Org. Lett. 12: 1928–1931. DiVirgilio, E.S., Dugan, E.C., Mulrooney, C.A., and Kozlowski, M.C. (2007). Org. Lett. 9: 385–388. Podlesny, E.E. and Kozlowski, M.C. (2012). Org. Lett. 14: 1408–1411. Asakura, N., Fujimoto, S., Michihata, N. et al. (2011). J. Org. Chem. 76: 9711–9719. Wencel-Delord, J. and Colobert, F. (2016). Synthesis 48: 2981–2996. Kakiuchi, F., Le Gendre, P., Yamada, A. et al. (2000). Tetrahedron: Asymmetry 11: 2647–2651. (a) Wesch, T., Leroux, F.R., and Colobert, F. (2013). Adv. Synth. Catal. 355: 2139–2144. (b) Hazra, C.K., Dherbassy, Q., Wencel-Delord, J., and Colobert, F. (2014). Angew. Chem. Int. Ed. 53: 13871–13875. (c) Dherbassy, Q., Schwertz, G., Chessé, M. et al. (2016). Chem. Eur. J. 22: 1735–1743.

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23 Dherbassy, Q., Wencel-Delord, J., and Colobert, F. (2016). Tetrahedron 72:

5238–5245. 24 Ma, Y.-N., Zhang, H.-Y., and Yang, S.-D. (2015). Org. Lett. 17: 2034–2037. 25 Newton, C.G., Wang, S.-G., Oliveira, C.C., and Cramer, N. (2017). Chem. Rev.

117: 8908–8976. 26 Zheng, J. and You, S.-L. (2014). Angew. Chem. Int. Ed. 53: 13244–13247. 27 Zheng, J., Cui, W.-J., Zheng, C., and You, S.-L. (2016). J. Am. Chem. Soc. 138: 28 29 30 31 32 33 34 35 36

5242–5245. Gao, D.-W., Gu, Q., and You, S.-L. (2014). ACS Catal. 4: 2741–2745. Li, S.-X., Ma, Y.-N., and Yang, S.-D. (2017). Org. Lett. 19: 1842–1845. Zhang, F.-L., Hong, K., Li, T.-J. et al. (2016). Science 351: 252–256. Yao, Q.-J., Zhang, S., Zhan, B.-B., and Shi, B.-F. (2017). Angew. Chem. Int. Ed. 56: 6617–6621. Liao, G., Yao, Q.-J., Zhang, Z.-Z. et al. (2018). Angew. Chem. Int. Ed. 57: 3661–3665. Yamaguchi, K., Yamaguchi, J., Studer, A., and Itami, K. (2012). Chem. Sci. 3: 2165–2169. Yamaguchi, K., Kondo, H., Yamaguchi, J., and Itami, K. (2013). Chem. Sci. 4: 3753–3757. Dherbassy, Q., Djukic, J.-P., Wencel-Delord, J., and Colobert, F. (2018). Angew. Chem. Int. Ed. 57: 4668–4672. Jia, Z.-J., Merten, C., Gontla, R. et al. (2017). Angew. Chem. Int. Ed. 56: 2429–2434.

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7 Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization and Kinetic Resolution Soufyan Jerhaoui, Françoise Colobert, and Joanna Wencel-Delord Université de Strasbourg/Université de haute Alsace, Laboratoire d’Innovation Moléculaire et Applications (UMR CNRS 7042), ECPM, 25 Rue Becquerel, 67087 Strasbourg, France

7.1 Synthesis of C-Stereogenic Molecules via C(sp2 )–H Functionalization 7.1.1

Desymmetrization

Over the last decade, despite exceptional development of the C–H activation field, stereoselective transformations implying direct metalation and subsequent functionalization of non-prefunctionalized substrates have remained a rather niche topic. The challenge lies in the design of a chiral external ligand, able to coordinate efficiently a metal catalyst (to avoid non stereoselective reactions catalyzed by a non-complexed metal) while conserving at least two free coordination sites in the coordination sphere of the metal, essential to accommodate a C–H substrate (generally two coordination sites are required to generate a metallacyclic-type intermediate). Besides, harsh and oxidative reaction conditions are frequently required for efficient C–H activation that appears as incompatible with efficient stereoinduction and/or stability of some chiral ligands. As direct functionalization of C(sp2 )—H bonds is favored over functionalization of C(sp3 )–H linkages, significant efforts have been endeavored on designing such direct transformation, focusing on prochiral substrates or racemic starting materials. Indeed, in the presence of a chiral catalyst, direct functionalization should deliver enantiopure products. A pioneering contribution in this field was reported as early as in 2008 by Yu and coworkers. [1] With regard to the potential of amino acid ligands in stoichiometric direct palladation of ferrocene cores [2], they hypothesized that these motifs could also be efficient and selective auxiliaries for asymmetric, catalytic direct functionalizations. Accordingly, a prochiral biaryl substrate 1, bearing a pyridine directing group (DG) was designed, and its stereoselective direct alkylation in the presence of BuB(OH)2 coupling partner was explored. As expected, chiral information during this desymmetrization reaction could be achieved with success using mono-N-protected amino acids (MPAA). The fine-tuning of the ligand structure allowed not only to select the C–H Activation for Asymmetric Synthesis, First Edition. Edited by Françoise Colobert and Joanna Wencel-Delord. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.

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7 Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization

optimal chiral inductor, affording the enantioenriched product 2 in 87% ee and 91% yield, but also a basic mechanistic information could be gathered, and a stereomodel of this reaction could hence be established (Scheme 7.1a). Therefore, it was found that amino acids act as bicoordinating ligands and the stereoinduction arises from the minimized steric repulsions between the newly generated chiral center and the bulky protecting group of ligand. This seminal work has virtually opened up a new avenue for asymmetric C–H activation with the amino acid ligands being still the privileged chiral inductors.

N

H

H R + BuB(OH)2

R

Pd(OAc)2, 10 mol% L1, 20 mol% Ag2O, 1 equiv BQ, 0.5 equiv 60 °C, 20 h, THF

HN L1:

(a) H

CO2Na +

Me H

Ar Ar = Ph

3

(b) H R

(c)

R

CO2Na Me H

3 (R = p-Me)

Pd(OAc)2, 5 mol% L2: Boc-lle-OH, 40 mol% R

2 87% ee 91% yield

O-(–)-Menthyl

KHCO3, 0.5 equiv BQ, 5 mol% O2, 90 °C, 48 h, tAmyl-OH

Phl(OAc)2, 1.5 equiv KOAc, 2 equiv 80 °C, 12 h, t-BuOH

O

*

O

Pd(OAc)2, 5 mol% L2: Boc-Ile-OH·0.5 H2O

H Bu

R

CO2H

1 R = o-Me

N

H

H

R O H N Pd N

PG

CO2Na *

H

Me Ar

H O

4 97% ee 73% yield

H

R O H N

Pd

O

ONa

PG

R Me * O

O 5 96% ee, 86% yield

Scheme 7.1 Pioneering work on enantioselective C(sp2 )–H functionalization via desymmetrization.

Two years later, following this first example, the same group reported a similar catalytic system for direct desymmetrization of diphenylacetic acids 3 [3]. Pd/MPAA complex (ligand: L2) efficiently promoted a direct olefination using styrenes and acrylates, furnishing the chiral products with up to 97% ee and 73% yield (Scheme 7.1b). Notably, this work clearly showcases the extraordinary potential of MPAA ligands; although these two transformations occur via different mechanism implying transmetalation step in the case of alkylation with a boronic acid and olefin insertion followed by H-elimination for oxidative Heck reaction, a similar stereomodel for the initial stereoselective metalation is operative, permitting excellent chirality transfer in both cases. Encouraged by the excellent results obtained for desymmetrization of diarylacetic acids 3, Wang and coworkers surmised that a closely related concept could be applied to synthesize chiral benzofuranones [4]. Indeed, desymmetrization of 3, followed by an intramolecular C–O coupling, should deliver such biologically relevant scaffolds via an unprecedented, truly sustainable pathway. The chief challenge concerns however the design of reaction conditions and the selection of a strong oxidant, allowing Pd(II)/Pd(IV) catalytic cycle and nontrivial C–O

Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization

bond formation. The fine-tuning of the reaction protocol showed that while the same MPAA ligand L2 promotes highly stereoselective metalation step by distinguishing between two aromatic substituents of 3, PhI(OAc)2 promotes oxidation of Pd(II) to Pd(IV), a key step to enhance intramolecular C—O bond formation event (Scheme 7.1c). Accordingly, a panel of chiral benzofuranones was delivered in moderate to high yields and excellent optical purity (89–96% ee). Synthesis of enantiomerically pure diarylmethylamines, important structures not only in medicinal chemistry but also for ligand design, is an additional key area of applications of MPAA. Indeed, direct desymmetrization of substrate 6, bearing an amine DG, appears as an appealing protocol to access rapidly chiral amines (Scheme 7.2a). In particular, installation of an iodine atom, handle for further functionalization, is particularly tempting. Following this hypothesis, direct stereoselective iodination of 6 bearing a triflamide protecting group was explored. Large screening of ligands displayed superiority of L3: N-benzoyl-protected leucine. Besides, a mixed base system, CsOAc, combined with Na2 CO3 was essential to achieve high level of conversion, and final improvement of the enantioinduction was reached by adding a small amount of DMSO acting as a trap of non-ligated Pd species. The optimized protocol turned out to be highly efficient for a small panel of diarylmethylamines affording the chiral amines in up to 99% ee under extremely mild reaction conditions [5]. Notably, unchanged efficiency of this reaction on gram scale combined with a robust deprotection method further illustrates the synthetic utility of this strategy to access otherwise difficult to synthesize enantiopure diarylamines. Subsequently, a closely related desymmetrization via arylation of nosyl-protected amine 8 was disclosed (Scheme 7.2b) [6]. The major advantage of this system is due to its compatibility with a nosyl-protected DG, rendering the overall transformation more useful and practical. Of note is that protection of the acid moiety of the ligand with an N-methoxyamide motif turned out to be essential to reach excellent conversion of the starting material.

H

NHTf R + l2

R H

(a)

6 R = o-Me

H

NHNs

R H

(b)

8 R = o-Me

Pd(OAc)2, 10 mol%, L3: Bz-Leu-OH, 40 mol% CsOAc, 3 equiv, Na2CO3, 3 equiv DMSO, 15 equiv 30 °C, 48 h, tAmyl-OH

I

O

NHTf *

O H R

R

H O

7 98% ee 80% yield Pd(OAc)2, 10 mol%, L4: Fmoc-L-Leu-NHOMe, 15 mol% Ag2CO3, 2.5 equiv, NaHCO3, 0.5 equiv R + Ar-BPin R BQ, 0.5 equiv DMSO, H2O 30 °C, 48 h, tAmyl-OH

Ar

N

O CF3 S OCs H N Pd OAc Ar H

Ph

NHNs * R 9

96% ee 90% yield

Scheme 7.2 Synthesis of enantiopure amines by desymmetrization.

Recently, the concept of synthesis of C-stereogenic molecules via direct desymmetrization was further swelled by developing a method for direct functionalization of a prochiral ring at distal meta position, as disclosed by Yu and coworkers

177

178

7 Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization

(Scheme 7.3) [7]. The C–H activation was achieved at this remote meta position, thanks to the use of a transient mediator, and its chiral character is capable of transferring stereoselective information yet allowing synthesis of the enantiopure products 11. Chiral norbornene derivative appeared as the optimal mediator promoting meta-selective arylation of diarylmethylamines 10. As shown on Scheme 7.3b [8], the arylation is driven at meta position due to the transient insertion of the norbornene scaffold into the 10-Int-B, thus relaying metal at distal position (10-Int-D). However, the enantioselectivity is arguably induced at the beginning of the overall catalytic system, when ortho metalation takes place. Me Boc

N

N R + Ar(Het)-l

R

N *

N

N

11 90% ee, 64% yield

R

DG Ho

(R) (S)

(+)-NBE-CO2Me

L2Pd(ll)X2

X

X

L

L

DG Pd

R

Ar

MeO2C

Hm

Ar

DG Pd

O O P O OH

L6

Ar

DG Ho Ar

OH

R H

Ar = m-ClPh

10 R = m-Me

L5

R

AgOAc, 3 equiv CHCI3, 100 °C

H

H

Boc

CF3

F3C

Me

Pd(OAc)2, 10 mol%, L5: pyridone ligand, 15 mol% (+)-NBE-CO2Me, 20–50 mol%, L6: (R)-BNDHP, 15 mol%

Hm

Ar E

E

10-Int-A

H DG Ar

–L X

E L Pd X R

DG Pd Ar

E Hm

10-Int-B 10-Int-F

DG H Ar

+L

DG

E Pd L

Ar

XR

H

E Pd L X 10-Int-C

10-Int-E R-X

DG H Ar

E Pd L

–HX

10-Int-D

Scheme 7.3 Desymmetrization via meta-selective functionalization.

Desymmetrization reactions catalyzed by various chiral ligands may occur via both Pd(II)/Pd(0) and Pd(II)/Pd(IV) catalytic cycles yet involving a diversity of catalytic transformations. The scope of such transformations is further complemented by intramolecular couplings occurring via Pd(0)/Pd(II)-type transformations. In such a case, the transformation is initiated by an oxidative addition of

Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization

Pd(0) into C—X or C—OTf bond, allowing installation of a metal catalyst within a substrate, thus enhancing a selective insertion of a metal into a CAr —H bond of a prochiral substrate. Further intramolecular coupling delivers a chiral product with generally excellent yields and high stereoselectivities. Synthesis of indanes 13 bearing quaternary stereocenters by means of direct enantioselective C–C coupling published in 2009 by Cramer is an early illustration of such a concept (Scheme 7.4). The key step of this reaction is a stereodetermining insertion of the preinstalled Pd into a CAr —H bond and an efficient transfer of the chiral information from TADDOL-based phosphoramidite L7 to the newly generated stereogenic center [9].

L7

Ar O O

Ar H R OTf R X

H 12

Ar O P NnBu2 O Ar

R

Pd(OAc)2, 5 mol% L7, 12 mol% NaHCO3, 3 equiv DMAc, 23 °C

Ar = 4-tBuPh HO R X 13

O O H L* Pd H X

Scheme 7.4 Desymmetrization of a preactivated substrate via Pd(0)/Pd(II) cycle.

Few years later, a conceptually similar approach was employed for the synthesis of chiral isoindoline scaffolds 15 (Scheme 7.5) [10]. This synthetic route toward original heterocyclic compounds implies Pd(0)-catalyzed desymmetrizative intramolecular alkenylation. Substrate design showed that phosphate moiety might be astutely used to preinstall Pd on 14 by means of initial oxidative addition. Thus located Pd catalyst, bearing a chiral ligand, is able to differentiate two prochiral aromatic rings, and the final reductive elimination affords the expected heterocyclic compounds. Interestingly, a ligand design was crucial to reach satisfactory level of enantiodiscrimination, and thus an auxiliary L8 featuring both an axial binaphthyl motif and a point-chiral phospholane unit was optimal. Under finely optimized reaction conditions, product 15 was delivered with ee up to 94% and high yields (typically approx. 80–90% yield). Recently, an additional example of desymmetrization via direct C–H activation using Pd(0) precursor was disclosed by Baudoin (Scheme 7.6) [11]. Interestingly, in order to build up 5,6-dihydrophenanthridine from prochiral aryl bromides 16, a new type of chiral ligands was designed. Indeed, this transformation occurs in the presence of a chiral bifunctional phosphine/carboxylate ligand L9. This ligand featuring the axial chirality of the BINOL scaffold was designed hypothesizing that an efficient and highly stereoselective transformation could

179

180

7 Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization

H H R

R O

N

O

OPh P OPh O

Pd(OPiv)2, 5 mol% L8, 10 mol% PivOH, 20 mol% Cs2CO3, 1.5 equiv 23 °C, 14 h, toluene

Me R

P

R

14 R = 4-Ph

L8

N

O

OR Me

R = TBDPS

15 94% ee 91% yield

Scheme 7.5 Synthesis of chiral isoindoline via desymmetrization.

be expected if a well-organized mononuclear ligand/metal complex is formed with the phosphine moiety providing requested electronic properties to the Pd catalyst and the carboxylate moiety being actively involved in the metalation step. In accordance to such a working hypothesis, the expected intramolecular arylation of prochiral 16 was achieved using Pd2 dba3 precatalyst together with ligand L9, delivering 17 in high yields and up to 97% ee. Noteworthy, both the presence of the carboxylate moiety on the ligand and important steric hindrance induced by the phosphine are crucial to reach high stereodifferentiation (as almost racemic transformation was observed while using a corresponding ester or ether ligand congeners). H

RO

R1

R1 N

H CO2R

Pd2dba3, 2.5 mol% L9, 10 mol%

O

Ar Ar C P Pd C O H O C O Expected key intermediate

Me Me

R1

Cs2CO3, 1.5 equiv 80 °C, 4Å MS, DME

R1

Br 16 R1 = H,R = Et

Me

N

17 97% ee 91% yield

P O CO2H Me L9

Scheme 7.6 Bifunctional phosphine/carboxylate ligands for intramolecular asymmetric direct arylation.

In addition to the herein presented protocols implying initial installation of Pd catalyst on a substrate via oxidative addition into C—X bond, in 2017 You and Zhu reported an alternative strategy involving C–H imidoylation reaction (Scheme 7.7) [12]. The authors surmised that if a prochiral substrate such as dibenzyl isocyanide 18 is used, in the presence of a Pd-precatalyst imidoyl palladium(II) intermediate, isoquinolines should be easily accessed. Such an intermediate is now perfectly designed to undergo an intramolecular desymmetrizative C–H imidoylation. The optimization study showed that the use of a monodentate phosphoramidite ligand is essential, and the optimal chiral induction is achieved when using SPINOL-derived ligand L10. Addition

Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization

of Cs2 CO3 and PivOH further improved the overall efficiency of the transformation, and under the optimized reaction conditions, the desired C–H imidoylation proceeded smoothly, delivering 3,4-dihydroisoquinolines 19 in up to 92% ee and high to quantitative yields. CO2R1 R2 H

H R2

NC

18 R1 = Et, R2 = 2-Cl

O P O

Ph N

Pd(OAc)2, 10 mol% L10, 20 mol% + Ar–I Cs2CO3, 1 equiv PivOH 0.6 equiv, H2O 1 equiv 80 °C, 1h, dioxane

CO2R1 R2 Ar 19 92% ee, 90% yield R

Ph

Desymmetrizing C–H activation

H N R H

Ph N

Ph L10

R2

N

*LXPd

Ar

Expected key intermediates

Pd L*

Ar

Scheme 7.7 Palladium-catalyzed enantioselective C(sp2 )–H imidoylation.

Although Pd is by far the most common catalyst for the stereoselective desymmetrizative C–H activation, an alternative and original transformation based on chiral Rh catalyst was disclosed in 2015 by Hartwig (Scheme 7.8). This research group has a long-standing interest in direct silylation reactions [13], and drawing inspiration from their catalytic systems, an enantioselective version of such a transformation allowing desymmetrization of benzophenone was intended [14]. The overall protocol starts by hydrosilylation of the prochiral ketones 20 (or alcohols). In situ generated (hydrido)silyl ether is thus prompt to interact with Rh catalyst, hence promoting regioselective and stereodiscriminant ortho metalation, followed by intramolecular silylation. Rh catalyst bearing catASium ligand L11 is the optimal catalyst to distinguish between two prochiral aromatic rings, thus furnishing benzoxazoles 21 in excellent yields and stereoselectivity. Besides, the synthetic value of this reaction arises from a strong modularity of the newly accessed chiral compounds; the enantiopure 21 may be easily converted into an array of optically pure alcohols.

O

H R

R H

[lr(cod)Ome]2, 0.1 mol% Et2SiH2, THF,rt

OSiEt2H R

R

[Rh(cod)Cl]2, 2.5 mol% L11, 5 mol% nbe, 2 equiv

O * R

50 °C, THF H 3C

20 R = 3-Me

CH3 PPh2

L11

CH3

H 3C Ph2P

S H3C

Scheme 7.8 Rh-catalyzed desymmetrizative hydrosilylation.

SiEt2 R

21 99% ee 85% yield

181

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7 Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization

7.1.2

Kinetic Resolution

Despite great potential of asymmetric C–H activation based on desymmetrization reactions, this strategy requires the use of finely designed substrates with two identical prochiral moieties to be functionalized. In consequence, its synthetic utility is somehow restricted, as only a limited number of chiral compounds are accessible via such a protocol. An alternative strategy has thus emerged, relating to kinetic resolution. Asymmetric C–H activation via kinetic resolution is a process during which a chiral catalyst is able to differentiate two enantiomers of a racemic substrate. The catalyst inserts therefore into a C—H bond of one enantiomer of the substrate, allowing its subsequent functionalization, whereas the remaining unreacted substrate becomes highly enantioenriched. This approach is fairly general as potentially a large number of chiral molecules can thus be accessed. However, its main limitation corresponds to the theoretical yield of the reaction that cannot exceed 50%. The pioneering work in this field was reported by Yu, who astutely used kinetic resolution to access enantiopure arylamines. Pd/MPAA is indeed able to differentiate between two enantiomers of Tf-protected chiral alkyl benzylamines 22 and to catalyze a selective iodination of the (R)-enantiomer of the substrate (Scheme 7.9). Remarkably, a fine ligand tuning combined with mild reaction conditions permit to reach high selectivity (up to 240), and thus iodinated enantioenriched benzylamines 23 were isolated in up to 97% ee and 46% yield, together with nonfunctionalized remaining starting material enantioenriched up to 93% [15]. H R

NHTf

H

Pd(OAc)2, 10 mol% L3: Bz-Leu-OH, 40 mol%

Alk

rac-22 R = 2-OMe-Ph Alk = Me

Alk

R

CsOAc, Na2CO3, I2 20 °C, 24–48 h, tAmyl-OH/DMSO

(S)-22 93% ee

R

H

NHTf

CO2Me

R

NHTf Alk

+

23 97% ee 46% yield Selectivity: 240

Other successful substrates H

I

NHTf

NHTf

OTBS

Scheme 7.9 Kinetic resolution of Tf-protected benzylamines.

The versatility of this transformation was further expanded by applying this protocol for direct functionalization of β-amino acids and β-amino alcohols, thus providing an access to a large panel of original chiral molecules, difficult to access via any other synthetic route. Following this seminal example of kinetic resolution, the potential of these transformations was further extended toward functionalization of commonly used and practical nosyl-protected benzylamines 24 (Scheme 7.10). As expected,

7.2 Synthesis of P-Central Chiral Molecules via C(sp2 )–H Functionalization H

NHNs

H

Pd(OAc)2, 10 mol% Alk + Ar-BPin L12: Boc-L-Phe-NHOMe 15 mol% R R Ag2CO3, 2 equiv Na2CO3, 3 equiv, BQ, 0.5 equiv H2O, 5 equiv, DMSO, 0.4 equiv rac-24 50 °C, 15 h, tAmyl-OH R = 2-Cl, Alk = Me

NHNs

Ar

Alk

+

Alk

R

(S)-24 98% ee 42% yield

Selectivity: 135

NHNs

25 93% ee 46% yield

Scheme 7.10 Kinetic resolution of Ns-protected racemic benzylamines.

a stereoselective arylation of 24 with arylboronic esters takes place in the presence of Pd-α-amino-O-methylhydroxamic acid ligand L12 (MPAHA), and the design of the hydroxamic-type ligand was crucial to ensure high efficiency and stereoselectivity of this transformation reaching selectivity up to 135. The scope of this transformation is broad with respect to the aryl coupling partner and the benzylamine substrates used. Besides, high efficiency of the coupling on gram scale combined with mild deprotection protocol at room temperature renders this strategy a truly powerful approach toward an array of enantiopure benzylamines [16]. In parallel, Yu discovered that racemic α-substituted phenylacetic acids undergo the same type of stereoselective functionalization (Scheme 7.11). In this case MPAA ligand L13 derived from O-protected threonine is particularly efficient in differentiating two enantiomers of α-hydroxy- and α-amino-phenylacetic acids 26, allowing kinetic resolution and selective C–H functionalization of S-enantiomer of 26, thus furnishing two chiral molecules with selectivity up to 56 [17].

H R1

OPiv/NHPiv CO2H +

rac-26 R1 = 3-Cl, OPiv

R2

Pd(OAc)2, 10 mol% L13: O-Bz-Boc-Thr-OH, 30 mol% KHCO3, 2 equiv

R2 H

OPiv/NHPiv

OPiv/NHPiv

CO2H +

CO2H

1 30 °C, 24–60 h, tAmyl-OH R

Selectivity: 56 R2 = CONMe2

(R)-26 77% ee

R1

27 92% ee 43% yield

Scheme 7.11 Kinetic resolution of α-hydroxyl- and α-amino-phenylacetic acids.

7.2 Synthesis of P-Central Chiral Molecules via C(sp2 )–H Functionalization P-chiral compounds are important motifs frequently encountered in biologically active scaffolds. Besides, P-stereogenic ligands are of key importance for asymmetric catalysis as the presence of this chiral element in close proximity to the metal gives promise of particularly efficient chiral induction. However, synthesis of P-chiral compounds is far from trivial, and the modularity of such compounds is often limited. Accordingly, design of conceptually innovative strategies

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7 Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization

to access these scaffolds presents a great scientific challenge. In particular, asymmetric C–H activation seems an appealing strategy to device alternative routes to construct original and otherwise difficult to access P-chiral molecules from simple precursors. The pioneering contribution in this field was reported by Park and Chang in 2014, when they disclosed a diastereoselective Ir-catalyzed desymmetrization of arylphosphoryls 28 (Scheme 7.12a) [18]. The authors hypothesized that a diphenylphosphine oxide, bearing a chiral alkoxy auxiliary, might undergo a stereoselective C–H functionalization, facilitated by a precoordination of the metal catalyst by O-atom. Rewardingly, the expected Ir-catalyzed C–H amidation occurred smoothly, and moderate level of chiral induction was observed (de up to 62%). Notably, modification of the chiral auxiliary from chiral alcohol to enantiopure C 2 -symmetric pyrrolidine congener (substrate 30) drastically improved the stereoselective outcome of this transformation, providing the expected phosphinic amides 31 with de up to 90% and high yields (Scheme 7.12b). Subsequently, regarding the key role of acidic additives in various C–H activation reactions, the authors surmised that an enantioselective transformation might be expected in the presence of a stereogenic carboxylic acid as a chirality source. Indeed, C–H amidation of prochiral phosphoryl substrate was effective in the presence of O,O′ -dipivaloyl-l-tartaric acid, but only modest ee of 31% was reached [19]. H

H O P O

R

R O +

S

R′

TsHN O * P O

R

H R

29 62% de

Ph

H O P N

30 R=H

R

50 °C, 48 h, DCE

28 R = 4-OMe

(a)

(b)

N3

O

[lrCl2(Cp*)]2, 2 mol% AgNTf, 8.5 mol% PivOH, 12 mol%

O

R + Ph

N3

O S

R′

[lrCl2(Cp*)]2, 2 mol% AgNTf, 8.5 mol% PivOH, 12 mol% 25 °C, 4 h, DCE

R Ph

H TsHN O * P N

R Ph

31 84% de 87% yield

Scheme 7.12 Pioneering work on synthesis of P-chiral compounds via desymmetrization.

Cramer astutely solved this challenging issue by designing a cooperative catalytic system combining a chiral Cp-derived Ir complex and an amino acid external ligand (Scheme 7.13). He discovered that the cooperative effect between a chiral [CpIr] catalyst and the simple tert-leucine-derived L14 might enhanced amidation of 32 with great efficiency and stereoselectivity, furnishing the expected chiral phosphine oxides 33 with up to 98% ee and 85% yield. Remarkably, important match/mismatch effect was observed when using the

7.2 Synthesis of P-Central Chiral Molecules via C(sp2 )–H Functionalization

OMe X

R

H O H P tBu

R

32 R=H

+

R′N3

[Cp Ir]2, 2 mol% L14, 24 mol% AgNTf2, 8.5 mol%

R′ H OHN P tBu

R

0 °C, 36 h, tAmylOH/dioxane

tBu

33 98% er 85% yield

R′ = p-Cl-C6H4SO2

Ir OMe I

R

I 2

CO2H NHPhth

L14

Scheme 7.13 Enantioselective amidation of prochiral P-phosphine oxides.

opposite enantiomer of the amino acid, and modification of the ligand structure resulted in a significant decrease of either efficiency or stereoinduction [20]. In parallel to the development of the abovementioned Ir-catalyzed transformation, several groups explored Pd-mediated couplings. In this context an interesting example of intramolecular desymmetrizative C(sp2 )–H activation furnishing P-chiral compounds was reported by Tang and coworkers (Scheme 7.14). Prochiral diaryl(2-bromoaryl)phosphonates 34 were used as starting materials, and Pd(0)/Pd(II) catalytic system was operative [21]. After initial installation of a Pd catalyst on a substrate by means of oxidative addition, the chiral catalyst is able to discriminate between prochiral OAr moieties. Enantioselective C(sp2 )–H activation thus takes place, furnishing after intramolecular arylation P-chiral biaryls 35. R2

H Br R1

O O P O

R2 H

34 R1 = 3-OMe; R2 = H

Pd(OAc)2, 4 mol% L15: 8 mol% Ph2CHCOOK, 1.5 equiv

R2

70 °C, 24 h, toluene

R1

O O P O O

L15

P

O

O

tBu

R2 35 88% ee 85% yield

Scheme 7.14 Enantioselective synthesis of oxaphosphinine 6-oxide.

In early 2015, Duan as well as Liu and Ma independently reported very similar intramolecular transformations, furnishing P-chiral compounds via desymmetrization (Scheme 7.15) [23]. In both cases intramolecular C–H arylation was conducted via Pd(0)/Pd(II) catalytic cycle with participation of TADDOL-derived phosphoramide ligand L16. Notably, high enantioselectivity (typically above 90%) was observed regardless the catalyst source. During the same period, an intermolecular Pd-catalyzed arylation was discovered by Han (Scheme 7.16) [24]. Remarkably and in coherence with the previous observations by Yu concerning desymmetrization of diphenyl-carboxylic acid derivatives, MPAA ligand L17 turned out to be a highly efficient chiral inductor when using phosphinamides 38 bearing an electron-poor diarylphosphonic

185

186

7 Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization

R

H O Rʹ Br P N

Pdcat L16 PivOH Base, solvent

Ph

H O Rʹ P N

R

Ph O P NR2 O

O O

H

Ph Ph R

R

L16a: R = Me L16b: R = Et

37

36 Duan and coworkers [22] Pd(OAc)2, 5 mol% L16a, 10 mol% K3PO4, 1.5 equiv PivOH, 30 mol% 80 °C, PhMe

Liu, Ma, and coworkers [23] Pd(dba)2, 8 mol% L16b, 10 mol% Cs2CO3, 1.5 equiv PivOH, 40 mol% 60 °C, hexane

37, R = H, Rʹ = Me 90% ee 94% yield

37, R = H, Rʹ = Et 89% ee 94% yield

Scheme 7.15 Intramolecular Pd(0)-catalyzed arylation of prochiral P-substrates.

R

H O P

N H H

ArF + Ar-BPin

Pd(OAc)2, 10 mol% L17, 20 mol% BQ, 0.5 equiv, Li2CO3, 3 equiv Ag2CO3, 1.5 equiv, 40 °C, DMF

L17: R 38 R = m-OMe

R

Ar O P

C6H4-p-OtBu O

N H H

ArF

R Ar = p-Me-C6H4

BocHN

OH

39 98% ee, 68% yield

Scheme 7.16 Synthesis of P-chiral molecules via intermolecular desymmetrization.

amide. The reaction occurs smoothly under mild reaction conditions (temperature of 40 ∘ C) and tolerates well an array of arylboronic esters coupling partners, yielding the expected P-stereogenic molecules 39 with excellent enantiopurity. More recently, Cramer exploited the potential of chiral CpX Rh catalysts to build up P-stereogenic scaffolds (Scheme 7.17a). In his pioneering work this chiral catalyst was used to desymmetrize diarylphosphinamide 40 via enantiodiscriminant direct metalation, followed by coupling with alkynes and final cyclization step. Of note is that the choice of the base is crucial for this catalytic system, as it directly impacts the reversibility of the metalation step yet influencing the overall chiral induction. Remarkably, this catalytic system is not only highly stereoselective, as the products are furnished in up to 92% ee, but also outstanding regioselectivity was observed for dissymmetric alkynes [25]. This protocol is therefore an efficient route to build up enantiomeric P(V) motifs 41. Few months later the same research group extended the potential of chiral CpX Rh catalysts by developing an alternative protocol for the synthesis of P-stereogenic compounds via kinetic resolution (Scheme 7.17b). As in the case of C-stereogenic compounds described above, such a transformation implies a selective functionalization of a racemic P-substrate 42 [26]. A new CpX Rh complex with an increased bulk was essential to differentiate the two enantiomers of the substrate, thus promoting C–H activation and following functionalization of one enantiomer significantly faster than the other one. When conducting

7.3 Synthesis of Chiral Organosilicon Molecules via C(sp2 )–H Functionalization

(a) Desymmetrization: prochiral substrate

R1

H O P

N H H

R1 40 R1 = H

ArF

R3 +

[CpXRh], 5 mol% (PhCO2)2, 5 mol% Ag2CO3, 2 equiv K2CO3, 1 equiv 90 °C, 16 h, tBuOH

R1 OMe O

P

N

R1

ArF Rh R3

R2

OMe

R2 41 92% ee 55% yield

R2 = Me, R3 = Ph

F F F

Ar : F

(b) Kinetic resolution: racemic susbtrate

F F

[CpXRh], R1

H O ArF P N + H Me 42 R1 = 4-NMe2

Ph

10 mol% (BzO)2, 10 mol% Ag2CO3, 2 equiv K2CO3, 1 equiv

R1

90 °C, 16 h, tBuOH

Ph

42 83 :17 dr 50% yield

OMe Rh

H O ArF 1 P + R N H Me

tBu

O Me P ArF N Ph Ph

43 95:5 dr 36% yield Selectivity: 43

OMe

Scheme 7.17 Enantioselective synthesis of P-chiral molecules via (a) desymmetrizative alkynylation and (b) kinetic resolution.

the reaction till approx. 50% conversion, the functionalized P-compound 43 was isolated in up to 90% ee and 36% yield, together with an enantioenriched remaining starting material 42 (66% ee and 50% yield), thus showing a selectivity of 43%.

7.3 Synthesis of Chiral Organosilicon Molecules via C(sp2 )–H Functionalization Organosilicon compounds are prominent molecules, and their applications in electronic devices, catalysts, and biologically active materials have been flourishing over the last decade. In particular chiral silicon compound are of great interest, but the synthetic methods to access such scaffolds are cruelly missing. Accordingly, application of the stereoselective C–H activation protocols to build up such moieties has been attracting a considerable attention of the scientific community. The pioneering contribution in this field was reported by Shintani, Hayashi, and coworkers (Scheme 7.18) [27]. Drawing inspiration from Shimizu et al. [28], the authors hypothesized that silicone stereogenic dibenzosiloles might be obtained via desymmetrizative intramolecular C–H arylation of prochiral 2-(arylsilyl)aryl triflates 44. Indeed, as in the case of desymmetrization leading to the formation of C-stereogenic molecules, a chiral catalyst might be able to distinguish two prochiral Ar moieties and enhance intramolecular C—C bond formation event

187

188

7 Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization Pd(OAc)2, 5 mol% L18, 5.5 mol% Et2NH, 2 equiv

H TfOtBu Si R

50–70 °C, 48h, toluene

H

tBu

H

R

Pd* R

tBu

Si

Ar = 46 Side product 33 :34 > 99: 1

C–H activation

tBu Si Pd

Pd H

H

PCy Fe PAr2

Si

R 45 98% ee 64% yield

H Si

tBu

Si

R

44 R = 2-CH = CMe2

TfO tBu

Me

L18:

3,5-Me2-4-MeOC6H2

Reductive elimination

tBu

Si

R

TfO 1,5-shift

H R

tBu

Si Pd

C–H activation

Reductive

tBu Si R

tBu

Pd elimination

Si

R

Scheme 7.18 Synthesis of dibenzosiloles via Pd-catalyzed desymmetrization.

yet furnishing the Si-chiral product. To achieve this general goal, the authors focused on Pd(0)/Pd(II) transformations involving the use of a preactivated substrate 44. In the initial study enantiopure Josiphos ligand was used in combination with Pd(OAc)2 catalyst, and the expected dibenzosiloles 45 were delivered in up to 98% ee and good yield. The mechanistic studies revealed that initial oxidative addition of Pd(0) into C—OTf bond is most likely the turnover-limiting step of the catalytic cycle followed by subsequent relatively fast enantiodiscriminant metalation and C—C bond-forming reductive elimination. During the catalytic cycle, 1,5-H-shift may also operate, leading to the formation of a side product 46. This side reaction may however be suppressed in the presence of the optimal ligand. Few months later, a synthesis of another family of Si-chiral molecules, spirosilabifluorene, was reported by Kuninobu, Takai, and coworkers (Scheme 7.19) [29]. In this case stereoselective C–H activation step was followed by intramolecular Si—C bond formation event, thus promoting smooth conversion of bis(biphenyl)silane 47 into the expected product 48. Remarkably, this reaction occurs via sequential double C–H activation, and good chiral induction is observed when applying Rh/BINAP catalytic system. Detailed mechanistic studies uncovered that two constitutional isomers Int-A and Int-B result from the first dehydrogenative bond formation and both may be converted into the spiro-products. Accordingly, the chirality of the overall transformation is controlled during the first dehydrogenative cyclization event, leading to Int-A and Int-B. The interconversion between the two isomers requires the presence of the Rh catalyst, involves cleavage of C(sp2 )—Si bonds, and occurs with retention of the configuration.

7.4 Synthesis of S-Chiral Molecules via C(sp2 )–H Functionalization H R Si

H

[{RhCl(cod}2], 0.5 mol% (R)-BINAP, 1.2 mol%

H

135 °C, 3 h,1,4-dioxane

R Si R

R H 47 R = 4-OMe

48 81% ee 95% yield

Enantioselection during the first C–Si bond formation H R Si

R Rh*

H

H Si

H

Rh

R H Si Rh HH

H

R

R

R –H2

H Si Rh

R

R

H R Si

H

Int-A

H R

R

R

Rh*

Si

R

SiH R

Int-B

Scheme 7.19 Synthesis of spirosilabifluorene via desymmetrization.

Besides, it should be highlighted that chiral Si complexes may also be built up via enantioselective intramolecular silylation of planar chiral compounds. These results are present elsewhere.

7.4 Synthesis of S-Chiral Molecules via C(sp2 )–H Functionalization Chiral sulfoxides are key scaffolds in asymmetric synthesis and biologically active compounds. Therefore, several different approaches have been designed to access enantiopure sulfoxides, such as stereoselective metal-catalyzed, metal-free, or enzymatic oxidation, kinetic resolution, or nucleophilic substitution of chiral sulfinate amides or esters [30–32]. However, these methods either require a stoichiometric amount of a chiral pool or are rather substrate specific, which makes synthesis of an unlimited panel of optically pure sulfoxides challenging. In order to provide a conceptually new protocol for the asymmetric synthesis of sulfoxides, Wang hypothesized that a direct C(sp2 )–H desymmetrization reaction could be envisioned, as for the synthesis of C- and P-stereogenic compounds [33]. Following this assumption Wang endeavored on designing an effective catalytic system (Scheme 7.20). Drawing inspiration from Yu and coworkers [1], the initial tests were performed using Pd catalyst in combination with MPAA, and, rewardingly, the desired product was generated with up to 92% ee when using

189

190

7 Central Chirality via Asymmetric C(sp2 )–H Activation Implying Desymmetrization Prochiral symmetric diarylsulfoxide: desymmetrization O S

H R1 +

R1

R2

Pd(OAc)2, 10 mol% L19: Ac-Leu-OH, 30 mol% Ag2CO3, 2 equiv 75 °C, 72 h, HFIP

H 49 R1 = 2-Me

O S*

H R1

R1 R2

R2 = CO2Me

50 98% ee 61% yield

Racemic nonsymmetric diarylsulfoxide: parallel kinetic resolution Me O S

F +

CO2Me

H 51 R1 = 2-Me, R2 = 2âTM-F

Pd(OAc)2, 10 mol% L10: Ac-Leu-OH, 30 mol% Ag2CO3, 2 equiv

Me O S*

F

Me

O S*

F

100 °C, 72 h, HFIP 52 53 CO2Me MeO2C 98% ee 99% ee 40% yield 25% yield

Scheme 7.20 Synthesis of enantiopure sulfoxide via enantioselective desymmetrization and parallel kinetic resolution.

simple Ac-Leu-OH ligand (L19) [33]. This transformation tolerates well a variety of substrates 49, bearing both electron-donating and electron-withdrawing substituents at all possible positions. Besides, the scope of the olefin coupling partner could be extended albeit small decrease in chiral induction was witnessed when using more sterically demanding acrylates or perfluorostyrene. Notably when using dissymmetric diarylsulfoxides 51, regiodivergent functionalization takes place, thus featuring a relatively rare phenomenon of parallel kinetic resolution. In such a case, the chiral catalyst is able to discriminate the two enantiomers of a racemic substrate and functionalize regioselectively each of them, thus furnishing two distinct enantiopure sulfoxides 52 and 53, separable via silica gel column.

7.5 Conclusions Synthesis of stereogenic molecules by means of C(sp2 )–H functionalization has been one of the pioneering examples of asymmetric C–H activation. Initially, C-stereogenic molecules have been accessed via desymmetrization of prochiral substrates using Pd catalyst in combination with MPAA ligands. Progressively, the scope of these transformations has expanded dramatically. Indeed, various prochiral substrates bearing synthetically useful DGs such as amine, carboxylic acid, or alcohol have been used, delivering enantiopure molecules difficult to access via other synthetic routes. Also, other metal catalyst, such as Rh, proved to be powerful in desymmetrization reactions. Remarkably, the concept of C–H desymmetrization has also been successfully used to construct original chiral molecular architectures, exhibiting P-, Si-, and S-central chirality, thus unlocking the door to the synthesis of yet unprecedented molecular scaffolds. In particular, aside from Pd catalyst, chiral Rh catalyst bearing stereogenic Cp-derived ligands stood out as catalyst of choice to perform few of such desymmetrization reaction.

References

Few years after the initial work on desymmetrization reaction, the scientific community has become attracted by complementary reactions implying kinetic resolution. In such a case a larger panel of substrates may be used as the reactions involve selective functionalization of a racemic starting material, as the chiral ligand is able to distinguish two enantiomers. Kinetic resolution concept has proven to be an appealing protocol to prepare a large diversity of enantiopure benzylamine derivatives. More recently a related transformation, i.e. parallel kinetic resolution, has been astutely employed to build up a variety of stereopure sulfoxides. In conclusion, over the last decade, unexpected progress has been achieved in this field of C–H activation. In the near future new catalytic systems will be devised, and certainly this approach will meet even larger echo for the synthesis of uncommon P-, Si-, and S-stereogenic scaffolds.

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Int. Ed. 54: 6265–6269. Liu, L., Zhang, A.-A., Wang, Y. et al. (2015). Org. Lett. 17: 2046–2049. Du, Z.-J., Guan, J., Wu, G.-J. et al. (2015). J. Am. Chem. Soc. 137: 632–635. Sun, Y. and Cramer, N. (2017). Angew. Chem. Int. Ed. 56: 364–367. Sun, Y. and Cramer, N. (2018). Chem. Sci. 9: 2981–2985. Shintani, R., Otomo, H., Ota, K., and Hayashi, T. (2012). J. Am. Chem. Soc. 134: 7305–7308. Shimizu, M., Mochida, K., and Hiyama, T. (2008). Angew. Chem. Int. Ed. 47: 9760–9764. Kuninobu, Y., Yamauchi, K., Tamura, N. et al. (2013). Angew. Chem. Int. Ed. 52: 1520–1522. Drabowicz, J. and Mikołajczyk, M. (1982). Org. Prep. Proced. Int. 14: 45–89. Kagan, H.B. (2008). Asymmetric synthesis of chiral sulfoxides. In: Organosulfur Chemistry in Asymmetric Synthesis (ed. T. Toru and C. Bolm), 1–29. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA. Han, J., Soloshonok, V.A., Klika, K.D. et al. (2018). Chem. Soc. Rev. 47: 1307–1350. Zhu, Y.-C., Li, Y., Zhang, B.-C. et al. (2018). Angew. Chem. 57: 5129.

193

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization of Metallacyclic Intermediate Xiaohong Chen 1,2 , Xue Gong 1,3 , Bo Wang 1 , and Guoyong Song 1 1 Beijing Forestry University, Beijing Key Laboratory of Lignocellulosic Chemistry, College of Materials Science and Technology, No. 35 Tsinghua East Road, Beijing 100083, China 2 Dalian Polytechnic University, Liaoning Key Laboratory of Pulp and Papermaking Engineering, College of Light Industry & Chemical Engineering, No. 1 Qinggongyuan, Dalian 116034, China 3 Beijing Forestry University, School of Science, No. 35 Tsinghua East Road, Beijing 100083, China

8.1 Introduction In the past decades, significant advancements have been made in the area of direct C–H functionalization, and this strategy has delivered various powerful tools that take advantage of the ubiquity of C—H bonds in chemical feedstocks [1–3]. The metal-catalyzed direct functionalization of C—H bonds provides a streamlined and step-economical synthesis of desired compounds with no pre-activation of the coupling partner, hence eliminating the generation of a stoichiometric amount of salt waste as in traditional cross-coupling reactions [4–7]. In particular, the catalytic enantioselective functionalization of C—H bonds represents a straightforward approach toward the generation of organic compounds having ether central, axial, or planar chirality from simple precursors in an atom-economical fashion [8–11]. C(sp2 )—H bonds are typically more sterically accessible and acidic than C(sp3 )–H counterparts, and a variety of systems for enantioselective C(sp2 )–H functionalization have been developed. The ubiquity of C(sp2 )—H bonds makes such transformations attractive, but they also pose several challenges. The first is the reactivity and selectivity of C—H bonds activation. To achieve this, directing groups (DGs) are often installed. Precoordination of the catalyst by a DG enhances the effective concentration of the catalyst in proximity to a substrate, leading to thermodynamically stable metallacyclic intermediates [12]. Another key problem is the control of the stereoselectivity of the reaction between the resulting M—C bond and the coupling partner, which should be controlled under an optimized chiral environment. The scope of this chapter is limited to the reaction implying the formation of a metallacyclic intermediate proceeding through a metal-catalyzed non-stereoselective C(sp2 )–H activation, followed by either an inter- or intramolecular stereoselective functionalization of metallacyclic intermediate. In common, the formation of reactive organometallic intermediates through C(sp2 )—H bonds activation undergoes four general mechanisms: oxidative C–H Activation for Asymmetric Synthesis, First Edition. Edited by Françoise Colobert and Joanna Wencel-Delord. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.

194

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

addition for electron-rich late metals, σ-bond metathesis for early metals, electrophilic C–H activation for electron-deficient late metals, and Lewis base-assisted C–H activation [13]. The following functionalization of a metallacycle typically proceeds via diastereoselective coordination of an unsaturated coupling partner with a metal center and migratory insertion into M—C bond. The enantioselective C(sp2 )–H functionalization reactions, in which C–H activation/cleavage is involved in the stereodiscriminant step, will not be discussed in this chapter.

8.2 Intramolecular Couplings 8.2.1

Palladium and Nickel Catalysis

Palladium-catalyzed dehydrogenative Heck reaction (also referred to the Fujiwara–Moritani reaction) through C–H activation of 1,4-quinones and indoles has been used as the key step in several total synthesis. In 2003, Stoltz and coworker reported an intramolecular oxidative C–H annulation of 3-substituted indoles 1 at C2 position by using Pd/ethyl nicotinate catalytic system, affording five- or six-membered indole derivatives 2 [14]. The first enantioselective variant for this transformation was reported by Oestreich group in 2008, using a novel class of PyOx ligands (such as L1 and L2) (Scheme 8.1) [15]. Optimization reactions indicated that the combination of Pd(OAc)2 and methyl ester PyOx ligand (L1) could provide the highest level of enantiocontrol in the presence of stoichiometric tert-butyl peroxybenzoate as an oxidant. Both the Z and E isomers of compound 1 gave cyclized product 2 with the same absolute configuration and in similar yields, while the enantioselectivities were dependent on alkene configuration (for Z, 57% ee; for E, 20% ee). The cyclization of cyclohexene derivative 3 could also be achieved with an analogue PyOX L2 as a ligand, which afforded spirocyclic indole 4 in 15% yield and 54% ee. The authors also reported the cyclization of N-tethered alkenes 5 under analogous reaction conditions, leading to the corresponding indole derivative 6a in 36% yield with 47% ee and pyrrole derivative 6b in 44% yield with 70% ee [16]. The catalytic cycle was supposed to involve an electrophilic palladation at C2 position followed by alkene insertion and β-H elimination [14]. In 2010, Oestreich attempted to construct six-membered ring by using the same chiral catalytic system, resulting in either no conversion (6d) or no stereoinduction (6c); this may be due to a change in the mechanism from an electrophilic palladation (C–H activation) to a Friedel–Crafts-type pathway (alkene activation) (Scheme 8.1) [16]. The 2-pyridone structural motif is common in various important biologically active compounds. Therefore, the preparation of 2-pyridone derivatives through C–H functionalization is of great interest and importance. In 2009, Nakao and Hiyama described the intramolecular hydroarylation of a N-tethered alkene at C6-position of pyridone unit, using a combination of nickel(0)/P(i Pr)3 /AlMe3 catalyst, offering mostly the exo-cyclization products in good selectivity [17]. In 2015, Cramer disclosed that the selectivity mode of the cyclization completely switched from exo to endo when a bulky N-heterocyclic carbene (NHC) ligand

8.2 Intramolecular Couplings

MeO2C Pd(OAc)2 (10 mol%) Ligand (40 mol%) PhO3tBu (1 equiv) AmyOH/AcOH, 80 °C

N 1

N

O

N HN

2 From Z: 57% ee From E: 20% ee

L1

iPr

O

N HN

N

N 3

L2

iPr

4, 15%, 54% ee As above N N

L1

n 5 (n = 1, 2)

n

6 (n = 1, 2)

n=1

n=2

N

N 6a, 36%, 47% ee

N

N

6b, 44%, 70% ee

6c, 17%, 3% ee

6d, no conversion

Proposed mechanism of 5-exo-trig cyclization by Stoltz (C−H activation) Pd(OAc)2 (10 mol%) Ethyl nicotinate (40 mol%) N

Pd N

57%

OBn

OBn L

N

OBn

N Pd

H

OBn

L Proposed mechanism of 6-exo-trig cyclization (Friedel–Crafts-type pathway) Pd(OAc)2 (10 mol%) L1 (30 mol%) O2 (1.0 bar), 80 °C Tert-Amyl alcohol/AcOH = 4 : 1 26%

N

Pd

N

L

N

N

7

8

H Pd L

Scheme 8.1 Pd-catalyzed intramolecular enantioselective dehydrogenative Heck reaction.

195

196

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

was employed under otherwise identical reaction conditions. Further studies were described when a chiral NHC ligand (L3) based on the isoquinoline framework was used in C–H annulation of 9; the enantioenriched pyridones 10a and 10b were isolated in 70% and 60% yield, respectively, and both in 57% ee [18] (Scheme 8.2). O

O

N

N

H 9a

O

Ni(COD)2 (10 mol%) L3 (15 mol%) AlMe3 (40 mol%) Toluene, 80 °C, 24 h

Ph

10a, 70%, 57% ee O

N N

Ph H

N L3

N H 9b

10b, 60%, 57% ee

Scheme 8.2 Ni-catalyzed intramolecular C–H annulation of pyridones.

8.2.2

Rhodium Catalysis

Rhodium catalysts have been commonly employed in enantioselective C(sp2 )–H activation and functionalization, proceeding via either a Rh(I)/Rh(III) [3] or a Rh(III) [2] catalytic cycle. Intramolecular Rh(I)/Rh(III) catalytic cycle commonly starts from a ortho-C–H activation (with a DG) through oxidative addition of a Rh(I) species into C—H bond to afford a metallacycle intermediate. Following selective coordination and migration insertion of a tethered alkene species into Rh—H bond gives an expanded rhodacycle. Final reductive elimination provides the cyclized product and regenerates the Rh(I) catalyst (Scheme 8.3). Pioneering work on Rh(I)/(III)-catalyzed intramolecular C–H activation in an enantioselective manner was reported by Murai and coworkers in 1997, where [Rh(COE)2 Cl]2 with a chiral phosphine ligand (R,S)-PPFOMe could catalyze the asymmetric C–H/alkene coupling of pyridine-tethered 1,5-dienes 11 [19]. 2-Pyridyl-directed (E,Z)-1,5-dienes or terminal alkene reacted smoothly well at 120 ∘ C to give the corresponding cyclopentanes 12 with 25–45% ee, while only racemic product was obtained in the case of (E,E)-1,5-diene. When 2-imidazolyl was used as a DG, the reaction could be carried out at a lower temperature (50 ∘ C), giving the corresponding cyclopentane 12d in 75% yield with an improved enantioselectivity (82% ee) (Scheme 8.4). In 2001, Ellman, Bergmann, and coworkers reported the intramolecular C–H addition of aromatic imines to tethered alkene with Wilkinson’s catalyst, in which imine served as a DG, thus giving a series of functionalized bicyclic compounds [20]. Three years later, an asymmetric variant of these reactions was developed by using a chiral phosphine ligand, leading to the first highly enantioselective catalytic reaction involving aromatic C—H bond activation [21]. Ligand screening for rhodium-catalyzed cyclization of ketimine 13a suggested

8.2 Intramolecular Couplings

DG

DG LnRh(I)

*

R R

Reductive elimination

Oxidative addition DG

DG

Rh(III) Ln H

Rh(III) H Ln

R

R

Insertion

Coordination

DG Rh(III) Ln

H R

Scheme 8.3 General catalytic cycle for Rh(I)/(III)-catalyzed intramolecular C–H activation. Me

[Rh(COE)2Cl]2 (5 mol%) (R,S)-PPFOMe (30 mol%) N

N

Four samples R 75–84% yields, 25–82% ee

11

12

R

OMe Fe PPh2 (R,S)-PPFOMe N

N

*

12a (120 °C) 78%, 28% ee

N

*

Et 12b (120 °C) 82%, 45% ee

N

*

12c (120 °C) 84%, 25% ee

N

* Et

12d (50 °C) 75%, 82% ee

Scheme 8.4 Rh-catalyzed asymmetric intramolecular cyclization of 1,5-dienes.

that phosphoramidite L4 embedded in chiral binaphthyl backbone provided the best enantioselectivity, generating imine-substituted indane 14a in 94% yield and 95% ee. The phosphoramidite/Rh ratio was optimized as 1.5 or 1, and higher ratios significantly slow the reaction rate without affecting enantioselectivity, suggesting that only one ligand is coordinated to the rhodium center. A series of ketimines having a tethered terminal alkene performed also well in this catalytic system, leading to chiral annulated products in high yield (90–95%) and excellent enantioselectivity (70–96% ee). In 2008, Ellman, Bergmann, and coworkers extended the scope of the reaction toward nonterminal alkenes, which are more difficult substrates for enantioselective C–H cyclization as Z/E isomerization may compete with the cyclization reaction [22]. The combination of [Rh(COE)2 Cl]2 and H8 -binol-derived phosphoramidite L5 was identified as

197

198

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

the optimal catalyst. 1,2-Disubstituted and 1,1,3-trisubstituted alkenes could thus undergo an enantioselective intramolecular hydroarylation via directed C–H activation, affording a range of chiral dihydrobenzofurans (14e–h) in high yields and high enantioselectivities (89–93% ee). In all cases, the reaction gave only the syn-isomer products, irrespective of alkene configuration, indicating that an isomerization event precedes the cyclization event (Scheme 8.5). BnN R2 X

[Rh(COE)2Cl]2 (5 mol%) Ligand (15 mol%)

R1

O P NR O

BnN R2

50–125 °C X = CH2, O

X

13

14

O P NR O

R1 R = (R)-(CHCH3Ph)2 L4

L5a: R = (R)-(CHCH3Ph)2 L5b: R = (iPr)2

For teminal alkenes (L4, toluene) BnN

BnN

BnN

BnN Ph

14a, 94%, 95% ee

14b, 96%, 90% ee

N

O

14c, 90%, 70% ee

14d, 95%, 96% ee

BnN

BnN

For nonteminal alkenes (dioxane) BnN

BnN Ph

O 14e, L5b 82%, 90% ee

O 14f, L5b 93%, 87% ee

O 14g, L5a 40%, 89% ee

O 14h, L5a 80%, 93% ee

Scheme 8.5 Rh-catalyzed asymmetric intramolecular cyclization via imine-directed C–H activation.

This methodology has been applied in the enantioselective synthesis of a biologically active dihydropyrroloindole 17 [23], a protein kinase C (PKC) inhibitor selective for isozyme β [24]. A short screening suggested that bis-(trifluoromethyl)benzyl imine was the best DG, which enabled a highly enantioselective C–H cyclization of indole compound 15. A key intermediate 16 was accessed in 61% yield and 90% ee after C–H cyclization and imine hydrolysis. The final PKC inhibitor 17 could be obtained through decarbonylation, substitution of indole at C3 position, C–N coupling, and deprotection processes (Scheme 8.6). In 2009, Ellman, Bergmann, and coworkers described that the enantioselectivity of an intramolecular C–H alkylation of substituted imidazoles could also be achieved using [Rh(COE)2 Cl]2 and (S,S′ ,R,R′ )-TangPhos ligand [25]. In this case, the alkene was tethered at 1-position of imidazole, and C–H activation occurred at C2. Under optimized conditions, the C–H alkylation of N-allylic imidazoles 18 having electron-poor and electron-rich substituents afforded the corresponding 5,5-fused ring products 19 with up to 92% yield and 98% ee, despite the high temperatures necessary for reaction (Scheme 8.7). The authors speculated that partial ligand dissociation to form a monodendate diphosphine may occur yet liberating a vacant coordination site.

8.2 Intramolecular Couplings RN

H

O

[Rh(COE)2Cl]2 (10 mol%) ent-L4 (20 mol%) Toluene, 90 °C

N 15

OMe

H Rh(DPPP)2Cl (5 mol%)

N

Then 10% AcOH/THF 61%, 90% ee

16

N

Xylene, reflux 86%

MeO

MeO

R = 3,5-(CF3)2-benzyl O

Br

P N

NP Br

Br

O K2CO3, THF, 85 °C 75%

O

O N H

Then CH3SO3H, CH2Cl2, 61%

N

P = 2,4-(OMe)2-benzyl

H N

Pd(OAc)2 (5 mol%) (R)-Binap (7.5 mol%) Aniline, Cs2CO3, toluene 62%

O

O

Ph

N OMe 17 PKC inhibitor

MeO

Scheme 8.6 Enantioselective synthesis of a PKC inhibitor via C—H bond activation.

[Rh(COE)2Cl]2 (10 mol%) (S,S′′,R,R′)-TangPhos (19 mol%)

N 18

THF, 135–175 °C 10 samples 71–92% yields, 53–98% ee

N

N

*

H

N 19

P t Bu H tBu P

(S,S′,R,R′)-TangPhos

Ph N

*

N 19a, 89%, 98% ee

N

*

N 19b, 91%, 97% ee

N MeO

*

N

19c, 92%, 81% ee

Ph

N

Ph

N

*

19d, 90%, 95% ee

Scheme 8.7 Rh-catalyzed enantioselective C–H cyclization of substituted imidazoles.

Over the past years, rhodium(III) complexes having a cyclopentadienyl ligand have been recognized as competent catalysts for chelation-assisted C–H functionalization reactions [2, 3, 5]. Enantioselective variants of these reactions became possible with the development of half-sandwich rhodium complexes bearing a chiral cyclopentadienyl ligand [10, 11]. In 2014, Cramer reported a mild enantioselective rhodium(III)-catalyzed intramolecular hydroarylation of aryl hydroxamates 20 to access functionalized dihydrobenzofurans 21 possessing a quaternary stereocenter with very good enantioselectivities (82–94% ee) [26]. The half-sandwich rhodium(I) complex Cat-1, bearing a monocyclopentadienyl ligand embedded in chiral binaphthyl backbone, was estimated as the optimal catalyst. A possible reaction mechanism for the present asymmetric C–H activation is proposed. Through ligand oxidation reaction with (BzO)2 and ligand exchange reaction with PivOH, Rh(I) complex Cat-1 can be converted to a Rh(III) complex Cpchiral Rh(OCOt Bu)2 , which then reacts with 20 to give a mixture of cyclized rhodium species through the reversible carboxylate-assisted concerted metalation–deprotonation (CMD) process.

199

200

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

The intramolecular coordination of an alkene unit to the metal center, followed by migratory insertion, gives bicyclized rhodium species, which undergoes reductive elimination to give the final product 21 with the regeneration of the catalyst. Although C–H activation is usually favored at less hindered ortho position (C6), reversibility of the C–H cleavage allows the equilibration toward the more sterically hindered metallacycle at C2 position, which is directly converted into the cyclized dihydrofurans. Besides the meta-alkoxy group in substrates acts as a secondary DG allowing a selective reaction at the more hindered ortho position (Scheme 8.8). One year later the OMOM derivative Cat-2 with the same ligand scaffold was used for the intramolecular coupling of aldehydes 22, which gave hydroxychromanes 23 in 45–98% yield and up to 85% ee [27]. The tricyclic phthalides 24, a common motif in many biologically active compounds, could be produced via subsequent lactonization step occurring at higher temperatures (Scheme 8.8). Transition metal-catalyzed reactions involving C—H and C—C bonds provide an access to unique organic transformations that would otherwise be difficult to achieve. In 2009, Cramer group [28] and Murakami group [29] independently reported the enantioselective rhodium-catalyzed synthesis of indanols from tert-cyclobutanols 25 through a cascade C—C/C—H bond activation catalyzed by rhodium complexes bearing bidentate chiral phosphine ligands L6 and L7, respectively. As a consequence, a series of indanol derivatives 26 were prepared in an enantio- and diastereoselective fashion. The proposed reaction pathway is initiated by the formation of a rhodium alkoxide species 27, which undergoes β-carbon elimination to give alkyl-rhodium species 28. Subsequent 1,4-Rh shift involving C—H bond activation forms a more stable Rh-aryl species 29. Final intramolecular migratory insertion of the carbonyl generates the quaternary stereocenter 30. This rhodium alkoxide then serves as a base to react with another cyclobutanol molecular, together with releasing indanol 26 as a product (Scheme 8.9) [28]. 8.2.3

Iridium Catalysis

Iridium-catalyzed intramolecular enantioselective C—H bond functionalization commonly proceeds through an Ir(I)/Ir(III) mechanism, which starts from a directed C–H oxidative addition, followed by selective coordination of a π-bond. Subsequent insertion of π-bond into Ir—C bond gives an expanded metallacycle. Reduction elimination affords final product and regenerates the catalyst (Scheme 8.10). In 2009, Shibata group reported the iridium-catalyzed synthesis of 4-substituted benzofurans and indoles through a directed C–H cyclization of α-aryloxy ketones and α-arylamino ketones [30]. An enantioselective variant of this reaction via an intramolecular C–H cyclization of 31 (where R1 = R2 = Me) was also reported. The combination of Ir(COD)2 (BArF 4 ) and (S)-H8 -binap as catalyst promoted the formation of 4-acetyloxindole 32a in 69% yield and 72% ee (Scheme 8.11). Five years later, Yamamoto and coworkers disclosed asymmetric intramolecular direct hydroarylation of 31, which gave a variety of enantioenriched 3-substituted 3-hydroxy-2-oxindoles in high

8.2 Intramolecular Couplings

O

O

6

N H

2

OMe

Cat-1 (5 mol%) (BzO)2 (5 mol%) PivOH, CH2Cl2, 23 °C

R

O

N H

*

Cat-1: R = OMe

HO

OMe

N H O

OBn

21a, 86%, 91% ee

*

OMe

N H O

OBn

21b, 64%, 84% ee

N H

N Rh

21d, 80%, 92% ee

Cpchiral

OMe

Rh

2

O

OMe

*

O

OAc

O

6

2

R

*

OMe

21c, 72%, 88% ee

Proposed mechanism O 6 OMe N CpchiralRh(OCOtBu)2 H O

O

O

O

O

O

R

21

20

Rh

R

*

O

R

OMe

N H

Cpchiral

OMe

N

6

+

O 2

R

R

O

Productive pathway O N Rh O

OMe

O

Cpchiral O

O

OMe N Rh Cpchiral

OMe

N H

R

O

R

R CpchiralRh(ethylene)2 Cat-1

(BzO)2

CpchiralRh(OBz)2

O OiPr Cat-2 (5 mol%) N (BzO)2 (5 mol%) H CHO DCE, 23 °C R1 O R2 22

PivOH

NHOiPr

O

O OH O

* 23

R1 R2

CpchiralRh(OCOtBu)2

R

O O

* 24

R R1 R2

Rh

Cat-2: R = OMOM

Scheme 8.8 Chiral half-sandwich Rh-catalyzed asymmetric intramolecular C–H cyclization of hydroxamates.

yields (69–99%) with complete regioselectivity and high enantioselectivities (80–98% ee) [31]. In this case, (R,R)-Me-BIPAM was used as a chiral ligand, and CONMe2 was employed as a DG. A plausible reaction mechanism for this reaction was proposed by Yamamoto group [31, 32]. A cationic Ir–H species [Ir(R,R)-Me-BIPAM](BArF 4 ) such as 33 with coordination of the two carbonyl groups of the amide can be formed by the direct oxidative addition of 31. Asymmetric hydroarylation of the ketone carbonyl group proceeded from 34 producing enantiomerically enriched iridium-alkoxide species 35, which liberates product 32 via reductive elimination with a concomitant regeneration of the active iridium catalyst (Scheme 8.11). Further mechanistic studies suggested that

201

202

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

OH R2

R1

HO

[Rh(COD)(OH)]2 (2.5–5 mol%)

R1

H

*

Ar2P

PtBu2

Fe

Me

R2

L6 or L7 (6–11 mol%) 26

25

F F

O

F

O

F

O

O

L6 Ar = 4-CF3C6H5

PPh2 PPh2

L7

Cramer: L6, toluene, 110 °C Murakami: L7, Cs2CO3, dioxane, 50 °C [Rh] [Rh]

[Rh]

[Rh]

O

O R2

R1

R2

R1 27

28

HO

n

N

*

R2

Et

*

26 R2 30

HO

HO OBn

* Ph

26a Cramer: 95%, 93% ee Murakami: 95%, 86% ee

26b (Cramer) 74%, dr = 91 : 9 96% ee

R1

R1

29 HO

Bu

O

O

Ph 26c (Cramer) 97%, 97% ee

Bu

* Bn 26d (Murakami) 98%, dr = 93 : 7 99% ee

Scheme 8.9 The synthesis of chiral indanols through Rh-catalyzed C–H/C–C activation of tert-cyclobutanols.

DG

DG LnIr

*

(I)

Reductive elimination

Oxidative addition DG

DG (III)

Ir

(III)

Ir H Ln

Ln H

Insertion

DG (III)

Ir

Coordination

Ln

H

Scheme 8.10 General catalytic cycle for Ir(I)/(III)-catalyzed intramolecular C–H functionalization.

8.2 Intramolecular Couplings

R1 O

O

O

H N

R2 O

Ligand (5 mol%) 135 °C

31

H O

R2

O [Ir] NH

Me2N

H O

O

[Ir]

Shibata and coworkers [30]: R1 = Me, (S)-H8-Binap, PhCl 1 example, 69%, 72% ee Yamamoto and coworkers [31]: R1 = NMe2, (R,R)-Me-BIPAM, DME 24 examples, 69–99%, 80–98% ee H

+ O

O NH

Me2N

O HO

Ph

O

O N H

F3C

Yamamoto 32b, 99%, 98% ee

Yamamoto 32c, 96%, 91% ee

+

32

O HO Et O

F3C

N H

Yamamoto 32d, 95%, 92% ee

O O

O P O

O P NMe2 (S)-H8-Binap

Me2N

O HO

Ph

PPh2 PPh2

[Ir] O O

35

N H

N H

R2

NH

Me2N

34

O Shibata 32a, 69%, 72% ee

R2

O

Me2N

Me2N

HO

OH R2 O N H

32

+

33 O

R1

Ir(COD)2(BArF4) (5 mol%)

Me2N

(R,R)-Me-BIPAM

Scheme 8.11 Ir(I)/(III)-catalyzed asymmetric intramolecular C–H addition to ketones.

the migratory insertion step is both the rate-limiting and enantiodetermining event. In 2015, Shibata reported that cationic iridium species with a chiral phosphine ligand could serve as an efficient catalyst for intramolecular C–H addition of N-alkenylindoles 36, which selectively gives chiral tricyclic indoles 37 and 38 in high yield with excellent enantioselectivity [33]. The 4-methoxyphenyl ketone group at the C3 position of the indoles operated as an efficient DG, resulting in exclusive alkylation at C2 position. In the case of alkenes having a small substituent, such as H or Et, the reaction gave 5-exo-cyclized products 37 in good to excellent enantioselectivities (up to 98% ee), wherein (S)-SEGPHOS was used as a chiral ligand. When phenyl-substituted alkene was used as a substrate, a 6-endo-cyclized indole 38 was obtained as the sole product in 98% yield with 84% ee in the presence of (S)-xylylBINAP ligand (Scheme 8.12). 8.2.4

Enantioselective Hydroacylation

Transition metal-catalyzed intramolecular hydroacylation has emerged as an atom-economical and efficient method for the synthesis of various carbocycles in an enantioselective manner [34–36]. The general reaction pathway starts with oxidative addition of an aldehyde C(sp2 )—H bond with a metal center to yield an acyl-metal hydride species. Coordination of a π-bond (C=C or C=O) with

203

204

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization Ar

O

O

R = H, Et Ar

O R

(S)-SEGPHOS 11 examples Ir(COD)2OTf 61–86% yields 37–98% ee (10 mol%)

O

N 37

N

Ar

36

R

O

O (S)-SEGPHOS

O

R = Ph

Ar = 4-MeOC6H5

Ph

(S)-xylylBINAP 98%, 84% ee

PPh2 PPh2

PAr2 PAr2

N (S)-xylylBINAP Ar = 3,5-xylyl

38

Scheme 8.12 Ir-catalyzed asymmetric C–H cyclization of indoles.

metal center, followed by insertion of π-bond into M–H, gives a metallacycle, which affords the final product and regenerates the catalyst through reductive elimination (Scheme 8.13). O

O H [M]

Reductive elimination

Oxidative addition O

O H

[M]

[M]

H

O Coordination

Insertion [M] H

Scheme 8.13 General catalytic cycle of intramolecular hydroacylation.

A pioneering work by Sakia and coworkers reported the first catalytic hydroacylation reaction in an enantioselective fashion in 1989 [37]. In the presence of [Rh(COE)2 Cl]2 (25 mol%) and (+)-DIPMC (50 mol%), 4-pentenals 39 having n Bu, t Bu, and Ph substituents were converted to the corresponding cyclopentanones 40 in 68–78% yields with 73–77% ee (Table 8.1, entry 1). Several years later, a cationic rhodium complex with a bidentate chiral ligand,

8.2 Intramolecular Couplings

Table 8.1 Rh-catalyzed intramolecular hydroacylation in an enantioselective fashion. O

O H

* R

R

Author

Substrate

Product

Catalyst

Description

1

Sakai

[Rh(COE)2Cl]2 (25 mol%) (+)-DIPMC (50 mol%)

R= nBu, Ph, tBu 3 samples 68–78%, 73–77% ee

2

Sakai

[Rh(R or S)-BINAP]ClO4 (5 mol%)

R = alkyl 6 samples 74–95%, 67–99% ee

[Rh(S)-BINAP]ClO4 or [Rh(S,S)-Chiraphos]ClO4 (4 mol%)

R = alkyl, ketone, silane 19 samples about 90%, 60–99% ee

O

O H

3

Bosnich

4

Suemune

[Rh(S)-BINAP]ClO4 (10 mol%)

R = aryl 14 samples 51–95%, 18–87% ee

5

Carreira

[Rh(C2H4)2Cl2]2 (4 mol%) L8 (8 mol%) PMe(tBu)2 (8 mol%) AgSbF6 (8 mol%)

R = aryl, alkyl 11 samples 54–90%, 80–97% ee

6

Morehead

[Rh(R)-BINAP]ClO4 (1 mol%)

R = aryl, alkyl, silane 8 samples 89–98%, 70–99% ee

CoCl2 (10 mol%) (R,R)-BDPP (10 mol%) Zn (50 mol%)

R = aryl, alkyl 5 samples 81–95%, 81–97% ee

* 40 R

39 R

O

O H

7

Yoshikai

8

Scanlon and Stanley

* 45 R

44 R O

O H

H

X

46

n

H 47

[Rh(COD)Cl]2 (2.5 mol%) (R)-DTBM-SEGPHOS (5 mol%) NaBArF4 (5 mol%) X n

O

9

Stanley

N

O N

H

48 R

*

49 R

O

R = aryl, alkyl 15 samples 45–99%, 82–99% ee

[Rh(COD)Cl]2 (2.5 mol%) (S)-MeO-BIPHEP (5 mol%) AgBF4 (5 mol%)

O

10 Stanley

* R 50

51

[Rh(COD)Cl]2 (2.5 mol%) (R)-DTBM-SEGPHOS (5 mol%) R NaBArF4 (5 mol%)

R = aryl, alkyl 14 samples 49–91%, 96–99% ee

O

R = aryl, alkyl 25 samples 23–98%, 92–99% ee

O

11 Stanley

X = CH2, O; n = 1, 2 8 samples 56–91%, 82–99% ee

N

N

52

53 R

R PPh2 PPh2 (+)-DIPMC

[Rh(COD)Cl]2 (2.5 mol%) (R)-Tol-BINAP (5 mol%) AgBF4 or AgSbF6 (5 mol%)

PPh2

PPh2

PPh2

PPh2 (S,S)-Chiraphos

O

(R,R)-BDPP

O O

PAr2 PAr2

Ar = Ph, (R)-BINAP 4-Me-C6H4, (R)-Tol-BINAP

PPh2 PPh2

O P N O

MeO MeO

L8

(S)-MeO-BIPHEP

PAr2 PAr2

O Ar = 3,5-(tBu)2-4-OMe-C6H2 (R)-DTBM-SEGPHOS

205

206

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

[Rh(R or S)-BINAP]ClO4 , was utilized at low catalytic charge (5 mol%), in asymmetric cyclization of 39 bearing primary, secondary, and tertiary alkyl substituents, which afforded chiral cyclopentanones in enantiomeric excesses ranging from 65% to 99% (Table 8.1, entry 2) [38]. Catalytic intramolecular hydroacylation of 4-substituted 4-pentenals were also reported by Bosnich with [Rh-BINAP]ClO4 [39]. Complete conversion of 4-pentenals having alkyls, esters, and ketones to the corresponding cyclopentanones with 69–99% ee was achieved, while in the case of 4-aryl-substituted substrates, application of (S,S)-Chiraphos as chiral ligand offered improved enantioselectivity (65–78% ee) (Table 8.1, entry 3). In 2011, the phosphoramidite–alkene ligands were also employed for rhodium-catalyzed hydroacylation of 4-pentenals for the first time by Carreira and coworker [40]. Ligand screening indicated that phosphoramidite L8 in combination with an achiral phosphine coligand gave cyclopentanones in good yield and excellent selectivity (Table 8.1, entry 5). In 2008, Castillón group demonstrated a new procedure for the total synthesis of a carbocyclic nucleoside 43, involving an enantioselective rhodium/DuPHOS-catalyzed synthesis of a chiral cyclopentanone 42 (85% yield, 95% ee) through the hydroacylation reaction of silyl ether 41 as the key step (Scheme 8.14) [41]. O

[Rh(S,S)-Me-DuPhos(NBD)]BF4 OH (5 mol%)

OTBS

NBD = Norborna-2,5-diene

H 2N

N OH

Acetone, reflux 85%, 95% ee 41

N

O

N 42

OTBS

N

Carbocyclic-ddA 43

Scheme 8.14 Total synthesis of a carbocyclic nucleoside through enantioselective hydroacylation.

Chiral indanones are very useful molecules for the synthesis of biologically active compounds. In 2005, Morehead group demonstrated that [Rh(R)-BINAP]ClO4 (2 mol%) could serve as an efficient catalyst for asymmetric hydroacylation of 2-alkenylbenzaldehydes 44, thus leading to formation of a series of chiral 3-substituted indanones 45 in 88–98% yields and 70–99% ee (Table 8.1, entry 6) [42]. In 2014, Yoshikai and coworker reported that this transformation could also be achieved by Co(I) catalyst in a stereoselective version, where Zn was used to reduce CoCl2 precatalyst and (R,R)-BDPP was used as a chiral ligand [43]. Methyl, ethyl, phenyl, and 4-fluorophenyl moieties were tolerated furnishing the corresponding indanones 45 in 81–95% yields and 81–97% ee, while the 2-alkenylbenzaldehydes having methoxy group or 4-pentenals completely shut down the reaction. Mechanistic studies indicated that the catalytic cycle consists in (i) C–H oxidative addition, (ii) insertion of the C=C bond into the Co—H bond, and (iii) C–C reductive elimination (Table 8.1, entry 7). The intramolecular hydroacylation of 1,1,2-trisubstituted alkenes 46 in an asymmetric mode was also reported by Scanlon and Stanley in 2016, by using the combination [Rh(COD)Cl]2 (2.5 mol%), (R)-DTBM-SEGPHOS (5 mol%) and Na(BArF 4 ) (5 mol%) [44]. This reaction implies hydroacylation and

8.2 Intramolecular Couplings

α-epimerization processes, thus generating cis-tetracyclic ketone products 47 in 56–91% yields with 82–99% ee (Table 8.1, entry 8). In 2014, Stanley group used a cationic rhodium species with (S)-MeO-BIPHEP for hydroacylation of N-vinylindole-2-carboxaldehydes 48 in an enantioselective manner, leading to formation of enantioenriched pyrrole- and indole-fused cyclic ketones 49 (95–99% ee) (Table 8.1, entry 9) [45]. Recently, this group applied this methodology toward the synthesis of the putative structure of the natural product yuremamine. In the key step, N-vinylindole 48a was cyclized under previous conditions, giving dihyropyrroloindolone 49a in 90% yield and 97% ee (Scheme 8.15) [46]. OTBS N

OTBS

CO2Et

CHO N

(1) DIBAL-H, –78 °C MeO MeO

(2) MnO2, rt OMe

MeO MeO

OMe

[Rh(COD)Cl]2 (2.5 mol%) (R)-MeO-BIPHEP (5 mol%)

OTBS O N

AgBF4 (5 mol%) THF, 60 °C, 12 h MeO 90%, 97% ee MeO

48a

OMe 49a

NMe2 OH

N

OH OH

HO OH HO Yuremamine

Scheme 8.15 Total synthesis of yuremamine via Rh-catalyzed enantioselective hydroacylation.

In 2015, Stanley described the catalytic hydroacylation of benzaldehyde 50 having an allyl group at ortho position by rhodium(I)/(R)-DTBM-SEGPHOS, which gave six-membered products 51 in an endo and enantioselective fashion (Table 8.1, entry 10) [47]. In the case of rhodium-catalyzed hydroacylation of N-allyl-substituted indoles or pyrroles 52, (R)-Tol-BINAP could serve as a chiral ligand, generating the corresponding six-membered indole or pyrrole derivatives 53 in 23–98% yields and 92–99% ee (Table 8.1, entry 11). The nonsteroidal aromatase inhibitor MR 20492 could be rapidly synthesized by using current enantioselective hydroacylation reaction (Scheme 8.16) [48]. In 2009, Dong and coworkers reported enantioselective synthesis of seven- and eight-membered heterocycles via Rh-catalyzed intramolecular hydroacylation of alkenes containing a heteroatom (such as O or S) (Scheme 8.17) [49]. In the case of terminal or 1,2-disubstituted alkenes 54, seven-membered cyclic ketones 55 were

207

208

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

CHO

O

CHO

O

N

N

N

N

N

See Table 8.1, Entry 11

Bu4HSO4 (20 mol%) NaOH, CH2Cl2, rt 57% yield

85% yield 95% ee Cl

Cl

Cl

(S,Z)-MR 20492

Scheme 8.16 The synthesis of nonsteroidal aromatase inhibitor MR 20492. O

O H X 54 X = O, S

R

[Rh-(R,R)-Me-DuPhos]BF4 (5 mol%) or

O

* X 55 O

[Rh-(R)-DTBM-SEGPHOS]BF4 (5 mol%)

H S

R

80–97% yields, 93–98% ee

n

n = 1, 85%, 99% ee n = 2, 86%, 93% ee

56 n = 1, 2 Proposed reaction pathway Rh = [Rh-chiral ligand]+ O R=H

Rh S

* S 57

n

O

O H Rh S

S

O H S

R O H

O

Rh R = Me

S

O

Rh S S

Scheme 8.17 Heteroatom-assisted intramolecular hydroacylation by rhodium catalysts.

obtained in 80–97% yield and 93–98% ee. 1,1-Disubstituted thioether tethered alkenes 56 are also suitable substrates, which could be converted to corresponding seven- and eight-membered products 57 in a chemio- and enantioselective version. Mechanistic studies indicated that the presence of an heteroatom is crucial for the reaction. It is believed that the heteroatom coordinates with rhodium center to promote the alkene hydroacylation over competing pathways, such as olefin isomerization, aldehyde decarbonylation, and catalyst decomposition. The current hydroacylation proceeds via C–H oxidative addition, alkene insertion,

8.2 Intramolecular Couplings

and reductive elimination to afford seven- and eight-membered-ring regioisomers, and the reductive elimination is not involved in the rate-determined step. The heteroatom-assisted strategy is also suitable for rhodium-catalyzed enantioselective ketone hydroacylation as reported by Dong and coworkers [50–52]. Catalytic intramolecular C–H addition of aldehyde to C=O tethered with an ether or thioether units was achieved with [Rh-(R)-DTBM-SEGPHOS]BF4 in an asymmetric manner, leading to formation of seven-membered ring analogues 59 in up to 99% ee (Scheme 8.18) [51, 52]. The basicity of the phosphine ligand plays a critical role in promoting hydroacylation over competitive decarbonylation. By using amines as a coordinating group, more efficient hydroacylation of 60 was observed as compared with the ether and sulfide analogues [52]. Seven-membered benzo[e][1,4]oxazepinones 61 (where n = 1) could be isolated with [Rh(R)-3,4,5-OMe-MeOBIPHEP]BF4 in 85–91% yields with 50–99% ee; while [Rh(R)-DTBM-SEGPHOS]BF4 could serve as efficient catalyst for synthesis chiral eight-membered benzo[c][1,5]oxazecinones 61′ (where n = 2) in high yields and enantioselectivities. Mechanistic studies suggested that the reaction proceeds via the same elementary steps as for alkene coupling partners and that ketone insertion is rate limiting (Scheme 8.18) [51]. O O

O

[Rh-(R)-DTBM-SEGPHOS]BF4 (5 mol%)

H O

X

X

O

O

[Rh-(R)-3,4,5-OMe-MeOBIPHEP]BF4 (5 mol%) H n = 1, 85–91% yields, 50–99% ee O N n [Rh-(R)-DTBM-SEGPHOS]BF4 R (5 mol%) 60 (n = 1) n = 2, 84–99% yields, 88–99% ee 60′ (n = 2)

O * N

(R)-3,4,5-OMe-MeOBIPHEP Ar = 3,4,5-(OMe)3C6H2 O

O

S

92%, 99% ee

94%, 99% ee

93%, 99% ee

N

86%, 93% ee

95%, 96% ee

n = 2, eight-membered product

O

O O Ph

Ph

Bu

N

O

n = 1, seven-membered product

O n

Ph

Bu

O

O O

t

Ph

Ph

n

O

O

PAr2 PAr2

MeO MeO

R

61 (n = 1) 61′ (n = 2)

O

O

O O P Rh P H O

O (R)-DTBM-SEGPHOS Ar = 3,5-(tBu)2-4-OMe-C6H2

59

O

PAr2 PAr2

O

R

15 samples 14–99% yields, 32–99% ee

R 58 X = O, S

O

O

O

O N P Rh P H O Ph

Scheme 8.18 Heteroatom-directed intramolecular ketone hydroacylation.

O N

Ph

209

210

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

8.3 Intermolecular Couplings A number of intermolecular enantioselective C–H functionalization have been established with metal catalysts, including Rh, Ir, Pd, Ni, and rare earth. Similar to intramolecular case, a DG is often employed in metal-mediated C–H activation to form a metallacyclic intermediate. Stereoselective coordination of an unsaturated coupling partner to the metal center and subsequent insertion gives an expanded metallacycle, which undergoes reductive elimination furnishing a chiral product and the regeneration catalyst. 8.3.1

Rhodium Catalysis

The chiral ligand is crucial for rhodium-catalyzed enantioselective C–H activation, especially for the functionalization of metallacyclic intermediates. In Rh(I)/Rh(III) catalytic system, a chiral bidentate phosphine ligand is commonly employed to induce stereoselection [3], while in Rh(III)-catalyzed C–H reactions, the chiral cyclopentadienyl ligated complexes are rather used [10, 11]. Imine is an efficient DG for intramolecular enantioselective C–H activation, which could also been used in intermolecular reactions. In 2010, Cramer and coworkers reported an example of imine-directed enantioselective C–H activation by using Rh(I) and chiral ligand (R)-3,4,5-OMe-MeOBIPHEP [53]. The reaction of electron-poor ketimine 62 with ethyl 2,3-butadienoate gave a lactam 63 in 60% yield and 68% ee. The reaction starts with the cyclometalation of the imines 62 with [Rh(COD)(OH)]2 . Then coordination of the allene followed by its insertion into C—Rh bond gives rhodium alkyl 65a, which could convert to allyl-rhodium species 65b. Subsequent nucleophilic allylation of the imine moiety, the stereocontrolled step, affords rhodium amido 66, which generates final product 63 and releases Rh(I) species (Scheme 8.19).

NH Ph O2N

+

[Rh(COD)(OH)]2 (5 mol%) CO2Et Ligand (6 mol%) Toluene, 100 °C O2N

62

Ph

Ph

[Rh] 64

O 2N

H 63 60%, 68% ee

O PAr2 PAr2

MeO MeO

(R)-3,4,5-OMe-MeOBIPHEP Ar = 3,4,5-(OMe)3C6H2 Ph HN [Rh]

NH [Rh]

EtO2C 65a

H N

Ph

NH

NH O 2N

Ph

O 2N EtO2C

[Rh] 65b

H

O2N

CO2Et

61

66

Scheme 8.19 Rh(I)-catalyzed enantioselective cyclization of ketamine with ethyl 2,3-butadienoate.

In early 2010, Zhao and coworkers described the synthesis of racemic indenamines via Rh(I)-catalyzed C–H annulation of ketimines 67 with alkynes [54]. An enantioselective example was also reported in the presence of (R,R)-DIOP

8.3 Intermolecular Couplings

ligand, leading to the corresponding product 68a in 65% yield and 51% ee (Scheme 8.20). One year later, Cramer used (S)-DTBM-MeOBiphep as a chiral ligand to provide a series of enantioriched indenamines 68 in 49–90% yields with 76–96% ee (Scheme 8.20) [55]. Zhao proposed that the catalytic cycle is initiated by the formation of the metallacycle 69 via imine-directed ortho-C—H bond activation of ketimine. Insertion of alkyne into Rh—C bond generates an alkenyl-rhodium species 70, which can form an indene-based amido complex 71 through intramolecular cyclization. Subsequent proton exchange releases the final product 68 and regenerates the catalyst [54]. R1

NH +

R1

NH2

R3

68 R 2

67

Ph2P

Zhao: [Rh(COD)(OH)]2 (2.5 mol%) (R,R)-DIOP (6 mol%), 1 sample Cramer: [Rh(COE)2(OH)]2 (2.5 mol%) (S)-DTBM-MeOBiphep (6 mol%) 19 samples, 43–90% yields, 76–96% ee R1

R1

[Rh]

R2

69 Ph

NH2

Ph

[Rh] NH R3

R3

71 R2 Ph

NH2 OMe

68a (Zhao) 65%, 51% ee

OMe 68b (Cramer) 81%, 84% ee

O2 N

S OMe 68c (Cramer) 89%, 93% ee

PAr2 PAr2

MeO

(S)-DTBM-MeOBiphep Ar = 3,5-(tBu)2-4-OMeC6H2 Ph

NH2

Ph Ph

PPh2

MeO R1

70

O

(R,R)-DIOP

NH [Rh]

NH

O

R3

R2

N

NH2 OMe

OMe 68d (Cramer) 74%, 80% ee

Scheme 8.20 Enantioselective Rh(I)-catalyzed C–H annulation of ketamines with alkynes.

Rhodium-catalyzed enantioselective C–H functionalization of ketones 72 with enynes, where carbonyl group played the role of a DG, was independently reported by Shibata group [56] and Tanaka group [57] in 2007 and 2008, respectively (Scheme 8.21). The earlier work by Shibata and coworkers used a cationic [Rh(S)-Binap]BF4 as a catalyst, giving the corresponding cyclization products 73 through aryl and alkenyl C—H bond activation in excellent enantioselectivity [56]. Tanaka group employed the combination of Rh(COD)2 BF4 with ether (R)-H8 -Binap or (R)-Binap, which could catalyze C–H functionalization of aromatic ketones 72 with enynes in an enantioselective manner [57]. The mechanism for this reaction was speculated by Shibata and coworkers [56], which is initiated by formation of a Rh(III)–H species 74 via carbonyl-directed oxidative addition. An intermolecular hydrorhodation of the alkyne moiety in enyne with 74 gives 75, which generates a rhodacycle 76 via intramolecular carborhodation. Subsequent reductive elimination releases product and regenerates catalyst. In 2015, Rovis group described the Rh(I)−bisphosphine-catalyzed asymmetric C–H addition of benzoxazoles 77 to α-substituted acrylates, leading to the formation of 2-alkylated benzoxazole derivatives 78 in moderate to excellent

211

212

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

H

R2

O

72

Z

Z

*

PPh2 PPh2

73 O Shibata: [Rh(S)-Binap]BF4 (5 mol%) Four samples, 37–76% yields, 91–97% ee Tanaka: [Rh(COD)2]BF4 (5 mol%) (R)-Binap or (R)-H8-Binap (5 mol%) Three samples, 34–55% yields, 94–98% ee R1 O R2 H

H Rh

R2

+

R1

O

Z

Rh

75

(R)-Binap

PPh2 PPh2

Z Rh

R1 74

R1

76

R1

O

(R)-H8-Binap

R2

Ph TsN

TsN

*

O Ph 73a Shibata: 69%, 92% ee Tanaka: 55%, 96% ee

BnO2C

*

EtO2C

Ph

*

BnO2C

EtO2C

O

O Ph 73c Shibata: 76%, 96% ee

O Ph 73b Shibata: 45%, 91% ee

OMe

*

73d Tanaka: 34%, 94% ee

Scheme 8.21 Enantioselective C–H cycloaddition of ketones with 1,6-enynes by cationic Rh(I) catalysts.

yields and good to excellent enantioselectivities (Scheme 8.22) [58]. The reaction of 2-deuterated-4-methylbenzoxazole with ethyl methacrylate gave the corresponding product 78a-D with 96% ee with exclusive D-incorporation at the β-position. This result appears to contradict a mechanism involving migratory insertion of a Rh(III) aryl (such as 79) or Rh(III) hydride across acrylate followed

N

EWG +

R1 O

R2

77

[Rh(COD)(OAc)]2 (5 mol%) L9 (10 mol%)

R2 N

*

R1

CH3CN, 100 °C 15 samples 31–98% yields, 68–96% ee

OMe

EWG N

O 78

PAr2 PAr2

MeO MeO N

H [Rh] GWE N

N

[Rh] O

O 80 H

79

N

*

CO2Et

O 78a, 88%, 94% ee

R2

[Rh] R2

H

*

CO2Et

N

D (45%)

D

(54%)

78a-D, 47%, 96% ee

N

EWG R2 O 82

81

N O

N O

EWG

OMe L9, Ar = 3,5-xylyl

[Rh]

*

CO2Et

O 78b, 67%, 87% ee

MeO2C N

*

O OTBS 78c, 76%, 96% ee

Scheme 8.22 Rh(I)-catalyzed asymmetric intermolecular hydroheteroarylation of α-substituted acrylates.

8.3 Intermolecular Couplings

by reductive elimination, which would deliver products deuterated at the α-position. A series of mechanistic studies suggested that this reaction begins with the formation of a Rh(III)-aryl species 79 via reversible C–H activation. Migratory insertion of alkene into Rh—C bond furnished intermediate 80, which isomerizes via a β-H elimination, hydrorhodation sequence to give the benzyl-Rh species 82. Protonation of 82 generated the final product 78 with liberation of the rhodium. Since the first example of [RhCp*Cl2 ]2 -catalyzed C–H activation of arenes in 2007 by Miura, Satoh, and coworker [59], explosive progress has been made in this area. Half-sandwich rhodium complexes bearing a cyclopentadienyl ligand have become a powerful catalyst for direct C—H bond functionalization [2, 5]. In 2011, Fagnou and coworkers [60] and Glorius and coworkers [61] independently reported the Rh(III)-catalyzed C–H functionalization of hydroxamates 83 with alkenes, leading to the formation of dihydroisoquinolinone derivatives 84 having one or two chiral carbon centers. The chiral variant for this transformation was developed by Ward, Rovis, and coworkers [62] and Cramer and coworker [63] in 2012 (Scheme 8.23). Ward and Rovis developed a supramolecular strategy toward chiral Cp environment, where Cat-3 is generated in situ upon O

O N H

OR1 +

[Rh]

R2

Selected products (Cat-3) O

NH

* * R2

R3

83

NH

* CO Me 2

84 R3

84a: 95%, 82% ee

N OR1 Rh Cp′

N OR1 Rh 85

O

O

O

Cp′

R3

R2

Selected products O

R R3 87 2

86

O 2N

Rh Cl

2

Bioti n

Engineered streptavidin

Ward and Rovis R1 = Piv, Cat-3 (0.66 mol%) 6 samples 30–95% yields, 12–86% ee

C(O)Me 84b: 30%, 86% ee O

O Ph

NH H

**

H 84f Cat-4: 59%, 83% ee Cat-5: 80%, 84% ee

84e Cat-4: 81%, 86% ee Cat-5: 85%, 91% ee

2-Naph Me

Me

Spa

cer

O2N

** O H

* Ph

84d Cat-4: 76%, 93% ee Cat-5: 82%, 87% ee

84c Cat-4: 89%, 92% ee Cat-5: 89%, 90% ee

NH

*

NH H

NH

*

O

O

O

NH

Cl

OR1 N Rh Cp′

O Me

Ph

Rh

Cramer R1 = Boc, Cat-4 (2 mol%) 21 samples 59–91% yields 70–94% ee

Rh

CO2Me

N Me Me

Antonchick and Waldmann R1 =Boc, Cat-5 (5 mol%) 22 samples 42–93% yields 80–93% ee

Scheme 8.23 Rh(III)-catalyzed enantioselective reaction of hydroxamates with alkenes via C–H activation.

213

214

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

mixing of a Cp*Rh(III) biotin derivative with an engineered streptavidin protein in buffered methanol. Under optimized conditions, benzhydroxamic acids (where R1 = pivaloyl) reacted well with alkenes (where R2 = CO2 R, COR, R3 = H), providing enantioriched dihydroisoquinolinone derivatives 84 in 30–95% yield with up to 86% ee [62]. Cramer employed a C 2 -symmetric chiral cyclopentadienyl synthesized from d-mannitol to coordinate with [Rh(C2 H4 )2 Cl]2 , thus offering a family of chiral half-sandwich rhodium catalyst, including Cat-4. In the presence of benzoyl peroxide as an oxidant, Cat-4 is converted into the corresponding Cp′ Rh(III) species, an efficient catalyst for intermolecular stereoselective C–H annulation of benzhydroxamic acids (where R1 = Boc) with a wide variety of alkenes [63]. Following this work in 2017, Antonchick and Waldmann synthesized in three steps and on gram scale a new class of chiral Cp ligand embodying four adjustable positions. The corresponding [Cp′ Rh(C2 H4 )2 ] complexes Cat-5 could thus be obtained after metalation [64]. Further study indicated that Cat-5 showed high reactivity and enantioselectivity toward the reaction of benzhydroxamic acids (where R1 = Boc) and alkenes, yielding the corresponding products. The transformation was believed to begin with the formation of a five-membered rhodacycle such as 85 via a CMD pathway [60, 61]. Coordination of an alkene to Rh center forms 86, which undergoes migration insertion to give a seven-membered rhodium species 87. Subsequent reductive elimination gives the final product and regenerates rhodium catalyst. In 2013, Cramer group reported a class of cyclopentadienyl ligands based on chiral binaphthyl backbones and their corresponding rhodium-ethylene complexes [65]. Rhodium complex Cat-6 bearing a bulky group at 3,3′ -position of the binaphthyl unit in the Cp ligand showed high activity and selectivity in enantioselective C–H allylation of N-methoxybenzamides 88 with allenes (Scheme 8.24). O

O

R2

OMe N + R1 H 88

*

NHOMe R2

R1

R2

[Rh] R2 89

Cp′

MeO

O

R

* MeO Cat-6: 80%, 93% ee Cat-7: 85%, 90% ee

Rh

Cat-7

OMe N Rh Cp′

89

92

O NHOMe

F3C

MeO Cat-6: 83%, 92% ee Cat-7: 78%, 91% ee

O NHOMe

NHOMe

*

*

MeO

O

MeO

O

5

CO2Me NH 6 Rh 4-F-C6H4

Cat-6: R = OTIP

91

NHOMe

4

7

Cramer: Cat-6 (5 mol%), (BzO)2 (5 mol%) 17 samples, 66–91% yields, 64–98% ee Antonchick and Waldmann: Cat-7 (5 mol%), (BzO)2 (5 mol%) 11 samples, 65–91% yields, 78–94% ee O O NOMe Rh NOMe Cp′ Rh 90

4-Br-C6H4

R

MeO Cat-6: 71%, 90% ee Cat-7: 67%, 88% ee

* HO Cat-6: 84%, 95% ee Cat-7: 65%, 94% ee

Scheme 8.24 Rh(III)-catalyzed enantioselective C–H allylation of N-methoxybenzamides with allenes.

8.3 Intermolecular Couplings

These reactions can be run under mild conditions and are compatible with a wide range of functional groups, thus giving allylated products in high yields and excellent stereoselectivities (64–98% ee). In 2017, the chiral Cp-ligated Rh(I) complex Cat-7, developed by Antonchick and Waldmann, could also be employed as an efficient and selective catalyst for C–H allylation of N-methoxybenzamides 88 [64]. Systematic catalyst screening indicated that excellent enantioselectivity was observed in the case of aryl groups substituted at 4- and 7-position in the Cp ligand. The substituent at 5-position did not affect the enantioselectivity, while the methylation at position 4 led to a sluggish reaction and deceased stereoselectivity. A plausible mechanism of this reaction in racemic version was proposed by Ma and coworkers [66]. The catalytic cycle starts by rhodation of 88 to form 90 via C–H activation. The coordination of less substituted C=C bond in allene unit with Rh center followed by insertion of this C=C bond into Rh–C linkage gives a seven-membered rhodium intermediate 92. Stereoinduction is believed to result from this selective insertion of the allene. Protonolysis with in situ generated H+ would yield the product 89 and regenerates the catalyst. In 2017, enantioselective C—H bond addition of aromatic compounds to nitroalkenes was reported by Ellman and coworkers, in the presence of a chiral cyclopentadienyl rhodium(III) dimer complex Cat-8 and AgSbF6 [67]. Promising selectivities were observed in the reactions between pyrrolidine benzamide 93 and nitroalkenes containing electro-poor, electro-neutral, and electro-rich aromatic substituents, thus giving the corresponding branched products 94 in 68–82% ee (Scheme 8.25).

N

O +

R

O 2N

Cat-8 (5 mol%) AgSbF6 (40 mol %)

N

O

R

Four examples 60–73% yields 68–82% ee

*

93 N

OMe

O

NO2

OMe I Rh I Cat-8

94 NO2

* Ph

N

NO2

O

N

* 73%, 82% ee

60%, 80% ee

NO2

O

*

* OMe

83%, 93% ee

N

NO2

O

CF3

2

Ph

60%, 68% ee

Scheme 8.25 Enantioselective C—H bond addition of pyrrolidine benzamide to nitroalkenes by a chiral Rh(III) complex.

In Rh(III)-catalyzed C–H activation reactions, diazo compounds could also be used as one-carbon components to couple with O-pivaloyl benzhydroxamic acids 95, delivering isoindolones 96 bearing a tetrasubstituted carbon [68, 69]. In 2014, Cramer reported the asymmetric version of this transformation by using chiral rhodium catalyst Cat-6. As a consequence, a series of chiral isoindolones 96 were isolated in high yields (52–94%) and high enantioselectivities (up to 93% ee) (Scheme 8.26) [70]. Substrate scope indicated that the size difference of the two substituents on diazo esters plays a prominent role in the control of

215

216

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization Cramer (2014) O N2 OPiv + N R 2 H

OR3

OR3

R2

96

R

NH

*

19 samples 52–94% yields 56–93% ee

O

95

O

Cat-6 (5 mol%) (BzO)2 (5 mol%)

Rh

R

O Cat-6: R = OTIP

O

O

O

O

MeO NH

OCHi(Pr)2

O 83%, 93% ee

N 97

OR3

+ R2 OPiv

O

N H

(iPr)2CHO O

Ph

Cat-8 (2.5 mol%) AgSbF6 (20 mol %)

N2

O

25 examples 65–98% yields 68–96% ee

N

O 98a: 95%, 90% ee

MeO2C

O N

NH O

(R)-98a O N

*

NH

O 98b: 95%, 96% ee

OMe I Rh I

2

99b Minor

OCHi(Pr)2

OCHi(Pr)2

NH

Cat-8

Rh R N OPiv N OCH(iPr)2 O O

O

*

R2 NH

*

Rh R N OPiv N

N

OMe

OR3

R

vs.

Ph

81%, 56% ee

R

O

N

MeO2C

O

98

O 99a Major

O

NH OCHi(Pr)2 Br

O 74%, 89% ee

O 88%, 92% ee

Song (2017)

O

NH

NH OCHi(Pr)2

O

OCHi(Pr)2 N

OCHi(Pr)2

NH (S)-98a O

OCHi(Pr)2

*

NH

O 98c: 75%, 86% ee

N

OCHi(Pr)2

*

NH

OMe

O 98d: 94%, 86% ee

Scheme 8.26 Rh(III)-catalyzed enantioselective C–H annulation of benzamides with diazo esters.

stereochemistry. In 2017, Song and coworkers developed the enantioselective C–H annulation of O-pivaloyl 1-indolehydroxamic acid 97 with diazo ester compounds [71]. The combination of half-sandwich rhodium(III) complex Cat-8 (2.5 mol%) and AgSbF6 (20 mol%) was optimized as the best catalyst, by which a variety of enantioenriched 1,2-dihydro-3H-imidazo[1,5-a]indol-3-one derivatives 98 bearing a tetrasubstituted stereogenic center were obtained in high yields and high stereoselectivities. The neutral complex Cat-8 alone showed poor catalytic activity, and the high loading of AgSbF6 (20 mol%) improved both reactivity and enantioselectivity of this reaction, arguably due to the inhibition of the formation of a stable Rh–I intermediate. The authors proposed that the

8.3 Intermolecular Couplings

metal-carbene species 99a can be generated preferably to avoid a steric repulsion between the large ester substituent and the bulky pivalate group, thus leading selectively to the corresponding (R)-98a (Scheme 8.26). Recently, chiral half-sandwich rhodium complexes have been applied in the preparation of chiral spirocyclic compounds via directed C–H activation. In early 2015, You group reported a dearomatization of β-naphthols 100 via annulation with alkynes, using Cat-1 as a precatalyst and Cu(OAc)2 and O2 as the combined oxidants (Scheme 8.27) [72]. Various highly enantioenriched spirocyclic enones 101 bearing an all-carbon quaternary stereogenic center were isolated in 11–98% yields and up to 94% ee. Both symmetrical and unsymmetrical alkyne coupling partners were compatible in this transformation. The catalytic cycle begins with the formation of 102 via deprotonation of the β-naphthol with the Rh catalyst. Subsequent C—H bond activation leads to the rhodacycle 103. Alkyne coordination and migratory insertion gives an eight-membered rhodacycle 104, and this is believed to be both the enantio- and regiodetermining (with unsymmetrical alkynes) step. A [1,3′ ]-reductive elimination from 105 produces the final product and generates the rhodium species. It should be noted that the π–π interaction between the phenyl substituent on the alkyne and 2-naphthol might partially contribute to the high regioselectivity when unsymmetrical alkynes were employed as the substrates [73]. Lam and coworkers employed a similar strategy to realize an asymmetric C–H oxidative spiroannulation of α-aryl cyclic 1,3-dicarbonyl compounds You and coworker [72] R3 OH

Cat-1 (5 mol%) (BzO)2 (5 mol %)

R3

+ R2

R

R2

O

Cu(OAc)2 (1 equiv) K2CO3 (2 equiv)

R1 100

R

R1

27 examples 11–98% yields, 72–94% ee

101

Rh

Cat-1: R = OMe

Cp′Rh(OAc)2 R3 Rh Cp′ O

Cp′ O

102

Rh OAc

R1

103

R1

O Br

81%, 17 : 1 rr 90% ee

Ph

Rh O 104

Cp′

O Cl

81%, 86% ee

nBu

Rh Cp′

R2

101

O

R1

R1

105

nBu

Ph Ph

R3

R2

Ph Ph

O Cl

98%, 84% ee

OHC

O Cl

69%, 90% ee

Scheme 8.27 Asymmetric dearomatization of naphthols via a Rh-catalyzed C–H annulation reaction.

217

218

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

106 with internal alkynes [74]. In this case either Cat-1 or Cat-9 (Cat-6, R = OTBDPS) were employed as a catalyst and gave spiroindenes 107 with high levels of enantiocontrol (Scheme 8.28). In 2016, Cramer and coworker reported the synthesis of spirocyclic indenyl sultams 109 via enantioselective C–H annulation of N-sulfonyl ketimines 108 and alkynes [75]. The use of a chiral half-sandwich rhodium Cat-1, in conjunction with a carboxylic acid additive 110, enabled an enantioselective and high yielding access to such spirocyclic sultams (Scheme 8.28). The asymmetric C–H annulation of pyrazolones 111 and alkynes was also developed by You and coworker recently, using a rhodium complex Cat-10 bearing monocyclopentadienyl ligands embedded in chiral 1,1′ -spirobiindane backbone [76]. This method enabled the transformation of a wide range of substrates into highly enantioenriched spiropyrazolones containing all-carbon quaternary stereogenic centers (Scheme 8.28). In 2014 and 2016, You group demonstrated asymmetric C–H oxidative alkenylation of biaryl derivatives 113 with olefins, which afforded axially chiral biaryls 114 in excellent yields with good enantioselective control (Scheme 8.29) [77, 78]. Chiral half-sandwich rhodium complexes bearing cyclopentadienyl ligands based on ether binaphthyl (Cat-1) [77] or 1,1′ -spirobiindane (Cat-10) [78] scaffold served as suitable catalysts for this transformation. Using the second-generation catalyst (Cat-10) compared with the first generation (Cat-1) allows to perform the reaction at room temperature, and better ee were obtained. The obtained axially chiral biaryls 114 were found as suitable ligands for rhodium-catalyzed asymmetric conjugate additions. By using the half-sandwich rhodium catalyst Cat-10, Wang and coworkers recently described a solvent-dependent asymmetric synthesis of alkynyl and monofluoroalkenyl isoindolinones through C–H activation of Nmethoxybenzamides 88 (Scheme 8.30) [79]. The alkynyl isoindolinones 116 were produced in MeOH (up to 86% yield and 99.6% ee), while the monofluoroalkenyl isoindolinones 117 could be formed in i PrCN (up to 98 : 2 Z/E, 93% yield and 86% ee). Notably, this study constitutes the first asymmetric synthesis of a chiral allene from achiral substrates by transition metal-catalyzed C–H activation, and it was identified as a reaction intermediate. The mechanism of this catalytic reaction was also proposed (Scheme 8.31). A five-membered rhodacycle 118 is formed through chelation-assisted C–H cleavable reaction of 88 with a Rh(III) specie Cp′ Rh(OBz)2 generated from the oxidation of Rh(I) complex Cat-10 with (OBz)2 . A regioselective migratory insertion occurs to form the seven-membered rhodacycle 119. Through a stereoselective C—F bond cleavage in 119 and followed a dissociation/association process, a chiral allene-rhodium specie 120 is obtained, which might be in equilibrium with the less favored isomer 121. Migratory insertion of the chiral allene into the Rh—N bond generates the E-alkenyl rhodium intermediate 122, which furnishes alkynyl isoindolinone 116 in MeOH through anti-β-F-elimination (path a) and Z-monofluoroalkenyl isoindolinone 117 in i PrCN through protonation (path b), respectively.

8.3 Intermolecular Couplings Lam and coworkers [74] R1 X

O

Y

R2

+

23 examples 56–94% yields, 11–97% ee

R1

O

Cat-1 or Cat-9 (5 mol%) Cu(OAc)2 (2 equiv)

R

R2 O

O X

R

Y

106

107

Cat-9: R = OTBDPS n

O2N Ph O

O

Rh

Bu S

Ph Ph O

O

O

tBuN

84%, 95% ee

80%, 97% ee

O

O

O

O

O

BnN 73%, 94% ee

66%, 81% ee

Cramer and coworker [75]

S N

O

+ O R1

R2

O S O NH

Cat-1 (2 mol%) 110 (5 mol%)

AgNTF2 (10 mol%) 20 examples 28–99% yields, 36–94% ee

108

R1 N N +

109 R2

111 t

Cy N N

Bu N N

O Ph

O Ph

Ph

Ph

94%, 95% ee

O R4

25 examples 19–99% yields, 82–99% ee R 3

R2

CO2H O 110

R1 N N

R4 Cat-10 (5 mol%) Cu(OAc)2 (2 equiv) R3

Bn N

R1

You and coworkers [76] O

O

R R2

112

Cat-10: R = OMe Cy N N

Cy N N PMB

99%, 96% ee

n

O Bu n

OMe

Rh

R

O PMB

S

PMB

Bu

56%, 96% ee

95%, 94% ee

Scheme 8.28 The synthesis of chiral spirocyclic compounds via Rh(III)-catalyzed C–H activation.

8.3.2

Iridium Catalysis

Generally iridium-catalyzed intermolecular enantioselective C–H activation is believed to proceed through a Ir(I)/Ir(III) cycle (Scheme 8.32). Directed C–H oxidative of substrate with Ir(I) complex gives a Ir(III) hydride intermediate. The coordination of an unsaturated coupling partner and subsequent migratory insertion, which are considered to be the enantiodetermining step, affords expanded metallacyclic intermediate. Finally, reduction elimination produces the desired product and releases the Ir(I) species. Alkenes as unsaturated coupling partners are commonly employed in iridium-catalyzed intermolecular enantioselective C–H activation, and the

219

220

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

N

N

Cat-1 or Cat-10 (5 mol%) (BzO)2 (5 mol%) R

+

R R

Cu(OAc)2 (20 mol%) Ag2CO3 (1 equiv)

R

113

114

N

Cat-1: R = OMe

N

N Ar

R CO2Et

Ar MeO

R OMe

Ar = 2-naphthyl Cat-1: 94%, 80% ee Cat-10: 92%, 90% ee

Rh

Rh

Cat-10: R = OMe

Cat-1: 76%, 78% ee Cat-10: 96%, 94% ee

Cat-10: 65%, 94% ee

Scheme 8.29 Rh(III)-catalyzed asymmetric C–H oxidative alkenylation of biaryl derivatives. O N H

OMe +

F

N OMe or

R1 R1 116

115

88

R

O

O

F R2

N OMe F R1 117

R2

R Rh

R2

Cat-10: R = OMe

Condition A: Cat-10 (6 mol%), (BzO)2 (6 mol %), 3 Å MS, PhCO2K, MeOH, 40 °C, 23 h O O O O N OMe

N OMe

N OMe

N OMe Cl

nBu

Ph

116a 71%, 96% ee

nBu

iPr

116b 75%, 96% ee

Me

Me

Cy 116c 45%, 94% ee

Cy 116d 46%, 99% ee

Condition B: Cat-10 (8 mol%), (BzO)2 (8 mol %), 5 Å MS, 4-EtC6H4, iPrCN, 40 °C, 23 h O

O

N OMe F n

Bu

N OMe F n

O N OMe F

Bu Me iPr Cy Ph 117a 117b 117c Z:E = 97 : 3 Z:E = 97 : 3 Z:E = 97 : 3 Major: 72%, 83% ee Major: 50%, 75% ee Major: 93%, 53% ee

O N OMe F

Cl Me

Cy 117d Z:E = 98 : 2 Major: 43%, 81% ee

Scheme 8.30 Rh(III)-catalyzed solvent-dependent asymmetric synthesis of alkynyl and monofluoroalkenyl isoindolinones.

earliest example was reported by Togni and coworkers [80]. A new class of cyclopentadienyl Ir(I) complexes containing a chiral bisphosphine was prepared and used with success in the direct hydroarylation of norbornene with benzamide 123. In the presence of [IrCp((R)-MeO-biphep)] (1 mol%), the C–H norbornylation product 124 was formed with an enantiomeric excess of up to 94%, albeit in low yield (12%) (Scheme 8.33). Because the current 18-electron catalyst requires

8.3 Intermolecular Couplings

Cp′Rh(ethylene)2 O N H

O

(BzO)2

OMe

N OMe

Cp′Rh(BzO)2

R1 116

R2

Pa th

O

a

R

N OMe H 117 R1 F R2

R2

b

F

anti-β-F-elimination

Pa

F

O

th

N OMe Rh 118 Cp′

O

H+

N OMe 122 Rh R1 Cp′ F R2

1

O

OMe N Rh Cp′ R2 1 R F F 119

O

F–

O

OMe N Cp′ Rh R2

R1

120

OMe N Cp′ Rh R2

R1 121

F

F

Scheme 8.31 The proposed mechanism of the asymmetric reaction catalyzed by rhodium(III) to synthesize alkynyl and monofluoroalkenyl isoindolinones.

DG

* R2

DG LnIr(I)

R1 Reductive elimination

Oxidative addition

DG (III)

Ir R1 R2

DG

Ln

Ir (III)

H

H Ln R1

Migratory insertion

DG (III)

Ir

R1

Ln

R2 Coordination

H

R2

Scheme 8.32 General procedure of iridium-catalyzed intermolecular C–H activation.

221

222

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

ligand dissociation processes to coordinate with substrates, likely a change of Cp hapticity from 𝜂 5 to 𝜂 3 (or 𝜂 1 ), or possible chelate phosphine opening, is necessary for a catalytic activity. In 2008, Shibata group used the combination of [Ir(COD)2 ]BF4 and (R)-MeO-biphep as a catalyst for the enantioselective C–H addition of o-methylacetophenone to norbornene, leading to formation of 126a in 58% yield and 70% ee (Scheme 8.33) [81]. Seven years later, Yamamoto group developed the highly enantioselective intermolecular hydroarylation of bicycloalkene through carbonyl-directed C—H bond cleavage of 125 [82]. A cationic iridium complex [Ir(COD)2 ](BArF 4 ) combined with a newly synthesized sulfur-linked bis(phosphoramidite) ligand (R,R)-S-Me-BIPAM was optimized as the best catalyst. The reaction provided norbornylated acetophenone or benzamide derivatives in moderate to excellent yields and good to excellent enantioselectivities. In the case of N,N-dialkylbenzamide, excellent enantioselectivity (up to 99% ee) and high selectivity for the mono-alkylation product (126d and 126e) were achieved under such protocol (Scheme 8.33). Togni and coworkers [80] [IrCp((R)-MeO-biphep)] (1 mol%)

+

12%, 94% ee

H2N O 123

PPh2 PPh2

MeO MeO H2N

O 124 (R)-MeO-biphep R

S

R R=

+

[Ir(COD)2] (5 mol%) Ligand (5 or 5.5 mol%)

+

R R O O 125 126 Shibata and coworkers [81]: (R)-MeO-biphep, 1 sample, 58%, 70% ee Yamamoto and coworker [82]: (R,R)-S-Me-BIPAM, 21 samples 42–96% yields, 81–99% ee MeO

O

(R,R)-S-Me-BIPAM

CO2Me

MeO N

N O

O P NMe2 O

O

Yamamoto Yamamoto Shibata 126a, 58%, 70% ee 126b, 82%, 88% ee 126c, 68%, 97% ee

O

O

Yamamoto Yamamoto 126d, 90%, 99% ee 126e, 54%, 99% ee

Scheme 8.33 Ir-catalyzed asymmetric C–H norbornylation of acetophenones or benzamide.

In 2013, Hartwig group demonstrated the intermolecular asymmetric ortho-C–H addition of indoles, thiophenes, pyrroles, and furans to bicycloalkenes, leading to formation of 2-alkylated heteroarenes 128 in enantioselective manner (Scheme 8.34) [83]. The neutral iridium complex [Ir(COE)Cl2 ]2 (1.5 mol%), combining with a bidentate phosphine bearing bulky substituents (R)-DTBM-SEGPHOS (3 mol%), was used as an efficient catalyst, which can tolerate a broad range of functional groups. The reactions of indoles (128a and 128d), thiophenes (128c), and pyrroles with bicycloalkenes afforded the corresponding C–H alkylation products in high yields with high enantiomeric

8.3 Intermolecular Couplings [Ir(COE)2Cl]2 (1.5 mol%) (S)-DTBM-SEGPHOS (3 mol%)

X + R 127 X = NH, O, S

*

P P

H

H N

Cl 129

O

R

O X

24 examples 21–98% yields, 39–99% ee

PAr2 PAr2

O

128 O Ar = 3,5-(tBu)2-4-OMe-C6H2 (R)-DTBM-SEGPHOS

P

*

P

H HN Cl

NH 128a

Turnover-limiting H [Ir] step

130

131 Br

N H 128a, 93%, 96% ee

MeO2C

O

128b, 87%, 78% ee

S 128c, 95%, 98% ee

N H 128d, 90%, 96% ee

Scheme 8.34 Ir-catalyzed intermolecular asymmetric hydroheteroarylation of bicycloalkenes.

excess. In the case of furans, lower enantioselectivities were observed (see 128b), and the reason is still unclear. Mechanistic studies indicated that the reaction starts from the formation of iridium hydride 129 via the oxidative addition of C2 position, which occurs much faster than overall catalytic cycle. The coordination of alkene with metal center gives 130. Subsequent insertion of double bond into Ir—C bonds leading to 131 is believed to be the turnover-limiting step. Final reductive elimination gives the product and regenerates the Ir(I) catalyst. Unstrained alkenes could also serve as alkylation reagents for intermolecular C–H functionalization in a stereoselective mode. In 2012, Shibata and coworkers described a cationic Ir(I)-catalyzed C2–H alkylation of indoles with alkenes, where the selectivity of linear or branched products was controlled by the DG and ligand. In presence of catalytic [Ir(COD)2 ](BArF 4 ) and chiral phosphine ligand (R)-SDP, the indole substrate 132, having a benzoyl DG, could react with styrene to give the corresponding alkylated indole 133 in 93% yield and 42% ee (Scheme 8.33) [84]. In 2016, this group reported the asymmetric ortho-C–H addition of acetanilides 134 to β-substituted α,β-unsaturated esters by employing either [Ir(COD){(S,S)-chiraphos}]OTf or [Ir(COD){(S)-Difluorphos}]OTf as a catalyst [85]. Both electron-donating and electron-withdrawing groups were tolerated in this reaction, and a variety of chiral 3,3-disubstituted propanoates 135 was isolated with high to excellent enantioselectivities (73–99% ee). In a proposed mechanism, amide-directed C—H bond cleavage produces iridium-hydride species 136. Subsequent hydrometalation to alkene provides intermediate 137, which undergoes reductive elimination to give product 135 (Scheme 8.35). In 2015, Nishimura group reported the Ir-catalyzed branch-selective hydroarylation of vinyl ethers with aromatic compounds via nitrogen-directed

223

+

Ph

Shibata (2012) [Ir(COD)2](BArF4) (10 mol%) (R)-SDP (10 mol%)

N Ph 132

H N

* N

93%, 42% ee O

133 (R)-SDP

Shibata (2017) [Ir(COD){(S,S)-chiraphos}]OTf or [Ir(COD){(S)-Difluorphos}]OTf (10 mol%)

H N

Ph2P Ac

H N H N Ir 136 H H N

Ir O

R 137

MeO

Ac CO2Me

135a, 80%, 86% ee

H N

Ph2P

CO2Me R 135

17 samples CO2Me 11–99% yields, 73–99% ee

134

PPh2

O

Ph

R Ac +

PPh2

Ph

O

(S,S)-chiraphos F F

O

F F

O

O

PPh2 PPh2

O (S)-Difluorphos

H CO2Me Cl

Ac

CO2Me 135b, 60%, 98% ee

H N

H N

Ac CO2Me

135c, 89%, 81% ee

Ac

CO2Me Ph 135d, 31%, 99% ee

Scheme 8.35 Cationic Ir-catalyzed intermolecular asymmetric hydroarylation of unstrained alkenes through amide-directed C–H activation.

8.3 Intermolecular Couplings

C–H activation, where 1,5-cyclooctadiene (COD) worked as a chelating ligand [86]. The enantioselective variants were also developed using a chiral diene ligand (S,S)-Fc-tfb. In the presence of catalytic [Ir((S,S)-Fc-tfb)Cl]2 and Na(BArF 4 ), the reactions of 2-phenylpyridine 138 with vinyl ethers afforded the branched alkylated products 139 with 76–77% ee (Scheme 8.36). One year later, the same group disclosed asymmetric C–H alkylation of N-sulfonylbenzamides 140 with vinyl ethers, catalyzed by hydroxoiridium/chiral diene complexes [87]. Chiral diene ligands based on a tetrafluorobenzobarrelene (tfb) framework all displayed high enantioselectivity in C–H alkylation of 3-methyl-N-sulfonylbenzamide, and (S,S)-Me-tfb was selected as the best one. Notably (R)-binap performed poorly in this reaction. The reaction exhibits broad functional group tolerance for both coupling partners, and representative examples include the use of alkyl (141c, 141d), aromatic (141a), and cyclic ether (141b) derivatives. In addition, a series of transformations were conducted from enantioenriched products, including modification of both the amide and ether moieties, with no erosion in enantiopurity. Mechanistic studies suggested that both C–H activation (from 140 to 142) and hydrometalation (from 142 to 143) are reversible. An irreversible carbometalation delivering 144 is presumably involved in the reaction, which can release the product via reductive elimination (Scheme 8.36). [Ir((S,S)-Fc-tfb)Cl]2 (5 mol%) Na(BArF4) (10 mol%)

N +

OR

N

F F

2 samples 82–92% yields, 76–77% ee

R = Et, Ph 138

F

139 O N H

Ms

+

140

Fc Fc

[Ir((S,S)-Me-tfb)(OH)]2 (2.5 mol%)

CONHMs

(S,S)-Fc-tfb F

OR

28 samples 60–97% yields, 83–99.5% ee

F

* OR

141

*

F

F

OR

F O

O N

Ms

N

Ir

Me

O Ms

Ms

Me

N (S,S)-Me-tfb

Ir H

Ir H

RO 143

CONHMs

CONHMs

*

* OPh 141a, 70%, 93% ee

RO 144

H 142

O 141b, 97%, 92% ee

Cl Cl

CONHMs

MeO

CONHMs

*

*

OBn

OBn

141c, 88%, 96% ee

141d, 93%, 97% ee

Scheme 8.36 Chiral diene/Ir-catalyzed enantioselective C–H addition of aromatic compounds to vinyl ethers.

225

226

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

The iridium/chiral diene has also been used for the intermolecular C–H annulation of N-acyl ketimines with 1,3-dienes in an enantioselective fashion, as reported by Nishimura and workers in 2013 (Scheme 8.37) [88]. By employing the combination of [Ir((S,S)-Me-tfb)Cl]2 and Na(BArF 4 ), the [3+2] annulation of N-acyl ketimines (147) in situ generated from 3-aryl-3-hydroxyisoindolin-1-ones (145) with 1,3-dienes afforded a family of spiroaminoindane derivatives 146 with high regio- and enantioselectivity (69–99.5% ee). Binap and the corresponding phosphoramidite did not show catalytic activity in this transformation. The substrates having electron-rich and electron-poor substituents, as well as various functionalized 1,3-dienes, were compatible with the catalyst, giving exclusively the corresponding chiral C–H annulation products. The authors proposed that the reaction starts with the formation of ketimine 147 via dehydration of 145. Ortho-C–H activation of 145 through oxidative addition gives an aryl-iridium(I) species 148. Coordination of 1,3-diene at the less substituted alkene moiety gives 149, which undergoes oxidative cyclization to form π-allyliridium(III) intermediate 150. Reductive elimination and subsequent protonolysis gives the product and regenerates the cationic iridium(I) species. HO

H N

O + R 1

R2

[Ir((S,S)-Fc-tfb)Cl]2 (2.5 mol%) Na(BArF4) (10 mol%) R1

R4 R5 R3

145

DABCO (5 mol%) 24 samples 47–95% yields, 69–99.5% ee

R2

R5 R4 HN

O

F F

F Me

146

O

(S,S)-Me-tfb

N

147

O

N

[Ir]

149

148

Cl 146a, 81%, 92% ee

146a

150

O HN

N

[Ir] N

N

151

O HN

O tBuO

Me

OH

[Ir]

OH

O [Ir]

F

R3

2C

HN

O HN

OMe 146b, 89%, 96% ee

146c, 88%, 95% ee

146d, 47%, 97% ee

Scheme 8.37 Iridium/chiral diene-catalyzed enantioselective C–H annulation of N-acyl ketimines with 1,3-dienes.

8.3.3

Other Metal Catalysis

The palladium-catalyzed Heck reaction is arguably one of the most important C—C bond-forming processes in synthetic organic chemistry. In 2015, Sigman and coworkers reported a catalytic and enantioselective intermolecular

8.3 Intermolecular Couplings

dehydrogenative Heck-type reaction of indoles 152 with trisubstituted-alkenyl alcohols 153 via C–H cleavage (Scheme 8.38) [89]. Initial ligand screening suggested trifluoromethyl-substituted pyridine oxazoline derivative L10 as a competent ligand for the synthesis of various chiral indoles. In the presence of Pd(MeCN)2 (OTs)2 and L10, the reactions of indoles with ethyl-substituted alkenes afforded indole derivatives bearing a quaternary all-carbon stereocenters in desirable enantioselectivity. In the case of methyl-substituted alkenes, a clear drop in enantiocontrol was however observed. Guided by computational analysis, various steric and electronic parameters of the ligands were calculated, and a simple correlation between the enantioselectivity and the natural bond orbital charge on the oxazoline nitrogen was revealed. Further studies indicated that the fluoro-derived L11 provided superior enantioselectivities than L10, especially in methyl-substituted alkenes. Two reasonable pathways are proposed for this transformation, either a Heck-type process proceeding via direct palladation through an electrophilic aromatic substitution-type process or a Wacker-type addition. The parallel reactions of an indole and an indole boronic ester with an alkene giving the same product 154a with similar levels of enantiocontrol strongly support the Heck-type mechanism.

N

+

R2

152

n

153

R3

R1

Pd(II)

OH

N

N

OH

2-Naphthyl L10, R′ = CF3, R″ = H L11, R′ = H, R″ = F

N

Standard conditions L10

O

N

OH R3

N X

R″

R′

R3

N

+

154

R1 [Pd]

R2

R2

R3

N

Wacker type

[Pd]

O n

CuSO4 (7 mol%), O2, rt 33 samples 31–83% yields, 68–92% ee

Heck type

R1

R2

Pd(MeCN)2(OTs)2 (10 mol%) L10 or L11 (20 mol%) OH

R1

nBu

O

nBu

N

X = H, 61%, 72% ee X = Bpin, 49%, 68% ee

Si(Me)2tBu Et

nBu

nBu

O N 154b 77%, 92% ee

N 154a Si(Me)2tBu O

O N 154c L10: 79%, 74% ee L11: 69%, 86% ee

Cy

O

N

N

154d L10: 83%, 74% ee L11: 72%, 84% ee

154e L10: 61%, 72% ee L11: 44%, 90% ee

Scheme 8.38 Pd-catalyzed enantioselective intermolecular dehydrogenative Heck-type reaction of indoles with trisubstituted-alkenyl alcohols.

In 2018, Chen and Xu reported Pd-catalyzed domino Heck spiroyclization between alkene-tethered aryl iodide 155 and α-diazocarbonyl compounds through C–H activation and carbene insertion, which resulted in a variety of

227

228

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

spiroindolines and spirodihydrobenzofurans containing two quaternary stereogenic centers in good to excellent yields (Scheme 8.39) [90]. The asymmetric version of this reaction was preliminarily investigated in this report with the chiral spiro phosphoramidite (L12) as the ligand, giving the optically active spiroindolines 156 with up to 80% ee (Scheme 8.39). N2 Ts N

Ar COOR′ Pd(OAc)2 (10 mol %) R

R

155

L12 (30 mol %) CsF (3 equiv) Toluene, 80 °C

Ts N

Ts N

I

Ts N

Ph O

COOMe

Ph

Ar COOR′ 156 Ts N

Me

L12 Ts N

Me +

+ Ph

P N

O

Ph

COOMe

64% yield, 40 : 60 dr 156a′, 42% ee 156a, 74% ee

Ph

COOMe

Ph

COOMe

74% yield, 39 : 61 dr 156b′, 39% ee 156b, 80% ee

Scheme 8.39 Pd-catalyzed enantioselective synthesis of spiroindolines and spirodihydrobenzofurans via domino Heck spiroyclization through C–H activation and carbene insertion.

In 1994, Rodewald and Jordan reported asymmetric C—H bond addition of 2-picoline to 1-hexene in the presence of H2 catalyzed by a cationic chiral zirconocene complex Cat-11 bearing a 𝜂 2 -(N,C) pyridyl unit [91]. The alkylated pyridine 158a was isolated in 19% yield and 58% ee (Scheme 8.40). Stoichiometric reactions of Zr-pyridyl complexes such as Cat-11 with alkenes yielded a series of azazirconacyles (159), which were identified as the possible intermediate in the catalytic transformation. In 2014, Hou and coworkers reported the first half-sandwich scandium complexes, which could be generated through acid–base reaction between the scandium trialkyl compounds with chiral binaphthyl-substituted cyclopentadiene ligands [92]. In combination with [Ph3 C][B(C6 F5 )4 ], the chiral scandium complexes such as Cat-12 can serve as excellent catalysts for the enantioselective C—H bond addition of pyridines 157 to various 𝛼-olefins, leading to the formation of a variety of enantioenriched alkylated pyridine derivatives 158. A possible reaction mechanism was proposed by the authors. The reaction of half-sandwich scandium dialkyl complex Cat-12 with an equimolar amount of [Ph3 C][B(C6 F5 )4 ] leads to the formation of a cationic Sc-benzyl species. A cationic chiral Sc-𝜂 2 -pyridyl species 159 is then formed by C–H deprotonation through 𝜎-bond metathesis pathway of 164 with the cationic Sc-benzyl species. The diastereoselective coordination of a 1-alkene to the Sc center in 159 could afford 160-1 preferably to avoid steric repulsion between the R substituent in the alkene and the Cp moiety of the catalyst. The subsequent 2,1-addition of the Sc–pyridyl bond to the coordinated alkene unit in 160-1 would give a five-membered Sc specie 161-1, which on reaction with

8.3 Intermolecular Couplings

Cat-11 (3 mol%)

N

n

n

+

Bu

H2

+

N

Bu *

+

N

Zr

158a

N

N

BPh4–

Zr

Cat-11

1 sample 18% yield, 56% ee

166

R Cat-12 (5 mol%) [Ph3C][B(C6F5)4] (5 mol%)

N +

R1

R2 N R

R2

20 examples 63–98% yields, 56–96% ee 158

157

N

nBu

*

N

Cat-12

N

I

Sc N

R =OTIP

n

N

R

*

Cy

Bu N

*

nBu

*

*

158a Cat-11: 18% yield, 56% ee Cat-12: 90% yield, 88% ee

158b (Cat-12)

158c (Cat-12)

81% yield, 94% ee

87% yield, 88% ee

94% yield, 82% ee

Cat-12 + [Ph3C][B(C6F5)4]

+

R R N

R

Sc

*

R

B(C6F5)4–

N

N

(R)-158

*

(S)-158 157

157

157

R R

H R

Sc R

N

Cpchiral Sc

Sc R

N

159

N 161-1

H R 161-2

R R

R

Sc R

N 160-1 major

vs.

N

)(

Sc R R

R

160-2 minor

Scheme 8.40 Zr- and Sc-catalyzed enantioselective C–H addition of pyridines to alkenes.

229

230

8 Non-stereoselective C(sp2 )–H Activation Followed by Selective Functionalization

2-picoline (C–H deprotonation) should release the alkylation product (R)-158 and regenerate 159 (Scheme 8.40). In 2017, Ackermann group reported the first iron-catalyzed asymmetric C–H alkylation of indoles by inner-sphere C–H activation [93]. The combination of Fe(acac)3 (10 mol%) and a NHC L13 enabled the C2–H addition of C3-imine-substituted indoles 162 to alkenylferrocenes and styrenes in the presence of CyMgCl and TMEDA, leading to the generation of 2-alkylated indole derivatives 163 in a enantioselective manner (68–92% ee). A N,N ′ -diarylated NHC L13, which possessed adamantly substituent at meta positions, was optimized as the best ligand. Based on deuterium-labeled reactions and kinetic studies, the authors proposed that the C–H metalation occurred through a ligand-to-ligand H-transfer (LLHT) manifold. This reaction starts from the reduction of the iron(III) precursor by the action of CyMgCl via β-hydrogen elimination from the mono-NHC-iron 164. The coordination of the alkene with the iron center generated the intermediate 165 in a reversible fashion. Subsequent kinetically relevant migratory insertion is induced by ligation of another indole unit 162, thus resulting in 166, which can further give 167 through a LLHT. Finally, the product 163 was generated, and the catalytic cycle was complete (Scheme 8.41).

NPMP

NPMP Me

[Fe(acac)3] (10 mol%) L13 (20 mol%)

H +

R″

N R′

CyMgCl, TMEDA THF, 45 °C, 16 h

N R′

∗

Ph Ad

N

R″ Me

163

162

Ph Me N BF4 L13

Ad

FeX3 PMP PMP N N Fe NHC

CyMgCl PMP N Fe

PMP N Fe

R″ NHC

N R′ 164

PMPN

PMP NHC N R R′ 167

Me N Fc Bn 163a 69%, 92% ee

H

N NHC R″ R' 165

N R′

R

N R′

166

N Fe 163

H N R′

NPMP Me

CHO

CHO ∗

161

MeO

Me ∗

N Fc Bn 163b 77%, 92% ee

∗

N Fc Bn 163c 53%, 80% ee N

CHO Me ∗

N PMP Bn 163c 95%, 84% ee N

Scheme 8.41 Asymmetric iron-catalyzed C–H alkylation enabled by remote ligand meta substitution.

References

8.4 Conclusion The enantioselective activation of C—H bond has evolved from structural and mechanistic studies to one method with significant implications in the areas of asymmetric organic synthesis over the past decade. Notably significant studies concerning the general understanding of C–H activation processes have been reported. Catalytic enantioselective transformation proceeding via a non-stereoselective C–H activation followed by selective functionalization of the metallacyclic intermediate provides a powerful strategy for construction of C—C, C—N, and C—O bonds in a stereocontrolled manner. Despite the significant progress made in recent years, further research efforts to design new chiral catalysts, expand the substrate scope, and improve the practicality and versatility of these processes are still required before enantioselective C–H activation finds widespread application in industrial and academic settings.

Acknowledgments This work was supported by the Fundamental Research Fund for the Central Universities (No.2017ZY25) and the National Natural Science Foundation of China (No. 21776020). G.S. thanks the National Program for Thousand Young Talents of China.

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239

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation Parthasarathy Gandeepan and Lutz Ackermann Georg-August-Universität Göttingen, Institut für Organische und Biomolekulare Chemie, Tammannstraße 2, 37077 Göttingen, Germany

9.1 Introduction Syntheses of alkenyl-substituted (hetero)arenes are of great interest, because alkenes can be easily converted to other functional groups, such as alkyl halides, alcohols, aldehydes, carboxylic acids, epoxides, and ketones. Aromatic compounds containing alkenyl moieties are omnipresent in numerous natural and bioactive molecules (Scheme 9.1) [1], functional materials [2], and powerful synthetic intermediates [3]. The geometry of the olefins not only determines the biological activities of the molecules [4] but also dictates the stereochemical outcome of their chemical transformations [5]. Hence, the synthesis of stereodefined olefins represents one of the major challenges in organic synthesis. Classical methods involve transformations of carbonyl groups into alkene moieties, such as Wittig-type reactions, which face the limitation of stoichiometric phosphorous by-product formations [6]. Over the past three decades, transition metal-catalyzed cross-couplings such as Suzuki–Miyaura, Negishi, Stille, and Hiyama couplings between metal reagents and (pseudo)halides proved synthetically reliable to construct alkenyl moiety with diastereoselectivities [7]. However, these conventional cross-couplings require stoichiometric organometallic reagents as well as prefunctionalized coupling partners and therefore suffer from nonavailability of starting materials and undesired waste formations. The cross-coupling of aryl electrophiles with alkenes, namely, the Mizoroki–Heck reaction, significantly improves the cross-coupling protocols for the diastereoselective alkenes construction, allowing the efficient synthesis of geometrically well-defined substituted alkenes (Scheme 9.2) [8, 9]. Despite of significant achievements in transition metal-catalyzed crosscoupling strategies, due to the increasing demands on environmental concerns and sustainability, recent developments have focused on the functionalization of readily accessible, otherwise inert, carbon–hydrogen (C—H) bonds [10]. Thus achieving recent years, significant advances have been achieved in the field of diastereoselective alkene construction via C–H activation technology, which uses less functionalized starting compounds and therefore ensures the improved C–H Activation for Asymmetric Synthesis, First Edition. Edited by Françoise Colobert and Joanna Wencel-Delord. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.

240

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

OH CO2H

HO

HO OMe

OH Resveratrol

Ferulic acid O

OH

HO

OH OMe

OMe Curcumin Me

Me

Me

O O

Me

O

Me O

O

O OMe

Auraptene

Licarin A Br

CH3 Me2N

NMe2

O N

Zimelidine

(Z )-Tamoxifen

N N

CO2H

N

Me Triprolidine

SK&F 89976-A

Scheme 9.1 Representative examples of natural and bioactive compounds bearing alkene.

atom and step economy as well as the overall efficacy of the organic synthesis [11]. These intriguing C(sp2 )–H activation processes enabled the assembly of diversely decorated alkenes in a diastereoselective fashion through different pathways, including (i) oxidative functionalizations of aromatic C—H bonds with alkenes (Fujiwara–Moritani-type reaction), (ii) nonoxidative coupling of C—H bonds with functionalized alkenes such as vinylic (pseudo)halides, (iii) addition of aromatic C—H bonds onto alkynes and allenes, and (iv) addition of

9.2 C–H Activation with Alkenes

(Het)Ar

M

+

(Het)Ar

X

+

(Het)Ar

X

+

X

M

H

X = Cl, Br, I, OTf, OMs, OTs;

Cat. [TM] R

Base

Cat. [TM] R

Base

Cat. [TM] R

Base

(Het)Ar

(Het)Ar

(Het)Ar

R

R

R

M = BR2, SiR3, SnR3, ZnX, MgX

Scheme 9.2 Cross-coupling routes to substituted alkenes.

formyl C—H bonds onto alkynes and allenes. This chapter aims at highlighting advances in diastereoselective formation of alkenes via C(sp2 )–H activation.

9.2 C–H Activation with Alkenes 9.2.1

Nondirected C–H Alkenylation

Transition metal-catalyzed arylations of alkenes represent one of the powerful routes to access highly substituted alkenes in a stereocontrolled manner. For instance, the Mizoroki–Heck reaction, a palladium(0)-catalyzed arylation of alkenes with aryl halides, is a well-established method to access highly decorated alkenes [8]. While the pioneering palladium(II)-mediated oxidative C–H alkenylations by Moritani and Fujiwara [12] were reported earlier than the Mizoroki–Heck reaction [13], the synthetic potential of Fujiwara–Moritani reaction was realized only in the past two decades. As shown in Scheme 9.3, the regeneration of the palladium(II) species from the palladium(0) is one of the crucial steps in Fujiwara–Moritani reactions. Recent discovery of efficient catalytic reaction conditions by the use of suitable oxidants attracted major attention. Thus, Fujiwara and coworkers [14] disclosed the synthesis of 3-phenylcinnamate (3) from alkene 2 and benzene (1a) using a catalytic amount of benzoquinone (BQ) and a stoichiometric quantity of t-BuOOH (Scheme 9.4). Related processes were also viable by the use of oxygen as the terminal oxidant as was developed by Ishii and coworkers [15] and Jacobs and coworkers [16]. However, oxidative alkenylation of substituted benzenes resulted in a mixture of isomers [11h]. In 2009, Yu demonstrated a palladium-catalyzed regioselective C–H alkenylation of substituted benzenes 1 with acrylates 4 in the presence of 2,6-bis(2-ethylhexyl)pyridine (5) as ligand under an oxygen atmosphere (Scheme 9.5a) [17]. The outcome of the positional selective C–H activation was rationalized by the steric bulk of the ligand [18]. A related process was also reported by Sanford to access multi-substituted alkenes via arylation of

241

242

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

H +

R

Cat. Pd(II)

R

[O]

R1

R1 H R1

[PdX 2]

[O]

HX

C–H Activation

Oxidation [Pd0 ]

[PdX]

Reductive elimination

HX

R1 Alkene insertion

[HPdX]

β-Hydride elimination

R

R

R R1

[PdX]

R1

Scheme 9.3 The Fujiwara–Moritani reaction. Pd(OAc)2 (1.0 mol%) BQ (10 mol%)

H + Ph

1a

CO2Et 2

t-BuOOH (1.3 equiv) AcOH:Ac2O (3 :1) 90 °C, 15 h

Ph Ph

CO2Et

3: 72%

Scheme 9.4 Palladium-catalyzed C–H alkenylation of benzene.

alkenes with monosubstituted benzenes [19]. Furthermore, the synthesis of substituted (E)-cinnamyl acetates 8 proved also viable by palladium-catalyzed oxidative C–H alkenylation of arenes 1 with allyl acetates 7 as was disclosed by Jiao (Scheme 9.5b) [20]. Diastereoselective alkene construction via simple arenes C–H activation is not limited to palladium catalysis. The early reports using ruthenium [21] catalysis as well as rhodium [22, 23] catalysis showcase the potential of C–H activation technology for the construction of substituted alkenes. The oxidative coupling of heteroarenes 9 with alkenes 4 by means of transition metal-catalyzed C–H activation provided a direct route to assemble heteroaryl-substituted alkenes 10 [11i]. For instance, Fujiwara studied the oxidative coupling of acrylates 4 with heteroarenes, such as furan, benzofuran, and indole, in the presence of palladium catalyst (Scheme 9.6) [14]. Further

9.2 C–H Activation with Alkenes

Pd(OAc)2 (1.0 mol%) Ligand 5 (12 mol%)

H +

CO2Et

R 4a

1

CO2Et

Ac2O (1.0 equiv) O2 (1 atm), 90 °C Bu

6

Bu N 5

Et

R

Et

CO2Et

CF3

CF3

CO2Et

F3C

CO2Et

CO2Et

70% (m/p = 80/20)

72% (m/p = 78/22)

62% (a) OMe

OMe H OAc

+

Pd(OAc)2 (5.0 mol%) Ag2CO3 (0.6 equiv)

OAc

n-C4H9CO2H (16 equiv) BQ (2.0 equiv) 110 °C, 48 h, air

Me

Me 8: 61%

7

1b (Solvent) (b)

Scheme 9.5 Palladium-catalyzed C–H alkenylation of substituted benzenes. Pd(OAc)2 (0.5 mol%) BQ (0.5 equiv)

H Het

+

CO2R 4

9

t-BuOOH (1.3 equiv) Ac2O, 50 °C, 12 h

CO2R Het 10 CO2Me

Me

O 75%

CO2Et

O

CO2Me

63%

N H 52%

Scheme 9.6 Palladium-catalyzed C–H alkenylations of heteroarenes.

developments in this field successfully extended the scope to include the construction of many other heteroarenes, such as pyrrole, thiophene, benzothiophene, indolizine, and imidazo[1,2-a]pyridine [24]. It is noteworthy that these palladium-catalyzed C–H olefinations generally yielded the thermodynamically more stable (E)-alkenes.

243

244

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

9.2.2

Directed C–H Alkenylation

Palladium-catalyzed directing group (DG)-assisted ortho-C–H activation strategies were commonly employed to prepare alkenes diastereoselectively [11h]. These reactions follow a general catalytic cycle similar to the one shown in Scheme 9.3. Here, the catalytic reactions commence with the coordination of the DG to the palladium catalyst followed by cyclopalladation via C–H cleavage to generate the key metallacycle. Regioselective insertion of alkenes to C—Pd bond of the key intermediate and subsequent β-H elimination resulted in E-olefin products. For instance, de Vries and van Leeuwen elegantly developed a method for the synthesis of substituted alkenes (E)-12 via directed ortho-C–H activation of anilides 11 with acrylates 4 under mild reaction conditions (Scheme 9.7a) [25]. Thereafter, ortho-C–H activations of (hetero)arenes were extensively studied by the use of various DGs, such as anilides [26], amines [27], carboxylic acids [28], pyridyl [29], silanols [30], ethers [31], thioethers [32], oximes [33], amides [34], esters [35], sulfoxides [36], phosphine oxides [37], phosphates [38], Me HN

Me

O H

+

HN

O

BQ (1.0 equiv) TsOH (5.0 equiv) AcOH/PhMe (1: 2, v/v) 20 °C, 16 h

4b

11

(a)

CO2n-Bu

Pd(OAc)2 (2.0 mol%)

CO2n-Bu

12: 72% t-Bu

t-Bu

t-Bu O

C

t-Bu t-Bu

+

CO2Et

Pd(OPiv)2 (10 mol%)

t-Bu O

AgOPiv (3.0 equiv) DCE, 42 h, 90 °C

N

C

t-Bu t-Bu

N

H CO2Et 4a

13 (b)

i-Pr i-Pr Si O

i-Pr i-Pr Si O +

H

Pd(OAc)2 (10 mol%) CO2Et Ac-Phe-OH (20 mol%) AgOAc (3.0 equiv) HFIP, 90 °C, 36 h N

N 15

14: 55% (m:p:o = 93:5: 2)

4a

(c)

Scheme 9.7 Palladium-catalyzed directed C–H alkenylations.

CO2Et 16: 71% (para:others = 8 :1)

9.2 C–H Activation with Alkenes

N-oxides [39], and alkenes [40] under palladium catalysis for the formation of alkenes in a diastereoselective manner. Very recently, the Yu group further developed a palladium-catalyzed meta-selective Fujiwara–Moritani reaction to stereoselectively form alkenes 14 by a template that operated by a 12-membered metallacycle (Scheme 9.7b) [41]. After this initial intriguing report, further progress in this field was achieved by Yu and coworkers [42], Tan and coworkers [43], Maiti and coworkers [44], and others [45], establishing new templates to expand the scope of arenes in meta-selective C–H alkenylation [46]. As shown in Scheme 9.7c, the construction of functionalized alkenes could also be achieved through palladium-catalyzed para-selective-C–H activation of arenes as disclosed by Maiti and coworkers [47]. The potential of rhodium catalysis in oxidative C–H alkenylation was realized after the seminal studies by Matsumoto, Yoshida, and coworkers [22]. In 2007, Satoh and coworkers [48] performed the synthesis of 7-vinylphthalides 18 from benzoic acids 17 and acrylates 4 in the presence of catalytic amount of rhodium catalyst, [Cp*RhCl2 ]2 (Scheme 9.8a) [48b]. Subsequently, the Glorius group extended the C–H alkenylation process to anilides 11, aromatic ketones 19, and amides 20 (Scheme 9.8b) [49]. Thereafter, a significant number of results were published to access (E)-alkenes via directed ortho-C–H activation strategy using rhodium catalysis [10o, 50]. The rhodium-catalyzed oxidative C–H alkenylation was not limited to electron-deficient alkenes, such as acrylates 4 and styrenes 21. Unactivated alkenes proved also viable for C–H alkenylation process under rhodium catalysis as was disclosed by Bergman/Ellman and coworkers [51] and later Li et al. [52] and Tanaka and coworkers [53] (Scheme 9.8c) [51]. Recent studies imply that C–H olefination process can be achieved through β-heteroatom elimination instead of β-H as well [54]. For instance, the Li group reported a method to access substituted (E)-allylic alcohols 30 as the major product with moderate diastereoselectivity by the use of 2-vinyloxiranes in rhodium-catalyzed C–H activation of (hetero)arenes 28 (Scheme 9.8d) [54d]. A related process employing 4-vinyl-1,3-dioxolan-2-ones 32 as the coupling partner delivers (E)-allylic alcohols 33 in higher diastereoselectivities (Scheme 9.8e) [54c]. Allylic electrophiles are also used to obtain substituted alkenes in rhodium-catalyzed C–H activation chemistry [55]. For example, Glorius showed the direct C–H allylation of arenes with allyl carbonates 35 in a regioselective manner (Scheme 9.8f ) [56]. Concurrently, a related process using allyl acetates was reported to obtain vinyl arenes instead of allyl arenes by Loh and coworkers [57]. The styryl product formation was rationalized by migratory isomerization of initially formed allylic product by the action of [Rh–H] complex formed within the catalytic cycle. Relatively inexpensive ruthenium complexes have been extensively applied in the diastereoselective alkene construction via oxidative C–H alkenylation process [11a,g, 58]. For instance, the Ackermann group developed an intriguing method to access substituted alkenes via a ruthenium-catalyzed C–H alkenylation of anilides 37 in water as an environmentally friendly and nonflammable reaction medium (Scheme 9.9a) [59]. The protocol also proved to be applicable for the amide ortho-C–H alkenylations. In addition to strongly coordinating DGs, weakly coordinating carboxylic acids 17

245

246

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

CO2n-Bu CO2H H

+

CO2n-Bu

CO2n-Bu

O

[Cp*RhCl2]2 (1.0 mol%) Cu(OAc)2 (0.5 equiv)

O

o-Xylene, 120 °C, 10 h Air

O +

O

n-BuO2C (a)

17

4b

DG H

(b)

+

Ph

DG: NHCOCH3 (11) 21 DG: COCH3 (19) DG: CONH2 (20)

MeO

(c)

H

25

DG

[Cp*RhCl2]2 (0.5 mol%) AgSbF6 (2.0 mol%)

Ph

Cu(OAc)2 (2.1 equiv) t-AmylOH, 120 °C, 16 h DG: NHCOCH3 (22); 80% 57% DG: COCH3 (23); 60% DG: CONH2 (24);

N

Cu(OAc)2 (2.1 equiv) THF, 75 °C, 20 h

+

O

[Cp*Rh(CH3CN)3](SbF6)2 (3.0 mol%)

N

PivOH (1.0 equiv) DCE, 25 °C, 16 h

28

O

N

29

H

+ O

Me

O O

31

CsOAc (1.0 equiv) TFE, 0 °C, 16 h

32

+

O

[Cp*Rh(CH3CN)3](SbF6)2 (5.0 mol%)

(e) N(i-Pr)2

OH

N

30: 94% (E:Z = 1.8 :1)

OMe NH

H

N

27: 53%

N

N

(d)

Cy

[Cp*RhCl2]2 (5.0 mol%) AgSbF6 (20 mol%)

MeO

26

H

34

18b: 15%

Cy N

+

O

n-BuO2C

18a: 66%

[Cp*RhCl2]2 (2.5 mol%) AgSbF6 (10 mol%) OCO2Me PivOH (1.0 equiv) Ph PhCl, 45 °C, 18 h 35

(f)

Scheme 9.8 Rhodium-catalyzed oxidative C–H alkenylations.

OMe NH OH

Me 33: 81% (E:Z = >20 :1) O

N(i-Pr)2 Ph

36: 63% (E:Z = 2 :1)

9.2 C–H Activation with Alkenes

Me

Me HN

[RuCl2(p-cymene)]2 (5.0 mol%) KPF6 (20 mol%)

O H +

CO2Et

Me 37

(a) O

Me 38: 87%

4a

On-Hept

O

[RuCl2(p-cymene)]2 (5.0 mol%) AgSbF6 (40 mol%)

+

CO2n-Bu

OMe 39

Cu(OAc)2·H2O (1.0 equiv) H2O, 120 °C. 20 h

i-Pr OMe

Ru

R

OMe 41

O

OMe

O Mes 42 (10 mol%)

O

H

OMe 40: 84%

Me

MesCO2 +

On-Hept CO2n-Bu

4b

CO2H

O CO2Et

Cu(OAc)2·H2O (1.0 equiv) H2O, 120 °C, 20 h

H

(b)

HN

H O

V2O5 (1.0 equiv) PhMe, 120 °C, 18 h

R OMe 43: 97%

4c Me Me H R=

Me

H H

H

O

(c) N

O OCO2Me

H +

N

O

Cu(OAc)2 (2.0 equiv) THF, 80 °C, 20 h

Me 44

[RuCl2(p-cymene)]2 (5.0 mol%) AgSbF6 (20 mol%)

Me

45

46: 69% (E:Z = 5 : 1)

(d)

Ph H

O

O

N H

O

Me

OAc

+ Ph

[RuCl2(p-cymene)]2 (5.0 mol%) AgSbF6 (20 mol%) DCE, 25 °C. 16 h

O O

N H

O 47

48

(e)

Scheme 9.9 Ruthenium-catalyzed oxidative C–H alkenylations.

49: 74% (E:Z = 6 : 1)

Me

247

248

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

[60], esters 39 [61], and ketones 19 [62] were also successfully applied in the C–H alkenylation process [58c]. In their recent studies, Ackermann and coworkers realized the oxidative coupling of aromatic esters 39 with alkenes 4 using catalytic amounts of each [RuCl2 (p-cymene)]2 and Cu(OAc)2 under an ambient air atmosphere (Scheme 9.9b) [61a]. A well-defined ruthenium(II) bis(carboxylate) catalyst [Ru(O2 CMes)2 (p-cymene)] (42) enabled the synthesis of meta-substituted alkenes 43 via a decarboxylative C–H alkenylation process as was reported by Ackermann and coworkers (Scheme 9.9c) [63]. Most commonly, the ruthenium-catalyzed oxidative C–H alkenylation process employing electron-deficient alkenes, such as acrylates and styrenes, delivered thermodynamically stable (E)-alkenes. The versatile ruthenium-catalyzed C–H activation technology was also amenable to the synthesis of substituted allylic olefins [64]. Thus, Kim examined the reaction of carboxamides 44 with allylic carbonates 45 in the presence of catalytic amounts of [RuCl2 (p-cymene)]2 (5.0 mol%) along with 2.0 equiv of Cu(OAc)2 (Scheme 9.9d) [64d]. In contrast, Jeganmohan reported the C–H allylation of N-methylbenzamides 47 at ambient reaction temperature in a redox-neutral fashion using allylic acetates 48 as the coupling partners (Scheme 9.9e) [64a]. In both the reactions, the (E)-alkene 46 and 49 were obtained as the major products, albeit with moderate diastereoselectivities. Recently, intense focus has been shifted to the use of 3d transition metal complexes in C–H activation chemistry, because of their large relative abundance in the Earth’s crust and their less toxic nature and because they are relatively inexpensive in comparison with 4d and 5d transition metal complexes [65]. In this regard, cobalt complexes were extensively applied in the stereoselective alkene construction via C–H activations [65c, 66]. Initial studies on oxidative coupling of alkenes with amides using simple cobalt(II) salts as the precatalyst delivered cyclized products in lieu of acyclic alkenes [67]. Alternatively, oxidative coupling of benzamides 50 with acrylates 4 in the presence of catalytic amounts of cobalt(III) complex [Cp*Co(CO)I2 ], along with 2.5 equiv of AgOAc, provided alkenylated products (E)-51 (Scheme 9.10a) [68]. In their independent studies, Li and coworkers [69] and Ackermann and coworkers [70] presented the C–H alkenylation of arenes with gem-difluorostyrenes 53 under cobalt catalysis, unraveling a new avenue to access fluoro-substituted (E)-alkenes 54 in good yields (Scheme 9.10b) [70]. Coupling of unactivated alkenes with arenes was also feasible via cobalt-catalyzed C–H activation, however by the assistance of bidentate DGs [71]. Notably, uncommon alkenes, such as 2-vinyloxiranes 29 [72] and 4-vinyl-1,3-dioxolan-2-one 58 [73], were also successfully applied in the C–H alkenylation process to deliver (E)-allylic alcohols 56 as the major product and decorated vinyl isoquinolines 59, respectively (Scheme 9.10c,d). The cobalt-catalyzed C–H activation technology well exploited to form allylated arenes by the use of allylic electrophiles [55]. Alternatively, Ackermann demonstrated a cobalt-catalyzed C–H/C–C activation process to achieve highly diastereoselective (Z)-selective alkenes 61 using ambient reaction conditions [74]. Here, a variety of substituted (hetero)arenes 55 reacted with vinylcyclopropanes 60 in the presence of catalytic amounts of [Cp*Co(CO)I2 ] to give alkenyl products 61 with excellent Z-selectivities (Scheme 9.11a). The detailed mechanistic studies and theoretical calculations by the authors indicated that the C–C

9.2 C–H Activation with Alkenes

O

Me NH CO2Et

+

H

O

CO2Et

4a

H +

N 2-py

51: 80%

F

Ph

N 2-py

K2CO3 (1.0 equiv) TFE, 25 °C, 20 h

F

52

F

[Cp*Co(CO)I2] (2.5 mol%)

53

[Cp*Co(MeCN)3](SbF6)2 (5.0 mol%) NaOAc (20 mol%)

N H

+

N OH

DCE, 60 °C, 12 h

O

55

56: 80% (E:Z = 1.8 : 1)

29

(c)

O

+ Ph

(d)

[Cp*Co(MeCN)3](PF6)2 (5.0 mol%) NaOAc (40 mol%) BPh3 (40 mol%)

NH H

57

Ph

54: 98% (E:Z = >99 : 1)

(b)

EtO

Me NH

AgOAc (2.5 equiv) DCE, 60 °C, 13 h

50

(a)

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

O

O

EtO

N

Ph

DCE, 60 °C, 12 h

58

59: 50%

Scheme 9.10 Cobalt-catalyzed oxidative C–H alkenylations.

cleavage is the rate- and diastereoselectivity-determining step. The activation energy barrier for the formation of (Z)-alkene was determined to be significantly lower than the (E)-isomer. By contrast, a related transformation under rhodium(III) catalysis preferentially delivered the (E)-alkenes (Scheme 9.11b). Very recently, C–H functionalization using manganese catalysis [65b] received significant attention and was exploited to assemble alkenes in a diastereoselective manner [75]. In this context, the Ackermann group developed a series of reactions involving manganese-catalyzed C–H activation with allyl carbonates 35 [75g], vinylic cyclopropane 60 [75c], dioxolanones 32 [75b], and perfluoroalkenes 68 [75a] to obtain substituted alkenes in a stereocontrolled manner (Scheme 9.12). The manganese(I) catalysis elegantly enabled the coupling of allyl carbonates 35 with aromatic ketimines 62 to deliver diversely substituted (E)-alkenes 63 as the major product with excellent levels of diastereocontrol (Scheme 9.12a). The organometallic C–H allylation processes employing vinylic cyclopropane 60 under manganese catalysis proceeded through an

249

250

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

H +

E E

N

[Cp*Co(CO)I2] (10 mol%) AgSbF6 (20 mol%) NaOPiv (20 mol%) DCE, 50 °C, 20 h E = CO2Me

2-py 55

60

(a)

E N

E

2-py 61: 93% (E:Z = 1 : 11)

[Cp*Rh(CH3CN)3](SbF6)2 (10 mol%) AgSbF6 (20 mol%) NaOPiv (20 mol%) E

H + N 2-py

E

DCE, 50 °C, 20 h

N

E = CO2Me

2-py

E E

55 (b)

60

61: 77% (E:Z= 2 : 1)

Scheme 9.11 Diastereoselective alkene formation via C–H/C–C functionalizations.

unprecedented C–H/C–C functionalizations (Scheme 9.12b). The observed major (E)-isomer products 65 were rationalized by the contribution of London dispersion interactions in stabilizing the key (E)-transition state as studied by DFT calculations. Furthermore, the versatile manganese catalysis enabled the allylation of amino acids 66 with dioxolanones 32 under racemization-free conditions via a decarboxylative C–H/C–O functionalization (Scheme 9.12c). The robust manganese(I) catalyst also allowed for C–H allylation of ketimines 62 with perfluoroalkenes 68 via C–H/C–F functionalizations to provide thermodynamically less favored (Z)-alkenes 69 in good yields with excellent diastereoselectivities (Scheme 9.12d).

9.3 C–H Activation with Alkenyl (Pseudo)halides In spite of the great developments in the oxidative C–H alkenylation strategies, they continue to be somewhat limited to (i) provide a (E)-alkenes and (ii) require activated alkenes, such as acrylates or styrenes, as well as terminal alkenes, while (iii) access to tri- and tetrasubstituted alkenes is rare. In sharp contrast, a significant number of reports on (hetero)arene C–H alkenylations using vinylic halides were published using noble metals, such as palladium, rhodium, and ruthenium [11i, 76]. In 2005, the Daugulis group elegantly exploited the β-bromo acrylate 71 in palladium-catalyzed directed C–H alkenylation of pivanilides 70 (Scheme 9.13a) [77]. Later, a significant number of protocols were developed using vinyl halides as the coupling partner in diastereoselective alkene formation via C–H activation under palladium catalysis [76]. An example to illustrate the potential of palladium-catalyzed C–H alkenylation of heteroarenes using alkenyl electrophiles is shown in Scheme 9.13b [78]. Here, Ackermann employed moisture-stable phosphates 74 as the coupling partner in azole C–H

9.3 C–H Activation with Alkenyl (Pseudo)halides

PMP N

Me

O

H +

OMe

Ph 62

[Mn2(CO)10] Me (5.0 mol%) + NaOAc (20 mol%) H3O

O Ph

1,4-Dioxane 120 °C, 14 h

O 35

PMP = 4-OMe-C6H4

63: 68% (E:Z = 47 : 1)

(a)

H

[MnBr(CO)5] (2.5 mol%) Cy2NH (20 mol%)

E

+

E

N 2-py 64

N

1,4-Dioxane 100 °C, 20 h

E

E = CO2Me

60

65: 52% (E:Z = 7 : 1)

(b) O

O

OBn PhthN

H

O

+

O

N 2-py 66

[MnBr(CO)5] (10 mol%) NaOAc (20 mol%) O

H

+

C7F15 F F

62 (d)

68

OH

THF, 100 °C, 12 h N 2-py 67: 90% (E:Z = 6.4 : 1)

32

PMP N

OBn

PhthN

(c)

Me

E

2-py

[MnBr(CO)5] (10 mol%) NaOAc (40 mol%)

Me H3

O+

O

C7F15 F

K2CO3 (1.0 equiv) 1,4-Dioxane 80 °C, 18 h PMP = 4-OMe-C6H4

69: 72% (E:Z= 3 : 97)

Scheme 9.12 Alkene synthesis via manganese-catalyzed C–H activation.

alkenylations [78b]. Unlike palladium catalysis, other noble metals such as rhodium and ruthenium that are frequently utilized in oxidative C–H alkenylation process are less explored in nonoxidative C–H alkenylation regime [79]. Very recently, Ackermann and coworkers constituted the ortho-selective C–H alkenylation of weakly coordinating benzoic acids 76 with alkenyl halides 77 under ruthenium catalysis (Scheme 9.13c) [79a]. The synthesis of substituted alkenes via highly diastereoselective C–H activation using alkenyl electrophiles was nicely achieved using 3d transition metal catalysts as well. Thus, few protocols have been known using copper catalysis for the coupling of hetero(arene) C—H bonds with vinyl halides [80]. Notably, Piguel exploited the copper-catalyzed C–H alkenylation as a key step in the synthesis of natural alkaloid annuloline (81) (Scheme 9.14a) [80c]. In their

251

252

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

CMe3

CMe3 HN

(a)

O H

HN +

Br

CO2Me

70 O

72: 85%

P(O)(OPh)2

H +

Pd(OAc)2 (5.0 mol%) dppe (7.5 mol%)

O

K3PO4 (2.0 equiv) NMP, 100 °C, 16 h

N

N 73

(b)

75: 72%

74 i-Pr MesCO2

O

OH

Me

(c)

CO2Me

AgOTf (1.0 equiv) DMF, 90 °C, 1h

71

O

Me Ru

O O

Mes

42 (10 mol%) PCy3(10 mol %)

H + Br

76

O

PdCl2 (5.0 mol%)

Ph

77

K2CO3 (2.0 equiv) NMP, 120 °C, 16 h Then K2CO3, MeI

O

OMe

Me

Ph

78: 56%

Scheme 9.13 Nonoxidative C–H alkenylation using palladium and ruthenium catalysis.

studies, Yamaguchi/Itami demonstrated the potential of nickel catalysis in C–H alkenylation via C–H and C–O activation strategy [81]. Here, azoles 73 were effectively coupled with enol derivatives or unsaturated esters 82 in the presence of catalytic amounts of Ni(cod)2 and 1,2-bis(dicyclohexylphosphino)ethane (dcype) (Scheme 9.14b). In contrast to the alkenylations of acidic C—H bonds (vide supra), the Ackermann group disclosed the synthetically useful alkenylation of otherwise inert C–H protocols by the use of cobalt catalysis [82]. In these processes, the combination of simple CoI2 and N-heterocyclic carbene (NHC) ligand IPrHCl efficiently performed C–H alkenylations with alkenyl acetates, phosphates, carbonates, and carbamates at 23 ∘ C (Scheme 9.14c) [82b]. Remarkably, the alkenylations proceeded in a stereoconvergent fashion, furnishing the (E)-diastereomers as the sole products with a diastereomeric mixture of alkenyl acetate. Moreover, the reisolated alkenyl acetate in a single (Z)-isomer was an indicative of an olefin isomerization process with in the catalytic process.

9.4 Hydroarylation 9.4.1

Hydroarylation of Alkynes

Transition metal-catalyzed intermolecular addition of (hetero)aromatic C—H bonds onto alkynes permits the synthesis of substituted alkenes with high

OMe

N N O

H

Br

OMe

CuI (10 mol%) Ligand (20 mol%)

OMe

LiOt-Bu (2.1 equiv) 1,4-Dioxane 100 °C, 16 h

+

MeO 79

80

O

OMe

MeO 81: 75%

NHMe Ligand: NHMe

(a) O

N H

+

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

PhO

O

(b)

O

73

82

H N 2-pym (c)

28

Ph

O

O

83: 80%

CoI2 (10 mol%) IPrHCl (10 mol%)

OAc +

K3PO4 (2.0 equiv) 1,4-Dioxane 150 °C, 24 h

N

Me

CyMgCl (2.0 equiv) DMPU, 23 °C, 16 h

(3.0 equiv) E:Z = 27 : 73 84

Scheme 9.14 Alkenylation of (hetero)arenes by copper, nickel, and cobalt catalysis.

OAc

Me + N

Ph

Me

Ph

2-pym 85: 83%

(Z)-84

254

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

R2 R3 [TM]

H

X

R1

R1

HX HX [TM]

R2 3

R

R1 R1

[TM] R3

[TM] R1

R3

R2

R2

Scheme 9.15 Alkene formation through alkyne hydroarylation.

levels of diastereoselectivity control along with complete atom economy (Scheme 9.15) [11c,i,k, 83]. Over the last three decades, significant advances were achieved in this field by the use of noble metals, such as palladium, platinum, rhodium, gold, and ruthenium [11c]. Despite of these great developments in hydroarylation of alkynes by the use of noble metal complexes, in the recent years 3d transition metal complexes were likewise elegantly exploited in these processes [84]. In this regard, a significant number of hydroarylation processes to access alkenes were developed using nickel catalysis [85]. Thus, Nakao/Hiyama developed a series of protocols to access heteroarene-derived alkenes 86 via hydroarylation of alkynes 85 [86]. For example, a simple catalytic system consisting of Ni(cod)2 , and tricyclopentylphosphine (PCyp3 ), enabled diastereoselective (E)-alkenes 86 formation from internal alkynes 85 and heteroarenes 9, such as indole, imidazole, azoles, benzofuran, and benzothiophene, under mild reaction conditions (Scheme 9.16a) [86f ]. Furthermore, the construction of perfluoroarene-substituted (E)-alkenes 89 was also viable through the nickel-catalyzed hydroarylation strategy in high levels of regio- and stereoselectivity (Scheme 9.16b) [87]. The stereoselective alkene synthesis was also feasible through a low-valent cobalt-catalyzed C–H activation [65c, 66g]. In an earlier example, Kisch employed cobalt catalysis for the hydroarylation of alkynes 91 with azoarenes 90 to access (E)-selective alkenes 92 in high yields and diastereoselectivities (Scheme 9.17a) [88]. In a related process, Yoshikai and coworkers elegantly showed that a variety of (hetero)aromatic substrates reacted with alkynes in the presence of catalytic amounts of simple cobalt salt CoBr2 along with stoichiometric amounts of Grignard reagents at ambient reaction temperature (Scheme 9.17b) [89]. The observed (E)-selectivity was rationalized by the syn insertion of alkyne onto the C—Co bond of key cyclometalated C–Co–H

9.4 Hydroarylation

+ n-Pr

Het

n-Pr

Ni(cod)2 (10 mol%) PCyp3 (10 mol%)

H n-Pr

n-Pr Het

PhMe, 35 °C, 6–40 h 9

86

85 Me

CO2Me

n-Pr

N

n-Pr

N

n-Pr

N

n-Pr

85%

94%

S

89%

47%

H + Me

F

t-Bu

F

F

Ni(cod)2 (10 mol%) PCyp3 (10 mol%)

Me

F

PhMe, 80 °C, 2.5 h

t-Bu

F

F F

F 87

(b)

n-Pr

O

n-Pr

F F

n-Pr

N

n-Pr

85%

(a)

Me

O

n-Pr n-Pr

n-Pr

N

92%

O

n-Pr

N

N

Me

Me

Me

N

O

88

89: 89%

Scheme 9.16 Nickel-catalyzed hydroarylation of alkynes. Ph N

N

Ph H

[CoH(N2)(PMe3)3] (25 mol%)

+

N

Ph N

Ph Ph

Neat, 85 °C, 2 h Cl

Ph

Cl 90

(a)

Cl

92: 70–80%

PMP Me

Cl

91

N

Ph H

+

CoBr2 (5.0 mol%) P(3-ClC6H4)3 (10 mol%) t-BuCH2MgBr (50 mol%) Pyridine (80 mol%)

Me

O

H+

Ph Ph

THF, 20 °C, 12 h Ph 62

PMP = 4-OMeC6H4

91

92: 90% (E:Z = 90 : 10)

(b)

PMP

PMP Me

Ph

N H

62

N

Co(PMe3)4 (10 mol%)

+

Ph

PhMe, MW 170 °C, 1 h Ph

(c)

Me

91

Ph

PMP = 4-OMeC6H4 93: 90%

Scheme 9.17 Low-valent cobalt-catalyzed hydroarylation of alkynes.

255

256

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

intermediate followed by reductive elimination of the resulting alkenylarylcobalt intermediate. Alternatively, Petit employed the well-defined low-valent cobalt catalyst Co(PMe3 )4 in the absence of any other additives for the C–H alkenylation of aromatic ketimines 62 with internal alkynes 91 under microwave (MW) at 170 ∘ C for one hour (Scheme 9.17c) [90]. Surprisingly, the protocol delivered alkene products 93 exclusively as the (Z)-isomer in sharp contrast with (E)-isomer obtained by Yoshikai and coworkers [89c]. A (E)-alkene product is formed initially followed by product’s isomerization at 170 ∘ C. This hypothesis is supported by the catalytic cycle of Kisch’s transformation. Moreover, the authors calculated that at 170 ∘ C (Z)-alkene 93 is 2.27 kcal more stable than (E)-isomer, which is high enough to achieve complete isomerization. The emergence of high-valent cobalt catalysis in C–H activation chemistry was also successfully applied in the alkenes formation [65c, 66a]. Thus, Matsunaga/Kanai realized C2-alkenylation of indoles 94 and pyrroles with alkynes 95 in the presence of catalytic amounts of cobalt(III) complex [Cp*Co(C6 H6 )](PF6 )2 (Scheme 9.18a) [91]. A recent report by Ellman elegantly exploited the high-valent cobalt catalysis to access functionalized alkenyl halides 100 with high levels of regio- and diastereoselectivity by three-component reaction of C(sp2 )—H bonds, terminal alkynes 98, and N-halosuccinimides 99 (Scheme 9.18b) [92].

H +

N O

Me2N

DCE, 80 °C, 20 h

Me

94

(a)

O H

+

97

Ph O

Me2N

96: 78%

+

N

Ph O

S (b)

N

95

O N

Me

[Cp*Co(C6H6)](PF6)2 (5.0 mol%) KOAc (10 mol%)

Ph

I

[Cp*Co(MeCN)3](SbF6)2 (10 mol%) AcOH (2.5 mol%) 1,4-Dioxane, 40 °C, 24 h

N

O

S

Ph I

98

99

100: 71%

Scheme 9.18 High-valent cobalt-catalyzed hydroarylation of alkynes.

Application of manganese complexes in C–H functionalization has progressively increased in recent years [65b]. Recently, Chen/Wang disclosed a method to obtain substituted alkenes in a stereoselective manner via a manganese-catalyzed directed arene C–H activation and hydroarylation of terminal alkynes 98 (Scheme 9.19) [93]. In a related process, indoles and pyrroles proved to be suitable for hydroarylation process as was examined by Li and coworkers [94].

9.4 Hydroarylation

[MnBr(CO)5] (10 mol%) Cy2NH (10 mol%)

H +

N

N

Et2O, 80–100 °C, 6 h

Ph

Ph

H 55

98

101: 76%

Scheme 9.19 Manganese-catalyzed hydroarylation of terminal alkynes.

Very recently, Ackermann devised an unprecedented manganese-catalyzed C–H activation/hydroarylation manifold for terminal alkynes 102 bearing leaving groups in proximity to the C–C multiple bond being fully tolerant of β-O leaving groups (Scheme 9.20) [95], in contrast to the previously known hydroarylations with concurrent β-O eliminations [75b,d,g]. The use of catalytic amounts of Brønsted acid AcOH enabled this chemo- and stereoselective hydroarylation process. Furthermore, the reaction was performed in both batch and flow. Under continuous flow operation, widely substituted allylic carbonates 103 and ethers were achieved in a step-economical manner within 20 minutes.

O H N 2-py

+

Me

MnBr(CO)5 (10 mol%) AcOH (20 mol%)

H

Me O

O

N 2-py

O

O O

1,4-Dioxane 100 °C, 20 min 52

102

103: 95%

Scheme 9.20 Manganese-catalyzed hydroarylation alkynes in flow.

9.4.2

Hydroarylation of Allenes

Allenes are class of key π-motifs [96], which are often employed as coupling partner in C–H activation reactions [97]. In 2007, Krische realized the C–H activation approach for the synthesis of prenylated arenes and alkenes through hydroarylation of dimethylallene (106) with aromatic and alkenyl tert-carboxamides in the presence of catalytic amounts of cationic iridium complex derived from [Ir(cod)2 ]BArF 4 and rac-BINAP (Scheme 9.21) [98]. Notably, the reaction afforded a mixture of olefin regioisomers 107a and 107b with secondary carboxamide 104. This isomerization probably occurred by a secondary amide-directed allylic C–H insertion of 107a. The experimental results showed that the reaction mechanism involved ortho-C–H activation by oxidative addition. This is followed by hydrometalation of the allene and consecutive C–C forming reductive elimination of the resulting primary σ-allyliridium delivering the prenylation product with regeneration of the cationic iridium(I) active species.

257

258

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

OMe O

OMe O N H

Me • 106

H

N R1

R2

[Ir(cod)2]BArF4 (5.0 mol%) rac-BINAP (5.0 mol%) THF, 120 °C, 24 h

R1 = H, R2 = Bn (104) R1, R2 = pyrrolidinyl (105)

Bn

N H

+ Me

Me

OMe O

Bn

Me

Me

Me

107a

(E)-107b 78% (3 : 1)

OMe O

OMe O N

+

N

Me Me 108a

Me Me 108b

70% (>20 : 1)

Scheme 9.21 Iridium-catalyzed hydroarylation of dimethylallene.

In 2010, Ma and coworkers established a method for a rhodium-catalyzed C–H activation of N-methoxybenzamides 109 for the hydroarylation of substituted allenes 110 (Scheme 9.22a) [99]. The reaction proceeded under mild reaction conditions with broad substrate scope. With optically active allenol substrates, optically active bicyclic lactone products were observed after the subsequent lactonization. The authors proposed a mechanism that involves amide-directed cyclorhodation, regioselective allene insertion, and protonolysis of C(sp2 )–rhodium intermediate. In a related C–H allylation process, Ye and Cramer utilized a chiral rhodium complex for the enantioselective synthesis of allylic olefins (Scheme 9.22b) [100]. Glorius and coworkers further expanded the scope of the rhodium-catalyzed hydroarylation of allenes by establishing a method to access [3]dendralene 116 from alkenes 114 and allenyl carbinol carbonates 115 (Scheme 9.22c) [101]. The reaction was highly stereoselective and compatible with different substituents on the allene substrates. Fu and coworkers applied rhodium catalysis to access highly unsaturated conjugated olefins 119 from enol carbamates 117 and substituted ethyl buta-2,3-dienoates 118 (Scheme 9.22d) [102]. In addition to alkenyl substrates, the reaction proved also to be compatible with aromatic amides and ketones. Ackermann and coworker reported an example of hydroarylation of allenes 121 with 2-phenoxypyridine 120, which contains a removable DG through a ruthenium(II)-catalyzed C–H activation (Scheme 9.23) [103]. The preliminary studies showed that the choice of solvent isopropanol was beneficial for this C–H allylation process.

9.4 Hydroarylation

OMe NH

O

n-Pr

•

H + MeO

n-Pr

109a

(a)

Me

H

OMe n-Pr NH n-Pr

O

OMe

MeOH/H2O, –20 °C 48 h 111: 90%

110

OMe NH

O

[Cp*RhCl2]2 (2.0 mol%) CsOAc (30 mol%)

[Rh] (5.0 mol %) (BzO)2 (5.0 mol %)

•

+

OMe NH

O Me

CH2Cl2, –20 °C, 18 h

MeO

OMe

109b

113: 89% (er: 93 : 7)

112 R [Rh] = R

Rh

R = OSi(i-Pr)3

(b) O Me N(i-Pr)2 + Ph

•

OMe

O

O

H

O

[Cp*Rh(MeCN)3](SbF6)2 (5.0 mol%) PivOH (50 mol%)

N(i-Pr)2

CH2Cl2, 60 °C, 3 h

Ph

Me 114

(c)

116: 79%

115

NMe2 O

O H

Ph

+

Me

NMe2 Me O O

[Cp*RhCl2]2 (2.5 mol%) AgSbF6 (10 mol%)

Me •

CO2Et

THP, 60 °C, 24 h

Ph CO2Et

117

(d)

118

119: 86%

Scheme 9.22 Rhodium-catalyzed hydroarylation of allenes.

[RuCl2(p-cymene)]2 (10 mol%) NaOAc (60 mol%)

O H

O O

N

•

+ n-Bu

TMS

i-PrOH, 80 °C, 42 h

O N O O

TMS n-Bu

120

121

Scheme 9.23 Ruthenium-catalyzed hydroarylation of allenes.

122: 43%

259

260

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

The scope of the C–H activation and hydroarylation to allenes was significantly improved by the Ackermann group by demonstrating a protocol using 3d transition metal cobalt catalysis in 2017 [104]. In their studies, 5.0 mol% of cobalt(III) catalyst [Cp*CoI2 (CO)] elegantly transformed a variety of 1,1-disubstituted allenes into (E)-alkenes as a single diastereoisomer in excellent yields by means of (hetero)aromatic C–H activation. Importantly, the substituents on the allene determined the position of the double bond on the product. For instance, bulky alkyl groups gave styrene derivatives 127, whereas the allylated product 126 was formed by the di-n-alkyl-substituted allenes 124 (Scheme 9.24). n-Bu

•

n-Bu 124

N

N

n-Bu n-Bu

N

[Cp*CoI2(CO)] (5.0 mol%) AgSbF6 (15 mol %) 1,4-Dioxane,120 °C 18 h

N H

123

n -Pent

126: 66%

N

N

n-Pent t-Bu

• t-Bu 125

127: 64%

Scheme 9.24 Cobalt(III)-catalyzed hydroarylation of allenes. CO2Bn

H N

•

NaOAc (2.0 equiv) PhMe, 50 °C, 24 h

N

N

(a)

+

Me

28

CO2Bn MnBr(CO)5 (5.0 mol%) N

Me N

N

129: 98%

128

Me H N N

(b)

28

+

•

N

Me Ph

MnBr(CO)5 (10 mol%) NaOAc (40 mol%) NaOAc (2.0 equiv) 1,4-Dioxane, 100 °C, 24 h

130

Ph N N

N

131: 84% (E:Z = 1 : 3)

Scheme 9.25 Manganese-catalyzed hydroarylation of allenes.

Very recently, manganese catalysis was exploited for the hydroarylation of allenes by the group of Rueping (Scheme 9.25a) [105]. Here, a variety of internal allenes were effectively transformed into (E)-alkenes 129 by means of

9.5 Hydroacylation

N H + N Me 132

•

t-Bu n-Bu

t-Bu

Ni(cod)2 (10 mol%) IPr (10 mol%)

N

t-Bu N

n-Bu

PhMe, 100 °C, 14 h

N Me

124 With NaOt-Bu (1.0 equiv): No base:

n-Bu N Me

133

134

82% 0%

0% 85%

i-Pr

i-Pr N

N i-Pr

i-Pr IPr

Scheme 9.26 Nickel-catalyzed hydroarylation of allenes.

manganese(I)-catalyzed C–H activation of N-pyrimidyl indoles 28 and pyrroles. In a related process, Wang reported a method to access allylic indoles 131 using 1,1-disubstituted allenes 130 as the coupling partner with a variety of (hetero)aryl substrates [106]. However, an unsymmetrically substituted allene delivered (Z)-isomer as the major product (Scheme 9.25b). Ackermann and coworkers reported the first nickel-catalyzed hydroarylation of allenes for the chemoselective synthesis of alkenylated and allylated products via C–H activation of heteroarenes (Scheme 9.26). The reaction of imidazoles 132 with 1,1-disubstituted allenes 124 in the presence of 10 mol% of the nickel catalyst, along with stoichiometric amounts of NaOt-Bu, chemoselectively delivered alkenylated products 133. In sharp contrast, allylated products 134 were formed in the absence of the base. The detailed mechanistic studies showed that isomerization of allylated product into alkenyl product occurred in the presence of base.

9.5 Hydroacylation 9.5.1

Hydroacylation of Alkynes

Transition metal-catalyzed activation of unactivated (hetero)aromatic C(sp2 )—H bonds followed by the addition onto alkynes provides an atom-economical approach to alkenes. A related process involves formyl C–H cleavage and subsequent addition to alkynes, setting the stage to access substituted vinyl ketones in a stereocontrolled manner [107]. A main challenge associated with this hydroacylation process is the competitive undesired decarbonylation [108]. After the breakthrough observation by Suggs in 1978 [109] on the significantly suppressed decarbonylation in β-chelating aldehydes, a large number of protocols were developed using a variety of chelating groups [107b]. Among other transition metals, rhodium was extensively applied to the synthesis of alkenes from aldehydes and alkynes via formyl C–H activation [107]. Thus, 2-hydroxy benzaldehydes 135 [110], 2-sulfido benzaldehydes 137 [111], and 2-amino benzaldehydes 140 were efficiently coupled with both terminal and internal alkynes to deliver the desired substituted vinyl ketones with high stereoselectivity (Scheme 9.27a–c).

261

262

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

OH

H +

n-Pr

n-Pr

135

(a)

[RhCl(cod)]2 (0.5 mol%) dppf (1.0 mol%) Na2CO3 (5.0 mol%)

O

OH

n-Pr

C6H6, 90 °C, 2 h

n-Pr

85

136: 99%

SMe O H +

[Rh(nbd)2](BF4) (5.0 mol%) dcpe (5.0 mol%) H

S

137

O

SMe O

Me2CO, 25 °C, 2.5 h

138

dcpe = Cy2P

S 139: 96%

PCy2

(b) NH2 O H + H

(CH2)5Me

140

(c)

[Rh(nbd)2](BF4) (5.0 mol%) dcpm (5.0 mol%)

(CH2)5Me

Me2CO, 55 °C, 2 h

141

dcpm = Cy2P

142: 94%

PCy2 Me

Me S Cbz

NH2 O

O N

+

H

Ph

[Rh(nbd)2](BF4) (5.0 mol%) dcpm (5.0 mol%)

Cbz

Me2CO, 55 °C, 3 h

H

S

Ph

i-Pr

i-Pr

(d)

O N

143

144: 73%

98

Scheme 9.27 Directed rhodium-catalyzed hydroacylation reactions.

Recently, rhodium-catalyzed hydroacylation technology was elegantly exploited for the synthesis of α-amino enones 144 from α-amino aldehydes 143 and alkynes 98, as was reported by Willis (Scheme 9.27d) [112]. Hydroacylation of aldehydes that do not bear any DG at the β-position can be achieved by the use of transient DG [113]. For instance, Jun and coworkers performed the hydroacylation of aldehydes 145 with terminal alkynes 146 in the presence of catalytic amounts of transient DG, 2-amino-3-picoline (148) under rhodium catalysis [114]. Here, the in situ formed imine DG enabled the C–H cleavage (Scheme 9.28). H

O

+ H 145

t-Bu

[RhCl(PPh3)3] (5.0 mol%) 148 (40 mol%) PhCO2H (20 mol%)

O

t-Bu N

PhMe, 80 °C, 12 h

146

CH3 Via:

N

CH3 NH2 148

147: 63%

N

[Rh]

Scheme 9.28 Transient DG approach to hydroacylation process.

9.5 Hydroacylation

Me

O Ph

H

+ Me

149

(a)

Ru(O2CCF3)2(CO)(PPh3)2 (10 mol%)

O Ph

i-PrOH (1.0 equiv) 2-MeTHF, 100 °C, 30 h

151: 81%

150 Me

O H +

150

O

n-Bu

O

[IrCl(cod)]2 (2.5 mol%) P(n-Oct)3 (10 mol%)

Me

PhMe (1.0 equiv) 120 °C, 15 h

Me 152

Me Me

Me 153: 81% (E:Z = 3 : 2)

(b)

Me

N Me 154

H

+ CO2Et

PdCl2(PhCN)2 (2.5 mol%) Xantphos (2.5 mol%) PhCOCl (20 mol%) Mesitylene, 140 °C, 20 h

155

(c)

O Me

N CO2Et Me n-Bu 156: 83% (E:Z = 98 : 2)

Scheme 9.29 Synthesis of α,β-unsaturated carbonyl compounds via hydroacylation.

The Krische group applied ruthenium catalysis to couplings of aldehydes 149 with internal alkynes 150 (Scheme 9.29a) [115]. Here, a variety of aromatic and aliphatic aldehydes elegantly transformed into α,β-unsaturated ketones 151. A related process was also viable under iridium catalysis, albeit with poor stereoselectivity, as was reported by Obora/Ishii and coworker(Scheme 9.29b) [116]. Recent studies by Tsuji and coworkers showcased the potential of palladium catalysis for the synthesis of (E)-α,β-unsaturated amides 156 from formamides 154 and internal alkynes 155 (Scheme 9.29c) [117]. The hydroacylation strategy to access substituted alkenes was not limited to the noble metal catalysis. In an earlier example, Tsuda/Saegusa studied an inexpensive first row transition metal nickel catalyst for the functionalization of aldehyde C—H bond with alkynes to obtain α,β-unsaturated ketones 158 (Scheme 9.30a) [118]. Recently, Hiyama and coworkers expanded the scope of nickel catalysis to formyl C–H activation [119]. In their studies the combination of nickel catalyst Ni(cod)2 and Lewis acid AlMe3 or BPh3 enabled the coupling of formamides 154 with alkynes 88 to provide acrylamides 159 in a stereocontrolled manner (Scheme 9.30b) [119c]. 9.5.2

Hydroacylation of Allenes

In an earlier study, Miura tested rhodium catalysis for the hydroacylation of allenes with salicylaldehydes 135 (Scheme 9.31). In this process, 1.0 mol% [RhCl(cod)]2 catalyst efficiently enabled the reaction of 3-methyl-1,2-butadiene (106) and salicylaldehyde (135) into acylphenol 161 in quantitative yield. However, the reaction gave product 162 with a mixture of two stereoisomers

263

264

9 Diastereoselective Formation of Alkenes Through C(sp2 )—H Bond Activation

O Me

H

+ n-Pr

n-Pr

Ni(cod)2 (5.0 mol%) P(n-C8H17)3 (10 mol%)

Ni(cod)2 (10 mol%) BPh3 (20 mol%) P(t-Bu)3 (40 mol%)

O N Me

H

+

Me

t-Bu

O Me

PhMe, 80 °C, 8 h

N Me

t-Bu Me

159: 75%

88

154

n-Pr

158: 93% (E:Z = 93 : 7)

85

(a)

Me

n-Pr Me

THF, 100 °C, 20 h

Me 157

O Me

(b)

Scheme 9.30 Nickel(0)-catalyzed formyl C–H activation.

Ph

163

OH

PhMe, 120 °C, 1 h

O Ph Me OH 165: 33%

Me

Ph

[RhCl(cod)]2 (1.0 mol%) dppf (2.0 mol%) Na2CO3 (10 mol%)

164: 59% +

Me

•

•

O

O Me

106 5h

O H OH 135

OH

[RhCl(cod)]2 (1.0 mol%) dppf (2.0 mol%) Na2CO3 (10 mol%) Pentane, 40 °C 22 h • n-C6H13 160

Me

161: 99% O n-C6H13 OH 162: 99% (E:Z = 94 : 6)

Scheme 9.31 Rhodium(I)-catalyzed hydroacylation of allenes with salicylaldehyde.

in the ratio of 94 : 6 for the allene substrate 1,2-nonadiene (160). In contrast, phenylallene (163) gave 92% product yield with the 64 : 36 ratio of regioisomers 164 and 165. In 2008, Willis and coworkers reported the elegant hydroacylation protocol for the synthesis of enantioselective β,γ-unsaturated ketones 164 from 2-methylthio benzaldehydes 137 and allenes 163 in the presence of a cationic rhodium complex {Rh[(R,R)-Me-DuPhos]}ClO4 under mild reaction conditions (Scheme 9.32a) [120]. The reaction was highly stereoselective to deliver the corresponding (E)-alkene as the sole product with high enantioselectivity. In addition to mono- and 1,1-disubstituted allenes, 1,3-disubstituted and 1,1,3-trisubstituted allenes also proved viable within the rhodium(I)-catalyzed hydroacylation process (Scheme 9.32b) [121]. Here the regioselectivities were highly controlled by the steric effects of substituents on the allenes.

9.6 Conclusion The regio- and stereoselective synthesis of alkenes represents an important as well as a challenging task in molecular synthesis. Many classical methods are based on carbonyl compounds as the starting materials, and transition

References SMe O •

+

SMe O

{Rh[(R,R)-Me-DuPhos]}ClO4 (10 mol%)

Ph H

Ph

Me2CO, 45 °C, 24 h n-Pent 163

137

n-Pent 164: 81% 92% ee

Me P Me Me P Me (R,R)-Me-DuPhos

(a) Me

• 166

O H

MeS

O

n-Pent

O n-Pent

MeS Me 168

[Rh(dppe)]ClO4 (10 mol%) Me2CO, 55 °C, 8 h

165

97% 1.25 : 1

O i-Pr

167

n-Pent 169

O i-Pr

MeS •

Me

+ MeS

n-Pent

+ MeS i-Pr

n-Pent n-Pent

170

(b)

92% 15 : 1

171

Scheme 9.32 Hydroacylation of allenes with β-S-substituted aldehydes.

metal-catalyzed cross-couplings are somewhat outdated due to the poor stereoselectivity and less atom economy. In the last two decades, the emergence of catalytic activation of otherwise inert C—H bonds has proven to be an attractive tool for the diastereoselective construction of alkenes in a highly step-economical manner. The formation of diversely substituted alkenes has been achieved by C–H activation chemistry with different strategies including, namely, (i) dehydrogenative twofold C–H activation, (ii) nonoxidative C–H alkenylation using functionalized alkenyl electrophiles, and (iii) addition of aromatic and formyl C—H bonds to alkynes and allenes. The advantages of these C–H alkenylation process are often mild reaction conditions, high overall efficacy, broad scope, use of easily available and unfunctionalized feed stocks, and less or no unwanted by-products. Despite these indisputable advances, the most successful transformations are generally demanding precious 4d and 5d transition metal complexes. The recent progresses in 3d transition metal-catalyzed C–H activation process often require high catalytic loading and elevated reaction temperatures. Although the low-valent cobalt- and iron-catalyzed C–H alkenylations are effective at ambient reaction temperature, the requirement of stoichiometric Grignard reagents and sensitive reaction conditions limits their utility in large-scale synthesis.

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Index a alkene cross-coupling routes 239, 241 directed C–H alkenylation cobalt complexes 248, 249 manganese catalysis 249–250 ortho-C–H activations 244, 245 palladium catalyst 244 rhodium catalysis 245, 246 ruthenium complexes 245, 247, 248 hetero(arene) C—H bonds 251, 253 hydroacylation 208, 261–265 hydroarylation 257–261 natural and bioactive compounds 239, 240 nickel catalysis 252 non-directed C–H alkenylation 241–243 non-oxidative C–H alkenylation 251, 252, 265 oxidative C–H alkenylation process 245, 248, 251 pathways 240 α–amino phenylacetic acid 183 α–hydroxyl acid 183 8-aminoquinoline (AQ) 108 anti-β-hydroxy-α-amino acids (anti-βhAAs) 111 atropopure biarylsulfoxides 161 atroposelective cross-coupling Pd-catalyzed C-H arylation biaryl sulfoxides 169–171 thiophene derivatives 167–169

Rh-catalyzed C-H arylation 171–172 axial chirality asymmetric couplings biphenols and binaphtols derivatives 155 copper-catalyzed reactions 153–154 HHDP 156, 157 iron-catalyzed reactions 155 vanadium-catalyzed reactions 154–155 atroposelective cross-coupling 167–172 compounds 151, 152, 172 diastereoselective C-H functionalization phosphates 162–163 sulfinyl 159–162 enantioselective C-H functionalization 163–165 proatropisomeric 151 stereoselective C-H functionalization 158–167 naphthylpyridines 158–159 transient chiral directing groupfa 165–167

b β-lactam ring 19 biaryl-sulfoxide substrates 159, 169 Binol-derived phosphoric acids (BPAs) 83, 96, 97, 140 bisoxazolines 7–8, 11, 22, 23, 28–30, 167, 169

C–H Activation for Asymmetric Synthesis, First Edition. Edited by Françoise Colobert and Joanna Wencel-Delord. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.

276

Index

c catalysis asymmetric intermolecular amination 60–64 asymmetric intramolecular amination 63–65 azides 56 carbamates 54 chiral amines 51, 52 chloramine-T 56 cyclic sulfonamides 53 enzymatic intramolecular amination 68–70 hypervalent iodine reagent 52 iminoiodinanes 53–55 intermolecular diastereoselective reactions 66–67 iodine(III) oxidants 55–57 iron-and manganese-porphyrins 52 Lewis acidic ruthenium(Salen) complex 56 mechanistic and stereochemical issues 56–59 metallanitrene species 53, 54 m-xylene tether 54 nitrene precursors 53 nitrenes 51 O-(sulfamoyl)-hydroxylamines 54 regiocontrolled nucleophilic additions 53 stereoselective intermolecular allylic 70–71 sulfamates 54, 55 sulfamides 54 synthesis of amines 51 transition metal-catalyzed reactions 67–69 ureas and guanidines 54 cationic iridium complex 222, 257 central chirality desymmetrization amino acids act 176 benzofuranones 177 bifunctional phosphine/carboxylate ligand 179, 180 C-H imidoylation reaction, Pd-catalyst 180

C-stereogenic molecules 177 diarylacetic acids 176 enantiopure diarylamines 177 isoindoline scaffolds 179 meta-selective arylation 178 non-ligated Pd species 177 nosyl-protected directing group 177 oxidative Heck reaction 176 Pd(II)/Pd(0) and Pd(II)/Pd(IV) catalytic cycles 178 prochiral biaryl substrate 175 Rh-catalyst 181 styrenes and acrylates 176 kinetic resolution 182–183 organosilicon compounds 187–189 P-chiral compounds alkynylation 187 CpX Rh complex 186 diphenylphosphine oxide 184 enantioselective amidation 184, 185 kinetic resolution 187 oxaphosphinine 6-oxide 185 Pd-catalyzed arylation 185 Pd(0)-catalyzed arylation 186 prochiral phosphoryl substrate 184 sulfoxides 189–190 C(sp2 )—H bonds non-stereoselective C-H activation 193 planar chirality 133 C(sp3 )-H funtionalizations achiral phosphine L5 ligated Pd complex 83 aryl (pseudo)halide 80 chiral fused indolines 3 80, 81 chiral phosphine ligands 83 chiral phosphine ligands display activity 83 chloroacetamide 88 C-X coupling chiral organosilicon compounds 89 3,3’-diaryl-binol phosphoric acid 89

Index

ligands screening 90, 92 secondary amines/hydrosilane 89 tertiary carbon stereocenter 89 cycloheptyl-fused indoline 81 cyclopropyl-fused azacycle 19 86 efficiency and stereoselectivity 91 2-ethyl substituted indoline 6a 83 examples 84 expanded ring products 83–86 follow-up study 80 halide/carboxylate ligand exchange 80 Ir catalysis 102–104 membered palladacyclic intermediates 82 ortho-susbtitution 82 Pd catalysis APAO ligands 95, 96 aryl halide 92 aza-heterocycles 97 benzoquinone 92 benzylic C(sp3 )-H arylation 101 bis(pinacolato)diboron 94–95 BPAs 97 carboxamide groups 97–98 chiral environment 92 chiral phosphoric acid 98 coordination and activation 101 cyclobutane 93–95 electron deficient aldehydes 101 enantioenriched N-compounds 96 ethylenediamine derived chiral ligand 100 example of 92, 93 isobutyric acid derivatives 99 mechanism of 91–93 mono-coordination site 98 mono N-protected chiral amino acid 97, 98 N-arylamide directed cyclopropane 93 neurological disorders 100 N-fluoro-2,4,6-trimethylpyridinium salt 101 stereocontrol 98

stoichiometric and covalent installation 100 tertiary carbon stereocenters 99–100 Pd(0)/Pd(II) mechanism 79 Pd-phosphine catalyst 86 phenyl and benzyl substituents 85–86 pivalic acid 80 Rh catalysis 102, 103 seven-membered palladacyclic intermediate 82 taddol phosphoramidite ligand L10 85 tertiary acetamides 88 trifluoroacetimidoyl chloride 86–87 unsymmetrical N-alkanes 81 Concerted-metalation-deprotonation (CMD) 79, 80, 82, 83, 89, 135, 143, 165, 199 copper 3, 7–8, 22, 23, 28, 33, 36, 42, 45, 52, 53, 55, 56, 153–156, 251, 253 copper-catalyzed reactions 153–154 cyclopentadienyl ligands 199, 213, 214, 218

d DFT computational studies 5 dialkylaminomethylferrocene 135 diaryldiketones 137 diastereoselective directed ortho-metalation (DoM) 133 diastereoselective functionalization alkene 239 chiral oxazoline auxiliary alkyl carboxamides 120 amide derivatives 119 asymmetric iodination 117 chiral directing group 117–118 cycloalkanes 119–120 cyclopropanes 119–120 direct arylation 120–121 γ-methylene C(sp3 )—H bonds 119 stereoselective acetoxylation 117 steric repulsion model 116, 118 γ-C(sp3)–H arylation

277

278

Index

diastereoselective functionalization (contd.) dipeptides/tripeptides 116 N-SO2 Py-protected aliphatic amines 114 N-phthaloyl-α-amino acids α-amino-β-lactam motif 111–112 8-aminoquinoline 108 anti-β-hydroxy-α-amino acids 111 asymmetric synthesis 108 celogentin C 108, 109 α-haloacetates and methyl iodide 109, 110 monodentate directing group 114, 115 palladium 113, 114 phthaloyl and phenyl groups 108, 109 reductive elimination 108 secondary C—H bonds 111, 112 unactivated β-methylene C(sp3 )—H bonds 110 preferred conformation aminoquinoline directing group 123, 124 1-Boc-3-aminopiperidine 126 CO in methanol 122 indole diterpenoid paspaline 125 picolinamide-directed arylation 122 3-Pinanamine 123, 124 piperaborenine 123 proline derivatives 123, 124 psiguadial B 125 racemic 77 121 rimantadinyl methylenes 126 teleocidin B-4 core 122 transannular C—H bond arylation 127 tripeptide 126, 127 diazo esters 215, 216 diazoethane 4 diazomethane 4, 11 diazonaphthoquinones 171–172

Dynamic kinetic asymmetric transformation (DYKAT) 159, 161

e electron donating groups 5, 6, 41, 101 electrophilic metal carbenoid 3, 5 enantioselective hydroacylation carbocyclic nucleoside 206 catalytic cycle 204, 206 chiral indanones 206 heteroatom 207–209 nonsteroidal aromatase inhibitor MR 20492 207 phosphoramidite–alkene ligands 206 rhodium complex 204, 205 yuremamine 207

f ferrocene derivatives 140, 141, 147 planar chirality 134 ferrocenyl pyridine catalysts 142 Friedel-Crafts-type pathway 194 Fujiwara-Moritani reactions 194, 241, 242, 245

h Heck-type reaction 227 Hexahydroxydiphenoyl (HHDP) 156, 157 hydroacylation alkynes 261–264 allenes 263–265 hydroarylation alkynes (E)-alkene product 256 catalytic system 254 cobalt catalysis 256 developments 254 manganese catalysis 256, 257 nickel catalysis 255 regio-and stereoselectivity 254 allenes cobalt 260 iridium complex 257, 258

Index

manganese 260 nickel 261 rhodium 258, 259 ruthenium 258

i imidoylation 144, 180, 181 intermolecular C–H insertion, regioselectivity chemoselectivity catalyst effects 34–35 diazo compounds 32–34 substrate functional groups 35–36 components 30, 32 diastereoselectivity catalyst effects 42–43 substrate effects 39–42 enantioselectivity 43–45 regioselectivity catalyst effects 38–39 diazo compound effects 39, 40 substrate effects 36–38 intramolecular C–H insertion chemoselectivity catalyst effects 13–15 substrate effects 14–17 diastereoselectivity 23–25 α-diazo ketone 12, 13 enantioselectivity bisoxazoline ligands 28 copper-bisoxazoline systems 28 C1 symmetric ligands 25, 26 C2 symmetric ligands 26 diastereomeric catalysts 28 α-diazocarbonyl compounds 25 α-diazo motif 29, 30 diphenyl bisoxazoline ligand 29 Maguire group 28 O–Rh–O plane 25, 26 synthesis of molecules 30, 31 regioselectivity entropic factors 17 3-membered rings 17 4-membered rings 18–20 5-membered rings 20 6-membered rings 20–23

steric/electronic factors 17 iridium 7, 11, 12, 35, 36, 43, 45, 68, 70, 102–104, 144, 200–203, 219, 221–223, 225, 226, 257, 258, 263 iridium catalysis intermolecular couplings acetophenones/benzamide 222 alkylation reagents 223, 224 bicycloalkenes 222, 223 cyclopentadienyl Ir(I) complexes 220 general procedure 221 N-acyl ketimines 226 vinyl ethers 223, 225 intramolecular couplings catalytic cycle 200 indoles 203, 204 ketone 201, 203 phenyl-substituted alkene 203 iron-catalyzed reactions 155, 156 iron-phthalocyanine (FePc) 169

l Ligand-to-ligand H-transfer (LLHT) 230

m metal carbenoid induced C–H insertion rhodium rhodium(II) carboxylates 10 metal ligated catalyst (MLn ) coordinates 5 4-methoxyphenyl ketone 203 Mizoroki-Heck reaction 239, 241 Mono-N-protected amino acid (MPAA) 93, 126, 135, 163, 165, 175–177, 182, 183, 185, 189, 190 Monoprotected aminoethyl amine (MPAAM) 100

n N-acyl ketimines 226 N-allylic imidazoles 198 naphthylpyridines 158–159 N-ferrocenyl amide 146

279

280

Index

N-heterocyclic carbene (NHC) 80, 81, 83, 102, 169, 170, 194, 196, 230, 252 nickel catalysis 194–196, 252, 254, 263 nitrogen extrusion 3–5, 7 N-methoxyferrocenecarboxamides 146 non-stereoselective C-H activation directing groups 193 enantioselective functionalization 193 enantioselective hydroacylation 203–209 iridium catalysis 203, 219–226 metal catalysis cationic Sc benzyl species 228, 230 Heck-type reaction 226–227 iron 230 spiroindolines and spirodihydrobenzofurans 228 Zr-pyridyl complexes 228 nickel catalysis 194–196 palladium catalysis 194–196 rhodium catalysts 200, 208 N-vinylindole-2-carboxaldehydes 207

o organosilicon compounds 89, 187–189

p palladium catalysis 135, 194–196, 242, 245, 250, 251, 263 palladium-catalyzed C–H alkenylation 242, 243 Pd/ethyl nicotinate catalytic system 194 phenyl-substituted alkene 203 planar chirality Au/Pt-catalyzed 146–147 diastereoselective synthesis 134 Ir/Rh-catalyzed 144–146 Pd0 catalysis enantioselective and diastereoselective synthesis 144 ferrocenes 140, 141

hetero-Diels-Alder reaction 141 imidoylation 144 TADDOL-derived phosphoramidite 141, 144 transition states 143 Pd(II) catalysis catalytic enantioselective 138, 139 cross-coupling reaction 136, 137 CuOTf/bis-oxazoline 134 diaryldiketones 137 dimethylaminomethylferrocene 134, 135 ferrocenyl ketones 139 Heck reaction 136, 137 plausible catalytic cycle 135, 136 sandwich-type structure 133 prochiral 2-(arylsilyl)aryl triflates 187 Protein kinase C (PKC) inhibitor 198 protonolysis 215, 226, 258 PyOx ligands 194 2-pyridone structural motif 194

r rhodium ortho-metalated arylphosphines 11 rhodium(II) carboxamidates 10 rhodium(II) carboxylates 9–10 selectivity and efficiency 8 rhodium catalysts intermolecular couplings alkyne coordination and migratory insertion 217 alkynyl and monofluoroalkenyl isoindolinones 218, 220, 221 biaryl derivatives 218, 220 chiral Cp ligand 214 cyclopentadienyl ligands 213–215 diazo compounds 215–216 enantioselective reaction 213 half-sandwich complexes 217 imine 210 ketones 211, 212 naphthols 217 nitroalkenes 215 spirocyclic sultams 218–219 stereoinduction 215 α-substituted acrylates 211, 212

Index

supramolecular strategy 213 intramolecular couplings chiral phosphine ligand 196 cyclopentadienyl ligand 199 1,5-dienes 197 enantioselectivity 198 2-imidazolyl 196 ketimines 197 meta-alkoxy group 200 monocyclopentadienyl ligand 199 phosphoramidite/Rh ratio 197 PKC inhibitor 198, 199 Rh(I)/Rh(III) catalytic cycle 196, 197 syn-isomer products 198 tert-cyclobutanols 200, 202 transition-metal catalyzed reactions 200 Wilkinson’s catalyst 196 rhodium catalysts intermolecular couplings N-methoxybenzamides 214 ruthenium 7, 11, 12, 54, 56, 57, 65, 67, 72, 242, 245, 247, 248, 250–252, 254, 258, 259, 263

s Schiff base copper complex 8 𝜎-orbital 6 SPINOL-derived phosphoramidite ligand 144 spirosilabifluorene 188, 189

t TADDOL-derived phosphoramidite 141, 144

v vanadium-catalyzed reactions 154–155

w Wilkinson’s catalyst 196 wittig-type reactions 239

y yuremamine 207

z Zr-pyridyl complexes

228

281