[1st Edition] 9780128050750, 9780128047095

Table of contents :
Content:
CopyrightPage iv
ContributorsPage vii
PrefacePage ixPedro J. Pérez
Chapter One - The Selection of Catalysts for Metal Carbene TransformationsPages 1-31Q.-Q. Cheng, M.P. Doyle
Chapter Two - Recent Advances in Asymmetric Metal-Catalyzed Carbene Transfer from Diazo Compounds Toward Molecular ComplexityPages 33-91N.J. Thumar, Q.H. Wei, W.H. Hu
Chapter Three - Copper(I)–Acetylides: Access, Structure, and Relevance in CatalysisPages 93-141S. Díez-González
Chapter Four - Phenol Derivatives: Modern Electrophiles in Cross-Coupling ReactionsPages 143-222C. Zarate, M. van Gemmeren, R.J. Somerville, R. Martin
Chapter Five - Transition Metal Alkane-Sigma Complexes: Synthesis, Characterization, and ReactivityPages 223-276A.S. Weller, F.M. Chadwick, A.I. McKay
IndexPages 277-287

Citation preview

Academic Press is an imprint of Elsevier 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 125 London Wall, London, EC2Y 5AS, United Kingdom First edition 2016 Copyright © 2016 Elsevier Inc. All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-12-804709-5 ISSN: 0065-3055 For information on all Academic Press publications visit our website at https://www.elsevier.com

Publisher: Zoe Kruze Acquisition Editor: Poppy Garraway Editorial Project Manager: Shellie Bryant Production Project Manager: Surya Narayanan Jayachandran Cover Designer: Greg Harris Typeset by SPi Global, India

CONTRIBUTORS F.M. Chadwick University of Oxford, Oxford, United Kingdom Q.-Q. Cheng The University of Texas at San Antonio, San Antonio, TX, United States S. Dı´ez-Gonza´lez Imperial College London, London, United Kingdom M.P. Doyle The University of Texas at San Antonio, San Antonio, TX, United States W.H. Hu Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Chemical Engineering, East China Normal University, Shanghai, China R. Martin Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Technology, Tarragona; ICREA, Passeig Lluı¨s Companys, Barcelona, Spain A.I. McKay University of Oxford, Oxford, United Kingdom R.J. Somerville Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Technology, Tarragona, Spain N.J. Thumar Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Chemical Engineering, East China Normal University, Shanghai, China M. van Gemmeren Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Technology, Tarragona, Spain Q.H. Wei Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Chemical Engineering, East China Normal University, Shanghai, China A.S. Weller University of Oxford, Oxford, United Kingdom C. Zarate Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Technology, Tarragona, Spain

vii

PREFACE This second volume of Advances in Organometallic Chemistry for 2016 contains five reviews focused in the chemistry of late transition metal complexes, with relevance in the areas of synthesis, reaction mechanisms, and catalysis. The importance of the metal-catalyzed carbene transfer from diazo compounds in synthetic organic chemistry is reflected by two contributions from Michael P. Doyle and Wenhao Hu, in Chapters 1 and 2, respectively. In the former, an update of the advances in the catalytic strategies and transformations involving electrophilic metal carbene intermediates is presented. Chapter 2 is mainly directed toward the use of this methodology in the synthesis of complex molecules, most of them involving asymmetric carbene transfer reactions. The relevance of copper-acetylide intermediates in the chemistry of copper complexes and alkynes is the topic of Chapter 3 by Silvia Dı´ez-Gonza´lez. These species have been extensively invoked in a number of catalytic transformations and have become crucial in the last decade in the context of click chemistry induced by this metal. Ruben Martin highlights in Chapter 4 the catalytic C–O bond activation in cross-coupling reactions, with particular emphasis to low reactive substrates such aryl esters, carbamates, and aryl ethers. The chemistry of transition metal sigma alkane complexes has been updated by Andrew Weller in Chapter 5. The synthesis, characterization, and reactivity of σ-alkane complexes is presented, assessing the importance of such species as intermediates in the activation of these unreactive hydrocarbons. It has been a pleasure interacting with the array of outstanding scientists participating in this volume. I wish to acknowledge their commitment to this task, which will undoubtedly be recognized by the community. My acknowledgment is also extended to the editorial team, Shellie Bryant and Surya Narayanan, for their abnegate efforts to produce this volume. PEDRO J. PE´REZ

ix

CHAPTER ONE

The Selection of Catalysts for Metal Carbene Transformations Q.-Q. Cheng, M.P. Doyle* The University of Texas at San Antonio, San Antonio, TX, United States *Corresponding author: e-mail address: [email protected]

Contents 1. 2. 3. 4.

Introduction Acceptor/Acceptor-Substituted Metal Carbenes Acceptor-Substituted Metal Carbenes Donor/Acceptor-Substituted Metal Carbenes 4.1 Alkyl/Acceptor-Substituted Metal Carbenes 4.2 Aryl/Acceptor-Substituted Metal Carbenes 4.3 Vinyl/Acceptor-Substituted Metal Carbenes 5. Donor- and Donor/Donor-Substituted Metal Carbenes 6. Summary Acknowledgments References

1 5 8 12 12 15 19 22 25 25 26

1. INTRODUCTION Metal carbenes have been formulated for a diversity of chemical transformations.1 They can be nucleophilic as, for example, in metathesis reactions, or electrophilic, as is found in an increasing array of chemical transformations and is the focus of this review. Electrophilic metal carbenes developed from understandings of Fischer carbenes and their reactions,2 whose mechanistic interpretations reached earlier known catalytic reactions of diazo compounds. Diazo compounds are susceptible to electrophilic attack by coordinatively unsaturated reagents that displace dinitrogen by back-bonding from the carbon-attached element, commonly transition metals, to produce the normally electrophilic metal carbene that is capable of transferring the carbene to an electron pair donor molecule (Scheme 1).

Advances in Organometallic Chemistry, Volume 66 ISSN 0065-3055 http://dx.doi.org/10.1016/bs.adomc.2016.07.002

#

2016 Elsevier Inc. All rights reserved.

1

2

Q.-Q. Cheng and M.P. Doyle

MLn M = Rh, Cu, Ag, Au, Fe, Co, Ru, Pd, Ir...

EPD=CR2

R2C N2

MLn

EPD:

N2

CR2

Electron pair donor

MLn CR2 Electrophilic metal carbene

Scheme 1 Metal carbene formation from diazo compounds.

Diazo ester

Metal carbene

R

R

N=N=C

LnM C CO2R⬘

CO2R⬘

Change of polarity

R N N C

R L nM C CO2R⬘

CO2R⬘ Nucleophilic center

Electrophilic center

Scheme 2 Change of polarity in the conversion of a diazo ester to the corresponding metal carbene.

Diazo compounds, especially diazocarbonyl compounds, made possible the ease of catalytic entry into metal carbenes,3 sometimes referred to as metal carbenoids. Unlike their aliphatic counterparts in diazoalkanes, especially diazomethane, diazocarbonyl compounds are relatively stable thermally and to weak acids. And among diazocarbonyl compounds, α-diazo esters have been the most utilized. An often overlooked outcome of the conversion of a diazocarbonyl compound to its metal carbene is the change in polarity of the carbenic carbon that accompanies this conversion (Scheme 2). This change renders the carbon position that is adjacent to the electron-withdrawing carbonyl group electrophilic due to its association with the ligated metal. Diazoacetates were the first of the diazocarbonyl compounds to be formed due to their ease of synthesis from glycine,4 and they have been

3

The Selection of Catalysts for Metal Carbene Transformations

the most utilized in transition metal-catalyzed reactions. Efforts to increase the stability of diazo compounds and to also increase their selectivity in catalytic reactions brought diazo ketoesters and diesters into the mainstream of catalytic reactions5; these diazo compounds require more severe reaction conditions for dinitrogen extrusion than do diazo esters. More recently, aryldiazoacetates, vinyldiazoacetates, and enoldiazoacetates have been introduced as having enhanced selectivity and reactivities in a greater diversity of catalytic chemical transformations.6 The dipolar nature of the metal carbenes formed from vinyl- and enoldiazoacetates gives them expanded capabilities for diverse chemical reactions.7 The metal carbenes formed from these diazo compounds have been designated by the terms “donor” and “acceptor” to specify the electron-donating or -withdrawing capabilities of the groups attached to the carbenic carbon and to differentiate them from one another (Scheme 3).8 This review surveys reactions that are formed from this classification of metal carbenes. The importance of electrophilic metal carbenes in catalytic reactions grew out of interests in catalytic cyclopropanation with expanding interests in selectivity, especially stereoselectivity.3,9 Basic understanding of this addition reaction spilled over to other addition processes and, as refinements in catalysts and diazo compounds progressed, into C–H insertion processes (often used with the more general term of “C–H functionalization”)10,11 Since the 1900s

Since the 1970s O CR⬘

H N=N=C

N=N=C CO2R

Diazoacetates

N=N=C CO2R

Diazoacetoacetates & diazomalonates

LnM C CO2R

N=N=C

OR⬙ CO2R

Vinyl- & aryldiazoacetates

Enoldiazoacetates

R⬘

R⬘

LnM C CO2R

Since the 2010s R⬘

CO2R

O CR⬘

H LnM C

Since the 1990s R⬘

LnM C CO2R

OR⬙ CO2R

Comparative standard

Destabilized

Stabilized

Stabilized

Acceptor metal carbenes

Acceptor/acceptor metal carbenes

Donor/acceptor metal carbenes

Donor/acceptor metal carbenes

Scheme 3 Range of diazo esters used for metal carbene formation.

4

Q.-Q. Cheng and M.P. Doyle

and ylide formation and reactions (Scheme 4).12,13 These transformations have received enormous attention and are the subjects of numerous reviews. We do not intend to duplicate this information in this review. Instead, we have captured what we believe are novel processes involving electrophilic metal carbenes, which are often not presented in reviews of traditional metal carbene transformations. Our review surveys the literature since 2013 to include what we believe are novel catalytic strategies and transformations that involve metal carbene intermediates. During this time access to metal carbenes from sources other than diazo compounds was becoming more noticeable (Scheme 5).

f

Scheme 4 Representative traditional transformations of metal carbenes.

d

c

Scheme 5 Multiple routes to metal carbenes.

The Selection of Catalysts for Metal Carbene Transformations

5

Gold-catalyzed processes that convert alkynes to α-carbonyl metallocarbenes have been developed,14 as have the conversion of donor–acceptor cyclopropenes to metallo-enolcarbenes (Scheme 5).15 These developments further define the vitality of metal carbenes for method development and synthesis.

2. ACCEPTOR/ACCEPTOR-SUBSTITUTED METAL CARBENES Advances in transition metal-catalyzed C–C bond coupling reactions have been among the most important contributions to synthetic methodology over the past decade, and diazo compounds have played a significant role in their development. Rhodium(III) complexes, ordinarily thought to be inert toward diazo compounds when compared with dirhodium(II), and acceptor/acceptor-substituted diazo compounds have proven to be efficient catalysts and reagents, respectively. Following the pioneering work of Yu and coworkers,16 a cationic rhodium(III)-catalyzed C–H cyclization reaction of oximes 1 with acceptor/acceptor-substituted diazo compounds 2 was reported by Glorius et al.17 Multisubstituted isoquinoline and pyridine N-oxides 3 were synthesized through a tandem C(sp2)–H activation/ carbene formation and migratory insertion/cyclization/condensation process (Scheme 6). Several other groups, such as Zhou,18,19 Li,20,21 and Chang,22 utilized the same strategy [rhodium(III)-catalyzed C(sp2)–H activation and diacceptor-substituted carbene transformation] in their methodology developments as well. In addition to rhodium(III) catalysts, cobalt(III) and iridium(III) catalysts were also successfully employed in similar carbeneinvolved C–H cyclization reactions by Glorius23 and Patel,24 respectively. Besides carbene functionalization of aromatic C(sp2)–H bonds,16 the Yu group also developed a cationic rhodium(III)-catalyzed cross-coupling reaction between alkyltrifluoroborates 4 and α-diazomalonates 5, furnishing the C(sp3)–C(sp3) bond coupled products 6 in high yields.25 The amide moiety of substrates 4 was crucial to the reactivity (Scheme 7). In comparison with cationic rhodium(III) catalysts, dirhodium(II) catalysts have a much longer history of their utilization in carbene transfer reactions and are still the most attractive candidates for acceptor/acceptorsubstituted carbene transformations. For instance, the dirhodium(II) carboxylate catalyst Rh2(esp)2 (esp ¼ α,α,α0 ,α0 -tetramethyl-1,3-benzenedipropionic acid) exhibited its unique efficiency in aromatic substitution and C(sp3)–H insertion reactions with 5-diazobarbituric acids26; and the chiral dirhodium(II)

6

Q.-Q. Cheng and M.P. Doyle

R N

OH

N2 R2

+ R1

MeOH, 60°C O H 1 2 R = H, alkyl, aryl; R1 = EWG; R2 = H, alkyl, aryl [Rh] – H

R

[Cp*RhCl2]2 (2.5 mol%) AgSbF6 (10 mol%)

N

R2 R1

3 Up to 99% yield – H 2O

C–H activation

R

R

N

N OH [Rh] 2

R1

– N2 Carbene formation R

R

N OH [Rh] O R1

O

R1

OH

[Rh] O

H

N R1

– [Rh]

R2

R2

R2

R N

Migratory insertion

OH OH

R2

OH

O

Scheme 6 Rh(III)-catalyzed C–H cyclization of oximes with acceptor/acceptorsubstituted diazo compounds.

O

O BF3K

X

+ R1

R2 N2

4 X = NMe2, N(OMe)Me X = Et, OtBu

[Cp*RhCl2]2 (2.5 mol%) AgOAc (15 mol%)

O

5

MeOH, 60°C

R2

O X

O R1

O

6 Up to 97% yield 5–8% yield

Scheme 7 Rh(III)-catalyzed cross-coupling of alkyltrifluoroborates with α-diazomalonates.

carboxamidate catalyst Rh2(S-IBAZ)4 (IBAZ ¼ isobutyl 4-oxoazetidine2-carboxylate) provided excellent stereoselectivities in asymmetric cyclopropanation of alkenes, alkynes, and allenes with α-cyano diazophosphonates and α-cyano diazoesters.27 Besides chiral dirhodium(II) complexes, the combination of achiral dirhodium(II) complexes and chiral cocatalysts is another intriguing strategy for asymmetric catalysis and sometimes even provides access to entirely new reactivity patterns. Recently, Schneider and coworkers reported such an

7

The Selection of Catalysts for Metal Carbene Transformations

example.28 Chiral phosphoric acid 10 and Rh2(OAc)4 acted synergistically to generate transient ortho-quinone methides and oxonium ylides from ortho-hydroxy benzhydryl alcohols 7 and α-diazo β-ketoesters 8, respectively, which underwent subsequent cyclization in a conjugate addition/ hemiacetalization event to produce densely functionalized chromans 9 with excellent stereocontrol (Scheme 8). The role of Rh2(OAc)4 is to generate the intermediate metal carbene whose reaction with water forms an intermediate oxonium ylide that through coordination with the chiral phosphoric acid directs stereoselective conjugate addition. Compared to rhodium catalysts, copper catalysts generally have lower abilities to facilitate dinitrogen extrusion from acceptor/acceptor-substituted Ar2

O CO2R

OH + Ar3

Ar1

Ar1

CHCl3, rt

N2

OH 7

Ar2

Rh2(OAc)4 (2 mol%) 10 (5 mol%)

O

8

9

Up to 87% yield, 96% ee

[Rh] – N2 10

OH CO2R OH Ar3

O CO2R

Ar3 H2 O

Ar2 Ar

Ar1

[Rh]

H

O HO O P O O ∗

Ar2

O [Rh] CO2R 3 O

H

Ar1

– [Rh] & 10

OH CO2R COAr 3 OH

CF3 10 CF3 O O P O OH CF3

10 CF3

Scheme 8 Rh(II)/phosphoric acid-catalyzed cyclization of ortho-hydroxy benzhydryl alcohols with α-diazo β-ketoesters.

8

Q.-Q. Cheng and M.P. Doyle

R3 R2 11

R3

O N R1

CO2R5

+ R4 N2 12

R4

Cu(tfacac)2 (10 mol%) Toluene, 4 Å MS, reflux

R2

CO2R5 N 1 R 13 Up to 94% yield

Scheme 9 Cu(II)-catalyzed condensation of imines with α-diazo β-ketoesters.

diazo compounds, presumably because of bidentate coordination of copper with the dicarbonyl of diazo compound, and thus higher reaction temperatures are usually required to achieve satisfactory conversion of diazo substrates in these transformations. In 2015, Yoshikai et al. reported a copper(II)-catalyzed condensation reaction of acyclic and cyclic imines 11 with α-diazo β-ketoesters 12, from which a variety of multisubstituted pyrroles 13 were generated under reflux conditions in toluene (Scheme 9).29

3. ACCEPTOR-SUBSTITUTED METAL CARBENES Diazoacetates are the oldest and most well known of the diazocarbonyl compounds. With one electron-withdrawing group and hydrogen attached to the diazo carbon, these diazo compounds generate acceptor-substituted metal carbenes in their catalytic reactions. Diazoacetates were the cornerstone for major discoveries in asymmetric catalysis involving metal carbene intermediates, especially those occurring by intramolecular addition or insertion.3 Compared with metal carbenes formed from relatively stable diazo compounds bearing two acceptor substituents, monoacceptor-substituted metal carbenes can be more readily generated from their corresponding diazo compounds. In 2013, Tang et al. reported an asymmetric formal [4+ 1]-cycloaddition of α-benzylidene-β-ketoesters 14 with O-aryl diazoacetates 15.30 By using a cationic copper(I) complex of chiral bisoxazoline ligand 17 as the catalyst, the reaction proceeded smoothly at room temperature to furnish tetrasubstituted 2,3-dihydrofurans 16 with high diastereo- and enantioselectivities (Scheme 10). The P
erez group is one of the major contributors to the chemistry of acceptor-substituted metal carbenes, especially those with coinage metals.31 As part of their continuous efforts on transition metal-catalyzed carbenemediated functionalization of methane,32,33 TpðCF3 Þ2 , Br CuðMeCNÞ and TpðCF3 Þ2 , Br AgðTHFÞ were synthesized and found to be active in C–H

9

The Selection of Catalysts for Metal Carbene Transformations

O

O R1

R2 CO2R3 14

CuCl (5 mol%) AgSbF6 (5 mol%) 17 (5.2 mol%)

+

OAr N2

CH2Cl2, 4 Å MS, rt

CO2Ar R1

O R2

R 3O 2C

15

16

R1 = aryl, alkyl; R2 = aryl, alkyl Ar = 2,6-iPr2C6H3

Up to 93% yield, 99:1 dr, 96% ee

[Cu] – N2

– [Cu]

O

H R1

14

O

OAr [Cu]

R 3O 2C

[Cu] CO2Ar

R2

Ph Me O

O N

N 17

Scheme 10 Cu(I)-catalyzed cyclization of α-benzylidene-β-ketoesters with O-aryl diazoacetates.

insertion of methane with ethyl diazoacetate in supercritical carbon dioxide (Scheme 11).34 The lower yield obtained with the copper(I) catalyst was due to its tendency to favor carbene dimerization, a reaction that was disfavored with its silver(I) analogue. To accomplish this transformation the P
erez group had to overcome nearly universal belief that methane was too unreactive to undergo C–H functionalization with a diazoacetate, but their earlier work suggested the high reactivity of their perfluorinated Tp-ligated catalysts.32 Besides diazoacetates, 2,2,2-trifluorodiazoethane (CF3CHN2), either preprepared or generated in situ, is another important acceptor-substituted carbene precursor, which has emerged as an attractive CF3-containing synthon in organic synthesis. Following the pioneering work of Carreira and coworkers [iron(III)- or cobalt(II)-catalyzed cyclopropanation35,36 and rhodium(II)-catalyzed cyclopropenation37], a series of X–H (X ¼ Si, B, P, S, N) bond insertion reactions with CF3CHN2 were recently achieved under the catalysis of Cu(MeCN)4PF6,38 and a AgSbF6-catalyzed N–H insertion with CF3CHN2 was presented as well.39

10

Q.-Q. Cheng and M.P. Doyle

N2 CH4

+

(160 atm.)

H

CH3

Tp(CF3)2,BrM(L) (2 mol%) CO2Et

scCO2 (90 atm.), 40°C M = Cu; L = MeCN M = Ag; L = THF

(0.25 mmol)

N N

Br

CO2Et

4% yield 33% yield

CF3 CF3

H

F3C

H

N N N N

F3C

Br Br CF3

CF3 Tp(CF3)2,Br

Scheme 11 Cu(I)- or Ag(I)-catalyzed C–H insertion of methane with ethyl diazoacetate.

O EWG 18

+ N2

O O 19

O

OMe Ru(II)–Pheox (1 mol%) EWG CH2Cl2, rt or 40°C

20

EWG = ester, ketone, amide PF6

(MeCN)4

OMe

O O

Up to 87% yield, >99:1 dr, 99% ee

Ru N

Ph

O Ru(II)–Pheox

Scheme 12 Ru(II)-catalyzed cyclopropanation of α,β-unsaturated carbonyl compounds with methyl (diazoacetoxy)acetates.

In addition to copper and silver catalysts, ruthenium catalysts have also been employed in acceptor-substituted carbene transformations, especially in cyclopropanation reactions. For instance, Iwasa group developed a chiral ruthenium(II)/phenyloxazoline complex [Ru(II)–Pheox], which efficiently catalyzed the cyclopropanation of α,β-unsaturated carbonyl compounds 18 with methyl (diazoacetoxy)acetates 19 (Scheme 12).40 They also used this ruthenium(II) catalyst in cyclopropanation reactions of vinylcarbamates with diazoacetates,41 as well as those between alkenes and diazomethylphosphonates.42 The advantage of ruthenium catalysts over the more traditional copper and rhodium catalysts for cyclopropanation reactions lies in the strong preference for trans diastereoselection in reactions with monosubstituted alkenes. Ruthenium(II) porphyrin catalysts have been utilized in metal carbene transformations by Che and coworkers. In 2014, they reported a novel

11

The Selection of Catalysts for Metal Carbene Transformations

three-component reaction of acceptor-substituted diazo compounds 21, nitrosoarenes 22, and alkynes 23.43 The ruthenium(II) porphyrin [Ru(p-Cl-TPP)CO] facilitated dinitrogen extrusion from 21 to generate a ruthenium carbene complex, which was trapped by 22 to form a nitrone intermediate. This in situ generated nitrone underwent 1,3-dipolar cycloaddition with 23 to give isoxazolines, and the subsequent rearrangement produced multifunctionalized aziridine 24 (Scheme 13). Note also that chiral cobalt(II) porphyrin-catalyzed intermolecular cyclopropanation44 and intramolecular C–H insertion45 of acceptor/acceptor-substituted diazo compounds were achieved by Zhang and coworkers, and cobalt(III) carbene radicals, rather than Fischer-type or metal-stabilized carbocation-type cobalt(II) carbenes, were suggested as key intermediates in these reactions.

N2 H

+

EWG 21

O N

+ R

R⬘

R

EWG

CH2Cl2, rt or 40°C

Ar 22

Ar N R⬘

[Ru(p-Cl-TPP)CO] (1 mol%)

24

23

O

Up to 96% yield, >99:1 dr

EWG = CO2Et, COAr⬘, PO(OMe)2 [Ru] – N2

[Ru] H

Ar

22 EWG

– [Ru]

N

Ar

O EWG

N

O

23

EWG

Ar N O EWG

R R⬘

Cl

N Cl

N Ru

Cl

N CON

Cl

[Ru(p-Cl-TPP)CO]

Scheme 13 Ru(II)-catalyzed three-component reaction of acceptor-substituted diazo compounds, nitrosoarenes, and alkynes.

12

Q.-Q. Cheng and M.P. Doyle

N2 R 2N

+

NR2

R⬘

CO2Et

Pd(dppb)(MeCN)2(PF6)2 (1.0 or 2.5 mol%)

R2N CH2NR2

1,4-dioxane, 60 or 80°C

R⬘

27 Up to 96% yield

25 26 R = benzyl, alkyl; R⬘ = H, aryl, alkyl

[Pd(II)]

–NR2 [Pd(0)]

CO2Et

–[Pd(0)]

C–N activation

[Pd]

NR2

[Pd]CH2NR2

26 –N2

R⬘

CO2Et

[Pd] CH2NR2 NR R2N[Pd] CH2NR2 2 R⬘

CO2Et

R⬘

CO2Et

Scheme 14 Pd(0)-catalyzed formal C–N insertion of aminals with diazoesters.

Palladium is one of the most broadly used transition metals in modern organic synthesis. The combination of its versatile catalytic activities and metal carbene chemistry opens up new possibilities for synthetic method development. Inspired by their previous observation that palladium(0) species could readily insert into the C–N bond of aminals,46 Huang and coworkers accomplished a formal C–N insertion of aminals 25 with ethyl diazoacetate 26 (R0 ¼ H), furnishing α,β-diamino acid esters 27 via a C– N activation and carbene migratory insertion pathway (Scheme 14).47 It is worth mentioning that other diazoesters 26 (R0 ¼ aryl, alkyl) were also suitable reagents for this transformation, albeit higher catalyst loading and reaction temperature were required. These donor/acceptor-substituted diazo compounds and their corresponding metal carbenes are further discussed in the following section.

4. DONOR/ACCEPTOR-SUBSTITUTED METAL CARBENES 4.1 Alkyl/Acceptor-Substituted Metal Carbenes Before Huang’s successful combination of C–N bond cleavage and metal carbene transformations (Scheme 14), a C–C bond cleavage strategy was also utilized in metal-catalyzed carbene transfer reactions. Inspired by rhodium(I)-catalyzed ring opening of benzocyclobutenols,48,49 Wang and coworkers developed a formal C–C insertion of benzocyclobutenols 28 with α-alkyl-α-diazoacetates 29 (R1 ¼ alkyl).50 The [Rh(cod)(OH)]2 dimer dissociated and then deprotonated 28 to give alkoxyl rhodium(I) species 31. The η2-coordination of the arene moiety to the rhodium center led to the

13

The Selection of Catalysts for Metal Carbene Transformations

dominant cleavage at the C(sp2)–C(sp3) bond through a β-carbon elimination process, affording an aryl rhodium(I) intermediate bearing ketone moiety. Subsequent rhodium carbene formation and migratory insertion followed by intramolecular aldol reaction and protonation completed the transformation (Scheme 15). Note that changing R1 from alkyl to aryl groups did not affect the efficiency of this process. The C(sp2)–H activation/carbene migratory insertion strategy that has been described at the beginning of Section 2 is also applicable to alkyl/ acceptor-substituted metal carbene transformations. More importantly, with catalysis by rhodium(III) complex 35 having a chiral Cp ligand with an atropchiral biaryl backbone, an enantioselective C–H cyclization of aryl hydroxamates 32 with α-alkyl-α-diazoacetates 33 was achieved by Cramer and coworkers, which represents a breakthrough in the development of asymmetric C–H cyclization reactions with diazo compounds (Scheme 16).51 Besides chiral rhodium(III) catalysts, other metal catalysts were also employed in asymmetric reactions involving alkyl/acceptor-substituted metal carbenes. In 2015, Feng et al. reported the synthesis of chiral allenoates 38 from terminal alkynes 36 and α-alkyl-α-diazoacetates 37 in the presence of chiral cationic guanidinium salt (guanidine-HBr) and copper(I) X

X

OH R

N2 +

R1

[Rh(cod)(OH)]2 (2.0 mol%) CO2R2

Toluene, 100°C 28 29 X = H, OMe; R = alkyl, aryl; R1 = alkyl, aryl

R1 CO R2 2 OH R 30 Up to 90% yield 28 – 31

[Rh] OH – H2O X [Rh] O

X

R1 CO R2 2 O [Rh] R

X

R1

R

31

b -Carbon elimination R1 X

CO2R2

X [Rh] O

29

OR2

[Rh] O

[Rh]

– N2 R

O

R R

O

Scheme 15 Rh(I)-catalyzed formal C–C insertion of benzocyclobutenols with diazoesters.

14

Q.-Q. Cheng and M.P. Doyle

O

N2 N H

R

OPiv

O

+ Alk O

32

iPr

35 (5 mol%) (BzO)2 (5 mol%)

O R

NH O

MeCN, 23°C

iPr

Alk

33

34

O

iPr iPr

Up to 92% yield, 93% ee

R⬘

R⬘ Rh

35 R⬘ = OTIPS

Scheme 16 Rh(III)-catalyzed C–H cyclization of aryl hydroxamates with α-alkyl-αdiazoacetates.

N2 +

R 36

CO2R⬘

Alk

CuX (15–50 mol%) Guanidine-HBr (5 mol%)

R

CH2Cl2, 30°C

H

37

Alk • 38

CO2R⬘

X = Br or Br(Me2S) Up to 99% yield, 94% ee O

N

Ph

N Ph H NH NH Br

Guanidine-HBr

Scheme 17 Cu(I)-catalyzed coupling between terminal alkynes and diazoesters.

complexes (Scheme 17).52 Moreover, they presented enantioselective N–H insertion reactions of secondary and primary anilines with α-alkyl-αdiazoacetates that were efficiently catalyzed by palladium(0) in combination with chiral guanidine derivatives.53 Enoldiazo compounds have proven to be versatile reagents for organic synthesis, which not only serve as precursors of metallo-enolcarbenes (see Section 4.3 for details) but also participate in the construction of functionalized diazo compounds.54,55 As part of our continuing efforts in this area, α-diazoesters 41 bearing β-quaternary carbon were synthesized via Lewis acid-catalyzed diastereoselective [3 + 2]-cycloaddition between

15

The Selection of Catalysts for Metal Carbene Transformations

OTBS CO2Me +

CO2Me R

CO2Me

N2 39

40

OTBS CO2Me CO2Me R CO2Me 42 Up to 73% yield

(1) Yb(OTf)3 (5 mol%) DCE, 4 Å MS, rt (2) Rh2(cap)4 (2 mol%) toluene, reflux

O Rh

Lewis acidcatalyzed [3 + 2]cycloaddition

N Rh

1,2-Ca→C migration

– [Rh]

4

Rh2(cap)4

TBSO R

N2 CO2Me CO2Me CO2Me 41

[Rh] TBSO

[Rh] – N2

[Rh] TBSO

CO2Me

CO2Me

b

R

CO2Me CO2Me

R

a

CO2Me CO2Me

Scheme 18 Rh(II)-catalyzed 1,2-C ! C migration of α-diazoesters bearing β-quaternary carbon.

silyl-protected enoldiazoacetate 39 and donor–acceptor cyclopropanes 40. Under the catalysis of dirhodium(II) carboxamidate catalyst Rh2(cap)4, the functionalized alkyl/acceptor-type diazo compounds 41 underwent a carbene formation/1,2-Ca ! C migration process to furnish the ring expansion products 42 (Scheme 18).56 It should be noted that no 1,2-migration of the secondary carbon Cb or the TBSO moiety, as was observed in a related system,55 was observed in this reaction.

4.2 Aryl/Acceptor-Substituted Metal Carbenes The Zhou group have made substantial contributions to the field of aryl/ acceptor-substituted metal carbene transformations, and one of their research foci lies in transition metal-catalyzed enantioselective heteroatom–hydrogen bond insertion reactions.12 In 2013, they disclosed a copper(I)/spirobisoxazoline (SpiroBOX)-catalyzed B–H insertion reaction of borane adducts 44 with α-aryl-α-diazoacetates 43, which provided a new C–B bond-forming methodology and an efficient approach to chiral organoboron compounds (Scheme 19).57 Note that a similar transformation was recently achieved under the catalysis of rhodium(I)/chiral diene complex.58

16

Q.-Q. Cheng and M.P. Doyle

N2 Ar

OR

+

A

BH3

Cu(MeCN)4PF6 (5 mol%) (Ra,S,S)-Ph-SpiroBOX (6 mol%) NaBArF (6 mol%)

O 44 43 R = aryl, alkyl; A = phosphine, amine

A BH2 OR

Ar

CH2Cl2, 25°C

O 45 Up to 96% yield, 94% ee

O N N

Ph Ph

O (Ra,S,S)-Ph-SpiroBOX

Scheme 19 Cu(I)-catalyzed B–H insertion of borane adducts with α-aryl-αdiazoacetates.

Zhou and coworkers also presented that an asymmetric intramolecular cyclopropanation involving aryl/acceptor-substituted metal carbenes was efficiently catalyzed by iron(II)/spirobisoxazoline complex.59 Moreover, a palladium(II)/spirobisoxazoline catalyst provided exceptional enantioselectivities in O–H insertion reactions of phenols with α-aryl-α-diazoacetates,60 while the palladium(II) complex of an axially chiral 2,20 -bipyridine ligand enabled highly enantioselective C–H functionalization of indoles by α-arylα-diazoacetates.61 In addition, Zhou and coworkers recently achieved asymmetric aromatic substitution of anilines with α-aryl-α-diazoacetates under the cooperative catalysis of an achiral dirhodium(II) complex and a chiral spiro phosphoric acid.62 The Hu group has been a leader in multicomponent reactions (MCRs) with donor/acceptor-substituted diazo compounds by using the “delayed proton transfer” strategy.13 As part of their continuous efforts on enantioselective electrophilic trapping of metal carbene-induced zwitterionic intermediates,63,64 a rhodium(II)/phosphoric acid-catalyzed three-component reaction of α-aryl-α-diazoacetates 46, N,N-disubstituted anilines 47, and imines 48 was achieved with excellent stereocontrol.65 The electrophilic addition of rhodium carbene generated from 46 to the phenyl ring of 47 formed a zwitterionic intermediate, which was then trapped by electrophile 48 (asymmetric control was realized during the trapping process in the presence of chiral phosphoric acid 50); and subsequent proton transfer completed the transformation (Scheme 20).

17

The Selection of Catalysts for Metal Carbene Transformations

R2 N2 Ar1

CO2R1

R3

N

Ar3

+

+

Rh2(OAc)4 (1 mol%) 50 (10 mol%)

N Ar2

47

46

R2

R3 N

NHAr3

CH2Cl2, 0°C

Ar2 Ar1 CO2R1 49 Up to 98% yield, >20:1 dr, 99% ee

R3

R2

48

[Rh] – N2

– [Rh] & 50 R2

N

R3

R2

N

N

R3

∗

O

O [Rh] Ar1

47

P

48 & 50

CO2R1 Ar1

[Rh] CO2R1

OR1 iPr

H Ar1

[Rh]O

O[Rh]

Ar1

O O H

OR1

Ar3

N Ar2

iPr

iPr O O P O i OH Pr

iPr

50

iPr

Scheme 20 Rh(II)/phosphoric acid-catalyzed three-component reaction of α-aryl-αdiazoacetates, N,N-disubstituted anilines, and imines.

Besides enantioselectivity, excellent chemoselectivity can also be achieved through the choice of catalysts. In 2014, Zhang et al. reported a cationic gold(I)-catalyzed C(sp2)–H functionalization of unprotected phenols 51 with α-aryl-α-diazoacetates 52 (Scheme 21).66 The gold(I) catalyst exclusively facilitated aromatic substitution, whereas competitive carbene O–H insertion of phenols was favored by other transition metal catalysts including those of rhodium, copper, and palladium.60,67 Diazooxindoles 54 served as another class of aryl/acceptor-substituted carbene precursors in this reaction, which were also employed in gold(I)-catalyzed68 and mercury(II)-catalyzed69 asymmetric cyclopropanations by Zhou and coworkers. Similarly, Sivasankar et al. recently presented a copper(I)/ diphosphine-catalyzed chemoselective insertion of aryl/acceptor-substituted carbenes into the N–H bond, in preference to the O–H bond, of aminophenols.70

18

Q.-Q. Cheng and M.P. Doyle

OH OH

(5 mol%) AgSbF6 (5 mol%)

N2 + Ar

R

(2,4-tBu2C6H3O)3PAuCl CO2R⬘

R

CH2Cl2, rt Ar

51

CO2R⬘ 53 Up to 99% yield

52 R⬘ = Me, Et

OH N2

R⬙ 51 +

O N H 54

(2,4-tBu2C6H3O)3PAuCl (5 mol%) AgSbF6 (5 mol%)

R⬙

CH2Cl2, rt

O N H

55 Up to 93% yield

Scheme 21 Au(I)-catalyzed C–H functionalization of phenols with α-aryl-αdiazoacetates and diazooxindoles.

Moreover, achieving high level of regioselectivity has long captured the interest of chemists and has until recently been a challenge. Davies and coworkers developed a new class of dirhodium(II) carboxylate catalysts bearing chiral cyclopropane moieties, for example, Rh2(R-BPCP)4. While the established dirhodium(II) tetraprolinate catalyst Rh2(R-DOSP)4 preferentially promoted carbene insertion into secondary C–H bonds as a result of competing steric and electronic effects, the sterically more demanding Rh2(R-BPCP)4 favored C–H functionalization of aryl-, vinyl-, or oxygenactivated primary C–H bonds. Thus highly regio- and enantioselective C–H insertion of substrates 57 containing primary benzylic, allylic, or methoxy C–H bonds was achieved with this catalyst (Scheme 22).71 It is worth mentioning that the preference for C(sp3)–H insertion over cyclopropanation, aromatic cycloaddition, and aromatic substitution indicated excellent chemoselectivity of this reaction as well. Additionally, aryl/acceptor-substituted diazo compounds were also successfully employed in rhodium(III)-catalyzed C–H cyclization reactions. In 2013, Rovis et al. reported the efficient synthesis of isoindolones 60 from aryl hydroxamates 32 and a variety of donor/acceptor-substituted diazo compounds 59 through a tandem C(sp2)–H activation/carbene formation and migratory insertion/cyclization process (Scheme 23).72 α-Aryl-αdiazoacetates, diazooxindoles, 1-aryl-2,2,2-trifluorodiazoethanes, and α-benzyl-α-diazoacetates were all suitable substrates for this transformation.

19

The Selection of Catalysts for Metal Carbene Transformations

R

N2 Ar

CO2Me

+ H CH2R

Rh2(R-BPCP)4 (0.5 mol%)

57

56

Ar

CH2Cl2, reflux

CO2Me

58 Up to 88% yield, 97% ee

O

O

Ph Ph

O Rh

4-PhC6H4

O Rh 4

Rh2(R-BPCP)4

Scheme 22 Rh(II)-catalyzed C–H insertion with α-aryl-α-diazoacetates.

O

O N H

R 32

[Cp*RhCl2]2 (1 mol%) CsOAc (20 mol%)

N2

OPiv +

R⬘

EWG

MeCN, 23°C

59 R⬘ = aryl, benzyl; EWG = C(O)X, CF3

R

NH R⬘

EWG

60 Up to 99% yield

Scheme 23 Rh(III)-catalyzed C–H cyclization of aryl hydroxamates with donor/acceptorsubstituted diazo compounds.

In contrast, monoacceptor-substituted diazo compounds dimerized rapidly under the reaction conditions, while diacceptor-substituted diazo compounds were almost unreactive. Chiral iridium(III) complexes containing bulky porphyrin ligands, prepared by Che and coworkers, served as effective catalysts for enantioselective intramolecular carbene insertion into saturated C–H bonds of α-aryl-αdiazoacetates to produce cis-β-lactones in good isolated yields with moderate enantiocontrol.73 Note that the porphyrin ligands stabilize the bonded metal against redox reactions and often allow low catalyst loading.

4.3 Vinyl/Acceptor-Substituted Metal Carbenes Enoldiazoacetates are most commonly employed as precursors of rhodiumenolcarbenes that serve as reactive dipolar species in formal [3 + 3]-cycloadditions with stable dipoles,7 as well as in other [3 + n]-cycloaddition processes (n ¼ 2,74,75 4,76,77 578). Our group have developed dirhodium(II)catalyzed formal [3+ 3]-cycloaddition reactions of enoldiazoacetates with nitrones,79 azomethine imines,80 N-acyliminopyridinium ylides,81 and

20

Q.-Q. Cheng and M.P. Doyle

TBSO

O

R2 NR2 +

R2

Cu(MeCN)4BF4 (5 mol%) 64 (6 mol%)

N

O

R1

CHCl3, 4 Å MS, rt

R1

N2 61

N

O

OTBS

NR2 63 Up to 96% yield, 98% ee O

62 R1 = aryl, alkyl; R2 = aryl, alkyl

– [Cu]

[Cu] – N2 Me Me TBSO

TBS

O

O

O

N

N NR2

Ph

[Cu]

O

Ph

Ph 64

O

Ph

N R2

[Cu] CONR2 R1

[Cu] – [Cu] TBSO NR2

TBSO 65

O

TBSO

O

62

[Cu] – [Cu]

NR2 [Cu]

O NR2

R2

N

O

[Cu]

R1

Scheme 24 Cu(I)-catalyzed [3 + 3]-cycloaddition of nitrones with enoldiazoacetamides.

isoquinolinium/pyridinium methylides,82 providing efficient and highly selective approaches to six-membered heterocycles. While dirhodium(II) catalysts were used in all the above cases, a copper(I)catalyzed formal [3 + 3]-cycloaddition reaction between enoldiazoacetamides 61 and nitrones 62 was recently uncovered.83 The copper(I) complex of the chiral bisoxazoline ligand 64 facilitated the formation of copper-enolcarbenes (in equilibrium with donor–acceptor cyclopropenes 65), and subsequent vinylogous attack by the nitrones followed by intramolecular cyclization produced cycloaddition products 63 (Scheme 24). Interestingly, changing the catalyst to copper(I) triflate switched the reaction pathway from [3+ 3]-cycloaddition to Mukaiyama–Mannich addition with the retention of diazo functionality, whereas dirhodium catalysts exhibited low reactivities with the recovery of nitrones under otherwise identical conditions. The copper triflate catalyst with more open coordination sites is favorable to promote a TBS migration process to furnish the Mannich addition product. According to the aforementioned studies, the combination of dirhodium(II) catalysts and enoldiazoacetates,7 as well as copper(I) catalysts and enoldiazoacetamides,83 has proven successful in metal enolcarbene transformations, especially in [3 + 3]-cycloadditions; in contrast, dirhodium(II) catalysts combined with enoldiazoacetamides were poorly

21

The Selection of Catalysts for Metal Carbene Transformations

reactive in [3 + 3]-cycloaddition process,83 but exhibited their unique efficiency in the following system.84 Rhodium(II) perfluorobutyrate [Rh2(pfb)4] facilitated dinitrogen extrusion from enoldiazoacetamides 61 to form rhodium-enolcarbenes, which then underwent intramolecular rearrangement with elimination of the rhodium catalyst to generate donor–acceptor cyclopropenes 65; simultaneously, carbonyl ylides were formed from α-diazoketones 66 with the promotion of Rh2(pfb)4 and then trapped by the cyclopropenes, rather than reacting with the rhodiumenolcarbenes, to produce annulation products 67 (Scheme 25). It should be noted that use of enoldiazoacetates or copper catalysts in this reaction afforded only minor amounts of their respective annulation products. The Davies group is one of the major contributors to the chemistry of vinyl/acceptor-substituted metal carbenes. Besides the established CPCR (cyclopropanation/Cope rearrangement)85,86 and CHCR (C–H functionalization/Cope rearrangement)87 reactions, one of their recent foci lies in transition metal-catalyzed [3 + 2]-cycloaddition with vinyldiazoacetates. For example, enantioselective [3 + 2]-cycloaddition between nitrones 62 and terminally substituted vinyldiazoacetates 68 was achieved by catalysis with Rh2(R-TPCP)4 (Scheme 26).88 Moreover, they presented a gold(I)-catalyzed enantioselective [3 + 2]-cycloaddition reaction of terminally substituted vinyldiazoacetates with enol ethers, in which the vinyl/acceptor-substituted metal carbenes served as three-carbon synthons, O

O TBSO

O

N2 NR2

+

Ar

N2

OR⬘

Rh2(pfb)4 (2 mol%)

O

OTBS

CHCl3, 4 Å MS, rt R⬘O

NR2 O 67 Up to 84% yield, >20:1 dr

O 66

61

Ar

[Rh] – N2

– N2 TBSO

O

O Rh n

NR2

C 3F 7 O Rh

[Rh]

4

– [Rh]

Rh2(pfb)4

O [Rh] NR2 +

TBSO 65

Ar

O

Scheme 25 Rh(II)-catalyzed α-diazoketones.

O

– [Rh]

OR⬘

annulation

between

enoldiazoacetamides

and

22

Q.-Q. Cheng and M.P. Doyle

R4

N2 R1

CO2R2

+

N

O

Rh2(R-TPCP)4 (2 mol%)

R4 N O

Pentane, rt

R3

R3

R1 CO2R2

69

68 62 R1 = alkyl; R3 = aryl; R4 = aryl

Up to 72% yield, 99% ee Ph Ph

O Rh Ph O Rh 4

Rh2(R-TPCP)4

Scheme 26 Rh(II)-catalyzed [3 + 2]-cycloaddition of nitrones with vinyldiazoacetates. O O R

N H

[Cp*RhCl2]2 (2 mol%) CsOAc (1 equiv.)

N2

OPiv +

EWG

MeCN, rt

R⬘

R⬘ EWG 71 Up to 97% yield

32 70 R⬘ = H, Me, aryl; EWG = ester, ketone

Scheme 27 Rh(III)-catalyzed vinyldiazoacetates.

C–H

NH R

cyclization

of

aryl

hydroxamates

with

rather than two-carbon synthons in the former case.89 Note that Sun and coworkers utilized gold(I) catalysts in their methodology developments involving vinyl/acceptor-substituted metal carbenes.90,91 Additionally, vinyl/acceptor-substituted diazo compounds were also subject to rhodium(III)-catalyzed C–H cyclization reactions with aryl hydroxamates 32. Unlike their alkyl-51 and aryl-substituted72 analogues, vinyldiazoacetates 70 (EWG ¼ ester) reacted as three-carbon components to afford azepinone derivatives 71 in high yields (Scheme 27).92 Vinyldiazoketones 70 (EWG ¼ ketone) were applicable in this transformation as well. However, a terminally substituted vinyldiazoacetate, namely styryldiazoacetate, only underwent intramolecular dipolar addition to give the corresponding pyrazole under identical reaction conditions.

5. DONOR- AND DONOR/DONOR-SUBSTITUTED METAL CARBENES Among donor- and donor/donor-substituted diazo compounds, diaryl diazomethanes are relatively stable and have been used as carbene precursors

23

The Selection of Catalysts for Metal Carbene Transformations

in several metal-catalyzed carbene transfer reactions. In 2013, Hu et al. reported a catalytic gem-difluoroolefination of diaryl diazomethanes 72 with the Ruppert–Prakash reagent (TMSCF3).93 On the basis of their previous study about copper-mediated trifluoromethylation of diazoesters with TMSCF3,94 trifluoromethyl copper(I) species (CuCF3) generated from CuI, CsF, and TMSCF3 was suggested as the active catalyst, which facilitated dinitrogen extrusion from 72 to form the copper carbene intermediate. Subsequent migratory insertion followed by β-fluoride elimination produced gem-difluoroolefin 73 (Scheme 28). Due to their stability, readily prepared and easily handled characteristics, N-tosylhydrazones have emerged as important reagents in this area, which can be transformed in situ into unstabilized diazo compounds in the presence of base.95,96 Under catalysis of palladium(0) complexes, a series of crosscoupling reactions involving N-tosylhydrazones have been developed, and the migratory insertion of palladium carbene was suggested to be the key step of the catalytic cycle.97,98 The Wang group has been a leader in the uses of palladium catalysis for cross-coupling with diazo compounds and the uses of N-tosylhydrazones to generate diazo compounds.99 In a 2015 contribution, they reported a palladium(0)-catalyzed carbene insertion into Si–Si bonds.100 The palladium catalyst activated the Si–Si bonds of compounds 75 via oxidative addition and reacted with diazo compounds that were generated in situ from N-tosylhydrazones 74 to form palladium carbene species; and the following migratory insertion and reductive elimination completed the transformation (Scheme 29). N2 Ar1

Ar2 72

+ TMSCF3

CF2

CuI (5 mol%), CsF (5 mol%) 1,4-dioxane/NMP (10:1), rt

Ar1

Ar2

73, up to 86% yield

(2 equiv.) CuI CsF CuCF3

– N2

Ar2

CuF b-Fluoride elimination

Carbene formation

CuCF3 Ar1

TMSCF3

Migratory insertion

Cu Ar1

F CF2 Ar2

Scheme 28 Cu(I)-catalyzed gem-difluoroolefination of diaryl diazomethanes with TMSCF3.

24

Q.-Q. Cheng and M.P. Doyle

NNHTs +

R

SiMe2F SiMe2F

Pd(dba)2 (4 mol%) P(OCH2)3CEt (8 mol%)

R⬘ LiOtBu (3 equiv.) 74 75 toluene, 60°C R = aryl, alkenyl, alkynyl; R⬘ = H, Me

LiOtBu

[Pd]

N2

SiMe2F [Pd] SiMe2F

+ R⬘

R

Oxidative addition

SiMe2F

FMe2Si

R⬘

R 76

Up to 99% yield

Reductive elimination

FMe2Si SiMe2F [Pd] – N2

– [Pd]

FMe2Si [Pd] SiMe2F

R R⬘ Migratory insertion

R Carbene formation

R⬘

Scheme 29 Pd(0)-catalyzed carbene insertion into Si–Si bonds.

NNHTs +

ArF H

CuI/1,10-phen (20 mol%) LiOtBu (3 equiv.)

ArF

R⬘ R R⬘ 1,4-dioxane/MeCN (1:1) 77 78 79 90°C R = aryl, alkyl; R⬘ = H, alkyl, aryl Up to 88% yield R

LiOtBu

ArFH – ArF[Cu]

[Cu] ArF

N2 R

+ R⬘

ArF [Cu]

[Cu] – N2

R

R⬘

ArF [Cu] R

R⬘

Scheme 30 Cu(I)-catalyzed alkylation of polyfluoroarenes with N-tosylhydrazones.

Besides palladium(0) catalysts, the Wang group has also utilized copper(I) catalysts in carbene transfer reactions from N-tosylhydrazones, especially when the other reactants bear relatively acidic C–H bonds.101 Recently, they reported a copper(I)-catalyzed cross-coupling between N-tosylhydrazones 77 and polyfluoroarenes 78.102 The reaction was initiated by deprotonation of 78 followed by transmetalation to generate polyfluoroaryl copper species, which then underwent a carbene formation/migratory insertion/protonation process to afford products 79 (Scheme 30).

The Selection of Catalysts for Metal Carbene Transformations

25

Additionally, rhodium(III) catalysts have shown their ability to activate C(sp2)–H bonds via oxidative addition and participate in carbene formation and migratory insertion. This strategy, which has been discussed extensively in the previous sections, was also applied to donor- and donor/donor-substituted carbene transfer reactions, and both diaryl diazomethanes103 and N-tosylhydrazones104 were successfully employed in these transformations.

6. SUMMARY As is evident from the examples presented in this chapter, catalystdriven electrophilic metal carbene chemistry is a rapidly evolving enterprise. No longer limited to copper and dirhodium(II), the range of catalysts now extends to those that include gold, silver, iron, cobalt, palladium, ruthenium, and iridium and shows activities with transition metal oxidation states, like that of rhodium(III), which were not previously thought to be viable. The carbon sources of carbenes have also seen a dramatic expansion—both in the carbene precursors (diazo compounds, cyclopropenes, alkynes) and in the stereoelectronic design of diazo compounds (donor and acceptor, for example) that are the most common reactants. These developments have also expanded the diversity of chemical transformations for which metal carbene chemistry is applicable. Once thought to have limited applicability, the field has grown to add new cycloaddition processes (e.g., [3+ 2]- and [3 + 3]-cycloadditions) to cyclopropanation and cyclopropenation ([2+ 1]-cycloaddition), to evolve the broad and continually developing area of ylide generation and reactions, and to link diverse processes such as catalytic coupling with carbene processes. Chiral ligands on the transition metal have made possible high enantiocontrol of these diverse transformations; and, as is evident in the many examples provided in this chapter, electrophilic metal carbene chemistry is applicable to the synthesis of highly complex chemical structures with high selectivities. The future holds numerous opportunities for further developments.

ACKNOWLEDGMENTS We are grateful for the support that our research has received over the years from the National Science Foundation and the National Institute of General Medical Sciences and, more recently, from UTSA and the Feik Foundation. The students and colleagues who have conducted this research are the innovators who have made rapid progress possible.

26

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REFERENCES 1. Moss RA, Doyle MP, eds. Contemporary Carbene Chemistry. New York, NY: John Wiley & Sons Inc; 2014. 2. D€ otz KH, Stendel J. Fischer carbene complexes in organic synthesis: metal-assisted and metal-templated reactions. Chem Rev. 2009;109:3227–3274. 3. Doyle MP, McKervey MA, Ye T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides. New York, NY: John Wiley & Sons Inc; 1998. € 4. Bredt J, Holz W. Uber das β-pericyclocamphanon ein beitrag zur aufkl€arung der konstitution des camphenons angelis (schiffscher dehydrocampher). J Prakt Chem. 1917;95:133–159. 5. Burke SD, Grieco PA. Intramolecular reactions of diazocarbonyl compounds. Org React. 1979;26:361–475. 6. Ford A, Miel H, Ring A, Slattery CN, Maguire AR, McKervey MA. Modern organic synthesis with α-diazocarbonyl compounds. Chem Rev. 2015;115:9981–10080. 7. Xu X, Doyle MP. The [3 + 3]-cycloaddition alternative for heterocycle syntheses: catalytically generated metalloenolcarbenes as dipolar adducts. Acc Chem Res. 2014;47:1396–1405. 8. Davies HML, Manning JR. Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion. Nature. 2008;451:417–424. 9. Lebel H, Marcoux J-F, Molinaro C, Charette AB. Stereoselective cyclopropanation reactions. Chem Rev. 2003;103:977–1050. 10. Doyle MP, Liu Y, Ratnikov M. Catalytic, asymmetric, intramolecular carbon– hydrogen insertion. Org React. 2013;80:1–131. 11. Doyle MP, Duffy R, Ratnikov M, Zhou L. Catalytic carbene insertion into C–H bonds. Chem Rev. 2010;110:704–724. 12. Zhu S-F, Zhou Q-L. Transition-metal-catalyzed enantioselective heteroatom– hydrogen bond insertion reactions. Acc Chem Res. 2012;45:1365–1377. 13. Guo X, Hu W. Novel multicomponent reactions via trapping of protic onium ylides with electrophiles. Acc Chem Res. 2013;46:2427–2440. 14. Yeom H-S, Shin S. Catalytic access to α-oxo gold carbenes by N–O bond oxidants. Acc Chem Res. 2014;47:966–977. 15. Deng Y, Doyle MP. Versatile donor–acceptor cyclopropenes in metal carbene transformations. Isr J Chem. 2016;56:399–408. 16. Chan W-W, Lo S-F, Zhou Z, Yu W-Y. Rh-catalyzed intermolecular carbenoid functionalization of aromatic C–H bonds by α-diazomalonates. J Am Chem Soc. 2012;134:13565–13568. 17. Shi Z, Koester DC, Boultadakis-Arapinis M, Glorius F. Rh(III)-catalyzed synthesis of multisubstituted isoquinoline and pyridine N-oxides from oximes and diazo compounds. J Am Chem Soc. 2013;135:12204–12207. 18. Zhou B, Chen Z, Yang Y, et al. Redox-neutral rhodium-catalyzed C–H functionalization of arylamine N-oxides with diazo compounds: primary C(sp3)–H/C (sp2)H activation and oxygen-atom transfer. Angew Chem Int Ed Engl. 2015;54:12121–12126. 19. Yang Y, Wang X, Li Y, Zhou B. A [4+1] cyclative capture approach to 3H-indole-Noxides at room temperature by rhodium(III)-catalyzed C–H activation. Angew Chem Int Ed Engl. 2015;54:15400–15404. 20. Yu S, Liu S, Lan Y, Wan B, Li X. Rhodium-catalyzed C–H activation of phenacyl ammonium salts assisted by an oxidizing C–N bond: a combination of experimental and theoretical studies. J Am Chem Soc. 2015;137:1623–1631.

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21. Qi Z, Yu S, Li X. Rh(III)-catalyzed synthesis of N-unprotected indoles from imidamides and diazo ketoesters via C–H activation and C–C/C–N bond cleavage. Org Lett. 2016;18:700–703. 22. Dateer RB, Chang S. Rh(III)-catalyzed C–H cyclization of arylnitrones with diazo compounds: access to N-hydroxyindolines. Org Lett. 2016;18:68–71. 23. Zhao D, Kim JH, Stegemann L, Strassert CA, Glorius F. Cobalt(III)-catalyzed directed C–H coupling with diazo compounds: straightforward access towards extended π-systems. Angew Chem Int Ed Engl. 2015;54:4508–4511. 24. Phatake RS, Patel P, Ramana CV. Ir(III)-catalyzed synthesis of isoquinoline N-oxides from aryloxime and α-diazocarbonyl compounds. Org Lett. 2016;18:292–295. 25. Lu Y-S, Yu W-Y. Cp*Rh(III)-catalyzed cross-coupling of alkyltrifluoroborate with α-diazomalonates for C(sp3)–C(sp3) bond formation. Org Lett. 2016;18: 1350–1353. 26. Best D, Burns DJ, Lam HW. Direct synthesis of 5-aryl barbituric acids by rhodium(II)catalyzed reactions of arenes with diazo compounds. Angew Chem Int Ed Engl. 2015;54:7410–7413. 27. Lindsay VNG, Fiset D, Gritsch PJ, Azzi S, Charette AB. Stereoselective Rh2(S-IBAZ)4-catalyzed cyclopropanation of alkenes, alkynes, and allenes: asymmetric synthesis of diacceptor cyclopropylphosphonates and alkylidenecyclopropanes. J Am Chem Soc. 2013;135:1463–1470. 28. Alamsetti SK, Spanka M, Schneider C. Synergistic rhodium/phosphoric acid catalysis for the enantioselective addition of oxonium ylides to ortho-quinone methides. Angew Chem Int Ed Engl. 2016;55:2392–2396. 29. Tan WW, Yoshikai N. Copper-catalyzed condensation of imines and α-diazo-βdicarbonyl compounds: modular and regiocontrolled synthesis of multisubstituted pyrroles. Chem Sci. 2015;6:6448–6455. 30. Zhou J-L, Wang L-J, Xu H, Sun X-L, Tang Y. Highly enantioselective synthesis of multifunctionalized dihydrofurans by copper-catalyzed asymmetric [4+1] cycloadditions of α-benzylidene-β-ketoester with diazo compound. ACS Catal. 2013;3:685–688. 31. Dı´az-Requejo MM, P
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39. Luo H, Wu G, Zhang Y, Wang J. Silver(I)-catalyzed N-trifluoroethylation of anilines and O-trifluoroethylation of amides with 2,2,2-trifluorodiazoethane. Angew Chem Int Ed Engl. 2015;54:14503–14507. 40. Chanthamath S, Takaki S, Shibatomi K, Iwasa S. Highly stereoselective cyclopropanation of α, β-unsaturated carbonyl compounds with methyl (diazoacetoxy) acetate catalyzed by a chiral ruthenium(II) complex. Angew Chem Int Ed Engl. 2013;52:5818–5821. 41. Chanthamath S, Nguyen DT, Shibatomi K, Iwasa S. Highly enantioselective synthesis of cyclopropylamine derivatives via Ru(II)-Pheox-catalyzed direct asymmetric cyclopropanation of vinylcarbamates. Org Lett. 2013;15:772–775. 42. Chanthamath S, Ozaki S, Shibatomi K, Iwasa S. Highly stereoselective synthesis of cyclopropylphosphonates catalyzed by chiral Ru(II)-Pheox complex. Org Lett. 2014;16:3012–3015. 43. Reddy AR, Zhou C-Y, Che C-M. Ruthenium porphyrin catalyzed three-component reaction of diazo compounds, nitrosoarenes, and alkynes: an efficient approach to multifunctionalized aziridines. Org Lett. 2014;16:1048–1051. 44. Xu X, Zhu S, Cui X, Wojtas L, Zhang XP. Cobalt(II)-catalyzed asymmetric olefin cyclopropanation with α-ketodiazoacetates. Angew Chem Int Ed Engl. 2013;52:11857–11861. 45. Cui X, Xu X, Jin L-M, Wojtas L, Zhang XP. Stereoselective radical C–H alkylation with acceptor/acceptor-substituted diazo reagents via Co(II)-based metalloradical catalysis. Chem Sci. 2015;6:1219–1224. 46. Xie Y, Hu J, Wang Y, Xia C, Huang H. Palladium-catalyzed vinylation of aminals with simple alkenes: a new strategy to construct allylamines. J Am Chem Soc. 2012; 134:20613–20616. 47. Qin G, Li L, Li J, Huang H. Palladium-catalyzed formal insertion of carbenoids into aminals via C  N bond activation. J Am Chem Soc. 2015;137:12490–12493. 48. Ishida N, Sawano S, Masuda Y, Murakami M. Rhodium-catalyzed ring opening of benzocyclobutenols with site-selectivity complementary to thermal ring opening. J Am Chem Soc. 2012;134:17502–17504. 49. Ding L, Ishida N, Murakami M, Morokuma K. sp3–sp2 vs sp3–sp3 C–C site selectivity in Rh-catalyzed ring opening of benzocyclobutenol: a DFT study. J Am Chem Soc. 2014;136:169–178. 50. Xia Y, Liu Z, Liu Z, et al. Formal carbene insertion into C–C bond: Rh(I)-catalyzed reaction of benzocyclobutenols with diazoesters. J Am Chem Soc. 2014;136: 3013–3015. 51. Ye B, Cramer N. Asymmetric synthesis of isoindolones by chiral cyclopentadienylrhodium(III)-catalyzed C–H functionalizations. Angew Chem Int Ed Engl. 2014;53: 7896–7899. 52. Tang Y, Chen Q, Liu X, Wang G, Lin L, Feng X. Direct synthesis of chiral allenoates from the asymmetric C–H insertion of α-diazoesters into terminal alkynes. Angew Chem Int Ed Engl. 2015;54:9512–9516. 53. Zhu Y, Liu X, Dong S, et al. Asymmetric N–H insertion of secondary and primary anilines under the catalysis of palladium and chiral guanidine derivatives. Angew Chem Int Ed Engl. 2014;53:1636–1640. 54. Xu X, Hu W-H, Doyle MP. Highly enantioselective catalytic synthesis of functionalized chiral diazoacetoacetates. Angew Chem Int Ed Engl. 2011;50:6392–6395. 55. Xu X, Qian Y, Zavalij PY, Doyle MP. Highly selective catalyst-dependent competitive 1,2-C ! C, -O ! C, and -N ! C migrations from β-methylene-βsilyloxy-β-amido-α-diazoacetates. J Am Chem Soc. 2013;135:1244–1247. 56. Cheng Q-Q, Qian Y, Zavalij PY, Doyle MP. Lewis acid/rhodium-catalyzed formal [3+3]-cycloaddition of enoldiazoacetates with donor–acceptor cyclopropanes. Org Lett 2015;17:3568–3571.

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57. (a) Cheng Q-Q, Zhu S-F, Zhang Y-Z, Xie X-L, Zhou Q-L. Copper-catalyzed B–H bond insertion reaction: a highly efficient and enantioselective C–B bond-forming reaction with amine–borane and phosphine–borane adducts. J Am Chem Soc. 2013;135:14094–14097. (b) Cheng Q-Q, Xu H, Zhu S-F, Zhou Q-L. Enantioselective copper-catalyzed B–H bond insertion reaction of α-diazoketones. Acta Chim Sin. 2015;73:326–329. 58. Chen D, Zhang X, Qi W-Y, Xu B, Xu M-H. Rhodium(I)-catalyzed asymmetric carbene insertion into B–H bonds: highly enantioselective access to functionalized organoboranes. J Am Chem Soc. 2015;137:5268–5271. 59. Shen J-J, Zhu S-F, Cai Y, Xu H, Xie X-L, Zhou Q-L. Enantioselective iron-catalyzed intramolecular cyclopropanation reactions. Angew Chem Int Ed Engl. 2014;53: 13188–13191. 60. Xie X-L, Zhu S-F, Guo J-X, Cai Y, Zhou Q-L. Enantioselective palladium-catalyzed insertion of α-aryl-α-diazoacetates into the O–H bonds of phenols. Angew Chem Int Ed Engl. 2014;53:2978–2981. 61. Gao X, Wu B, Huang W-X, Chen M-W, Zhou Y-G. Enantioselective palladiumcatalyzed C–H functionalization of indoles using an axially chiral 2,20 -bipyridine ligand. Angew Chem Int Ed Engl. 2015;54:11956–11960. 62. Xu B, Li M-L, Zuo X-D, Zhu S-F, Zhou Q-L. Catalytic asymmetric arylation of α-aryl-α-diazoacetates with aniline derivatives. J Am Chem Soc. 2015;137: 8700–8703. 63. Qiu H, Li M, Jiang L-Q, et al. Highly enantioselective trapping of zwitterionic intermediates by imines. Nat Chem. 2012;4:733–738. 64. Zhang D, Qiu H, Jiang L, Lv F, Ma C, Hu W. Enantioselective palladium(II) phosphate catalyzed three-component reactions of pyrrole, diazoesters, and imines. Angew Chem Int Ed Engl. 2013;52:13356–13360. 65. Jia S, Xing D, Zhang D, Hu W. Catalytic asymmetric functionalization of aromatic C–H bonds by electrophilic trapping of metal-carbene-induced zwitterionic intermediates. Angew Chem Int Ed Engl. 2014;53:13098–13101. 66. Yu Z, Ma B, Chen M, Wu H-H, Liu L, Zhang J. Highly site-selective direct C–H bond functionalization of phenols with α-aryl-α-diazoacetates and diazooxindoles via gold catalysis. J Am Chem Soc. 2014;136:6904–6907. 67. Liu Y, Yu Z, Zhang JZ, Liu L, Xia F, Zhang J. Origins of unique gold-catalysed chemo- and site-selective C–H functionalization of phenols with diazo compounds. Chem Sci. 2016;7:1988–1995. 68. Cao Z-Y, Wang X, Tan C, Zhao X-L Zhou J, Ding K. Highly stereoselective olefin cyclopropanation of diazooxindoles catalyzed by a C2-symmetric spiroketal bisphosphine/Au(I) complex. J Am Chem Soc. 2013;135:8197–8200. 69. Cao Z-Y, Zhou F, Yu Y-H, Zhou J. A highly diastereo- and enantioselective Hg(II)catalyzed cyclopropanation of diazooxindoles and alkenes. Org Lett. 2013;15:42–45. 70. Ramakrishna K, Murali M, Sivasankar C. Chemoselective carbene insertion into the N–H bond over O–H bond using a well-defined single site (P–P)Cu(I) catalyst. Org Lett. 2015;17:3814–3817. 71. Qin C, Davies HML. Role of sterically demanding chiral dirhodium catalysts in siteselective C–H functionalization of activated primary C–H bonds. J Am Chem Soc. 2014;136:9792–9796. 72. Hyster TK, Ruhl KE, Rovis T. A coupling of benzamides and donor/acceptor diazo compounds to form γ-lactams via Rh(III)-catalyzed C–H activation. J Am Chem Soc. 2013;135:5364–5367. 73. Wang J-C, Zhang Y, Xu Z-J, Lo VK-Y, Che C-M. Enantioselective intramolecular carbene C–H insertion catalyzed by a chiral iridium(III) complex of D4-symmetric porphyrin ligand. ACS Catal. 2013;3:1144–1148.

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74. Smith AG, Davies HML. Rhodium-catalyzed enantioselective vinylogous addition of enol ethers to vinyldiazoacetates. J Am Chem Soc. 2012;134:18241–18244. 75. Xu X, Leszczynski JS, Mason SM, Zavalij PY, Doyle MP. Expedient access to substituted 3-amino-2-cyclopentenones by dirhodium-catalyzed [3+2]-annulation of silylated ketene imines and enoldiazoacetates. Chem Commun. 2014;50:2462–2464. 76. Davies HML, Ahmed G, Churchill MR. Asymmetric synthesis of highly functionalized 8-oxabicyclo[3.2.1]octene derivatives. J Am Chem Soc. 1996;118:10774–10782. 77. Schwartz BD, Denton JR, Lian Y, Davies HML, Williams CM. Asymmetric [4+3] cycloadditions between vinylcarbenoids and dienes: application to the total synthesis of the natural product (–)-5-epi-vibsanin E. J Am Chem Soc. 2009;131:8329–8332. 78. Lee DJ, Ko D, Yoo EJ. Rhodium(II)-catalyzed cycloaddition reactions of non-classical 1,5-dipoles for the formation of eight-membered heterocycles. Angew Chem Int Ed Engl. 2015;54:13715–13718. 79. Wang X, Xu X, Zavalij PY, Doyle MP. Asymmeric formal [3+3]-cycloaddition reactions of nitrones with electrophilic vinylcarbene intermediates. J Am Chem Soc. 2011;133:16402–16405. 80. Qian Y, Zavalij PY, Hu W, Doyle MP. Bicyclic pyrazolidinone derivatives from diastereoselective catalytic [3+3]-cycloaddition reactions of enoldiazoacetates with azomethine imines. Org Lett. 2013;15:1564–1567. 81. Xu X, Zavalij PY, Doyle MP. Highly enantioselective dearomatizing formal [3+3] cycloaddition reactions of N-acyliminopyridinium ylides with electrophilic enol carbene intermediates. Angew Chem Int Ed Engl. 2013;52:12664–12668. 82. Xu X, Zavalij PY, Doyle MP. Catalytic asymmetric syntheses of quinolizidines by dirhodium-catalyzed dearomatization of isoquinolinium/pyridinium methylides— the role of catalyst and carbene source. J Am Chem Soc. 2013;135:12439–12447. 83. Cheng Q-Q, Yedoyan J, Arman H, Doyle MP. Copper-catalyzed divergent addition reactions of enoldiazoacetamides with nitrones. J Am Chem Soc. 2016;138:44–47. 84. Cheng Q-Q, Yedoyan J, Arman H, Doyle MP. Dirhodium(II)-catalyzed annulation of enoldiazoacetamides with α-diazoketones: an efficient and highly selective approach to fused and bridged ring systems. Angew Chem Int Ed Engl. 2016;55:5573–5576. 85. Davies HML, Stafford DG, Doan BD, Houser JH. Tandem asymmetric cyclopropanation/Cope rearrangement. A highly diastereoselective and enantioselective method for the construction of 1,4-cycloheptadienes. J Am Chem Soc. 1998; 120:3326–3331. 86. Guzma´n PE, Lian Y, Davies HML. Reversal of the regiochemistry in the rhodiumcatalyzed [4+3] cycloaddition between vinyldiazoacetates and dienes. Angew Chem Int Ed Engl. 2014;53:13083–13087. 87. Davies HML, Lian Y. The combined C–H functionalization/Cope rearrangement: discovery and applications in organic synthesis. Acc Chem Res. 2012;45:923–935. 88. Qin C, Davies HML. Rh2(R-TPCP)4-catalyzed enantioselective [3+2]-cycloaddition between nitrones and vinyldiazoacetates. J Am Chem Soc. 2013;135:14516–14519. 89. Briones JF, Davies HML. Enantioselective gold(I)-catalyzed vinylogous [3+2] cycloaddition between vinyldiazoacetates and enol ethers. J Am Chem Soc. 2013; 135:13314–13317. 90. Zhang D, Xu G, Ding D, Zhu C, Li J, Sun J. Gold(I)-catalyzed diazo coupling: strategy towards alkene formation and tandem benzannulation. Angew Chem Int Ed Engl. 2014;53:11070–11074. 91. Xu G, Zhu C, Gu W, Li J, Sun J. Gold(I)-catalyzed diazo cross-coupling: a selective and ligand-controlled denitrogenation/cyclization cascade. Angew Chem Int Ed Engl. 2015;54:883–887. 92. Cui S, Zhang Y, Wang D, Wu Q. Rh(III)-catalyzed C–H activation/[4+3] cycloaddition of benzamides and vinylcarbenoids: facile synthesis of azepinones. Chem Sci. 2013;4:3912–3916.

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93. Hu M, He Z, Gao B, Li L, Ni C, Hu J. Copper-catalyzed gem-difluoroolefination of diazo compounds with TMSCF3 via C–F bond cleavage. J Am Chem Soc. 2013;135:17302–17305. 94. Hu M, Ni C, Hu J. Copper-mediated trifluoromethylation of α-diazo esters with TMSCF3: the important role of water as a promoter. J Am Chem Soc. 2012;134: 15257–15260. 95. Fulton JR, Aggarwal VK, de Vicente J. The use of tosylhydrazone salts as a safe alternative for handling diazo compounds and their applications in organic synthesis. Eur J Org Chem. 2005;2005:1479–1492. 96. Shao Z, Zhang H. N-Tosylhydrazones: versatile reagents for metal-catalyzed and metal-free cross-coupling reactions. Chem Soc Rev. 2012;41:560–572. 97. Barluenga J, Vald
es C. Tosylhydrazones: new uses for classic reagents in palladiumcatalyzed cross-coupling and metal-free reactions. Angew Chem Int Ed Engl. 2011;50:7486–7500. 98. Xia Y, Hu F, Liu Z, et al. Palladium-catalyzed diarylmethyl C(sp3)–C(sp2) bond formation: a new coupling approach toward triarylmethanes. Org Lett. 2013;15: 1784–1787. 99. Xiao Q, Zhang Y, Wang J. Diazo compounds and N-tosylhydrazones: novel crosscoupling partners in transition-metal-catalyzed reactions. Acc Chem Res. 2013;46:236–247. 100. Liu Z, Tan H, Fu T, et al. Pd(0)-catalyzed carbene insertion into Si–Si and Sn–Sn bonds. J Am Chem Soc. 2015;137:12800–12803. 101. Liu Z, Wang J. Cross-coupling reactions involving metal carbene: from C¼C/C–C bond formation to C–H bond functionalization. J Org Chem. 2013;78:10024–10030. 102. Xu S, Wu G, Ye F, et al. Copper(I)-catalyzed alkylation of polyfluoroarenes through direct C–H bond functionalization. Angew Chem Int Ed Engl. 2015;54: 4669–4672. 103. Qiu L, Huang D, Xu G, Dai Z, Sun J. Realized C–H functionalization of aryldiazo compounds via rhodium relay catalysis. Org Lett. 2015;17:1810–1813. 104. Hu F, Xia Y, Ye F, et al. Rhodium(III)-catalyzed ortho alkenylation of N-phenoxyacetamides with N-tosylhydrazones or diazoesters through C–H activation. Angew Chem Int Ed Engl. 2014;53:1364–1367.

CHAPTER TWO

Recent Advances in Asymmetric Metal-Catalyzed Carbene Transfer from Diazo Compounds Toward Molecular Complexity N.J. Thumar, Q.H. Wei, W.H. Hu* Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Chemical Engineering, East China Normal University, Shanghai, China *Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Insertion Reaction 2.1 C–H Functionalization 2.2 N–H Insertion 2.3 O–H Insertion 2.4 S–H Insertion 2.5 Si–H Insertion 2.6 B–H Insertion 3. Cycloadditions 3.1 [2C + n] Cycloaddition 3.2 [3C + n] Cycloaddition 3.3 [4C + n] Cycloaddition 3.4 [5C + n] Cycloaddition 3.5 [6C + n] Cycloaddition 3.6 Miscellaneous 4. Ylide Formation 4.1 Trapping Tactic 4.2 Cascade Reaction 5. Summary Acknowledgments References

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1. INTRODUCTION Metal-based catalysis for the decomposition of diazo compounds has been known for more than a century.1 In particular, they have been extensively used as precursors of metal carbenes, a key putative intermediate that is generated from the reaction between a metal complex and a diazo compound via the loss of dinitrogen. The catalytic cycle for the conversion of a diazo compound to a metalstabilized carbene, and subsequent transfer of the metal-carbene intermediate to diverse transformations such as cyclopropanation, cyclopropenation, C–H insertions, heteroatom–hydrogen insertions, ylide-forming reactions, 1,2-migration, Wolff rearrangement, dimerization, olefination, oligomerization, polymerization, or cross-coupling reactions are shown in Scheme 1. With the appropriate catalyst design, these transformations afford diverse and complex molecules from simple starting materials accompanied by high degrees of chemo-, regio-, diastereo-, and enantioselectivity. Recently, this diazo chemistry has been well summarized in a number of excellent reviews.1 Herein we have focused on the most recent advances in synthetic transformations since 2011 with the hope that this chapter will help to the development of new transformations in the area.

N2 R

N2 R′ C–H insertion / C–H functionalization / C–H activation N–H insertion, O–H insertion, S–H insertion Si–H insertion, B–H insertion MLn Cyclopropanation/cyclopropenation [2C+n],[3C+n],[4C+n],[5C+n],[6C+n]

MLn R

R′

Ylide formation Cascade reaction, trapping tactic

EWG H Acceptor carbene

EWG

EWG LnM

LnM

LnM

EDG Donor–acceptor carbene

EWG Acceptor–acceptor carbene

EDG = Electron-donating groups EWG = Electron-withdrawing group

Scheme 1 Metal-carbene formation from diazo molecule, its reactivity, and types of metal carbenes.

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2. INSERTION REACTION Since carbon–heteroatom (C–X) bonds are ubiquitous and generally are one of the most active parts of organic compounds, the research on construction of C–X bonds is an important process. Transition metal-catalyzed insertion of carbenes ligands, in situ generated from diazo compounds, into the heteroatom–hydrogen (X–H, X ¼ N, O, S, Si, etc.) bonds are the straightforward way to construct the carbon–heteroatom bond. In short, insertion reactions, also known as α,α-substitution reactions of diazocarbonyl compounds, consist of the replacement of the diazo function by two new substituents, where one is a hydrogen atom and the other a heteroatom or a carbon. Of the various X–H combinations, C–H, N–H, and O–H insertion reactions have been the most studied and developed. The prospective of insertion reactions in organic synthesis has much improved recently, and there now exist a large family of reactions especially involving N- and O-based functionalities. Furthermore, the ability to incorporate asymmetric synthesis into some of these processes has achieved synthetically competitive levels. Enantioselective insertion processes have been advanced a great deal in the last 5 years as mentioned (Scheme 2).

2.1 C–H Functionalization Carbon–hydrogen bonds are the most common in organic compounds and thus the selective functionalization of C–H bonds is one of the most encompassing transformations nowadays. However, it is still challenging because of the inert and stable properties of C–H bonds. Fox group reported an enantioselective, Rh2(S-NTTL)4-catalyzed C–H functionalization of indoles by α-alkyl-α-diazoesters (Scheme 3A). The reaction pathway

Scheme 2 Mechanistic pathway for insertion reactions of metal carbenes.

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Scheme 3 Rhodium- or palladium-catalyzed C–H functionalization of indoles.

involves an intermediate with an oxocarbenium character. The rhodium– carbene intermediates generated from α-alkyl-α-diazoesters react with indoles at C(3) to give R-alkyl-R-indolylacetates in high yield and enantioselectivity. The asymmetric induction may occur via dynamic kinetic resolution of a rhodium enolate intermediate and the results were satisfactory for α-alkyl-α-diazoesters (Scheme 3).2 A new strategy was later developed by Hu group to achieve the asymmetric C–H functionalization of indoles via enantioselective protonation. It is based on the use of Rh2(OAc)4 and chiral phosphoric acids with aryl diazoacetates as the carbene source (Scheme 3B). Reaction of the metal–carbene intermediate with an indole at C-3 position generates a zwitterionic species. A bifunctional chiral phosphoric acid serves as a chiral proton shuttle and helps the proton transfer process via an enantioselective protonation to finish the reaction providing good to high enantioselectivity (up to 94% ee) in excellent yield (up to 99% yield).3 A further study with α-alkyl-α-diazoesters using palladium-based catalysts with chiral 2,20 -bipyridine ligand afforded indol-3-acetates with up to 98% ee (Scheme 3C). In addition, this strategy was also useful for the asymmetric O–H insertion in phenols using α-alkyl-α-diazoesters: α-aryl-αaryloxy acetates were obtained with up to 99% ee, a strategy later expanded within the field of asymmetric synthesis.4 The potential of C–H functionalization for the smooth synthesis of complex molecules was reported by Davies group for 2,3dihydrobenzofurans by using two sequential C–H functionalization steps (Scheme 4)5: a rhodium-catalyzed enantioselective intermolecular

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Scheme 4 Sequential C–H functionalization leading to dihydrobenzofurans.

Scheme 5 C–H bond functionalization of unprotected phenols with α-aryl-αdiazoacetates.

C–H insertion followed by a palladium-catalyzed C–H activation/C–O cyclization. Further modification of the 2,3-dihydrobenzofuran structures was achievable by a subsequent palladium-catalyzed intermolecular Heck-type sp2 C–H functionalization step. A tris(2,4-di-tert-butylphenyl)phosphite-derived gold complex promoted the C–H bond functionalization of unprotected phenols, generated from the decomposition of α-aryl α-diazoacetates, in moderate to excellent yields at room temperature (Scheme 5).6 An interesting feature of this reaction is the unique C–H bond functionalization instead of O–H insertion and/or C]C bond cyclopropanation. This protocol also favors acyl-protected anilines affording the corresponding para C–H bond functionalization products in moderate to good yields. This scalable methodology is also useful for the synthesis of intermediate for cannabinoid CB1 receptors and arylboron derivatives. Because of its mild reaction conditions, this protocol seems appropriate for the late-stage modification of significant entities. A highly site-selective C–H functionalization of primary C–H bonds has already effectively accomplished, at variance with the established, dirhodium tetraprolinate catalyzed, preferential C–H functionalization of secondary C–H bonds. The key point stands on the use of the bulky catalyst dirhodium tetrakis[(R)-(1-(biphenyl)-2,2-diphenylcyclopropanecarboxylate)] that forces the Rh-carbene C–H bond interaction to occur at primary C–H sites. Davies

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group applied this catalytic system (Scheme 6)7 to the late-stage primary C–H functionalization of complex molecules such as ()-α-cedrene or a steroid. Furthermore, these reactions proceed with high levels of asymmetric induction. This study illustrates that highly site-selective C–H functionalization can be achieved without the need of directing groups. This study indicates that the catalyst can be the major controlling element of the site selectivity of C–H functionalization: primary C–H bonds of benzylic, allylic, and methoxy substrates were successfully modified with this catalyst. In another work by Davies group with methyl ethers (Scheme 7),8 the enantioselectivity and yields dropped when an electron-withdrawing group is present on the benzene ring. Moreover, mixtures of products were observed when the two benzylic sites showed similar steric environments like 4-ethyltoluene. These limitations were surpassed by introducing 2,2,2-trichloroethyl aryl and heteroaryl diazoacetates, a new class of reagents for carbene C–H bond functionalization in the presence of dirhodium triarylcyclopropane carboxylate catalyst [Rh2(R-BPCP)4], that facilitated the enantioselective intermolecular C–H functionalization of a range of methyl ethers with high levels of site selectivity and enantioselectivity when compared to sterically similar primary and secondary C–H bonds. Furthermore, this reagent also enables C–H functionalization with relatively unreactive substrates. Catalyst-controlled selective C–H bond functionalization of brucine, a natural product that contains 22 C–H bonds in different chemical environments, was studied leading to three distinct brucine derivatives in a catalystcontrolled fashion, proving the potential of this approach to offer late-stage diversification of complex molecules. Rh2(TPA)4-catalyzed carbene transfer promoted the formation of the C–H insertion product in 50% yield as a single diastereomer (Scheme 8).9 On the other hand, the use of Rh2(Oct)4

Scheme 6 C–H bond functionalization of primary C–H bonds in toluene derivatives.

Scheme 7 C–H bond functionalization of methyl ethers.

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Scheme 8 Effect of the rhodium catalyst on site-selective C–H bond functionalization of brucine.

induced the formation of Stevens rearrangement product in 74% yield. A bulky catalyst should generally favor functionalization of the less-sterically encumbered C–H bond. However, Rh2(S-BTPCP)4 enabled an unexpected selective C–H insertion at the methine position in 39% yield as a single diastereomer. This study proves that manipulation of the favored site for functionalization in a catalyst-controlled manner is possible. Moreover, Davies group applied sequential C–H functionalization strategy as a key step in the total syntheses of Dictyodendrins A and F. The common N-alkylpyrrole core of these molecules is fully functionalized by rhodium(II)-catalyzed double C–H functionalization at the C2 and C5 positions (Scheme 9).10 Doyle group reported the Rh(II)-catalyzed cis-selective asymmetric intramolecular C–H functionalization reaction of enoldiazoacetamides giving β-lactam derivatives as only cis-diastereoisomer in high yield with up to 99% enantiomeric excess, but copper(I) and silver(I) catalysts have shown up variations in reactivity and selectivity toward this reaction. The enantioinduction relies on the influence of the silylenol group of the carbene moiety. The reaction occurs via formation of donor–acceptor cyclopropene as intermediate, the Buchner reaction being totally excluded in these transformations (Scheme 10).11

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Scheme 9 Rh-catalyzed regioselective C–H functionalization in one step of the total synthesis of Dictyodendrins A and F.

Scheme 10 Enantioselective C–H bond functionalization of enoldiazoacetamide.

Scheme 11 Rh-catalyzed synthesis of benzo-γ-sultams.

The Rh-catalyzed intramolecular aromatic C–H functionalization of N,N-diaryl diazosulfonamides results in efficient synthesis of 1-aryl-benzoγ-sultams or 1-aryl-1,3-dihydrobenzo[c]isothiazole-2,2-dioxides in 65–99% yields under mild conditions, with high efficiency, and using low catalyst loadings. This is the first example of diazosulfonamides, a new class of compounds suitable for the preparation of N-aryl-substituted benzo-γ-sultams that are not accessible before (Scheme 11).12 Transition metal-catalyzed asymmetric C(sp2)–H insertion reactions are scarce. Zhou group reported on the asymmetric arylation reaction of α-arylα-diazoacetates with aniline derivatives cooperatively catalyzed by dirhodium(II) trifluoroacetate complex and chiral spiro phosphoric acids (SPAs; Scheme 12).13 A method for the synthesis of α-diarylacetates having versatile building blocks with a diaryl tertiary chiral center in good

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Scheme 12 Enantioselective catalytic arylation of α-aryl-α-diazoacetates.

Scheme 13 Rhodium-catalyzed cameroonan-7α-ol.

cyclization

step

in

the

synthesis

of

()-

Scheme 14 C–H bond functionalization step in total synthesis of (+)-lithospermic acid.

yields (up to 95%) with high enantioselectivities (up to 97% ee). The enantioselectivity is controlled by a chiral SPA-promoted proton shift in a zwitterionic intermediate. The first total synthesis of enantiomerically pure ()-cameroonan-7α-ol demonstrates the strategic efficiency of C–H bond functionalization in natural product synthesis. Rh(II)-catalyzed C–H functionalization of α-diazoβ-ketoester readily gives cyclized products in 85% yield (Scheme 13).14 Total synthesis of (+)-lithospermic acid reported by Yu group was significantly assisted by two key C–H functionalization reactions, including an intramolecular asymmetric C–H carbene insertion using Davies’ Rh(II) catalyst to construct the chiral dihydrobenzofuran from the diazo reagent. The C–H insertion reaction proceeded smoothly at room temperature and provided the trans-dihydrobenzofuran core in good yield and diastereoselectivity (85%, 8:1 dr) (Scheme 14).15

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The key enantio-determining step in total synthesis of Maoecrystal V reported by Davies group, a highly modified ent-kauranoid, is the Rh-catalyzed asymmetric C–H bond functionalization for the construction of a key benzofuran intermediate precursor in 84% ee (Scheme 15).16 The rhodium and chiral Brønsted acid-cocatalyzed process for the electrophilic trapping of zwitterionic intermediates by imines has been extensively studied by Hu group. Reactive electrophiles used to trap the zwitterionic intermediates, which normally undergo a formal C–H bond insertion reaction, allowed to obtain polyfunctionalized indole and oxindole derivatives in a single step with excellent diastereoselectivity and enantioselectivity. Oxindole core was synthesized in situ from N,N-disubstituted diazoacetamides via a rhodium(II)-catalyzed intramolecular C–H functionalization leading to a zwitterion intermediate which in the presence of the Brønsted acid-activated imine gave oxindole molecule. Rhodium acetate was selected as the catalyst for the initiation step, and several chiral PPAs were screened to catalyze the imine activation. Analogously, 3-substituted indoles were prepared by intermolecular C–H functionalization of indoles using phenyldiazoacetates and a PPA-activated imine, again using rhodium(II) catalysis. Polyfunctionalized indole and oxindole derivatives were obtained in a single-step transformation with excellent diastereoselectivity and enantioselectivity (Scheme 16).17

Scheme 15 C–H functionalization in total synthesis of ()-Maoecrystal V.

Scheme 16 Enantioselective C–H bond functionalization of indoles and synthesis of oxindole via trapping reactions.

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On successful trapping of a zwitterionic intermediate for C–H functionalization of indole with excellent chemo-, diastereo-, and enantioselectivity, Hu group advanced within this strategy to include pyrrole to trap zwitterionic intermediates derived from pyrrole and diazo compounds. An effective catalytic system, based on palladium (II) with chiral Brønsted acids, was found to catalyze an enantioselective three-component reaction of unprotected pyrroles, diazoesters, and imines. In this reaction, highly enantioselective C–H bond functionalization of an unprotected pyrrole is observed, through palladium–carbene activation, to produce pyrrole derivatives bearing two stereogenic centers in a diastereoselectively tunable fashion. The mechanism involves the formation of a zwitterionic intermediate from pyrrole and palladium carbene to attack imine to form the desired trapped product under the control of chiral phosphoric acids. Chiral palladium(II) phosphate is responsible for enantioinductive transformations. This study represents the first highly enantioselective reaction in palladium carbene-mediated transformations, entirely diverse from rhodium/chiral PPA cocatalysis (Scheme 17).18 New transformations based on the asymmetric electrophilic trapping of active intermediates generated from metal carbenes and catalytic asymmetric functionalization of aromatic C–H bonds with a similar strategy have been described. A first asymmetric functionalization of aromatic C–H bonds through reaction of N,N-disubstituted anilines with α-diazoesters and imines in the presence of Rh(II)/chiral phosphoric acid cocatalysts was studied by Hu group. The presence of the imine as the third component in this reaction allows it to participate as a reactive electrophile and trap the metal-carbene-induced zwitterion intermediate. This strategy provides an efficient route for densely substituted β-aminoesters with all-carbon benzylic quaternary stereocenters, an important skeleton in medicinal chemistry (Scheme 18).19

Scheme 17 Enantioselective palladium(II) phosphate-catalyzed reaction of diazoacetates, pyrroles, and imines.

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Scheme 18 Catalytic asymmetric aromatic C–H bond functionalization by trapping of a metal-carbene intermediate.

2.2 N–H Insertion The C–N bond has a significant place in both synthetic and naturally made molecules. Among the various methods for C–N bond formation, insertion of α-diazocarbonyl compound into an N–H bond is one of the straightforward routes to α-amino acid derivatives. It is generally accepted that N–H insertion most likely proceeds via a secondary protic ammonium ylide intermediate, having both acidic ammonium ion and basic carbon centers. This highly unstable and reactive intermediate may undergo [1,2] Stevens, [2,3]sigmatropic rearrangements, or [1,2] proton shifts. Insertion reactions were extensively studied by Zhou group using chiral ligand systems. An asymmetric N–H insertion of various α-alkyl-αdiazoesters with anilines catalyzed by chiral spiro copper catalyst was accomplished with excellent enantioselectivity (up to 98% ee) and provided an efficient approach for the preparation of optically active α-amino acid derivatives and the chiral arylalanine herbicide (R)-flamprop-M-isopropyl, a crop protection agent. A stepwise insertion mechanism involving a proton transfer as the rate-limiting step was supported by correlations between the electronic properties of the substrates and the enantioselectivity of the reaction as well as by the observation of a first-order kinetic isotope effect. The chiral spiro copper catalysts, a novel binuclear structure, allow for efficient chiral induction in the asymmetric N–H insertion reactions (Scheme 19).20 In a advanced study by the same group, enantioselective N–H insertion reaction of α-diazoketones by using cooperative catalysis by dirhodium(II) carboxylates and chiral SPAs has been described: fast reaction rates and mild and neutral conditions offer a new access to synthetically important chiral α-aminoketones, versatile building blocks in organic synthesis. This strategy is useful for the preparation of a chiral insertion product which could be readily converted to (L)-()-733,061, which is a selective antagonist for the NK1 receptor (Scheme 20).21

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Scheme 19 N–H bond functionalization by carbene insertion of α-alkyl-α-diazoesters with anilines.

Scheme 20 Enantioselective N–H bond insertion of α-diazoketones.

Moody group reported the total synthesis of Telomestatin, a potent enzyme telomerase inhibitor, consisting of seven oxazole rings and one sulfur-containing thiazoline in a macrocyclic arrangement. The key steps in this total synthesis are the use of dirhodium(II)-catalyzed reactions of diazocarbonyl compounds to generate six oxazole rings. This approach has allowed access to synthetic oxazoles with different degrees of conformational planarity that bind strongly and stabilize G-quadruplex structures. The power of rhodium-carbene methodology in organic chemical synthesis provides a structural framework for developing new potential therapeutic agents for cancer (Scheme 21).22

2.3 O–H Insertion The history of O–H bond insertion reactions with diazocarbonyl substrates is almost similar of their N–H counterparts. Transition metal-assisted enantioselective O–H insertion reaction of carbene units through the decomposition of diazo compounds in the presence of hydroxylic compounds (water, alcohols, phenols, or carboxylic acids) forms a new C–O bond, via insertion of the carbene into the O–H bond, to provide chiral α-alkyloxy or α-aryloxy carbonyl compounds, which are useful synthetic intermediates for the construction of natural products and biologically active

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Scheme 21 Synthesis of tris-oxazole fragment en route to the total synthesis of Telomestain.

Scheme 22 Copper-catalyzed asymmetric intramolecular phenolic O–H insertion.

molecules. Various chiral metal complexes have been developed to catalyze the carbenoid insertion into O–H bonds with high enantioselectivity. Zhou group reported the copper-catalyzed intramolecular insertion of carbene groups into phenolic O–H bonds in the presence of spirobisoxazoline ligands, affording chiral 2-carboxy dihydrobenzofurans, dihydrobenzopyrans, and tetrahydrobenzo[b]-oxepines in high yields (86–99%) and excellent enantioselectivities (94–99% ee). The reaction proceeds under mild and neutral conditions and affords cyclic ethers with five- to sevenmembered rings. This strategy is also applied to the synthesis of (R,S,S, S)-()-nebivolol, an antihypertensive drug (Scheme 22).23 Moreover, asymmetric O–H bond insertion reactions between α-arylα-diazoacetates and phenols under mild and neutral method resulted in optically active α-aryl-α-aryloxyacetates. Palladium complexes of chiral spiro-bisoxazoline ligands were found as efficient and highly enantioselective catalysts for the reaction. The insertion product can be easily transformed into tomoxetine, a well-known chiral drug for the treatment of psychiatric disorders (Scheme 23).24

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Scheme 23 Palladium-catalyzed asymmetric O–H insertion of α-aryl-α-diazoacetates into phenols.

Scheme 24 Rh2(OAc)4-catalyzed O–H insertion in total synthesis of (+)-steenkrotin A and ()-steenkrotin A.

Ding and coworkers recently reported the first enantioselective total synthesis of ()-steenkrotin A and (+)-steenkrotin A. The key step in the context of this review is the O–H bond functionalization by carbene insertion catalyzed by rhodium acetate in 73% and 75% yields, respectively (Scheme 24).25

2.4 S–H Insertion In line with previous sections, a direct approach for the construction of C–S bonds is through the insertion of a carbene group into a S–H bond. This methodology offers a versatile way of placing sulfur-containing substituents adjacent to carbonyl groups in ketones and esters. Zhou group reported the highly enantioselective S–H bond insertion reaction using cooperative catalysis of dirhodium(II) carboxylates and chiral SPAs. A 31P NMR study showed that no ligand exchange between dirhodium(II) carboxylates and SPAs occurred in the reaction. The dirhodium(II) carboxylate catalyzed the decomposition of diazo compounds to generate the sulfonium ylide, and the chiral SPAs was proposed as a chiral proton shuttle for the proton

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shift in reaction (Scheme 25).26 This method is also applied to the synthesis of chiral sulfur-containing compounds such as (S)-thiomandelate and (S)Eflucimibe. Recently, even electron-rich iron complexes27 or engineered myoglobin-based catalysts28 have been also evaluated for the S–H insertion and found to give moderate to good insertion products.

2.5 Si–H Insertion Access to chiral silanes in a highly enantioenriched form remains a great challenge and the development of new methods continues to be an active area of research because α-chiral silanes are particularly valuable intermediates in stereoselective synthesis. A direct and efficient approach that has been increasingly explored recently is the transition metal-mediated asymmetric carbene insertion into the Si–H bond of silanes. Xu et al. reported the first rhodium(I)-catalyzed asymmetric Si–H insertion reaction of α-diazoesters in the presence of chiral bicyclo[2.2.2]octadiene ligands (Scheme 26).29 This system tolerated a broad range of substrates including α-diazophosphonates, employed for the first time in Si–H insertion, and gave versatile chiral α-silyl esters and phosphonates with excellent

Scheme 25 S–H bond functionalization by carbene insertion of α-aryl-α-diazoesters with mercaptan.

Scheme 26 Asymmetric Si–H insertion of α-diazoesters.

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enantioselectivities (up to 99% ee). The insertion mechanism proceeds via a concerted pathway, with a stereospecific rhodium(I)-carbene intermediate. Si–H insertion reaction was also a key step in the stereoselective total synthesis of the antibiotic ()-virginiamycin M2. The enantioenriched silane (S)-isomer precursor was prepared via a Rh(II)- or Cu(I)-catalyzed carbene Si–H insertion with high ee (Scheme 27).30 X–H carbene insertion has also been developed with high selectivity over β-hydride elimination. The Si–H insertion reaction of triethylsilane with 3-diazo-4-phenyl-dihydrofuran-2-one (Scheme 28)31 resulted in both excellent yield (92%) and diastereoselectivity (>95:5). The analog insertions into S–H of ethane- and benzenethiol or into N–H bonds of aniline take place smoothly affording the insertion products. O–H insertion reactions of allyl and ethyl alcohols proceeded with good yield of the α-functionalized product; however, diastereoselectivity is modest. Significantly, no cyclopropanation was observed from allyl alcohol.

2.6 B–H Insertion Remarkable progress has been made in the direct formation of C–B bonds through C–H bond activation. However, the electron-deficient B–H bond does not readily undergo insertion reaction with electron-deficient Fischer-type metal carbenes like other X–H bonds. An efficient approach by Zhou group to chiral organoboron compounds via copper-catalyzed B–H bond insertion reaction with amine- and phosphine–borane adducts was accessible with high yield and enantioselectivity. Cu(MeCN)4PF6 was used as catalyst and chiral spirobisoxazoline ligand (Ra,S,S) as ligand.

Scheme 27 Rh(II)-catalyzed Si–H carbene insertion in the total synthesis of ()-virginiamycin M 2 .

Scheme 28 X–H insertion reactions of cyclic α-diazocarbonyl compounds.

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The B–H bond insertion reaction provides a new C–B bond-forming methodology (Scheme 29).32 Xu group reported the rhodium(I)-catalyzed asymmetric B–H insertion of α-diazo carbonyl compounds with amine–borane adduct leading to highly enantioenriched α-boryl esters and ketones under mild conditions. The chiral bicyclo[2.2.2]octadiene ligand has facilitated the high enantioselectivities (93–99% ee) to the synthesis of these interesting organoboranes which are potential intermediates in organic synthesis (Scheme 30).33 Similarly, another reliable way to build boron–carbon bonds was reported by Curran and Li. Rh(II) salts catalyzed the reactions between NHC boranes and diazocarbonyl compounds giving stable α-NHC-boryl carbonyl compounds in good yields. The reaction is tolerated by a variety of NHC borane and diazocarbonyl components. It presumably occurs by insertion of a transient rhodium carbene into a boron–hydrogen bond of the NHC borane. Data available indicate that NHC boranes are superb carbenophiles and highly reactive toward rhodium carbenes (Scheme 31).34

Scheme 29 Copper-catalyzed B–H bond carbene insertion reactions.

Scheme 30 Rh(I)-catalyzed asymmetric B–H insertion reactions of α-diazoketones and esters.

Scheme 31 Rhodium-catalyzed B–H carbene bond insertion reactions.

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3. CYCLOADDITIONS Metal-catalyzed cycloaddition reactions are most important tools for synthesis in organic chemistry enabling them to build carbocyclic and heterocyclic structures. These structures can then be used to develop a broad range of functional materials, including pharmaceuticals, agrochemicals, dyes, and optics. Cycloaddition plays a major role in the synthesis of natural products and biologically active substances. This review provides several examples of metal-catalyzed cycloaddition reactions, including [2 + 1], [3+ 2], or [4+ 2], among others. Attention is also given to intramolecular reactions, which often provide a rapid and efficient route to polycyclic compounds, and to the stereochemistry of the reactions, with particular emphasis in those developing enantiomeric excesses.

3.1 [2C + n] Cycloaddition The cyclopropane ring is found as a basic structural element in a wide range of natural products and biologically active compounds. Moreover, cyclopropane motifs have also been used as versatile synthetic intermediates in the synthesis of more functionalized compounds, the metal-catalyzed cyclopropanation of olefinic bonds using diazo compounds being the most developed methodology. Recently, several chiral rhodium catalysts have been developed for intermolecular cyclopropanation reactions. Davies and coworkers described a new class of chiral triarylcyclopropane carboxylate catalysts Rh2(R-BTPCP)4 showing its high efficiency and selectivity in diastereo- and enantioselectivity cyclopropanations with of donor/acceptor carbene groups (Scheme 30).35 Moreover, they developed a heterogeneous immobilized recyclable silicasupported dirhodium(II) tetraprolinate catalyst (Rh2(S-DOSP)3(S-silicaSP)) for the enantioselective cyclopropanation and cyclopropenation of donor/ acceptor carbenes, having similar level of yield and enantioinduction (97%) to Rh2(S-DOSP)4.36 When cyclopropanation with electron-deficient alkenes is catalyzed by chiral dirhodium(II) tetracarboxylates, Rh2(S-TCPTAD)4, high levels of enantioselectivity up to 98% ee were achieved, in comparison with other rhodium(II) catalyst (Scheme 32).37 The uses of electron-deficient alkenes in cyclopropanation reactions using rhodium-catalyzed decomposition of diazo compounds are rare. Charette and coworkers reported a highly stereoselective Rh2(S-TCPTTL)4-catalyzed system with diacceptor diazo compounds (NO2, CN, or COOMe and

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Scheme 32 Rh2(R-BTPCP)4-catalyzed cyclopropanation reactions.

Scheme 33 Rh2(S-TCPTTL)4 and Rh2(S-IBAZ)4-catalyzed cyclopropanation with diacceptor diazo compounds.

PMP-ketone) as effective carbene precursors. High levels of diastereo- and enantioselectivity were found, the products being further transformed into valuable products (Scheme 33).38 They have also developed the first catalytic asymmetric synthesis of diacceptor cyclopropane derivatives, using a α-cyano diazophosphonate and Rh2(S-IBAZ)4 as the chiral catalyst, under mild reaction conditions. Because of the isosteric character of carboxylates and phosphonates, α-cyano cyclopropylcarboxylates also have been obtained under similar reaction conditions. The scope was also extended to the development

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of the first catalytic enantioselective method for the synthesis of diacceptor alkylidenecyclopropanes (Scheme 33).39 Charette and coworkers also reported the first general route to complex fluorinated cyclopropanes, catalyzed by Rh2(OPiv)4 with di- and trisubstituted fluorinated olefins, that led to the corresponding polysubstituted fluorocyclopropanes in yields up to 99% with up to 99:1 dr.40 The same group also reported enantioinduction in the synthesis of halo-cyclopropanes using a chiral rhodium catalyst [Rh2{(S)-IBAZ}4]: a series of highly functionalized chiral halo-cyclopropanes were prepared in good yields, moderate diastereoselectivity up to 91:9 dr with excellent enantiomeric ratios up to 99% ee.41 A method for the synthesis of chiral heteroleptic rhodium(II) tetracarboxylate catalysts using the tetrachlorophthaloyl unit, an efficient polarity-control group, which facilitates the separation of each synthesized catalyst, has been also reported. These complexes were evaluated toward enantioinduction in the asymmetric cyclopropanation of alkenes with α-nitro diazoacetophenones.42 Tilset and coworkers synthesized several rhodium(I) N-heterocyclic iminocarbene-type catalysts and evaluated their activity in cyclopropanation reactions for diastereoselective purposes.43 Further studies indicate that the efficiency of cis-diastereoselectivity can be improved by evaluating different activating agents for cis-diastereoselective cyclopropanation of various alkenes and α-diazoacetates (yields up to 99% with cis-selectivities higher than 99%).44 Metal-catalyzed intermolecular reactivity of α-diazocarbonyl compounds having α-alkyl substitution is usually slower than β-hydride migration, so chemoselectivity of α-alkyl diazoesters that tolerate β-hydrogens is challenging. Fox developed an enantioinductive mixed-ligand catalyst Rh2(S-PTTL)3TPA that has improved the activity of the structurally similar chiral crown complex Rh2(S-PTTL)4 in the asymmetric cyclopropanation and cyclopropenation of α-alkyl-α-diazoesters.45 They have also reported that Rh2(OPiv)4 catalyzed the cyclopropanation and cyclopropenation of cyclic α-diazocarbonyl compounds, containing β-tertiary C–H bonds, with styrene to proceed with high selectivity over β-hydride elimination with yields up to 88% with 95:5 dr (Scheme 34).46 Hansen examined (halodiazomethyl)phosphonates, a new class of diazo compounds, as reagents for diastereoselective intermolecular Rh2(esp)2-catalyzed cyclopropanation with alkenes. Their activity was moderate to high in terms of yields (up to 82%) with high diastereomeric ratios (17:1) under 0.1 mol% catalyst loadings.47

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Scheme 34 Cyclopropanation/cyclopropenation reactions of cyclic diazocarbonyl compounds.

Scheme 35 Ru(II)-pheox-catalyzed asymmetric cyclopropanation of α,β-unsaturated carbonyl compound with diazo acetates.

Recently, ruthenium(II) pheoxazoline catalysts have also appeared as enantioinductive catalysts for the cyclopropanation of terminal alkenes with succinimidyl diazoacetate as the carbene source with good results (yields up to 99% with trans selectivity >99:1 and 99% ee).48 Cyclopropanation of vinylcarbamate derivatives with diazoesters resulted in cyclopropylamines in high yield, with excellent diastereoselectivity (up to 96:4) and enantioselectivity (up to 99% ee).49 Moreover, electron-deficient olefins also gave the corresponding dicarbonyl cyclopropanes in high yields with excellent diastereoselectivity (up to >99:1) and enantioselectivity (up to 99% ee) (Scheme 35).50 Similarly, diethyl diazomethylphosphonate and alkenes, including α,β-unsaturated carbonyl compounds, afforded cyclopropylphosphonates in high yields and with excellent diastereoselectivity (up to 99:1) and enantioselectivity (up to 99% ee).51 Access to alkylidenecyclopropanes with high diastereoselectivity (up to 99/1) and enantioselectivity (up to 99% ee) has also achieved by Ru(II)-pheox-catalyzed asymmetric intermolecular cyclopropanation of allenes with succinimidyl diazoacetate.52 Other transition metals have been found to be successful in this area. Zhou reported the first example of the asymmetric cyclopropanation of olefins with diazooxindole by using (R)-difluorphos/Hg(II) complex53 as the catalyst with

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moderate enantiomeric results. The asymmetric version of this reaction was developed by Zhou and Ding using a spiroketal bisphosphine derived and a chiral digold complex. Both cis- and trans-1,2-disubstituted alkenes give spirocyclopropyloxindoles (yield/ee up to 95%) that are useful in medicinal research.54 Bis(oxazoline) (BOX) ligands of copper-catalyzed cyclopropanation of both cis- and trans-1,2-disubstituted alkenes lead to the corresponding trisubstituted cyclopropanes with high levels of diastereoand enantioselectivity (>99:1 trans/cis and up to 98% ee) (Scheme 36).55 Cobalt-based metalloradical catalysis (MRC) have been described for asymmetric cyclopropanation with acceptor/acceptor-substituted diazo reagents giving high enantioselectivity with a distinct sense of diastereoselectivity, the direct synthesis of chiral E-1,1-cyclopropaneketoesters being achieved from a broad range of alkenes with simple KDA. Further, iodide-promoted stereospecific epimerization of E-diastereoisomer into Z-diastereoisomer with retention of optical purity has been described, these two processes providing a practical access to both E- and Z-cyclopropane in a highly asymmetric manner (Scheme 37).56 Arnold and coworkers reported that the iron–heme moiety in a cytochrome P450 enzyme (CYP450) can function as a catalyst in the cyclopropanation of olefins under anaerobic conditions.57 In a more recent study, Carreira et al. developed a user-friendly olefin-cyclopropanation technique employing in situ generated diazomethane under basic conditions.58

Scheme 36 Asymmetric cyclopropanation of Z and E alkenes.

Scheme 37 Co(II)-catalyzed diastereo- and enantioselective cyclopropanation of various alkenes.

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In the total synthesis of (–)-paeonilide, Reiser and Harrar described that asymmetric intermolecular cyclopropanation between furan-3-methyl ester and tert-butyl diazoacetate in the presence of copper(I) triflate and ligand generated cyclopropane in moderate yield 58% with 83% ee.59 Total synthesis of (+)-norrisolide includes cyclopropanation of furan-2-one with dimethyl 2-diazomalonate in the presence of M€ uller’s catalyst to provide 60 cyclopropane in 70% yield and 60–70% ee. Intramolecular cyclopropanation affords a practical route to cyclopropanefused systems. Use of the chiral Co(II) porphyrin metalloradical catalyst was found as very effective for highly asymmetric intramolecular cyclopropanation of α-acceptor-substituted diazoacetates into enantioenriched 3-oxabicyclo [3.1.0]hexan-2-one derivatives with dr 99:1 and yield/ee up to 99% (Scheme 38).61 Iwasa group reported intramolecular cyclopropanation of trans-allylic diazoacetates and alkenyl diazo ketone in a water/ether biphasic medium to give 98% ee and 99% yields using a recyclable water-soluble Ru(II)–pheox catalyst.62 Ru(II)-pheox also catalyzed the asymmetric intermolecular cyclopropanation of allenes with succinimidyl diazoacetate affording alkylidenecyclopropanes in high yields, diastereoselectivities (up to 99/1) and enantioselectivities (up to 98% ee). The same trend gave the corresponding bicyclic alkylidenecyclopropane-fused γ-lactones in high yields and enantioselectivities.63 Zhou group employed iron complexes containing chiral spiro-bisoxazoline ligands for the olefin cyclopropanation with diazoesters to prepare synthetically useful chiral [3.1.0]bicycloalkanes (Scheme 39).64

Scheme 38 Co(II)-catalyzed asymmetric intramolecular cyclopropanation of allyllic diazoacetates.

Scheme 39 Enantioselective iron-catalyzed intramolecular cyclopropanation of α-diazoesters.

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The first highly enantioselective intramolecular cyclopropanation of electron-deficient olefins with monosubstituted diazoacetates, in the presence of the Ru(II)-pheox catalyst, gave access to chiral cyclopropane-fused γ-lactones in high yields (up to 99%) with excellent enantioselectivities (ee up to 99%), which are important intermediates for the synthesis of various bioactive compounds.65 First enantioselective total synthesis of the diterpenoid natural product (+)-salvileucalin B was reported by Reisman group including a coppercatalyzed arene cyclopropanation step to prepare a highly functionalized norcaradiene bearing a fully substituted cyclopropane ring (Scheme 40).66 Nakada group reported the total synthesis of a potent, naturally occurring 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor, (+)colletoic acid, with a step involving the highly enantioselective catalytic asymmetric intramolecular cyclopropanation of an α-diazo-β-keto diphenylphosphine oxide, using CuBF4 with bisoxazoline ligands (91% ee, 79% yield).67 The synthetic utility of the transition metal-catalyzed intramolecular Buchner cyclization of α-diazoketones in the area of sesquiterpenoid natural product synthesis was reported by Maguire group in the asymmetric synthesis of cis-7-methoxycalamenene. Intramolecular Buchner process applied for synthesis of compounds possessing the bicyclo-[5.3.0]decane skeleton, characteristic of many sesquiterpenoid natural products.68 A copper-catalyzed intramolecular cyclopropanation is the remarkable step for construction of a bicyclo[3.3.1]nonane core used in the total synthesis of Polycyclic Polyprenylated Acylphloroglucinols, a procedure that has been improved with α-diazo β-keto sulfone, resulting in a later stage synthetic intermediate, with better yield.69 Rh2(esp)4 catalyzed the intramolecular cyclopropanation of indole-derived chlorodiazoacetate as the key step in the preparation of the cyclohexanone core of the biologically remarkable welwitindolinone C series of compounds.70

Scheme 40 Cyclopropanation step in total synthesis of (+)-salvileucalin B.

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Transition metal-catalyzed [2 + 1] cycloadditions of carbenes generated from diazoesters to internal/terminal alkynes afford respective nonracemic cyclopropenes with the corresponding chiral catalysts. Recently, Zhang developed a highly asymmetric cyclopropenation, based on the aforementioned cobalt metalloradical catalyst, of aryl/vinyl alkynes with acceptor/ acceptor-substituted diazo reagents (R-cyanodiazoacetamides and R-cyanodiazoacetates). This methodology led to trisubstituted cyclopropenes in high yields with excellent enantiocontrol of the all-carbon quaternary stereogenic centers. The catalytic system features a high degree of functional group tolerance (Scheme 41).71 Katsuki group employed Ir(salen) complexes as catalysts in the enantioselective cyclopropenation of donor/acceptor- or acceptor/acceptorsubstituted diazo compounds with 1-alkynes and arylacetylenes providing highly enantioenriched cyclopropenes (84–98% ee) with a functionalized quaternary carbon as versatile building blocks. This catalytic system tolerates a variety of functional groups and shows a remarkably broad substrate scope (Scheme 41).72 Hashimoto reported the [Rh2(S-tbpttl)4]-catalyzed, 1,2-hydride shift tolerated, enantioselective cyclopropenation reactions of 1-alkynes with 2,4-dimethyl-3-pentyl α-alkyl-α-diazoacetates affording the cyclopropenes with good to high chemoselectivities (Scheme 42).73

Scheme 41 Iridium- and cobalt-catalyzed asymmetric alkyne cyclopropenation.

Scheme 42 Enantioselective cyclopropenation of terminal alkynes with 2,4dimethyl-3-pentyl-2-alkyl-2-diazoacetates catalyzed by [Rh2(S-tbpttl)]4.

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Recently, Davies demonstrated that silver triflate is an effective catalyst for the cyclopropenation of disubstituted alkynes using donor/acceptorsubstituted diazo compounds to give cyclopropenes in yields up to 98%, which were inaccessible via rhodium catalysis.74 Further expansion of this work to enantioinductive versions of this reaction led to the discovery that only a binuclear gold catalyst, (S)-xylyl-BINAP(AuCl2), activated by AgSbF6 provides high enantioselectivites (up to 97% ee). The use of silver catalysts proved unsuccessful. These studies reveal that chiral digold cationic complexes are capable of high asymmetric induction in the cyclopropenation of internal alkynes with donor/acceptor carbenes. The exact structure of the active catalyst has not been clarified, as the possibility of a mixed gold–silver complex may be involved in the catalysis according to mass spectroscopy data (Scheme 43).75 Charette developed the first catalytic asymmetric synthesis of diacceptor cyclopropane derivatives, using a α-cyano diazophosphonate/α-cyano cyclopropylcarboxylates and Rh2(S-IBAZ)4 as chiral catalyst, under mild reaction conditions (Scheme 44).39 Perez and coworkers developed Cu(I) complexes and studied their activity for alkyne racemic cyclopropenation reaction with EDA.76 In a one-pot cascade reaction described by Doyle, a dirhodium catalyst induced the intramolecular cyclopropenation of enol diazoacetates followed

Scheme 43 Gold(I)-catalyzed asymmetric cyclopropenation of internal alkynes.

Scheme 44 Rh2(S-IBAZ)4-catalyzed cyclopropenation with diacceptor diazo compounds.

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by a Buchner reaction, to provide straightforward access to bicyclo[5.3.0]- and bicyclo[3.2.2]nonatriene derivatives in high yields and selectivities without the use of additives.77 In a study by Davies group, an enantioselective synthesis of bicyclo[1.1.0]butanes rings with Rh2(R-BTPCP)4 as the catalyst and α-allyldiazoesters was achieved under low catalyst loadings ratio. The reaction is controlled by the appropriate choice of catalyst and catalyst loading to provide 2-arylbicyclo[1.1.0]butane carboxylates with high levels of asymmetric induction (70–94% ee) (Scheme 45).78 Fox and coworkers reported the cyclobutanation of t-butyl (E)-2diazo-5-arylpent-4-enoates with Rh2(S-NTTL)4 giving enantiomerically enriched bicyclobutanes, in a process involving consecutive steps employing a Cu-catalyzed homoconjugate addition/enolate trapping step (Scheme 46).79 A Ag(I) N-heterocyclic carbene complex catalyzed the three-component [2+ 2 + 1] cycloaddition of the diazoesters with aryldehydes and alkyne via generation of carbonyl ylide intermediate which undertook an endo-type 1,3-dipolar cycloaddition to provide the desired dihydrofurans in high regioand diastereoselectivities, using α-aryl or α-alkenyl diazoesters (Scheme 47).80

Scheme 45 Rh2(R-BTPCP)4-catalyzed bicyclo[1.1.0]butane carboxylate formation.

Scheme 46 Multicomponent Rh2(S-NTTL)4-catalyzed enantioselective bicyclobutanation.

Scheme 47 Silver mediate [2 + 2 + 1] cycloaddition reaction.

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3.2 [3C + n] Cycloaddition Recent work in the literature supports the proposal that gold carbenes are more reactive than rhodium carbenes. In a report by Davies group, the reaction of vinyldiazoacetates with enol ethers catalyzed by the binuclear gold complex (R)-DTBMSegphos(AuCl)2 activated by silver hexafluoroantimonate gives highly functionalized cyclopentene derivatives possessing three stereocenters constructed in a highly enantioselective single-step [3 +2] cycloaddition. The reaction is initiated by nucleophilic attack of the vinyl ethers at the vinylogous position of the gold vinylcarbene intermediate (Scheme 48).81 In contrast, the Rh2(S-DOSP)4-catalyzed reaction of cyclic enol ether with styryldiazoacetate resulted in an entirely different product via combined C–H insertion/Cope rearrangement (CHCR) affording the vinylogous Mukaiyama aldol-type product in a highly diastereo- and enantioselective ratio. The formal [3 + 2] cycloaddition product was obtained with neither C–H insertion nor cyclopropanation products observed (Scheme 48).82 Liu and Pagar reported gold-catalyzed [3 + 2] cycloadditions of ethyl diazoacetate, nitrosoarenes, and vinyldiazo carbonyl species resulting in diazo-isoxazolidine derivatives with high stereoselectivity. Further, treatment of these isoxazolidines under the same catalytic conditions gives benzo[b]azepine derivatives via 1,2-H shift/[3,3] rearrangements, as inferred from deuterium-labeling experiments. Nitrones act as electrophiles in this reaction (Scheme 49).83

Scheme 48 Gold vs rhodium in carbene transfer reactions to enol ethers.

Scheme 49 Three-component [3 + 2] cycloaddition: synthesis of benzoazepines.

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Hashimoto reported the asymmetric total synthesis of guaiane sesquiterpene ()-englerin A, a potent inhibitor of the growth of renal cancer cell lines, in which a chiral Rh(II) complex catalyzed the enantioselective carbonyl ylide cycloaddition with a vinyl ether dipolarophile. This is a key step to construct the oxabicyclo[3.2.1]octane framework with concomitant introduction of the oxygen substitutent at C9 on the exo-face with good diastereoselectivity (exo/endo ¼ 87:13) and a high enantioselectivity of 95% ee for the exo-cycloadduct (Scheme 50).84 Dirhodium-catalyzed intramolecular [3 + 2] cycloaddition reaction of alkynyl-tethered styryl diazoesters results in bicyclic cyclopentadiene derivatives in high yields and selectivity. The mechanism involves catalytic metalcarbene intermediate formation, followed by carbene/alkyne metathesis and termination with a formal [3 + 2] cycloaddition in which a β-H shift is proposed in case of alkyl alkyne-tethered substrates (Scheme 51).85 The intramolecular cycloaddition cascade rapidly generates molecular complexity with well-defined stereochemical information. Thus, an intramolecular rhodium(II)-catalyzed [3 + 2] cycloaddition results in the formation of

Scheme 50 Enantioselective carbonyl ylide cycloaddition of α-diazo-β-ketoester with vinyl ethers.

Scheme 51 Rh(II)-catalyzed intramolecular [3 + 2] cycloaddition.

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a single spirolactone product in good yield, giving highly functionalized rigid polycyclic systems that contain a spiro[6.4]moiety, en route to the (5,7) core of molecules that were isolated from the Schisandra genus. This reaction mechanism involves initial carbonyl ylide formation, followed by a chemo-, regio, and diastereoselective intramolecular cycloaddition reaction on the exocyclic double bond of the dipolarophiles (Scheme 52).86 Stemofoline alkaloids are within the most potent acetylcholine receptor antagonists and also exhibit in vivo antioxytocin activity as well as antitumor activity against gastric carcinoma. The first enantioselective approach to construct the bridged polycyclic core of these alkaloids begins with 2-deoxy-D-ribose and features a novel cascade of reactions that culminates in the intramolecular dipolar cycloaddition of an acyclic diazo imine intermediate to form the cage-like tricyclic core of the stemofoline alkaloids using rhodium acetate catalysis (Scheme 53).87 In a study by Doyle group on reactions of nitrones and a β-TBSOsubstituted vinyldiazoacetate, dirhodium catalysts directed the process toward [3 + 3]-cycloaddition products. 3,6-Dihydro-1,2-oxazines are produced in high yields and selectivities. High enantiocontrol occurs with catalysis by N-phthaloyl-(S)-(amino acid)-ligated dirhodium carboxylates (Scheme 54).88 But when unsubstituted vinyldiazoacetate were used instead, in dirhodium (II)-catalyzed reactions with nitrones, a novel and unexpected pathway occurred to produce tricyclic products by concerted [3 +2] addition instead of [3 +3] cycloaddition. The overall reaction takes place through a four-step sequential [3 + 2] cycloaddition/cyclopropanation/rearrangement pathway in which the

Scheme 52 Intramolecular rhodium(II)-catalyzed [1,3]-dipolar cycloaddition reaction.

Scheme 53 Rhodium-catalyzed diastereoselective dipolar cycloaddition cascade for key tricyclic intermediate.

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dirhodium vinylcarbene intermediate activates the adjacent vinyl group toward [3 + 2] cycloaddition with the nitrone (Scheme 54).89 In a similar study by Davies group with nitrones and vinyldiazoacetates again that formal [3+ 2] cycloaddition was observed, leading to 2,5-dihydroisoxazoles with high levels of asymmetric induction. The cascade reaction includes a vinylogous addition event, followed by an iminium addition ring-closure/ hydride migration/alkene isomerization cascade forced by dirhodium tetrakis(triarylcyclopropanecarboxylates) as the optimum catalysts for this conversion (Scheme 54).90 Liu and coworkers developed cycloaddition reactions between nitrosobenzenes and alkenylgold carbene groups. Quinoline oxides were synthesized in satisfactory yields under mild conditions. The utility of this reaction is demonstrated by the wide scope of substrates and nitrosobenzenes employed (Scheme 55).91

Scheme 54 Rh(II)-catalyzed [3 + 3] and [3 + 2] cycloaddition of nitrones with enoldiazoacetate.

Scheme 55 Gold-catalyzed [3 + 3] formal cycloaddition of nitrosobenzenes with alkenyldiazocarboxylates.

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According to Doyle group, variation in the silyl ether and carboxylate ester groups of enoldiazoacetates does not affect the [3 + 3] cycloaddition process that occurs through a metal-carbene pathway in dirhodium(II)-catalyzed reactions. However, variation of the substituents at the vinylogous position can inhibit this cycloaddition route. The reaction pathway with Cu(II) and Ag(I) changed from that with dirhodium(II) and is consistent with one involving Lewis acid addition to the diazo carbon to form a diazonium ion intermediate. In short, this process is complementary to its metal-carbene counterpart, which is catalyzed by dirhodium(II) species and inhibited from occurring with enol diazoacetate, and illustrates that a duality of mechanistic pathways can account for the same transformation (Scheme 56).92 Doyle group also reported an efficient and highly enantioselective [3 + 3] cycloaddition reactions of N-iminopyridinium ylides with enol diazoacetates in the presence of a chiral dirhodium catalyst, which provides an effective access to bicyclic and tricyclic 1,2,3,6-tetrahydropyridazine derivatives. In this transformation, steric effects have an important influence on the control of selectivity since dirhodium catalysts with bulky ligands [Rh2(S-PTTL)4] instead of [Rh2(S-PTA)4] generate dramatic improvements in selectivity control. Yields, high regioselectivities and excellent enantioselectivities are controlled by the catalysts and reaction conditions (Scheme 57).93 Further study by Doyle group on isoquinolinium/pyridinium methylides with enoldiazoacetate in the presence of dirhodium catalyst

Scheme 56 Dipolar intermediates catalytically generated for metal carbene or Lewis acid adduct [3 + 3] cycloaddition reactions.

Scheme 57 [3 + 3] Cycloaddition N-iminopyridinium ylides.

of

enolcarbene

reactive

dipoles

with

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verified the [3 + 3] cycloaddition, instead of [2 + 3] cycloaddition, in high yields and high enantioselectivities using Rh2(S-PTIL)4 as the catalyst. The reaction outcome was solvent-, catalyst-, and temperature dependent with a competing process that formed a product apparently derived from [3 + 2] cycloaddition of dicyanomethylide to donor–acceptor cyclopropene. The donor–acceptor cyclopropene is in equilibrium with the dirhodiumbound enolcarbene and undergoes both enantioselective [3 + 3] cycloaddition from the dirhodium-bound enolcarbene and diastereoselective [3 + 2] cycloaddition through an uncatalyzed reaction of the cyclopropene with isoquinolinium or pyridinium methylides. Increasing the mol% of catalyst loading suppresses the [3 + 2] cycloaddition pathway (Scheme 58).94 The first highly enantioselective base-metal-catalyzed vinylcarbene transformation has been reported by Doyle group. The copper(I) tetrafluoroborate/bisoxazoline system catalyzed the [3 + 3] cycloaddition reaction of enoldiazoacetamides with nitrones with excellent yield and enantioselectivity under exceptionally mild conditions. Mannich addition products were formed in high yields when the catalyst was changed to copper(I) triflate. Copper catalysts exhibit their unique advantages by switching the reaction pathway between Mannich addition and [3 + 3] cycloaddition. This study is also the first example of intermolecular reaction with vinyldiazoacetamides (Scheme 59).95

Scheme 58 [3 + 3] Cycloaddition of catalytically generated enolcarbene reactive dipoles with isoquinolinium/pyridinium methylides.

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Scheme 59 Copper-catalyzed [3 + 3] cycloaddition of enoldiazoacetamide and nitrones.

R

R

R OH

EWG Rh2(esp)2 (1 mol%) N2

R

R

R R

EWG

ZnCl2 (10 mol%)

R

R

H O EWG EWG

H R Formal [4+1] cycloaddition

R R R

O

EWG EWG

R

H R yield up to 86% up to 4:1 dr

Scheme 60 Rhodium-catalyzed [4 + 1] cycloaddition for tetrahydrofurans.

Scheme 61 Rh2(OAc)4 metal-catalyzed [4 + 2] benzannulation of pyrroles.

3.3 [4C + n] Cycloaddition [4 + 1] Cycloaddition of homopropargyl alcohols with diazo dicarbonyl compounds using Rh2(esp)2/ZnCl2 catalysis involves tandem O–H insertion/Conia-ene cyclization and provides easy access to various substituted tetrahydrofurans, exhibiting complete E-selectivity in the case of nonterminal alkynes (Scheme 60).96 Electrophilic rhodium enal-carbenes, derived from rhodium(II)-catalyzed decomposition of a new class of enaldiazoketone and -esters, have been employed in the first direct catalytic [4 + 2] benzannulation of pyrroles leading to substituted indoles. In contrast to the D€ otz, Wulff, and Merlic benzannulations, which use stoichiometric Fischer carbenes, this new benzannulation strategy involves catalytically generated rhodium enalcarbenenes. This strategy was applied to the synthesis of the natural product leiocarpone as well as a short synthesis of a potent and selective adipocyte fatty-acid binding protein (A-FABP) inhibitor (Scheme 61).97

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Cu(II)- or Rh(II)-catalyzed intramolecular [4 + 2] cycloaddition of α-diazo indolo amido esters was used to assemble a heavily functionalized azapolycyclic ring system. Cu(hfacac)2- or Rh2(OAc)4-catalyzed reaction of an α-diazo indolo diester that contains a tethered oxa-pentenyl side chain gives a reactive furo[3,4-b]indole which undergoes a subsequent [4 + 2] cycloaddition across the tethered π-bond to form the oxobridged intermediate. This intermediate further proceeded in wet EA to give diol. This diol is obtained via nitrogen assisted opening of the oxobridge in the cycloadduct followed by the addition of water. It provides a clue for an eventual synthesis of scandine and some related Aspidosperma alkaloids (Scheme 62).98 Davies group reported a regio-, diastereo-, and enantioselective synthesis of 1,4-cycloheptadienes via efficient [4+ 3] cycloaddition between vinylcarbenes and dienes using the dirhodium tetracarboxylate as catalyst in hydrocarbon solvents. The reaction proceeds with the opposite regiochemistry to the traditional tandem cyclopropanation/Cope rearrangement. Up to three new stereogenic centers can be generated with excellent stereocontrol by choosing of diene and vinyldiazoacetate, cycloheptadienes appropriately (Scheme 63).99 The most important step in the synthesis of (+)-batzelladine B is a rhodiumcatalyzed formal [4 + 3] cycloaddition. Reaction between N-amidinylpyrrole

Scheme 62 Intramolecular [4 + 2] cycloaddition of α-diazo indolo amido esters.

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Scheme 63 Diastereoselective formal [4 + 3] cycloaddition.

Scheme 64 [4 + 3] Cycloaddition step in the synthesis of (+)-batzelladine B.

Scheme 65 Rh2(OAc)4-catalyzed intramolecular [5 + 2] cycloaddition step in the synthesis of an oxacolchinine analog.

and (S)-pantolactonyl α-diazo ester, a donor–acceptor carbene precursor, provided an entry to the dehydrotropane that contains all of the functional groups required for synthesis of the vessel fragment (Scheme 64).100

3.4 [5C + n] Cycloaddition A Rh-catalyzed intramolecular [5 + 2] cycloaddition of a carbonyl ylide intermediate as a key step in the total synthesis of (5R)-5methyl-6-oxa-desacetamido colchicine, in which both seven-membered rings of the polycyclic framework are formed in a single operation. The cycloaddition product was further efficiently converted into the interesting 11,12-dihydro-6-oxacolchicine analog 24 in a single step (Scheme 65).101 A new type of intermolecular rhodium(II)-catalyzed [5 + 3] cycloaddition of an isolable pyridinium zwitterion with enol diazoacetate enables the formation of the rare eight-membered diazocine derivatives under mild conditions with high functional group tolerance (Scheme 66).102

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Scheme 66 Rh-catalyzed [5 + 3] cycloaddition of pyridinium zwitterions.

Scheme 67 Reactions of tropone with diazoketones and diazoesters.

3.5 [6C + n] Cycloaddition Carbonyl ylides derived from α-diazoketone and diazodiketoesters have different reactivity toward tropone, using [Rh2(S-TCPTTL)4] as catalyst. α-Diazoketones undergo facile [6 + 3] cycloaddition reactions to give bridged tricyclic compounds in moderate to good yields and with excellent stereoselectivity, whereas diazodiketoesters undergo 1,3-dipolar cycloaddition affording the corresponding cycloadducts in good to high yields and with excellent enantioselectivity (Scheme 67).103

3.6 Miscellaneous Guerrero developed a cyclopentannulation sequence that depends on the bifunctional reactivity of the reagent. The two-step method for the cyclopentannulation of enol silane and stabilized diazoalkanes is studied separately in chronological Mukaiyama–Michael and diastereoselective α,α0 diketone coupling. Di-, tri-, and tetrasubstituted enones are available for annulation under this procedure (Scheme 68). The methyl 3-(tertbutyldimethylsiloxy)-2-diazo-3-butenoate is used as a bifunctional reagent for a two-step annulation: the enol silane interacts first with the electrophilic β-carbon of a conjugated enone and then the diazo group participates in a Cu(I)-catalyzed formal α,α0 -diketone coupling (Scheme 68).104

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O R2

R1

TBSOTf (~20 mol%) 0°C

R4

R3

R1

OTBS R2 R4

R3

O O

(CuOTf)2 •PhH (10 mol%)

O OCH3 N2

BOX ligand (22 mol%)

R2 COOEt

1

R

OMOM R4

R3 yield up to 95% up to 19:1 dr

Scheme 68 Cu(I)-catalyzed cyclopentannulation of conjugated enones.

Scheme 69 Macrocyclization of oxetane.

Lacour group reported an unusual macrocyclization, in a one-pot Rh(II)catalyzed condensation, of oxetanes and α-diazocarbonyls that led to a rare type of functionalized 15-membered macrocyclic ring. The reaction requires high concentration and mild reaction conditions (Scheme 69).105

4. YLIDE FORMATION 4.1 Trapping Tactic Over the past decades, it has been well established that the transition metalcatalyzed decomposition of diazo compounds can undergo ylide formation which can either be trapped by suitable dipolarophiles, undergo cyclization, or verify a subsequent rearrangement to give heterocycles. The in situ trapping of an active intermediate, generated from metal-carbene intermediates and an X heteroatom (X ¼ N, O, S, etc.), has promoted the discovery of synthetically useful transformations, which allow rapid assembly of structurally complex molecules with high chemo-, diastereo-, and enantioselectivity. Thus, the transition metal-catalyzed multicomponent reactions (MCRs) of diazo compounds and anilines/alcohols with electrophiles not only provide a novel approach for the efficient construction of polyfunctional molecules but also provide solid experimental evidence for the existence of the protic onium ylide intermediates (Scheme 70). In 2003, Doyle, Hu, and coworkers observed106 the formation of an interesting α,β-diamino ester product, during the study of the rhodium(II)-catalyzed aziridination of aryl diazoacetates with aryl imines, when unpurified imines containing unreacted aniline precursors were used

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Scheme 70 Trapping of protic onium ylides with electrophiles.

as the substrates. The products incorporated the structural features of the diazo compound, aniline and imine. This transformation could be rationalized to proceed via the formation of a protic ammonium ylide from rhodium-carbene and aniline. Ammonium ylide then undergoes the proton transfer to afford the N–H insertion product or, on the other hand, undergoes nucleophilic addition to the imine moiety to afford an intermediate, followed by a delayed proton transfer yielding the three-component product. This discovery opens the door for the development of MCRs via electrophilic trapping of protic onium ylides. Following this output, Hu and coworkers continued expanding the scope of electrophiles and also further development of MCRs based on the trapping of protic oxonium ylides. In a study to generate a diversified structural motif in one step by protic oxonium intermediates trapping with additional electrophiles prior to the “delayed proton transfer” process, Hu group developed a rhodiumcatalyzed intramolecular three-component cascade Michael–aldol-type reaction of diazoacetates, alcohols, and bifunctional aromatic compound through successive trapping of active intermediates. Alcohol reacts with rhodium-carbene to generate an oxonium ylide intermediate which is selectively trapped by the chalcone unit in a Michael addition manner. The newly generated intermediate is further trapped by the intramolecular tethered aldehyde unit in an aldol addition manner, followed by a delayed proton transfer process to afford cyclized product in good yields (Scheme 71).107 Later, Hu and coworkers described the use, for the first time, of carboxylic acids as precursors to generate oxonium ylides previously to interception with electrophiles. In this study, the Rh2(OAc)4-catalyzed three-component reaction of diazo compounds with carboxylic acids and N-Boc imines afforded a series of β-amino alcohol derivatives in good

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Scheme 71 Rhodium-catalyzed intramolecular three-component cascade Michael– aldol-type reaction.

Scheme 72 Rh(II)-catalyzed three-component reaction of benzoic acids, diazoacetophenones, and N-Boc imines.

HO

N2 R1

COOR2

Br

Ar2 (1) 1 mol% Rh2(OAc)4 N 15 mol% Zr(IV)-BINOL (2) TEA, DCM, 30°C Ar1

N O

Ar2

Ar1 R1 COOR2

yield up to 83% >95:5 dr up to 94% ee

Scheme 73 Three-component reaction with one-pot subsequent cyclization toward chiral morpholines.

yields with moderate diastereoselectivities. Oxonium ylide generation from carboxylic acids and the rhodium carbenes followed by a Mannich-type trapping of the ylide intermediates with N-Boc imines gives β-amino alcohols. Hydrogen bonding between carboxylic oxonium ylides and N-Boc imines is important for a successful ylide-trapping process (Scheme 72).108 The development of a robust and versatile Rh(II)/Zr(IV)-BINOL cocatalytic system gives high diastereo- and enantiocontrol in the threecomponent reaction of alcohols, diazo compounds, and aldimines/aldehydes, with one-pot subsequent cyclizations to chiral morpholines, and with excellent functionality tolerances. This catalytic system provides rapid and diversity-oriented synthesis (DOS) of different types of chiral nitrogen and/or oxygen-containing polyfunctional heterocycles (Scheme 73).109 According to a initial study by Hu group on the trapping of oxonium ylides with alkynes by Pd(II) catalysis resulted in a formal [4 + 1] cyclization furnishing 2,5-dihydrofuran derivatives as the major product over those from other traditional reaction pathways. The autotandem catalytic process is proposed to occur via Pd(II)-catalyzed intermolecular oxonium ylide

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formation and subsequent intramolecular trapping of the ylide with Pd(II)activated alkynes (Scheme 74).110 Gold(I)-catalyzed formal [4 + 1] cycloaddition of α-diazoesters and propargyl alcohols also provides a variety of 2,5-dihydrofurans. The reaction most likely occurs through a 5-endo-dig cyclization of a α-hydroxy allene intermediate. The reaction shows a broad substrate scope and the functional group tolerance with amendable to enantioselective catalysis (Scheme 74).111 Copper(I)- or rhodium(II)-catalyzed stereoselective construction of diazocarbonyl compounds with β-hydroxyketones affords polysubstituted tetrahydrofurans with excellent diastereoselectivity under mild conditions. The reaction occurs via carbene O–H insertion reaction, but is diverted by an intramolecular aldol reaction, in a process that tolerates a wide range of β-hydroxyketones and diazo compounds (Scheme 75).112 Tetrahydrofurans and pyrrolidines, types of PTP1B inhibitors, were synthesized from β-hydroxyketones or β-aminoketones and diazo compounds under Rh(II) catalysis. Reaction proceeds through a metal carbene-induced oxonium ylide or ammonium ylide formation followed by an intramolecular aldol-type trapping of these active intermediates. This strategy resulted in a

Scheme 74 Transition metal-catalyzed trapping of oxonium ylide with alkynes.

Scheme 75 Synthesis of polysubstituted tetrahydrofurans by Rh- and Cu-catalyzed diverted O–H insertion reaction.

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series of highly substituted tetrahydrofurans and pyrrolidines in high yields with good to excellent diastereoselectivities. This method could be applied to the synthesis of optically active multisubstituted tetrahydrofurans by asymmetric induction (Scheme 76).113 Highly stereoselective metal-catalyzed diverted N–H insertion of a range of diazocarbonyl compounds with β-aminoketone derivatives gives highly substituted proline derivatives. Different metal catalysts (rhodium(II) carboxylate dimers, copper(I) triflate, and iron(III) porphyrin) are effective for this method under mild conditions. The reaction starts as a metallocarbene N–H insertion but is diverted by an intermolecular aldol reaction. This diverted carbene insertion strategy is based on the complementary use of N-PMP aminoketones and ketocarbamates. Overall, this method gives pyrrolidines bearing removable protecting groups on the nitrogen atom which can be deprotected under standard conditions to give the NH pyrrolidines. These results show the advantages of the present strategy for the construction of pyrrolidines as it enables the facile further N functionalization of pyrrolidines (Scheme 77).114 Trapping the protic ammonium ylides with the appropriate electrophiles could provide quick access to a variety of important motifs.

Scheme 76 Synthesis of tetrahydrofurans and pyrrolidines by intramolecular aldoltype trapping of onium ylides.

Scheme 77 Rhodium(II)-catalyzed synthesis of highly substituted pyrrolidines.

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A rhodium(II)/chiral phosphoric acid cooperative catalysis strategy was applied to MCRs by Hu group, involving trapping of highly reactive protic carbamate ammonium ylides with imine electrophiles. The diastereoselectively switchable enantioselective three-component reaction of diazoacetates, carbamates, and aryl imines gives access to both syn- and anti-R-substituted R,β-diamino acid derivatives with a high-level control of chemo-, diastereo-, and enantioselectivity. Basic diamine products poison the phosphoric acid catalyst, but tartaric acid used as an additive could efficiently neutralize the basic diamine product and regenerate the chiral phosphoric acid. A switch in diastereoselectivity was observed when BINOLbased phosphoric acids bearing different substituents were applied which affect the intrinsic reaction kinetics in a designed way to activate the desired component selectively. Since both enantiomeric phosphoric acids are available as a cocatalyst, each possible enantiomeric product could be produced by simply choosing the combination of catalysts (Scheme 78).115 α-Amino phosphonic acid compounds act as enzyme inhibitors, antibiotics, plant growth regulators, and haptens of catalytic antibodies. An enantioselective chiral rhodium-catalyzed three-component coupling reaction of α-diazophosphonates, anilines, and electron-deficient aldehydes gives a series of α-amino-β-hydroxyphosphonates in good to high yields and with good to high enantioselectivities. The complexes Rh2(S-PTAD)4 and Rh2(S-PTTL)4 were found to be the most efficient catalysts for these systems. The enantioinduction provides evidence for the intermediacy of a metal-bound ammonium ylide in the nucleophilic addition step. The high enantioselectivity of the addition of ylide to the C]O group of aldehyde in

Scheme 78 Rh(II)/chiral PPA-cocatalyzed three-component reaction of diazoacetates, carbamates, and imines.

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these reactions is due to the coordination of the N-ylide intermediate to the chiral rhodium catalyst (Scheme 79).116 MCRs have usually one sequential pathway to give one type of product skeleton. However, MCRs which involve more than one type of reaction pathway starting from the same participants are rare. One of such developed reaction by Hu group is the rhodium(II)-catalyzed three-component reaction of diazo compounds with anilines and 4-oxo-enoates by a switch in the reaction pathway controlled by the addition sequence of the starting materials leading to divergent products. Such addition order influences the reaction outcome: this three-component reaction can proceed through either aza-Michael addition/ammonium ylide generation/intramolecular aldol addition pathway to give diversely substituted pyrrolidines, or via a ylide generation/Michael addition pathway to form linear α-amino ester derivatives in good yields with high diastereoselectivities (Scheme 80).117 The lack of examples of trapping ylides by conjugated nitroolefins was covered by Hu group that reported the Rh(I)–diene-catalyzed reaction of aryldiazoacetates, aromatic amines, and β-nitroacrylates, resulting in CHO

N2

O Ar1 P OMe MeO

Ar2

NH2 EWG

2 mol% Rh2(S-PTAD)4 DCM, 40°C 12–15 h

O

NHAr2

O

NHAr2

MeO P

Ar1

MeO P

Ar1

MeO H

MeO HO

OH GWE

H GWE yield up to 86% syn/anti upto 94:6 up to 98% ee (syn)

Scheme 79 Three-component coupling reaction of diazophosphonates, anilines, and electron-deficient aldehydes.

Scheme 80 Effect of the addition sequence of the substrates in the three-component reaction.

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polyfunctional aminosuccinates in good yields and with high diastereo- and enantioselectivity. The Rh(I)–chiral diene complex is efficient to generate Rh(I)-associated ammonium ylides from aryldiazoacetates and anilines. The reaction mechanism involves enantioselective trapping of Rh(I)-associated ammonium ylides by nitroacrylates. The ammonium ylides exhibited unique reactivity and undergo reaction with nitroacrylates in a Michael addition-type fashion affording polyfunctionalized nitrogen-containing molecules in high diastereo- and enantioselectivity (Scheme 81).118 Moreover, Sun group reported a stereodivergent strategy by trapping in situ formed intermediates to construct diverse five-membered N-heterocycles in a single step. The metal-catalyzed tandem annulation of amino alkynes and diazo compounds gave 2,3-dihydropyrroles and 2-methylene and 3-methylene pyrrolidines. The reaction proceeds via copper-catalyzed tandem annulations through allenoate formation and subsequent intramolecular hydroamination. Overall, the rhodium-catalyzed protocol features a carbene insertion into the N–H bond and subsequent Conia-ene cyclization (Scheme 82).119 After a successful study based on the use of cyclic enamine as substrate in a trapping process to produce polyfunctional molecules in a single synthetic step, further interest on using an acyclic enamine to afford a zwitterionic intermediate trapping product has been reported by Hu group. A palladium(II)/chiral phosphoric acid-catalyzed three-component reaction of aryldiazoacetates, enamines, and imines was developed, but the reaction did not evolve as expected. In this three-component reaction, one-bond cleavage and three-bond formation take place in one step to produce a new molecule bearing two stereogenic centers including one quaternary carbon center in excellent diastereoselectivity and high enantioselectivity. It is a process that involves C–N cleavage, modification of the amino fragment, and selective reassembly of the modified fragment affording α-amino-δ-oxo pentanoic acid derivatives. A keto-iminium is proposed

NH2

N2 Ar

COOMe

2 mol% [Rh(C2H4)2Cl]2 4.1 mol% ligand

R2OOC

R1 COOMe

toluene, rt

NO2

MeOOC Ph

Ph

NO2 H COOR2 upto 65% yield COOMe upto 95:5 dr HN Ar upto 97:3 ee R1

(ligand)

Scheme 81 Rhodium(I)-catalyzed three-component reaction involving an amine, diazoester, and nitroacrylate.

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10 mol% CuCl MeCN, 60°C, 12 h R1

N2 Ar N2 R1

COR2 COR3

N PG yield 80% ee 99:1

R3OC

COR2

PG HN

COOR2

N PG

yield up to 70% H up to dr 4.3:1 COOR3 up to ee 97:3 R2

R1

3 mol% Rh2(esp)2 10 mol% ZnCl2 DCM, 60°C, 8 h

N2 Ar

COOR2

10 mol% CuCl MeCN, 60°C, 18 h

COOR3 R1

N PG

R2

yield up to 82% up to 1:0 E/Z up to 98:2 ee

Scheme 82 Rh- and Cu-catalyzed tandem reaction between diazo compounds and amino alkynes.

O N2 Ar1

N

COOR

Ar4

N

Ar2

Ar3

Ar2 [PdCl(η3-C3H5)]2 (5 mol%) O (R)-PA (10 mol%) Ar1 CHCl3, 4 Å MS, –10°C Ar3 Ar4 N then H3O+ COOR H yield up to 74% up to dr 96:4 up to ee 96:4

R O OH P O O R R = 3,5-(CF3)2-C6H3

Scheme 83 Pd(II)/CPA-catalyzed reaction of aryldiazoacetates, enamines, and imines.

Scheme 84 Mechanism of Pd(II)/CPA-catalyzed reaction of aryldiazoacetates, enamines, and imines.

as a key intermediate and a chiral palladium/phosphate complex is proposed as the active catalyst (Schemes 83 and 84).120

4.2 Cascade Reaction Recently, Davies group reported the rhodium-catalyzed reactions of tertiary propargylic alcohols with methyl aryl- and styryldiazoacetates resulting in

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tandem oxonium ylide formation/[2,3]-sigmatropic rearrangement, instead of the expected O–H insertion. The 2,3-sigmatropic rearrangement proceeds through cleavage of the O–H bond to generate a diradical intermediate which favors 2,3-sigmatropic rearrangement with donor/acceptor carbenes and more highly functionalized propargylic alcohols. The allenes are produced with high enantioselectivity (88–98% ee) using dirhodium tetraprolinate complex, Rh2(S-DOSP)4. The most important feature is the existence of a twopoint attachment during ylide formation and the diradical character of the [2,3]-sigmatropic rearrangement (Scheme 85).121 Donor/acceptor-substituted rhodium carbenes are useful for the synthesis of medium-sized carbocycles. A range of vinyldiazoacetates and allyl alcohols were found to be suitable partners for the synthesis of cyclopentanes in exceptional yields and stereocontrol by Davies group. Rhodium-catalyzed reactions of vinyldiazoacetates with (E)-1,3-disubstituted 2-butenols generate cyclopentanes, having four stereogenic centers with very high levels of stereoselectivity (99% ee, 97:3 dr). The reaction proceeds by a carbene-initiated domino sequence consisting of five distinct steps: rhodium-bound oxonium ylide formation, [2,3]-sigmatropic rearrangement, oxy-Cope rearrangement, enol–keto tautomerization, and finally an intramolecular carbonyl ene reaction. The low catalyst loadings, readily available starting materials and in-depth understanding of the mechanistic details, make this an important method for accessing cyclopentane cores to common prostaglandin antagonist antiglaucoma agents (Scheme 86).122 Similarly, the cyclohexanes are also formed as single stereoisomers in good yields through a one-pot reaction of vinyldiazoacetates and allyl alcohols by a rhodium-carbene initiated domino reaction. The reaction cascade mechanism includes a tandem ylide formation/[2,3]-sigmatropic rearrangement, oxy-Cope rearrangement, and type II carbonyl ene, in an overall process that take place with a high degree of stereocontrol.

Scheme 85 Asymmetric tandem ylide formation/[2,3]-sigmatropic rearrangement of diazoketones with propargylic alcohols.

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Scheme 86 One-pot domino sequence for the synthesis of a cyclopentane.

Scheme 87 One-pot domino sequence for the synthesis of a cyclohexane.

Scheme 88 Three-step synthesis of ()-Preussin.

The products are formed with excellent stereocontrol (>97:3 dr, 99% ee) (Scheme 87).123 The pyrrolidine alkaloid ()-Preussin, an antifungal, antiviral, and antibacterial agent that also induces apoptosis in several human cancer cell lines, can be synthesized from decanal and diethyl 3-diazo-2-oxopropylphosphonate in three steps in overall yield of 40%. The key step is the highly stereoselective Cu-catalyzed ylide formation and then a [1,2]-Stevens rearrangement. This strategy is applicable for preussin analogs, for the rapid construction of all-cis-substituted pyrrolidines alkaloids. This stereoselective sequence can be useful for asymmetric synthesis of preussin, employing chiral amines in the aza-Michael reaction (Scheme 88).124

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EtOOC N2

(1) 1 mol% Rh2(OAc)4 6 mol% Chiral-ZrMs DCM, –10 °C

O O

R1

COOMe HO

R

(2) rt, 12 days without solvent

EtOOC H

O

O

R

yield up to 60% up to 91:9 dr up to 94% ee

OH

MeOOC R1

Scheme 89 One-pot three-component cascade/subsequent epoxidation to eight stereogenic centers.

Polycyclic ring systems having multiple stereogenic centers into the target skeleton are an efficient approach to increase the complexity of chemically generated molecules. Moreover, fused O-heterocyclic compounds such as hydroepoxyisochromene are widely found in drugs and natural products. Applying multicomponent cascade reactions is powerful and efficient for constructing these complex molecules from simple starting materials in an operationally step-economic fashion. Very recently, Hu group report an enantioselective three-component/Diels–Alder process to make functionalized hydroepoxyisochromene scaffold with fused polycyclic system containing six chiral carbon centers. Subsequent one-pot epoxidation of the product allows making more complex molecule with up to a total of eight chiral centers (Scheme 89).125 This method demonstrates an atom and step-economic strategy for the rapid construction of poly ring-fused O-heterocyclic compounds with high molecular complexity from simple starting materials.

5. SUMMARY This account describes a summary of influence transformations of diazo compounds catalyzed by transition metal complexes which are widely used in organic synthesis to construct complicated natural or synthetic molecules in an efficient way, most of them with enantiomeric excesses. The past 5 years have been creative in the history of α-diazocarbonyl chemistry, despite the fact that it has been in existence for over a century. The driving force for all of these recent developments has been high chemoselectivity along with stereo and enantioselectivity. Diazo chemistry is being more widely adopted by chemists to target much more elaborate molecules in total synthesis than one decade ago. Furthermore, several metal catalysts exhibit unique levels of tolerance toward several acids and bases, making them one of the most suitable catalysts for reactions involving the transformation of unstable diazo compounds generated in situ. The use of sterically demanding

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ligands and mild reaction conditions has enabled several diazo transformation reactions via cyclopropenation, cyclopropanation, carbonyl ylide formation and dipolar cycloaddition, C–H functionalization, and insertion reaction. All these transformations are also finding increasing use in the construction of natural products. Catalysts derived from some of transition metal like rhodium have been well established for these transformations, irrespective of limitations in terms of their substrate scope, reaction efficiency, selectivity, and overall economy. Moreover, compared with other transition metals, rhodium catalysts often showed unique catalytic activity and selectivity, especially in C–H functionalization and cycloaddition reactions. Based on these examples mentioned in review, it is clear that the potential of metal-catalyzed diazo transformations is yet large, and further work is required to develop new catalysts and design novel chiral ligands. In addition, a deeper understanding of the mechanisms leading to the unique reactivity and selectivities of metal-carbene intermediates and determining the active structures of the catalytic species involved in these processes are yet to be more developed. Finally, the growth of multicatalysis strategy/tandem reactions and multicomponent reactions in synthetic applications and further studies on late-stage modification of natural and biologically active compounds are desirable future topics in this field. We foresee that diazo chemistry will continue to be used to make complex natural products and combinatorial libraries.

ACKNOWLEDGMENTS We greatly thank the National Natural Science Foundation of China (NSFC) (Grant No. 21332003). We are also grateful to our talented coworkers, whose names are shown in the references, for their outstanding contributions.

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68. McDowell PA, Foley DA, O’Leary P, Ford A, Maguire AR. Asymmetric synthesis of cis7-methoxycalamenene via the intramolecular Buchner reaction of an α-diazoketone. J Org Chem. 2012;77:2035–2040. 69. Uetake Y, Uwamori M, Nakada M. Enantioselective approach to polycyclic polyprenylated acylphloroglucinols via catalytic asymmetric intramolecular cyclopropanation. J Org Chem. 2015;80:1735–1745. 70. Zhang M, Tang W. Synthesis of functionalized cyclohexenone core of welwitindolinones via rhodium-catalyzed [5+1] cycloaddition. Org Lett. 2012;14:3756. 71. Cui X, Xu X, Lu H, Zhu S, Wojtas L, Zhang PX. Enantioselective cyclopropenation of alkynes with acceptor/acceptor-substituted diazo reagents via Co(II)-based metalloradical catalysis. J Am Chem Soc. 2011;133:3304–3307. 72. Uehara M, Suematsu H, Yasutomi Y, Katsuki T. Enantioenriched synthesis of cyclopropenes with a quaternary stereocenter, versatile building blocks. J Am Chem Soc. 2011;133:170–171. 73. Goto T, Takeda K, Shimada N, et al. Highly enantioselective cyclopropenation reaction of 1-alkynes with α-alkyl-α-diazoesters catalyzed by dirhodium(II) carboxylates. Angew Chem Int Ed. 2011;50:6803–6808. 74. Briones JF, Davies HML. Silver triflate-catalyzed cyclopropenation of internal alkynes with donor-/acceptor-substituted diazo compounds. Org Lett. 2011;13:3984–3987. 75. Briones JF, Davies HML. Gold(I)-catalyzed asymmetric cyclopropenation of internal alkynes. J Am Chem Soc. 2012;134:11916–11919. 76. Martı´n C, Sierra M, Alvarez E, Belderrain TR, Perez PJ. Hydrotris(3mesitylpyrazolyl)borato-copper(I) alkyne complexes: synthesis, structural characterization and rationalization of their activities as alkyne cyclopropenation catalysts. Dalton Trans. 2012;41:5319–5325. 77. Xu XF, Wang XB, Zavalij PY, Doyle MP. Straightforward access to the [3.2.2] nonatriene structural framework via intramolecular cyclopropenation/Buchner reaction/cope rearrangement cascade. Org Lett. 2015;17:790–793. 78. Qin CM, Davies HML. Enantioselective synthesis of 2-arylbicyclo[1.1.0]butane carboxylates. Org Lett. 2013;15:310–313. 79. Panish R, Chintala SR, Boruta DT, Fang YZ, Taylor MT, Fox JM. Enantioselective synthesis of cyclobutanes via sequential Rh-catalyzed bicyclobutanation/Cu-catalyzed homoconjugate addition. J Am Chem Soc. 2013;135:9283–9286. 80. Liu YF, Wang Z, Shi JW, Chen BL, Zhao ZG, Chen Z. NHC-Ag(I)-catalyzed threecomponent 1,3-dipolar cycloaddition to provide polysubstituted dihydro-/tetrahydrofurans. J Org Chem. 2015;80:12733–12739. 81. Briones JF, Davies HML. Enantioselective gold(I)-catalyzed vinylogous [3+2] cycloaddition between vinyldiazoacetates and enol ethers. J Am Chem Soc. 2013;135: 13314–13317. 82. Lian Y, Davies HML. Combined C-H functionalization/cope rearrangement with vinyl ethers as a surrogate for the vinylogous Mukaiyama aldol reaction. J Am Chem Soc. 2011;133:11940–11943. 83. Pagar VV, Liu RS. Gold-catalyzed cycloaddition reactions of ethyl diazoacetate, nitrosoarenes, and vinyldiazo carbonyl compounds: synthesis of isoxazolidine and benzo[b]azepine derivatives. Angew Chem Int Ed. 2015;54:4923–4926. 84. Hanari T, Shimada N, Kurosaki Y, et al. Asymmetric total synthesis of ()-Englerin A through catalytic diastereo- and enantioselective carbonyl ylide cycloaddition. Chem Eur J. 2015;21:11671–11676. 85. Zheng Y, Mao YC, Weng YC, Zhang XL, Xu XF. Cyclopentadiene construction via Rh-catalyzed carbene/alkyne metathesis terminated with intramolecular formal [3+2] cycloaddition. Org Lett. 2015;17:5638–5641. 86. Rodier F, Rajzmann M, Parrain JL, Chouraqui G, Commeiras L. Diastereoselective access to polyoxygenated polycyclic spirolactone through a rhodium-catalyzed [3+2]

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cycloaddition reaction: experimental and theoretical studies. Chem Eur J. 2013;19:2467–2477. Fang C, Shanahan CS, Paull DH, Martin SF. Enantioselective formal total syntheses of didehydrostemofoline and isodidehydrostemofoline through a catalytic dipolar cycloaddition cascade. Angew Chem Int Ed. 2012;51:10596–10599. Wang XC, Xu XF, Zavalij PY, Doyle MP. Asymmeric formal [3+3]-cycloaddition reactions of nitrones with electrophilic vinylcarbene intermediates. J Am Chem Soc. 2011;133:16402–16405. Wang XC, Abrahams QM, Zavalij PY, Doyle MP. Highly regio- and stereoselective dirhodium vinylcarbene induced nitrone cycloaddition with subsequent cascade carbenoid aromatic cycloaddition/N-O cleavage and rearrangement. Angew Chem Int Ed. 2012;51:5907–5910. Qin CM, Davies HML. Rh2(R-TPCP)4-catalyzed enantioselective [3+2]-cycloaddition between nitrones and vinyldiazoacetates. J Am Chem Soc. 2013;135:14516–14519. Pagar VV, Jadhav AM, Liu RS. Gold-catalyzed formal [3+3] and [4+2] cycloaddition reactions of nitrosobenzenes with alkenylgold carbenoids. J Am Chem Soc. 2011;133:20728–20731. Qian Y, Xu XF, Wang XC, Zavalij PJ, Hu WH, Doyle MP. Rhodium (II)- and copper(II)-catalyzed reactions of enol diazoacetates with nitrones: metal carbene versus Lewis acid directed pathways. Angew Chem Int Ed. 2012;51:5900–5903. Xu XF, Zavalij PJ, Doyle MP. Highly enantioselective dearomatizing formal [3+3] cycloaddition reactions of n-acyliminopyridinium ylides with electrophilic enol carbene intermediates. Angew Chem Int Ed. 2013;52:12664–12668. Xu XC, Zavalij PJ, Doyle MP. Catalytic asymmetric syntheses of quinolizidines by dirhodium-catalyzed dearomatization of isoquinolinium/pyridinium methylides— the role of catalyst and carbene source. J Am Chem Soc. 2013;135:12439–12447. Cheng QQ, Yedoyan J, Arman H, Doyle MP. Copper-catalyzed divergent addition reactions of enoldiazoacetamides with nitrones. J Am Chem Soc. 2016;138:44–47. Urabe F, Miyamoto S, Takahashi K, Ishihara J, Hatakeyama S. Formal [4+1]-cycloaddition of homopropargyl alcohols to diazo dicarbonyl compounds giving substituted tetrahydrofurans. Org Lett. 2014;16:1004–1007. Dawande SG, Kanchupalli VK, Kalepu J, Chennamsetti HB, Lad BS, Katukojvala S. Rhodium enalcarbenoids: direct synthesis of indoles by rhodium(II)-catalyzed [4+2] benzannulation of pyrroles. Angew Chem Int Ed. 2014;53:4076–4080. Padwa A, Zou Y, Cheng B, Li H, Riley ND, Straub CS. Intramolecular cycloaddition reactions of furo[3,4-b]indoles for alkaloid synthesis. J Org Chem. 2014;79:3173–3184. Guzman PE, Lian Y, Davies HML. Reversal of the regiochemistry in the rhodiumcatalyzed [4+3] cycloaddition between vinyldiazoacetates and dienes. Angew Chem Int Ed. 2014;53:13083–13087. Parr BT, Economou C, Herzon SB. A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials. Nature. 2015;525:507. Termath AO, Ritter S, K€ onig M, et al. Synthesis of oxa-B-ring analogs of Colchicine through Rh-catalyzed intramolecular [5+2] cycloaddition. Eur J Org Chem. 2012;2012:4501–4507. Lee DJ, Ko D, Yoo EJ. Rhodium(II)-catalyzed cycloaddition reactions of non-classical 1,5-dipoles for the formation of eight-membered heterocycles. Angew Chem Int Ed. 2015;54:13715–13718. Murarka S, Jia ZJ, Merten C, Daniliuc CG, Antonchick AP, Waldmanns H. Rhodium (II)-catalyzed enantioselective synthesis of troponoids. Angew Chem Int Ed. 2015;54:7653–7656. Bel MD, Rovira A, Guerrero CA. Cyclopentannulation of conjugated enones using a vinyldiazomethane-based reagent. J Am Chem Soc. 2013;135:12188–12191.

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105. Rix D, Garrido RB, Zeghida W, Besnard C, Lacour J. Macrocyclization of oxetane building blocks with diazocarbonyl derivatives under Rhodium(II) catalysis. Angew Chem Int Ed. 2011;50:7308–7311. 106. Wang Y, Zhu Y, Chen Z, Mi A, Hu WH, Doyle MP. A novel three-component reaction catalyzed by dirhodium(II) acetate: decomposition of phenyldiazoacetate with arylamine and imine for highly diastereoselective synthesis of 1,2-diamines. Org Lett. 2003;5:3923–3926. 107. Jiang J, Guan XY, Liu SY, et al. Highly diastereoselective multicomponent cascade reactions: efficient synthesis of functionalized 1-indanols. Angew Chem Int Ed. 2013;52:1539–1542. 108. Zhai CW, Xing D, Qian Y, Ma CQ, Hu WH. Trapping of carboxylic oxonium ylides with N-Boc imines for the facile synthesis of β-amino alcohol derivatives. Synlett. 2014;25:1745–1750. 109. Tang M, Xing D, Huang H, Hu WH. Divergent synthesis of chiral heterocycles via sequencing of enantioselective three-component reactions and one-pot subsequent cyclization reactions. Chem Commun. 2015;51:10612–10615. 110. Shi TD, Guo X, Tenga SH, Hu WH. Pd(II)-catalyzed formal [4+1] cycloaddition reactions of diazoacetates and aryl propargyl alcohols to form 2,5-dihydrofurans. Chem Commun. 2015;51:15204–15207. 111. Wang J, Yao X, Wang T, et al. Synthesis of 2,5-dihydrofurans via a gold(I)-catalyzed formal [4 + 1] cycloaddition of α-diazoesters and propargyl alcohols. Org Lett. 2015;17:5124–5127. 112. Nicolle SM, Lewis W, Hayes CJ, Moody CJ. Stereoselective synthesis of highly substituted tetrahydrofurans through diverted carbene O-H insertion reaction. Angew Chem Int Ed. 2015;54:8485–8489. 113. Jing CC, Xing D, Gao LX, Li J, Hu WH. Divergent synthesis of multisubstituted tetrahydrofurans and pyrrolidines via intramolecular aldol-type trapping of onium ylide intermediates. Chem Eur J. 2015;21:19202–19207. 114. Nicolle SM, Lewis W, Hayes CJ, Moody CJ. Stereoselective synthesis of functionalized pyrrolidines by the diverted N-H insertion reaction of metallocarbenes with β-aminoketone derivatives. Angew Chem Int Ed. 2016;55:3749–3753. 115. Jiang J, Xu HD, Xi JB, et al. Diastereoselectively switchable enantioselective trapping of carbamate ammonium ylides with imines. J Am Chem Soc. 2011;133:8428–8431. 116. Zhou CY, Wang JC, Wei JH, et al. Dirhodium carboxylates catalyzed enantioselective coupling reactions of a-diazophosphonates, anilines, and electron-deficient aldehydes. Angew Chem Int Ed. 2012;51:11376–11380. 117. Jing CC, Xing D, Qian Y, Shi T, Zhao Y, Hu WH. Diversity-oriented threecomponent reactions of diazo compounds with anilines and 4-oxo-enoates. Angew Chem Int Ed. 2013;52:9289–9292. 118. Ma XC, Jiang J, Lv SY, et al. An ylide transformation of rhodium(I) carbene: enantioselective three-component reaction through trapping of rhodium(I)-associated ammonium ylides by b-nitroacrylates. Angew Chem Int Ed. 2014;53:13136–13139. 119. Liu K, Zhu CH, Min JX, Peng SY, Xu GY, Sun JT. Stereodivergent synthesis of N-heterocycles by catalyst-controlled, activity-directed tandem annulation of diazo compounds with amino alkynes. Angew Chem Int Ed. 2015;54:12962–12967. 120. Zhang D, Zhou D, Xia F, Kang ZH, Hu WH. Bond cleavage, fragment modification and reassembly in enantioselective three-component reactions. Nat Commun. 2015;6:5801. 121. Li ZJ, Boyarskikh V, Hansen JH, Autschbach J, Musaev DG, Davies HML. Scope and mechanistic analysis of the enantioselective synthesis of allenes by rhodium-catalyzed tandem ylide formation/[2,3]-sigmatropic rearrangement between donor/acceptor carbenoids and propargylic alcohols. J Am Chem Soc. 2012;134:15497–15504.

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122. Parr BT, Davies HML. Davies highly stereoselective synthesis of cyclopentanes bearing four stereocentres by a rhodium carbene-initiated domino sequence. Nat Commun. 2014;5:5455. 123. Parr BT, Davies HML. Stereoselective synthesis of highly substituted cyclohexanes by a rhodium-carbene initiated domino sequence. Org Lett. 2015;17:794–797. 124. Rosset IG, Dias RMP, Pinho VD, Burtoloso ACB. Three-step synthesis of ()Preussin from decanal. J Org Chem. 2014;79:6748–6753. 125. Tang M, Wu Y, Lui Y, et al. One-pot enantioselective multi-component cascade reactions for synthesis of chiral functionalized hydro-epoxyisochromenes: a rapid access to molecular complexity. Acta Chim Sin. 2012;74:54–60.

CHAPTER THREE

Copper(I)–Acetylides: Access, Structure, and Relevance in Catalysis S. Díez-González1 Imperial College London, London, United Kingdom 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Oxidative Coupling Reactions 2.1 Glaser and Hay Coupling Reactions 2.2 Oxidative Cross-Coupling Reactions 3. Cross-Coupling Reactions 3.1 Group 10-Mediated Reactions: Sonogashira Cross-Coupling 3.2 Copper-Mediated Cross-Couplings: Catalytic Castro–Stephens Reactions 3.3 Copper-Mediated Cross-Coupling of Diazo Compounds 4. Other Coupling Reactions 4.1 Carboxylation and Carboxylative Coupling Reactions 4.2 A3-Coupling Reactions 5. 1,3-Dipolar Cycloadditions 5.1 Azide–Alkyne Cycloadditions and Click Chemistry 5.2 Other Cycloaddition Reactions 6. Miscellaneous Reactions 7. Conclusions References

94 96 96 101 104 104 107 109 112 112 115 117 117 122 126 128 129

ABBREVIATIONS Bz benzoyl CAAC cyclic (alkyl)(amino) carbene CuAAC copper-catalyzed azide–alkyne cycloaddition DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DMAc dimethylacetamide DMEDA N,N0 -dimethylethylenediamine dppe 1,2-bis(diphenylphosphino)ethane ee enantiomeric excess Advances in Organometallic Chemistry, Volume 66 ISSN 0065-3055 http://dx.doi.org/10.1016/bs.adomc.2016.08.001

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IPr 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene NHC N-heterocyclic carbene phen phenanthroline TBHP tert-butyl hydroperoxide TBTA tris(benzyltriazolylmethyl)amine TMEDA N,N,N0 ,N0 -tetramethylethylenediamide TMS trimethylsilyl

1. INTRODUCTION Ethyne-1,2-diylcopper(I) [Cu2C2] was the first organocopper(I) compound ever reported.1 Prepared by bubbling acetylene through a solution of CuCl in aqueous ammonia, this energetic reagent is stable while wet, but explosive when dry. The explosive decomposition of [Cu2C2] can be initiated by either heating above 120°C, impact, or electric spark. On the other hand, alkynide copper(I) derivatives were only reported a century later,2 but they have become increasingly popular due to their straightforward synthesis,3 commercial availability, and remarkable thermal and shock stability. Actually, in spite of the Cu–C bond, some of these yellow-orange compounds are among the most stable copper(I) derivatives and might be stored for prolonged periods of time,4 which is directly linked to their polymeric structures. Homoleptic [CuC^CR] complexes remain rare in the literature and only recently have the solid structures for R ¼ t-Bu, n-Pr, and Ph been elucidated.5 tert-Butylethynylcopper(I) displayed a C20 cluster structure with an interlocking of a distorted Cu8 ring with two hexagonal C6 rings. Each of the rings was supported by μ,η1,1-C^C–Cu2 and μ,η1,2-C^C–Cu2 bonding, while μ3,η1,1,2-C^C–Cu3 and μ4,η1,1,1,1,2-C^C–Cu4 bridging modes were found to bring the Cu atoms of different rings together (Fig. 1). On the other hand, phenylethynylcopper(I) has a polymeric ladderane structure with short copper(I)–copper(I) distances, ranging from 2.49 to 2.83 A˚ and μ,η1,2-C^C bridging ligands. Hence, both steric and electronic properties of the alkynyl ligands have a strong influence on the actual structures. The use of additional ligands does improve the solubility of the obtained complexes, but still lead to highly aggregated species with a range of σ- and π-interactions solid structures.6 This review will focus on catalytic/synthetic applications of copper alkynyl derivatives. Nevertheless, this family of compounds has found other interesting applications, including luminescent complexes,7

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Fig. 1 Schematic drawing of the cluster assembly of three interlocking [CuC^C(t-Bu)] ring: central Cu8 unit (medium gray) and two peripheral C6 units (dark gray and light gray). Reproduced from Chui, SSY, Ng, MFY, Che, C-M. Structure determination of homoleptic AuI, AgI, and CuI aryl/alkylethynyl coordination polymers by X-ray powder diffraction. Chem Eur J. 2005;11:1739–1749 with permission.

fluorescence quenchers for copper detection in living cells,8 or preparation of semiconducting nanowires and thin metallic nanowires by self-assembling.9 We do not intend to provide a comprehensive view of the uses of copper(I)–acetylide in organic chemistry, and in consequence, “classical” organocopper reactivity (i.e., 1,2- or 1,4-addition to (conjugated) carbonyl compounds) will not be covered.10 Instead, the central role of copper acetylides in the catalytic transformations of alkynes and how the reaction conditions might affect the actual structure of the acetylide intermediates (and the mechanistic rationale) will be discussed while providing a historical perspective for the development of each transformation.

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2. OXIDATIVE COUPLING REACTIONS Copper can easily access 0, +I, +II, and +III oxidation states, and in consequence, its redox chemistry is extremely rich with both one-electron (radical reactions) and two-electron processes (organometallic processes) possible. Even if other reagents can be used in the laboratory, oxygen is a particularly desirable oxidant as it is directly related to the biological role of copper and it can act as a sink for electrons (oxidase activity), or a source of oxygen atoms for incorporation in the organic product (oxygenase activity). Copper enzymatic oxidizing systems are highly performant and have inspired generations of chemists for the development of a wide variety of oxidative processes under typically mild reaction conditions.11

2.1 Glaser and Hay Coupling Reactions The oxidation of copper(I) phenylacetylide into diphenyldiacetylene in air was discovered by Glaser in the XIXth century (Scheme 1).12 This transformation has become a standard procedure for the homocoupling of terminal alkynes thanks to its many variations that nowadays do not involve the isolation of any organometallic species.13 Among these, the Hay coupling,14 reported almost 100 years after the Glaser’s ground-breaking work, deserves particular mention. Indeed, the use of TMEDA as bidentate ligand in these reactions significantly improved the solubility of the copper species, allowing for substoichiometic metal loadings, and milder reaction conditions while also improving the overall outcome of the reactions (Scheme 1). Early proposals on the involvement of free radicals in the Glaser coupling were gradually abandoned as evidence against such intermediates gathered in Glaser12a

CuCl (2 equiv.) Ph

H

Ph

Cu

NH4OH, EtOH

O2 (0.5 equiv.) NH4OH, EtOH

Ph

Ph + H2 O

14b

Hay

CuCl (5 mol%) TMEDA (5 mol%) Ph

H

O2 (0.5 equiv.) Acetone, 28°C

Ph

Ph + H2O

Scheme 1 Original Glaser and Hay coupling reactions.

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the literature. Notably, Bohlmann and coworkers showed that when two electronically different alkynes were used in these reactions, the homocoupled products remained predominant, which would not be expected with free radicals.15 Furthermore, they also showed that in acidic media more acidic alkynes dimerized more slowly and only in the presence of a copper(I) salt. In consequence, the activation of alkynes toward deprotonation via the formation of a π-complex was postulated for the first time and dimeric copper(II) acetylides complexes were proposed as intermediates in order to account for the observed second-order dependence of the reaction rate on the concentration of alkyne (Fig. 2). Extensive work by Fedenok supported this proposal by showing that under buffered conditions (NEt3, AcOH, pyridine), all copper in the reaction was in +II oxidation state, with dioxygen oxidizing CuI species and regenerating the active CuII centers.16 Nevertheless, when nonbuffered pyridine was used in these coupling reactions, the regeneration of copper(II) by oxygen was significantly slower, with copper(I) species actively involved in the couplings.17 Unfortunately, the role of copper(I) could not be further clarified due to the complex dependence of the rate and order of the reaction on the concentration of the alkyne and CuCl. These early studies clearly showed that the actual mechanism was highly dependent on the conditions employed, and even if some recent advances have been made, the mechanistic complexity of this reaction remains to be entangled. Still, species shown in Fig. 2 represents a widely accepted mechanistic rationale. The first DFT study on this reaction, on the Glaser–Hay variant in particular, unveiled a complex mechanistic picture in which a copper(I)/(III)/ (II)/(I) would take place with two molecules of homocoupled product formed in each catalyst turnover and oxygen acting as an oxidant for copper(I) intermediates (Scheme 2).18 The copper center was found to form first a π-complex with acetylene that would then evolved to a copper acetylide intermediate via a proton transfer reaction assisted by the TMEDA

L L R

2

Cu 2X Cu

R

L L

Fig. 2 Intermediate dimeric copper(II) acetylides in Glaser couplings.

Scheme 2 First computed mechanism for the Glaser–Hay coupling reaction.

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ligand. This intramolecular process was found to be favored both kinetically and thermodynamically with respect to a second TMEDA molecule abstracting the acetylenic proton. In the next step, oxygen would react with the metal center to form a bis(μ-oxo)dicopper(III) intermediate. The reactivity of copper(I) complexes with dioxygen has been consistently studied for decades due to its important implications in catalysis as well as in biochemistry, and indeed, this proposal was supported by the experimental preparation of similar complexes with amine ligands.19 Two consecutive proton transfers from the protonated amine to the [Cu2(μ-O2)] core would then break the dimer and form a monomeric copper(III) acetylide that would generate an equivalent of diacetylene and a copper(II) hydroxide via a dicopper transition state. This hydroxide would then react with another molecule of alkyne and through a similar sequence form a second molecule of diacetylene and a copper(I) aqua complex, closing the catalytic cycle. It is important to note that the reduction of a (TMEDA)copper(II) complex to copper(I) by terminal alkynes has been directly observed by X-ray absorption spectroscopy and in situ electron paramagnetic resonance, with the formation of the corresponding diynes.20 These observations also explain why copper(II) salts might also be used as catalyst precursors in these coupling reactions, as well as in many other copper(I)-mediated reactions involving alkynes (vide infra). These results shed some new light on the role of the ligand in this reaction, which was found to actively participate in the reaction and not only avoid the formation of polymeric, insoluble forms of copper acetylide derivatives. On the other hand, concerns about the suitability of the chosen level of theory to study copper–oxo complexes21 and the high free energy values (instead of the reported potential energy barriers) justified a second theoretical study of the Hay coupling.22 In this case, only intermolecular deprotonations by TMDEA were considered, and the oxygen activation step was studied in much more detail (Scheme 3). It was found that the cleavage of the O]O bond takes place in two steps, first forming a copper(III)-η2-peroxo complex upon the transfer of two electrons from the copper to the ligand. This spin-crossing from triplet to singlet would most likely take place through a low barrier minimum energy crossing point.23 A second two-electron transfer would then occur upon reaction with another copper(I)–acetylide to form a similar Cu2O2 core to the originally proposed (see Scheme 2). Then, two consecutive protonations involving protonated TMEDA would lead to a monomeric copper(III) hydroxide. From this point, a much different reaction pathway was found

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Me2N

NMe2

Me2N

O2

Cu

NMe2 Cu O O

Me2N

NMe2

NMe2

Me2N

Cu

Cu O

TMEDA–H

Me2N

O

Cu

Me2N

TMEDA

NMe2 TMEDA–H

OH

NMe2

Me2 N Cu N Me2

2 Me2N

NMe2 Cu

NMe2

Me2N Cu

Cu HO Cu

Me2N

NMe2

TMEDA + H2O

Cu Me2N

NMe2

Scheme 3 Revised computational proposal for the Glaser–Hay coupling reaction.

with this hydroxide reacting with the original copper(I)–acetylide to form a copper(II) dimer with bridging acetylide ligands by a concomitant electron transfer from one copper center to the other. Protonation of the hydroxide ligand by TMEDA–H+ would eventually lead to the elimination of water and form another copper(II) dimer which would easily undergo reductive elimination to generate the coupling product and close the catalytic cycle. The computed energy barrier for this reaction was of only 17.5 kcal mol1 (free energy) and was linked to the alkyne deprotonation step. Hence, it explained the experimental observations of reactions proceeding smoothly at room temperature. Whereas such mild reaction conditions and the fact that reactions might be carried out in the presence of water are beneficial for these (and other related) coupling reactions, this high reactivity implies that the Glaser–Hay homocoupling typically competes with any other transformation if inert conditions are not employed. Even if an excess alkyne might be used, such a side reaction generally decreases the yields and complicates the purification of the desired products.

101

Copper(I)–Acetylides

2.2 Oxidative Cross-Coupling Reactions The first example of asymmetrical diyne preparation through a crosscoupling reaction was reported by Cadiot and Chodkiewicz via the coupling of a terminal alkyne and a bromoalkyne (see Section 3 for more nonoxidative cross-coupling reactions).24 However, oxidative Glaser–Hay conditions have proven more powerful in this context, with either two different terminal alkynes (one of them in large excess)25 or one terminal alkyne and one propionic acid via a decarboxylative cross-coupling reaction.26 Over the years, an increasing number of nucleophiles have found application in these oxidative couplings, many of them stoichiometric in copper. Seminal work by Knochel and coworkers involved the cross-coupling of aryl magnesium halides and alkynyl lithium reagents (Scheme 4).27 It was proposed that an arylcopper(I) complex reacted with the organolithium reagent to form a mixed lithium aryl(alkynyl)cuprate that upon reaction with chloranil would generate the cross-coupled product. In spite of being efficient and proof of concept for the real potential of copper-mediated oxidative cross-couplings, this methodology suffers from the generation of superstoichiometric amounts of metal waste and the use of chloranil as oxidant.28 The oxidative cross-coupling of a nucleophilic trifluoromethylating reagent has had a much bigger impact as it represents the first efficient and tolerant methodology for the formation of C(sp)–CF3 bonds. The original report employed again a stoichiometric amount of copper and phenanthroline ligand; a slow addition of the reactants was also necessary to ensure good yields and avoid the formation of undesired homocoupled products.29 Moreover, it was soon found that 20 mol% of the CuI/phen system was enough to ensure good yields in cross-coupled products (Scheme 5).30 (1) i-PrMgCl·LiCl (1.1 equiv.) THF, 0°C Ar X

Ar

R

(2) CuCl·2LiCl (1.2 equiv.), –50°C (3) R Li (2 equiv.), –50°C (4) Chloranil (1.3 equiv.), –78°C O

ArCu R

Li

ArCu

R

Li

Cl

Cl

Cl

Cl O Chloranil

Scheme 4 Oxidative cross-coupling of organolithium and magnesium reagents.

102

S. Díez-González

CuI (20 mol%) phen (20 mol%) R

N

H + TMS CF3 (4 equiv.)

R

CF3

KF (5 equiv.) Air, DMF, 100°C

N O

Cu

N

N

O

F3 C

F3 C

Cu

O2

O

O

Cu N

N

N H

CF3

Cu

F3 C

N

O H

N

O

N

N Cu

CF3

Cu

N

R

CF3

N

N

CF3

N Cu OH F3 C

TMS OH

H

F3C R

TMS CF3

N

Cu

O

HO

Cu N

CF3 N

= N

N

N

N

Scheme 5 Copper-mediated oxidative trifluoromethylation of alkynes and proposed mechanism.

A DFT study on this reaction found that an in situ generated [(phen) Cu–CF3] species would react with oxygen to form a η1-superoxocopper(II) intermediate.31 Reaction with another molecule of the CuCF3 species would eventually form a bis(μ-oxo)dicopper(III) intermediate, the lowest energetic point in the proposed catalytic cycle. Sequential reaction of two molecules of alkyne via hydrogen bond interaction with this copper(III) intermediate would lead to two-proton transfer processes to give a copper(III) hydroxide that would undergo reductive elimination, and form the final product and complete the catalytic cycle. These cross-coupling reactions are by no means limited to C-nucleophiles.32,33 For instance, phosphorylation reactions have been reported with 10 mol% of CuI and 20 mol% of an N-additive to form

103

Copper(I)–Acetylides

CuI (10 mol%) O NEt3 or NHEt2 (10 mol% ) H + H P R2 Air, DMSO, 55°C R3

R

L

O P R2 R3

O H P OMe OMe

L O

Cu

R

O L

L Cu

Ph O 2 Ph L

L

Ph

O

Ph

HO

L

OMe OMe Ph

Cu L

Cu

P

O

L

L

Cu

O MeO P HO Cu MeO O L L

Ph

L = NMe3

Scheme 6 Copper-assisted phosphorylation of alkynes and proposed mechanism.

the corresponding alkynylphosphonates in very high yields (Scheme 6).34 A theoretical study of this reaction disclosed a similar mechanistic picture than for the trifluoromethylation reactions with a significant difference: the alkyne would interact with the copper center first, leading to an electrophilic copper(III) acetylide upon oxidation by O2 to then react with the dialkyl phosphonite (Scheme 6).35 This proposal is in accordance with the experimental observation of formation of polymeric (insoluble) copper acetylide derivatives during the reaction. These transformations are sometimes referred to as “umpolung” oxidative couplings since the copper acetylide might act as the electrophile upon oxidation to copper(III).4b However, it seems apparent that a better mechanistic understanding is necessary in order to establish unarguably which reagent is acting as nucleophile or electrophile in each coupling reaction. Several oxidative cross-coupling reactions involving the activation of C–H bonds have also been reported. However, examples involving the dehydrogenative cross-coupling of activated arenes and azoles are consider to take place via copper(II)/copper(0) catalytic cycles and therefore will not be discussed here.36 On the other hand, the activation of C–H bonds adjacent to a nitrogen center followed by coupling with a copper(I)–acetylide has been reported to proceed smoothly at room temperature in the presence of CuBr with tert-butyl hydroperoxide as the oxidant of the starting compound, either a methylamine or a glycine derivative (Scheme 7).37 Similarly, benzylic C–H bonds can be oxidized by DDQ, leading to the coupling with alkynes in the presence of a copper catalyst (Scheme 7).38

104

S. Díez-González

Ar'

Ar

N H

NHR

CuBr (10 mol%) TBHP (1 equiv.)

Ar

+ Ar' DCM, RT

O

TBHP

Ar

Ar'

NHR

N

N H

NHR O

Cu

O

Ph

Ar

+

CuOTf (1 mol%) DDQ (1.5 equiv.)

Ph

PhCl, 120°C

Ar

R

R

R

DDQ Ph

Cu

Ar

Scheme 7 Cross-dehydrogenative coupling of alkynes and amines or benzylic derivatives.

3. CROSS-COUPLING REACTIONS 3.1 Group 10-Mediated Reactions: Sonogashira Cross-Coupling It is fair to say that palladium-catalyzed cross-coupling reactions have changed forever how chemists envision retrosynthetic analysis, particularly for bisarylic molecules. Even though these reactions had been known in the presence of copper for over a century, the use of palladium, together with very intense research by both academic and industrial laboratories, has allowed for extremely competent catalytic systems, with a very broad substrate scope and current application in large-scale production.39 Original work on the coupling of haloarenes and terminal alkynes by Heck40 and Cassar41 employed palladium as the only metal source and required harsh conditions, whereas Sonogashira and Hagihara showed soon after that a substoichiometric amount of CuI enabled the alkynylation reaction at room temperature.42 It has since been proposed that copper–acetylides act as the transmetallating agents in these couplings. However, even if the individual mechanistic steps in crosscoupling reactions are well established (oxidative addition, transmetallation, and reductive elimination), the actual nature of these elementary reactions

105

Copper(I)–Acetylides

[Pd], [Cu] Ar X +

R

H

R

Ar Base

LnPdII

Ar X

Base H

Ar Cu

R

X

Base

Oxidative addition

[Pd0Ln]

R

H

transmetallation

CuX LnPdII Ar

Ar CuX

R Reductive elimination

R

H

R

Scheme 8 Sonogashira reaction and proposed mechanism in the presence of a copper(I) cocatalyst.

is far from being understood, and the use of copper in the case of Sonogashira reactions brings an additional layer of complexity to this understanding. It is generally agreed on that the base present in the Sonogashira reactions facilitates the formation of the copper–acetylide intermediates that would then transmetallate the alkynyl moiety onto a palladium(II) center (Scheme 8).43 This simple picture is blurred not only by the complex behavior of copper acetylides in solution but also by the possibility of ligand transfer processes between the palladium and the copper species. Recent kinetic studies have shown that this cross-coupling reaction is first order dependent on the concentration of copper, indicating that the transmetallation is the ratedetermining step and that copper acetylides and [Pd(Ar)(X)Ln] are the resting states of the catalyst.44 On the other hand, studies with ferrocenyl polyphosphine ligands showed that preisolated copper complexes performed better than simple CuI in a model Sonogashira reaction (Scheme 9) and avoided the undesired formation of diynes or enynes, commonly observed by-products in these reaction.45 In this case, no coupling was observed in the absence of a palladium source. Catalytic tests, together with NMR studies, showed that a tridentate ligand could be transferred between the copper and the palladium centers. These results are therefore relevant for systems using more labile monodentate phosphines, as well as those with other good additives for copper, such as N-ligands. Also, the reported observations imply that

106

S. Díez-González

MeO

Br +

Ph

H

[PdCl(allyl)]2 (0.5 mol%) K2CO3 (2 equiv.) DMF, 130°C, 24 h

Ph2 P

[Cu]

L

GC conversion

CuI (5 mol%)

—

99% >99% (3 h)

MeHN

Cu

Ar X

Resting state

R

Base H

Ar NHMe Base H

R

MeHN

R

Cu X

Scheme 11 Model reaction and proposed mechanism with [Cu(DMEDA)2]Cl2H2O/ DMEDA.

Copper(I)–Acetylides

109

showed that the resting state of the catalyst was a ligand-free polymeric form of alkynylcopper. The role of the secondary amine here would be dual: to solubilize such polymer as well as to form a monomeric acetylide, the actual active species in this reaction,57 via complexation.58 Furthermore, the strong donor properties of the ligand would also facilitate the next proposed step in the cycle, an oxidative addition of the haloarene. This mechanistic sequence is supported by DFT calculations59 as well as experimental work showing that copper(III) species bearing an aryl and an acetylide ligand are intermediates in these reactions.60 Arguably at present copper catalysis does not necessarily represent a cheaper or more sustainable alternative to palladium-based systems for these cross-coupling reactions. Nevertheless, and as it was already observed by Castro and Stephens,53 in the presence of copper catalysts ortho-substituted aryl halides (or trisubstituted vinyl halides) are suitable coupling partners, whereas such substrates are typically inactive with palladium catalysis conditions. This has notably led to a straightforward access to diverse heterocycles via cross-coupling/cyclization cascade reactions. This reactivity has an obvious synthetic interest since indoles, isoquinolines, isocumarins, dihydro-benzofuranes, or furanones, just to name a few, might be prepared using this methodology.55 More importantly for this review, it confirms that copper species can mediate these cross-couplings since no such products are obtained with palladium catalysts. Indeed, much controversy around not only reported copper but also iron or gold catalysts for cross-coupling has recently raised in the literature.61 Even if it undeniable that palladium contamination might be relevant in some reported systems,62 overall it cannot explain all copper-based reports in this context.

3.3 Copper-Mediated Cross-Coupling of Diazo Compounds It is well established that the reaction of metal carbenes and alkynes leads to the formation of the corresponding cyclopropene derivatives. However, as early as in 1965, it was reported that copper sulfate could mediate the crosscoupling of ethyl diazoacetate and 1-octyne with no traces of the expected cyclopropene.63 Despite the interest of this transformation, it remained unexplored for almost 20 years due to the low yields and the formation of several by-products, including polymers. In 2004, Fu reported an extremely simple and performing catalytic system for these cross-coupling reactions (Scheme 12).64 In acetonitrile at room temperature, no cyclopropenation or

110

S. Díez-González

O 1

+

R

R

H

R1

MeCN, RT

N2

R2

O

CuI (5 mol%)

2

Scheme 12 Copper-catalyzed synthesis of alkynoates. R1

R2

R1

R2

or N2

R2

Conditions

3

+

R

R3 •

H R1

NNHTs

2

R = COOMe From a-diazoesters From N-tosylhydrazones CF3 O

[Cu(NCMe)4]PF6 (5 mol%) O N

(5 mol%)

Cu O

O

Me

N

2

N

N N (6 mol%) N Cs2CO3 (3 equiv.), 1,4-dioxane, 90°C

R1

(5 mol%)

K2CO3 (1 equiv.), DCE, 45°C

SiR3

R2

CuI (20 mol%) + R3Si

NNHTs

N N

H

LiOt-Bu (1.4 equiv.) 1,4-dioxane, 110°C

R2 R1

Scheme 13 Cross-coupling reactions of secondary carbenes and terminal alkynes.

oligomerization was observed, and only trace amounts of the corresponding allenes, fumarate, and maleate by-products were obtained. Interestingly, when secondary carbene precursors were used instead, the reactions afforded trisubstituted allenes exclusively, provided that basic conditions and a suitable ligand were employed (Scheme 13).65 The origin of these two possible reaction products relies on the regioselective protonation of the copper–propiolate intermediate (vide infra). This is most likely to be determined by both steric and electronic factors, since when silyl-substituted alkynes were coupled with secondary carbenes, alkynoates became again the principal reaction product (Scheme 13).66 Two different mechanistic proposals can be found in the literature for these cross-coupling reactions with the copper center interacting first either with the alkyne or with the carbene (Scheme 14).67 In the first case, based on the well-established palladium-catalyzed coupling of diazo compounds,68 a copper–acetylide would be first formed to then react with

111

Copper(I)–Acetylides

R1 R2

N2

R3 LnCuI

N2

H

R1

R3

[Cu] 2

R R3

R1

H H

N2

[Cu] R2

R3 R

[Cu]

R3

H H

2

H

Cu–C bond

R2

R1

N2

R1 R2 [Cu]

R1

R3

H

R1 • R2

R3

Scheme 14 Mechanistic proposal for the cross-coupling of diazo and alkynes.

the diazo compound (either preisolated or formed in situ from the corresponding tosylhydrazone). A migratory insertion of the alkynyl ligand to the copper carbene would afford a propargylic derivative. Hydrolysis of the copper–carbon bond would generate a propargylic product, whereas protonation at the C^C would deliver an allene. Alternatively, a copper carbenoid could be formed first, to then evolve to the same intermediate upon reaction with the alkyne.69 To date, very little mechanistic insights on these reactions can be found in the literature. Whereas it is noteworthy that the reaction of a preformed copper–acetylide and α-diazoester did not lead to the formation of any cross-coupled product,65a such acetylides have been supported by recent DFT calculations.70 Nevertheless, the influence of ligands on the mechanistic sequence or factors affecting the selectivity of the protonation step remains unexplored since the reported calculations focused on rationalizing the formation of propargylic compounds from silyl-substituted alkynes. A related reaction, the 2:1 coupling of in situ generated arynes and alkynes has also been reported in the presence of CuCl (Scheme 15).71 In this case, a formal insertion of two equivalents of arynes into the acetylenic C–H bond takes place. The selectivity of insertion of highly reactive arynes is noteworthy since only the product issue of a 1:1 coupling was formed as the minor product in some of the reported entries.

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S. Díez-González

CuCl (5 mol%) KF (4.4 equiv.)

TMS +

R

H

OH

R

+

19-Crown-6 (4.4 equiv.) THF, 50°C

R 40–77%

0–38% H R R

H

Cu Cu

Cu

R

Scheme 15 Aryne–alkyne coupling reactions.

4. OTHER COUPLING REACTIONS The stoichiometric reactions of alkynyl organolithium or organomagnesium compounds with electrophiles are well established in the literature. Nevertheless, catalytic versions of these reactions were soon sought after in order to avoid the generation of stoichiometric amounts of metal waste as well as to broaden the functional group tolerance of this methodology. Indeed, copper-mediated coupling reactions now offer a straightforward access to propiolates or propionic acids (carboxylation reactions), or propargylic amines (A3 coupling). Both families of compounds are extremely useful synthons in organic chemistry toward heterocycles, biorelevant compounds, and materials.72

4.1 Carboxylation and Carboxylative Coupling Reactions CO2 has gained an increasing popularity as reagent in organic synthesis in the last few years.73 This has been partially motivated by the societal concern over the increasing levels of this greenhouse gas in the atmosphere and its consequences on our global climate. It is unclear whether the use of CO2 as reactant can be part of the solution to such a complex issue, but in any case CO2 remains an abundant, inexpensive, and nontoxic C1 carbon source to access carboxylic acids, esters, lactones, or polymers. In 1994 the copper-catalyzed synthesis of propargylic esters from terminal alkynes, CO2, and bromoalkenes was reported by Inoue.74

113

Copper(I)–Acetylides

R1 [Cu] CuI (4 mol%)

[Cu]

+ R2 X

H + CO2

O R1 O R2

Conditions

Results

K2CO3 (6 equiv.), DMAc, 100°C

5 entries, 50–89%

[CuCl(IPr)] (10 mol%)

K 2CO3 (2 equiv.), DMF, 60°C

28 entries, 42–93%

CuI (8 mol%), PEt3 (8 mol%)

Cs2CO3 (3 equiv.), DMAc, RT

20 entries, 20–99%

IPr =

N

N

Scheme 16 Copper-catalyzed formation of propiolates.

An alkylating reagent was used in order to displace the reaction equilibrium toward the carboxylated products as decarboxylation occurred at temperatures as low as 35°C (Scheme 16). This observation was not surprising since the insertion of CO2 in organocopper complexes was known to be reversible,75 and indeed, copper catalysts have been used in a number of decarboxylative reactions.76 Furthermore, early stoichiometric studies had shown that the use of a strong σ-donor ligand was critical for the outcome of the reaction,77 and milder conditions and a broader substrate scope were later achieved by using N-heterocyclic carbenes78 or alkyl phosphines79 as ancillary ligands.80 In order to access propyolic acids directly more elaborated catalytic systems were required. In this case it is crucial to keep the reaction conditions mild in order to avoid the decarboxylation of the copper propynoate intermediate. The first reported examples for this reaction were unsurprisingly based on very strong σ-donor ligands such as phenanthroline81 and polyNHC ligands82 (Scheme 17). The latter example is particularly interesting since it evidenced a notable synergic effect of transition metal catalysis and organocatalysis. Indeed, in this poly-NHC system, half of the imidazol-2-ylidene moieties would support the formation of a copper acetylide, whereas the other half would activate CO2,83 which would turn the formation of the copper propionate an intramolecular process. This proposal is slightly different from the generally accepted mechanism for these reactions, where no preactivation of CO2 is available

114

S. Díez-González

N N N

Ph

Cu

PAr3

NO3

N

PAr3

N

Ph

N

N

Poly-NHC + 0.5 equiv. CuCl

R1

N

R1 O

1

R

Cu

N

H

N

B

N

N

N

N

Ar = Ph or 4-F-C6H4

Cl

N

N

N

Cu

N

N CO2

N

N

Cu

O

N N

N

B⋅HCl

Scheme 17 Catalysts for the synthesis of propionic acids from terminal alkynes.

LCuX H

R1

O R1

LCuX

CO2

LCu O

R1

H

H

O

R2 Y

B

R1 2

R

1

R

O

O B

R1 LCu

B⋅HX

1

R

O O

BH

R1 H

HO

Scheme 18 Proposed mechanism for carboxylation reactions.

(Scheme 18). Assisted deprotonation of the starting alkyne by the carbonate base would form a copper–acetylide intermediate. No detailed studies on these have been reported for this reaction and hence their actual structure remains unknown. The following step, insertion of CO2 into the copper–carbon bond is believed to be accelerated by the presence of strong σ-donor ligands on the copper center.75,77,84 The formed copper– propiolate might then be hydrolyzed into the corresponding carboxylic acid or reacted with an alkyl halide to form an ester derivative instead. Interestingly, the insertion step might better be described as a nucleophilic attack since DFT calculations showed no interaction between copper and

Copper(I)–Acetylides

115

CO2 in the located transition state.85 On the other hand, the steric profile of the ligands and their donor properties could be of importance in this reaction. Indeed, a computational article in early 2010, only months before the effect of ligands in these reactions was reported, found the insertion of CO2 into an (NHC)Cu–C(ethynyl) bond to be endothermic by 30 kcal mol1.86 However, the model NHC used, 1,3-dimethylimidazol-2-ylidene, is significantly less sterically hindering than IPr,78 which could explain the lack of correlation between the theoretical and experimental reports. On the other hand, these calculations were carried out in the context of the related carboxylation of boronic esters, and to date a single example has been reported for the carboxylation of an alkynyl boronic ester, under quite forcing conditions.87

4.2 A3-Coupling Reactions The reaction of an Aldehyde, an Amine, and a terminal Alkyne (AAA ¼ A3) in the presence of a transition metal catalyst is generally known as A3 coupling. The catalytic addition of an alkyne to an in situ generated imine (or enamine) in the presence of copper species has been steadily developed since the first general methodology was reported in the 1990s.88 A variety of catalytic systems have allowed for the use of challenging primary amines, the replacement of the aldehyde by acetals or 1,1-dihaloalkanes, and the enantioselective preparation of propargylic amines.89 The mechanism of this subtype of Mannich coupling remains again poorly understood, but it is commonly proposed that a copper–acetylide would be formed under catalytic conditions (most probably assisted by π-coordination of the copper and the starting amine) and attack the iminium ion (or imine, depending on the substrates) in order to form the observed propargylic amines (Scheme 19). In fact, the isolation of polymeric alkynylcopper(I) species from these reactions has been reported, as well as the use of such polymers as the copper catalyst in a solvent mixture of water and DMSO.90 However, when cationic copper complexes bearing biphenylphosphine ligands were employed as catalysts in this reaction,91 no alkynylcopper derivatives could be isolated from the reaction mixtures, even if the original compounds were shown to be highly effective in the A3 coupling.92 Further stoichiometric experiments pointed toward the formation of a copper–amine intermediate instead, which would support the formation of a propargyl amine via π-coordination, without the involvement of

116

S. Díez-González

R3 R2

O

O R1

H

R2 H

N

+

R1

+

R3 R4

+

R2 N

[Cu]

R4

H

1

R

R3

N

R3

H

R2 N

HO R3

R2

R4

N R1

R

1

CuL R4

H

H

Base R4

LCuX

R3

R4

LCu

R

Base

2

N R4 1

R 3

Scheme 19 A coupling and proposed mechanism. LCu

X

O

HN

H

R

HN

H

L Cu

N H

N H

R

+

X

H L Cu N

N

H

H

N OH

H

HO H

R

R

X

H OH L Cu

N

X

N

H2O

Scheme 20 Alternative mechanism for the copper-mediated A3 coupling.

a copper(I)–acetylide (Scheme 20). Even if only pyrrolidine and formaldehyde were considered in this study, it is obvious that further studies are required in order to clarify the role of the copper catalyst in this coupling reaction.

117

Copper(I)–Acetylides

5. 1,3-DIPOLAR CYCLOADDITIONS 5.1 Azide–Alkyne Cycloadditions and Click Chemistry 1,3-Dipolar cycloadditions, commonly referred to as Huisgen cycloadditions,93 represent one of the most powerful methodologies for the preparation of a wide range of five-membered heterocycles. Classically carried out under thermal conditions, these [3 + 2] cycloaddition reactions remain very popular reactions particularly due to the development of metalcatalyzed versions.94 Indeed, the copper-catalyzed azide–alkyne cycloaddition (CuAAC; Scheme 21) has become the first fashionable reaction of the XXI century and it has served as proof of concept of the relevance of Click chemistry, a term coined by Sharpless in 2001.95 Even if L’abb
e had already reported a copper(I)-catalyzed [3 + 2] cycloaddition reaction in 1984,96 the full potential of this reactivity was overlooked until 2002, when Sharpless97 and Meldal98 reported independently that copper(I) species mediated the cycloaddition of azides and alkynes to yield 1,4-disubstituted-1,2,3-triazoles as single products.99 One of the biggest achievements of this transformation is how quickly it has found a myriad of applications in a variety of fields such as polymer and material science,100 biology,101 or carbohydrate chemistry.102 Early efforts in understanding the mechanism of the CuAAC reaction focused on rationalizing the observed regioselectivity as well as the outstanding accelerating effect of the copper catalysts.103 DFT calculations showed that π-coordination of the copper center onto a model alkyne (propyne) lowered its pKa by 10 units.104 However, a cycloaddition reaction involving such an intermediate, without the deprotonation of the terminal alkyne, actually had a higher energy barrier than the uncatalyzed, thermal reaction. Indeed, only the intermediacy of a copper(I)–acetylide could account for the dramatic increase in the rate of the reaction. Using mononuclear copper– acetylides, the calculations showed that the copper-catalyzed reaction is a

R1 N3 +

R2

conditions

R1

N

N

N R2

Thermal conditions Copper(I) catalyst

R1 +

N

N

N

R2

Mixture of products Only product

Scheme 21 Cycloaddition reaction of azides and terminal alkynes.

118

S. Díez-González

N N N R1

R2

N

R2

CuLn

R2 N

N

CuLn–1

R1

R2

R2 N

CuLn–1 N

N

R2 1

R

CuLn–2 N R1 N

‡

CuLn–2 N N N R1

Scheme 22 Early mechanistic proposal for the CuAAC.

stepwise process in which the N3 nitrogen of the azide would attack the C2 carbon of the acetylide forming a then unusual six-membered copper(III) metallacycle transition state (Scheme 22). A reductive elimination would then lead to a triazolide–copper(I) intermediate, which might be easily hydrolyzed to form the final triazole and close the catalytic cycle. Such proposal represents a decrease in the calculated energetic barriers of around 10 kcal mol1 and rationalizes the complete regioselectivity obtained experimentally. The fact that these reactions are typically run in the presence of air and/or water is by no means incompatible with the intermediacy of copper– acetylides since it is well established that these species can be stable even in acidic aqueous solutions.105 The fact that homocoupled product issue of a Glaser reaction is rarely encountered in this reactions is a clear indication of the very strong driving force of these cycloadditions, a must in Click chemistry. Similarly, the use of an external base is not required for highly active cycloaddition catalysts. On the other hand, questions around the actual nuclearity of this reaction mechanism quickly raised since copper–acetylides tend to form polymeric species and exist in solution in dynamic equilibrium of different species (vide supra). Indeed, it was soon established that at low copper concentrations and in the presence N-additives such as phenanthroline, the reaction is second order in copper.104,106 Furthermore, di- and tetranuclear copper–acetylides were computed to display an enhanced reactivity toward azides, when compared to mononuclear ones.107 Notably, the computed copper⋯copper distances and geometries were very similar to the known ladder structures of polymeric alkynylcopper(I) complexes (vide supra, Fig. 4), which were consequently

119

Copper(I)–Acetylides

Cu R

R O

O

Cu

2.556 Å

Cu R

2.54–2.88 Å

Cu

Cu

O

O

Cu DFT proposals

Fig. 4 Dinuclear copper(I) species.

Ph N N N N

N

S

N

NH

NH

Ph N N

N

N Ph

HN

S

N

TBTA

N

N

N N N

N

N

H N

HN

N

N

N

N

Fig. 5 TBTA and related ligands in CuAAC.

shown to be able to catalyze the reaction, even if the reactivity was not outstanding.108 Similarly, the dimeric structure of Cu(OAc)2 also inspired its application in CuAAC.109 In this case, the copper(II) salt has to be reduced under the reaction conditions, which has been shown to be possible.20 Nevertheless, it is important to note that the order of the CuAAC reaction in copper does not delimit the actual composition of the catalytically active species and the mechanistic picture for this reaction remains far from clear as exemplified by the reports on tris-triazole (and related) ligand-based catalytic systems. Polytriazoles, and TBTA in particular, represent one of the first family of ligands developed specifically for this cycloaddition reaction (Fig. 5).110 Extensive kinetic studies revealed that the choice of the bestperforming ligand among these tertiary amines depends on the actual reaction conditions, such as concentration, pH value, and coordinating ability of the solvent. These factors were shown to modify the kinetic profiles as well as the optimal metal/ligand ratios.111 Considering the relatively low configurational stability of these ligands and the rich coordination chemistry of copper, it is conceivable that the actual active species and the rate-determining step in this reaction could differ depending on the conditions and the employed copper source/ligand combination.112 Hence, it is not overly surprising that strongly coordinating ligands, and N-heterocyclic carbenes in particular, have played a major role

120

S. Díez-González

not only in the development of highly performing catalytic systems99b but also in the mechanistic understanding of this transformation.113 For starting with, a well-defined copper–acetylide cluster bearing bidentate NHCs as ancillary ligands displayed a much higher activity that the previously reported polymeric species.108,114 The X-ray analysis of this compound (CCDC 1042359) showed that two of the copper atoms were σ-coordinated by four acetylide ligands, whereas the other six copper centers were connected to one NHC and two acetylides, one in a σ- and another in a π-coordination mode (Scheme 23). Considering its stability, this cluster was proposed to be the catalyst resting state and it could indeed be activated upon addition of acid to release the active dinuclear acetylide complexes supported by the NHC framework.115 Significantly, such dinuclear copper acetylides (with a different NHC ligand) were first evidenced by means of mass spectrometry,116 and even more remarkably, isolated and fully characterized when using a cyclic (alkyl)(amino) carbene (CAAC).117 In this work, a bis(copper)triazolide was also identified and the kinetic studies showed that both mono- and dimeric pathways are active under catalytic conditions, but that the latter is strongly favored (Scheme 24). The great interest that the CuAAC reaction has gathered has definitely inspired a number of recent mechanistic proposals in other copper-mediated transformations. Without diminishing their relevance, dinuclear copper acetylides cannot necessarily be easily extrapolated to other reactions and if something has become obvious thanks to the CuAAC reaction is that factors such as the ligand or solvent can modify the actual active species and therefore should be taken into account.

3

R

R Cu

R

Cu

N N

H

N Cu

Cu

N N R

R

R

Cu environments in CCDC 1042359 R = COOEt

Scheme 23 Isolated copper(I)–acetylide species with NHCs.

N N

N Ar

N

R

Ar

121

Copper(I)–Acetylides

LCuX

Et Et

L=

R2

N

HX 2

R

R2 N R

N

N

L Cu

R1

2

R R2

CuL

LCu

N

N

R1

2

X CuL

L Cu

X N

LCuX

CuL

R2

CuL

X

R1N3

N N N R1

Scheme 24 Mechanistic proposal with L ¼ CAAC.

It is important to note that not all copper-mediated reactions of azides and alkynes lead to the formation of the corresponding triazoles. Noteworthy are the formation of 2,5-disubstituted-1,2,3-triazoles with a palladium(0)/copper(I) bimetallic catalytic system,118 as well as the reactions of electron-poor azides. For the latter, a number of catalytic systems (all of them ligand-based) have been reported for the formation of 4-substituted-1-sulfonyl-1,2,3-triazoles from the corresponding sulfonyl azides.119 However, in this case the corresponding copper–triazolide intermediate has a N–N bond whose cleavage is particularly straightforward, leading to the formation of the corresponding ketimines species that can be then trapped with different nucleophiles such as amines, imines, or water (Scheme 25).120 More strikingly, the reaction of ketoazides and alkynes was reported to form 2,5-disubstituted oxazole instead of triazoles (Scheme 26).121 DFT calculations, together with crossover experiments, precluded the involvement of alkynylcopper species in this case. Instead, they supported a mechanism involving the formation of a copper–nitrene from the starting azide and formation of the oxazole motif after π-coordination of the alkyne to this intermediate in order to form the observed oxazole.122

122

S. Díez-González

S O

R2

[Cu]

R1

N3

R2

+

N2

[Cu]

O

R O2S

N

N

N

R

N

N

R2N

N

H2O

R1O2S

H N

R2 O

R4

R3N

R2NH R2

R1O2S

N

2

H

R2

[Cu]

SO2R1

[Cu] 1

R2 R2 NSO2R1

R4

NSO2R1 N

R3

Scheme 25 Reactivity of N-sulfonyl copper–triazolide intermediates.

O R

1

+ N3

R2

[Cu] O

R1

via

R1 N

R2

[Cu]

N

O

R2

Scheme 26 Reaction of carbonylazides and alkynes.

5.2 Other Cycloaddition Reactions The formation of copper–acetylide derivatives has the general effect of rising the HOMO of the dipolarophile and hence it is not surprising that azides are not the only reactive dipoles for such species.123 Indeed, in the early work published by Sharpless and Fokin, in situ generated nitrile oxides were also studied for the synthesis of 3,5-disubstituted isoxazoles and their calculations with monomeric copper–acetylides presented a very similar mechanistic picture with this dipole (Scheme 27).104 However, comparatively little attention has been paid to this transformation since, which is probably related to the fact that many of these reactions are known to run smoothly in aqueous media without the need of adding a copper source.124 The same mechanistic rationale has also been proposed for the intramolecular Diels–Alder cycloaddition of inactivated alkynes.125 These reactions proceeded smoothly in the presence of one equivalent of base, suggesting the formation of a copper–acetylide under catalytic conditions (Scheme 28). Labeling experiments together with the fact that only terminal alkynes reacted in the presence of copper species, unlike with gold(I) catalysts, further support this proposal. Nevertheless, no additional mechanistic studies have been reported to date for this transformation. In the case of diazocarbonyl compounds, a third type of propargyl/ allenyl anion dipole type, electron-deficient alkynes might be used in cycloaddition reactions in the presence of a Lewis acid, but no simple alkyl or aryl alkynes.126 Instead, such inverse electron demand cycloaddition reactions can be mediated by copper(I) catalysts, provided that alkynyl anions are used

123

Copper(I)–Acetylides

R1

R2

N O +

[Cu]

N

and/or water

R1

O

R2

Scheme 27 Synthesis of isoxazoles. X

X

CuI (10 mol%) NEt3 (1 equiv.)

R

via

DCM, RT R

Y

Y

X

R Y

Cu

X = C(CO2Me)2, NTs, C(SO2Ph)2, O Y = CH2, O

Scheme 28 Copper(I)-mediated Diels–Alder reaction.

R

2

(1) CuCN⋅6LiCl, –17°C Li

N (2) N2 O

via R

O R1

R2

R1

2

H N

CuLn and N R2

N

O H R CuLn

1

Scheme 29 Lithium acetylides-diazocarbonyl compounds’ cycloadditions.

as cycloaddition partners (Scheme 29).127 Otherwise, the alkynylation product was obtained instead (see Section 3.3). With the support of some preliminary mechanistic studies, the authors proposed that this reaction has a similar catalytic cycle than the CuAAC reaction, with copper–acetylides and pyrazolyl–copper species as intermediates. It is important to note that even if the scope of the reaction was explored with one equivalent of the copper salt, the authors state that the substoichiometric amounts of copper(I) can promote these transformations. Considering a different family of dipoles, aza-allyl type dipoles, the copper-catalyzed azomethine imine–alkyne cycloaddition reaction was first reported in 2003. A combination of CuI/amine led to the corresponding bicyclic oxopyrazolidines in good yields, and with high enantioselectivities when a phosphaferrocene-oxazoline ligand was used (Scheme 30).128 Unsurprisingly, copper–acetylide derivatives were assumed to be intermediates in this reactions, but some experimental evidence only appeared in the literature in 2012, when structurally stable dimeric copper phenylacetylide(S)-BINAP was shown to be active in this reaction when using only 2.5 mol%

124

S. Díez-González

* O

O N

N

R2

+

H

CuI (5 mol%) Cy2NMe (0.5 equiv.)

N

P

N Ph

Ph

DCM, RT

Cu

2

R1

R1

H

P Cu

R

P

P *

Scheme 30 Azomethine imine–alkyne cycloaddition reactions.

N R

L=

CuOAc (5 mol%) L (5.5 mol%)

NBz

1

N

DCM, 0°C

R

Ph

R2

H

R2

N

H

O

N N

R1

+ 2

O

NHBz

N Ph

NBz

R1

AcOH

LCuOAc R2

N

CuL + 1

R

N NBz HOAc

R

NHBz

1

R2

Scheme 31 Alkynylation of azomethine imines.

(Scheme 30).129 Furthermore, these mechanistic studies strongly supported a stepwise reaction (1,2-addition of copper–acetylide onto the dipole followed by intramolecular cyclization). It is important to note that in the case of C,N-cyclic azomethine imines only the product issue of a C1-alkynylation was obtained under similar catalytic conditions, with no trace of the related cycloadduct (Scheme 31).130 These reactions must be carried out in the absence of a basic additive since the acid formed in the reactions upon the formation of a copper-acetylide intermediate was postulated to play an essential role. Protonation of the azomethine imine would lead to its electrophilic activation toward a nucleophilic attack by the copper acetylide, leading to the observed reaction product. Indeed, the use of a chiral Brønsted as the cocatalyst in these reactions led to improved enantioselectivities and a broader substrate scope. Nitrones, another aza-allyl type dipole, are probably the most popular dipoles for copper-mediated cycloadditions with alkynes, together with azides. Commonly known as the Kinugasa reaction, the original reports were published in the 1970s, with preisolated copper acetylides and nitrones

125

Copper(I)–Acetylides

in anhydrous pyridine to produce β-lactams (Scheme 32).131 In this reaction, the initial cycloadduct rearranges into its corresponding enolate and a final protonation step delivers the observed 2-azetidinone. The use of ligands such as dppe or phenanthroline allows for the reaction to be catalytic in copper, avoiding the use of preisolated acetylides.132 Indeed, nowadays there are a number of user-friendly systems reported for this reaction in protic media including in water and “on water” conditions.133 Ligand design has also led to the synthesis of β-lactams with high enantioselectivities.134 A recent theoretical study supported important similarities between the Kinugasa and the CuAAC reactions, with a dicopper–acetylide formed as intermediate under catalytic reactions (Scheme 33).135 Nucleophilic attack of the oxygen in the nitrone would eventually lead to a six-membered R1

H

+ Ph

N 2

R

Ph

R1 Pyridine, RT R2

R2 N

Cu

O

R1

N O

Cu Ph

O

Scheme 32 Original Kinugasa reaction. LCuX Ph L=

N N

Ph

H

A

X

CuL A, Et3N Ph

H HN Ph CuL Ph • O Ph

L Cu

X Ph

H

+ Et3NH X X H

CuL

N Ph

H Ph

A, Et3N

Ph N H

Ph Ph

L Cu

H

+ Et3NH X

OCuL

Ph

LCu CuL Ph Ph

Ph N

Ph

Ph

O N Ph

Ph

X CuL

Ph

O N

‡

LCu CuL

Ph

O Ph H

X

O N Ph

Scheme 33 Proposed mechanism for the Kinugasa reaction.

H

Ph

O

126

S. Díez-González

copper(III) transition state and the formation of a C–C bond. The C–O bond would form in the next step, upon a formal reductive elimination. After decoordination of one of the copper centers and protonation of the nitrogen atom, a ring-opening step would generate a ketene intermediate. Cyclization via a nucleophilic attack would again be assisted by the copper center and would lead to the corresponding enolate with the final product being released after hydrolysis and tautomerization.

6. MISCELLANEOUS REACTIONS The transition metal-catalyzed nucleophilic substitution reaction of propargylic substrates represents a straightforward access to synthetically useful organic compounds such as propargylic amines. Even if they remain far less developed than allylic substitutions, different metals have been reported for these reactions, with ruthenium occupying a prominent place in the literature.136 Nevertheless, several high-performing copper catalysts have also been developed in the last few years, including chiral ones.137 Compared to Lewis and Brønsted acids, transition metal catalysis has the limitation of only being applicable to monosubstituted alkynes.138 This is due to the accepted intermediacy of metal–allenylidene species (Scheme 34). Such complexes are well established with other metals such as ruthenium, which readily reacts with propargylic alcohols to form stable complexes.139 However, allenylidene have proved far more elusive with Group 11 metals, and to date a single example with silver has been disclosed.140 C-, N-, O-, and S-nucleophiles have been used under copper catalysis, but recent advances have mainly focused on N-nucleophiles since this methodology represents a straightforward path to propargylic amines, which are versatile synthons (see also Section 4.2). The copper-catalyzed amination of propargylic acetates was first reported in the 1990s,141 and it took almost

OAc 1

+

Nu H

Nu

[CuI] 1

R

R

R1

R1 I

[Cu ]

•

•

[CuI]

Scheme 34 Nucleophilic substitution reactions and proposed key intermediates.

127

Copper(I)–Acetylides

15 years for the asymmetric version to be developed with either pybox142 or biphep143 ligands. Stoichiometric experiments in the latter case did not allow for the isolation of a copper allenylidene; however, a catalytically active dimeric copper acetylide could be fully characterized.144 Based on an almost first-order dependence of the reaction to the copper salt and the linear relationship between the ee of the ligand and the final product, a monomeric copper acetylide bearing one phosphine ligand was proposed as the active species in this reaction. The full catalytic cycle, supported by DFT calculations, is shown in Scheme 35. After formation of a copper acetylide, the acetate group on the substrate would be protonated and then eliminated to form a carbocation. This electrophilic intermediate would be stabilized by resonance as a copper–allenylidene, which was found to have a relatively weak Cu–C bond. Nucleophilic attack by the amine would form a first propargylic amine that would undergo a proton atom shift to the acetylenic position before being liberated. It is important to note that even if a similar cycle is expected to be operative in related substitution reactions, the actual active species might be different depending on the catalytic system. Indeed, dimeric species have recently been privileged in copper-catalyzed propargylic etherification reactions.145 NR2 1

LCuX

R

OAc NR2

R1 + Base

R1 LCu

Base·H OAc

NHR2 1

R1

R

CuL

CuL

Base·H

OH

HNR2 •

O

• CuL

R1

R

Base

1

CuL Base Base·AcOH

Scheme 35 Proposed mechanism for the copper-mediated propargylic amination reaction.

128

S. Díez-González

HNR3R4 (3 equiv.) CuBr (20 mol%) THF, 100°C

NR2

NR2

NR3R4 1

R

R1

R2

R2 R5 (3 equiv.) CuCl (20 mol%)

R1 R

2

THF, 100°C

CuI Cu

NR2

NR2

R1

+ R5

R2

1

R

Scheme 36 Substitution reactions of propargyl amines.

HNR2 [Cu], [ox]

HO

[Cu]

O

R1

R2 N N N

R2N3

R1

NR2 Cu

R1

[Cu]

R1

O R1

R2N–CHO R1

R1

Scheme 37 Cleavage of a C–C bond in propargylic alcohols.

These propargylic amines can also undergo substitution reactions with secondary amines or monosubstituted alkynes via a copper(I)-mediated C(sp)–C(sp3) bond cleavage (Scheme 36).146 Amines are poor leaving groups, but such C–C activation would be assisted by the lone pair of the nitrogen to form an iminium intermediate that readily undergoes fragment exchange,147 preventing the formation of Glaser-type by-products. Primary propargylic alcohols undergo similar reactions under oxidative conditions (Scheme 37).148 In this case, it has been proposed that the alcohol group is first oxidized to aldehyde to then react with an amine additive forming a hemiaminal. A copper acetylide would then form upon the cleavage of a C–C bond, to form a diyne, or a 1,4-disubstituted triazole if an organic azide is present (see Sections 2.1 and 5.1 for further details).

7. CONCLUSIONS Even if major advances have been made, the mechanism and the structure of the actual species involved in these alkyne transformations remain mostly speculative. The well-established tendency of copper to form

Copper(I)–Acetylides

129

polynuclear complexes and the ease of ligand exchange at the metal center make every single mechanistic study a challenging quest. Albeit caution should be applied when extrapolating to other reactions, the intense research around CuAAC has definitely revived the area and shed new light in the understanding of copper acetylide chemistry. This is of great importance not only to improve the efficiency and sustainability credentials of the discussed copper-mediated transformations but also for the discovery of novel ones.

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25. For relevant examples, see: (a) Zheng Q, Hua R, Wan Y. An alternative CuClpiperidine-catalyzed oxidative homocoupling of terminal alkynes affording 1,3-diynes in air. Appl Organomet Chem. 2010;24:314–316; (b) Wang D, Li J, Li N, Gao T, Hou S, Chen B. An efficient approach to homocoupling of terminal alkynes: solvent-free synthesis of 1,3-diynes using catalytic Cu(II) and base. Green Chem. 2010;12:45–48; (c) Maue M, Bernitzki K, Ellermann M, Schrader T. Bifunctional bisamphiphilic transmembrane building blocks for artificial signal transduction. Synthesis. 2008;2247–2256. 26. Yu M, Pan D, Jia W, Chen W, Jiao N. Copper-catalyzed decarboxylative crosscoupling of propiolic acids and terminal alkynes. Tetrahedron Lett. 2010;51:1287–1290. 27. Dubbaka SR, Kienle M, Mayr H, Knochel P. Copper(I)-mediated oxidative crosscoupling between functionalized alkynyl lithium and aryl magnesium reagents. Angew Chem Int Ed. 2007;46:9093–9096. 28. For the formation of similar compounds via the oxidative coupling of boronic acids and alkynes, see: (a) Pan C, Luo F, Wang W, Ye Z, Cheng J. Ligand-free copper(I)-catalyzed Sonogashira coupling of arylboronic acids with terminal alkynes. Tetrahedron Lett. 2009;50:5044–5046; (b) Rao H, Fu H, Jiang Y, Zhao Y. Highly efficient coppercatalyzed synthesis of internal alkynes via aerobic oxidative arylation of terminal alkynes. Adv Synth Catal. 2010;352:458–462; (c) Yasukawa T, Miyamura H, Kobayashi S. Copper-catalyzed, aerobic oxidative cross-coupling of alkynes with arylboronic acids: remarkable selectivity in 2,6-lutidine media. Org Biomol Chem. 2011;9:6208–6210. 29. (a) Chu L, Qing F-L. Copper-mediated aerobic oxidative trifluoromethylation of terminal alkynes with Me3SiCF3. J Am Chem Soc. 2010;132:7262–7263. See also, (b) Tresse C, Guissart C, Schweizer S, et al. Practical methods for the synthesis of trifluoromethylated alkynes: oxidative trifluoromethylation of copper acetylides and alkynes. Adv Synth Catal. 2014;356:2051–2060 (CF3–); (c) Jiang X, Chu L, Qing F-L. Copper-mediated oxidative cross-coupling reaction of terminal alkynes with α-silyldifluoromethylphosphonates: an efficient method for α,α-difluoropropargylphosphonates. Org Lett. 2012;14:2870–2873 (CF2P(O)(OR)–2); (d) Besset T, Poisson T, Pannecoucke X. Access to difluoromethylated alkynes through the Castro-Stephens reaction. Eur J Org Chem. 2014;7220–7225 (CF2COOEt–). 30. Jiang X, Chu L, Qing F-L. Copper-catalyzed oxidative trifluoromethylation of terminal alkynes and aryl boronic acids using (trifluoromethyl)trimethylsilane. J Org Chem. 2012;77:1251–1257. 31. Jover J, Maseras F. Computational characterization of a mechanism for the coppercatalyzed aerobic oxidative trifluoromethylation of terminal alkynes. Chem Commun. 2013;49:10486–10488. 32. For SCF3–, see: Pluta R, Nikolaienko P, Rueping M. Direct catalytic trifluoromethylthiolation of boronic acids and alkynes employing electrophilic shelf-stable N-(trifluoromethylthio)phthalimide. Angew Chem Int Ed. 2014;53:1650–1653. For SeCF3–, see: Lefebvre Q, Pluta R, Rueping M. Copper catalyzed oxidative coupling reactions for trifluoromethylselenolations—synthesis of R-SeCH3 compounds using air stable tetramethylammonium trifluoromethylselenate. Chem Commun. 2015;51:4394–4397. 33. Even if no mechanistic studies have been reported to date, reactions with N-nucleophiles are assumed to go through the formation of copper(II)–acetylides and hence will not be further discussed her. For selected references, see: (a) Peterson LI. A novel synthesis of ynamines. Copper catalyzed oxidation of phenylacetylene in the presence of secondary amines. Tetrahedron Lett. 1968;51:5357–5360; (b) Hamada T, Ye X, Stahl SS. Copper-catalyzed aerobic oxidative amidation of terminal alkynes: efficient synthesis of ynamides. J Am Chem Soc. 2008;130:833–835; (c) Jia W, Jiao N.

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34.

35. 36.

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109. (a) Shai C, Cheng G, Su D, Xu J, Wang X, Hu Y. Copper(I): a structurally simple but highly efficient dinuclear catalyst for copper-catalyzed azide-alkyne cycloaddition. Adv Synth Catal. 2010;352:1587–1592. (b) Gonda Z, Nova´k Z. Highly active coppercatalysts for azide-alkyne cycloadditions. Dalton Trans. 2010;39:726–729. 110. Chan TR, Hilgraf R, Sharpless KB, Fokin VV. Polytriazoles as copper(I)-stabilizing ligands in catalysis. Org Lett. 2004;6:2853–2855. 111. (a) Rodionov VO, Presolski SI, Gardinier S, Lim YH, Finn MG. Benzimidazole and related ligands for Cu-catalyzed alkyne–alkyne cycloaddition. J Am Chem Soc. 2007;129:12696–12704. (b) Rodionov VO, Presolski SI, Diaz DD, Fokin VV, Finn MG. Ligand-accelerated Cu-catalyzed azide–alkyne cycloaddition: a mechanistic report. J Am Chem Soc. 2007;129:12705–12712. (c) Bevilacqua V, King M, Chaumonet M, et al. Copper-chelating azides for efficient click conjugation reactions in complex media. Angew Chem Int Ed. 2014;53:5872–5876. 112. Kalvet I, Tammiku-Taul J, M€aeorg U, T€amm K, Burk P, Sikk L. NMR and DFT study of the copper(I)-catalyzed cycloaddition reaction: H/D scrambling of alkynes and variable reaction order of the catalyst. ChemCatChem. 2016;8:1804–1808. 113. (a) Nolte C, Mayer P, Straub BF. Isolation of a copper(I) triazolide: a “click” intermediate. Angew Chem Int Ed. 2007;46:2101–2103. (b) Dı´ez-Gonza´lez S, Nolan SP. [(NHC)2Cu]X complexes as efficient catalyst for azide–alkyne Click chemistry at low catalyst loadings. Angew Chem Int Ed. 2008;47:8881–8884. 114. Makarem A, Berg R, Rominger F, Straub BF. A fluxional copper acetylide cluster in CuAAC catalysis. Angew Chem Int Ed. 2015;54:7431–7435. 115. Berg R, Straub J, Schreiner E, Marder S, Rominger F, Straub BF. Highly active dinuclear copper catalysts for homogeneous azide–alkyne cycloadditions. Adv Synth Catal. 2012;354:3445–3450. 116. Worrel BT, Malik JA, Fokin VV. Direct evidence of a dinuclear copper intermediate in Cu(I)-catalyzed azide-alkyne cycloadditions. Science. 2013;340:457–460. For a related example with a phosphine ligand, see: Iacobucci C, Reale S, Gal J-F, De Angelis F. Dinuclear copper intermediates in copper(I)-catalyzed azide–alkyne cycloaddition directly observed by electrospray ionization mass spectrometry. Angew Chem Int Ed. 2015;54:3065–3068. 117. (a) Jin L, Tolentino DR, Melaimi M, Bertrand G. Isolation of bis(copper) key intermediates in Cu-catalyzed azide-alkyne “click reaction” Sci Adv. 2015;1: e1500304. (b) Jin L, Romero EA, Melaimi M, Bertrand G. The Janus face of the X ligand in the copper-catalyzed azide–alkyne cycloaddition. J Am Chem Soc. 2015;137:15696–15698. 118. (a) Kamijo S, Jin T, Huo Z, Yamamoto Y. Synthesis of triazoles from nonactivated terminal alkynes via the three-component coupling reaction using a Pd(0)–Cu (I) bimetallic catalyst. J Am Chem Soc. 2003;125:7786–7787. (b) Kamijo S, Jin T, Huo Z, Yamamoto Y. A one-pot procedure for the regiocontrolled synthesis of allyltriazoles via de Pd–Cu bimetallic catalyzed three-component coupling reaction of nonactivated terminal alkynes, allyl carbonate, and trimethylsilyl azide. J Org Chem 2004;69:2386–2393. 119. For early examples, see: (a) Yoo EJ, Ahlquist M, Kim SH, et al. Copper-catalyzed synthesis of N-sulfonyl-1,2,3-triazoles: controlling selectivity. Angew Chem Int Ed. 2007;46:1730–1733; (b) Wang F, Fu H, Jiang YY, Zhao YF. Copper-catalyzed cycloaddition of sulfonyl azides with alkynes to synthesize N-sulfonyltriazoles ‘on water’ at room temperature. Adv Synth Catal. 2008;350:1830–1834; (c) Raushel J, Fokin VV. Efficient synthesis of 1-sulfonyl-1,2,3-triazoles. Org Lett. 2010;12:4952–4955; (d) Cano I, Nicasio MC, Perez PJ. Copper(I) complexes as catalysts for the synthesis of N-sulfonyl-1,2,3-triazoles from N-sulfonylzides and alkynes. Org Biomol Chem. 2010;8:536–538.

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120. For early examples with different nucleophiles, see: (a) Bae I, Han H, Chang S. Highly efficient one-pot synthesis of N-sulfonylamidines by Cu-catalyzed three component coupling of sulfonyl azide, alkyne, and amine. J Am Chem Soc. 2005;127:2038–2039; (b) Cho SH, Yoo EJ, Bae L, Chang S. Copper-catalyzed hydrative amide synthesis with terminal alkyne, sulfonyl azide, and water. J Am Chem Soc. 2005;127:16046–16047; (c) Cassidy MP, Raushel J, Fokin VV. Practical synthesis of amides from in situ generated copper(I) acetylides and sulfonyl azides. Angew Chem Int Ed. 2006;45:3154–3157; (d) Whiting M, Fokin VV. Copper-catalyzed reaction cascade: direct conversion of alkynes into N-sulfonylazetidin-2-imines. Angew Chem Int Ed. 2006;45:3157–3161; (e) Cho SH, Chang S. Rate-accelerated nonconventional amide synthesis in water: a practical catalytic aldol-surrogate reaction. Angew Chem Int Ed. 2007;46:1897–1900. 121. Cano I, A´lvarez E, Nicasio MC, P
erez PJ. Regioselective formation of 2,5disubstituted oxazoles via copper(I)-catalyzed cycloaddition of acyl azides and 1-alkynes. J Am Chem Soc. 2011;133:191–193. 122. Haldo´n E, Besora M, Cano I, et al. Reaction of alkynes and azides: not triazoles through copper–acetylides but oxazoles through copper–nitrene intermediates. Chem Eur J. 2014;20:3463–3474. 123. Stanley LM, Sibi MP. Enantioselective copper-catalyzed 1,3-dipolar cycloadditions. Chem Rev. 2008;108:2887–2902. 124. For selected examples, see: (a) Scobie M, Threadgill MD. Tumor-targeted boranes. 4. Synthesis of nitroimidazole-carboranes with polyether-isoxazole links. J Org Chem. 1994;59:7008–7013; (b) Raihan MJ, Kavala V, Kuo C-W, Raju BR, Yao C-F. ‘On water’ synthesis of chromeno-isoxazoles mediated by [hydroxyl(tosyloxy)iodo]benzene (HTIB). Green Chem. 2010;12:1090–1096; (c) Trogu E, Vinattieri C, De Sarlo F, Machetti F. Acid-base-catalysed condensation reaction in water: isoxazolines and isoxazoles from nitroacetates and dipolarophiles. Chem Eur J. 2012;18:2081–2093. 125. (a) F€ urstner A, Stimson CC. Two manifolds for metal-catalyzed intramolecular Diels– Alder reactions of unactivated alkynes. Angew Chem Int Ed. 2007;46:8845–8849. For a related reaction, see: (b) Khoshkholgh MJ, Balalaie S, Bijanzadeh HR, Gross JH. Copper(I) iodide catalyzed domino Knoevenagel hetero-Diels-Alder reaction of terminal acetylenes: synthesis of pyrano[2,3-c]pyrazoles. Synlett. 2009;55–58 126. Maas G, Diazoalkanes. In: Padwa A, Pearson WH, eds. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Towards Heterocycles and Natural Products. Hoboken: Wiley; 2003:623–680. 127. Qi X, Ready JM. Copper-promoted cycloaddition of diazocarbonyl compounds and acetylides. Angew Chem Int Ed. 2007;46:3242–3244. 128. Shintani R, Fu GC. A new copper-catalyzed [3+2] cycloaddition: enantioselective coupling of terminal alkynes with azomethine imines to generate five-membered nitrogen heterocycles. J Am Chem Soc. 2003;125:10778–10779. 129. Imaizumi T, Yamashita Y, Kobayashi S. Group 11 metal amide-catalyzed asymmetric cycloaddition reactions of azomethine imines with terminal alkynes. J Am Chem Soc. 2012;134:20049–20052. 130. (a) Hashimoto T, Omote M, Maruoka K. Catalytic asymmetric alkynylation of C1-substituted C,N-cyclic azomethine imines by CuI/chiral Brønsted acid co-catalyst. Angew Chem Int Ed. 2011;50:8952–8955. See also: (b) Hashimoto T, Takiguchi Y, Maruoka K. Catalytic asymmetric three-component 1,3-dipolar cycloaddition of aldehydes, hydrazides, and alkynes. J Am Chem Soc. 2013;135:11473–11476; (c) Das D, Sun AX, Seidel D. Redox-neutral copper(II) carboxylate catalyzed α-alkynylation of amines. Angew Chem Int Ed. 2013;52:3765–3769. 131. Kinugasa M, Hashimoto S. The reactions of copper(I) phenylacetylide with nitrones. J Chem Soc Chem Commun. 1972;466–467.

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132. (a) Okuro K, Enna M, Miura M, Nomura M. Copper-catalysed reaction of arylacetylenes with C,N-diarylnitrones. J Chem Soc Chem Commun. 1993; 1107–1108. (b) Ye M-C, Zhou J, Tang Y. Trisoxazoline/Cu(II)-promoted Kinugasa reaction. Enantioselctive synthesis of β-lactams. J Org Chem. 2006;71:3576–3582. (c) Mames A, Stecko S, Mikołajczyk P, Soluch M, Furman B, Chmielewski M. Direct, catalytic synthesis of carbapenams via cycloaddition/rearrangement cascade reaction: unexpected acetylenes’ structure effect. J Org Chem. 2010;75:7580–7587. 133. Chigrinova M, MacKenzie DA, Sherratt AR, Cheung LLW, Pezacki JP. Kinugasa reactions in water: from green chemistry to bioorthogonal labelling. Molecules. 2015;20:6959–6969. 134. For leading references, see: (a) Miura M, Enna M, Okuro K, Nomura M. Coppercatalyzed reaction of terminal alkynes with nitrones. Selective synthesis of 1-aza-1-buten-3-yne and 2-azetidinone derivatives. J Org Chem. 1995;60:4999–5004; (b) Shintani S, Fu GC. Catalytic enantioselective synthesis of β-lactams: intramolecular Kinugasa reactions and interception of an intermediate in the reaction cascade. Angew Chem Int Ed. 2003;42:4082–4085. 135. Santoro S, Liao R-Z, Marcelli T, Hammar P, Himo F. Theoretical study of mechanism and stereoselectivity of catalytic Kinugasa reaction. J Org Chem. 2015;80:2649–2660. 136. (a) Nishibayashi Y. Transition-metal-catalyzed enantioselective propargylic substitution reactions of propargylic alcohol derivatives with nucleophiles. Synthesis. 2012;44:489–503. (b) Bauer EB. Transition-metal-catalyzed functionalization of propargylic alcohols and their derivatives. Synthesis. 2012;44:1131–1151. (c) Ljungdahl N, Kann N. Transition-metal-catalyzed propargylic substitution. Angew Chem Int Ed. 2009;48:642–644. 137. (a) Zhang L, Fang G, Kumar RK, Bi X. Coinage-metal-catalyzed reactions of propargylic alcohols. Synthesis. 2015;47:2317–2346. (b) Zhang D-Y, Hu X-P. Recent advances in copper-catalyzed propargylic substitution. Tetrahedron Lett. 2015;56:283–295. 138. (a) Detz RJ, Hiemstra H, van Maarseveen JH. Catalyzed propargylic substitution. Eur J Org Chem. 2009;6263–6279. (b) Miyake Y, Uemura S, Hishibayashi Y. Catalytic propargylic substitution reactions. ChemCatChem. 2009;1:342–356. 139. Cadierno V, Gimeno J. Allenylidene and higher cumulenylidene complexes. Chem Rev. 2009;109:3512–3560. 140. Asay M, Donnadieu B, Schoeller WW, Bertrand G. Synthesis of allenylidene lithium and silver complexes, and subsequent transmetalation reactions. Angew Chem Int Ed. 2009;48:4796–4799. 141. Imada Y, Yuasa M, Nakamura I, Murahashi S-I. Direct azole amination: C–H functionalization as a new approach to biologically important heterocycles. J Org Chem. 1994;59:2282–2284. For the reaction of propargylic chlorides, see: Hennion GF, Hanzel RS. The alkylation of amines with t-acetylenic chlorides. Preparation of sterically hindered amines. J Am Chem Soc. 1960;82:4908–4912. 142. Detz RJ, Delville MME, Hiemstra H, van Maarseveen JH. Enantioselective coppercatalyzed propargylic amination. Angew Chem Int Ed. 2008;47:3777–3780. 143. Hattori G, Matsuzawa H, Miyake Y, Nishibayashi Y. Copper-catalyzed asymmetric propargylic substitution reactions of propargylic acetates with amines. Angew Chem Int Ed. 2008;47:3781–3783. 144. Hattori G, Sakata K, Matsuzawa H, Tanabe Y, Miyake Y, Nishibayashi Y. Coppercatalyzed enantioselective propargylic amination of propargylic esters with amines: copper–allenylidene complexes as key intermediates. J Am Chem Soc. 2010; 132:10592–10608. 145. Nakajima K, Shibata M, Nishibayashi Y. Copper-catalyzed enantioselective propargylic etherification of propargylic esters with alcohols. J Am Chem Soc. 2015;137:2472–2475.

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146. (a) Sugiishi T, Kimura A, Nakamura H. Copper(I)-catalyzed substitution reactions of propargylic amines: importance of C(sp)–C(sp3) bond cleavage in generation of iminium intermediates. J Am Chem Soc. 2010;132:5332–5333. (b) Kim Y, Nakamura H. Copper(I)-catalyzed deacetylenative coupling of propargylic amines: an efficient synthesis of symmetric 1,4-diamino-2-butynes. Chem Eur J. 2011;17:12561–12563. 147. See Section 4.2 for more details on addition reactions to enamines and imines. 148. Kang Y-W, Cho YJ, Ko K-Y, Jang H-Y. Copper-catalyzed carbon–carbon bond cleavage of primary propargyl alcohols: β-carbon elimination of hemiaminal intermediates. Catal Sci Technol. 2015;5:3931–3934.

CHAPTER FOUR

Phenol Derivatives: Modern Electrophiles in Cross-Coupling Reactions C. Zaratea,1, M. van Gemmerena,1, R.J. Somervillea, R. Martina,b,* a

Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Technology, Tarragona, Spain ICREA, Passeig Lluı¨s Companys, Barcelona, Spain *Corresponding author: e-mail address: [email protected] b

Contents 1. Introduction 2. Carbon–Carbon Bond Formation 2.1 KTC-Type Coupling Reactions 2.2 Negishi-Type Coupling Reactions 2.3 Suzuki–Miyaura-Type Couplings 2.4 Mizoroki–Heck-Type Coupling Reactions 2.5 Stille-Type Couplings 2.6 Reactions Involving Other Organometallic Compounds: Organolithium and Organoaluminum Reagents 2.7 Miscellaneous C–C Bond-Forming Reactions 3. Carbon–Heteroatom Bond-Forming Reactions 3.1 C–N Bond Formation 3.2 C–B Bond Formation 3.3 C–Si Bond Formation 3.4 C–P Bond Formation 4. Hydrogenolysis of C–O Bonds 4.1 Ethers 4.2 Carbamates 4.3 Esters 4.4 Alcohols 5. Conclusions and Outlook Acknowledgments References

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Both authors contributed equally to this work.

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1. INTRODUCTION Metal-catalyzed cross-coupling reactions have evolved from mere curiosities to mature and indispensible tools in our synthetic arsenal.1 The tremendous impact of these methodologies is illustrated by the fact that it is rather difficult to find an advanced total synthesis that does not take recourse to this methodology. Not surprisingly, these techniques have found widespread use in both pharmaceutical and academic laboratories. Although remarkable levels of sophistication have been reached, the vast majority of these processes are still conducted with organic halide counterparts. The difficulties encountered in accessing organic halides in a both chemo- and regioselective manner, particularly in advanced synthetic intermediates, together with the inevitable generation of toxic halogenated waste still constitute serious drawbacks when designing cross-coupling reactions, particularly for late-stage diversification. To this end, chemists have embarked on a quest to find alternate cross-coupling counterparts with improved flexibility, generality, and practicality. Among these alternatives, phenol derivatives are particularly appealing as these are naturally abundant, nontoxic, readily available, and unique reaction intermediates in organic synthesis.2 Additionally, their implementation in cross-coupling reactions would be particularly attractive for the design of orthogonal cross-coupling strategies in the presence of organic halides. The means to utilize C–O electrophiles has undoubtedly gained considerable momentum, emerging as powerful and environmentally friendly coupling partners in the cross-coupling arena.3 Despite the obvious advantages posed by the use of phenol derivatives, the vast majority of catalytic C–O functionalization reactions are based on particularly activated phenol derivatives possessing rather weak C–O bonds such as aryl tosylates, triflates, mesylates, and nonaflates (Scheme 1). Ironically, the success of these reactions

Scheme 1 C–O electrophiles in cross-coupling reactions.

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’

Scheme 2 Evolution of the metal-catalyzed functionalization of C–O bonds.

has contributed to the perception that phenol derivatives with high bonddissociation energies, such as aryl esters, carbamates, and aryl ethers, could not be employed as coupling partners via C–O bond cleavage (Scheme 1). In 1979, Wenkert discovered that catalytic Kumada–Tamao–Corriu (KTC) reactions could be applied to aryl methyl ethers via a counterintuitive C(sp2)–OMe cleavage (Scheme 2).4 Although no doubt an incredible step forward, this reactivity remained dormant for 25 years, probably due to the success of Pd-catalyzed Suzuki–Miyaura, Negishi, and Stille-type crosscoupling reactions.1 Fortunately, inspiration is oftentimes in the eye of the beholder, and Dankwardt revisited Wenkert’s work in 2004 by discovering that electron-rich ligands are particularly suited to catalytic C–O bond cleavage scenarios (Scheme 2).5 As judged by the wealth of literature data reported in the last 10 years, it is evident that significant advances have been realized in the C–O functionalization of aryl ethers aryl esters or aryl carbamates C–O electrophiles that could result in site-selectivity issues in the presence of multiple C–O reaction sites.3 Taking into consideration that the catalytic functionalization of less activated C–O bonds is still a relatively unexplored terrain, we identified the need to review the current state of the art for the utilization of aryl esters, carbamates, and aryl ethers as surrogates for organic halides in homogeneous cross-coupling reactions. Therefore, the utilization of particularly activated allyl, propargyl, allenyl derivatives, or phenol derivatives with particularly weak C–O bonds such as aryl sulfates, phosphates, and sulfonates is beyond the scope of this review. Likewise, stoichiometric reactions and heterogeneous C–O bond-functionalization reactions will not be treated in detail. This review is organized into three sections according to the type of transformation and includes mechanistic considerations and future avenues, when applicable.

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2. CARBON–CARBON BOND FORMATION 2.1 KTC-Type Coupling Reactions Among all cross-coupling reactions involving the activation of C–O bonds, the KTC reaction has been studied most intensively. This can probably be attributed to the high reactivity of Grignard reagents, which renders the activation of the C–O bond particularly facile when compared with lessreactive nucleophilic components. Indeed, the utilization of Grignard reagents in C–O bond cleavage can be traced back to a number of noncatalyzed reactions reported in the 1950s6 with vinyl ether motifs. Undoubtedly, these initial findings set the scene for the implementation of a variety of challenging catalytic C–O bond-functionalization techniques. 2.1.1 Historical Background: Uncatalyzed Reactions and Stoichiometric Experiments In 1951, Hill reported that activated 1-aryl-substituted vinyl ethers reacted rapidly with aryl Grignard reagents to give access to 1,1-diaryl-substituted olefins in moderate to good yields (Scheme 3, left).6 Subsequently, the same group demonstrated that analogous reactivity could be found when cyclic vinyl ethers such as 3,4-dihydro-2H-pyran or furan derivatives were employed, affording alcohol backbones possessing appropriately substituted alkenes on the side chain or ketone derivatives, respectively (Scheme 3, right).7 Some years later, Meyers and colleagues described analogous reactivity for aryl methyl ethers bearing an oxazoline directing group at the ortho position (Scheme 4).8 Such substrates were reported to react with both Grignard A

C

Scheme 3 Uncatalyzed reactions of Grignard reagents with acyclic and cyclic ethers.

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reagents and organolithium species to give the substitution products in moderate to high yields. Importantly, ether functions other than methoxy motifs could be utilized, invariably leading to functionalization at the ortho-position to the directing group. The authors proposed that the reaction occurs via nucleophilic aromatic substitution, with the Li+ or Mg2+ ions coordinated to the oxazoline nitrogen atom and the ethereal oxygen atom. The formation of this type of intermediate nicely explains both the increased reactivity and the selectivity for ortho- over para-ether groups, which would not be expected if the oxazoline served as a simple electron-withdrawing group stabilizing a Meisenheimer-type complex. Later, the use of other directing groups in similar substitution reactions was reported.9 Yamamoto and colleagues studied the reactivity of Ni complexes supported by phosphine or bipyridine ligands with ester groups in a stoichiometric fashion in order to determine the factors influencing the site selectivity of the C–O bond cleavage (Scheme 5).10 These investigations revealed that aryl or enol esters follow a different selectivity profile; while phenolderived esters undergo Ccarbonyl–O cleavage (Scheme 5, type A), structurally related enol-derived esters resulted in Cvinyl–O functionalization (Scheme 5, type B). According to these seminal studies employing ester derivatives, similar site selectivity could be achieved between the Calkyl–O or Caryl–O bonds

Scheme 4 Uncatalyzed reactions of aryl methyl ethers with either Grignard reagents or aryl lithium reagents induced by an oxazoline directing group.

Scheme 5 Regioselectivity studies on the cleavage of C–O bonds in ester derivatives by Ni(0).

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of aryl alkyl ethers. To this end, Milstein and coworkers found that pincer ligands containing an appropriate methoxy residue on the aryl backbone followed an intriguing selectivity profile depending on the metal used.11 Whereas rhodium complexes selectively activated the Caryl–O bond, nickel species triggered Calkyl–O scission, a rather surprising finding considering the ability of Ni catalysts to cleanly promote the Caryl–O bond cleavage in anisole-type derivatives. This discrepancy can be explained by the inherent nature of the pincer ligand backbone, as it is able to favor activation of the Calkyl–O bond by facilitating precoordination of the nickel center while preventing its binding to the π-system. 2.1.2 Ethers In 1979, Wenkert reported that aryl and vinyl ethers are suitable counterparts in KTC cross-coupling reactions with Grignard reagents (Scheme 6).4 The scope of these reactions included the coupling of either PhMgBr or MeMgBr with NiCl2(PPh3)2 as precatalyst; however, the use of alkyl Grignard reagents possessing β-hydrogens led to unproductive reduction events, and low yields were systematically observed for non-π-extended aromatic rings, a recurrent drawback that continues to be observed years later. It was found that enol ethers reacted at a considerably faster rate than simple aryl ethers, an observation that is in line with the stoichiometric studies reported by Hill.6 Interestingly, the use of furan as the coupling partner gave 1,3-dienes in which both C–O bonds could be activated with equal ease. Despite the considerable potential of Wenkert’s work,4 these findings were unfortunately overlooked due to the success of Pd-catalyzed crosscoupling reactions of organic halides that were reported in the mid-

Scheme 6 Ni-catalyzed KTC reactions of aryl and vinyl ethers.

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1970s. However, this pioneering work has been the basis for the use of C–O electrophiles in cross-coupling reactions via C–O bond cleavage, triggering the development of many new catalytic transformations that can seem counterintuitive at first sight. Following up on Wenkert’s studies, Kumada demonstrated that silyl enol ethers are competent counterparts in Ni-catalyzed cross-coupling reactions with Grignard reagents (Scheme 7).12 Intriguingly, the reaction took place under ligand-free conditions using simple Ni(acac)2 as the precatalyst. Unfortunately, the coupling of related aryl silyl ethers was not reported, an observation that is in line with the demonstration by Hill6 that unbiased aryl C–O electrophiles are considerably less reactive. Unlike Wenkert’s work, the use of silyl enol ethers and dppf as the ligand allowed, for the first time, the coupling of aliphatic Grignard reagents possessing β-hydrogens, albeit in lower yields. Johnstone and colleagues developed a Ni-catalyzed KTC cross-coupling reaction of aryl phenyltetrazole ethers with Grignard reagents (Scheme 8).13 Although the substrates were rather sophisticated, the ability to couple alkyl organometallic species that could otherwise undergo parasitic β-hydride elimination is particularly noteworthy. In contrast to Wenkert’s work,4

Scheme 7 Ni-catalyzed KTC reactions of silyl enol ethers.

Scheme 8 Ni-catalyzed KTC reactions of aryl heteroaryl ethers.

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non-π-extended phenol derivatives posed no problems, thus increasing the synthetic utility of this method. Surprisingly, different catalysts were found to be optimal depending on the substrate used, a testament to the sensitivity of this methodology toward subtle changes in the electronic and steric properties of the corresponding coupling partners. Later investigations showed that other heteroaromatic ether motifs could be used with both Grignard reagents and organolithium species.14 Aiming at the synthesis of selectively substituted alkenol derivatives, Kocienski studied the KTC reaction of 5-alkyl substituted 2,3-dihydrofurans and analogous pyrans (Scheme 9).15 In these studies, homoallylic alcohols were obtained in high yields from 2,3-dihydrofurans in a stereospecific fashion, and a number of functional groups on the alkyl side chain could be tolerated. Although lower rates were found for analogous 2,3dihydropyrans, the desired products could still be obtained in good yields. Importantly, the authors demonstrated that silyl and stannyl substituents could be accommodated at C5, thus giving access to valuable stereodefined vinyl silanes and/or stannanes. Unfortunately, significant amounts of reduced products were invariably observed when employing alkyl Grignard reagents possessing β-hydrogens. In 2013, Martin utilized an N-heterocyclic carbene (NHC)-Ni catalyst system to enable the Ni-catalyzed KTC cross-coupling reactions of dihydrofurans with aryl and alkyl Grignard reagents under exceptionally mild conditions at temperatures as low as
30°C (Scheme 10).16 The authors found a marked increase in catalytic activity when using NHCs as ligands in combination with LiCl. Under these conditions, more reactive functional

Scheme 9 Ni-catalyzed KTC reactions of cyclic vinyl ethers.

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°

Scheme 10 Low-temperature Ni-catalyzed KTC reactions of cyclic vinyl ethers.

groups such as aryl tosylates, pivalates, and methyl ethers were tolerated. Likewise, good yields were obtained for alkyl Grignard reagents possessing β-hydrogens. The authors tacitly demonstrated the intermediacy of nickel π-allyl complexes by observing a stereoselectivity switch at 40°C via Z/E isomerization. Strikingly, whereas RMgBr consistently provided high yields, the utilization of RMgCl failed to provide the corresponding coupling products. These observations were found to contradict a “classical” oxidative addition pathway, suggesting the involvement of Lewis acid assistance by the Mg2+ cation on the Grignard reagent and the intermediacy of Ni(0)-ate complexes. Although previous studies demonstrated that regular anisole derivatives were considerably less reactive than the corresponding π-extended aryl ethers, Dankwardt reported that the use of certain electron-rich phosphines could be used to address this problem, obtaining in all cases high yields, even for challenging substrate combinations.17 The influence of the ligand backbone was examined and PCy3 and PhPCy2 were identified as the most promising candidates to promote the C–OMe cleavage in combination with a Ni(II) precatalyst. Under these conditions, a wide number of aryl alkyl ethers could be employed with equal ease, including silyl ethers (Scheme 11). Dankwardt’s report inspired others to expand the substrate scope of this reaction by fine-tuning the ligand backbone and/or the substrate (Scheme 12). For example, in 2008 Shi described the methylation of anisole derivatives using only 1.2 equivalents of MeMgBr under conditions closely resembling those reported by Dankwart.18 The same group then employed

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E °

Scheme 11 Ni-catalyzed KTC coupling reactions of anisoles using PCy3 as the ligand (given percentages correspond to conversions).

and

and

and

Scheme 12 Ni-catalyzed KTC coupling reactions of aryl methyl ethers using phosphine or NHC ligands.

the knowledge acquired from developing this reaction to effect sequential C(sp2)–O bond activation of differently substituted aryl ether19 and aryl silyl ether motifs.20 In 2011, Wang and Xie developed modified alkyldicyclohexylphosphine ligands for effecting KTC reactions of aryl and vinyl ethers, allowing for the significant reduction in the quantity of

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Grignard reagents utilized when compared to Dankwardt’s original report.21 Prompted by the high reactivity of electron-rich trialkylphosphines toward C–O bond cleavage, Nicasio demonstrated the utilization of NHCs in the KTC reactions of anisole derivatives.22 Subsequently, Sun reported a mixed catalytic system involving both phosphine and NHC ligands.23 Tobisu and Chatani significantly expanded the scope of the KTC reactions of aryl ethers by using alkynyl24 or alkyl Grignard reagents lacking β-hydrogens and NHC ligands.25 This allowed the synthesis of organic semiconductors in a straightforward fashion.26 More recently, Tobisu and Chatani described a rather intriguing cross-coupling reaction of simple aryl methyl ethers with alkyl Grignard reagents possessing β-hydrogens using dcype as the ligand.27 The reactions occurred in high yields regardless of whether anisoles, π-extended systems, or vinyl ethers were used. Of particular importance was the finding that the reactivity was highly dependent on the counterion utilized in the corresponding Grignard reagent, an observation that is reminiscent of the work developed by Martin in 2013 that dealt with the KTC reaction of cyclic vinyl ethers employing NHC ligands (Scheme 10).16 The noninnocent behavior of the counterion in KTC reactions suggested that C–O bond cleavage in either aryl or vinyl ethers might not occur via “classical” oxidative addition but rather through the formation of Ni(0)-ate intermediates (Schemes 10 and 12). Motivated by this perception, Wang and Uchiyama carried out a computational study on the Ni-catalyzed arylation of anisole and reinforced the notion that Caryl–O bond cleavage does not occur via “classical” oxidative addition (Scheme 13).28 The energetically most favorable pathway found by the authors involved the formation of a Ni(0)-ate complex by coordination of the Grignard reagent and the in situ generated [Ni(PCy3)2] to the anisole derivative. This nickelate complex participates in the subsequent Lewis acidassisted Caryl–O bond activation, which leads to the formation of a biaryl Ni(II) complex, while at the same time transferring the methoxide anion to the magnesium center. Although further experimental evidence is required to confirm these findings, they are in line with the hydrogenolysis mechanism reported by the Martin group, which invokes pathways other than generally proposed C–O bond-oxidative addition.29 Although nickel catalysts have been shown to be particularly efficient in the KTC reactions of aryl ethers, several studies have demonstrated the viability of using other metal catalysts. For example, in 2014 Kambe disclosed a ligand-free Rh-catalyzed cross-coupling reaction of aryl vinyl ethers with aryl Grignard reagents en route to styrene-type derivatives and observed that

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B

Scheme 13 Theoretical study on the C(sp2)–OMe cleavage in KTC reactions.

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Scheme 14 Rh-catalyzed KTC reactions of vinyl aryl ethers (given percentages correspond to conversions).

the Cvinyl–O bonds were selectively activated (Scheme 14).30 The authors also demonstrated that the optimized conditions could be successfully applied to silyl ethers. Experiments toward understanding the mechanism of this reaction gave strong support for the involvement of diarylrhodate intermediates, as analytically pure [RhAr2(COD)]
[Li(DME)3]+ could be isolated and characterized. Taking this into consideration, the authors proposed that a Rh(I)ate species triggers an initial carbometalation that is followed by β-alkoxy elimination to deliver the coupling product. At the same time, an [ArRh (I)] species would be formed that would react rapidly with the corresponding Grignard reagent to form the active Rh(I)-ate species. Recently, Zeng and coworkers reported that simple chromium salts, in the absence of ligand, could be employed as catalysts in the KTC reactions of either aryl or alkyl Grignard reagents with aryl ethers bearing a tert-butyl

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Scheme 15 Cr-catalyzed ortho-directed KTC reactions of aryl ethers.

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Scheme 16 Ni-catalyzed KTC reaction of benzyl ether derivatives.

imine directing group at the ortho-position (Scheme 15).31 Although the prerequisite for a directing group significantly limits the applicability of this reaction, its inclusion allows for site selectivity in the presence of methoxy groups located at either the meta or para positions. In addition to the studies focussing on the activation of C(sp2)–O bonds in aryl ether derivatives, significant efforts have also been directed toward the activation of less-reactive C(sp3)–O bonds. The group of Shi disclosed the first KTC reactions of a variety of benzyl ethers using NiCl2(dppf ) as the catalyst and MeMgBr as the coupling partner (Scheme 16).32 Although the scope of these reactions allowed for the coupling of benzyl derivatives without the need for π-extended systems, the reaction remained limited to alkyl Grignard reagents. Interestingly, the authors found that their methodology is complementary to the KTC cross-coupling of aryl ethers; in this manner, excellent site-selective functionalization of either C(sp2)–O or C(sp3)–O

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bonds could be achieved depending on the reagents utilized. Although these reactions were limited to benzylic ethers, the Shi group subsequently reported an iron-catalyzed protocol that enables the KTC cross-coupling reaction of homobenzylic ether derivatives.33 One might first assume that the iron catalysts is capable of promoting C(sp3)–OMe bond cleavage; however, control experiments indicated otherwise. In particular, it was demonstrated that the basicity of the Grignard reagent triggered an initial elimination that resulted in the formation of a styrene motif. Subsequent carbometalation with an additional Grignard reagent led to a benzylic Grignard reagent that produced the final product upon aqueous workup. Since 2011, the Jarvo group has disclosed a series of reports detailing their studies on the Ni-catalyzed stereospecific cross-coupling reactions of benzyl ether electrophiles with a number of organometallic species.34 In particular, the authors developed a Ni-catalyzed stereospecific KTC reaction of π-extended benzyl ethers possessing either aromatic or aliphatic substituents at the α-position (Scheme 17). Interestingly, the nature of the ligand turned out to be critical, and three sets of conditions were developed depending on whether the substrate or Grignard reagent utilized possessed β-hydrogens or not. In particular, it was found that dppe was crucial for suppressing undesired β-hydride elimination when aliphatic nucleophilic components were employed. In all cases, the reaction proceeded with net inversion of configuration suggesting that oxidative addition probably takes place via an η3-Ni(II) complex or SN2 mechanism followed by a stereoretentive

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Scheme 17 Stereospecific KTC reaction of benzyl methyl ethers with Grignard reagents.

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transmetalation and reductive elimination. Unfortunately, however, the limitation to substrates with π-extended backbones remained a considerable drawback. The limitation of stereospecific KTC reactions to π-extended backbones was addressed by the Jarvo group through a systematic study of the nature of the leaving group, revealing that methoxyethyl benzyl ethers were superior counterparts when compared to other benzyl ethers (Scheme 18).35 Prompted by an otherwise analogous effect discovered by Liebeskind when using benzyl thioethers,36 Jarvo attributed the successful use of methoxyethyl benzyl ethers in KTC reactions to the ability of the magnesium cation to strongly chelate the corresponding diether-containing group, significantly weakening the benzylic C–O bond and accelerating the rate of oxidative addition and transmetalation. Two sets of conditions were developed, and whereas DPEPhos resulted in the coupling of MeMgBr, the use of dppo allowed for the coupling of heteroaryl organometallic components. In the latter case, however, a polyaromatic motif was required for the reaction to occur. In some cases, an erosion in enantioselectivity was observed, presumably due to bimolecular racemization from reaction of in situ generated Ni(II) with the oxidative addition of the Ni(0)Ln species. Recently, the same group studied the Ni-catalyzed KTC reaction of 2aryl-substituted tetrahydrofurans (Scheme 19).37 As expected, the reaction resulted in selective activation of the benzylic C–O bond; unfortunately, however, the cross-coupling reaction required the presence of a π-extended backbone. The study demonstrated that cis-substituted tetrahydrofurans

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Scheme 18 Stereospecific Ni-catalyzed KTC of non-π-extended systems with benzyl methoxyethyl ethers.

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Scheme 19 Stereospecific Ni-catalyzed ring opening of tetrahydrofurans with Grignard reagents via benzylic C–O bond cleavage.

afforded syn-configured products, whereas trans-configured starting materials invariably provided anti-configured products. A variety of substituents at C3, C4, or C5 were tolerated, and in all cases good to excellent yields and high stereospecificities were obtained, even when preparing isotopically labeled materials.37b As judged by the literature data on KTC reactions of aryl, benzyl, or vinyl ethers via C–OMe cleavage, it becomes evident that remarkable levels of sophistication have been achieved. At present, a wide variety of cyclic or acyclic C(sp2)–/C(sp3)–O bonds can be activated with equal ease. Still, a number of challenges remain, such as: (1) finding a general solution for the lack of reactivity of substrate combinations without π-extended backbones; (2) addressing the inability of unactivated alkyl ethers to undergo KTC reactions; and (3) the clarification of the mechanism by which these reactions operate. We anticipate that fine-tuning of ligand backbones together with in-depth mechanistic studies will allow chemists to rise to many of these challenges while also opening new vistas in the field. 2.1.3 Carbamates In 1989, Kocienski reported the first Ni-catalyzed KTC reaction of vinyl carbamates with Grignard reagents (Scheme 20).38 In line with the considerable high reactivity of vinyl ethers, these reactions occurred with retention of the double bond geometry. In 1995, F
er
ezou extended the scope of these reactions to alkynylmagnesium bromides using PPh3 as the ligand and

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EtMgBr as the reductant to generate in situ the propagating Ni(0)Ln species.39 Unlike Kocienski’s protocol, certain substrate combinations gave products having undergone partial isomerization of the double bond. Subsequently, Betzer described a KTC protocol that allowed for expanding the scope of the Grignard reagent to alkenyl, aryl, and benzyl nucleophiles.40 As evident from the results compiled in Scheme 20, most of the substrates utilized in either Kocienski’s, F
er
ezou’s, or Betzer’s protocols featured an adjacent stereodiad with a methyl substituent at the α-position and a (protected) hydroxy group at the β-position.41 As part of a research aimed at promoting directed ortho metalation techniques (DoM), Snieckus reported the first use of aryl carbamates as C–O electrophiles in KTC reactions in 1992 (Scheme 21).42 Using Ni(acac)2 as precatalyst under ligand-free conditions, a wide variety of aryl carbamates could be coupled with excellent results. In 2009, Nakamura reported an improved catalytic protocol using a hydroxyphosphine ligand (L1) under otherwise similar reaction conditions.43 Unfortunately, both protocols did not allow the coupling of Grignard reagents possessing β-hydrogens. Challenged by this limitation, Garg discovered that the combination of FeCl2 with

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Scheme 20 Ni-catalyzed KTC of vinyl carbamates described by Kocienski, F
er
ezou, and Betzer.

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Scheme 21 Ni- and Fe-catalyzed KTC of aryl carbamates with Grignard reagents.

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NHC precursor L2 accommodated a diverse set of substitution patterns, including alkyl Grignard reagents possessing β-hydrogens.44 The usefulness of this methodology was highlighted by the ability of carbamates to be used as directing groups to promote directed ortho metalation, allowing for sequential C–C bond-forming techniques from readily available precursors. 2.1.4 Esters In 2009, Shi reported the first use of vinyl esters as coupling partners in KTC couplings using FeCl2 as the precatalyst (Scheme 22).45 The reaction could be conducted under ligand-free conditions with a variety of Grignard reagents. For substrates possessing electron-withdrawing substituents, LiCl was required for obtaining good yields. In contrast, lessactivated naphthyl or styryl derivatives required the use of L2, a combination that was later applied by Garg for the coupling of aryl carbamates.44 It is noteworthy that these reactions could be implemented with alkyl Grignard reagents possessing β-hydrogens, a testament to the particularly high chemoselectivity profile of iron salts when compared with other metal catalysts used for similar means. As part of a program aimed at implementing Fe catalysis in crosscoupling reactions,46 F€ urstner extended the scope of Fe-catalyzed KTCtype reactions to 2-pyrone substrates and alkyl Grignard reagents, rapidly obtaining 2,4-dienoic acids in high yields and high stereoselectivities (Scheme 23).47 The newly introduced substituent was obtained in the cisrelative configuration to the unsaturated motif. Notably, the reaction time and temperature dictated whether cis- or trans-configured double bonds were obtained, an example of product distribution by either kinetic or thermodynamic control.

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o

Scheme 22 Fe-catalyzed KTC reactions of vinyl pivalates with Grignard reagents.

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°

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Scheme 23 Fe-catalyzed KTC reactions of 2-pyrones.

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Scheme 24 Fe-catalyzed KTC reactions of vinyl acetates.

The scope of the Fe-catalyzed KTC reaction of vinyl esters, originally described by Shi,45 was recently extended by von Wangelin to acetate coupling partners and NMP as additive under ligand-free conditions (Scheme 24).48 The authors found that the use of FeCl3 as the precatalyst and in situ formed ArMgBrLiCl reagents allowed for the coupling of lesssterically demanding substrate combinations. From a mechanistic standpoint, the authors proposed rate-determining olefin coordination prior to oxidative addition. Although control experiments ruled out the involvement of heterogeneous catalysis, an alternative radical mechanism could not be excluded with absolute certainty. A comparison of the KTC methodologies presented earlier indicates that the use of carbamates as coupling partners is more general than the corresponding ester derivatives, as both aryl and vinyl counterparts can be utilized with equal ease regardless of whether alkyl or aryl Grignard reagents are employed. Indeed, the use of aryl ester derivatives in KTC reactions is still problematic due to the difficulties encountered in selectively activating the C(sp2)–O bond over the Ccarbonyl–O bond. Additionally, the use of aryl Grignard reagents remains limited to a small set of vinyl acetates as electrophilic partners, thus constituting new opportunities for chemists in the years to come.

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2.1.5 Benzyl Alcohols Prompted by the use of allylic alcohols in cross-coupling reactions,49 Shi studied the possibility of using naphthols as coupling partners in KTC reactions without the need for protecting group manipulations (Scheme 25).50 The key strategy for achieving this goal was the conversion of naphthols to the corresponding magnesium naphtholates under the reaction conditions. Taking this into consideration, the authors discovered a protocol using methylmagnesium bromide to promote the initial formation of a magnesium naphthoate followed by treatment with a nickel catalyst and the corresponding Grignard reagent, thus triggering the targeted C–C bond-forming event via formal C(sp2)–OH cleavage. This naphthoate formation could be corroborated by X-ray crystallographic analysis of [NpOMgBr(THF)2]2. In these species, the naphtholate oxygen is coordinated to two magnesium ions, which provide sufficient Lewis acidity to enable the oxide anion to act as a leaving group. While no doubt an enormous step forward in the area of C–O bond cleavage, this method is unfortunately limited to π-extended backbones. Subsequently, Shi extended the scope of the Ni-catalyzed KTC reactions to benzyl alcohols via formal C(sp3)–OH bond cleavage by utilizing a protocol based on PCy3 or dcype (L3) as ligand (Scheme 26).51 Unlike the functionalization of C(sp2)–OH bonds,50 these reactions could accommodate non-π-extended backbones, although superior results were found for naphthyl-type substrates. Unfortunately, these processes were found to be limited to aryl or benzyl Grignard reagents, as alkyl organometallic species possessing β-hydrogens predominantly resulted in reduced products.

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Scheme 25 Ni-catalyzed KTC reaction of naphthols.

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Scheme 26 Ni-catalyzed KTC reaction of benzyl alcohols.

Undoubtedly, the ability to use free alcohols as counterparts holds promise to revolutionize the C–O bond cleavage arena as no prefunctionalization would be required. Although the strategy of salt formation represents a proof of concept for effecting the targeted C–OH bond cleavage, the scope of these reactions remains rather limited. Given the acidity of free alcohols and basicity of Grignard reagents, it is evident that innovative strategies will be required to widen the scope of the coupling partners utilized in KTC reactions.

2.2 Negishi-Type Coupling Reactions Although considerably less reactive than Grignard or organolithium reagents, organozinc derivatives have become privileged synthons in catalytic C–C bond-forming reactions. In light of the remarkable advances that have been made involving the use of Grignard reagents for activating C(sp2)– or C(sp3)–O bonds, it comes as no surprise that there is considerable interest in realizing the potential of organozinc compounds in these reactions. 2.2.1 Esters In 2008, Shi reported the Ni-catalyzed cross-coupling reaction of aryl pivalates and in situ generated arylzinc chlorides (Scheme 27).52 As for the KTC reaction of aryl esters, π-extended systems were considerably more reactive than their phenyl congeners. With this in mind, good yields could still be obtained for electron-poor aryl esters or indene backbones. The authors proposed a “classical” organometallic pathway involving the oxidative addition of aryl pivalates to Ni(0) species followed by a transmetalation and a final reductive elimination to deliver the expected biaryl motifs.

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Scheme 27 Ni-catalyzed Negishi-type coupling reactions of aryl pivalates.

Scheme 28 Stereospecific Ni-catalyzed Negishi coupling reactions of benzyl ester derivatives.

Continuing their research into stereospecific KTC reactions via C(sp3)–O bond cleavage, the Jarvo group reported the Ni-catalyzed Negishi-type reaction of organozinc derivatives with enantioenriched secondary benzyl ester reagents (Scheme 28).53 The use of less-reactive organozinc compounds was expected to be problematic due to the propensity of alkyl organometallic species toward destructive β-hydride elimination or radicaltype pathways that could ultimately erode the enantiopurity of the products. These challenges were addressed through the systematic optimization of the leaving group, leading to the identification of (methylthio)acetates as the optimal substrates. This is presumably due to the chelating effect in these species. Thus, a number of enantioenriched secondary benzyl alcohol derivatives bearing 2-naphthyl or heteroaryl substituents could be coupled in good to excellent yields and with essentially perfect stereospecificity. Even substrates prone to racemization, such as 3-indoyl substituted species or benzhydryl derivatives, could be employed with equal success, highlighting the ability of this approach to suppress epimerization pathways. Notably, this

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Scheme 29 Stereospecific Ni-catalyzed coupling of Me2Zn with 6-aryl δ-valerolactone.

methodology is particularly sensitive to the nature of the organometallic species employed, as Et2Zn requires a different set of reaction conditions. In 2014, Jarvo reported an expansion of their previous methodology to the stereospecific ring opening of 6-aryl-substituted enantioenriched δ-valerolactone derivatives with Me2Zn (Scheme 29).54 These reactions also proceeded with exceptional stereospecificities; however, the protocol is primarily restricted to naphthyl- and heteroaryl-substituted substrates, a recurring limitation in catalytic C–O bond cleavage reactions. 2.2.2 Ethers Due to the exceptional bond-dissociation energy required for effecting C(sp2)–OMe cleavage, one might wonder whether cross-coupling reactions of aryl ethers with less-reactive organozinc derivatives could ever be implemented. This challenge was met by Uchiyama and Wang, who used dianion-type organozincates ArZnMe3Li2 that were generated in situ from Me4ZnLi2 (prepared by exposing ZnCl2 to an excess of MeLi in THF/ Et2O) and appropriately substituted aryl iodides (Scheme 30).55 As for other C–O bond cleavage processes, a significant preference for π-extended substrates was observed regardless of the identity of the nucleophilic component. Notably, these conditions could even be applied to substrates prone to racemization without any apparent erosion of enantiopurity. Intriguingly, aryl pivalate substrates provided inferior results to aryl methyl ethers, which contrasts with the prevailing dogma that the lower the bond-dissociation energy, the higher the reactivity of the C–O electrophile. The authors rationalized these results on the basis of the competitive addition of the

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Scheme 30 Ni-catalyzed Negishi coupling of dianion-type organozincates with aryl ethers.

nucleophilic aryl zinc species to the carbonyl group of the pivaloyl motif. Although the authors favored a catalytic cycle involving an oxidative addition, transmetalation, and reductive elimination, no mechanistic experiments were conducted, thus leaving ample room for the proposal of alternative scenarios. As judged by the available literature data, the development of Negishitype cross-coupling reactions via C–O bond cleavage is still in its infancy compared to the KTC reactions. Indeed, a rather limited set of substrates can be employed in these methodologies. The considerably lower reactivity of organozinc derivatives when compared with Grignard reagents may hamper the implementation of these processes for C–O functionalization. However, we anticipate that further efforts would be highly rewarding given the excellent functional group tolerance of organozinc derivatives. To this end, recent reports on the use of metal salts capable of dramatically modulating the reactivity of organozinc compounds hold promise as a way of enhancing the synthetic applicability of Negishi cross-coupling reactions with C–O electrophiles.

2.3 Suzuki–Miyaura-Type Couplings Although significant advances have been reported in metal-catalyzed crosscoupling reactions using Grignard reagents or organozinc derivatives, the air and moisture sensitivity of these coupling partners may still represent a drawback that limits the synthetic applicability of these protocols. Chemists have therefore investigated alternate counterparts with increased flexibility, practicality, and generality. Among these, boronic acids or esters have shown to be viable alternatives to commonly employed Grignard reagents or

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organozinc derivatives in a variety of C–C bond-forming reactions. Their air stability and commercial availability have been crucial to their widespread use in both academic and pharmaceutical laboratories. Not surprisingly, a number of Suzuki–Miyaura-type cross-coupling reactions involving C–O bond cleavage have been designed. 2.3.1 Carbamates In 2009, the groups of Garg and Snieckus independently reported the first Suzuki–Miyaura-type cross-coupling reactions of aryl carbamates (Scheme 31).56 Intriguingly, Snieckus et al. found that the water liberated by the boroxine/boronic acid equilibrium had a nonnegligible impact on reactivity, and found that a 10:1 ratio of these compounds gives optimal results. The authors hypothesized that this ratio was critical for forming the intermediate boronates involved in the transmetalation step. This behavior cannot be extrapolated to Garg’s protocol due to the presence of significantly larger amounts of potassium carbonate that could serve both as a drying agent and as the promoter of borate formation within the catalytic cycle. Later, the groups of Garg, Snieckus, and Houk presented a mechanistic study of the Suzuki–Miyaura-type cross-coupling of aryl carbamates and concluded that the reactions proceed through a sequence of oxidative addition, transmetalation, and reductive elimination steps, with transmetalation being rate limiting.57 The authors suggested that the selectivity between the cleavage of the Caryl–O bond and the weaker Ccarbonyl–O bond can be explained by a switch between a five-membered transition state (aided by the carbonyl C]O bond) in the former and a three-membered transition state in the latter case. In 2010, Shi and colleagues broadened the applicability of the reaction by including both vinyl and aryl carbamate substrates. Boroxines were used as the nucleophilic entities and stoichiometric water was required.58 In 2011, Kappe reported that microwave irradiation significantly increases the reaction efficiency of the Ni-catalyzed Suzuki–Miyaura

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Scheme 31 Ni-catalyzed Suzuki–Miyaura-type arylation of aryl carbamates.

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coupling of aryl carbamates, with complete conversions obtained after only 10 min.59 More recently, Tobisu and Chatani demonstrated that the crosscoupling of boronic acids or boronic esters with aryl or vinyl carbamates is not limited to Ni-based catalysts, and that Rh precatalysts can be used with similar efficiencies and selectivities.60 Continuing their research into stereospecific Ni-catalyzed benzylic C(sp3)–O functionalization reactions, the Jarvo group described a set of conditions that promote the stereospecific Suzuki–Miyaura arylation of benzyl carbamates (Scheme 32).61 Although all previous literature data on stereospecific transformations via C–O bond cleavage proceeded via inversion of configuration, the authors found that the nature of the ligand dictated the selectivity pattern when using a particular carbamate motif: whereas the use of SIMes (L2) resulted in inversion of configuration, the use of PCy3 yielded the corresponding arylated product with retention of configuration. Although mechanistic experiments were not performed to understand the origin of this intriguing observation, the authors propose that chelation of the carbamate motif to a Ni catalyst based on PCy3 results in an oxidative addition with retention of configuration. In contrast, when SIMes (L2) is present, oxidative addition is thought to proceed through the common pathway in which inversion of configuration occurs. In both cases, oxidative addition is proposed to take place via an η3-Ni(II) intermediate, thus resembling the oxidative addition step of an allylic system. Presumably, this η3-coordination explains the lower reactivity observed for non-π-extended backbones, a recurrent drawback observed in a wide variety of C–O functionalization techniques. In a related report, the group of Lu recently described the synthesis of biarylmethanes in water, starting from simple benzylic carbamates and utilizing a Pd-NHC catalyst.62

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Scheme 32 Stereospecific Ni-catalyzed Suzuki–Miyaura arylation of benzyl carbamates.

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Rueping and coworkers have recently reported the first Suzuki– Miyaura-type coupling of aryl carbamates and pivalates with (9-BBN)-alkyl species possessing β-hydrogens. Although this discovery no doubt constitutes a step forward, the method is limited to particularly activated naphthyl and biphenyl systems as well as linear alkyl boranes.63 2.3.2 Esters The first Suzuki–Miyaura cross-coupling reaction of boronic acids and ester derivatives was reported by Kuwano and Yokogi using benzyl derivatives and Pd(II) precatalysts (Scheme 33).64 The alcoholic solvent employed in this transformation was suggested to facilitate the transmetalation step prior to the final reductive elimination. In 2008, the groups of Garg and Shi independently developed Ni-catalyzed protocols for the Suzuki–Miyaura-type cross-coupling of aryl ester derivatives (Scheme 34).65 It is worth noting that these reactions are highly reminiscent of the use of aryl carbamates reported by Garg and Snieckus.56 Whereas Garg utilized aryl boronic acids with aryl pivalates as coupling partners, Shi employed the corresponding boroxines in the presence of stoichiometric amounts of water and a wide variety of different aryl ester motifs. Both groups highlighted the synthetic utility of the newly developed .

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Scheme 33 Suzuki–Miyaura-type arylation of benzyl acetates. . .

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Scheme 34 Ni-catalyzed Suzuki–Miyaura-type arylations of aryl esters.

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protocols in the context of multistep syntheses. Shi proposed a “classical” cross-coupling mechanism consisting of a Ni(0)/Ni(II) couple and oxidative addition, transmetalation, and reductive elimination. Such a scenario was later corroborated by Liu in a computational study of the reaction of aryl acetates with aryl boronic acids.66 Based on the stoichiometric studies by Yamamoto and colleagues in the context of KTC-type reactions,10 aryl acetates would be expected to undergo undesirable Ccarbonyl–O bond cleavage with reasonable ease. Indeed, theoretical calculations revealed a considerably lower activation barrier for Ccarbonyl–O bond cleavage than the desired Caryl–O functionalization. However, Ccarbonyl–O activation was found to be reversible, with the resulting Ni(II)-acyl complex not able to undergo easy transmetalation. This can therefore be considered a prototypical Curtin–Hammett situation in which selectivity arises from two interconverting isomers, one of which leads to the desired the Caryl–O bond cleavage product due to its lower kinetic energy barrier. Molander subsequently disclosed a related protocol using potassium heteroaryltrifluoroborates as the nucleophilic component and a limited set of π-extended aryl pivalate substrates.67 The synthetic applicability of the Suzuki–Miyaura arylation of aryl esters was demonstrated by Tu and coworkers by preparing fluorescent (hetero)-aryl-substituted anthracene derivatives using a pyridine-bridged pincer NHC-Ni complex supported by PCy3.68 The use of vinyl acetate derivatives as coupling partners in Suzuki– Miyaura-type reactions has been reported using Pd, Rh, and Ni catalysts. Specifically, Larhed and coworkers described a Pd-based protocol using boronic acids as nucleophilic entities that gave the corresponding vinylated compounds (Scheme 35).69 The authors considered two possible pathways: (1) initial transmetalation of the Pd(II) precatalyst and boronic acid to form an aryl palladium(II) species, followed by carbometalation of the vinyl acetate, and final β-elimination to release the target vinylated arene; (2) initial hydropalladation of vinyl acetate, followed by β-elimination to deliver ethylene, then carbometalation with the in situ generated aryl palladium(II) species,

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Scheme 35 Pd-catalyzed Suzuki–Miyaura-type arylations with vinyl acetate.

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Scheme 36 Complementary ipso- or cine-Suzuki–Miyaura arylation of vinyl acetates.

and a final β-hydride elimination. Although it is difficult to distinguish both pathways, mass spectrometry measurements allowed for the detection of some of the putative reaction intermediates, which supported pathway (2). In 2009, Lee and Kwong disclosed a Rh-catalyzed protocol displaying a similarly broad scope of boronic acids using vinyl acetate as coupling partner. The authors proposed a mechanism consisting of oxidative addition, transmetalation, and reductive elimination.70 Kuwano subsequently described two complementary Rh-based catalytic systems (Scheme 36).71 In the earlier system,71a the combination of a Rh-catalyst and dppb as the ligand was found to give ipso-substitution selectively. Stereochemical studies suggested a mechanistic scenario based on an oxidative addition, transmetalation, and reductive elimination. In their subsequent report,71b a catalyst system containing COD as the ligand was found to yield the products of cine-substitution with 1-substituted vinyl acetates. The authors proposed a mechanism involving an initial transmetalation to Rh(I) followed by carbometalation and β-hydride elimination. Hydrorhodation with reversed regioselectivity followed by elimination of Rh acetate would close the catalytic cycle and explain the observed cine-substitution. Minor amounts of the ispo-substitution product would form either by the mechanism proposed in their previous communication or by imperfections in the regioselectivity of the carbometalation step. In 2010, Shi disclosed a Ni-catalyzed protocol allowing for the coupling of diversely substituted vinyl acetate derivatives with boroxine coupling partners (Scheme 37).72 Although no mechanistic studies were reported, the authors favor a “classical” mechanistic scenario consisting of oxidative addition, transmetalation, and reductive elimination. Interestingly, the reaction occurs in the presence of an aryl acetate, representing a testament to the higher reactivity of vinylic motifs when compared with aryl acetate backbones.

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Scheme 37 Ni-catalyzed Suzuki–Miyaura-type arylation of vinyl acetates.

to

Scheme 38 Stereospecific Ni-catalyzed Suzuki–Miyaura-type arylations of benzyl pivalates.

Taking into consideration the inherent interest in enantioenriched triarylmethane derivatives,73 Jarvo and Watson independently developed stereospecific Suzuki–Miyaura-type cross-couplings of benzyl pivalate derivatives (Scheme 38).61,74 Whereas Jarvo employed a catalytic system that is analogous to the one previously described for carbamate substrates,61 Watson employed a ligand-free Ni(COD)2 protocol using boroxines as coupling partners.74 As expected, inversion of configuration was obtained regardless of whether boronates or boroxines were employed as the nucleophilic component. Preliminary mechanistic investigations by Watson concluded that the stereochemical outcome is determined by an inversion of configuration during the oxidative addition step, which is followed by stereoretentive transmetalation and reductive elimination. More recently, Fan and Yang described a catalytic system employing an air-stable Ni(II)-precatalyst, providing good yields for the arylation of racemic and achiral benzyl pivalates.75

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2.3.3 Ethers In 2004, Kakiuchi reported the first Ru-catalyzed Suzuki–Miyaura crosscoupling reactions of aryl neopentyl boronic esters and aryl ethers possessing alkyl ketones located at the ortho-position (Scheme 39).76a Notably, alkenyl and alkyl boronates provided acceptable yields when the catalyst loading was increased to 10 mol%. Intrigued by these results, Kakiuchi studied the metalation of a model substrate, and demonstrated that C–H functionalization is kinetically favored, and that equilibration allows for the thermodynamically favored C–O bond cleavage.76b Based on this observation, a sequential C–H functionalization/C(sp2)–OMe arylation reaction was designed, resulting in double functionalization of the substrate. Prompted by the work of Kakiuchi, Zhao and Snieckus used the same catalytic protocol but extended the directing group strategy by using amides located at the ortho position (Scheme 40).77 The methodology displayed a broad scope for both the aryl ether and the boronic ester, but unfortunately required the need for a directing group to effect the transformation.

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Scheme 39 Ketone-directed Ru-catalyzed Suzuki–Miyaura coupling reaction with aryl ethers.

Scheme 40 Amide-directed Ru-catalyzed Suzuki–Miyaura coupling of aryl ethers.

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Although no doubt a tremendous step forward, the need for an appropriate ortho-directing group prevented the application of these reactions to other substrates. Tobisu and Chatani demonstrated the ability of nickel catalysts to effect the Suzuki–Miyaura coupling of aryl methyl ethers in the absence of directing groups (Scheme 41).78 As for other cross-coupling reactions carried out with aryl methyl ether substrates, this reaction is best suited to π-extended systems. Under the optimized reaction conditions, a limited set of anisole derivatives bearing electron-withdrawing substituents at the para position could be employed, albeit in considerably lower yields. The authors speculated that a “classical” cross-coupling mechanism involving oxidative addition, transmetalation, and reductive elimination might be operative. They also proposed the intermediacy of Meisenheimer-type complexes that are formed via partial dearomatization of the aromatic ring, an observation that might correlate well with the higher reactivity found for π-extended aromatic backbones. Tobisu and Chatani subsequently reported the expansion to vinyl alkyl ethers, thereby broadening the applicability of their initial catalytic system.79 Interestingly, the configurations of the double bonds involved were found to equilibrate under the reaction conditions. The authors concluded that the products underwent equilibration, as the starting materials were found to be configurationally stable under the reaction conditions. In 2014, Tobisu and Chatani reported a catalytic system based on ICyHCl that is capable of promoting the cross-coupling reactions of both benzyl methyl ethers and simple anisole derivatives, a limitation encountered on the previous protocol based on PCy3 (Scheme 42).78,80 The same authors recently reported a homocoupling protocol of π-extended methoxyarenes using B2(nep)2.81 This transformation is based on the ability of the Ni(COD)2/ICy catalytic system to undergo an initial C–OMe bond borylation followed by a Suzuki–Miyaura-type coupling between the in situ generated aryl boronate and the remaining aryl methyl ether.

Scheme 41 Ni-catalyzed Suzuki–Miyaura reaction of boronic esters with aryl methyl ethers.

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Scheme 42 Ni-catalyzed Suzuki–Miyaura reactions of aryl and benzyl methyl ethers.

Scheme 43 Ni-catalyzed Suzuki–Miyaura cross-coupling of naphthols with boroxines.

2.3.4 Alcohols Following their initial work on Ni-catalyzed KTC reactions of simple phenols,50,51 the Shi group reported a direct Suzuki–Miyaura-type crosscoupling reaction via formal Pd-catalyzed C(sp2)–OH bond cleavage (Scheme 43).82 The authors argued that the phenolate derivative generated upon treatment of the substrate with an appropriate base might facilitate the corresponding transmetalation step. The coordination to the Lewis-acidic boron center would substantially increase the leaving group capabilities of the alcoholate oxygen. In line with this notion, the authors found that triethyl borane as additive had a beneficial effect on reactivity. These results gained credence by the crystallization of an analog to the putative naphtholate boronic ester adduct, demonstrating that such a compound was competent as reaction intermediate. Unfortunately, the reaction was limited to π-extended systems. In 2015, Shi reported an extension to the mutual activation approach that encompasses benzylic C(sp3)–OH bonds (Scheme 44).83 The reported methodology differs from the previously described protocol for aromatic C(sp2)–OH bonds because Pd(PPh3) was found to be particularly competent catalyst in the absence of external additives. As for the previous study, the

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Scheme 44 Pd-catalyzed Suzuki–Miyaura reactions of benzyl alcohols with boroxines.

authors proposed a mutual activation mechanism consisting of the coordination of the alcohol functionality to the boroxine, forming an adduct that can participate in the subsequent Suzuki–Miyaura arylation. It is evident that considerable progress has been achieved when performing C–C bond-forming reactions via C–O bond cleavage using welldefined organometallic components. Despite the advances realized, a wide number of methodologies are still restricted to the utilization of π-extended systems in order to obtain satisfactory results. Unfortunately, these intriguing observations have not been correlated with a deeper mechanistic understanding, an aspect that could lead to the discovery of conceptually new processes in the future.

2.4 Mizoroki–Heck-Type Coupling Reactions Although the use of well-defined organometallic species has contributed to the perception that C–O electrophiles can successfully be employed as organic halide surrogates, a nonnegligible number of these reagents are both air and moisture sensitive, and the use of these species generates a considerable amount of waste. Therefore, chemists have been challenged to design alternate catalytic C–C bond-forming reactions that avoid the use of organometallic compounds. 2.4.1 Esters In 2004, Shimizu disclosed a Pd-catalyzed Mizoroki–Heck-type reaction of benzyl trifluoroacetates with appropriately substituted olefins (Scheme 45).84 The reaction was found to be limited to trifluoroacetate derivatives and to electron-withdrawing olefins, including acrylates and styrenes. Mechanistic studies were carried out with some of the putative reaction intermediates and supplied evidence for a mechanism consisting of oxidative addition of the Cbenzyl–O Bond to Pd(0), resulting in η1-benzylic Pd(II) intermediates that likely coexist with the corresponding η3-species, followed by insertion into the double bond, and a final β-hydride elimination.85

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Scheme 45 Pd-catalyzed Mizoroki–Heck-type reactions of benzylic trifluoroacetates.

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Scheme 46 Pd-catalyzed enantioselective Mizoroki–Heck-type reaction of benzylic trifluoroacetates.

Prompted by these precedents, Yang and Zhou reported an asymmetric variant of the Mizoroki–Heck-type reaction with benzyl trifluoroacetate electrophiles and cyclic olefins (Scheme 46).86 A variety of ligands were examined and the best enantioselectivities with a wide variety of substituted benzyl trifluoroacetates were found when using finely tuned phosphoramidite ligands. As for the corresponding olefin counterpart, both 2,3- and 2,5-dihydrofurans could be used as starting materials with similar results, and N-Boc-2,3-pyrrolidine and cyclopentene could be utilized to obtain excellent enantioselectivities. Although one might expect that isomerization of the double bond within the five-membered ring could take place to give achiral products, this was not the case. In 2012, Watson disclosed a significant step forward in Mizoroki–Hecktype reactions via C–O bond cleavage using aryl pivalates as substrates (Scheme 47).87 The reaction was found to tolerate a wide range of aryl and vinyl pivalates, although harsh conditions were required for substrates not featuring extended π-systems. Interestingly, the authors reported an alternative protocol that avoids air-sensitive Ni(COD)2 by using bench stable Ni(II)Cl2DME as the precatalyst and Zn dust as the reductant.

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Scheme 47 Ni-catalyzed Mizoroki–Heck-type reaction of aryl pivalates.

Scheme 48 Stereospecific intramolecular Mizoroki–Heck-type reactions of benzyl ethers.

2.4.2 Ethers Jarvo and colleagues reported a stereospecific intramolecular Mizoroki– Heck reaction of enantioenriched benzyl alkyl ethers (Scheme 48).88 In general, good to excellent results were observed with naphthyl-substituted or heteroaryl-substituted backbones, and in all cases products were obtained that were derived from an inversion of configuration at the benzylic position. As for other stereospecific transformations, however, non-π-extended systems bearing simple phenyl groups proved to be particularly challenging. The authors found that in these cases the use of a methoxyethyl ether leaving group is advantageous. A mechanism was proposed involving the initial coordination of the olefin to the Ni(0)-catalyst, followed by an oxidative addition with inversion of configuration. The subsequent migratory insertion and β-hydride elimination reactions are stereospecific, thus fixing the double bond geometry in substrates containing doubly substituted olefins. Despite the elegant work of Jarvo, examples of intermolecular variants of Mizoroki–Heck reactions using benzyl alkyl ethers or aryl alkyl ethers are absent in the literature. We certainly anticipate that progress along these lines will bring new knowledge in this field of expertise while dramatically expanding the efficiency and practicality of one of the less-studied reactions in the field of C–O bond cleavage.

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2.5 Stille-Type Couplings The only examples reported using Stille-type couplings were described by Pettus using benzoate derivatives (Scheme 49).89 Unfortunately, these reactions are limited to rather particular substrates that favor the initial oxidative addition step, and moderate yields are generally obtained, suggesting that significant improvements would be required to explore the full potential of this transformation.

2.6 Reactions Involving Other Organometallic Compounds: Organolithium and Organoaluminum Reagents Organolithium reagents rank among the most used organometallic reagents in organic synthesis. Although the seminal work of Murahashi and coworkers in 1979 demonstrated the feasibility of their use in cross-coupling reactions,90 their implementation in these processes has been hampered by their high reactivity, which leads to low functional group tolerance and low yields due to competitive pathways such as β-hydride elimination. Prompted by the seminal work of Murahashi and the work of Feringa using Pd catalysts in related endeavors,91 Rueping and colleagues disclosed a Ni-catalyzed cross-coupling of aryl methyl ethers with neosilyllithium (Scheme 50).92 Unlike other C–O bond functionalizations, a variety of non-π-extended systems could be employed with equal ease. Several synthetic transformations of the trimethylsilyl group into other useful functionalized backbones highlighted the application profile of this methodology. The authors proposed a

Scheme 49 Pd-catalyzed Stille-coupling reaction using benzoate derivatives.

OMe R

+

Li

SiMe3

SiMe3

Ni(COD)2 (1–10 mol%) PhMe, 50–80°C

82%

SiMe3

SiMe3

SiMe3 Ph

99%

R

SiMe3 HO

99%

61%

Scheme 50 Ni-catalyzed cross-coupling of aryl methyl ethers with neosilyllithium.

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“classical” mechanism consisting of oxidative addition, transmetalation, and reductive elimination; however, it is unclear how oxidative addition into a very strong C(sp2)–OMe bond could take place in the absence of typically required supporting ligands. Certainly, a study focused on the mechanism of this transformation would clarify whether other scenarios come into play. Very recently, Hornillos and Feringa reported a study on the Ni-catalyzed cross-coupling reactions of aryl and heteroaryl lithium species with a series of different leaving groups, including aryl methyl ethers.93 Unfortunately, a limited number of examples were provided, so the potential of these transformations has not been fully explored. Taking into consideration these results, Rueping reported the reaction between various vinyl ether derivatives with neosilyllithium (Scheme 51).94 The protocol was shown to be suitable for several vinyl methyl ethers as well as for silyl enol ethers. Thus, the methodology gives access to a broad range of allyl trimethylsilane derivatives, which are highly valuable intermediates for organic synthesis. In all cases, high stereospecificities were observed and the reactions occurred with retention of the double bond configuration. Recently, Tobisu and Chatani published the Ni/NHC-catalyzed methylation of anisole derivatives using trimethylaluminum (Scheme 52).95 This transformation is the first example of the cross-coupling of challenging phenol derivatives with organoaluminum reagents. Interestingly, other trialkylaluminum reagents with longer alkyl chains provided similar results. Rueping and Schoenebeck then expanded the scope of this transformation by developing a catalytic system that is partially capable of avoiding competing β-hydride elimination by means of a bidentate trialkylphosphine ligand (Scheme 52).96 In situ-prepared primary trialkylaluminum reagents with different chain lengths could be coupled with several aryl methyl ethers in

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Scheme 51 Ni-catalyzed cross-coupling of vinyl alkyl and silyl ethers with neosilyllithium.

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Scheme 52 Ni-catalyzed cross-coupling reactions of aryl methyl ethers with R3Al.

excellent to good yields, whereas other Li-, Mg-, or Zn-based nucleophilic reagents gave worse results. Unfortunately, acyclic tertiary trialkylaluminum compounds led to a mixture of branched and linear products. As expected from the high reactivity of R3Al as well as the strongly basic conditions, a low functional group tolerance was observed in both Tobisu and Chatani’s and Rueping’s protocols. The authors confirmed the presence of an interaction between the aryl methyl ether and the trialkylaluminum reagent by NMR spectroscopy, representing the first experimental proof of the previously suggested Lewis acidanisole coordination. Computational studies also support the proposal that coordination significantly aids the C–OMe bond-oxidative addition and favors the formation of Ni(II)(OMe)(Ar) intermediates. Moreover, the presence of a Ni(II) intermediate was underlined by the quantitative formation of product when the LNi(II)Cl(Ar) complex (L ¼ dppf ) was reacted with AlEt3. However, this observation should not be considered conclusive since the ligand utilized differs from that used in the catalytic conditions (dcype).

2.7 Miscellaneous C–C Bond-Forming Reactions 2.7.1 Reactions of Benzyl Esters with Various Nucleophiles In the early 1990s, Murai and coworkers reported a cobalt-catalyzed carbonylation–hydrosilylation sequence using benzyl acetate substrates (Scheme 53).97 The reaction converted these compounds into the corresponding homobenzylic silyl ethers using carbon monoxide and trimethylsilane. The authors proposed that the reaction proceeds through the initial formation of silyl–cobalt intermediates, which set the stage for an oxidative addition en route to trimethylsilyl acetate and a benzyl cobalt species. The latter was proposed to rapidly react with CO to afford an acyl cobalt intermediate that promotes a hydrosilylation. The aldehyde that is

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Scheme 53 Co-catalyzed carbonylation/hydrosilylation of benzyl acetates.

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Scheme 54 Pd-catalyzed cross-coupling of benzyl acetates with dimethylmalonates.

liberated undergoes an additional hydrosilylation to deliver the silyl ether product. Prompted by Murai’s report, Legros and Fiaud studied the possibility of promoting Pd-catalyzed C–C bond-forming reactions of benzyl acetates with dimethylmalonates (Scheme 54).98 The authors found that the reaction remained limited to benzylic acetates derived from substrates with extended π-backbones, an observation that was attributed to the requirement for partial dearomatization via π-allyl-Pd complexes. Interestingly, nonnegligible stereospecificity was observed when the reaction was carried out with enantiopure secondary benzyl acetates. In all cases, products underwent net inversion of configuration. Unfortunately, however, significant amounts of styrenes were observed, probably due to competitive β-hydride elimination with secondary benzyl acetates. More interestingly, the authors described the use of chiral ligands in combination with racemic secondary benzyl acetates, obtaining promising yields and stereoinductions with (S,S)-BDPP or (R,R)-i-Pr-DUPHOS. In 2007, Yokogi and Kuwano extended Legros’s studies to substrates without extended π-systems using dppf as the ligand (Scheme 55).99 Lower yields were obtained for unsubstituted diethylmalonates, likely due to the propensity of the substrate to undergo double substitution reactions.

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Scheme 55 Pd-catalyzed reaction of benzyl acetates with active methylene compounds.

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Scheme 56 Pd-catalyzed decarboxylative reactions of benzyl esters.

Subsequently, Kuwano disclosed an intramolecular protocol in which the malonate and the acetate motif were connected through a tether.100 Recently, Hirano and Miura reported the successful Pd/(R)-H8BINAP-catalyzed asymmetric benzylic alkylation of π-extended benzyl pivalates with a wide range of active methylene compounds.101 Mal and Roy then described heterobimetallic Pd–Sn catalysts capable of promoting substitution reactions of benzylic alcohol substrates, although the reactivity resembles the classical Friedel–Crafts-type reaction.102 Tunge and Chruma have reported decarboxylative processes via C(sp3)– O cleavage for the installation of alkynes and ketones at the benzylic position (Scheme 56).103 Unfortunately, the scope of these reactions is essentially limited to substrates with π-extended backbones. In 2010, Chruma described an otherwise similar transformation using benzyl diphenylglycinate imines; in this case, however, decarboxylation results in benzophenone imine protected amines as products.104 In 2016, Chen and Han disclosed complementary protocols for the reaction between benzyl pivalates and phenyl acetonitrile derivatives giving either benzylation products or the corresponding stilbene derivatives

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Scheme 57 Ni-catalyzed reactions of phenyl acetonitrile derivatives with benzyl pivalates.

resulting from HCN elimination (Scheme 57).105 In both reports, a broad range of benzyl substrates and nucleophiles was presented, encompassing both π-extended backbones and phenyl-type substrates. Mechanistically, the authors propose that the reactions proceed through a “classical” sequence of oxidative addition, ligand exchange, and reductive elimination. The difference between the two protocols was attributed to base-induced elimination of HCN occurring for the stilbene formation, favoring transconfigured olefins predominantly. 2.7.2 α-Arylations with Aryl Esters Although remarkable advances have been reported using benzyl esters with nucleophilic entities (Schemes 53–57), these methods are restricted to substrates that can rapidly undergo oxidative addition. In order to bypass this restriction, Itami and Yamaguchi initiated a research program to realize the potential of α-arylation reactions of pronucleophiles with aryl esters. Specifically, the authors described the means to promote an α-arylation of ketone derivatives (Scheme 58).106 Their catalytic system involved the use of a thiophene bridged bis(dicyclohexyl)phosphine ligand and enabled the reaction of various activated and nonactivated aryl pivalates with differently substituted ketones. The authors succeeded in isolating the product of oxidative addition between the ligand-stabilized Ni(0)-species and the 2-naphthol-derived pivalate. The resulting Ni(II)-complex was characterized by X-ray crystallography.107 Stoichiometric and catalytic experiments

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Scheme 58 Ni-catalyzed α-arylation of ketones, esters, and amides.

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Scheme 59 Ni-catalyzed enantioselective α-arylation of cyclic ketones with aryl esters.

revealed that this compound was a competent reaction intermediate and a suitable Ni(II) precatalyst. In 2015, the same group reported an extension of the methodology to phenylacetic acid derivatives, cyclic amides, and aryl pivalates.108 Although the work of Itami and Yamaguchi suggested that a rather electron-rich ligand was required for effecting the α-arylation of aryl esters via C–O bond cleavage, Martin demonstrated that enantioselective α-arylation of cyclic ketones could be conducted using chiral BINAP derivatives with cyclic ketones and high levels of enantioselectivity (Scheme 59).109 Under these conditions, α-branched cyclic ketones reacted with both activated and nonactivated aryl pivalates to give virtually enantiopure α-arylated ketones, thereby generating a quaternary stereocenter in an enantioselective fashion. Additionally, the nucleophile part could be varied to include larger substituents on the reactive site, heteroatoms on the nucleophilic carbon center, substitution on the backbone, as well as larger rings. With this study, the potential to use challenging C–O bond activations in the context of enantioselective reactions was highlighted. This is complementary to the protocols discussed earlier that deal with stereospecific reactions on substrates with preexisting stereocenters.

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2.7.3 Reductive Coupling Reactions In recent years, cross-electrophile coupling reactions have become powerful alternatives to classical nucleophilic/electrophile regimes based on stoichiometric, well-defined, and, in many instances, air-sensitive organometallic species.110 At present, the vast majority of these processes remain confined to organic halides, giving the perception that C–O electrophiles could not be employed as coupling partners in these endeavors. In 2005, Gosmini successfully implemented a Co-catalyzed reductive cross-electrophile coupling of aryl halides and vinyl acetate derivatives using bipyridine as ligand and manganese as reductant (Scheme 60).111 Under these conditions, a series of aryl chlorides and bromides, including heteroaryl derivatives, could be coupled with a variety of vinyl acetates. Continuing their research into catalytic reductive carboxylation reactions using carbon dioxide as a C1 synthon,112 the Martin group demonstrated the viability of promoting reductive carboxylation techniques using aryl and benzyl esters as electrophiles via C–O cleavage (Scheme 61).113 Although π-extended backbones were required when dealing with aryl ester derivatives,

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Scheme 60 Co-catalyzed reductive coupling of aryl halides and vinyl acetates.

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Scheme 61 Ni-catalyzed reductive carboxylations of aryl and benzyl esters.

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Scheme 62 Ni-catalyzed reductive amidation of aryl and benzyl pivalates with isocyanates.

the use of traceless directing groups allowed for the coupling of regular aromatic motifs via C–O cleavage. It was postulated that the presence of a hemilabile directing group dramatically accelerated the rate of oxidative addition and opened coordination sites at the Ni center that facilitated the binding of CO2. The Martin group conducted control experiments that allowed them to rule out the presence of in situ generated organomanganese species. This pointed to a mechanistic scenario based on the intermediacy of Ni(I) species that are able to react rapidly with carbon dioxide prior to a singleelectron transfer mediated by Mn, thus regenerating the active Ni(0) catalyst while forming a manganese carboxylate that upon hydrolytic workup generates the desired carboxylic acid. Recently, Martin reported the Ni-catalyzed reductive amidation of aryl pivalates with both alkyl and aryl isocyanates via C(sp2)– and C(sp3)–O bond cleavage (Scheme 62).114 Although the C–O cleavage protocol was restricted to naphthalene derivatives, the use of aryl halides gave access to the corresponding benzamides without requiring a π-extended backbone. Like for other related reductive coupling protocols, benzylic C–O electrophiles were considerably more reactive than aryl C–O bonds, probably due to the higher propensity of benzylic electrophiles to undergo oxidative addition. 2.7.4 C–H/C–O Coupling Reactions Although the means to promote cross-electrophile couplings represents a significant step toward the implementation of C–O electrophiles in crosscoupling methodologies, the need for prefunctionalization of both coupling partners still represents a limitation. To this end, Kakiuchi investigated the possibility of using vinyl acetates in combination with ruthenium-catalyzed C–H bond-functionalization (Scheme 63).115 Using this protocol, a variety

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Scheme 63 Ru-catalyzed C–H/C–O coupling of arenes and vinyl acetates.

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Scheme 64 Co-catalyzed C–H functionalization/arylation with aryl carbamates.

of vinyl acetates and arenes possessing ortho-pyridine, -oxazoline, or tetrazole directing groups gave similar yields of the desired products. In 2012, Song and Ackermann reported on the use of cobalt catalysis to enable the reaction of a variety of aryl carbamates with arenes possessing ortho-pyridyl and -pyrimidyl directing groups (Scheme 64).116 Control experiments pointed toward a pathway that depends on the inherent kinetic C–H acidity of the substrates. The authors subsequently reported an extension of their protocol that includes indole derivatives, alkenyl acetates, and alkenyl carbamates.117 Itami and Yamaguchi developed a Ni-catalyzed arylation of oxazole and thiazole derivatives using aryl pivalates as counterparts (Scheme 65).118 A wide range of (benz)oxazoles and thiazoles could be reacted with aryl pivalates under these conditions to give the cross-coupling products in good to excellent yields, although activated aryl pivalates were required. A number of features deserve further consideration: (1) the choice of dcype

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Scheme 65 Ni-catalyzed C–H activation/arylation of (benz)oxazole and thiazole derivatives using aryl pivalates.

(L3) as the ligand was found to be crucial for the reaction to proceed; (2) cesium carbonate was found to be superior to other related inorganic bases. Itami, Yamaguchi, and Lei continued the work on this catalytic system by conducting a mechanistic study. The authors provided extensive data in favor of a mechanism consisting of an oxidative addition of the aryl pivalate to Ni(0)(dcype) followed by ligand exchange, C(sp2)–H functionalization, and a final reductive elimination. The nickel(II) complex resulting from oxidative addition into the C(sp2)–O bond of 2-naphthyl pivalates was isolated, constituting the first evidence that C(sp2)–O bond cleavage in aryl esters may indeed involve direct oxidative addition.107 In 2014, a computational study aimed at elucidating the precise role of the Cs2CO3 base was reported.119 The calculations confirmed that C–H functionalization is rate determining and proceeds through a concerted– metalation–deprotonation pathway in the absence of base. Interestingly, Cs2CO3 was found to react with the oxidative addition intermediate, giving an adduct of type [Ni(dcype)(naph)][PivOCsCsCO3]. Coordination of the azole to the Ni(II) center results in a significant increase in the azole acidity and leads to a lower barrier for the C–H functionalization event. Itami and Yamaguchi subsequently disclosed a related catalytic system that enables the use of N-substituted (benz)imidazoles as substrates in otherwise analogous reactions.120 Very recently, Carpentier and Kirillow reported the possibility of performing C–H/C–OMe coupling with yttrium and scandium complexes. Although these reactions occurred in a stoichiometric fashion, this report demonstrated the ability of certain early transition metals to activate C–O bonds.121 Recently, Shi and coworkers have reported a Ni/Cucatalyzed C–O/C–H coupling of aryl carbamates and polyfluoroarenes. The authors proposed polyfluoroarylcuprates(I) as the active transmetalating

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species to the ArNi(II)OR intermediates generated through the oxidative addition of the C–O bonds to Ni(0).122 Overall, the reactions summarized in this chapter on miscellaneous reactions involving the activation of C–O bonds demonstrate the potential of C– O electrophiles in catalytic cross-coupling processes. The diversity of the reaction partners, ranging from reductive couplings with appropriate electrophile partners to challenging nucleophilic entities, indicates that much remains to be discovered.

3. CARBON–HETEROATOM BOND-FORMING REACTIONS Unlike the wealth of literature data on catalytic C–C bond-forming reactions using C–O electrophiles, the means to promote C-heteroatom bond formation remains rather unexplored. Taking into consideration that catalytic C-heteroatom bond formation has significantly contributed to streamlining the syntheses of many pharmaceuticals and other molecules that display significant biological properties,123 chemists have been challenged to implement otherwise similar protocols via C–O bond cleavage.

3.1 C–N Bond Formation Aromatic C–N bonds rank among the most ubiquitous motifs in, for example, pharmaceuticals, agrochemicals, electronic materials, polymers, or liquid crystals.124 Metal-catalyzed amination of aryl, vinyl, and heteroaryl (pseudo)halides has emerged as a platform for forging C–N bonds, with the Buchwald–Hartwig amination being the most established and powerful methodology used for this purpose.125 Although the use of Pd125 and Cu126 catalysts in C(sp2)–N bond formation has become routine, the employment of Ni catalysts in this type of reaction has received much less attention.127 Unlike with organic halides, the use of C–O bond-functionalization techniques in C–N bond formation is particularly challenging due to the inherent difficulty in promoting C–O bond oxidative addition and, when dealing with aryl esters and carbamates, the proclivity for O–C(O)R hydrolysis under basic conditions. As part of their studies on C–O bond cleavage, Tobisu and Chatani described a seminal Ni-catalyzed catalytic amination of aryl methyl ethers using L7 as the ligand (Scheme 66).128,129 Interestingly, whereas NHCs provided the best results, commonly employed PCy3 in C– O functionalization delivered the product in considerably lower yields. Unfortunately, high catalyst loadings were required, the protocol was restricted to cyclic amines, and regular anisoles were several orders of

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Scheme 66 Ni-catalyzed amination of aryl methyl ethers.

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Scheme 67 Ni-catalyzed amination of aryl pivalates.

magnitude less reactive than π-extended systems. Still, however, promising reactivity was still observed for heteroaryl rings without a pronounced difference in reactivity between π- or non-π-extended systems.130 Additionally, the functional group tolerance was rather problematic due to the strongly basic conditions. Tobisu and Chatani subsequently found that the drawbacks associated with the amination of aryl methyl ethers could be overcome by using aryl pivalates or carbamates instead (Scheme 67).131 Surprisingly, the strong basic conditions did not result in competitive hydrolysis of the ester functionality. Importantly, not only π-extended systems but also regular arenes were competent substrates regardless of the electronics of the aromatic ring. The higher reactivity of aryl pivalates when compared to aryl methyl ethers allowed the reaction to be conducted under considerably milder reaction conditions, thus significantly improving its chemoselectivity. Garg and coworkers demonstrated that a NiCl2DME precatalyst in combination with PhBpin as a mild reducing agent could efficiently catalyze the amination of aryl carbamates and sulfamates.132 The air stability and lower cost of this Ni(II) precatalyst render this amination a practical alternative to previously reported Ni-catalyzed amination techniques. As for the

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Ni-catalyzed amination of aryl pivalates reported by Tobisu and Chatani,131 π-extended systems and regular arenes could be coupled with equal efficiency, and nitrogen-containing heterocycles such as N-methylindolyl and pyridylcarbamates could also provide the corresponding aminated products in moderate to excellent yields. It should be noted that none of the methodologies mentioned earlier included the amination of benzylic alcohol derivatives via C(sp3)–O bond cleavage.

3.2 C–B Bond Formation The versatility and pivotal role of organoboron compounds as synthons in organic synthesis has attracted the attention of the synthetic community, making them attractive vehicles for further applications. Although traditional synthetic methods for the preparation of aryl and benzyl boronic acids involve the use of Grignard reagents or organolithium species,133 the high reactivity and air sensitivity of these compounds required the design of alternate borylation protocols. In recent years, significant advances have been achieved via the Miyaura borylation and C–H borylation techniques.134,135 Unfortunately, however, the need for organic halides as well as the lack of regioselectivity control in C–H functionalization reactions with unbiased substrate combinations are drawbacks that must be overcome. To this end, chemists have focused their attention on exploiting the opportunity of using C–O electrophiles for forging C(sp2)–B and C(sp3)–B bonds.136 In 2011, Shi and coworkers reported the borylation of (hetero)aryl carbamates via a Ni-catalyzed C(sp2)–O bond activation using [NiCl2(PCy3)2] as precatalyst and B2nep2 as the boron source (Scheme 68).137 Under these conditions, aryl pivalates, benzoates, and carbonates could also be borylated, albeit with moderate efficiencies. Notably, N-containing heterocycles such as those in carbazole, indole, and quinoline carbamates were equally tolerated. As expected, stereoelectronic effects played a crucial role, with both

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Scheme 68 Ni-catalyzed amination of aryl carbamates reported by the group of Shi.

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electron-donating rings and substituents possessing ortho-substituents significantly eroding the yields. A prototypical Ni(0)/Ni(II) couple was proposed, invoking a classical oxidative addition, transmetalation, and a final C–B bond reductive elimination. Inspired by their previous catalytic borylation and silylation of nitriles,138 Tobisu and Chatani developed a base-free Rh-catalyzed borylation of aryl 2-pyridyl ethers via the selective cleavage of C(sp2)– and C(sp3)–OPy bonds, a useful directing group in C–H bond functionalization reactions (Scheme 69).139,140 The combination of [RhCl(COD)]2, electron-rich ligands such as PCy3 or IMesMe, and B2pin2 as the borylating reagent was crucial for obtaining high yields. The reaction proceeded with an excellent selectivity profile, even for precursors possessing other C–O bonds on the ring. In all cases, functionalization took place exclusively at the C–O bond possessing an ortho-pyridyloxy unit. The authors proposed a mechanism consisting of the initial formation of a Rh(I)Bpin specie, allowing for a C(sp2)–O bond cleavage via a concerted pathway in which the Lewis-acidic boryl moiety coordinates to the nitrogen atom of the pyridyl unit (Scheme 70). Deuterium-labeling experiments showed that ortho C–H functionalization was relatively slow compared with the activation of the C(aryl)–O bond and the scrambling of the C(pyridyl)–H, thus explaining why C–H borylation at the ortho-position of the pyridyloxy group was not observed. Tobisu and Chatani later demonstrated the generality of Rh-based catalysts for this type of reaction by designing a related borylation of aryl and alkenyl pivalates. This finding showed, for the first time, that Rh catalysts are capable of activating the C–O bond of aryl ester derivatives (Scheme 71).141 Unfortunately, high temperatures, high catalyst loadings, and poly(hetero) aromatic substrates were required to achieve high yields. A catalytic cycle

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Scheme 69 Rh-catalyzed borylation of aryl 2-pyridyl ethers.

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O R

Bpin

N

RhI-Bpin

R

O

N Bpin

pinB

Bpin III

R

O

N

O

Rh Bpin Ln

RhILn R

LnRhI HN B pin Proposed C-O activation mode

B2pin2

Scheme 70 Mechanistic proposal of the Rh-catalyzed C-OPy cleavage/C–B formation.

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Scheme 71 Rh-catalyzed borylation of aryl and alkenyl pivalates.

similar to that shown in Scheme 70 was proposed, but it was not confirmed whether C–OPiv bond cleavage occurs via a concerted mechanism by means of a six-membered rhodacycle transition state, or whether it takes place via oxidative addition to form a [Rh(III)OPiv] intermediate (Scheme 71). Recently, Tobisu and Chatani have reported a related methodology for the borylation of C(sp2)– and C(sp3)–OPy bonds using NiCl2DME as catalyst and PCy3 HBF4 as ligand.142 These findings constitute a significant step towards the development of cost-efficient borylation protocols. Additionally, this borylation reaction allowed for the coupling of more challenging substrates, including a stereoretentive borylation of secondary benzylic ethers. In contrast to previously developed C–O bond borylation methodologies in which C–OMe bonds remained unreactive, Martin recently

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C(sp3) OMe borylation

C(sp2) OMe borylation/iodination

Scheme 72 Ni-catalyzed borylation of aryl and benzyl methyl ethers via C–OMe cleavage.

reported the first ipso-borylation of aryl methyl ethers via C–OMe bond cleavage using a Ni/PCy3 regime in combination with weak bases (Scheme 72).143 Importantly, such a transformation represents an alternative to the previously reported ortho-, meta-, and para-borylative protocols of anisole derivatives, in which the methoxy group has been used as a mere regiocontrol element.135,144 Interestingly, no homocoupling via Suzuki– Miyaura coupling of the in situ generated aryl boronate was detected in the crude mixtures, an observation that differs from the one later reported by Tobisu and Chatani.81 Although π-extended backbones were generally more reactive, regular anisole derivatives possessing electron-withdrawing groups could also be utilized. Strikingly, an orthogonal site selectivity was observed depending on the boron reagent utilized; while the combination of B2pin2 with CsF promoted a C(sp3)–O borylation, a protocol based on B2nep2/HCO2Na resulted in exclusive C(sp2)–B bond formation. This selectivity profile was rationalized by the different electronic and steric properties of the in situ generated nucleophilic boron reagents. Following up on their interest in designing cross-coupling reactions via C(sp2)– or C(sp3)–OH cleavage, the Shi group described a catalytic borylation of benzyl alcohols, which represent a rare example of a C– heteroatom bond formation via C–OH cleavage (Scheme 73).145 As expected, substrates with π-extended backbones were considerably more reactive than regular phenylmethanol compounds. Interestingly, the addition of Ti(Oi-Pr) as a Lewis acid was required to activate the latter. The

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Scheme 73 Pd-catalyzed borylation of arylmethanols with B2pin2.

authors proposed a mechanism based on oxidative addition of the benzylic C(sp3)–OH to Pd(0) assisted by the Lewis acid, followed by transmetalation and reductive elimination. Unfortunately, no alcohols possessing β-hydrogens were included, an observation that is likely correlated with the ability of the in situ generated benzyl palladium complexes to trigger a competitive β-hydride elimination. Notably, the authors’ preliminary experiments showed that phenols could be used as coupling partners, no doubt a step forward in future C–O bond-functionalization techniques.

3.3 C–Si Bond Formation Organosilanes are invaluable intermediates in organic synthesis and important building blocks in pharmaceuticals, material sciences, and medicinal chemistry.146 The wide variety of transformations that are within reach using organosilanes as precursors, including C–heteroatom bond formation, oxidations, or C–C bond formations, renders organosilanes powerful intermediates in organic synthesis, even in the context of total synthesis.146,147 Classical protocols for their synthesis include the use of stoichiometric organolithium or Grignard reagents via metalation techniques from the corresponding organic halide.146a However, in recent years, alternative catalytic methods involving the silylation of nitriles,138a organic halides,148 or C–H functionalization techniques135,149 have shown to be viable synthetic alternatives. Despite the remarkable advances realized, the need for organic halides, high temperatures, precious metal catalysts (Pd, Rh, or Ir), or the presence of proximal directing groups represent drawbacks for the implementation of these techniques by the synthetic community. In order to address these limitations, in 2014 the Martin group reported the first catalytic C–O bond functionalization/C–Si bond formation using aryl esters as coupling partners and silylboronates reagents (Scheme 74).150 It was found that Ni and Cu catalysts act in a synergistic fashion, a rather intriguing observation

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Scheme 74 Ni-catalyzed silylation of aryl and benzyl pivalates.

Scheme 75 Mechanistic proposal for the Ni/Cu-catalyzed silylation of C–O bonds.

as the Ni/Cu couple has rarely been utilized in cross-coupling methodologies.151 The transformation was distinguished by its generality, accommodating both π-extended systems and regular arenes with similar ease, as well as by its chemoselectivity profile in the presence of a wide variety of functional groups. Unlike other C–O bond activation methodologies, this C–Si bondforming protocol was not sensitive to the presence of ortho-substituents. Additionally, the reaction could be applied to benzylic C(sp3)–O bonds, holding promise for the design of future stereospecific or even enantioselective transformations. The observation that Cu and Ni catalysts act in concert in a silylation event was somewhat indicative of a silylcuprate intermediate being involved in promoting transmetalation with the corresponding ArNi(II)OPiv en route to ArNi(II)SiEt3 (Scheme 75). A final reductive elimination would

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regenerate the propagating Ni(0)Ln while delivering the targeted aryl silane. This proposal remains rather speculative and other mechanistic pathways, including single-electron transfer processes or Ni(I) intermediates, could not be ruled out.

3.4 C–P Bond Formation Organophosphorus compounds have not only been utilized extensively as ligands in catalysis and coordination chemistry but have also found widespread application in medicinal chemistry, agrochemicals, and material sciences.152 Classical approaches for forging C–P bonds include the utilization of either organolithium species, Grignard reagents, or phosphorous halides. Unfortunately, these methods are rather problematic due to their air sensitivity, toxicity, and poor chemoselectivity profiles. In 2015, Chen and Han reported the first phosphorylation of phenol derivatives, specifically aryl and benzyl pivalates, by using dcype as the ligand and K2CO3 as a base (Scheme 76).153 It is noteworthy that this phosphorylation worked with equal efficiency regardless of whether (hetero)polyaromatics or non-πextended systems were utilized or not. The reaction was proposed to proceed via a classical Ni(0)/Ni(II) catalytic cycle involving an oxidative addition of the C(sp2)–OPiv bond, a transmetalation, and a final C(sp2)–P bondreductive elimination. There is a general consensus that the recent years have witnessed significant progress in the area of C–O bond cleavage for forging C–heteroatom bonds. However, the recently reported methodologies cannot compete in efficiency and applicability with the numerous Pd-catalyzed cross-coupling protocols using aryl halides. Undoubtedly, future efforts such as a systematic study of the mechanisms by which these reactions operate will contribute to the improvement of these methodologies and enable a more widespread exploitation of C–O electrophiles.

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Scheme 76 Ni-catalyzed phosphorylation of aryl and benzyl pivalates.

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4. HYDROGENOLYSIS OF C–O BONDS The development of homogeneous catalytic techniques for the defunctionalization of robust C–O bonds to C–H bonds has provided chemists with an alternative functionalization strategy based on the unique reactivities of ethers, esters, and carbamates. Furthermore, significant advances have been made toward practical methods for the deoxygenation of phenols and benzyl alcohols, a particularly attractive scenario within the context of lignin degradation and functionalization.154

4.1 Ethers The deoxygenative reduction of aryl ethers has traditionally been conducted with stoichiometric bases,155 organoalkali-metal compounds,156 and heterogeneous Raney nickel under high hydrogen pressures154b,157 or within the area of electrocatalysis.158 However, these methods suffer from low functional group tolerance and may cause the over-reduction of other unsaturated functional groups, including the corresponding aromatic backbones. Overcoming these challenges has obviously been a driving force for the development of reductive cleavage protocols. Additional impetus has also been provided by the desire to control the deoxygenation of lignin, a renewable biopolymer made of aromatic units joined by ether linkages, in order to exploit it as a source of aromatic building blocks.154 The Martin group reported the first catalytic reductive cleavage of C– OMe bonds in 2010 (Scheme 77) and took the first step toward liberating chemists from the cumbersome methods described earlier.159 The catalytic system required a mixture of Ni(COD)2/PCy3 and commercially available tetramethyldisiloxane as the reducing agent. Isotope-labeling studies with DSiEt3 confirmed that the silane is the hydride source. As for other C–O cleavage reactions, π-extended systems were considerably more reactive

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Scheme 77 Ni-catalyzed hydrogenolysis of aryl methyl ethers.

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than anisole derivatives. However, regular aromatic rings with groups ortho to the methoxy group, such as pyridines, esters, oxazolines, and pyrazoles, all underwent C–O cleavage in an efficient manner. Although electronic effects might come into play, the lack of reactivity of compounds possessing such groups in either meta or para position suggests that chelation-assisted cleavage is the most plausible scenario. In addition to the inherent interest generated by the new hydrogenolysis event, this study is also important in that it demonstrated a strategy for using aryl methyl ethers as temporary directing groups by preparing three different regioisomeric products from 2-naphthol (Scheme 78). Several months later, Tobisu and Chatani independently reported a closely related hydrogenolysis protocol (Scheme 79).160 As for the protocol described by Martin,159 the C(sp2)–O bond was cleaved preferentially over a weaker benzylic C(sp3)–O bond.159 Neither Chatani nor Martin addressed the mechanism of the transformation in their first reports. Taking as an initial working hypothesis a simple catalytic cycle involving the rate-determining oxidative addition of the C–OMe bond followed by σ-bond metathesis and reductive elimination, the Martin group strove to identify the mechanism of C–OMe reductive cleavage in these systems (Scheme 80).29 They discovered subtleties underlying this methodology that have had repercussions for the development of other C– O cleavage reactions.159 First, oxidative addition of the C–OMe bond was explored. Significantly, the oxidative addition complex could not

Scheme 78 Traceless directing group strategy for arene functionalization.

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Scheme 79 Ni-catalyzed reductive cleavage of aryl methyl ethers.

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Ni(COD)2 + 2 PCy3

H

Et3Si

OMe H

Et3Si Cy3P Ni SiEt3 Cy3P

H

PCy3 PCy3 Ni SiEt3

PCy3 Ni PCy3

OMe PCy3 Ni

Et3SiOMe PCy3

SiEt3 O Me

Scheme 80 Proposed mechanism for the hydrogenolysis of aryl ethers by R3SiH.

be isolated, neither directly by reacting 2-methoxynaphthalene with Ni(COD)2/2PCy3 nor indirectly from Ni(PCy3)2Cl(2-naphthyl) via anion metathesis. Instead, in the absence of cyclooctadiene, catalytically inactive Ni(CO)(PCy3)2 and naphthalene were produced. These products were explained by rapid β-hydride elimination from the initial methoxy complex to form a Ni-hydride complex, which releases naphthalene through reductive elimination. The formation of catalytically inactive Ni(CO)(PCy3)2 in the absence of cyclooctadiene suggested that this ancillary ligand has “noninnocent” character that might stabilize the active species within the catalytic cycle113,143,150,159 and prevent β-hydride elimination. An enlightening clue to the identity of the active species was discovered when a stoichiometric reaction of Ni(COD)2, PCy3, and Et3SiH was monitored by 1H and 29Si NMR spectroscopy. Rapid consumption of Et3SiH was observed by 1H NMR but was not followed the appearance of any additional 29Si signals. This lack of 29Si NMR signals was rationalized by the formation of paramagnetic Ni(I)-silyl species, and their persistence throughout the reaction was confirmed by EPR spectroscopy. Interestingly, a characteristic multiplet was observed by 1H NMR spectroscopy at
15 ppm, suggesting the formation of diamagnetic dimeric Ni(I) species with a d9– d9 interaction and bridging hydrides. This hypothesis was supported by comparison with the 1H NMR spectrum of dimeric (dcype)Ni(μ-H)2. The authors ruled out Ni(I)-hydrides as reaction intermediates and postulated that the Ni(I)–SiR3 species was involved in the catalytic cycle,

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observations that were additionally supported by computational studies. Taking all the data into account, a mechanism was proposed involving η2-coordination of the key Ni(I)–SiR3 species to the aryl ether, followed by migratory insertion, a [1,2]-shift to form R3SiOMe and a Ni(I)-aryl intermediate (Scheme 80). This ultimately undergoes σ-bond metathesis with the silane to provide the desired reduced product and recover the propagating Ni(I)–SiR3 species. Because the rate-determining step involves arene dearomatization, the proposed mechanism also explains the increased reactivity of π-extended systems compared to regular anisole derivatives. Following the first reports by Martin and Chatani, the field of C–Oreductive cleavage underwent significant growth, starting with the nickelcatalyzed selective hydrogenolysis of aryl ethers developed by Hartwig,161 and extending to heterogeneous and transition metal free systems.162,163 In 2011, Hartwig reported the Ni-catalyzed homogeneous hydrogenolysis of Caryl–O bonds in diaryl, alkyl aryl, and benzyl ethers with dihydrogen (Scheme 81).161 Unlike previous metal-catalyzed hydrogenation methodologies,157 over-hydrogenation of the aromatic ring could be avoided. An important feature of Hartwig’s contribution was the application of the methodology to lignin model compounds, showing the prospective impact of C–O reductive cleavage for biomass degradation and functionalization. Mechanistic investigations by Agapie et al. shed light on the mechanism of the Ni-catalyzed hydrogenolysis of Caryl–OMe bonds (Scheme 82).164 Specifically, the authors developed a system containing a (diphosphinearyl)methyl ether ligand that would promote the reaction in an intramolecular fashion and allow isolation of the corresponding reaction intermediates (Scheme 81). It was shown that the hydride source is derived from the ether group via β-hydride elimination, rather than from dihydrogen. These results differ from Martin’s studies, where the silane is the reducing agent, and is in contrast with speculation by Hartwig that the hydride originates from dihydrogen.

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Scheme 81 Ni-catalyzed hydrogenolysis of aryl and benzyl ethers with hydrogen.

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Scheme 82 Mechanistic studies of the Ni-catalyzed hydrogenolysis of C(sp2)–OMe bonds.

Two independent computational studies of this mechanism were recently published in quick succession by the Chung and Surawatanawong groups.165,166 Chung scrutinized the role of the excess NaOt-Bu in the Ni/ NHC-catalyzed hydrogenolysis of aryl alkyl and diaryl ethers reported by the Hartwig group. It has been demonstrated that the presence of the base both improves the yield and reduces the reaction temperature. Chung proposed that in the case of Ph–OPh hydrogenolysis, the tert-butoxy anion coordinates to nickel prior to the rate-determining C–O oxidative addition step. Due to the extra electron density, the resulting complex is considerably more stable than the analogous base-free product (Scheme 83, Mechanism A); however, the authors also mentioned that an SNAr-like pathway could compete with base-assisted oxidative addition for certain substrates. The mechanism for the hydrogenolysis of aryl methyl ethers was found to diverge. Rather than undergoing σ-CAM with H2 or classical β-hydride elimination from the Ni–OMe complex, a five-centered direct hydrogen transfer might form a nickel formaldehyde complex and the reduced product. After evaluating Martin’s finding that the Ni(COD)2/PCy3 system involves nickel(I) species, Chung argued that the NHC pathway involves a Ni(0)/Ni(II) cycle because the bulkiness of the NHC ligand disfavors the comproportionation of Ni(SIPr)2 and [cis-(SIPr)2NiH2] to form the equivalent dimeric Ni(I) species.29 The DFT study carried out by Surawatanawong highlighted the different insights that can be gleaned from the same reaction when it is studied from a different angle.166 The study was particularly focussed on the fate of the hydrogen atoms (Scheme 83, Mechanism B). Somewhat surprisingly, the oxidative addition mechanism proposed by Surawatanawong corresponds

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Scheme 83 Theoretical calculations on the Ni-catalyzed hydrogenolysis of C–O bonds.

to the base-free pathway proposed by Chung. In contrast to the results of Chung, the calculated energy barrier for C–OMe oxidative addition to the Ot-Bu-containing complex was higher than to the base-free complex.165 In fact, although both groups studied the formation of Ni(SIPr)(Ot-Bu)
, Surawatanawong argued that the main role of the excess base is to shift the equilibrium from Ni(SIPr)2 to Ni(SIPr)(Ot-Bu)
, which allows Ni(SIPr)(η2-PhOMe) to form more easily. The discovery that the formation of Ni(SIPr)(η2-PhOMe) is energetically less favorable than Ni(SIPr)(η2PhOPh) may provide some explanation for why the mechanisms of both substrates diverge. As for Chung’s study, the transition state for β-hydride elimination could not be located. Instead, a concerted σ-CAM process was also invoked to transfer a hydride from the methoxo ligand. Liberation of benzene results in the formation of a formaldehyde complex. In the presence of H2, the formaldehyde complex undergoes hydrogen transfer via a second σ-CAM process which allows for the recovery of the catalytically active Ni species. If H2 is absent, however, theoretical calculations supported the experimental findings that the subsequent formation of a nickel carbonyl complex leads to a catalytic dead end.29 In 2015, the Chatani group published a methodology in which the need for an external reductant was replaced by reaction conditions that exploited the ability of the methoxy group to undergo β-hydride elimination.167 Although oxidative addition of the C–OMe bond has so far eluded

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Scheme 84 Ni-catalyzed reductive cleavage in the absence of external reductant.

experimental verification, Chatani and coworkers envisaged that the correct ligand choice could favor the desired oxidative addition/β-hydride elimination pathway (Scheme 84). Systematic screening of NHC ligands showed that employing a newly developed ligand with 2-adamantyl substituents, I(2-Ad), produced high yields of the reductive C(sp2)– and C(sp3)–O cleavage product. Interestingly, PCy3, which is necessary in many C–O bond cleavage methodologies, could not produce any of the reduced product without the presence of an external reductant. The Martin group also observed a similar effect in the PCy3 system, with only stoichiometric reduction possible in the absence of silane.29,159 Notably, this method tolerates pendant alkenes and ketones, substrate classes that are reduced in the presence of stoichiometric amounts of silanes or hydrogen.168 No mechanistic studies were carried out to provide direct support for the proposed catalytic cycle, but indirect evidence was obtained by changing the leaving group from ethoxy to methoxy and comparing the resulting yields. The decrease in yield supports the conclusion that β-hydride elimination occurs from an in situ generated Ni–OR complex. Although nickel catalysts are used in the majority of C–O cleavage methodologies, Wang recently reported the ability of simple and commercially available Fe catalysts to catalyze this reaction in combination with LiAlH4 or H2 (Scheme 85).169 Unfortunately, the need for strong reductants dramatically limited the chemoselectivity profile of the method. Still, however, this method could be applied to lignin model compounds under a hydrogen atmosphere. Although the mechanism is unclear, the authors proposed that Fe clusters or nanoparticles formed from the reduction of the Fe(acac)3 could be the catalytically active species. Subsequently, Wang showed that under otherwise identical conditions, Co(II) precatalysts could be utilized with similar efficiency.170 As for the iron-based process, the presence of both LiAlH4 and KOt-Bu severely limited the functional group tolerance of the reaction.

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As discussed throughout this chapter, metal complexes have been used to activate etheric C–O bonds. Pincer complexes have been of particular interest as they are often stable and well defined, facilitating studies of their reactivity and structure.171 Despite the numerous stoichiometric examples dealing with the use of pincer-type complexes in C–O bond functionalization,172 a limited number of catalytic transformations have been reported. Building on previous stoichiometric studies,171b,173 Goldman developed an iridium complex that can effectively catalyze the reductive cleavage of aryl alkyl ethers, and in doing so illustrated the potential impact of applying pincer complexes to catalytic C–O bond functionalization.174 This report built on the stoichiometric studies reported by the Goldman group. Unlike the reactions discussed in previous sections, this reaction occurs via a distinctive dehydroaryloxylation pathway whereby the alkyl group becomes the source of the hydrogen atom. The mechanism of the transformation is proposed to occur via C–H oxidative addition followed by α-migration of the OAr group, as proposed to occur for the previously reported stoichiometric reaction.175 The reaction is distinguished by low catalyst loadings and a different selectivity profile to that reported for Ni-catalyzed C–O bond-functionalization reactions (Scheme 86).

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Scheme 85 Iron-catalyzed reductive cleavage of aryl and benzyl ethers.

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Scheme 86 Ir-catalyzed reductive cleavage catalyzed by an Ir pincer complex.

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4.2 Carbamates Following the seminal report by Martin,159 Garg identified aryl carbamates as suitable C–O electrophiles to undergo catalytic hydrogenolysis. In line with Martin’s reports, the best results were accomplished with PCy3 as the ligand and tetramethyldisiloxane as the reducing agent (Scheme 87).176 In order to showcase the synthetic potential of their reaction, the authors focused on heterocycles that are relevant to the pharmaceutical industry and demonstrated the synthesis of C4-substituted indoles from the more readily available C5-indoles via cine-substitution.

4.3 Esters As part of their studies on the catalytic reductive cleavage of aryl methyl ethers, Chatani and Tobisu reported the nickel-catalyzed hydrogenolysis of aryl esters.160 In line with Martin’s initial studies,29,159 the combination of PCy3 as the ligand and a silane as the reducing agent turned out to be particularly efficient and the desired arenes were obtained in high yields (Scheme 88). The ability of the pivalate group to act as a temporary directing group was highlighted with a four-step synthesis of a terphenyl derivative. Mechanistic aspects of this transformation were briefly addressed by considering the role of the R3SiH as a Lewis acid in the

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Scheme 87 Ni-catalyzed hydrogenolysis of aryl carbamates.

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Scheme 88 Ni-catalyzed reductive cleavage of aryl pivalates.

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formation of a Ni(II)-hydride. However, the assumption that oxidative addition of the Ar–OPiv bond occurs before σ-bond metathesis between HSiR3 and the Ni(II)–OPiv species was not supported with experimental evidence.

4.4 Alcohols It is evident from the evidence presented earlier that the deoxygenation of phenol derivatives allows for the exploitation of esters, carbamates, and ethers as temporary directing groups. However, these reactions are not yet ideal from an atom economy standpoint. Ideally, these strategies should be applicable to the removal of free phenolic moieties found in biomassderived feedstocks. In 2015, Nozaki et al. demonstrated that phenols could be reductively cleaved with dihydrogen without reduction of the unsaturated aromatic rings (Scheme 89, left).177 The transformation was proposed to occur via an outer-sphere mechanism involving metal–ligand cooperation on hydroxycyclopentadienyl iridium complexes. Liu also showed that reaction of phenols with a mixture of LiAlH4/KOt-Bu at 180°C resulted in the cleavage of aromatic C(sp2)–OH bonds.178 The first inner-sphere reductive cleavage of the C(sp2)–OH bond was reported by the Nakao group and employed a nickel catalyst bearing a highly electron-rich NHC ligand (Scheme 89, middle).179 In this case, the authors invoked a mechanistic pathway consisting of the in situ formation of an aryl silyl ether that undergoes oxidative addition, deoxygenation via O–Si bond formation upon reaction with a second equivalent of silane, and reductive elimination to form the C–H bond. Concurrently, Shi disclosed the reductive cleavage of phenols with B2pin2. In this protocol, the Lewis-acidic boron atom reduces the

Scheme 89 Reductive cleavage of aromatic C(sp2)–OH bonds.

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electron density of the C–O bond and the Lewis basic phenolic oxygen atom weakens the B–B bond, thus decreasing the energy required for the C–O bond-oxidative addition (Scheme 89, right).180 Free amines and nitrogencontaining heterocycles could be tolerated, and benzyl hydroxyl groups could be reduced in good yields. However, the reaction could not be extended to simple phenol rings, and only moderate yields were obtained for biaryl systems Unfortunately, the experimental data provided did not allow the authors to establish the mechanistic rationale behind these results. Since the first demonstration of the catalytic reductive cleavage of unactivated C–O bonds,4 the far-reaching consequences of this discovery have made an immediate impact. Indeed, the rapid proliferation of methodologies employing different metals, reducing agents, and substrates is testament to the considerable importance of the reaction. In the future, issues such as the reluctance of anisole derivatives to undergo C–O cleavage, the elevated reaction temperatures and catalyst loadings, the low substrate scope of the phenol cleavage reactions, and the lack of consensus regarding the mechanism must be addressed.

5. CONCLUSIONS AND OUTLOOK The seminal work of Wenkert in 1979 undoubtedly set the basis for modern cross-coupling reactions via catalytic functionalization of C–O bonds in aryl esters, carbamates, or aryl ethers. As judged by the impressive development of these technologies in recent years, it is evident that Wenkert’s work was a giant leap forward and opened up new vistas in a relatively unexplored terrain. A common feature of these reactions is the superior ability of low valent Ni catalysts to facilitate the functionalization of challenging C–O bonds. This is a rather striking outcome considering the general lack of reactivity found with Pd species, which are privileged catalysts in cross-coupling reactions of otherwise related aryl sulfonates. Although remarkable levels of sophistication have been achieved when using aryl esters, carbamates, or ethers, these methods are unfortunately not as general as classical metal-catalyzed cross-coupling reactions of organic halides. Additionally, a number of these technologies remains essentially confined to π-extended systems, probably due to the intermediacy of Meisenheimer-type complexes or dearomatization pathways. Unlike the reactions employing organic halides or organic sulfonates, the means to promote enantioselective catalytic protocols based on the C–O bond cleavage of aryl esters, carbamates, or ethers is virtually absent in the literature and constitutes a formidable opportunity in

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years to come. Additionally, the underlying mechanisms by which many of these reactions operate remain rather speculative. In view of the available literature data, it is apparent that a “classical” regime based on oxidative addition of the C–O bond, followed by transmetalation and reductive elimination, might not be operative in some cases and that other scenarios might come into play. We certainly anticipate that unraveling the intricacies of these processes will lead to the discovery and development of conceptually new processes. Although significant efforts will need to be conducted, fortune certainly favors the brave, and we predict a bright future for the use of phenol derivatives as modern electrophiles in cross-coupling reactions.

ACKNOWLEDGMENTS We thank ICIQ, the European Research Council (ERC-277883), MINECO (CTQ201565496-R & Severo Ochoa Excellence Accreditation 2014–2018, SEV-2013-0319), and the Cellex Foundation for support. C. Zarate, M. van Gemmeren, and R. J. Somerville thank MINECO, the Alexander von Humboldt Foundation, and the “La Caixa” Severo Ochoa program for predoctoral and postdoctoral fellowships.

REFERENCES 1. (a) Miyaura N. Cross-Coupling Reactions. A Practical Guide. Berlin: Springer-Verlag; 2002. (b) de Mejeire A, Diedrich F. Metal-Catalyzed Cross-Coupling Reactions. 2nd ed. Weinheim, Germany: Wiley-VCH; 2004. (c) Tsuji J. Palladium Reagents and Catalysts: New Perspectives for the 21st Century. 2nd ed. New York, NY: Wiley-VCH; 2004. (d) Nicolaou KC, Bulger PH, Sarlah D. Palladium-catalyzed cross-coupling reactions in total synthesis. Angew Chem Int Ed Engl. 2005;44:4442. 2. Rappoport Z. The Chemistry of Phenols. Chichester, UK: John Wiley & Sons Ltd.; 2003. 3. For selected reviews on C–O electrophiles, see: (a) Yu DG, Li BJ, Shi Z-J. Exploration of new C-O electrophiles in cross-coupling reactions. Acc Chem Res. 2010;43:1486; (b) Li BJ, Yu DG, Sun CL, Shi Z-J. Activation of “inert” alkenyl/aryl C-O bond and its application in cross-coupling reactions. Chem Eur J. 2011;17:1728; (c) Rosen BM, Quasdorf KW, Wilson DA, et al. Nickel-catalyzed cross-couplings involving carbon-oxygen bonds. Chem Rev. 2011;111:1346; (d) Tobisu M, Chatani N. Catalytic transformations involving the activation of sp2 carbon–oxygen bonds. Top Organomet Chem. 2013;44:35; (e) Yamaguchi J, Muto K, Itami K. Recent progress in nickelcatalyzed biaryl coupling. Eur J Org Chem. 2013;19; (f ) Tehetena M, Garg NK. Niand Fe-catalyzed cross-coupling reactions of phenol derivatives. Org Process Res Dev. 2013;17:129; (g) Cornella J, Zarate C, Martin R. Metal-catalyzed activation of ethers via C-O bond cleavage: a new strategy for molecular diversity. Chem Soc Rev. 2014;43:8081; (h) Tobisu M, Chatani N. Cross-couplings using aryl ethers via C-O bond activation enabled by nickel catalysts. Acc Chem Res. 2015;48:1717; (i) Tobisu M, Chatani N. Nickel-catalyzed cross-coupling reactions of unreactive phenolic electrophiles via C–O bond activation. Top Curr Chem. 2016;41:374. 4. (a) Wenkert E, Michelotti EL, Swindell CS. Nickel-induced conversion of carbonoxygen into carbon-carbon bonds. One-step transformations of enol ethers into olefins and aryl ethers into biaryls. J Am Chem Soc. 1979;101:2246. (b) Wenkert E,

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emond E, Chatani N. Rhodium (I)-catalyzed borylation of nitriles through the cleavage of carbon-cyano bonds. J Am Chem Soc. 2012;134:115. (c) Kinuta H, Kita Y, R
emond E, Tobisu M, Chatani N. Novel synthetic approach to arylboronates via rhodium-catalyzed carbon–cyano bond cleavage of nitriles. Synthesis. 2012;44:2999. (d) Kinuta H, Takahashi H, Tobisu M, Mori S, Chatani N. Theoretical studies of rhodium-catalyzed borylation of nitriles through cleavage of carbon–cyano bonds. Bull Chem Soc Jpn. 2014;87:655.

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139. Kinuta H, Tobisu M, Chatani N. Rhodium-catalyzed borylation of aryl 2-pyridyl ethers through cleavage of the carbon–oxygen bond: borylative removal of the directing group. J Am Chem Soc. 2015;137:1593. 140. For selected C–H bond functionalization reactions that employ 2-pyridyloxy as ortho directing group, see: (a) Kakiuchi F, Igi K, Matsumoto M, Hayamizu T, Chatani N, Murai S. A new chelation-assistance mode for a ruthenium-catalyzed silylation at the C-H bond in aromatic ring with hydrosilanes. Chem Lett. 2002;31:396; (b) Ma W, Ackermann L. Ruthenium(II)-catalyzed C–H alkenylations of phenols with removable directing groups. Chem Eur J. 2013;19:13925; (c) Yao J, Feng R, Wu Z, Liu Z, Zhang Y. Palladium-catalyzed decarboxylative coupling of α-oxocarboxylic acids with C(sp2)–H of 2-aryloxypyridines. Adv Synth Catal. 2013;355:1517; (d) Liu B, Jiang H-Z, Shi B-F. Palladium-catalyzed oxidative olefination of phenols bearing removable directing groups under molecular oxygen. J Org Chem. 2014;79:1521. 141. Kinuta H, Hasegawa J, Tobisu M, Chatani N. Rhodium-catalyzed borylation of aryl and alkenyl pivalates through the cleavage of carbon–oxygen bonds. Chem Lett. 2015;44:366. 142. Tobisu M, Zhao J, Kinuta H, Furukawa T, Igarashi T, Chatani N. Nickel-catalyzed borylation of aryl and benzyl 2-pyridyl ethers: a method for converting a robust ortho-directing group. Adv Synth Catal. 2016;358:2417. http://dx.doi.org/10.1002/ adsc.201600336. 143. Zarate C, Manzano R, Martin R. Ipso-borylation of aryl ethers via Ni-catalyzed C–OMe cleavage. J Am Chem Soc. 2015;137:6754. 144. For selected electrophilic aromatic borylations (ortho- & para-selectivity), see: (a) Muetterties EL. Synthesis of organoboranes. J Am Chem Soc. 1960;82:4163; (b) Del Grosso A, Pritchard RG, Muryn CA, Ingleson MJ. Chelate restrained boron cations for intermolecular electrophilic arene borylation. Organometallics. 2010;29:241; (c) Niu L, Yang H, Wang R, Fu H. Metal-free ortho C–H borylation of 2-phenoxypyridines under mild conditions. Org Lett. 2012;14:2618. 145. Cao Z-C, Luo F-X, Shi W-J, Shi Z-S. Direct borylation of benzyl alcohol and its analogues in the absence of bases. Org Chem Front. 2015;2:1505. 146. (a) In: Patai S, Rappoport Z, eds. The Chemistry of Organic Silicon Compounds. New York: Wiley & Sons; 2000. (b) Bains W, Tacke R. Silicon chemistry as a novel source of chemical diversity in drug design. Curr Opin Drug Discov Devel. 2003;6:526. (c) Sun D, Ren Z, Bryce MR, Yan S. Arylsilanes and siloxanes as optoelectronic materials for organic light-emitting diodes (OLEDs). J Mater Chem C. 2015;3:9496. 147. Denmark SE, Regens CS. Palladium-catalyzed cross-coupling reactions of organosilanols and their salts. Acc Chem Res. 2008;41:1486. 148. For selected examples of metal-catalyzed silylation reactions of aryl halides, see: (a) Denmark SE, Kallemeyn JM. Palladium-catalyzed silylation of aryl bromides leading to functionalized aryldimethylsilanols. Org Lett. 2003;5:3483; (b) McNeill E, Barder TE, Buchwald SL. Palladium-catalyzed silylation of aryl chlorides with hexamethyldisilane. Org Lett. 2007;9:3785; (c) Yamanoi Y, Nishihara H. Direct and selective arylation of tertiary silanes with rhodium catalyst. J Org Chem. 2008;73:6671; (d) Minami Y, Shimizu K, Tsuruoka C, Komiyama T, Hiyama T. Synthesis of HOMSi reagents by Pd/Cu-catalyzed silylation of bromoarenes with disilanes. Chem Lett. 2013;43:201. 149. For selected silylation protocols via metal-catalyzed CdH bond functionalization, see: (a) Lu B., Falck J.R. Efficient Iridium-catalyzed C–H functionalization/silylation of heteroarenes. Angew Chem Int Ed. 2008;120:7618; (b) Oyamada J., Nishiura M., Hou H., Scandium-catalyzed silylation of aromatic C–H bonds. Angew Chem Int Ed. 2011;50:10720; (c) Cheng C., Hartwig J.F., Rhodium-catalyzed intermolecular C–H silylation of arenes with high steric regiocontrol. Science 2014;343:853;

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CHAPTER FIVE

Transition Metal Alkane-Sigma Complexes: Synthesis, Characterization, and Reactivity A.S. Weller1, F.M. Chadwick, A.I. McKay University of Oxford, Oxford, United Kingdom 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction: C–H σ-Complexes and Their Role in C–H Activation 2. Comments on Nomenclature 3. Scope of This Review 3.1 General Comments Regarding the Synthesis of σ-Alkane Complexes 3.2 In Situ Solution Synthesis and Characterization Using Photoejection of a Ligand 3.3 NMR Studies: Photogeneration Strategies 3.4 NMR Studies: Protonation of Metal Alkyls at Very Low Temperatures 3.5 Characterization of Alkane Complexes Using Preorganized Vacant Sites 3.6 Hydrogenation of Alkenes in the Solid State 4. Conclusions Notes Added in Proof Acknowledgments References

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1. INTRODUCTION: C–H σ-COMPLEXES AND THEIR ROLE IN C–H ACTIVATION The controlled, selective, functionalization of alkanes via the activation of C–H bonds is central to the development of new methodologies that enable complexity to be introduced into simple fossil and bioderived natural resources, or already-sophisticated molecules.1–8 Indeed, it is estimated that 90% of petrochemical-derived products arise from a small pool of simple hydrocarbon precursors9; and the discovery of apparently abundant sources of methane, ethane, and propane in shale and offshore gas fields provides Advances in Organometallic Chemistry, Volume 66 ISSN 0065-3055 http://dx.doi.org/10.1016/bs.adomc.2016.09.001

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increased motivation to study the conversion of simple hydrocarbons into fuels and commodity chemicals.10 Heterogeneous C–H activation catalysts are used extensively in industrial processes to produce simple olefins (e.g., ethene, propene, and styrene) from their corresponding, even simpler, saturated hydrocarbon feedstocks. Such unsaturates are key intermediates in commodity (e.g., co-monomers in olefin polymerization) and fine chemical synthesis. However, dehydrogenation processes using these catalysts require very high temperatures (up to 900°C), which although, in part, is to balance the favorable entropic (loss of H2) and unfavorable enthalpic contributions, also derives from the relative activity of the catalytic sites in such materials.11,12 As such energy-intensive conditions also encourage carbon–carbon bond breaking and isomerization processes, this means that they cannot generally be applied straightforwardly to the selective synthesis of more complex molecules; although tailored “single-site” heterogeneous catalysts can offer high activities and greater scope and selectivity.13 In contrast, catalytic methodologies using homogeneous, well defined, transition metal catalysts offer the potential to dictate selectivity and reduce energetic barriers for such processes. For example (Fig. 1), the selective dehydrogenation of alkanes to give olefins using welldefined molecular catalysts occurs at relatively low temperatures (less than 200°C and even lower if a sacrificial hydrogen acceptor is used) with the corollary that high selectivity is often achievable.14,15 An exciting recent extension to such processes is the formation of aromatics from the dehydroaromatization of linear light alkanes,16 that then offers the possibility of further functionalization through additional C–H activation such as aromatic oxidative vinylation.17 The upgrading of low-value light alkanes, that are volatile and of relatively low energy density, to higher molecular-weight hydrocarbons for use as transportation fuels also has C–H activation at its

Fig. 1 C–H activation for alkane functionalization.

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core.18–20 The functionalization of alkanes to produce, for example, linear alkylboronates21 or alkylsilanes22 that are valuable synthetic equivalents for further derivatization in fine chemical or materials synthesis is also an increasingly useful methodology. C–H activation catalysis is not limited to transition metal-based systems, and posttransition metal complexes such as Hg(II) and Tl(III) salts are well established to activate alkanes.8,23,24 Aside from C–H functionalizations that operate via outersphere or radical pathways, such as carbene25 or oxo transfer reactions,26 transition metal-mediated activations are proposed to proceed via direct coordination of the alkane C–H bond with the metal center, engaging in a three-center two-electron interaction, i.e., a σ-alkane complex.5,27–32 Such complexes are closely related to dihydrogen complexes,33–35 as well as borane and silane σ-complexes.36 Dihydrogen offers the prototypical blueprint for bonding in such σ-complexes, in which the weakly basic H–H bond also requires a supporting π-basic interaction from the metal to the σ*–H2 orbital. Thus stable dihydrogen complexes are often reported with later transition metals with d6 electron counts (or greater), and with supporting bulky ligands (such as PCy3) that shield the binding site of the small H2 ligand. The dihydrogen ligand typically bonds with metal centers with bond enthalpies of 80–100 kJ mol
1.33–35 In contrast with H2, the essentially nonpolar C–H σ-bond in alkanes has additional steric interactions from alkyl groups that disfavor approach to a metal center. A further difference between H2 and alkane complexes is demonstrated by computational studies that have shown that the dominant component to the M⋯H–C interaction is one of donation from the C–H bond to the metal, while back donation into the C–H σ* orbital is attenuated, as this orbital (in CH4, for example) is higher in energy than the corresponding one in H2.37–40 Alkanes are thus poor ligands, coordinating only weakly to metal centers, typically with bond enthalpies of less than 60 kJ mol
1.27,33,37,41 Interestingly, when the effects of sterics are reduced by studying gas-phase reactions of alkanes with naked metal cations, methane has been shown to bind more strongly than dihydrogen, although this is also modified by the increased electrophilicity of the naked cation that encourages strong σ-donation from the alkane.33 Silanes (HSiR3) and boranes (H3BNR3), that are (valence) isoelectronic with alkanes, bind more strongly with metal centers than alkanes, in part, due to the strong polarization of the (δ
)H–E(δ+) bond. The possibility of backbonding to low-lying Si–H σ* orbitals also operates for silanes,33,36 but for H3BNMe3 the corresponding orbital has been suggested to be too high in energy for productive backing bonding.42,43 There are thus

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Fig. 2 Comparison of selected Mn(η5-C5H4R)(CO)2L σ-complexes and markers for their relative stability. L ¼ propane,44 H2,45 H3BNMe3,43 HSiPh2F.46 scCO2 ¼ super critical CO2.

a number of comparisons of the relative stability of σ-complexes of H2, alkanes, silanes, and boranes33,34; and the set shown in Fig. 2 represents examples of σ-complexes observed or isolated using solution techniques, selected to highlight differences in stability when the same metal fragment is used. Thus the general trend is that in solution σ-alkane complexes are only stable, if at all, at very low temperatures; while σ-dihydrogen, silane, and borane complexes are significantly more stable and can be characterized using solution techniques and single-crystal diffraction techniques, which of course requires single crystalline material to be obtained by (often slow) recrystallization. Returning to σ-alkane complexes specifically, as well as the fundamental theoretical interest and experimental challenges associated with the generation and study of very reactive species at low temperature,47,48 such complexes are now well established as being intermediates in C–H activation processes. The coordinated C–H bond in such complexes can be cleaved by a variety of pathways: σ-bond metathesis (in which the precursor σ-complex is only very weakly bound in the preceding intermediate complex), σ-complex-assisted metathesis (in which σ-complexes are intermediates that precede and follow C–H activation), C–H oxidative cleavage (overall C–H oxidative addition when one considers the separated metal fragment and alkane), electrophilic activation, and 1,2-additions across M–X bonds (Fig. 3). The distinction between which pathway is operating in specific cases can be nuanced,49 and these processes have been discussed in detail elsewere.1,2,28,50–54 For the purposes of this perspective review, the role of σ-alkane complexes as intermediates in C–H activation is what is important. The central problem to the formation of such key intermediate complexes is the fact that alkanes are poor nucleophiles (ligands), especially

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Fig. 3 C–H bond activation pathways that evolve from σ-alkane complexes.

compared with arenes or olefins where the π-systems encourage coordination to a metal center,55,56 and indeed C–H activation is much more established as a useful synthetic technique for such substrates.55,57 Indeed, this weak ligation of the alkane can lead to situations where binding of the alkane with the metal center, rather than C–H activation, can become rate limiting.31,53,58 Pertinent to this, and as will be discussed, it is noteworthy that the majority of synthetic routes to σ-alkane complexes in solution involve in situ photochemical activation routes in neat alkane solvent. These conditions are designed to generate a highly reactive low-coordinate unsaturated metal fragment ready for ligation of the alkane, which is present in large excess. Under standard laboratory conditions used for synthesis or catalysis such photolytic routes are generally not practicable or even possible, with the corollary that alkane coordination can become uncompetitive with the binding of other ligands, for example, olefin-product inhibition in alkane dehydrogenation.14

2. COMMENTS ON NOMENCLATURE The nomenclature surrounding three-center two-electron M⋯H–E interactions, of which alkane σ-complexes form a subset, has recently been discussed by Parkin, Green, and Green,59,60 offering an extension to those suggested by Perutz and Hall in their seminal 1996 review on alkane complexes.27 In general, of course, the bonding classification of these interactions relies on knowledge of the structure, and in particular whether the M⋯H–E structural reporters suggest a significant contribution to bonding for the constituent atoms (Fig. 4).61–63 Structures derived from single-crystal

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Fig. 4 Agostic vs σ-alkane complexes.

diffraction studies are obviously very useful in this regard with regard to both M⋯E distance and M–E–H bond angle. Solution NMR data can also provide more accessible data, via a significant changes in δ(E/H) chemical shift on coordination, or reduction in E–H coupling constants as the E–H orbitals become coopted into interaction with the metal.33,36,64 Ultimately detailed computational studies using techniques such as quantum theory of atoms in molecules (QTAIM)65 and Natural Bond Order (NBO) analyses may be required to unpick the precise nature of the bonding.66–73 For example, in QTAIM descriptors of the minimum of the bond path between atoms such as the electron density (ρ, small and positive), Laplacian (r2ρ, small and positive), and total energy density (H, small and negative) all can be used to help characterize the bonding.65,74 The additional benefit of this approach is that computationally derived descriptors can be compared directly with experimentally determined ones from charge density studies.74,75 σ-Complexes are also closely related to complexes that show agostic M⋯H–C interactions. Although the term agostic, as rigorously defined,63 can be used to refer to those situations in which (saturated) hydrocarbons coordinate in an intermolecular motif with a transition metal fragment solely via C–H bonds, such compounds are commonly referred to as σ-alkane complexes.33 Agostic is more generally used to describe intramolecular M⋯H–C interactions (Fig. 4). Two examples from our own research group serve to exemplify two extremes of M⋯H–C interactions in agostic interactions (Fig. 5). In [Rh(PiPr3)3][BArF4] [ArF ¼ 3,5-(CF3)2(C6H3)], a β–C–H agostic interaction from an isopropyl methine group has close Rh⋯H–C distances of 1.91(9) and 2.494(12) A˚, respectively. The Rh⋯H–C angle is small, 114 degree, while the M–P–C angle is also distorted considerably to 73.8(4) degree, cf. 128.3(2) degree for a comparable nonagostic interaction in the same molecule.76 In geometric terms, it may thus be considered a “closed”60 η2-M⋯H–C interaction. In contrast, the valence isoelectronic

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Fig. 5 A comparison of two agostic M⋯H–C complexes.

complex [PtMe(PiPr3)2][1-H-closo-CB11Me11] has longer Pt⋯H–C distances, ˚ for its γ–agostic interaction, a wider Pt⋯H–C angle 2.24(4) and 2.859(7) A (124 degree) and an only slightly perturbed P–C–C angle [108.2(4) degree cf. 117.98(3) degree for a nonagostic], suggesting an “open”60 η1-M⋯H–C descriptor.77 These differences may, in part, be due to the difference in the trans ligand to the agostic interaction, methyl vs phosphine. In both these cases, the M⋯H–C interactions are not observed by solution NMR techniques, even at low temperature, as rapid site exchange is occurring. These descriptors follow on from the elegant early work of Crabtree in the use of Burgi–Dunitz trajectories to describe the approach of a C–H bond to a metal center.78 A further distinction comes from agostic and “anagostic” descriptions of bonding,63 the latter being M⋯H–C interactions that are best described (at the limit) as an electrostatic interaction between a C–H bond and a filled metal orbital, say a dz2 orbital in a square planar d8 metal complex. At the extreme this may be considered to be a hydrogen bonding interaction and thus might be expected to show distinct low-field chemical shift changes.71 Of course the reality of bonding is not so binary, and the distinction between purely covalent (agostic) and electrostatic (anagostic) can be blurred.72

3. SCOPE OF THIS REVIEW Although transient and difficult to observe, the coordination chemistry of σ-alkane complexes is now becoming established due to the developments in characterization techniques (e.g., in situ fast time-resolved infrared, NMR spectroscopy, and diffraction) alongside synthetic methodologies that allow for their observation. Although the number of such

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complexes still remains relatively small compared to other σ-complexes (boranes, silanes, and especially dihydrogen and agostic complexes) their growing number and diversity promises much for the future in terms of the development of their fundamental structure and bonding and their role in selective C–H bond activation and functionalization. There have been a number of major reviews, collected monographs, and special issues of journals focusing on the organometallic chemistry of the alkanes as well as their role in C–H activation chemistry.1,2,6,27,33,47,52,79–81 In this review, the synthesis and characterization of σ-alkane complexes are presented, and the onward reactivity of relatively well-defined examples discussed, with the emphasis on recent results some of these previous reviews may not have captured. The elegant, albeit, indirect evidence for the intermediacy of such complexes in C–H activation processes which arises from thorough kinetic, isotope-labeling, and computational studies has been reviewed elsewhere and are generally not discussed in detail here.1,2,32,51,80,82–85

3.1 General Comments Regarding the Synthesis of σ-Alkane Complexes Given the weak binding of alkanes with metal centers, and the concomitant transient nature of the resulting complexes, a number of synthetic routes have been developed for their synthesis and characterization. Fig. 6 outlines these approaches. Addition of an exogenous alkane ligand, generally the solvent of reaction or as a gas, to a low coordinate electronically unsaturated metal–ligand fragment can generate the desired complex. Such a lowcoordinate complex can be generated via photoejection of a ligand (often, although not exclusively, CO) which when performed in situ in alkane solvent, or bath gas, forms the corresponding alkane complex, which can then be analyzed by infrared or NMR spectroscopy (Fig. 6A).47,48 Although these examples are most common, the weak binding of the alkane ligand in the resulting metal σ-complex combined with the facile recombination of the ejected ligand reduces the lifetime of the alkane complex so that low temperatures (200 K or below), very fast analysis timescales (up to milliseconds at room temperature) and/or continuous irradiation need to be deployed to observe the corresponding alkane complexes. Direct reaction of an alkane ligand with a preorganized vacant site on a metal (Fig. 6B) can be promoted by sterically bulky ligands that protect the metal center that also may provide additional stabilization toward alkane binding via hydrophobic pockets.86 Irreversible loss of a ligand in metal-organic framework

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Fig. 6 General approaches to the generation of σ-alkane complexes. Top: Addition of exogenous alkane ligand to a coordinately unsaturated complex. Bottom: Generation of the alkane ligand directly on the metal center by direct modification of a precursor complex.

(MOF) materials that retains structural integrity can also generate such a vacant site.87 Interestingly, these metal sites are rather open and additional intermolecular alkane/alkane interactions are shown to significantly enhance binding at the metal.88 Protonation of an alkyl group can form the alkane complex directly when performed at very low temperature in CDFCl2 solvent (163 K or lower, Fig. 6C), but warming results in displacement of the alkane to form a solvento complex.89 Finally, generation of the alkane complex can be achieved directly, and irreversibly, in the solid state by solid/gas reactivity90–93 between a stable alkene precursor complex and H2 (Fig. 6D). Although this harnesses the stabilizing benefits of the solidstate environment, dissolution in solvent removes this and rapid alkane dissociation occurs. Thus no one methodology currently offers a complete solution for the generation, characterization (solution NMR and solid-state techniques), and onward reactivity of alkane complexes.

3.2 In Situ Solution Synthesis and Characterization Using Photoejection of a Ligand The possibility that alkanes may act as ligands in organometallic chemistry, however weak, was initially firmly established by evidence arising from in

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situ spectroscopic techniques such as infrared and UV–visible spectroscopy. This area has been thoroughly reviewed27,48,79 and so only the key points are highlighted here, as pertinent to the stability and reactivity of σ-alkane complexes. Initially matrix isolation experiments, for example photolysis of Cr(CO)6 in mixed matrices (Ar/CH4 at 20 K),94 showed that the matrix used had an effect on the resulting absorption maxima observed in both infrared and UV–visible spectra, suggesting alkane coordination with the metal center. Solution photolysis studies on metal carbonyls necessarily required higher temperatures than the matrix studies, although these are generally still well below room temperature if the lifetime of the alkane complex is to be extended; and the concomitant development of fast timeresolved infrared spectroscopy (TRIR) techniques as the carbonyl ligands provide an excellent, albeit indirect, spectroscopic reporter that are diagnostic for alkane coordination. An early example of this was the use of TRIR combined with 13C-isotopic labeling to determine the overall structure of Cr(CO)5(cyclohexane), although the specific details of how the alkane interacts with the metal center could not be resolved.95 As common to many of these photolysis reactions the alkane complex decays rapidly, with a halflife of less than 20 μs, often to regenerate the starting carbonyl (Fig. 7). The photogenerated precursor {Cr(CO)5} complex has an even shorter lifetime of 15 ps.96 As well as providing very strong evidence for the generation of σ-alkane complexes, these and related experiments allow for both the strength of alkane binding and the activation parameters for alkane substitution to be determined. For example, photoacoustic calorimetric studies on in situ generated M(CO)5(alkane) complexes (M ¼ Cr, Mo, W; alkane ¼ pentane, heptane, cyclohexane) have been used to quantify the metal–alkane bond enthalpy. W(CO)5(heptane), as an example, was found to have a bond

Fig. 7 General scheme for photogeneration of alkane complexes in situ. Supporting ligands are commonly CO or cyclopentadienyl-type ligands.

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strength for the metal–alkane interaction of 56(12) kJ mol
1.97 Gas-phase TRIR studies also shed light on the relative binding strengths of alkane ligands. For example, measuring the position of equilibrium between {W(CO)5} and W(CO)5(alkane) with regard to partial pressure of alkane leads to an observed trend that longer chain alkanes bind more strongly than shorter chain ones in the gas phase, while cyclic alkanes bind more strongly than linear ones, although the errors reported are large.98 Fig. 8 shows this for a selected set of data. Comparison of these data with C–H orbital energies suggests that within the individual groups of cyclic and acyclic alkanes, respectively, higher energy orbitals lead to stronger binding, although comparisons between different groups is not so good, suggesting that other factors such as sterics may also be important. Similar trends have been reported for the relative stability of Rh(η5-C5Me5)(CO)(alkane) complexes compared with Rh(η5-C5Me5)(CO)Kr as measured by TRIR in noble gas solvents (i.e., Kr), which sit in preequilibrium with the corresponding C–H activated product.99 In this case, the alkane polarizabilities showed a generally positive correlation with relative stabilities for this simple equilibrium. Interestingly cyclic alkane complexes were more stable than this simple analysis would predict (Fig. 8), and noncovalent interactions and entropic factors (solvation) were mooted as being important. Despite these, and other, detailed and elegant studies, a satisfying overarching rationale for

Fig. 8 Equilibrium measurements and binding enthalpies for W(CO)5(alkane) and Rh(η5C5Me5)(CO)(alkane) complexes, as determined by gas phase (W) and liquefied noble gas (Rh) TRIR experiments.

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these observations was not determined, in part, due to the errors inherent in the experiment and complication of accounting for effects due to krypton solvent. Nevertheless, as will be discussed, they are fully consistent with stability studies in many other systems. Later work on the relative stability of σ-complexes with regard to their intermolecular C–H activation products has revealed a considerably more nuanced situation. For larger and cyclic alkanes steric factors and chain–migration events become increasingly important in determining the relative lifetimes of the σ-complexes, as shown by a combined TRIR/computational study on the generation and reactivity of Rh(η5-C5Me5)(CO)(alkane) and Rh(η5-C5H5)(CO)(alkane) complexes.83 In essence larger ring sizes, although destabilizing the σ-complexes through steric interactions, especially with bulky (η-C5Me5)–ancillary ligands, also result in higher barriers to C–H activation and thus longer lifetimes for the σ-complex; e.g., Rh(η5-C5H5)(CO)(cyclopentane) τ(298 K) ¼ 5.9(0.2) ns, Rh(η5-C5Me5)(CO)(cyclooctane) τ(298 K) ¼ 74.3(4.0) ns. Migrations between different Rh⋯H–C bonds on the alkane were also shown to be particularly important with larger cyclic alkanes.100 Kinetic studies using UV–visible laser flash photolysis have shown that for reaction of photogenerated M(arene)(CO)2(alkane) or M(CO)5(alkane) [M ¼ group 6 metal] with carbon monoxide the entropy of activation for alkane substitution is strongly negative, and that variations in rates of substitution result from a difference in the ΔS{ term between alkanes. Thus, for the same metal fragment but with different alkanes (e.g., pentane to decane), although ΔH{ values are rather leveled, ΔS{ can be more negative especially

Fig. 9 Activation parameters determined for the reaction of various alkane complexes with CO. As measured by UV/Vis flash photolysis.

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for shorter chain and cyclic alkanes (Fig. 9).101–103 The proposal is that the longer chain alkanes have greater freedom of motion when displaced than do cyclic alkanes, and this is the origin for the greater relative stability of the cyclic alkane complexes. These overall negative entropies of activation, coupled with the very short (picoseconds) lifetimes of species such as {M(CO)5}, suggests that displacement of an alkane by an incoming ligand is unlikely to follow a dissociative mechanism. More likely is that an associative– interchange mechanism operates. Measured volumes of activation support that an interchange mechanism is accessible,104 as does the more negative entropy of activation of heavier members of a triad [i.e., W(CO)5 vs Cr(CO)5] which can be explained by a more associative character in the transition state.101 Similar mechanisms have been tentatively suggested for the reaction of Re(η5-C5H5)(CO)2(alkane) with CO.105,106 However, as ΔS{ values are notoriously difficult to obtain accurately, especially from TRIR experiments due to the errors associated with extrapolating data, caution needs to be exercised in use of their absolute values. Given that entropy (which will have significant solvent and temperature dependence) and sterics are shown to play such an important role in the lifetimes of σ-alkane complexes it is not surprising that there may be a number of competing factors operating which will be both system and temperature specific. For example concentrations of the exogenous ligand will have a pronounced effect on relative rates and lifetimes, not only for associative-type processes, but also in dissociative processes due to increased competition with the fast back reaction of the {M(CO)5} fragment, for example, with CO. This is especially true when comparing lifetimes from different experimental techniques such as TRIR vs in situ NMR spectroscopy where experimental concentrations can be very different.44 As discussed the choice of metal center, as well as the alkane, has a significant effect on the reactivity of the transition metal alkane complexes, which has repeatedly been shown to decrease on going across a group and especially down a triad; i.e., they become more stable.101,105–107 For example Mn(η5-C5H5)(CO)2(propane) reacts with CO 430 times faster than Re(η5-C5H5)(CO)2(propane).44 That is to say the Re–alkane complex is considerably more stable. Presumably this reflects better energy match of the M⋯H–C bond with increasing Z(effective) across a group, or increased orbital overlap and entropic considerations associated with the 5d metal. However, perhaps not

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unexpectedly given the increased accessibility of higher oxidation states down a group, C–H activation (oxidative cleavage) now becomes more likely. For example, using TRIR, Re(η5-C5H5)(CO)2(CH4) is found to be in fast reversible equilibrium with the C–H activation product Re(η5C5H5)(CO)2(H)(CH3), whereas Mn(η5-C5H5)(CO)2(CH4) is not.108 This mirrors, for example, silane coordination chemistry in which Mn (η5-C5H5)(CO)2(η2-HSiFEt2) is a σ-complex, whereas Re(η5-C5H5) (CO)2(H)(SiEt3) sits as the product of oxidative cleavage.109 The steric bulk of the ancillary ligands also make a difference: with bulkier ligands (e.g., η-C5Me5 vs η-C5H5, or η-C6Me6 vs η-C6H6) leading to shorter lived complexes.102,110 Lower temperatures also increase the lifetimes of σ-alkane complexes. For example Mn(η5-C5H5)(CO)2(ethane) has a lifetime of 2.0 μs at 298 K but it is considerably longer at 135 K, 126(6) s, as measured by TRIR.111 Direct evidence for the intermediacy of alkane complexes in C–H activation (i.e., oxidative cleavage to give the corresponding alkyl hydride) has been obtained using TRIR. For example, as mentioned, photolysis of Rh(η5-C5Me5)(CO)2 in liquid Kr generates the highly reactive Rh(η5C5Me5)(CO)Kr, which when generated in the presence of an alkane (d12–neopentane, for example) results in the formation of a transient complex assigned to the σ-alkane complex Rh(η5-C5Me5)(CO)(C(CD3)4).112 This evolves to give a product characterized as Rh(η5-C5Me5)(CO)(D) ((D2C)C(CD3)3). These and other33,48,83,99,100,113–117 TRIR studies show σ-alkane complexes are observable intermediates, if only very short lived (nanoseconds timescale), in C–H activation (Fig. 10). Overall, studies into the generation and onward reactivity of σ-alkane complexes using TRIR and associated techniques broadly indicate that relatively stable alkane complexes with respect to substitution of the weakly bound alkane ligand will be formed from heavier transition metals with a small ancillary ligand set (i.e., η5-C5H5 rather than η5-C5Me5), cyclic alkanes and at low temperature. Thus Re(η5-C5H5)(CO)2(n-heptane) has been shown to have an exceptionally long lifetime at room temperature (t1/2  25 ms),118 while Re(η5-C5H5)(CO)2(c-pentane) (t1/2  125 ms) is even more stable.106 As in the solution phase alkane loss via substitution by solvent or other Lewis base (e.g., photoejected CO) is likely to be the major decomposition pathway then these stability markers are important in the design of systems that offer increased lifetimes. As the next section shows, it is these design principles that carry over into systems stable enough that they can be observed by the relatively slow technique of NMR spectroscopy.

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Fig. 10 The time-dependent absorbances observed when Rh(η5-C5Me5)(CO)2 is photolyzed in Kr(liq.) at 165 K in the presence of d12-neopentane. 1946 cm
1 ¼ Rh(η5-C5Me5) (CO)Kr; 1947 cm
1 ¼ Rh(η5-C5Me5)(CO)(C(CD3)4); and 2008 cm
1 ¼ Rh(η5-C5Me5)(CO) (D)((D2C)C(CD3)3). Adapted with permission from Bengali AA, Schultz RH, Moore CB, Bergman RG. Activation of the C–H bonds in neopentane and neopentane-d12 by (η5-C5(CH3)5)Rh(CO)2: spectroscopic and temporal resolution of rhodium–krypton and rhodium–alkane complex intermediates. J Am Chem Soc 1994;116:9585–9589. Copyright 1994 American Chemical Society.

3.3 NMR Studies: Photogeneration Strategies While TRIR spectroscopy has extensively used to demonstrate the existence of alkane complexes in solution and provides lifetimes and reaction kinetic data, the structural detail concerning bonding of the alkane with the metal center is indirect and limited. In particular, the mode of interaction between the alkane and metal center cannot be easily resolved by IR spectroscopy (e.g., η1, η2, etc.) nor the isomers that are favored (e.g., M⋯H3C– or M⋯H2C–) nor the thermodynamic and kinetic relationships between these (i.e., movement of the metal between different C–H groups: chain walking1,32). Thus, although TRIR spectroscopy is sensitive and works on very fast timescales (e.g., milliseconds), the slower (1 s) NMR spectroscopy is the go-to technique to determine molecular structure and dynamics due to the exquisite detail it gives by considering the combination of symmetry, chemical shift, coupling constants, and variation of temperature. As shown, alkane complexes, when prepared in solution, have short lifetimes even at low temperatures. This means that low temperature in situ methods for their generation and analysis by NMR spectroscopy are necessary. Although this has a disadvantage that a more sophisticated experimental set up is required to

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photochemically generate the active species directly in the spectrometer probe, such experiments have been made routine by a number of groups.47,119 This has allowed for low temperature, in situ, NMR spectroscopy to provide a remarkably detailed analysis of σ-alkane complexes. The observation by TRIR that Re(η5-C5H5)(CO)2(n-heptane) is relatively stable at room temperature inspired a study using in situ NMR photolysis techniques at 180 K. Photolysis of Re(η5-C5H5)(CO)3 in neat cyclopentane, rather than n-heptane (freezing points n-heptane ¼ 182 K; cyclopentane ¼ 179 K), resulted in the formation of Re(η5-C5H5) (CO)2(c-pentane), which after about 30 min of irradiation reached a maximum concentration (Fig. 11), although the starting material is still dominant (greater than 80%).120 Back reaction with liberated CO or decomposition to form insoluble (η5-C5H5)2Re2(CO)5 are competitive with alkane binding. Nevertheless 1H NMR spectroscopy, especially the high-field hydride region, unambiguously signals the formation of a σ-alkane complex. A relative integral 2H signal (relative to a new Cp-resonance) is observed at δ
2.32, assigned to the Re⋯H2C motif, which can be resolved as a binomial quintet [J(HH) ¼ 6.6 Hz]. This indicates that both protons associated with the CH2 unit are interacting with the metal center on the NMR timescale, and a rapid equilibrium between bridging and terminal C–H groups was proposed in which mutual exchange between two alternative η2-Re⋯H–C structures occurs. A J(CH) value of 112.9 Hz was measured, which is significantly reduced from free alkane [129 Hz], consistent with weakening of the C–H bond. Assuming rapid exchange

Fig. 11 (A) Formation of Re(η5-C5H5)(CO)2(η2-C5H10) by in situ photolysis and (B) rapid exchange between geminal protons via an bifurcated intermediate.

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between bridging and terminal positions for the geminal protons associated with Re⋯H2C interaction, J(CH)  96 Hz for a σ-coordinated C–H bond is estimated. A significant 13C upfield shift of the contact carbon, δ
31.2, further reports on coordination of the alkane. The ground state structure is likely Re(η5-C5H5)(CO)2(η2-C5H10), and this has been confirmed by calculation.37 Irradiation in neat d10–cyclopentane results in the disappearance of the high-field proton signal in the 1H NMR spectrum, consistent with solvent coordination (cyclopentane) at the metal center. In situ photolysis of Re(η5-iPrC5H4)(CO)3 in neat pentane at 163 K leads to the formation of three isomers associated with metal binding at the C1, C2, and C3 positions in Re(η5-iPrC5H4)(CO)2(pentane), as signaled by three different high-field environments being observed in the 1 H NMR spectrum (Fig. 12).121 There is a slight preference for binding at the CH2 sites over the CH3, and slow site exchange between these positions was determined using ROESY NMR spectroscopy. Other NMR data are similar to the cyclopentane analog, signaling a similar binding mode of both alkanes. The same experiment but using 2,2,4,4-d4-pentane resulted in the disappearance of one of the high-field signals in the 1H NMR spectrum, i.e., that associated with the C2/C4 position. By using various d- and 13 C-labeled isotopomers of pentane a significant isotopic perturbation of equilibrium (IPE, also known as equilibrium isotope effect)143 was observed. Importantly, these large IPE shifts indicate that the interaction between the metal and the CH2 or CH3 groups alkane is η2 and not the bifurcated η1,η1 that the time-averaged NMR spectra might suggest, by that M⋯H–C is favored over M⋯D–C binding when the two possible modes are at equilibrium with one another. A similar conclusion is come to when cis-1,2-d2-cyclopentane is used as the solvent. It was also noted that the observed chemical shift of the bound C–H protons was directly related to the fraction of time each methylene or methyl group in pentane spends bound with the metal, while the value of J(CH) also decreases similarly, e.g., 13CH3, 13CH2D, and 13CHD2: 116.5, 113.2, and 108.2 Hz, respectively.

Fig. 12 The three isomers associated with pentane binding in Re(η5-iPrC5H4)(CO)2 (pentane).

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Building on these studies toward understanding the intimacies of the binding mode of the alkane ligand, a detailed investigation of the binding of cyclohexane with {Re(η5-C5H5)(CO)2} at 173 K was reported, i.e., Re(η5-C5H5)(CO)2(c-C6H12).122 As this alkane exists in the chair form at these low temperatures, and exchange between different chair forms is slow, the axial and equatorial C–H groups are distinct and thus offer the opportunity for preferential binding. In order to achieve these low temperatures with the high melting cyclohexane (melting point ¼ 280 K) a 60:40 mixture with, for example, d12-pentane was used. In the resulting 1H NMR spectrum two resonances are observed in the high-field region, at δ
6.17 and 0.49. The former shows a reduced J(CH) coupling constant compared to the latter [96.5 vs 125.0 Hz], with the larger value being close to that observed in free cyclohexane. Based on H,H coupling patterns and use of selectivity deuterated cyclohexane, the higher field resonance that signals a σ-interaction was assigned to the bound axial C–H group. Even though axial binding is favored (K  2.9), there is a fast equilibrium between axial and equatorial isomers (Fig. 13) that was confirmed by variable temperature NMR experiments. For example cooling resulted in a separation of the two resonances from 6.65 ppm (173 K) to 6.91 ppm (145 K). The barrier to exchange between these two sites was estimated using DFT and ab initio calculations to be 14.6 kJ mol
1. 1,2- and 1,3-shifts around the ring were calculated as being higher energy (21 and 29 kJ mol
1, respectively), the higher barrier consistent that these chain-walking82,123,124 events are not observed experimentally at low temperatures. The axial binding preference was suggested to be due to weaker axial C–H bonds in cyclohexane being better donors than their equatorial partners. Hyperconjugative effects of proximal C–H vs C–C bonds were suggested to be important in determining this (highlighted in Fig. 13). By changing an ancillary ligand from CO to PF3 in the precursor, a significant change occurs in the binding and activation of the resulting alkane

Fig. 13 Axial and equatorial isomers in Re(η5-C5H5)(CO)2(cyclohexane). Chemical shifts in brackets are estimated values based on empirical data for each proton that would be observed if no exchange were occurring.

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complex, as measured by a combined NMR (185 K) and TRIR (292 K) spectroscopic study using Re(η5-C5H5)(CO)(PF3)(alkane).117 In particular, the alkane ligand (pentane, cyclopentane, and cyclohexane) undergoes rapid and reversible C–H oxidative cleavage at the metal center so that the σ-alkane complexes are in equilibrium with their alkyl hydride partners. Lower temperatures, and use of pentane and cyclopentane rather than cyclohexane, lead to data that suggest an increase in the relative proportion of the alkyl hydride products. For these rapidly equilibrating mixtures NMR spectroscopy only reveals a time-averaged picture of these processes, signaled by J(CH) values (e.g., 75 Hz for cyclopentane) that sit in between those expected for the σ-complex (e.g., 113 Hz) or the alkyl hydride (e.g., 70 Hz). As TRIR is a significantly faster spectroscopic technique than NMR, monitoring the CO-stretching region allows for the observation of bands assigned to both σ- and oxidative cleavage products. Extending this powerful, combined, NMR and TRIR spectroscopic methodology, a systematic approach to identifying relatively long-lived σ-complexes under comparable conditions of concentration, laser irradiation, and temperature has been reported.125 Re(Tp)(CO)2(cyclopentane) [Tp ¼ trispyrazol-1-yl borate] was identified by TRIR as having a lifetime of 19(1) min at 200 K, which is broadly similar to the Cp-analog under similar conditions.106,126 Analysis using in situ photolysis and NMR spectroscopy at 190 K confirmed this assignment and also that the alkane binds η2- with the metal center (Fig. 14). Use of c-C5H9D resulted in the observation of a significant IPE, demonstrating rapid exchange between bound and unbound geminal protons in the cyclopentane ligand. The lifetime of the σ-alkane complex when generated in situ in the NMR experiment was measured as being significantly longer than the TRIR experiment (2 h at 190 K). As pointed out, the stability of σ-complexes is likely strongly influenced by impurities in the system which could well differ between the two techniques. Nevertheless, both techniques are qualitatively aligned in identifying long-lived alkane complexes. This combined approach was also used to study the use of Re(η-C5H31,2-tBu2)(CO)2(N2) as a precursor for generating alkane complexes.127 Photoinduced N2 loss is efficient, and in cyclopentane at 190 K generates the corresponding alkane complex, which was identified as Re(η-C5H31,2-tBu2)(CO)2(η2-C5H10) as determined by chemical shift, J(CH) coupling constants, and IPE measurements (the latter using c-C5H9D). TRIR measurements allow for an agostic complex arising from intramolecular coordination of the tBu groups to be discounted, as the lifetime of the

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Fig. 14 Bottom: High-field region of 1H NMR spectrum obtained following 266 nm laser irradiation of Re(Tp)(CO)2(cyclopentane) in cyclopentane at 190 K with expansion shown in inset. Top: Spectrum after irradiation in d1-cyclopentane (C5H9D) showing the high-field IPE shift. Adapted with permission from Duckett SB, George MW, Jina OS, et al. A systematic approach to the generation of long-lived metal alkane complexes: combined IR and NMR study of (Tp)Re(CO)2(cyclopentane). Chem Commun 2009:1401–1403. Copyright 2009 Royal Society of Chemistry.

Fig. 15 Three different isomers observed in Re(η5-C5H5)(CO)2(η2-dimethylbutane).

photogenerated alkane product with respect to reaction with CO varied depending whether n-heptane or cyclopentane was used—signaling alkane coordination. As expected the cyclic alkane complex was more stable. These t Bu-substituted are less stable than simple Cp-analogs, presumably due to steric factors. The same paper also reported the generation of Re(η5C5H5)(CO)2(η2-2,2-dimethylbutane). Three different isomers were observed (Fig. 15), although binding of the tBu group in the alkane is dominant. As shown, the {Re(L)(CO)2} motif has proven to be a particularly useful one for the generation, stabilization, and characterization at low temperature

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of σ-alkane complexes. The analogous manganese complexes, generated from in situ photolysis of Mn(η5-C5H5)(CO)3, can also be generated in a similar manner.44 However, due to the much higher susceptibility of the 3d metals toward loss of alkane (see Section 3.1) extremely low temperatures are necessary for their observation by “slow” techniques such as NMR spectroscopy. Liquid propane and butane have correspondingly low melting points (85 and 134 K) and also exists as liquids at room temperature under the modest pressures. In situ photolysis of Mn(η5-C5H5)(CO)3 in liquid propane at 135 K, for example, and study by NMR spectroscopy leads to the observation of two isomers of the bound σ-alkane complex: Mn(η5-C5H5) (CO)2(η2-C3H8), in which the methyl or methylene groups interact with the metal center.44 D-labeling experiments using DH2CCH2CH3 or H3CCD2CH3 demonstrated η2-coordination (through the expected IPE) and the identity of the isomer chemical shifts (Fig. 16). Similar results were obtained for Mn(η5-C5H5)(CO)2(η2-C4H10). Comparison of the decay of these alkane complexes with their Re-analogs demonstrated longer lifetimes for the 5d metal complexes, as expected: M(η5-C5H5)(CO)2(η2-C4H10), Mn ¼ 5.5 min (136 K), and Re ¼ 13 min (171 K). Although this lifetime is short for the Mn variants, it is enough for spectroscopic measurement at 135 K. These NMR observations are supported by TRIR studies on the generation and lifetimes of these complexes. In a similar manner, Mn(η5-C5H5)(CO)2(η2-C2H6) and Mn(η5-C5H5)(CO)2(η2-isopentane) can also be prepared. NMR spectroscopy at 133 K (in a solvent mixture with liquid propane) reveals three isomers are formed, binding through the C1– H, C4–H, and C3–H positions. Steric hindrance is suggested to disfavor the formation of the C2–H isomer (Fig. 17).111 Recent work has extended the metal–ligand fragment away from {Re (η5-C5H5)}-type systems. The {Re(Tp)(CO)2} system discussed earlier showed that alkane complexes could be supported by ancillary nitrogenbased ligands. Oxygen-based supporting ligands can also be used, as demonstrated by use of Kl€aui’s ligand [Co(η5-C5H5){P(OEt)2}3]
(LOEt) to generate the precursor Re(LOEt)(CO)3. In situ photolysis in a range alkane solvents (cyclopentane, cyclohexane, and pentane) at low temperatures formed the corresponding σ-alkane complexes, Fig. 18.128 Following the reaction with cyclopentane by flash photolysis allowed for complex formation and decay, to mainly give the starting tricarbonyl, to be followed [t1/2 ¼ 470 s at 200 K], from which activation parameters could be derived. In particular ΔS{ is large and negative [
156(29) J K
1 mol
1], suggesting

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Fig. 16 High-field region of 1H NMR spectrum obtained at 133 K after laser irradiation of Mn(η5-C5H5)(CO)3 in (A) propane (with resolution enhancement shown in inset); (B) 1-d1propane; (C) 2,2-d2-propane; and (D) 13C1-propane. Adapted with permission from Calladine JA, Duckett SB, George MW, et al. Manganese alkane complexes: an IR and NMR spectroscopic investigation. J Am Chem Soc 2011;133:2303–2310. Copyright 2011 American Chemical Society.

an associative mechanism for the decay process, being larger than that measured for Re(η-C5H5)(CO)2(cyclopentane) [
78(10) J K
1 mol
1].106 Low temperature in situ NMR spectroscopy confirmed that Re(LOEt) (CO)2(C5H10) was formed on photolysis in cyclopentane, but only in 4.5% photochemical yield. Cyclohexane (as axial and equatorial isomers) and pentane (three isomers) also act as ligands when photolysis is performed in the appropriate solvent. However due to the broad signals observed in the NMR spectrum, and poor signal to noise, the precise details of

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Fig. 17 Possible isomers for isopentane binding in Mn(η5-C5H5)(CO)2(η2-isopentane). The η2-C2–H isomer is not observed.

Fig. 18 Using Kl€aui’s ligand [Co(η5-C5H5){P(OEt)2}3]
in the synthesis of alkane σ-complexes.

preferences for different binding modes was not determined as accurately as for the related Cp systems. DFT calculations, however, confirm the expected η2 Re⋯H–C binding motifs. Although CO-stretching bands suggest that the LOEt ligand is a better donor that Cp or Tp there is no evidence for a significantly different degree of C–H bond activation in this system compared to others. Exploring chemical space with not only a different ligand set, but also a different 5d metal, W(η6-hexaethylbenzene)(CO)3—which is isoelectronic

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with Re(η5-C5H5)(CO)3—forms a σ-alkane complex when photolyzed in pentane at 163 K.129 This provides the first NMR data for a group 6 alkane complex. In contrast to all the Re-systems described earlier, the pentane only binds with the metal center through the terminal methyl group, and not with the C2/C3 methylene positions to any significant extent. This is signaled by a single high-field resonance observed for the bound alkane methyl group, that is a triplet [J(HH) ¼ 6.5 Hz]. Use of 13C-labeled pentane allowed for a value of J(CH) ¼ 118.5 Hz to be determined, consistent with an intact alkane ligand. The analogous 2,2-dimethylbutane complex shows M⋯H–C interactions only through the terminal positions of the alkane, and for the one of the isomers a small but significant J(WH) was measured [less than 20 Hz]—confirming the interaction of the alkane with the 183W metal center. Returning to W(η6-hexaethylbenzene)(CO)2(η2-pentane) ROESY experiments indicate that the terminal methyl groups are undergoing intramolecular exchange between bound and free groups. Presumably this occurs via rapid chain walking of the metal fragment along the alkane methylene groups, via unobserved W⋯H2CR2 complexes. In separate experiments, consistent with CH2 binding being possible, W(η6hexaethylbenzene)(CO)2(η2-cycloheptane) can be observed to be formed. Calculations shed light as to the preference for terminal alkane binding. Binding of C2 and C3 methylene groups forces the pentane to adopt a trans, gauche conformation that lies 2.6 kJ mol
1 above the C1-binding mode, in which the pentane binds in an all-trans conformation (Fig. 19). The bulky hexaethylbenzene causes this difference, whereas for Cp system, where the steric bulk is considerably less, pentane can adopt an all-trans conformation for every binding position. In principle, with all else being equal, cationic metal fragments should bind alkanes more strongly than neutral ones, due to that the major binding interaction is one of charge transfer from the low-lying C–H σ-bond to the

Fig. 19 Favored (CH3-bound) and disfavored (CH2-bound) isomers associated with pentane binding in W(η6-hexaethylbenzene)(CO)2(η2-pentane).

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metal center. Calculations have indicated this to be the case, for example the binding of methane is significantly stronger with the, hypothetical, {Re(η5C5H5)(CO)(NO)}+ fragment compared with neutral {ReCp(CO)2}, while for anionic {Re(η5-C5H5)(CO)(CN)}
it is considerably weaker.130 A similar analysis favorably compares [W(η6-C6H6)(CO)(NO)(pentane)]+ with W(η6-C6H6)(CO)2(pentane).39 Calculations on pincer systems [Pd (PONOP)(CH4)]2+ vs [Rh(PONOP)(CH4)]+ (PONOP ¼ 2,6(tBu2PO)2C5H3N) also show stronger binding in the former, but this could not be experimentally realized (see Section 3.4).131 A logical target, then, is the synthesis of cationic σ-alkane complexes. Given the precedent in neutral systems for photogeneration of σ-alkane complexes in neat alkane solvent, a significant hurdle in the synthesis of cationic alkane complexes comes from the lack of solubility of cationic systems in saturated hydrocarbons. In addition, a counterion that does not coordinate is required. Both solvent (in a large excess) and counterion can thus be competitive with alkane binding. As shown in Sections 3.4 and 3.6, for [Rh(PONOP)(η2-H4C)][BArF4]89 in solution, and [Rh(iBu2PCH2CH2PiBu2)(η2:η2-C7H12)][BArF4]132 in the solid state, solvent (CDFCl2), and anion coordination, respectively, reduce the lifetimes of the corresponding σ-alkane complexes. Hitting this sweet spot, a cationic system with solubilizing ancillary groups combined with a very weakly coordinating perfluorinated anion,133 [Re(η5hexaethylbenzene)(CO)3][Al(OC(CF3)3)4], in a hydrofluorocarbon solvent (HFC, CF3CH2CF3, dipole moment 1.98 D) identified as not binding competitively with the alkane, is shown to form an alkane complex. Photolysis in the presence of cyclopentane at 193 K results in the formation of the σ-alkane complex (Fig. 20), [Re(η6-hexaethylbenzene)(CO)2(η2-C5H10)][Al(OC (CF3)3)4], as signaled by a low-field signal being observed in the 1H NMR spectrum, δ
3.74 [quintet, J(HH) ¼ 6.7 Hz].134 A slightly reduced value of J(CH) 112.7 Hz was measured, compared to free cyclopentane. Although moderately stable at 193 K, warming to 236 K resulted in immediate

Fig. 20 Synthesis of [Re(η5-hexaethylbenzene)(CO)2(η2-C5H10)][Al(OC(CF3)3)4].

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decomposition. As common for all alkane complexes observed in solution, rapid exchange between geminal C–H groups was noted. The barrier to ring walking (i.e., 1,2- and 1,3-shifts) was considerably larger, and could only be detected at higher temperatures (213 K, activation barrier 50 kJ mol
1). Detailed studies suggest that the 1,2-shifts are slightly faster than 1,3-shifts. These chain-walking barriers are noted to be higher than observed in other systems, consistent with a stronger binding of the alkane ligand in this cationic system that also is sterically not particularly demanding.121,129,135 This increased stability is highlighted when a mixture of neutral Re(η5C5H5)(CO)2(η2-C5H10) and cationic [Re(η6-hexaethylbenzene)(CO)2(η2C5H10)][Al(OC(CF3)3)4] was prepared in CF3CH2CF3 solvent. The neutral system has a significantly shorter half-life [0.75(16) h
1, 193 K] compared with the cationic [1.87(0.3) h
1, 213 K]. These observations mirror those of the relative stability of neutral and cationic dihydrogen complexes.33 The analogous pentane complex can also be prepared. As for the neutral pentane complex W(η6-hexaethylbenzene) (CO)2(η2-C5H12),129 [Re(η6hexaethylbenzene)(CO)2(η2-C5H12)][Al(OC(CF3)3)4] shows a preference for methyl binding from the three possible isomers. The use of cationic systems and high dielectric noncoordinating solvents offers a new perspective on the synthesis and onward reactivity in solution of alkane-σ complexes. This has been demonstrated by using protonolysis methodologies in polar solvents at very low temperature, as is discussed next.

3.4 NMR Studies: Protonation of Metal Alkyls at Very Low Temperatures Unlike the photogeneration methodologies deployed for the in situ generation of a reactive metal fragment in the presence of a very large excess of alkane (i.e., the solvent), an alkane ligand can be directly generated at a metal center by protonation of the corresponding alkyl complex. Protonation of metal alkyls to eliminate alkanes is a well-known technique in organometallic chemistry to generate a cationic complex with a vacant site.136 Reversible reductive C–H bond formation from alkyl hydrides, probed by use of d-labeled alkyl hydrides137–139 or dynamic NMR spectroscopy,140,141 has been used to provide evidence for transient (unobserved) alkane complexes by virtue of rapid exchange between the hydride (or deuteride) and protons on the alkyl group, facilitated by a relatively slow loss of the transient alkane from the metal center. In particular the Ir(III) complex [Ir(PONOP)(H) (CH3)][BArF4] undergoes rapid proton exchange between Ir–H and Ir–CH3 via a transient, higher energy, Ir(I) σ–methane complex, which itself was

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Fig. 21 Top: Synthesis of [Rh(PONOP)(η2-H4C)][BArF4]. Bottom: 1H and 13C NMR spectrum of [Rh(PONOP)(η2-H413C)][BArF4] in CDCl2F at 163 K. Adapted with permission from Bernskoetter WH, Schauer CK, Goldberg KI, Brookhart M. Characterization of a rhodium(I)– methane complex in solution. Science. 2009;326:553–556.

determined to be relatively stable toward loss of methane. Consistent with that the rhodium congener would likely show higher stability for the Rh(I) oxidation state compared with the Rh(III), protonation of the Rh(PONOP) CH3 in CDFCl2 solvent at 163 K afforded [Rh(PONOP)(η2-H4C)] [BArF4]89 and not the corresponding alkyl hydride (Fig. 21). This σ–methane complex is stable to methane loss at very low temperature, but warming to
87°C results in the loss of methane to form a proposed solvent-bound adduct, [Rh(PONOP)(CDFCl2)][BArF4], recently characterized for the CD2Cl2 analog.142 The σ–methane complex was unambiguously characterized using NMR spectroscopy at very low temperature. For example, the 1H NMR spectrum shows a characteristic high-field shifted signal [δ
0.86, J(RhH) ¼ 6.3 Hz] for the methane ligand that is undergoing rapid site exchange between bound and terminal C–H groups. The 13C{1H} NMR spectrum of the 13C-enriched complex shows a quintet at δ
41.7, significantly upfield shifted from free methane [δ
4.9], but with a J(CH) only a little smaller. Isotopic labeling using [Rh(PONOP) (η2-D3CH)][BArF4] shows the expected IPE143 by a slightly upfield shifted resonance in the 1H{2H} NMR spectrum [δ
1.02] due to the preference for C–D bonds to adopt nonbridging positions. A DFT study in the isolated cation indicated that the methane binds in a η2-motif with the metal center ˚ ], while the methane dissociation enthalpy was determined [Rh⋯C 2.380 A

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to be 71.3 kJ mol
1. The stability of the methane σ-complex at these low temperatures could, in part, be due to the fact that substitution to give the solvent complex follows a dissociative mechanism, as shown for other group 9 pincer complexes,144,145 and so it is independent of solvent concentration. Although the entropy of activation for this process has not been determined experimentally, calculations that recreate well the experimentally determined overall free energy of activation also point to a dissociative mechanism for the loss of methane. It is noteworthy that [Rh(PONOP)(η2H4C)][BArF4] is valence isoelectronic with PtCl2(L)(η2-H4C), species that are postulated as intermediates in Shilov-type oxidation of methane.31 Typical experiments afforded the methane σ-complex in a 8:1 ratio compared to the methane loss product, although if the temperature is controlled carefully greater than 10:1 ratios can be obtained. In a similar way protonation at 123 K in CDFCl2/CD2Cl2 of the (remarkably stable toward β-elimination) Rh(I)–ethyl complex Rh(PONOP) CH2CH3 gives [Rh(PONOP)(η2-H3CCH3)][BArF4], Fig. 22.135 This ethane σ-complex is considerably less stable than its methane partner, and loses ethane quite quickly at 141 K (t1/2  5.5 h). This difference in stability is suggested to be due to increased steric pressure between the alkane and the PONOP ligand, the point being made that the tBu groups form a perfect pocket to stabilize the near spherical CH4 ligand. Despite the considerable experimental difficulties, full characterization by NMR spectroscopy was possible. At 130 K two signals are observed in the 13C{1H} NMR spectrum for the bound alkane, at δ
31.6 and 11.7. Likewise the 1H NMR spectrum displays two environments for the alkane, δ
0.83 and 1.13. These data are consistent with one Rh⋯H3C interaction. A DFT-calculated structure suggests a η2-motif with the metal center, but one that is weaker ˚ vs 2.380 A ˚ , respectively. than the methane complex, e.g., Rh⋯C 2.431 A The ethane dissociation enthalpy was calculated to be 4 kJ mol
1 lower than the methane complex. The ethane complex is extremely sensitive to loss of alkane. Although in typical experiments a 2:1 ratio of σ–ethane complex and the ethane loss product were obtained, ratios of 6:1 were observed in samples where “extreme caution was used to prevent warming of the NMR tube during sample preparation and manipulation.” Complete decomposition of the σ–ethane complex within seconds can occur if the conditions are not perfect. Upon warming to 141 K the methyl groups undergo site exchange between bound and free ends of the alkane ligand, showing that a dynamic process was occurring, the barrier of which was determined to be 30(4)

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Fig. 22 (A) Synthesis and DFT-calculated structure of [Rh(PONOP)(η2-H3CCH3)][BArF4]. (B) DFT-calculated structure and (C) showing details of the σ-interaction. Adapted with permission from Walter MD, White PS, Schauer CK, Brookhart M. Stability and dynamic processes in 16VE iridium(III) ethyl hydride and rhodium(I) σ-ethane complexes: experimental and computational studies. J Am Chem Soc 2013;135:15933–15947. Copyright 2013 American Chemical Society.

Fig. 23 Suggested pathway for chain walking via an η2:η2 transition state. Inset shows a higher energy Rh(III) dihydride alkene intermediate.

kJ mol
1. This is alkane “chain walking,”82,123,124 and the mechanism, as probed by DFT calculations, involves exchange of the two carbon positions via a η2:η2 transition state in which a C–H bond from each carbon binds to the metal center (Fig. 23). An alternative mechanism involves reversible oxidative cleavage of a C–H bond to form an Rh(III) alkyl hydride, which then undergoes β-H transfer to give a dihydride ethene complex. Reinsertion at

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the other carbon atom and reductive coupling completes the sequence. This proceeds with a considerably greater barrier (50 kJ mol
1), and thus is not favored. In other words the Rh retains its Rh(I) oxidation state, as might be expected. It will be interesting to see if other σ-alkane complexes can be generated by the same route. Attempts to extend this methodology to different pincer ligands or group 10 metals have so far not met with success, but reactivity studies are so far rather limited and so this method should not be discounted.131 The NMR studies described in these two previous sections have, undoubtedly, led to major advances in our understanding of the structures and dynamics of σ-alkane complexes, building upon the enabling work by TRIR. However, as pointed out,47,89,135 these experiments do not yield pure material and, due to the limitations of the experimental technique (solubility at low temperature, sample size) only small quantities of precursor complexes can be used (e.g., between 1 and 15 mg). When combined with the extremely low temperatures and temporal constraints on stability this means that these techniques are not appropriate for the synthesis of material in the bulk. Methodologies where σ-alkane complexes are isolated in the solid state could offer such an opportunity, if the synthetic routes are as reliable and rational as those developed for solution studies. Steps toward achieving this are discussed next.

3.5 Characterization of Alkane Complexes Using Preorganized Vacant Sites As described, the vacant site on the metal center necessary for binding an alkane ligand can be generated by photochemical techniques. An alternative methodology is the preorganization of such a vacant site in the complex that then interacts with the alkane ligand when in the solid state, formed either by recrystallization from hydrocarbon solvent or addition of gaseous alkanes to the solid-crystalline material. As these metal–alkane interactions are weak at best, noncovalent interactions that are encouraged by the solid-state environment are important in stabilizing such complexes. When these additional interactions are removed by solvation the alkane ligands undergo dissociation, and so far none of the complexes described in this section have solution spectroscopic data that report alkane binding. Nevertheless, they act as important structural descriptors for alkane binding that partners the elegant solution work already described.

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The first crystallographic evidence interaction of an alkane interacting with a metal center was provided in 1997 by the characterization of an iron(II) porphyrin in which an n-heptane molecule (derived from solvent of crystallization) was found to be in close approach to the metal center.146 The double A-frame porphyrin complex Fe(DAP) (Fig. 24) was synthesized with the intention that the structural motif presented a preorganized vacant metal site in which large exogenous ligands would be excluded from binding at the axial sites. Recrystallization from C6H5F/n-heptane and subsequent analysis by single-crystal X-ray diffraction resulted in a structure that suggested the close approach of a heptane molecule to the metal center, in which the alkane bridges between two independent Fe(DAP) molecules. Unfortunately the analysis of the alkane binding mode was not unambiguous, as the n-heptane molecule shows positional disorder involving a oneatom displacement along the alkane chain. Modeling with 50% occupancy of the two orientations leads to two different Fe⋯C distances of 2.8 and ˚ , metrics that were supported by DFT analysis that also suggested a 2.5 A 2 η -interaction between the alkane and the metal. These distances are long but argued to be within the range expected for moderate-to-weak agostic interactions. Analysis of the bonding suggests donation from the C–H bond to the metal, and also increased binding energies with longer alkyl chains (comparing CH4 and C4H10, for example: 44 kJ mol
1 vs 68 kJ mol
1). As noncovalent interactions were not explicitly taken into account this is likely due to increased polarizabilities/orbital energy match arguments. These complexes do not persist in solution. A similar preorganization of a vacant site is also demonstrated in uranium complexes that are suggested to show evidence for alkane

Fig. 24 (A) The double A-frame porphyrin ligand and (B) representation of the disorder model for n-heptane binding in Fe(DAP)(n-heptane).

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Fig. 25 (A) Synthesis of [U(ArO)3tacn(alkane)]; (B) molecular structure of [U(ArO)3tacn (methylcyclopentane)] showing selected short contacts between the supporting macrocyclic ligand and the alkane molecule; and (C) QTAIM molecular graphs [U{N(SiMe3)2}2]2(μ-C6H6) ambient (left) 3.2 GPa (right) with the H of the U⋯H agostic interaction labeled with an arrow. (B) Adapted with permission from Castro-Rodriguez I, Nakai H, Gantzel P, Zakharov LN, Rheingold AL, Meyer K. Evidence for alkane coordination to an electron-rich uranium center. J Am Chem Soc 2003;125:15734–15735. Copyright 2003 American Chemical Society. (C) Adapted with permission from Arnold P, Prescimone A, Farnaby J, Mansell S, Parsons S, Kaltsoyannis N. Characterizing pressure-induced uranium C–H agostic bonds. Angew Chem Int Ed 2015;54:6735–6739. Copyright 2015 John Wiley and Sons.

coordination by a relatively close approach of a C–H bond to the metal center.86 Recrystallization of highly reactive, unsaturated, [U(ArO)3tacn] from a pentane solution containing 50 equiv. of a variety of linear and cyclic alkanes (Fig. 25A) produces single crystals from which the resulting X-ray diffraction studies showed an approach of the alkane with the U(III) center. The structures show disorder of the alkane ligand that could not be fully resolved and thus hydrogen atom positions were not refined. Structures resulting from coordination of methylcyclohexane and neohexane ligands produced the best data. [U(ArO)3tacn(c-C6H11Me)] shows a U⋯C distance ˚. of 3.864(7) A˚, while neohexane results in a shorter contact, 3.731(8) A Although discussed as having a σ-type orbital interaction, these distances are well beyond the combined covalent radii of U and C (3.34 A˚).

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When compared with those of the rhodium σ-alkane complexes which have ˚ ],38 even when the Rh⋯C distances shorter by nearly 1.5 A˚ [e.g., 2.389(3) A difference in the respective covalent radii between U and Rh are taken into account [1.96 and 1.42 A˚, respectively147], these distances are long. Although a DFT analysis suggested a modest interaction between the uranium and alkane (less than 2% contribution from a C–H orbital), significant host–guest interactions were proposed between the alkane and the peripheral tert-butyl groups on the ligand framework (Fig. 25B). These long U⋯C interactions perhaps represent, at best, the upper limit of a σ-interaction in these species. A recent, detailed, combined experimental and computational (QTAIM) study on agostic U(III)⋯H3C interactions in [U{N(SiMe3)2}2]2(μ-C6H6) provides useful structural and bonding baseline data relevant to the identity of any σ-alkane complexes of uranium.73 Here, analysis by single-crystal X-ray diffraction was performed under the conditions of ambient and high (3.2 GPa) ˚ pressure. At ambient pressure, the closest U⋯C distance is 3.022(3) A ˚ which shortens to 2.95(2) A at high pressure (Fig. 25C). Although the location of the hydrogen atoms was not experimentally determined, they were optimized computationally. QTAIM analysis shows that while there is no U⋯H bond path at ambient pressure, one appears at high pressure. The bond properties, as calculated by QTAIM, place this new interaction as an agostic interaction, albeit weak [e.g., bond critical point U⋯H ρ ¼ 0.029 au]. Delocalization, natural localized molecular orbital and bond index data reinforced the conclusion for the presence of a U–H interaction at high pressure, but one that is absent under ambient pressures. That this tipping point in bonding in [U{N(SiMe3)2}2]2(μ-C6H6) pivots between two U⋯C distances that are both significantly shorter than those measured in, for example, [U(ArO)3tacn(c-C6H11Me)] supports the conclusion that the alkane proximal to the metal center in the latter complex is probably best described as being due to a host–guest interaction rather than a true σ-alkane complex. Although not a preorganized metal site, coordination of alkanes to a K+ center has been observed in the solid-state in a set of structures [K2(XAT) (alkane)], alkane ¼ 3-methylpentane, cyclopentane, hexane, pentane, and silane (Me3Si)2O [XAT ¼ 4,5-bis(2,6-dimesitylanilino)-2,7-di-tert-butyl-9, 9-dimethylxanthene].148 These come from recrystallization of [K2(XAT)] from the appropriate alkane, even in the presence of an arene (toluene). Interestingly, when crystallized from toluene alone, the methyl and Caryl–H groups of the arene are shown to interact with the K+ center, rather than the π-system, forming a coordination polymer (Fig. 26). These set of complexes show relatively short K⋯C distances of between 3.2 and 3.6 A˚

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Fig. 26 Structures of [K2(XAT)(hexane)] and [K2(XAT)(toluene)].

to the methylene or methyl groups and are noted to be shorter than both those found in [U(ArO)3tacn(alkane)] [e.g., 3.864(7) A˚] and comparable K+⋯ arene interactions. Attempts to observe these interactions by low temperature NMR spectroscopy in solution where not successful, suggested to be due to rapid exchange between bound and free alkane. DFT calculations using dispersion correction suggest a significant stabilization of the alkane fragment through noncovalent interactions; while fragment analysis suggests the main component of bonding between the metal and the alkane is due to a cation-induced dipole electrostatic interactions rather than σ-donation of the C–H bond. Thus, although not true σ-complexes, these structures serve to illustrate that not all close approaches between a metal and an alkane are covalent in nature, as well as the recurring theme of stabilization of alkane binding being supported by noncovalent interactions. Interestingly, when such electrostatic interactions are enhanced by using an “anionic–alkane” such as a methyl-substituted borate [MeB(C6F5)3]
, that also take advantage of increased polarity induced by the electronegativity differences between boron and carbon for example, these interactions are strong enough to persist in solution.149–152 Low-coordinate metal centers, that are potentially preorganized for an intermolecular interaction with a C–H bond, have also been shown to form coordination polymers in the solid state by forming σ-interactions between one metal center and an adjacent C–H bond from another molecule in the crystalline lattice. There are two examples of this behavior reported (Fig. 27). The low-coordinate Rh(I) complex (PBP)Rh [PBP ¼ 1,3-bis((di-tert-butylphosphanyl)methyl)-2,3-dihydro-1H-benzo [d][1,3,2]diazaborole] can formed in situ by reduction of the corresponding hydrido-triflate complex.153 The boryl-pincer ligand has a

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Fig. 27 (A) (PBP)Rh and (B) Rh2(μ-O2CC6Hi2Pr3)4 showing the intermolecular Rh⋯H–C interactions apparent in the solid state. Only selected aryl–iPr groups are shown.

particularly high trans-influence, leading to a vacant site trans to the B-atom. Recrystallization from aromatic solvent resulted in a solid-state structure that demonstrated an intermolecular η2-Rh⋯H–C σ-interaction between the Rh center and a distal C–H bond on the aromatic ligand ˚, backbone of an adjacent molecule, Rh⋯H–C 2.18(2) and 2.766(2) A respectively. This Rh⋯C distance is quite long, certainly at the upper end of what might be considered to be a significant interaction [sum of ˚ ],147 and calculations on an isolated model the covalent radii ¼ 2.77 A complex using a surrogate benzene ligand show the binding energy of the arene to be 50 kJ mol
1, although no details were given as to whether this structure captures the key metrics of the experimentally determined one, or detailed discussion of the nature of the bonding. There was no evidence for this interaction, or a similar one from a solvent molecule, persisting in solution, although NMR data and onward reactivity trends suggest a low-coordinate Rh(I) center is accessible. A related intermolecular Rh⋯H3C interaction, albeit weak, was identified by Barata and coworkers in the previously published structure of the dimer Rh2(μ-O2CC6Hi2Pr3)4.62,154 Here a weak interaction between an isopropyl methyl group on the bridging acetate ligand and the axial site on the Rh2 dimer was noted when the extended packing motif was considered [Rh⋯C 2.74, 2.80 A˚], even though in the original publication this complex was reported as being unusual for having no axial ligation. No further details of this interaction were given, but the relatively long distance and apparent tridentate motif suggest a trifurcated η1:η1:η1 interaction. Preorganized vacant sites that are available for alkane binding can also be generated in MOF materials if the metal–ligand complexes that form structural nodes in such materials are also unsaturated. In a series of papers,87,88,155

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MOFs based upon Fe(II), Mn(II), Co(II), Cr(II), and Cu(II) metal nodes are shown to interact with light alkanes (and alkenes), as probed structurally by powder neutron diffraction experiments at very low temperatures (10 K or lower) using deuterated alkanes. Although these materials have been studied for reasons of gas storage or separation, they also provide important structural information as to the interaction of light alkanes with open metal sites, as well providing insight into other factors that enhance binding strengths. A significant advantage of this synthetic methodology is that MOF materials can be prepared in bulk quantities (100’s g scale for some frameworks156) meaning that, in principle, so can the resulting σ-alkane complexes. The redox active, high spin, MOF Fe2(dobc) [dobc4
¼ 2,5-dioxido1,4-benzenedicarboxylate] contains an open metal site available for binding ligands, that is directed into the open pore. If the activated material is dosed with deuterated alkanes (ethane or propane) at 300 K, and cooled to 4 K in order reduce any positional disorder problems, powder neutron diffraction experiments demonstrate that alkane adsorption occurs at one site only: the open metal center.87 Dosing with alkenes (e.g., C2D4) produces the corresponding π-bound complexes (Fig. 28). Weak interactions are present between the methyl group of ethane, or the methylene of propane, and the ˚ , Fe–D 2.59(2), 2.59(2) A ˚ ], Fig. 28B. These distances metal center [Fe–C  3 A 1 1 perhaps suggest an bifurcated η :η bonding motif. The heat of adsorption, calculated using a single-site model, showed that ethane binds less strongly than propane [
25 and
33 kJ mol
1], in line with the increasing polarizabilities of these alkanes. Although the precise nature of the bonding between metal and alkane was not directly addressed in this contribution, a follow-up computational study using a partially truncated model for Fe2(dobc) indicated a weak σ-interaction between ethane and the Fe center, while noncovalent (dispersion) interactions were also shown to be important in stabilizing the observed motif.157 Using the same framework, but now with high spin Co(II), the experimental powder neutron diffraction structure at 10 K of the ethane-dosed material also demonstrates binding at a metal site, and a slightly closer interac˚ ].155 Powder tion than for Fe(II) is suggested [Co–D 2.34(4), 2.50(4) A diffraction studies on ethane-dosed Mn2(dobc) where not as conclusive, possibly due to framework disorder. Nevertheless they showed ethane binding at a single metal site, and also a secondary binding site that sits in the hexagonal channels of the framework and is nonmetal based (Fig. 28C). This additional binding is suggested to be due to the larger pores of the Mn–MOF associated with the greater ionic radius of Mn(II) vs Fe(II).

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Fig. 28 (A) A portion of the solid-state structure of Fe2(dobdc)2C2D4 as determined by analysis of neutron powder diffraction data; (B) details of alkane and alkene binding; (C) Mn2(dobc)(C2D6) showing the secondary binding site; and (D) details of alkane and alkene binding with Co2(dobc). (A, B) Adapted with permission from Bloch ED, Queen WL, Krishna R, Zadrozny JM, Brown CM, Long JR. Hydrocarbon separations in a metal-organic framework with open iron(II) coordination sites. Science. 2012;335:1606–1610. (C, D) Adapted with permission from Geier SJ, Mason JA, Bloch ED, et al. Selective adsorption of ethylene over ethane and propylene over propane in the metal–organic frameworks M2(dobdc) (M ¼ Mg, Mn, Fe, Co, Ni, Zn). Chem Sci 2013;4:2054. Copyright 2013 Royal Society of Chemistry.

A very detailed powder neutron diffraction study of d4–methane adsorbed into the pores of Cu3(btc)2 at 8 K [btc2
¼ 1,3,5-benzenetricarboxylate] shows that CD4 actually binds preferentially to the windows of the octahedral pores, with the exposed metal sites (the axial positions on Cu–Cu dimers) being filled as secondary binding sites.88 The methane is disordered in a threefold motif over the metal center and so detailed M⋯H distances were not reported, but the M⋯C distances are comparable with those in ˚ ; Cu⋯C, 2.847 reported for other framework materials [Cr⋯C, 3.09(2) A ˚ (5) A], Fig. 29. Interestingly, this, albeit disordered, motif is similar to that

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Fig. 29 Structure of approximately half of the unit cell of Cr3(btc)2 dosed with 2.2 CD4 per Cr atom showing the metal binding site only. The methane is disordered in a threefold motif over the metal center. Adapted with permission from Hulvey Z, Vlaisavljevich B, Mason JA, et al. Critical factors driving the high volumetric uptake of methane in Cu3(btc)2. J Am Chem Soc 2015;137:10816–10825. Copyright 2015 American Chemical Society.

reported for dimeric Rh2(μ-O2CC6H2iPr3)4 in which the axial sites are also weakly ligated with a methyl group (vide infra).62 A significant enhancement to the binding of methane to the open metal site was provided when noncovalent interactions with proximal methane molecules adsorbed in the window sites was taken into account. This, again, highlights the important role of noncovalent forces in stabilizing metal–alkane interactions. Similar comments have been made regarding the consideration of noncovalent interactions in the binding strength of alkanes in discrete metal complexes.39,83,158,159

3.6 Hydrogenation of Alkenes in the Solid State The relatively instability of alkane complexes produced by solution routes that are, at best, stable only at very low temperatures or have very short lifetimes at room temperature, often derives from loss of alkane by substitution by solvent or another Lewis base. When coupled with the experimental limitation of in situ synthesis being often less than 100% this leads to a significant barrier to the rational generation of single crystalline material suitable to study by diffraction techniques, and especially single-crystal X-ray diffraction. Moreover, as demonstrated, there are significant stability enhancements that come from noncovalent interactions in the solid state. By simply removing the solvent and taking advantage of single-crystal to single-crystal solid/gas reactions91–93 a number of alkane σ-complexes have

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been generated directly in the solid state. Addition of H2 to single crystals of [Rh(L2)(NBD)][BArF4] (NBD ¼ norbornadiene, L2 ¼ R2PCH2CH2PR2, R ¼ iBu,132 Cy38) leads to hydrogenation of both double bonds in the diene and the generation of the resulting norborane σ-complex directly in the solid state: [Rh(L2)(η2:η2-C7H12)][BArF4] (Fig. 30). In many respects, this is similar to the direct generation of methane and ethane in a Rh(I) coordination sphere by protonation of the corresponding alkyl (see Section 3.4). These alkane σ-complexes have sufficient stability to allow for their characterization by single-crystal X-ray diffraction and solid-state NMR techniques. The Cy-substituted complex is far more stable than the iBu analog. The latter is only stable in the solid state at temperatures below 253 K. Above this temperature, the NBA ligand is lost (hours for single crystalline sample) and a [BArF4]
coordinated zwitterion is formed: [Rh(iBu2PCH2CH2PiBu2)(η6(CF3)2(C6H3)BArF3)]. Crystallinity is lost during this final transformation. By contrast the Cy-analog is indefinitely stable (4 months), even at 298 K. The solid-state structure of both [Rh(iBu2PCH2CH2PiBu2)(η2:η2C7H12)][BArF4]132 and [Rh(Cy2PCH2CH2PCy2)(η2:η2-C7H12)][BArF4]38

Fig. 30 (A) Synthesis of [Rh(L2)(η2:η2-C7H12)][BArF4] and decomposition product, [Rh(L2) (η6-(CF3)2(C6H3)BArF)3]; (B) molecular structure of the cation in [Rh(iBu2PCH2CH2PiBu2) (η2:η2-C7H12)][BArF4]; (C) molecular structure of the cation in [Rh(Cy2PCH2CH2PCy2) (η2:η2-C7H12)][BArF4]; and (D) detailed view of the alkane–Rh interaction. Adapted with permission from Pike SD, Chadwick FM, Rees NH, et al. Solid-state synthesis and characterization of σ-alkane complexes, [Rh(L2)(η2,η2-C7H12)][BArF4] (L2 ¼ bidentate chelating phosphine). J Am Chem Soc 2015;137:820–833. Copyright 2015 American Chemical Society.

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shows a close approach of the alkane ligand to the Rh(I) center, with Rh⋯C ˚ and 2.389(3)/2.400(3) A˚, respectively, distances of 2.494(10)/2.480(11) A which lies at the shorter range of previously reported agostic C–H interactions to Rh(I).76 For the iBu analog disorder of the NBA fragment between 2 equiv. conformations, in which either set of endo-C–H bonds bind to the metal center, meant that the hydrogen atoms associated with the alkane were placed in calculated positions. However, for the Cy-version, which is discussed in detail here, the structural refinement showed no disorder and the H-positions were located and refined. The close Rh⋯C distances, short Rh⋯H distances ˚ ] and acute Rh–H–C angles [both 104(3) degree] suggest a [1.93(4), 1.95(4) A 2 2 η :η binding of the alkane ligand with the metal center. A QTAIM and NBO study on these systems showed that the bonding can be best described as a significant, but weak, σ–Rh⋯H–C interaction, dominated by σCH ! Rh donation. For example the QTAIM analysis shows a curved bond path between Rh and H–C, which in combination with significant electron density between Rh and H and diminished electron density between C and H signals such an interaction. A small lengthening of the C–H bonds involved with the metal is also indicated by these calculations, which are within the 3σ-limit of error for the single-crystal X-ray diffraction experiment. An alkane binding energy of 77 kJ mol
1 was calculated for the isolated cation. The Rh–P distances in these NBA adducts are considerably shorter than in the NBD starting materials [e.g., Cy–NBD: Rh–P 2.294(1), 2.285(1); Cy–NBA: Rh–P 2.1932(7), 2.1950(7) A˚] consistent with the weak binding of the trans-disposed alkane. 31P{1H} magic angle spinning solid-state NMR spectroscopy (MAS SSNMR) also demonstrated this, by a significantly increased value for J(RhP) observed for the alkane complexes compared with the diene precursor: 210 Hz vs 123 Hz, respectively. The stability of the [Rh(Cy2PCH2CH2PCy2)(η2:η2-C7H12)][BArF4] also allows for detailed solid-state NMR experiments to be performed, and in particular use of indirect detection techniques to determine the 1H NMR spectrum using HETCOR SSNMR experiments.160 This leads to identification of the σ-interaction in the 298 K experimental spectrum, at a chemical shift at
2 ppm, as expected for such an interaction at a Rh(I) center in solution.89 This single-crystal to single-crystal transformation from diene to alkane fragment is proposed to be able to occur due to a “crystalline molecular flask”161 resulting from the [BArF4]
anions that form an octahedral cage around the metal fragment (Fig. 31). This gives a cavity in which the cationic fragment, and especially the organic fragment, can undergo reorganization on hydrogenation as it moves from bidentate alkene (NBE) to bidentate

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Fig. 31 (A) Packing diagrams showing the relationship of six of the closest [BArF4]
anions in [Rh(Cy2PCH2CH2PCy2)(η2:η2-C7H12)][BArF4], with aryl groups present; (B) aryl group removed; (C) and expansion of local environment. (D) Contour electron density plot and selected QTAIM parameters. Adapted with permission from Pike SD, Chadwick FM, Rees NH, et al. Solid-state synthesis and characterization of σ-alkane complexes, [Rh (L2)(η2,η2-C7H12)][BAr(F)4] (L2 ¼ bidentate chelating phosphine). J Am Chem Soc 2015;137:820–833. Copyright 2015 American Chemical Society.

alkane (NBA). Interestingly calculations on isolated cations show that the [BArF4]
coordinated zwitterions are essentially equally stable for the Cy and iBu systems, and are both the expected thermodynamic products arising from alkane loss. That this final product forms for iBu, and not Cy, is thus suggested to be due to differences in constraints (kinetic or thermodynamic) imposed by the crystalline environment of [BArF4]
anions/phosphine ligands for each complex; for example, the reorganization energy associated with loss of alkane and coordination of the anion. Dissolution of either alkane complex at very low temperature in CDFCl2 (133 K) leads to displacement of the alkane and formation of the corresponding [BArF4]
coordinated zwitterion. Thus, although these complexes provide a unique platform to study alkane complexes in exquisite detail in the solid state they do not provide access to complexes stable in solution. However, as the methodology relies on simple addition of H2 gas to a relatively stable alkene precursor under ambient conditions synthesis is only limited by the quantity of starting material that can be produced in single crystalline form. Moreover, unlike solution techniques, synthesis is essentially quantitative and

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irreversible. This means that research scale quantities of pure alkane complexes can be prepared and stored (in an argon-filled glove box), making subsequent investigations into their reactivity and structures considerably more straightforward in this sense than solution-based studies. This stability of the [Rh(Cy2PCH2CH2PCy2)]+/[BArF4]
combination for stabilizing alkane coordination in the solid state has recently been exploited in the synthesis and structural characterization of a light alkane coordinated to a metal center, pentane: [Rh(Cy2PCH2CH2PCy2)(η2:η2C5H12)][BArF4].162 This comes from a simple addition of H2 to a pentadiene precursor (Fig. 32). The orientation of the organic fragment signals the formation of the σ-alkane complex, moving from utilization of the alkene π orbitals to the saturated alkane through C–H interactions, and the structural refinement shows that the pentane binds through the 2,4 positions as a ˚ ; and bis-σ-alkane ligand: e.g., Rh⋯C, 2.514(4); Rh⋯H 2.24(5) A Rh–H–C, 98(4) degree. Although the resulting pentane complex is less

Fig. 32 Precursor pentadiene complex [Rh(Cy2PCH2CH2PCy2)(η2:η2-C5H8)][BArF4] and alkane complex [Rh(Cy2PCH2CH2PCy2)(η2:η2-C5H12)][BArF4]. Adapted with permission from Chadwick FM, Rees NH, Weller AS, Kra€mer T, Iannuzzi M, Macgregor SA. A rhodium–pentane sigma-alkane complex: characterization in the solid state by experimental and computational techniques. Angew Chem Int Ed 2016;55:3677–3681. Copyright 2016 John Wiley and Sons.

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thermally stable than that NBA analog, decomposing at 298 K over 15 min, the low temperature single-crystal X-ray diffraction data are of sufficient quality to allow for the location of the hydrogen atoms associated with the σ-interaction. These experimental data, in combination periodic DFT calculations and QTAIM studies that capture the solid-state environment, show that the alkane binds in an η2:η2-with the metal, but more weakly than NBA when compared at the same level of theory. Noncovalent interactions (a recurring theme in the stabilization of alkane-σ complexes) in the form of van der Waals and C–F⋯H–C dihydrogen bonds were also shown to be significant (Fig. 33). Low temperature variable temperature SSNMR experiments suggested that the pentane ligand was fluxional in the solid state, and a computational metadynamics study in the solid state confirmed this, indicating that although the 2,4-isomer is marginally more favored at 150 K (the same temperature as the X-ray diffraction experiment) at higher temperatures alternative isomers such as the 1,3-isomer likely dominate, although the barrier between the two is calculated to be small (15–25 kJ mol
1). Such a movement is related to the chain walking events that have been shown to directly44,121,135 or indirectly82,123,124 occur in solution for transient σ-alkane complexes.

Fig. 33 (A) Noncovalent interaction plot for [Rh(Cy2PCH2CH2PCy2)(η2:η2-C5H12)][BArF4]. Broad areas ¼ van der Waals interactions, disks ¼ C–F⋯H–C dihydrogen bonds and (B) free energy surface from metadynamics sampling at T ¼ 150 K. Adapted with permission from Chadwick FM, Rees NH, Weller AS, Kra€mer T, Iannuzzi M, Macgregor SA. A rhodium–pentane sigma-alkane complex: characterization in the solid state by experimental and computational techniques. Angew Chem Int Ed 2016;55:3677–3681. Copyright 2016 John Wiley and Sons.

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4. CONCLUSIONS As this review shows there is a rich coordination chemistry associated with the σ-alkane complexes. The initial studies of 50 years ago that first used spectroscopic/matrix isolation methods for measurements on very short-lived transient complexes is now refined so that in solution alkane complexes can be generated with lifetimes that allow for a detailed study by NMR and IR spectroscopies, while in the solid-state engineering of conditions and the local environment can lead to almost indefinite stability. Despite these advances it is notable there are no reported examples of group 10 (Ni-triad) alkane complexes, a significant omission given the central role complexes of these metals play in C–H activation chemistry. Moreover, there are no reports of a σ-alkane complex in which solution (e.g., NMR spectroscopy) and solid-state (single-crystal X-ray diffraction) data both show evidence for binding of the alkane. Preparing such a complex by solution techniques in which the weak binding of the alkane ligand is strong enough to be retained over the timescales and temperatures required for the growth of single crystals is challenging; while σ-alkane complexes prepared in the solid-state suffer the same problems when dissolved in solution, even at low temperature. As Perutz and Hall suggested in their review over 20 years ago: “… that if a ligand shell could be suitably arranged to trap or hold an alkane in the correct place for binding to the metal center, the resulting complex would be stabilized.”27 This comment speaks to the influence, as this review details is now well established, that noncovalent interactions have on stabilizing σ-alkane complexes. An associated area that has not received significant attention is the use of multimetallic systems to stabilize σ-complexation, as each metal, if appropriately spatially orientated, should have a positive additive effect on the overall stability of the alkane complex. Calculations on bimetallic systems based upon {MCp0 (CO)2} (M ¼ Re, Mn, Cp0 ¼ linked Cp systems) in which two metal centers interact essentially independently with the alkane ligand show this, and binding energies are increased substantially compared to the monometallic analogs.37 Such multimetallic systems would also model, in part, the formation of σ-alkane complex in heterogeneous catalyst systems.163 Given the advances in solution- and solid-statebased synthesis techniques over the last 20 years these comments and observations suggest that approaches that combine the advantages of solid state, solution, multiple binding sites, and noncovalent outersphere interactions could well prove profitable in isolating a complex that meets

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the exacting demands for solution and solid-state characterization and onward reactivity. The resulting opportunity for selective, and catalytic, alkane C–H activation in such complexes is an exciting prospect and one that also may offer robust organometallic solutions to the efficient utilization of fossil-derived hydrocarbon resources.2,3,5,29

Notes Added in Proof Two recent results further highlight the utility of the single-crystal solid/gas approach in generating relatively stable σ-alkane complexes in the solid state (Section 3.6). The first is the demonstration of selective C–H activation at the bound alkane in [Rh(Cy2PCH2CH2PCy2)(η2:η2-C7H12)][BArF4], by H/D exchange with exogenous D2. Various isotopomers and isotopologues were unambiguously characterized using a combination of single-crystal neutron diffraction, variable temperature SSNMR, and periodic DFT calculations. These studies also reveal that remarkably low energy fluxional processes are occurring at the bound alkane in the solid state.164 The second is the synthesis and characterization, by single-crystal X-ray diffraction, of the sigma alkane complex [Rh(Cyp2PCH2CH2PCyp2)(η2:η2-C7H12)] [BArF4] (Cyp ¼ cyclopentyl).165

ACKNOWLEDGMENTS The EPSRC for an Established Career Fellowship (ASW, EP/M024210), SCG Chemicals (FMC). Stuart Macgregor, Malcolm Green, and Maurice Brookhart for useful discussions.

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INDEX Note: Page numbers followed by “f ” indicate figures, “t” indicate tables, and “s” indicate schemes.

A Acceptor/acceptor-substituted metal carbenes alkyltrifluoroborates, 5, 6s α–diazo β–ketoesters, 6–7, 7s α–diazomalonates, 5, 6s dirhodium(II) complexes, 6–7 ortho–hydroxy benzhydryl alcohols, 6–7, 7s Acceptor-substituted metal carbenes α–benzylidene–β–ketoesters, 8, 9s α,β–unsaturated carbonyl compounds, 10, 10s aminals, C–N insertion of, 12, 12s C–H insertion, 8–9 cyclopropanation, 9 ethyl diazoacetate, 8–9, 10s nitrosoarenes, 10–11, 11s palladium, 12 ruthenium(II) porphyrin catalysts, 10–11 2,2,2-trifluorodiazoethane (CF3CHN2), 9 A3-coupling reactions copper-mediated, mechanism for, 115–116, 116s definition, 115 Mannich coupling, 115 propargylic amines, 115–116 Agostic vs. σ-alkane complexes, 227–229, 228f Alkane complexes, preorganized vacant site anionic–alkane, 255–256 C6H5F/n-heptane, 253, 253f Cr3(btc)2, unit cell of, 259–260, 260f double A-frame porphyrin complex Fe(DAP), 253, 253f Fe2(dobdc)
2C2D4, 258, 259f fragment analysis, 255–256 iron(II) porphyrin, 253 [K2(XAT)(hexane)], 255–256, 256f [K2(XAT)(toluene)], 255–256, 256f M⋯X distances, 259–260

metal–ligand complexes, 257–258 MOF, 257–258 noncovalent interactions, 252 powder neutron diffraction study, 259–260 QTAIM, 253–255 Rh2(μ–O2CC6Hi2Pr3)4, 256–257, 257f (PBP)Rh, 256–257, 257f Rh⋯X distance, 256–257 rhodium σ–alkane complexes, 253–255 single-site model, 258 surrogate benzene ligand, 256–257 U⋯C interactions, 253–255 uranium complex, 253–255 [U(ArO)3tacn)], 253–255, 254f Alkenes, hydrogenation of, 260–265 Alkyl/acceptor-substituted metal carbenes aryl hydroxamates, C–H cyclization of, 13, 14s benzocyclobutenols, C–C insertion of, 12–13, 13s diazoesters, 13–14, 14s enoldiazo compounds, 14–15 terminal alkynes, 13–14, 14s Alkyltrifluoroborates, 5, 6s Alkynyl ligands, 94, 110–111 α,α–substitution reactions. See Insertion reaction α–benzylidene–β–ketoesters, 8, 9s α–diazo β–ketoesters, 6–7, 7s α–diazoketones, 70 α–diazomalonates, 5, 6s Aryl/acceptor-substituted metal carbenes α–aryl–α–diazoacetates, 16, 17s aryl hydroxamates, 18–19, 19s borane adducts, B–H insertion of, 15, 16s multicomponent reactions (MCRs), 16 palladium(II) complex, 16 phenols, C–H functionalization of, 17, 18s porphyrin ligands, 19 Aryl carbamates C–B bond-formation, 192–193, 192s 277

278 Aryl carbamates (Continued ) C–N bond-formation, 192–193, 192s Ni-catalyzed hydrogenolysis of, 207, 207s Aryl hydroxamates, 18–19, 19s Aryl pivalates C–B bond-formation, 191, 191s C–N bond-formation, 191, 191s Ni-catalyzed reductive cleavage of, 207–208 Autotandem catalytic process, 73–74 Azomethine imine alkyne cycloaddition reactions, 123, 124s alkynylation of, 124, 124s

B

[BArF4]anions, 262–264, 263f (+)-Batzelladine B, 68–69, 69s Benzoate derivatives, 179, 179s Benzoazepines synthesis, 61, 61s Benzo–γ–sultams, 39, 40s Benzyl alcohols free alcohols, 163 naphthols, 162, 162s salt formation, 163 X-ray crystallographic analysis, 162 β–hydride elimination, 53, 200–201, 203–204 [2C+n] cycloaddition, 53 ethers, 200–201, 203–204 β–lactams, 124–125 B–H insertion α-diazoketones and esters, 50, 50s carbene, 49–50, 50s chiral organoboron compounds, 49–50 NHC, 50 rhodium carbene, 50 Bidentate ligands, 107–108 Bis(oxazoline) (BOX) ligands, 54 Bond-dissociation energy, 165–166 Boroxine/boronic acid equilibrium, 167–168 Brucine, 38–39, 39s Buchner cyclization, 57

C CAAC. See Cyclic (alkyl)(amino) carbene (CAAC) Carbon–carbon bond formation KTC-type coupling reactions, 146–163

Index

miscellaneous C–C bond-forming reactions, 181–190 Mizoroki–Heck-type coupling reactions, 176–178 Negishi-type coupling reactions, 163–166 organometallic compounds, 179–181 Stille-type couplings, 179 Suzuki–Miyaura-type couplings, 166–176 Carbon–heteroatom bond-formation C–B aryl and alkenyl pivalates, 193–194, 194s aryl carbamates, 192–193, 192s aryl methanols, 195–196, 196s aryl pivalates, 191, 191s aryl 2-pyridyl ethers, 193, 193s catalytic borylation, 195–196 C-OPy cleavage, 193–194, 194s C–N aryl methyl ethers, 190–191, 191s aryl pivalates, 191, 191s metal-catalyzed amination, 190–191, 191s Ni-catalyzed catalytic amination, 190–191, 191s PhBpin, 191–192 C–P aryl and benzyl pivalates, 198, 198s organophosphorus compounds, 198 C–Si aryl and benzyl pivalates, 196–197, 197s metalation techniques, 196–197 organosilanes, 196–197 silylation, 197–198, 197s Carbon–heteroatom (C–X) bonds, 35 Carbonylazides, 121, 122s Carbonyl ylides, 70 Carboxylation coupling reactions, 112–115, 114s Cascade reaction cyclohexane, 80–81, 81s cyclopentane, 80, 81s donor/acceptor-substituted rhodium carbenes, 80 hydroepoxyisochromene, 82

Index

()-preussin, 81, 81s 2,3-sigmatropic rearrangement, 79–80, 80s tertiary propargylic alcohols, 79–80 vinyldiazoacetates, 80 Catalytic borylation, 195–196 Catalytic Castro–Stephens reactions bidentate ligands, 107–108 copper catalysis, 109 [Cu(DMEDA)2]Cl2
H2O, 108–109, 108s ligand-accelerated catalysis, 108–109 Chain-walking barriers, 246–248 C6H5F/n–heptane, 253, 253f C–H functionalization α–alkyl–α–diazoesters, 35–36 α–aryl–α–diazoacetates, 40–41, 41s benzo–γ–sultams, 39, 40s brucine, 38–39, 39s Buchner reaction, 39 (–)–cameroonan-7α–ol, 41, 41s diazoesters, 43, 43s dictyodendrins, 39, 40s dihydrobenzofurans, 36–37, 37s dirhodium tetraprolinate, 37–38 enoldiazoacetamide, 39, 40s imines, 43, 43s indoles, 35–36, 36s (+)–lithospermic acid, 41, 41s (–)–Maoecrystal V, 42, 42s metal-carbene intermediate, trapping of, 43, 44s methyl ethers, 38, 38s oxindole derivatives, 42, 42s polyfunctionalized indole, 42, 42s proton transfer process, 35–36 pyrrole, 43, 43s rhodium–carbene, 35–36 toluene derivatives, 37–38, 38s unprotected phenols, 37, 37s zwitterionic intermediates, 43 C–H insertion/cope rearrangement (CHCR), 61 Chiral morpholines, 73, 73s Chiral rhodium catalyst, 53 Chiral SPAs, 47–48 C–H oxidative cleavage, 240–241 C–H σ-complexes

279 alkane functionalization, C–H activation for, 224–225, 224f dihydrogen, 225–226 H3B
NMe3, 225–226 M⋯H–C interaction, 225–226 M–X bonds, 226, 227f silanes (HSiR3), 225–226 three-center two-electron interaction, 225–226 Classical organometallic pathway, 163 [2C+n] Cycloaddition 2–arylbicyclo[1.1.0]butane carboxylates, 59–60, 60s β–hydride elimination, 53 Bis(oxazoline) (BOX) ligands, 54 Buchner cyclization, 57 chiral halo–cyclopropanes, 53 chiral rhodium catalyst, 53 cobalt-based metalloradical catalysis (MRC), 55 cobalt metalloradical catalyst, 58, 58s cyclopropane ring, 51 cyclopropylamines, 54 cytochrome P450 enzyme (CYP450), 55 diacceptor cyclopropane derivatives, 59, 59s diazo acetates, 54, 54s donor/acceptor carbenes, 51 E-and Z-cyclopropane, 55, 55s electron-deficient olefins, 54 intramolecular cyclopropanation of allyllic diazoacetates, 56, 56s α–diazoesters, 56, 56s (+)-norrisolide, 56 (–)-paeonilide, 56 polycyclic polyprenylated acylphloroglucinols, 57 Rh2(S–NTTL)4, 60 Rh2(S–TCPTTL)4, 51–53, 52s Rh2(R-BTPCP)4-catalyzed cyclopropanation, 51, 52s (+)–salvileucalin B, 57, 57s silver mediate [2+2+1] cycloaddition, 60, 60s silver triflate, 59 spiroketal bisphosphine, 54 terminal alkynes, enantioselective cyclopropenation of, 58, 58s

280 [3C+n] Cycloaddition benzoazepines synthesis, 61, 61s carbonyl ylide formation, 62–63 cascade reaction, 63–64 C–H insertion/cope rearrangement (CHCR), 61 donor–acceptor cyclopropene, 65–66 enoldiazoacetamides, 66, 67s enoldiazoacetates, 65 gold vs. rhodium, 61, 61s isoquinolinium/pyridinium methylides, 65–66, 66s isoxazolidines, 61 key tricyclic intermediate, 63, 63s Lewis acid addition, 65, 65s Mannich addition, 66 N–iminopyridinium ylides, 65, 65s nitrones, 63–64, 64s nitrosobenzenes, 64s quinoline oxides, 64 Rh(II)–catalyzed intramolecular [3+2] cycloaddition, 62–63, 62s stemofoline alkaloids, 63 vinyldiazoacetamides, 66 vinyldiazoacetates, 61 [5C+n] Cycloaddition, 69 [6C+n] Cycloaddition, 70 Cobalt-based metalloradical catalysis (MRC), 55 Cobalt metalloradical catalyst, 58, 58s C–O bonds electrophiles, 144–145, 144s hydrogenolysis of alcohols, 208–209 carbamates, 207 esters, 207–208 ethers, 199–206 metal-catalyzed functionalization of, 144–145, 145s C(sp2)–OH bonds, 208–209, 208s C(sp2)–OMe bonds, 202, 203s Conia–ene cyclization, 78 Copper–acetylides, 118 Copper(I)–acetylides carboxylation coupling reactions, 112–115 A3-coupling reactions, 115–116 cross–coupling reactions, 104–111

Index

CuCC(t-Bu), 94, 95f 1,3-dipolar cycloadditions, 117–126 miscellaneous reactions, 126–128 oxidative coupling reactions, 96–103 phenylethynylcopper(I), 94 Copper-assisted phosphorylation, 102–103, 103s Copper catalysis, 109 Copper-catalyzed intramolecular insertion, 46, 46s Copper-mediated oxidative trifluoromethylation of, 101, 102s C-OPy cleavage, 193–194, 194s Cross–coupling reactions catalytic Castro–Stephens reactions bidentate ligands, 107–108 copper catalysis, 109 [Cu(DMEDA)2]Cl2
H2O, 108–109, 108s ligand-accelerated catalysis, 108–109 C–O electrophiles in, 144–145, 144s diazo compounds alkynoates, copper-catalyzed synthesis of, 109–110, 110s aryne–alkyne, 111, 112s mechanistic proposal for, 110–111, 111s secondary alkynes, 110, 110s secondary carbenes, 110, 110s group 10-mediated reactions catalytic tests, 105–106 ferrocenyl polyphosphine ligands, 105–106 ligand transfer processes, 105 Ni–Cu bimetallic complexes, 106–107, 107f palladium, 104–106 phosphine ligands, 106 Pincer ligands, 106–107 Sonogashira reaction, 105, 105s transmetallation, 104–105 Cross–dehydrogenative coupling, 103, 104s Cr(CO)6 photolysis, 231–232 Crystalline molecular flask, 262–264 Cs2CO3, 189–190 CuAAC reaction, 117–119, 118s, 119f Cu(I)-catalyzed cyclopentannulation, 70, 71s Cyclic (alkyl)(amino) carbene (CAAC), 120, 121s

281

Index

Cyclic vinyl ethers, 150–151, 150–151s [4+n] Cycloaddition α–diazo indolo amido esters, 68, 68s (+)-batzelladine B, 68–69, 69s dirhodium tetracarboxylate, 68 electrophilic rhodium enal-carbenes, 67 homopropargyl alcohols, 67 pyrroles, benzannulation of, 67, 67s Cyclohexane, 80–81, 81s Cyclopentane, 80, 81s Cyclopropylamines, 54

D Dehydroaryloxylation pathway, 206 Delayed proton transfer, 71–72 Dianion-type organozincates, 165–166, 166s Diazocarbonyl compounds, 122–123, 123s Diazo compounds, 1 alkynoates, copper-catalyzed synthesis of, 109–110, 110s aryne–alkyne, 111, 112s diazoacetates, 2–3 diazo ester, 2, 2–3s mechanistic proposal for, 110–111, 111s metal carbene formation, 1, 2s secondary alkynes, 110, 110s secondary carbenes, 110, 110s Dictyodendrins, 39, 40s Diels–Alder cycloaddition, 122, 123s Dihydrobenzofurans, 36–37, 37s Dimethylmalonates, 182, 182s 1,3-Dipolar cycloadditions azide–alkyne and click chemistry alkynes, 121, 122s carbonylazides, 121, 122s copper–acetylides, 118 CuAAC reaction, 117–119, 118s, 119f cyclic (alkyl)(amino) carbene (CAAC), 120, 121s five-membered heterocycles, 117 Glaser reaction, 118 NHCs, 119–120, 120s N-heterocyclic carbenes, 119–120 N-sulfonyl copper–triazolide intermediates, 121, 122s π-coordination, 117–118

polymeric alkynylcopper(I) complexes, ladder structures of, 118–119 TBTA, 119, 119f terminal alkyne, 117–118, 117s Dirhodium(II) carboxylates, 47–48 Dirhodium tetracarboxylate, 68 Diversity-oriented synthesis (DOS), 73 Diverted carbene insertion, 75 D-labeled alkyl hydrides, 248–250 Donor–acceptor cyclopropene, 65–66 Donor/acceptor-substituted metal carbenes alkyl/acceptor, 12–15 aryl/acceptor, 15–19 vinyl/acceptor, 19–22 Donor/acceptor-substituted rhodium carbenes, 80 Donor-and donor/donor-substituted metal carbenes diaryl diazomethanes, 22–23, 23s gem-difluoroolefin, 22–23 N-tosylhydrazones, 23, 24s Pd(0)-catalyzed carbene insertion, 23, 24s polyfluoroarenes, 24, 24s Double A-frame porphyrin complex Fe(DAP), 253, 253f

E E–and Z–cyclopropane, 55, 55s Electron-deficient olefins, 54 Enoldiazoacetamides, 21–22, 21s, 66, 67s Esters hydrogenolysis, C–O bonds, 207–208 KTC-type coupling reactions, 160–161 Mizoroki–Heck-type coupling reactions, 176–177 Negishi-type coupling reactions, 163–165 Suzuki–Miyaura-type couplings, 169–172 Ethers β–hydride elimination, 200–201, 203–204 hydrogenolysis, C–O bonds, 199–206 KTC-type coupling reactions, 148–158 Mizoroki–Heck-type coupling reactions, 178 Negishi-type coupling reactions, 165–166 Suzuki–Miyaura-type couplings, 173–174

282

F Fe2(dobdc)
2C2D4, 258, 259f Ferrocenyl polyphosphine ligands, 105–106

G Glaser reaction, 118 Group 10-mediated reactions catalytic tests, 105–106 ferrocenyl polyphosphine ligands, 105–106 ligand transfer processes, 105 Ni–Cu bimetallic complexes, 106–107, 107f palladium, 104–106 phosphine ligands, 106 Pincer ligands, 106–107 Sonogashira reaction, 105, 105s transmetallation, 104–105

H Huisgen cycloadditions. See 1,3-Dipolar cycloadditions Hydroepoxyisochromene, 82 Hydrogenolysis, C–O bonds alcohols, 208–209 carbamates, 207 esters, 207–208 ethers aryl and benzyl ethers, 202, 202s aryl methyl ethers, 199–200, 199s β–hydride elimination, 200–201, 203–204 C(sp2)–OMe bonds, 202, 203s C–OMe reductive cleavage, 200–201, 201s dehydroaryloxylation pathway, 206 deoxygenative reduction, 199 external reductant, 204–205, 205s iron-based process, 205 lignin, 199 NHC pathway, 203 nickel catalysts, 205 NMR spectroscopy, 201–202 oxidative addition mechanism, 203–204 PCy3, 204–205 Ph–OPh, 203 Pincer complexes, 206, 206s

Index

Hydropalladation, 170–171 Hydrorhodation, 171

I Insertion reaction B–H insertion, 49–50 metal carbenes, 35–36, 35s In situ solution synthesis alkane complexes, photogeneration of, 231–232, 232f Cr(CO)6 photolysis, 231–232 cyclic alkanes, 232–234 krypton solvent, 232–234 Mn(η–C5H5)(CO)2(ethane), 235–236 photoacoustic calorimetric studies, 232–234 Re(η–C5H5)(CO)2(CH4), 235–236 Rh(η–C5H5)(CO)(alkane), 232–234 time-resolved infrared spectroscopy (TRIR), 231–232 UV–vis laser flash photolysis, 234–235 W(CO)5(alkane), equilibrium measurements, 232–234, 233f Iron(II) porphyrin, 253 Isoquinolinium/pyridinium methylides, 65–66, 66s Isoxazoles synthesis, 122, 123s

K [K2(XAT)(hexane)], 255–256, 256f [K2(XAT)(toluene)], 255–256, 256f Keto–iminium trapping, 78–79 Kinugasa reaction, 124–125, 125s Kl€aui’s ligand, 243–245, 245f KTC-type coupling reactions benzyl alcohols free alcohols, 163 naphthols, 162, 162s salt formation, 163 X-ray crystallographic analysis, 162 carbamates aryl carbamates, 159–160, 159s EtMgBr, 158–159 PPh3, 158–159 vinyl carbamates, 158–159, 159s esters FeCl3, 161 ligand-free conditions, 160

Index

2-pyrones, 160, 161s vinyl acetates, 161, 161s vinyl pivalates, 160, 160s ethers anisole derivatives, 151, 152s aryl and vinyl ethers, 148, 148s aryl heteroaryl ethers, 149–150 benzyl methoxyethyl ethers, 157–158, 157s benzylmethyl ethers, 156–157, 156s C–O electrophiles, 148–149 C(sp2)–OMe cleavage, 153, 154s, 155–156 counterion, 153 cyclic vinyl ethers, 150–151, 150–151s Grignard reagents, 151–153 nickel catalysts, 153–154 NiCl2(dppf ), 155–156 phosphines, 151, 152s silyl enol, 148–149, 149s tetrahydrofurans, 157–158, 158s trialkylphosphines, 151–153 uncatalyzed reactions and stoichiometric experiments acyclic ethers, 146, 146s aryl methyl ethers, 146–147, 147s C–O bonds, cleavage of, 147, 147s cyclic ethers, 146, 146s Grignard reagents, 146–147 Ni catalysts, 147 nucleophilic aromatic substitution, 146–147 Kumada–Tamao–Corriu (KTC) reactions, 144–145, 145s

L Lewis acid addition, 65, 65s Ligand transfer processes, 105 (+)–Lithospermic acid, 41, 41s

M Magic angle spinning solid-stateNMR spectroscopy (MAS SSNMR), 262 Mannich coupling, 115 M⋯X distances, 259–260 MCRs. See Multicomponent reactions (MCRs)

283 Metalation–deprotonation pathway, 189–190 Metal-based catalysis cycloadditions [2C+n], 51–60 [3C+n], 61–66 [4C+n], 67–69 [5C+n], 69 [6C+n], 70 miscellaneous, 70–71 insertion reaction B–H, 49–50 C–H functionalization, 35–43 N–H, 44–45 O–H, 45–47 S–H, 47–48 Si–H, 48–49 ylide formation cascade reaction, 79–82 trapping tactic, 71–79 Metal carbenes, 1 insertion reactions of, 35–36, 35s transformations acceptor/acceptor-substituted, 5–8 acceptor-substituted, 8–12 donor/acceptor-substituted, 12–22 donor-and donor/donor-substituted, 22–25 traditional transformations of, 3–4, 4s Metal-catalyzed cross–coupling reactions, 144 Metal-organic framework (MOF), 230–231, 257–258 M⋯H–C interaction, 225–226 Michael–aldol-type reaction, 72, 73s Miscellaneous C–C Bond-forming reactions aryl esters, α–arylations of aryl pivalates, 184–185 benzyl esters, 184–185 cyclic amides, 184–185 ketone derivatives, 184–185, 185s benzyl esters benzyl acetate substrates, 181–182, 182s chiral ligands, 182 dimethylmalonates, 182, 182s dppf, 182–183 methylene compounds, 182–183

284 Miscellaneous C–C Bond-forming reactions (Continued ) phenyl acetonitrile derivatives, 183–184, 184s C–H/C–O coupling reactions aryl carbamates, 188, 188s Cs2CO3, 189–190 metalation–deprotonation pathway, 189–190 oxazole and thiazole derivatives, 188–189, 189s vinyl acetates, 187–188, 188s reductive coupling reactions aryl and benzyl pivalates, 186–187, 186–187s aryl halides, 186, 186s C–O electrophiles, 186 reductive amidation, 187, 187s reductive carboxylations, 186–187, 186s vinyl acetate, 186, 186s Miscellaneous cycloaddition, 70–71 Miscellaneous reactions metal–allenylidene species, 126 nucleophilic substitution, 126–127, 126s propargylic amines, 126, 127–128s transition metal catalysis, 126 Mizoroki–Heck-type coupling reactions esters aryl pivalates, 177, 178s benzyl trifluoroacetates, 176, 177s cyclic olefins, 177 vinyl pivalate, 177 ethers benzyl alkyl ethers, 178, 178s olefin, 178 Multicomponent reactions (MCRs), 16 M–X bonds, 226, 227f

N N–Boc imines, 72–73, 73s Negishi-type coupling reactions esters aryl pivalates, 163, 164s benzyl ester derivatives, 164–165, 164s classical organometallic pathway, 163 Me2Zn, 165 racemization, 164–165 radical-type pathways, 164–165

Index

ethers bond-dissociation energy, 165–166 C–O functionalization, 166 dianion-type organozincates, 165–166, 166s N–Heterocyclic carbene (NHC), 150–151 N–H insertion α–alkyl–α–diazoesters, 44, 45s α–diazocarbonyl compound, 44 α–diazoketones, 44, 45s chiral spiro copper catalyst, 44 proton transfer, 44 telomestatin, 45, 46s Nickel catalysts, 153–154, 205 N–iminopyridinium ylides, 65, 65s Nitrones, 124–125 NMR metal alkyls, protonation of chain walking, 250–252 D–labeled alkyl hydrides, 248–250 Rh(PONOP)(H3CCH3)][BArF4], 250, 251f Rh(PONOP)(η2–H4C)][BArF4], 248–250, 249f Shilov-type oxidation, 248–250 σ–alkane complexes, 252 σ–methane complex, 248–250 photogeneration strategies chain-walking barriers, 246–248 C–H oxidative cleavage, 240–241 cyclohexane, 240, 240f isomer chemical shifts, 242–243 isopentane, 242–243, 245f J(CH) coupling constants, 241–242 Kl€aui’s ligand, 243–245, 245f Mn(η–C5H5)(CO)3, 242–243, 244f pentane binding, 239, 239f Re(η–C5H5)(CO)2(η2-C5H10), 238–239, 238f Re(η5–C5H5)(CO)2(η2–2,2– dimethylbutane), 241–242, 242f Re(Tp)(CO)2, 240–241, 242f [Re(η–hexaethylbenzene) (CO)2(η2–C5H10)][Al(OC (CF3)3)4], 246–248, 247f TRIR spectroscopy, 237–238 W(η–hexaethylbenzene) (CO)2(η2–pentane), 245–246, 246f

285

Index

(+)-Norrisolide, 56 Nucleophilic substitution, 126–127, 126s

O O–H insertion α–aryl–α-aryloxyacetates, 46, 47s copper-catalyzed intramolecular insertion, 46, 46s diazo compounds, 45–46 (+)–steenkrotin, 47, 47s ()–steenkrotin A, 47, 47s One-pot subsequent cyclizations, 73, 73s Organometallic compounds β–hydride elimination, 179–181 neosilyllithium, 179–180, 179s trialkylaluminum, 180–181 trimethylaluminum, 180–181, 181s Oxetane macrocyclization, 71, 71s Oxidative coupling reactions cross–coupling reactions alkynes, copper-assisted phosphorylation of, 102–103, 103s asymmetrical diyne preparation, 101 C–H bond activation, 103 cross–dehydrogenative coupling, 103, 104s DFT, 102 of nucleophilic trifluoromethylating reagent, 101, 102s of organolithium and magnesium reagents, 101, 101s umpolung oxidative couplings, 103 Glaser and Hay coupling reactions alkynes, 96–97 catalyst precursors, 97–99 computational proposal for, 99–100, 100s copper(I) phenylacetylide, 96 free radicals, 96–97 intermediate dimeric copper(II) acetylides in, 96–97, 97f intermolecular deprotonations, 99–100 N,N,NʹNʹ– tetramethylethylenediamine (TMEDA), 96–99 O¼O bond cleavage, 99–100 two-electron transfer, 99–100

P (–)–Paeonilide, 56 Palladium, 104–106 Pentadiene precursor complex, 264–265, 264f Phenanthroline, 113 Phenol derivatives carbon–carbon bond formation KTC-type coupling reactions, 146–163 miscellaneous C–C bond-forming reactions, 181–190 Mizoroki–Heck-type coupling reactions, 176–178 Negishi-type coupling reactions, 163–166 organometallic compounds, 179–181 Stille-type couplings, 179 Suzuki–Miyaura-type couplings, 166–176 carbon–heteroatom bond-formation C–B, 192–196 C–N, 190–192 C–P, 198 C–Si, 196–198 C–O bonds, hydrogenolysis of alcohols, 208–209 carbamates, 207 esters, 207–208 ethers, 199–206 Phenyl acetonitrile derivatives, 183–184, 184s Phenyltetrazole ethers, 149–150 Phosphines, 151, 152s Photoacoustic calorimetric studies, 232–234 Pincer complexes, 206, 206s Pincer ligands, 106–107 Polyfunctionalized indole, 42, 42s Poly–NHC ligands, 113 Polysubstituted tetrahydrofurans, 74, 74s Porphyrin ligands, 19 Powder neutron diffraction study, 259–260 ()–Preussin, 81, 81s Propargylic amines reaction C–C bond in, 128, 128s copper-mediated, 126–127, 127s substitution reactions of, 128, 128s Propiolates, 112–113, 113s Protic ammonium ylides, 75–76

286 Protic onium ylides, 71, 72s Proton transfer process, 35–36 Pyridinium zwitterions, 69, 70s Pyrrole, 43, 43s benzannulation of, 67, 67s Pyrrolidines, 74–75, 75s

Q Quantum theory of atoms in molecules (QTAIM), 227–228, 261–262

R Re(η–C5H5)(CO)2(CH4), 235–236 Re(η–C5H5)(CO)2(η2–C5H10), 238–239, 238f Re(η5–C5H5) (CO)2(η2–2,2–dimethylbutane), 241–242, 242f Re(Tp)(CO)2, 240–241, 242f Reductive amidation, 187, 187s Reductive carboxylations, 186–187, 186s [Rh(L2)(η2:η2–C7H12)][BArF4], 260–261, 261f Rh(PONOP)(H3CCH3)][BArF4], 250, 251f Rh(PONOP)(η2–H4C)][BArF4], 248–250, 249f Rh⋯X distance, 256–257 Rhodium–carbene, 35–36 Rhodium(III)-catalyzed C–H cyclization, 5, 6s Rhodium σ–alkane complexes, 253–255 Ruthenium(II) porphyrin catalysts, 10–11

S Secondary carbenes, 110, 110s Shilov-type oxidation, 248–250 S–H insertion, 47–48 σ-Alkane complex synthesis, 230–231, 231f σ–Donor ligands, 113–114 Si–H insertion α–chiral silanes, 48 α–diazoesters, 48–49, 48s triethylsilane, 49 virginiamycin M2, 49, 49s Silanes (HSiR3), 225–226 Silver mediate [2+2+1] cycloaddition, 60, 60s Silver triflate, 59

Index

Single-site model, 258 Sonogashira reaction, 105, 105s Spiroketal bisphosphine, 54 ()–Steenkrotin A, 47, 47s Stemofoline alkaloids, 63 Stereodivergent strategy, 78 Stille-type couplings, 179 Surrogate benzene ligand, 256–257 Suzuki–Miyaura-type couplings alcohols benzylic C(sp3)–OH bonds, 175–176, 176s boroxines, 175, 175s carbamates aryl carbamates, 167–168, 167s benzyl carbamates, 168, 168s boroxine/boronic acid equilibrium, 167–168 SIMes (L2), 168 esters aryl ester derivatives, 169–170, 169s benzyl acetates, 169, 169s benzyl pivalates, 172, 172s cross–coupling mechanism, 169–170 hydropalladation, 170–171 hydrorhodation, 171 Rh-catalyst, 171 transmetalation, 170–171 vinyl acetate derivatives, 170–171, 170–171s ethers alkyl ketones, 173, 173s amides, 173, 173s aryl and benzyl methyl ethers, 174, 175s aryl methyl ethers, 174, 174s cross–coupling mechanism, 174

T Telomestatin, 45, 46s Tetrahydrofurans, 157–158, 158s N,N,Nʹ,Nʹ–Tetramethylethylenediamine (TMEDA), 96–99 Three-center two-electron interaction, 225–226 Time-resolved infrared spectroscopy (TRIR), 231–232 Transition metal alkane-sigma complexes

287

Index

alkane complexes, preorganized vacant site, 252–260 alkenes, hydrogenation of, 260–265 C–H σ-complexes, 223–227 in situ solution synthesis, 231–236 ligand, photoejection of, 231–236 NMR studies metal alkyls, protonation of, 248–252 photogeneration strategies, 237–248 nomenclature comments, 227–229 σ–alkane complex synthesis, 230–231 Transmetallation, 104–105 Trapping tactic, protic onium ylides, 71, 72s Trialkylaluminum, 180–181 Trialkylphosphines, 151–153 Trimethylaluminum, 180–181, 181s Tropone reactions, 70s Two agostic M⋯H-C complexes, 228–229, 229f

U U⋯C interactions, 253–255 Umpolung oxidative couplings, 103 Unprotected phenols, 37, 37s

V Vinyl/acceptor-substituted metal carbenes dirhodium(II) catalysts, 20 enoldiazoacetamides, 21–22, 21s enoldiazoacetates, 19–20, 20s nitrones, [3+3]-cycloaddition, 20 vinyldiazoacetates, 21–22, 22s Vinyldiazoacetates, 80

W W(η–hexaethylbenzene) (CO)2(η2–pentane), 245–246, 246f

Y Ylide formation cascade reaction, 79–82 trapping tactic α–amino phosphonic acid compounds, 76–77 ammonium ylide, 71–72 aryldiazoacetates, 78–79, 79s autotandem catalytic process, 73–74 chiral morpholines, 73, 73s Conia-ene cyclization, 78 cyclic enamine, 78–79 delayed proton transfer, 71–72 diastereoselectivity, 75–76 diazophosphonates, 76–77, 77s diversity-oriented synthesis (DOS), 73 diverted carbene insertion, 75 keto-iminium, 78–79 Michael–aldol-type reaction, 72, 73s multicomponent reactions (MCRs), 71 N-Boc imines, 72–73, 73s one-pot subsequent cyclizations, 73, 73s oxonium ylide, 73–74, 74s polysubstituted tetrahydrofurans, 74, 74s protic ammonium ylides, 75–76 protic onium ylides, 71, 72s pyrrolidines, 74–75, 75s rhodium(II)/chiral phosphoric acid cooperative catalysis strategy, 75–76 stereodivergent strategy, 78 tetrahydrofurans, 74–75, 75s three-component coupling reaction, 76–77, 77s

Z Zwitterionic intermediates, 43