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Transition-Metal-Catalyzed C-H Functionalization of Heterocycles
Transition-Metal-Catalyzed C-H Functionalization
of Heterocycles
Edited by
Tharmalingam Punniyamurthy
Indian Institute of Technology Guwahati
Guwahati, India
Anil Kumar
Birla Institute of Technology and Science, Pilani
Pilani, India
Volume 1
This edition first published 2023
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v
Contents
List of Contributors xiii

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

Tariq M. Bhatti, Eileen Yasmin, Akshai Kumar, and Alan S. Goldman
1.1 Introduction 1
1.2 Electrophilic C–H Bond Activation and Concerted Metalation Deprotonation 2
1.2.1 The (Very) Early Years - from Mercury to the Palladium Era 2
1.2.2 Modern Concerted Metalation Deprotonation 4
1.2.3 Classic Electrophilic C–H Activation 6
1.2.3.1 Electrophilic Auration of Arenes 6
1.2.3.2 The Shilov Reaction 7
1.2.3.3 Post-Shilov Electrophilic Activation 8
1.3 Oxidative Addition 9
1.3.1 Stoichiometric Oxidative Addition of C–H Bonds 9
1.3.2 Mechanistic Pathways and the Oxidative Addition Continuum 12
1.3.3 Catalytic Reactions Proceeding via Oxidative Addition 13
1.3.3.1 H/D Exchange 13
1.3.3.2 Alkane Dehydrogenation 14
1.3.3.3 Alkane Dehydrogenation by High-Oxidation-State Catalysts 17
1.3.3.4 Applications of Dehydrogenation in Heterocyclic Chemistry 18
1.3.3.5 Borylation 19
1.4 Insertion Reactions 21
1.5 Site-directed C–H Activation 24
1.6 Sigma-Bond Metathesis 26
1.6.1 Hydrogenolysis and the Discovery of Four-Centered Transition States 26
1.6.2 C–H Activation in Actinide Complexes 28
1.6.3 Identification of a New Mechanism 29
1.6.4 Emerging Applications of Sigma Bond Metathesis 29
1.6.5 Hydromethylation of Olefins 29
1.6.6 Pyridine Hydroalkylation by Orthometalation 30
1.7 1,2-Addition 32
1.7.1 Metal Oxos and Imidos 32
1.7.2 Metal Alkylidenes 33
1.7.3 Intermolecular C–H Activation by 1,2-Addition 33
1.8 Sigma Complexes: Unifying Intermediates in C–H Activation 35
1.9 Base Metals in C–H Activation 37
1.10 Conclusions and Future Outlook 41
Acknowledgments 41
vi Contents
2 Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms 61

B. Prabagar and Zhuangzhi Shi
2.1 Introduction 61
2.1.1 Importance of Pyrrole, Furan and Thiophene Derivatives 61
2.1.2 General Reactivities of Pyrrole, Furan, and Thiophene 61
2.2 Transition Metal-Catalyzed C–H Functionalization of Pyrroles 63
2.2.1 C–H Arylation of Pyrroles 63
2.2.2 C–H Alkylation of Pyrroles 69
2.2.3 C–H Alkenylation of Pyrroles 74
2.2.4 C–H Alkynylation of Pyrroles 77
2.2.5 C–H Borylation of Pyrroles 80
2.2.6 C–H Amidation of Pyrroles 81
2.2.7 C–H Silylation of Pyrroles 82
2.3 Transition Metal-Catalyzed C–H Functionalization of Furans 84
2.3.1 C–H Arylation of Furans 84
2.3.2 C–H Alkenylation of Furans 86
2.3.3 C–H Alkylation of Furans 88
2.3.4 C–H Alkynylation of Furans 89
2.3.5 C–H Borylation of Furans 89
2.3.6 C–H Silylation of Furans 89
2.4 Transition Metal-Catalyzed C–H Functionalization of Thiophenes 91
2.4.1 C–H Arylation of Thiophene 91
2.4.2 C–H Alkylation of Thiophene 95
2.4.3 C–H Alkenylation of Thiophene 98
2.4.4 C–H Alkynylation of Thiophene 98
2.4.5 C–H Borylation of Thiophene 100
2.4.6 C–H Silylation of Thiophene 100
2.4.7 C–H Amidation of Thiophene 102
2.5 Conclusions and Prospective 102
3 Functionalization of Five-membered Heterocycles with Two Heteroatoms 109

Jung Min Joo
3.1 Introduction 109
3.2 Arylation 110
3.2.1 Arylation of Oxazole and Thiazole 110
3.2.1.1 C-2 Arylation of Oxazole and Thiazole 110
3.2.1.2 C5 Arylation of Oxazole and Thiazole 115
3.2.1.3 C4 Arylation of Oxazole and Thiazole 117
3.2.2 Arylation of Imidazole 117
3.2.2.1 C2 Arylation of Imidazole 117
3.2.2.2 C5 Arylation of Imidazole 119
3.2.3 Sequential and Multi-arylation of 1,3-azoles 121
3.2.4 Arylation of Pyrazole 123
3.2.5 Arylation of Isoxazole 126
3.3 Alkenylation 127
3.3.1 Alkenylation of Oxazole and Thiazole 127
3.3.1.1 C2 Alkenylation of Oxazole and Thiazole 127
3.3.1.2 C5 Alkenylation of Oxazole and Thiazole 129
3.3.1.3 C4 Alkenylation of Oxazole 131
3.3.2 Alkenylation of Imidazole 131
3.3.3 Alkenylation of Pyrazole 131
3.3.4 Alkenylation of Isoxazole 133
Contents vii
3.4 Alkynylation 134

3.4.1 Alkynylation with Haloalkynes 134
3.4.2 Alkynylation with gem-Dihaloalkenes 135
3.4.3 Alkynylation with Terminal Alkynes 135
3.5 Alkylation 136
3.5.1 Alkylation of Oxazole and Thiazole 136
3.5.1.1 C2 Alkylation of Oxazole and Thiazole 136
3.5.1.2 C5 Alkylation of Oxazole and Thiazole 139
3.5.2 Alkylation of Imidazole 139
3.5.3 Alkylation of Pyrazole 141
3.6 C–H Heteroatom Bond Forming Reactions 141
3.6.1 Borylation 141
3.6.2 Silylation 142
3.6.3 Thiolation 142
3.6.4 Amination 143
3.7 Conclusions 143
Acknowledgments 144
4 Transition Metal-Catalyzed C–H Functionalization of Indole Benzenoid Ring 155

Vikash Kumar, Rajaram Maayuri, Lusina Mantry, and Parthasarathy Gandeepan
4.2 C4 Functionalization 155
4.2.1 C4 Alkylation 156
4.2.2 C4 Arylation 159
4.2.3 C4 Alkenylation 161
4.2.4 C4 Alkynylation 163
4.2.5 C4 Allylation 163
4.2.6 C4 Acylation 165
4.2.7 C4 Annulation Reactions 165
4.2.8 C4 Amidation 169
4.2.9 C4 Chalcogenation 170
4.3.2 C5 Selenylation 173
4.5.1 C7 Alkylation 175
4.5.3 C7 Alkenylation 176
4.5.4 C7 Alkynylation 177
4.5.5 C7 Carbonylation 182
4.5.6 C7 Amination/amidation 183
4.5.7 C7 Silylation 185
4.6 Conclusions and Outlook 185
Acknowledgments 186
5 Transition Metal-Catalyzed C2 and C3 Functionalization of Indoles 193

Pinki Sihag, Meledath Sudhakaran Keerthana, and Masilamani Jeganmohan
5.2 C2/C3-Functionalization of Indoles 194
viii Contents
5.2.1 Arylation of Indoles 194

5.2.1.1 Non-chelation Assisted C2 Arylation of Indoles 195
5.2.1.2 Chelation-Assisted C2 Arylation of Indoles 197
5.2.1.3 C3 Arylation of Indoles 200
5.2.2 Heteroarylation 201
5.2.2.1 C2 Heteroarylation 201
5.2.2.2 C3 Heteroarylation 203
5.2.2.3 C2 Alkenylation of Indoles 204
5.2.2.4 C3 Alkenylations of Indoles 210
5.2.2.5 C2 Alkynylation of Indoles 211
5.2.2.6 C3 Alkynylations of Indoles 213
5.2.2.7 C2 Allylation of Indoles 213
5.2.2.8 C3 Allylations of Indoles 217
5.2.2.9 C2 Acylation of Indoles 218
5.2.2.10 C3 Acylations/formylations of Indoles 219
5.2.2.11 C2 Alkylation of Indoles 221
5.2.2.12 C3 Alkylation of Indoles 227
5.2.3 C2 Nitration of Indoles 229
5.2.3.1 C2 Borylation of Indoles 229
5.2.3.2 C3 Borylations of Indoles 229
5.2.4 Cyanation of Indoles 230
5.2.4.1 C2 Cyanation of Indole 230
5.2.4.2 C3 Cyanation of Indoles 231
5.2.5 Annulation of Indoles 232
5.2.5.1 C2 Amidation of Indoles 237
5.2.6 Miscellaneous Reactions 238
5.3 Conclusions 240
Acknowledgments 241
6 C(sp2)–H Functionalization of Indolines at the C7-Position 251

Neeraj Kumar Mishra and In Su Kim
6.1.1 C−H Bond Arylation of Indolines at C7-Position 252
6.1.2 C−H Bond Alkenylation (Olefination) of Indolines at the C7-Position 260
6.1.3 C−H Bond Alkynylation of Indolines at the C7-Position 265
6.1.4 C−H Bond Alkylation of Indolines at the C7-Position 268
6.1.5 C−H Bond Allylation of Indolines at the C7-Position 279
6.1.6 C−H Bond Acylation of Indolines at the C7-Position 282
6.1.7 C−N Bond Formations at the C7-Position of Indolines 287
6.1.7.1 C7-Amination and/or Amidation of Indolines 287
6.1.7.2 C7-Nitration of Indolines 296
6.1.8 C−H Bond Cyanation of Indolines at the C7-Position 298
6.1.9 C−B, C−O, C−P, and C−S Bond Formation of Indolines at the C7-Position 299
6.1.9.1 C−B Bond Formation 300
6.1.9.2 C−O Bond Formation 300
6.1.9.3 C−P Bond Formation 303
6.1.9.4 C−S Bond Formation 303
6.1.10 C−H Bond Halogenation of Indolines at the C7-Position 306
6.1.11 C−H Bond Trifluoroalkylation of Indolines at the C7-Position 307
6.2 Conclusions 308
Contents ix
7 Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms 319
Tanumay Sarkar, Subhradeep Kar, Prabhat Kumar Maharana, Tariq. A. Shah, and Tharmalingam Punniyamurthy
7.2 C−C Bond Formation 320
7.2.1 Alkylation 320
7.2.1.1 Copper Catalysis 320
7.2.1.2 Nickel Catalysis 321
7.2.1.3 Palladium Catalysis 322
7.2.1.4 Rhodium Catalysis 325
7.2.2 Alkenylation 326
7.2.2.3 Cobalt Catalysis 328
7.2.3 Alkynylation 330
7.2.3.1 Copper-Mediated Reactions 330
7.2.4 Arylation 333
7.2.4.3 Cobalt Catalysis 337
7.2.4.4 Iron Catalysis 337
7.3 C−N Bond Formation 340
7.3.1 Copper Catalysis 340
7.3.2 Iron Catalysis 342
7.3.3 Miscellaneous 344
7.4 C−P Bond Formation 344
7.4.2 Manganese-Mediated Reaction 345
7.4.3 Silver-Mediated Reaction 345
7.4.4 Palladium Catalysis 346
7.5 C−S Bond Formation 346
7.5.2 Iron Catalysis 348
7.5.3 Silver Catalysis 348
7.5.4 Rhodium Catalysis 349
7.6 C−O Bond Formation 349
7.7 C−Halogen Bond Formation 349
7.8 Conclusions and Outlook 350
Acknowledgments 350
xi
Brief Contents
Volume 1:

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

Tariq M. Bhatti, Eileen Yasmin, Akshai Kumar, and Alan S. Goldman
2 Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms 61

B. Prabagar and Zhuangzhi Shi
3 Functionalization of Five-membered Heterocycles with Two Heteroatoms 109

Jung Min Joo
4 Transition Metal-Catalyzed C–H Functionalization of Indole Benzenoid Ring 155

Vikash Kumar, Rajaram Maayuri, Lusina Mantry, and Parthasarathy Gandeepan
5 Transition Metal-Catalyzed C2 and C3 Functionalization of Indoles 193

Pinki Sihag, Meledath Sudhakaran Keerthana, and Masilamani Jeganmohan
6 C(sp2)–H Functionalization of Indolines at the C7-Position 251

Neeraj Kumar Mishra and In Su Kim
7 Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms 319
Tanumay Sarkar, Subhradeep Kar, Prabhat Kumar Maharana, Tariq. A. Shah, and Tharmalingam Punniyamurthy
Volume 2:
8 Functionalization of Pyridines, Quinolines, and Isoquinolines 357

Jun Zhou and Bing-Feng Shi
9 Transition Metal-catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives 393
Christian Bruneau and Rafael Gramage-Doria
10 Functionalization of Chromenes and Their Derivatives 435

Laura Cunningham, Sundaravel Vivek Kumar, and Patrick J. Guiry
xii Brief Contents
11 Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles 485

Rajeev Sakhuja and Anil Kumar
12 Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles 543

Neha Jha and Manmohan Kapur
13 C–H Functionalization of Saturated Heterocycles Beyond the C2 Position 567

Amalia-Sofia Piticari, Natalia Larionova, and James A. Bull
14 Asymmetric Functionalization of C–H Bonds in Heterocycles 609

Olena Kuleshova and Laurean Ilies
15 Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases 631

Yong Liang and Stanislaw F. Wnuk
16 C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides 657

Morgane de Robichon, Juba Ghouilem, Angélique Ferry, and Samir Messaoudi
17 Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals 683

Harshita Shet and Anant R. Kapdi
18 Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products 703

François Richard, Elias Selmi-Higashi, and Stellios Arseniyadis
Index 727
xiii
List of Contributors
Stellios Arseniyadis University of Rennes, CNRS

Queen Mary University of London ISCR-UMR6226, F-35000 Rennes, France
Department of Chemistry
Mile End Road Parthasarathy Gandeepan
London, E1 4NS, UK Department of Chemistry
Indian Institute of Technology Tirupati
Tariq M. Bhatti Tirupati – Renigunta Road, Settipalli Post
Department of Chemistry and Chemical Biology, Rutgers Tirupati 517506, India
The State University of New Jersey
New Brunswick, New Jersey 08903, United States Juba Ghouilem
Université Paris-Saclay, CNRS, BioCIS
Christian Bruneau 92290, Châtenay-Malabry, France
Institut des Sciences Chimiques de Rennes UMR6226
University of Rennes, CNRS Alan S. Goldman
ISCR-UMR6226, F-35000 Rennes, France Department of Chemistry and Chemical Biology, Rutgers
The State University of New Jersey
James A. Bull New Brunswick, New Jersey 08903, United States
Imperial College London Patrick J. Guiry
Wood Lane, London, W12 0BZ, UK Centre for Synthesis and Chemical Biology
UCD School of Chemistry, University College Dublin
Laura Cunningham Belfield, Dublin 4, Ireland
Centre for Synthesis and Chemical Biology
UCD School of Chemistry, University College Dublin Laurean Ilies
Belfield, Dublin 4, Ireland RIKEN Center for Sustainable Resource Science
2-1 Hirosawa, Wako
Morgane de Robichon Saitama 351-0198, Japan
CY Cergy-Paris Université, CNRS, BioCIS
Equipe de Chimie Biologique Masilamani Jeganmohan
95000 Neuville sur Oise, France Department of Chemistry
Indian Institute of Technology Madras
Angélique Ferry Chennai 600036, India
CY Cergy-Paris Université, CNRS, BioCIS
Equipe de Chimie Biologique Neha Jha
95000 Neuville sur Oise, France Department of Chemistry
Indian Institute of Science Education and Research Bhopal
Rafael Gramage-Doria Bhauri, Bhopal 462066, India
Institut des Sciences Chimiques de Rennes UMR6226
xiv List of Contributors
Jung Min Joo Vikash Kumar

Department of Chemistry Department of Chemistry
Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu Indian Institute of Technology Tirupati
Seoul 02447, Republic of Korea Tirupati – Renigunta Road, Settipalli Post
Tirupati 517506, India
Anant R. Kapdi
Department of Chemistry Rajaram Maayuri
Institute of Chemical Technology Department of Chemistry
Nathalal Parekh Road, Matunga Indian Institute of Technology Tirupati
Mumbai 400019, India Tirupati – Renigunta Road, Settipalli Post
Tirupati 517506, India
Manmohan Kapur
Department of Chemistry Prabhat Kumar Maharana
Indian Institute of Science Education and Research Bhopal Department of Chemistry
Bhauri, Bhopal 462066, India Indian Institute of Technology Guwahati
Guwahati 781039, India
Subhradeep Kar
Department of Chemistry Natalia Larionova
Indian Institute of Technology Guwahati Department of Chemistry
Guwahati 781039, India Imperial College London
Wood Lane, London, W12 0BZ, UK
Meledath Sudhakaran Keerthana
Department of Chemistry Yong Liang
Indian Institute of Technology Madras Department of Molecular Medicine
Chennai 600036, India Beckman Research Institute of the City of Hope
Duarte, CA 91010, US
In Su Kim
School of Pharmacy Lusina Mantry
Sungkyunkwan University Department of Chemistry
Suwon 16419, Republic of Korea Indian Institute of Technology Tirupati
Tirupati – Renigunta Road, Settipalli Post
Olena Kuleshova Tirupati 517506, India
RIKEN Center for Sustainable Resource Science
2-1 Hirosawa, Wako Samir Messaoudi
Saitama 351-0198, Japan Université Paris-Saclay, CNRS
BioCIS, 92290, Châtenay-Malabry, France
Akshai Kumar
Centre for Nanotechnology Neeraj Kumar Mishra
Indian Institute of Technology Guwahati School of Pharmacy
Guwahati 781039, India Sungkyunkwan University
Suwon 16419, Republic of Korea
Anil Kumar
Department of Chemistry Amalia-Sofia Piticari
Birla Institute of Technology and Science, Pilani Department of Chemistry
Pilani 333031, India Imperial College London
Wood Lane, London, W12 0BZ, UK
Sundaravel Vivek Kumar
Centre for Synthesis and Chemical Biology B. Prabagar
UCD School of Chemistry, University College Dublin School of Chemistry and Chemical Engineering
Belfield, Dublin 4, Ireland Nanjing University, Nanjing 210093, China
List of Contributors xv
Tharmalingam Punniyamurthy Nathalal Parekh Road, Matunga

Department of Chemistry Mumbai 400019, India
Guwahati 781039, India Bing-Feng Shi
François Richard Zhejiang University
Queen Mary University of London 38 Zheda Rd., Hangzhou 310027, China
Mile End Road, London, E1 4NS, UK Zhuangzhi Shi
School of Chemistry and Chemical Engineering
Rajeev Sakhuja Nanjing University
Department of Chemistry Nanjing 210093, China
Birla Institute of Technology and Science, Pilani
Pilani 333031, India Pinki Sihag
Tanumay Sarkar Indian Institute of Technology Madras
Department of Chemistry Chennai 600036, India
Guwahati 781039, India Stanislaw F. Wnuk
Department of Chemistry and Biochemistry
Elias Selmi-Higash Florida International University
Queen Mary University of London Miami, FL 33199, US
Mile End Road, London, E1 4NS, UK Eileen Yasmin
Tariq. A. Shah Indian Institute of Technology Guwahati
Department of Chemistry Guwahati 781039, India
University of Kashmir
Srinagar 190006, India Jun Zhou
School of Chemistry and Chemical Engineering
Harshita Shet Changsha University of Science and Technology
Department of Chemistry Changsha 410114, China
Institute of Chemical Technology
xvii
Preface
Heterocycles are ubiquitous structural scaffolds in bioactive molecules, functional materials and natural products. The
complexity in their structural aspect has ensured humanity with a series of diversified novel compounds, unveiling an
array of reactivity and stability. Synthesis and modification of heterocyclic compounds is thus an ever-expanding field in
synthetic chemistry. Over the past three decades, transition metal-catalyzed C-H bond functionalization has attracted con-
siderable attention as an atom-economical and sustainable technology for the carbon-carbon and carbon-heteroatom bond
formations. This approach has allowed rapid access to a library of functionalized heterocyclic compounds from simple
substrates via divergent synthetic methodologies. The objective of this book is to focus on the developments in transition
metal-catalyzed C-H functionalization of heterocycles. The methods described will allow for unprecedented disconnec-
tions in complex heterocyclic molecules. Through its eighteen chapters the reader would get an up-to-date of the C-H bond
functionalization developed for a particular type of heterocycle. They are organized according to the type of heterocyclic
structural frameworks.
A brief history of C-H activation and the mechanistic aspects of transition metal-catalyzed C-H bond activation reactions
is presented in chapter 1.
In the subsequent chapter, the principal focus is on the developments of C-H arylation, alkenylation, alkynylation, alkyl-
ation, borylation, silylation and amidation of five-membered heterocycles with a single heteroatom viz. pyrroles, furans
and thiophenes.
The transition metal-catalyzed C-H functionalization of five-membered heterocycles with two heteroatoms, viz. oxa-
zoles, thiazoles, imidazoles, and pyrazoles has been emphasized in chapter 3. Key factors for the regioselectivity and mech-
anistic details are also demonstrated.
Chapter 4 pertinently focusses on the transition metal-catalyzed site-selective C-H functionalization of benzene core of
indoles. The chapter is organized based on the site of functionalization and subdivided based on the type of reactions.
Chapter 5 details the site-selective C-2 and C-3 functionalization of indoles leading to the formation of carbon-carbon
and carbon-heteroatom bonds, including arylation, alkenylation, allylation, alkylation, borylation, cyanation, amidation
and annulation while the next chapter effectively describes the transition metal-catalyzed site-selective C-7 functionaliza-
tion of indolines using diverse coupling partners.
The transition metal-catalyzed C-H bond functionalization of benzo-fused azoles with two or more heteroatoms is pre-
sented in chapter 7.
In chapter 8, the transition metal-catalyzed direct C(sp2)-H bond functionalization of pyridine, quinoline, and isoquino-
line derivatives is demonstrated in accordance with the mechanism and scope of the methodology.
In chapter 9, an in-depth discussion of the transition metal-catalyzed C-H bond functionalization of diazines and benzo-
diazines has been conferred. Mechanism of selected reactions and late stage C-H bond olefination of Gefitinib (an anti-
cancer drug) are established. Subsequently, chapter 10 discusses the methods developed for the C-H bond functionalization
of chromene derivatives using transition-metal-catalysts, also including some key mechanistic cycles.
In chapter 11, the C-H functionalization of imidazo-fused heterocycles under transition metal-catalysis has been rele-
vantly disclosed along with the generalized mechanism.
Chapter 12 discusses the methodologies of transition metal-catalyzed dehydrogenative annulation of heterocycles
leading to generation of fused heterocycles while in chapter 13, the transition metal-catalyzed C(sp3)-H bond functional-
ization of saturated heterocycles has been covered at positions remote from the heteroatom.
xviii Preface
In chapter 14, the methods for the asymmetric C-H bond functionalization of heterocycles have been discussed wherein,
most of the reactions covered proceed through inner-sphere C-H activation mechanisms.
A concise overview of strategies for direct functionalization of nucleobases, including uracil, pyrimidine and purine with
alkyl, alkenyl or (hetero)aryl groups is provided in chapter 15.
In chapter 16, different strategies to access C-aryl glycosides by C(sp2)-H and C(sp3)-H functionalization under the tran-
sition-metal-catalysis has been overviewed.
Synthesis of natural products and pharmaceutical drugs employing late-stage C-H functionalization strategy has been
emphasised in chapter 17 whereas late-stage C-H functionalization of bioactive molecules, including marketed pharma-
ceuticals and agrochemicals, clinical candidates, and natural products using transition-metal-catalysis is described in the
last chapter of the book.
The book is intended to be a valuable reference source for graduate students and researchers working in the field of
organic synthesis and process development in academia and industry. The chapters written by an outstanding team of
international authors will hopefully be an interesting read and meet the demand of all the readers concerned in further
development of C-H functionalization reactions in the field of heterocyclic chemistry.
Tharmalingam Punniyamurthy
Guwahati, India
August 2022
Anil Kumar
Pilani, India
August 2022
1
Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

Tariq M. Bhatti1, Eileen Yasmin2, Akshai Kumar2,3,4, and Alan S. Goldman1
1
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, United States of America
2
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam, India
3
Centre for Nanotechnology, Indian Institute of Technology Guwahati, Guwahati, Assam, India
4
Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati, Assam, India
1.1 Introduction
The C–H bond is the most common linkage in organic chemistry and, surely not entirely by coincidence, is also one of the
least reactive groups. The bonds of carbon to hydrogen are, of course, terminal bonds in any organic molecule. Therefore,
they cannot contribute to the complexity of a molecule in the same way as C–O, C–N, or, most importantly, C–C bonds.
This terminal nature is shared, for the most part, with bonds to halogens or alkali metals, but (with the exception of C–F
bonds) those bonds are generally far more reactive; indeed, in contrast with C–H bonds, bonds of carbon to halogens, and
even more so to alkali (and other) metals, are viewed by organic chemists as particularly desirable points of opportunity to
create new bonds and increase molecular complexity.
The standard graphical depiction of organic molecules indicates C–H bonds by default, highlighting that the ubiquitous
C–H bond is the singular “unfunctional group” of organic chemistry. Thus, the ability to effect transformations of C–H
bonds is potentially the most powerful class of reactions in organic chemistry. Yet for most of the history of organic chem-
istry the selective functionalization of the most common C–H bonds (sp2 and especially sp3) was considered a largely unre-
alistic goal – however desirable it might be – and was the subject of very little active pursuit.
The challenge of functionalizing C–H bonds has been attributed most simplistically to their high bond strength, but this
is certainly an incomplete explanation at best. The homolytic bond energy of H–F for example is far greater than that of
typical C–H bonds yet no chemist would ever consider H–F to be unreactive. But a high homolytic bond strength combined
with very low polarity and the absence of a lone pair of electrons begins to account for their general lack of reactivity. In
comparing H–C bonds to other covalent H–element bonds, one observes that cleavage by polar reagents is generally uphill
for C–H bonds.
Despite this general tendency to be unreactive, however, there are a fair number of reagents that will readily react with
C–H bonds. O2 is certainly cheap, abundant, and effective in this respect. But this leads to the next great obstacle toward
achieving useful C–H bond functionalization: selectivity. The ubiquitous nature of C–H bonds means that there are often
multiple, and often very similar, possible sites of initial attack. And if that challenge is somehow addressed, one then faces
the unpleasant fact that an initial C–H bond functionalization generally leads to a molecular product with C–H bonds that
are both (a) weaker than those of the starting material, and therefore typically more reactive with respect to homolytic
cleavage, (b) more polar, and therefore typically more reactive in a heterolytic sense. Thus, even if one successfully and
selectively functionalizes a C–H bond, secondary reactions lie waiting to prey upon the initial product.
Thus it is not surprising that for most of the 20th century useful examples of C–H bond functionalization were quite
limited. But in part thanks to the groundwork laid at the end of that century in the field of organotransition chemistry, the
past few decades have seen an explosion of examples of transition metal chemistry exploited to yield highly valuable and
elegant organic transformation. This volume highlights many of the most elegant of such examples. In this introductory
chapter we discuss the fertile ground from which they emerged. Our perspective has of course been shaped by that of many
Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, First Edition. Edited by Tharmalingam Punniyamurthy and Anil Kumar.
© 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.
2 1 Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization
others in the field, including those put forth in numerous excellent reviews [1]. The diversity of these and other reviews
reflects the remarkably interdisciplinary range of approaches and perspectives that have been brought to bear on the
inspiring challenge of functionalizing C–H bonds.
1.2 Electrophilic C–H Bond Activation and Concerted Metalation Deprotonation
1.2.1 The (Very) Early Years - from Mercury to the Palladium Era
In the modern historiography and taxonomy of C–H bond activation, electrophilic chemistry is often considered the ear-
liest class of mechanisms discovered, whereas concerted metalation deprotonation (CMD) is perhaps the most recent
important example. The distinction between these two classes of mechanisms, however, is less clear upon careful
consideration. In that context we note that this lack of a clear boundary between various classes of C–H activation extends
well beyond this particular example; indeed, blurry lines are more the rule than the exception [2].
Although CMD was first described independently in 2005–2006 by Davies and Macgregor [3], Daugulis [4], Maseras and
Echavarren [5], its importance was first particularly recognized and exploited by Fagnou [6]. However, despite being rec-
ognized relatively recently, CMD is perhaps the operative pathway for the first selective C–H bond functionalizations ever
identified. The term is used to refer to a mechanism in which a C–H bond is associated with a vacant site on an electrophilic
metal center (typically an electrophilic, late transition metal) through an initial sigma complex (3-center-2-electron bond).
This leads to an acidification of the C–H bond, which enables a basic ligand, most classically a carboxylate, to abstract the
hydrogen as proton and often dissociate synchronously with carbon-metal bond formation.
Selective functionalization of “unactivated” C–H bonds by a transition metal can arguably be dated back to 1891 [7].
BASF used fuming sulfuric acid to oxidize naphthalene to phthalic anhydride, a key intermediate for production of
synthetic indigo dye [8]. During one batch, Eugene Sapper, the technician on duty, decided to stir the hot mixture of acid
and naphthalene with the nearest object available – a mercury thermometer. The thermometer broke and the mercury
entered the reactor, where it was quickly taken into solution. However unplanned, this procedural deviation sharply
increased the yield of phthalic anhydride and was quickly commercialized by BASF. It also appears to have initiated
academic research into reactions of mercury with aromatic compounds.
Thus in 1892, Jacob Volhard, then at Friedrichs-Universität Halle, discovered that aqueous mixtures of mercuric chloride
and sodium acetate could mercurate thiophene alpha to sulfur [9]. With a bit of heating, both alpha positions could be
substituted. This reaction, however, only afforded modest conversions, and it led to complex mixtures.
O O O
S S + S (Volhard,1892)
+ HgCl2 + NaOAc
OH HO OH
Hg(OAc)
+ Hg(OAc)2 + AcOH (Dimroth,1898)
O O HgX O O
N+ -O N+ + -O N+ + -O N+ HgX
-O + Hg(OAc)2
(Westheimer,1950)
HgX
Hg(OAc)2 in nitrobenzene, 150 °C: 57% 43%
Hg(CIO4)2 in 60% HClO4, 23 °C: 11% 89%
During his habilitation at the University of Tubingen in 1898, Otto Dimroth observed that boiling benzene with
mercury(II) acetate resulted in the formation of phenylmercuric acetate [10]. Acetic acid was formed as the byproduct,
accounting for the proton displaced from benzene. Phenol displayed even faster kinetics. It reacts with mercuric
acetate at ambient temperature in aqueous media with a bias toward ortho mercuration. Ortho and para mercuration
of toluene was also observed [11]. Additionally, thiophene undergoes cleaner mercuration using Dimroth’s conditions.
Dimroth noted that this was a general electrophilic reaction for aromatic compounds, akin to sulfonation, nitration,
and bromination [12].
But even at this early stage of investigation, there are hints that electrophilic aromatic substitution could not be the entire
story. That would not account for the ortho-selectivity in the mercuration of nitrobenzene [12], which overrides the meta-
directing tendency of the nitro group. Additionally, in 1907, Reissert reported [13] that the methyl group of nitrotoluene
could be mercurated – an sp3 C–H bond functionalization.
These early examples remained curiosities for some time, and were seldom the preferred way to access organomercury
compounds. Indeed, in 189 pages of preparations of organomercury compounds in Goddard and Goddard’s 1928 textbook
Organometallic Chemistry [14], only a handful of preparations involve direct reaction on C–H bonds [15]. And from a the-
oretical point of view, mechanistic understanding would await the development of physical organic chemistry methods.
Starting in the 1920s, significant research was done on the regiochemistry of mercuration of aromatic systems. In 1921,
Dimroth studied the mercuration of nitrobenzene, anisole, and phenetole [16]. Burton, Hammond, and Kenner described
the orientation of products obtained from mercuration of o-nitrotoluene [17]. Samuel Coffey conducted more detailed
studies on the mercuration of nitrobenzene and nitrotoluene [18] and noted deviations from the expected meta substitution
pattern. Henry and Sharp described the regioselectivity of mercuration of alkylphenols and alkylphenolaldehydes [19].
Frank Whitmore was particularly prolific in this area during his stay at Northwestern University from 1920 to 1929, report-
ing the mercuration of a suite of aromatic systems [20].
These early experiments did not consider the intimate role of the anion in forming carbon-mercury bonds. That is, it was
assumed that mercuric acetate, mercuric perchlorate, or mercuric acid with perchloric acid catalyst all effected the same
transformation. The general assumption was indeed that mercuration occurred simply through electrophilic aromatic
substitution. A progression of investigations beginning in the 1950s, however, led to the acceptance of a concerted TS with
the acetate ligand of Hg(OAc)2 intimately involved in deprotonation concomitant with carbon-mercury bond formation.
In 1950, Frank Westheimer and William Klapproth found that in the mercuration of nitrobenzene with Hg(OAc)2 at
150°C, the ortho and para products (57%) are formed in preference to the meta (43%) product [21]. Mercury perchlorate
however conformed to the expected meta-orienting patterns of the nitro group. The anion mattered.
After some preliminary studies [22], Herbert C. Brown came into agreement with Westheimer and Klapproth, articu-
lating a difference between Hg(OAc)2 and Hg(ClO4)2, when he wrote:
The results indicate that the attacking species in the uncatalyzed [i.e. without perchloric acid] reaction is a less
selective agent than that involved in the perchloric acid-catalyzed reaction [23].
Due to the relatively low proportion of ortho product in the mercuration of toluene, Brown noted that the TS must be
sterically demanding [24]. Winstein and Traylor elaborated on this observation by studying the kinetics of the reverse
reaction, acetolysis of diphenylmercury [25], and proposed a cyclic, concerted TS involving proton transfer to the
alkyl ligand concomitant with acetate coordination to mercury. Transition states know no direction, and so this argu-
ably represents the first portrayal of a mechanism which aligns with the modern understanding of the concerted
metalation-deprotonation.
R
R
R Hg
R
H + Hg
H
O O O O
C C
CH3 CH3
Kresge and Brennan in 1966 arrived at a similar description of the key TS along the path to carbon-mercury bond
formation through kinetic isotope effect (KIE) measurements [26]. In the mercuration of benzene by Hg(OAc)(ClO4),
they observed a KIE of 6.0. They interpreted this to indicate that proton transfer from an intermediate sigma complex
is the rate-limiting step of mercuration, and furthermore that the acetate group serves as the proton acceptor and
dissociates in concert. They left open the possibility that proton transfer may occur through a cyclic TS or to the sol-
vent medium.
Attention to kinetic isotope effects led to an interesting connection. In 1968, Davidson and Triggs surveyed a series of
transition metal and post-transition metal acetates [27] – mercury (II), thallium (III), lead(IV), gold(III), palladium(II),
platinum(II) – in the metalation of benzene. In some cases, metal aryl complexes could be isolated whereas in others they
decomposed to biphenyl – an oxidative cross coupling reaction with precipitation of metal. And along the way, they explic-
itly identified similarities between the mechanisms of C–H activation by mercury(II) acetate and palladium(II) acetate:
It is clear that there is a strong resemblance between palladation and mercuration especially on account of the large
primary isotope effect (kH/kD = ca. 5.0). The steady-state treatment, if correct, implies that transfer of a proton from
some intermediate containing a benzene molecule and palladium(II) ion is rate-determining.
Strong support for Winstein and Traylor’s proposed mechanism eventually arrived in 1980 with the work of Roger Roberts
and colleagues [28]. Building on prior low-temperature nuclear magnetic resonance (NMR) studies of arenemercurinium
intermediates in sulfur dioxide by George Olah in 1976 [29], they proposed two consecutive pre-equilibria followed by a
slow carbon-mercury bond forming step.
ArH + HgX 2 [π complex ] [σ complex ]+ [X− ] → arylmercury product
The term sigma complex as used by Roberts refers to a Wheland intermediate, rather than the 3-center-2-electron
bonding of metal interactions with C–H bonds. The formation of the π complex is accompanied by a modest entropy loss,
and is unaffected by added trifluoroacetate anion in the case of Hg(TFA)2. This argues against ionization as a requirement
for reaction. The subsequent steps are associated with a large decrease in entropy to reach the key TS (−20.3 eu±3.0 eu and
−31.8 eu±1.9 eu for benzene and toluene, respectively) with rigid geometric requirements. They additionally observed a
large primary KIE (kH/kD) of approximately 6 and 7 for benzene and toluene, respectively – indicating rate-limiting proton
transfer in the TS (which they concluded was the breakdown of a sigma complex). Hammett analysis indicated a modest
buildup of charge in the TS. These factors led them to question whether a discrete sigma complex need be invoked. Instead,
the experimental evidence all seemed to agree with the cyclic TSe described by Winstein and Traylor, which resembles the
current definitional model of concerted metalation deprotonation.
In revisiting these experiments, it’s difficult if not impossible to completely separate concerted metalation deprot-
onation from proton transfer to solvent, or proton transfer via solvent shuttling. These minor differences in the
pathway of proton transfer span either side of the definition of concerted metalation deprotonation and electrophilic
insertion. As a credit to the researchers who developed this model, none asserted one pathway (intramolecular versus
intermolecular proton transfer) over the other – instead, they left open the possibility for both. Likewise, this work
preceded the direct observation of agostic bonding, non-classical dihydrogen complexes, and C–H sigma complexes.
These are species that are now recognized as preliminary metal-substrate interactions that are central to C–H
activation.
1.2.2 Modern Concerted Metalation Deprotonation

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

O + base
Both coupling partners require
B prefunctionalization
O R
X Pd (cat.) R Mizoroki-Heck reaction

+ base
R Olefin does not require
prefunctionalization
Pd (cat.) R Fujiwara-Moritani
+ base Neither partner requires
R prefunctionalization
The reaction was discovered by Yuzo Fujiwara in 1967, while completing his doctorate at Osaka University in the group
of Ichiro Moritani, during the course of studies on the stereochemistry of nucleophilic attack on palladium olefin complexes
[33]. In the initial example, the complex (di-μ-chlorobis(styrene)dipalladium(II)) was treated with acetic acid in benzene,
leading to trans-stilbene formation and alpha phenethyl acetate. Their early description of this process appears to have
been influenced by prior work on nucleophilic addition and oxidation of palladium olefin complexes [32a]. Whereas the
key role of the acetate anion was quickly appreciated in this oxidative cross-coupling [32c], the connection to the emerging
mechanistic understanding of the role of acetate in mercuration may not have been recognized right away.
The substrate scope of the Fujiwara-Moritani reaction is fairly broad [34] and it is generally conducted at moderate tem-
peratures (80–110°C). Yields tend to be modest, <50%, and side reactions (alkene dimerization, acetoxylation) also occur.
Monosubstituted and disubstituted olefins, and even ethylene can be used [32c]. Electron-deficient alkenes such as acrylo-
nitrile, methyl acrylate, and acrolein are tolerated [35]. Benzene, toluene, xylenes, naphthalene, furan, thiophene, seleno-
phene, and ferrocene [35, 36] are all viable aromatic coupling partners. Anisole, chlorobenzene, and nitrobenzene may also
be used [37] and, as in the case of mercuration, the regioselectivity of substitution is not as sensitive to substituent directing
effects as conventional electrophilic aromatic substitution reactions. On this basis, Fujiwara and colleagues considered the
possible involvement of palladium(II) aryl complexes as intermediates. They further identified a first-order dependence on
each of the components of the reaction – the olefin, palladium(II) acetate, and the aromatic ring. With the benefit of hind-
sight, this would align with the models developed by Olah and Roberts for mercuration: initial reversible formation of a
palladium(II) aryl complex (direct arylation) followed by rate-limiting olefin insertion. But as it turns out, direct pallada-
tion of arenes using palladium(II) acetate exists on a continuum of reactivity between classical depictions of electrophilic
aromatic substitution and concerted metalation deprotonation. Metalation may occur through a mechanism similar to
electrophilic aromatic substitution – with nucleophilic attack on an electrophilic metal center to form a Wheland
intermediate. But with electron-deficient arenes and with relatively acidic protons, proton transfer becomes rate-limiting.
In this case, carbon-palladium bond formation occurs in concert with proton transfer to ligand [38]. Recently, such a con-
certed pathway has been observed experimentally using time-resolved infrared spectroscopy [39].
This continuum was uncovered during a renaissance of interest in direct metalation strategies in the early 2000s that was
driven in large part by the lab of Keith Fagnou at the University of Ottawa. In their initial studies of direct arylation
reactions, they observed that electron-deficient arenes underwent palladation with palladium(II) acetate at similar – if not
faster – rates than electron rich arenes. The importance of carboxylate was likewise identified in early reaction screening.
In a 2006 paper [38], they observed that increasing fluorine substitution on a benzene ring increased the rate of biaryl
formation in a cross coupling with palladium(II) acetate, in a trend that paralleled the acidity of the fluoroarene. Using
density functional theory (DFT) calculations, they identified a concerted TS similar to the one depicted by Winstein and
Traylor in 1955. Similar findings were obtained in contemporaneous experimental and computational work by Maseras
and Echavarren [5]. MacGregor also reported the same concerted mechanism, in a system that benefited from chelation
assistance [3].
This was quickly recognized by Fagnou and colleagues as an approach complementary to electrophilic aromatic
substitution. Using palladation, even electron-poor arenes and heterocycles were amenable to palladium-catalyzed C–C
coupling reactions. As was noted in the earliest studies of concerted metalation deprotonation in the context of mercura-
tion, nitrobenzene yielded to C–H activation by palladium(II) acetate [40]. So too did N-oxides of pyridine, pyrazine,
quinoline, and other azines [41]. Swapping palladium(II) acetate with palladium(II) pivalate was also rewarded with
higher activities [42]. This was soon employed in intramolecular sp2- sp3 cross coupling reactions [43].
Since this seminal work, there has been a surge in applications of CMD and it likely stands as the dominant and most
versatile mode of C–H activation in synthetic organic chemistry. But it’s also reasonable to wonder what took so long. First,
advances in computational chemistry put the concerted TS (proposed decades earlier) on a firm footing. Secondly, the field
was primed for advances in organometallic catalysis. C–H activation itself had been well recognized and reached a degree
of maturity by the 1990s [1a]. Breakthroughs in cross-coupling [44] illustrated the power of organopalladium species. But
thirdly, and perhaps just as importantly, was the naming of the concept. By coining the name concerted metalation depro-
tonation, a specific mechanistic motif was consolidated under a simple descriptive name, helping to focus and inspire a
remarkably productive race for its development as a tool in organic synthesis.
1.2.3 Classic Electrophilic C–H Activation

The term electrophilic C–H activation has acquired two related definitions. In the context of aromatic systems, it is the
formation of a carbon-metal bond through nucleophilic attack of the aromatic system on a metal center – typically a high
oxidation state, late transition metal. This is reminiscent of classical understandings of electrophilic aromatic substitution
(SEAr), with formation of a Wheland intermediate followed by proton transfer to restore aromaticity. This is embodied by
the auration of arenes. In the second sense, with initial precedent set by the discoveries of Alexander Shilov in the 1960s, it
entails direct reaction of a high oxidation state, late transition metal center with a C–H bond (including sp3 C–H bonds)
followed by deprotonation.
1.2.3.1 Electrophilic Auration of Arenes

In 1926, after just a year of doctoral studies under Morris S. Kharasch at the University of Maryland, Horace S. Isbell [45]
submitted a dissertation on the preparation of organogold compounds. Some of this was an extension of earlier reports
using Grignard reagents to nucleophilically attach alkyl groups to gold centers by displacement of halides [46]. But another
remarkable portion described the direct, rapid formation of aryl gold complexes from aqueous solutions of gold(III) chlo-
ride in contact with benzene [47]. Hydrogen chloride is immediately evolved as a byproduct, followed by precipitation of
gold(I) chloride. Chlorination of benzene is the result; but along the way, phenyl auric dichloride may also be isolated as
an intermediate during this process. Other compounds with “active” hydrogen atoms, such as malonic acid, are also
chlorinated in this way. And if the reaction is conducted in the presence of chlorine gas, gold(II) chloride can be reoxidized
to gold(III) chloride, rendering the process catalytic.
Research into the organometallic chemistry of gold(III) advanced slowly for many years. We posit that it failed to attract
the interest of the wider chemistry community for a few reasons. The price of gold is certainly high among them, particu-
larly if it doesn’t offer a compelling advantage over stoichiometric mercury(II) or differentiate itself from cheaper Lewis
acid catalysts like aluminum(III) and iron(III) in aromatic functionalization. Secondly, strongly coordinating motifs such
as nitrile groups [48] tend to intercept the gold center and inhibit ring auration thus limiting substrate scope. The same is
true for other coordinating species, particularly water [49]. Thirdly, gold displays some “Goldilocks” behavior. Electron-
poor systems, such as nitrobenzene, are unreactive; and very electron rich systems, such as aniline, form unstable products.
Lastly, the dramatic success of palladium catalysis, with its diversity of mechanisms and applications, from the 1950s
through the early 2000s may have stunted research into other precious metal catalysts.
Maturation in thinking about organometallic chemistry was required to fully appreciate the value of gold. For example,
the susceptibility to coordination can be used advantageously, such as in the directed auration of substituted pyridines [50].
In the absence of such pre-coordination, auration of aromatics displays a regioselectivity pattern consistent with nucleo-
philic aromatic substitution, with gold preferentially reacting with positions with higher electron density [51]. This is not
at all a shortcoming. This strong regioselective preference on the basis of well-known orienting principles of aromatic sys-
tems has come to be an attractive feature of gold’s C–H activation chemistry. It is complementary to palladium with its
generally poorer regioselectivity in aromatic C–H activation.
Expanding the scope of auration required a more careful analysis of reaction intermediates. Kerk and Boersma discov-
ered that the products of auration under Kharasch and Isbell’s conditions were dimeric [49]. Parkin and Liddle found that
these dimers could be converted to monomers by sigma-coordinating ligands such as phosphines and pyridines [52]. This
proved key to unlocking catalytic transformations of gold. An early demonstration of this was by Fuchita and coworkers in
2001 [51], who found that 2,6-lutidine stabilizes monomeric adducts formed from the reaction of gold(III) chloride with
substituted aromatics. In each case, only a single regioisomeric product was observed, which was isolable and could even
be handled in air. Subsequent reaction of these arylgold intermediates with phenylacetylene afforded diaryl acetylenes in
an oxidative cross-coupling reaction.
R Me R
Cl
HCCPh
Au N Ph
Cl
R Me R = H, Me R
There has been particular success in the past 20 years in catalytic arylation and oxidative arylation using gold(III) cata-
lysts [53].
1.2.3.2 The Shilov Reaction

The pathway for the emergence of the direct electrophilic activation of C–H bonds was paved by Garnett and Hodges [54]
in 1967 who used the system (K2PtCl4/CH3COOH/H2O) to catalyze an H/D exchange of a range of aromatic hydrocarbons
with isotopic water. To quote their paper [54a],
The results of this work are of importance to fundamental catalysis since the present system constitutes the homo-
geneous analog of the conventional heterogeneous method which utilizes prereduced group VIII transition metals
as catalysts, platinum being the most active.
They went on to state that the chemistry of adsorbed molecules and that of inorganic coordination compounds are very
much interrelated via the formation of a π-complex. Their report provides an efficient and rapid method of labeling organic
compounds with deuterium and tritium and is significant due to the use of milder conditions which homogenous catalysis
offers, leading to the foundation for similar labeling processes of other compounds.
A few years later, in 1971, Hodges and co-workers reported that alkanes H/D exchange of alkanes was also effected
under these conditions [55]. And quite notably, the order of reactivity of C–H bonds was primary>secondary>tertiary – a
trend in which the stronger C–H bonds are more reactive, opposite expectation and trends shown by other reagents that can
react with alkanes (e.g. radical), but a trend that ultimately was discovered to be characteristic of C–H activation by
transition metal complexes. The work of Garnett and Hodges however had already caught the attention of Alexander
Shilov whose group reported in 1969 [56], that exchange of deuterium and hydrogen takes place when methane or ethane
was heated with K2PtCl4 in a D2O/CD3CO2D mixture under relatively mild conditions. Methane, notably, has the strongest
C–H bond of any alkane. Most importantly, the Shilov lab soon reported actual functionalizations of light alkanes to give
the corresponding alkyl chlorides and alcohols [57].
[PtCl4]2-
CH4 + [PtCl6] 2- + H2O (Cl-) CH3OH (CH3Cl) + [PtCl4]2- + 2 HCl
H2O, 120 °C
The use of PtIV as a stoichiometric reagent would seem to defeat the economic value of using platinum(II) catalytically,
as well as leading to confusion at a purely scientific level. Nevertheless, the efficiency of this system in carrying out selective
C–H activation of the most inert of C–H bonds under mild conditions was clearly revolutionary, and ‘Shilov chemistry’ has
certainly proven to be one of the most influential developments in the field of C–H activation [58].
Extensive mechanistic investigations of Shilov and related PtII-based systems have since been conducted [59], particu-
larly by Labinger and Bercaw [1b, 60]. In the first step of the mechanistic cycle, methane undergoes C–H activation by a
platinum(II) complex to form a methylplatinum(II) intermediate. The product then undergoes oxidation to yield a
methylplatinum(IV) species. Nucleophilic attack then occurs at the methyl group by H2O, resulting in the reduction of the
platinum center back to give back the platinum(II) species. This generalized mechanism set the basis for various other C–H
functionalization reactions involving a platinum center.
Pt II + RH Pt II + H+
R
ROH + H +
RCl Pt IV
H 2O
Cl- Pt II
Pt IV
R
The nature of the C–H activation, the initial step in the Shilov cycle was the subject of a seminal computational study by
Siegbahn and Crabtree in 1996 [61]. The authors considered that the platinum(II) center might undergo C–H oxidative
addition, followed by deprotonation. This was, however, calculated to have a barrier higher – although not so much higher
that it could be ruled out definitively – than an alternative pathway in which, methane, coordinated to Pt(II)Cl2(OH2),
transfers a proton to a neighboring chloride. The authors referred to this as a “σ-bond metathesis”. Their nomenclature
however may reflect the limited categories of the time recognized for C–H activation reactions. The term σ-bond metath-
esis (discussed below) had been used to refer to reactions of the type M–X+A–Y=M–Y+A–X (A=H for the most part).
Clearly the term is appropriate in such cases, as they are (stoichiometrically) simple examples of two σ-bonded species
exchanging partners. In the Siegbahn-Crabtree pathway, however, the chloride that accepts the proton never departs;
instead, it loses the proton to solvent and thus the term σ-bond metathesis seems less than ideal. It is our view that CMD
would have been a better description, but the term CMD had yet to be coined. Even more descriptive would be a term later
coined by Davies and Macgregor, “ambiphilic metal ligand activation” or AMLA[1g]. Most precisely by this nomenclature
system, this is an AMLA(4) process, where the number in parentheses refers to the number of atoms involved in the pro-
ton-transfer TS, as distinguished from a classic carboxylate-assisted CMD which is an AMLA(6) process.
O O
X H O H
M H
M C M C
C
AMLA(4) AMLA(6)
AMLA (ambiphilic metal ligand activation) TSs
Platinum(II) is required to effect the C–H activation step, but the next step, conversion to a Pt(IV) alkyl is required to
achieve functionalization. Platinum(IV) is likely unable to effect C–H activation, at least in part because of difficulty access-
ing a vacant coordination site. This could be envisioned to occur via either transfer of the alkyl from platinum(II) to
platinum(IV), or via electron-transfer from the platinum(II) alkyl. Labeling experiments with isotopically enriched 195Pt
demonstrate that the reaction proceeds through electron transfer [60g].
The electron-transfer pathway leads to the challenge of avoiding oxidation of the lower oxidation state species prior to
alkylation. This problem was initially circumvented, albeit impractically, with the use of platinum(IV) as the oxidant – in
that case, any oxidation of unmethylated platinum(II) is a degenerate reaction.
The final step involves formation of a bond between carbon and a heteroatom (O or Cl) at the Pt(IV) methyl complex. This
step involves nucleophilic attack at the carbon center; several studies have shown that there occurs an inversion of stereochem-
istry at the carbon center [60c, 60d]. Although the pictorial mechanism depicts the attack to be occurring at a six-coordinate
platinum species, there is reason to believe that the nucleophile attacks at a five-coordinate platinum species [1b].
1.2.3.3 Post-Shilov Electrophilic Activation

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

Oxidative addition may be defined as any reaction in which the addition of one or more ligands to a metal center results in an
increase in formal oxidation state of the metal center; for example addition of H+ which increases the formal oxidation state
by 2 units. The most common usage, however, is for the net insertion of a metal center (regardless of the mechanism) into a
bond X–Y to give M(X)(Y) where X and Y each acquire a formal charge of −1 and thus the charge of M is increased by 2.
Oxidative addition rose to prominence in organometallic chemistry with the 1962 report of H2 adding, reversibly, to
Vaska’s Complex [68].
H
PPh3 PPh3
Cl Ir CO + H2 Cl Ir H
Ph3 P Ph3P
CO
This reaction caused some consternation in the chemical community which had generally regarded H2 addition (e.g. to
olefins) as a reduction (the confusion, which occasionally still arises, derives from the ambiguity of assigning negative or
positive charges to H). As inorganic chemists think in terms of electronic structure, however, and the relationship between
hydrides and the corresponding halides for example is very clear, Vaska correctly argued that H2 addition should be viewed
as (formally) oxidative [68, 69]. Much more questionable, however, was Vaska’s extension of this argument to H2 addition
being oxidative in a physical sense – even though much of his own very rigorous data suggested the opposite [69]. Complexes
that are more electron-rich generally have a greater tendency to undergo additions that are physically oxidative, e.g. halo-
genation. But Ir–H bonds are not particularly polar and therefore other factors determine the relative thermodynamics of
H2 addition to different complexes. In retrospect, it is clear that the thermodynamics of H2 addition were in many cases less
favorable for those derivatives of Vaska’s complex that are more electron-rich [69, 70]. Nevertheless for many years it was
accepted that complexes that are more electron-rich would undergo any oxidative addition more favorably. In the context
of oxidative addition of C–H bonds; this proved to be misleading. At the very least it contributed to a failure to see the close
relationship between various types of reactions that resulted in C–H bond cleavage and metal-carbon bond formation, in
particular oxidative addition and electrophilic addition.
The first example of oxidative addition of C–H bonds is often attributed to Chatt in 1965 [71], shortly after Vaska’s report.
He found that gen erating Ru(0)(dmpe)2 resulted in addition of both C–H bonds of naphthalene and those of the phosphi-
nomethyl groups [72].
H
P P
P
CH2 Ru P
“Ru(Me 2PCH 2 CH2 PMe2 )2 ” P Ru CH2
P
P P
H
P
P
P Ru
P
H
This surely seemed to support the notion that very electron-rich complexes were key to activating inert C–H bonds. But,
ironically enough, it was much later found by Roddick that Ru[(C2F5)PCH2CH2P(C2F5)2]2, a much less electron-rich ana-
logue of Ru(dmpe)2, was apparently more reactive toward the addition of C–H bonds [73].
The year 1965 also saw the report by Cope and Siekman of a cyclometalation of an azobenzene (i.e. the activation of one
of the ortho-phenyl C–H bonds) [74]. Whereas the net reaction is not an oxidative addition, and it might perhaps best be
described as electrophilic activation, in retrospect at least the possibility of C–H addition followed by loss of HCl can cer-
tainly be considered. The value of ortho directing groups and the ambiguity between the usual categories of C–H addition
seems to have been foreshadowed by this discovery decades before these concepts came to the fore.
Cl N
N
N M M
K2 Pt(II)Cl4 N N
+ N Cl
or r.t.
Pd(II)Cl2 2 weeks
M = Pd, Pt
Most of the early examples of C–H activation involved aryl C–H bonds or intermolecular additions, or frequently both
(e.g. cyclometalation of a PPh3 ligand) [75, 76].
PPh3 PPh2
PPh3
Ph3P Ir Cl Ir
H Cl
PPh3 PPh3
A particularly notable class of such reactions was discovered by Shaw. With 1,3-bis[(di-t-butyl)phosphino)methyl]
benzene, cyclometalation gives rise to an extremely stable pincer structure. Complexes of nickel, palladium, platinum, rho-
dium, and iridium were all synthesized via cyclometalation of the diphosphine [77].
Pt Bu2
MCl 2(NCPh)2 M Cl
Pt Bu2 M = Pd, Pt
M = Pd, Pt
Pt Bu2
H
Pt Bu2
Pt Bu2 MCl3 •(H2 O) n Cl
M
M = Rh, Ir
H
Pt Bu2 M = Rh, Ir
These complexes and derivatives thereof would ultimately play a supporting role for a vast range of catalytic and other
valuable reactions, including many examples involving oxidative addition of unactivated C–H bonds [78].
An important example of intermolecular oxidative addition of a C–H bond was reported in 1970 by Green, who found
that benzene undergoes C–H addition to Cp2W. This fragment, which has a valence electron count (VEC) of 16e, was gen-
erated from Cp2WH2 either by photolysis [79] or by hydrogenation of olefin [80] (two approaches that were subsequently
employed countless times in the field of C–H activation). Note that whereas 16e square planar species like Vaska’s Complex
do not add unactivated C–H bonds, and even add H2 relatively slowly and reversibly (i.e. not very exergonically), Cp2W
appears to add the benzene C–H bond too rapidly to allow its observation and the thermodynamics of addition are too
favorable to allow rapid reversibility.
hν
H H
W W
H -H2
+ C6H6
In 1982 Bergman [81] and Graham [82] independently reported pentamethylcyclopentadienyl (Cp*) iridium complexes
that effected the first well characterized examples of oxidative addition of alkane C–H bonds. Thus C–H bond activation
had finally been achieved to give well characterized products, with the corresponding metal carbon bonds, without
assistance through coordination at another site or the help of π electrons. This breakthrough captured the imagination of
the chemical community and brought C–H activation to the forefront unlike any prior reaction.
H hν
Ir -H2
Me3P H
R = cycloalkyl, n-alkyl
+ R-H H
Ir
L R
hν
Ir -CO L = PMe3 (Bergman);
CO L = CO (Graham)
OC
In both cases, irradiation was presumed to generate the corresponding 16e species via loss of H2 or CO respectively, which
(like Green’s Cp2W fragment [79, 80]) underwent rapid C–H addition.
As much as the addition of fully unactivated alkane C–H bonds rightfully attracted attention, arguably the most
exciting aspect of this chemistry was the regioselectivity. With Cp*Ir(PMe3), Bergman found kinetic preference for
activation that correlated positively, rather than inversely, with C–H bond strength, for example: aryl>1°>2°>>3°.
This finding was soon supported and elaborated upon in work by Graham (who observed addition of the very strong
methane C–H bond [83]), Jones [84], Flood [85], Field [86] and others – and with metals other than iridium. This
selectivity has profound implications. In general, most reagents or catalysts capable of effecting C–H bond cleavage
will (not surprisingly) preferentially react with weaker C–H bonds. Thus this chemistry indicated that transition
metal complexes could show complementary, orthogonal, selectivity. This suggested particular promise with respect
to n-alkanes and more generally n-alkyl groups. Functionalization of the terminal position versus internal position
would be more desirable in many cases, but based on normal considerations of bond strengths it is expected to be
disfavored. Moreover, the surprising correlation of kinetics with C–H bond strength suggested a way around a poten-
tially formidable barrier to catalytic alkane functionalization: specifically, the initial functionalization of an alkane
invariably leads to a product with C–H bonds weaker than that of the parent alkane. Therefore, with the use of any
reagent or catalyst which reacts with a preference for weaker C–H bonds, the initial product which will undergo
further conversion relatively rapidly, limiting its yield. The conversion of methane to methanol, for example is
relatively easy; the hard part is stopping there and not converting the product to CO2. As noted above, the Shilov
system had already shown promise in this respect [56–58]; the well characterized stoichiometric reactions now put
this on firmer conceptual ground.
Aryl and vinyl C–H bonds are stronger than alkyl, but the preference for their addition seemed less surprising than the
preference for stronger bonds within the alkyl series; the π-electron system was thought to “pre-activate” these bonds to
some extent. Elegant work by Jones indeed demonstrated that coordination of arene π-system preceded aryl C–H bond
addition by Cp*Rh(PMe3) [84a, 84b]. On the other hand, Bergman showed that in the case of ethylene (certainly a much
better π-donor than arenes), C–H addition was not preceded by π-coordination; in fact, the ethylene π-complex was formed
via initial C–H activation(!) [87]
1.3.2 Mechanistic Pathways and the Oxidative Addition Continuum

A stoichiometric reaction that results in oxidative addition generally poses no ambiguity, regardless of the mechanistic
pathway. But the practical importance of oxidative addition (which applies to any class of organometallic reaction mecha-
nisms) generally derives from reactions in which it describes an intermediate, especially in a catalytic cycle. Intermediates,
however, are not typically observed but are usually inferred from experimental mechanistic or computational studies. In
many cases, there is little doubt of the intermediacy of the products of oxidative additions, but exceptions are not uncommon.
A particular class in which this is often the case is the reaction class that may best be called sigma-bond metathesis (SBM),
of which an example of particular relevance to C–H activation is shown below.
M − R + R' − H → M − R' + R-H (R, R'=hydrocarbyl or H)
However, the term SBM was first used to imply a specific mechanistic pathway (discussed in its own section below), in
reference to d0 complexes and this is clearly very distinct from oxidative addition. For complexes in which M has two or
more d-electrons, a net SBM can be envisioned to proceed via oxidative addition followed by reductive elimination, con-
certedly via a four-centered TS as is assumed to be the case for d0 complexes, or on a continuum anywhere in between. In
addition to this continuum, which refers to the degree of M–H bond formation along the reaction pathway, there is the
question of whether there is any intermediate along the pathway. Thus a species in which the M–H bond is fully formed
can be either an intermediate or a TS. Fortunately, as such questions become more difficult to answer they also tend to
become less physically significant. The question of whether a reaction proceeds through a species with a very brief but
finite lifetime has no obvious significance with respect to the design of a catalyst intended to favor the reaction by lowering
the overall barrier (presumably the actual TS has physical properties very similar to a very shallow energy minimum that
may precede it).
“classical” Oxidative
σ -Bond Hydrogen
Metathesis σ -CAM Migration
R’ H R’ H R’ H
M R + R’ H M R’ + R H
M R M R M R
R, R’ = H, hydrocarbyl, etc.
continuum of TSs
Various nomenclatures have been adopted, with each generally associated with a different degree of M–H bond formation.
SBM is clearly the appropriate term (for the mechanism as well as the stoichiometry) in the absence of any M–H bond
formation (including d0 metals). For dn metals, terms given crudely in increasing order of the implied M–H bond formation
include: Metal-Assisted σ-Bond Metathesis (Hall and Hartwig [88]), σ-Complex Assisted Metathesis (σ-CAM; Perutz and
Sabo-Etienne [89]), Oxidatively Added Transition State (OATS; Eisenstein [90]) and, implying a fully formed M–H bond in
the TS, Oxidative Hydrogen Migration (OHM) (Goddard and Periana [91]). Love’s review on the continuum of C–H bond
activation offers an insightful discussion of this topic [2].
1.3.3 Catalytic Reactions Proceeding via Oxidative Addition

1.3.3.1 H/D Exchange
Whereas the discovery of a stoichiometric reaction may provide the starting point for the development of a catalytic reac-
tion, it is also common for discovery of a catalytic reaction to precede and even lead to the stoichiometric example. In 1970,
Parshall at DuPont reported [92] that (η5–Cp)2TaH3 and L2IrH5 (L=PEt3, PMe3, PPhEt2) catalyzed the deuteration of
benzene by D2. They proposed that the reactions proceeded via loss of H2 (or D2) from the hydride(deuteride), oxidative
addition of a C–H(D) bond, and C–H(D) elimination. This preceded – by a few months – Green’s report of addition of the
benzene C–H bond to (η5–Cp)2W (a fragment generated by loss of H2 from (η5–Cp)2WH2).
Parshall and other DuPont researchers, including Tebbe, subsequently found a broad range of complexes that catalyzed
H/D exchange between D2 and C–H bonds, including TaH5(dmpe)2, (η5–Cp)2NbH3, ReH5(PPh3)3 and RuHCl(PPh3)3 [93].
General principles of arene C–H activation were soon elucidated, including the much greater activity of aryl versus alkyl
C–H bonds, and the tendency to avoid activation of C–H bonds ortho to non-coordinating groups such as CH3 or CF3.
Electron-withdrawing substituents on the aryl ring generally favored exchange, although the effect was not large (and even
absent in the case of (η5–Cp)2TaH3).
MHn
+ H2 - H2
D2
MHn-2
D D
H
M M H
D D
D HD
M D
M H D
M
RuHCl(PPh3)3 was found to catalyze H/D exchange of both the ortho-aryl and methyl C–H bonds of Ph2P(CH2CH2CH3).
The rates were approximately equal, which was explained in terms of the more favorable ring size required for cyclometa-
lation of the methyl versus the aryl (four- versus five-membered, respectively) compensating for the intrinsically higher
activity of the aryl C–H bonds. Accordingly, the phenoxy group of Ph2P(OPh) was reported to undergo ortho deuteration
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eyes with her own liquid eyes, and seemed ready to fall into his
arms, when I got up behind him and lighted a giant fire cracker and
put it under his chair and just as the fuse was sputtering, I said, “Pa,
ma wants you at the hotel,” and the fireworks went off, the woman
threw a fit and Pa raised up out of the smoke and looked at me and
said, “Now, where in hell did you come from just at this time?” and
the head waiter took the woman into a private room to bring her out
of her fit, the waiters opened the windows to let the smoke out, and
the crowd stampeded, and the police came in to pull the place and
find the anarchist who threw the bomb, and Pa took me by the hand
and we walked up the sidewalk to a corner, and when we got out of
sight of the crowd Pa said, “Hennery, your ma ain’t here, is she?” in
a pitiful tone, and I said no she wasn’t along with me this trip, and Pa
said, “Hennery, you make me weary,” and we walked along to the
hotel, Pa asking me so many questions about home that it was a like
a catekism.
The Fireworks Went Off—the Woman Threw a Fit, and Pa
Raised Out of the Smoke.
When we got to the hotel and went to Pa’s room and I told him what I
had been doing since he abandoned me, he said he was proud of
me, and now he had plenty of work and adventure for me to keep
him in.
He said he had tried several airships, by having someone else go up
in them, and that he was afraid to go up in one himself, and he
seemed glad that I had been ballooning around home, and he said
he could use me to good advantage.
I asked him about the woman he was talking to about marriage, and
he said that was all guff, that she had a husband who had invented a
new airship, and he was trying to get title to it for use in America, for
war purposes, and that the only way to get on the right side of these
French women was to talk about marriage and money, because for
money any of them would leave their husbands on fifteen minutes’
notice. He said he had arranged for a trial of the airship the next day,
from a place out in the country, and that I could go up with the
inventor of the ship and see how it worked and report, so we went to
bed and I slept better than I had since I shipped on the cattle ship.
In the morning while we were taking baths and preparing for
breakfast, I found that Pa had been flying pretty high on government
money, and he had all kinds of gold and paper money and bonds,
and he made people think he owned most of America.
Pa asked me how the people at home looked upon his absence, and
if they advanced any theories as to the cause of his being abroad,
and I told him that everybody from the President down to Rockefeller
knew about what he was out looking after, and that when I left Bob
Evans at Fortress Monroe he told me to tell Pa to send a mess of
airships to him so he would meet them when he got to San
Francisco, as he wanted to paralyze the Japs if they got busy around
the fleet, which pleased Pa, and he said, “Just tell the people to wait,
and I will produce airships that can fight battles in the clouds, but it
will take time.”
Then we went out in the country about a dozen miles, and met the
inventor and his wife, and the inventor filled a big balloon that looked
like a weiner sausage with gas that he made over a fire out in a field,
and the inventor and I got on a bamboo frame under the balloon, and
he turned on the gasoline that runs the wheel for steering, and they
cut her loose and we went up about fifty feet and sailed around the
country a half mile either way and watched Pa and the wife of the
inventor as they sat under a tree and talked politics.
We came back after a while and Pa was proud of me for having so
much nerve, and I told him the government at home was
complaining because Pa didn’t go up in the airships, cause they said
he couldn’t buy airships intelligently unless he tried them out, and
that if he didn’t look out they would send some expert out to take his
place and spend the money, and as we were landed on the ground I
dared Pa to get on the frame and go up with us for a little spin, and
he was afraid the woman would think he was a coward if he didn’t,
so he got up and straddled the ridge pole of the bamboo frame, and
said he would take a whirl at it if it killed him. The balloon thing
couldn’t quite lift all of us, so I got off and give her a lift, and up she
went with the inventor steering, and Pa hanging on for dear life and
saying, “Now I lay me down to sleep.”
Up She Went with the Inventor Steering, and Pa Hanging On

for Dear Life.
I have seen some scared men in my life, but when the machine got
up about as high as a house, so Pa couldn’t get off, and the woman
waved a handkerchief at Pa, he swallowed his Adam’s apple and
said, “Let her go Gallagher,” and Gallagher, the Frenchman, let her
go.
Well, you’d a died to see the thing wobble and see Pa cling on with
his feet and hands. For about a quarter of a mile she went queer, like
a duck that has been wing-tipped, and then she began to descend.
First she passed over a lot of cows that women were milking, and
the cows stampeded one way and the women the other way, and the
women were scared more than the cows, cause when they got out
from under the ship they prayed, but the cows didn’t.
Then the ship struck a field where about forty women were piling
onions on the ground, and it just scattered women and onions all
over the field, and of all the yelling you ever heard that was the
worst.
Pa yelled to them that if he ever got off that hay rack alive he would
pay the damages, and he thought he was swearing at them. Then
the worst thing possible happened. The airship went up over a tree,
and Pa was scared and he grabbed a limb and let go of the bamboo,
and there he was in the top of a thornapple tree. The balloon went
over all right, and the inventor steered it away to where it started
from, and the woman and I watched Pa. The thorns were about two
inches long and more than a hundred of them got into Pa and he
yelled all kinds of murder, and then the women who owned the cows
and onions the ship had wrecked surrounded the tree with hoes and
rakes and pitchforks, and they made such a frantic noise that Pa did
not dare to come down out of the tree. So Pa told us to take the train
back to Paris and send the American Consul and the police and a
hook and ladder company to get him down and protect him.
I told Pa I didn’t want to go off and leave him to be killed by strange
women, and maybe eaten by wolves before morning, but he said,
“Don’t talk back to me, you go and send that patrol wagon and the
hook and ladder truck, and be quick about it or I won’t do a thing to
you when I catch you.”
So we went and put the airship in a barn and went back to town and
turned in a police and fire alarm to rescue Pa. The chief said there
was no use in going out there in the country before morning,
because the women couldn’t get up the thornapple tree and Pa
couldn’t get down. So I went to bed and dreamed about Pa all night,
and had a perfectly lovely time.
CHAPTER X.
Pa Had the Hardest Time of His Life in Paris—Pa Drinks Some Goat
Milk Which Gives Him Ptomaine Poison in His Inside Works—Pa
Attends the Airship Club in the Country—Pa Draws on American
Government for $10,000.
Pa has had the hardest time of his life in Paris, and if I ever pitied a
man it was Pa.
You see that last fly in the airship pretty near caused him to cash in
his chips and go over the long road to the hereafter, cause he got
blood poison from the thorns that run into him where he landed in the
top limbs of the thorn apple tree, and he sprained his arm and one
hind leg while being taken down with a derrick, and then before we
left the country town for Paris he drank some goat’s milk, which gave
him ptomaine poison in his inside works, and a peasant woman who
sewed up his pants where they were torn on the tree pricked him
with a needle, and he swelled up so he was unable to sit in a car
seat, and his face was scratched by the thorns of the tree, and there
were blotches all over him, so when we got to Paris the health
officers thought he had smallpox and sent him to a pest house, and
they wouldn’t let me in, but vaccinated me and turned me loose, and
I went to the hotel and told about where Pa was and all about it, and
they put our baggage in a sort of oven filled with sulphur and
disinfected it and stole some of it, and they made me sleep in a dog
kennel, and for weeks I had to keep out of sight, until Pa was
discharged from the hospital, and the friends of Pa out at the airship
club in the country got Pa’s airship that he bought for a government
out of the tree and took it to the club and presented a bill for two
hundred dollars, and I only had seven dollars, so they held it for
ransom.
Gee, but I worried about Pa!
Well, one day Pa showed up at the hotel looking like he had been in
a railroad wreck, and he was so thin his clothes had to be pinned up
with safety pins, and he had spent all his money and was bursted.
The man who hired Pa in Washington to go abroad and buy airships
for the government told Pa to use his own money for a month or two
and then draw on the secretary of the treasury for all he needed, so
before Pa went to the hospital he drew on his government for ten
thousand dollars, and when he came back there was a letter for him
from the American consul in Paris telling him to call at the office, so
Pa went there and they arrested him on the charge of skull dugging.
They said he had no right to draw for any money on the government
at Washington. Pa showed his papers with the big seal on, and the
consul laughed in Pa’s face, and Pa was hot under the collar and
wanted to fight, but they showed him that the papers he had were no
good, and that he had been buncoed by some fakir in Washington,
who got five hundred dollars from Pa for securing him a job as
government agent, and all his papers authorized him to do was to
travel at his own expense and to buy all the airships he wanted to
with his own money, and Pa had a fit. All the money he had spent
was a dead loss, and all he had to show for it was a punctured
airship, which he was afraid to ride in.
Pa swore at the government, at the consul and at the man who
buncoed him, and they released him from arrest when he promised
that he would not pose any more as a government agent, and we
went back to the hotel.
“Well, this is a fine scrape you have got me in,” says Pa, as we went
to our room. “What in thunder did I have to do about it?” says I, just
like that. “I wasn’t with you when you framed up this job and let a
man in Washington skin you out of your money by giving you a soft
snap which has exploded in your hands. Gee, Pa, what you need is
a maid or a valet or something that will hold on to your wad.” Pa said
he didn’t need anybody to act as a guardian to him, cause he had all
the money he needed in his letter of credit to the American Express
Company in Paris, and he knew how to spend his money freely, but
he did hate to be buncoed and made the laughing stock of two
continents.
So Pa and I went down to the express office, and Pa gave the man
in charge a paper, and the grand hailing sign of distress, and he
handed out bags of gold and bales of bills, and Pa hid a lot in his
leather belt and put some in his pockets, and said: “Come on, Henry,
and we will see this town and buy it if we like it.”
Well, we went out after dark and took in the concert halls and things,
and Pa drank wine and I drank nothing but ginger ale, and women
who waited on us sat in Pa’s lap and patted his bald head and tried
to feel in his pockets, but Pa held on to their wrists and told them to
keep away, and he took one across his knee and slapped her across
the pajamas with a silver tray, and I thought Pa was real saucy.
A head waiter whispered to me and wanted to know what ailed the
old sport, and I told him Pa was bitten by a wolf in our circus last
year and we feared he was going to have hydrophobia, and always
when these spells come on the only thing to do was to throw him into
a tank of water, and I should be obliged to them if they would take Pa
and duck him in the fountain in the center of the cafe and save his
life.
Pa was making up with the girl he had paddled with the silver tray,
buying champagne for her and drinking some of it himself out of her
slipper, when the head waiter called half a dozen Frenchmen who
were doing police duty and told them to duck Pa in the fountain, and
they grabbed him by the collar and the pants and made him walk
turkey towards the fountain, and he held on to the girl, and the
Frenchmen threw Pa and the girl into the brink with a flock of ducks,
and they went under water, and Pa came up first yelling murder, and
then the girl came up hanging to Pa’s neck, and she gave a French
yell of agony, and Pa gave the grand hailing sign of distress and
yelled to know if there was not an American present that would
protect an American citizen from the hands of a Paris mob. The
crowd gathered around the circular fountain basin, and one drunken
fellow jumped in the water and was going to hold Pa’s head under
water while the girl found his money, when Pa yelled “Hey, Rube,”
the way they do in a circus when there is a fight, and by ginger it
wasn’t a second before half a dozen old circus men that used to
belong to the circus when Pa was manager in the States made a
rush for the fountain, knocked the Frenchmen gally west and pulled
Pa out of the water and let him drain off, and they said, “Hello, old
man, how did you happen to let them drown you?” and Pa saw who
the boys were and he hugged them and invited them to all take
something and then go to his hotel.
When Pa paid the check for the drinks they charged in two ducks
they said Pa killed in the tank by falling on them. But Pa paid it and
was so tickled to meet the old circus boys that he gave the girl he
went in swimming with a twenty franc note, and after staying until
along towards morning we all got into and on top of a hack and went
to the hotel and sat up till daylight talking things over.
We found the Circus boys were on the way to Germany to go with
the Hagenbach outfit to South Africa to capture Wild Animals for
circuses, and when Pa told the boss, who was one of Hagenbach’s
managers, about his airship and what a dandy thing it would be to
sail around where the lions and tigers live in the Jungle, and lasso
them from up in the air, out of danger, he engaged Pa and me to go
along, and I guess we will know all about Africa pretty soon.
The next day we went out to the club where Pa keeps his airship,
with the boss of Hagenbach’s outfit and a cowboy that used to be
with Pa’s circus, to practice lassoing things. They got out the
machine and Pa steered it, and the boss and I were passengers, and
the cowboy was on the railing in front with his lariat rope, and we
sailed along about fifty feet high over the farms, until we saw a big
goat. The cowboy motioned for Pa to steer towards the goat, and
when we got near enough the cowboy threw the rope over the goat’s
horns and tightened it up, and Mr. Goat came right along with us,
bleating and fighting. We led the goat about half a mile over some
fences, and finally came down to the ground to examine our catch,
and we landed all right, and Hagenbach’s boss said it was the
greatest scheme that ever was for catching wild animals, and he
doubled Pa’s salary and said we would pack up the next day and go
to the Hagenbach farm in Germany and take a steamer for South
Africa in a week.
They were talking it over and the cowboy had released the goat,
when that animal made a charge with his head on our party. He
struck Pa below the belt, butted the boss in the trousers until he laid
down and begged for mercy, stabbed the cowboy with his horns and
then made a hop, skip and jump for the gas bag, burst a hole in it,
and when the gas began to escape the goat’s horns got caught in
the gas bag and the goat died from the effects of the gas, and we
were all glad until about fifty peasant women came across the fields
with agricultural implements and were going to kill us all.
Pa said, “Well, what do you know about that,” but the women were
fierce and wanted our blood. The boss could talk French, and he
offered to give them the goat to settle it, but they said it was their
goat any way, and they wanted blood or damages.
Pa said it was easier to give damages than blood, and just as they
were going to cut up the gas bag the boss settled with them for
about twenty dollars, and hired them to haul the airship to the
nearest station, and we shipped it to Berlin and got ready to follow
the next day.
Pa says we will have a high old time in Africa. He says he wants to
ride up to a lion’s den in his airship and dare the fiercest lion to come
out and fight, and that he wouldn’t like any better fun than to ride
over a royal bengal tiger in the jungle and reach down and grab his
tail and make him synawl like a tom cat on a fence in the alley.
He talks about riding down a herd of elephants and picking out the
biggest ones and roping them; and the way Pa is going to scare
rhinoceroses and hippopotamuses and make them bleat like calves
is a wonder.
I think Pa is the bravest man I ever saw, when he tells it, but I
noticed when we had that goat by the horns and he was caught in a
barbed wire fence, so the airship had to slow down until he came
loose, Pa turned as pale as a sheet, and when the goat bucked him
in the stomach Pa’s lips moved as though in praying. Well, anyway,
this trip to Africa to catch wild animals is going to show what kind of
sand there is in all of us.
CHAPTER XI.
The Boy and His Pa Leave France and Go to Germany, Where They
Buy an Airship—They Get the Airship Safely Landed—Pa and the
Boy With the Airship Start for South Africa—Pa Shows the Men
What Power He Has Over the Animal Kingdom.
I was awful glad to get out of France and into Germany, and when
we had got the airship safely landed at the Hagenbach stock farm
and boxed and baled ready to load on a boat for South Africa, and all
hands had drank a few schooners of beer, and felt brave enough to
tackle any wild animal that walks the earth, I listened to the big talk
and the gestures, though I couldn’t understand a word they said,
except when they held up their fingers for more beer.
I felt that we had got among Americans again, because all a German
needs to be an American is to be able to talk a little broken English.
The French are all right in their way, but they are too polite. If a
Frenchman wants to order you out of his place he is so polite about it
that you think he wants you to stay there always and be at home.
If a German wants you to get out he says “Rouse” in a hoarse voice,
and if you don’t rouse he gives you a swift kick in the pants and you
instinctively catch on to the fact that you are due some other place.
The Germans that are with us on the animal hunt in South Africa all
speak English, and while at the Hagenbach farm Pa convinced
everybody that he was the bravest animal man in the world, “cause
he would go up to any cage where the animals had been tamed and
act as free with them as though he did not know fear,” and he went
around in his shirt sleeves the way he used to in the circus, and
would pat a lion on the head, and if the animal growled Pa would
scowl at him and make the lion believe Pa was king of beasts.
Pa has found that putting on a pair of automobile goggles and
getting down on his hands and knees and crawling towards the
animal in captivity frightens the animal into a fit, but I guess when he
tries that stunt on wild animals on the veldt of Africa he will find it
does not work so well.
I expect to have to bring Pa back the way they transport canned
sausage, after a few wild lions and tigers and hippopotamuses have
used him for a cud to chew on.
Before we took the steamer for South Africa I had the first serious
talk with Pa that I have had since I joined him in Paris. I said, “Pa,
don’t you think this idea of chasing wild animals in Africa with an
airship is going to be a sort of a dangerous proposition?” and Pa
began to look brave, and he said, “Hennery, this is an age of
progress, and we have to get out of the rut, and catch up with the
procession and lead it. The old way of capturing wild animals by
enticing them into baited traps and letting them touch a spring and
imprison themselves is about as dangerous as catching mice in a
wire trap with a piece of cheese for bait.
“Of course, we shall take along all of the traps and things usually
used for that purpose, because roping animals from an airship is
only an experiment, and we want to be on the safe side, but if the
airship proves a success I will be considered the pioneer in airship
wild animal capturing, and all animal men will bow down to your Pa,
see, and my fortune will be made. We will get into the animal country
and locate a few lions and tigers, first, and sail over their lairs in the
jungle, and while I hold the steering apparatus our cowboys will sit
on the bamboo rails of the ship and throw the rope over their necks,
and when they find we have got them where the hair is short they will
lie down and bleat like a calf, and when we dismount and go up to
them to tie their legs they will be so tame they will eat out of your
hand.
“I have got it all figured out in my mind and I don’t want you or
anybody else to butt in with any discouraging talk, for I won’t have it.”
“But suppose the airship gets caught in a tree?” I said to Pa. “Well,
then, we will tie up and catch baboons,” said Pa. “Everything goes
with your Pa, Hennery.”
Well, it was like moving a circus to get the stuff loaded for South
Africa, as we had more than fifty cages to put animals in to bring
home, and tents and food enough for an arctic expedition, and over
two hundred men, and several tame lionesses and female tigers to
use for decoys, and some elephants for Judases to rope in the wild
animals, and when we got started it was more than a week before
we struck the coast of Africa, and all there was to do on the trip was
to play poker and practice on the tame animals.
We almost lost a tame lioness. Pa wanted to show the men what
power he had over the animal kingdom and he induced the manager
to turn Carrie Nation, the big lioness, loose on deck, while Pa put on
his auto goggles and scared her. Gee, but I thought I was an orphan
for sure. The boys had trained that lioness to be a retriever, like a
water spaniel, and on every trip some of the boys would jump
overboard when there was no sea on and let Carrie jump over the
rail and rescue them, so when they let her out she thought there was
going to be a chance for her to get her regular salt water bath, and
that it was expected that she would do her stunt at rescuing a human
being.
When she was let out of her cage and the crowd was lined up all
around the rail, and she saw Pa in the middle of the deck, on all
fours, with the black goggles on, she looked around at the crowd of
her friends as much as to say, “What is the joke?” but she sidled up
to Pa and lashed her tail around and began to play with Pa as a
kitten would play with a ball of yarn.
She put her paw on Pa and rolled him over, and when Pa got right
side up and crawled towards her looking fierce, she side stepped
and cuffed him on the jaw and everybody laughed except Pa.
Then Pa thought he would make a grandstand play and drive her
back in her cage, and he started towards her real fast on his hands
and knees, and gave a “honk-honk” like an auto, and we thought she
was scared, but I guess she wasn’t frightened so you would notice it,
for she jumped sideways and got around behind Pa, and I said, “Sick
him, Carrie,” and by gosh she grabbed Pa by the slack of his pants
and made a rush for the railing, and before I could grab her by the
tail she jumped right overboard with Pa in her mouth, and landed
kersplash in the deep blue sea, with Pa yelling to the men to take her
off.
Pa Gave a “Honk, Honk” Like an Auto, But the Lion Wasn’t

Frightened So You Would Notice.
We all rushed to the rail, and I began to cry, but the boys told me not
to be scared, as Carrie would bring Pa to the yawl all right.
The men launched a life boat and the lioness was swimming around
with Pa in her teeth, as though she was a dog with a rag doll in its
mouth.
Pa was swallowing salt water and saying something that sounded
like “Now I lay me,” and Carrie was trying to keep his head out of the
water by lifting hard on his pants, and finally the life boat got near
them and they grabbed Pa by the legs and pulled him in and he laid
down in the bottom of the boat, and the lioness climbed over the side
and began to shake herself, and then she licked the salt water off,
and when the boat came alongside she jumped up on the deck and
rolled over and turned somersaults, and then they pulled Pa on deck
and when he got his sea legs on he said to the manager of the
expedition and the captain of the boat, “Gentlemen, I have rescued
your lion, and I claim salvage, and you can give me credit for
whatever she is worth as a show animal,” and then Carrie went to
her cage, and everybody patted Pa on the back and made him think
he had saved a thousand-dollar lion from drowning.
Pa asked me to accompany him to our stateroom, and when the
door was closed and he saw my tear-stained face, he said, “You
think you are dam smart, don’t you? I heard you say sick him to that
old moth-eaten lion, and now don’t you ever interfere with my plans
again. I got that lion so frightened by my fierce look, and the noise I
made, that she jumped overboard, and I went along to save her.
Now, help me off with my clothes and rub me down, and I will go out
and chase a tiger round the deck, and make it climb up into the
rigging and beg to be taken down. That is the kind of a man your Pa
is,” and Pa began to shuck himself, and I rubbed him down as if he
was a race horse. I can see that when we come to the wild animal
fields Pa is going to astonish the natives.
We landed at a port in South Africa in the night, and before morning
we had all our stuff on a special train and about daylight we pulled
out for a place about three hundred miles from the coast, and the
next day we were in camp with the tents all up and the cages in
place, and had engaged two hundred negroes with no clothes on to
help us.
When they saw the airship spread out ready to be filled with gas
when we got ready to use it, some of them deserted, but we got
others to take their places.
I suppose when we fill that gas bag with chemical gas and it begins
to flop around, there won’t be a negro left in Africa.
We were in wild animal country all right. The first night the lions in
the jungle kept us awake, and Carrie Nation answered every time
the wild lions bellowed, until Pa had to go and maul her with a
bamboo club.
The next morning there were lion tracks all around camp, and Pa
says the trouble is going to be that the lions will hunt us instead of
our having to go after them.
A drove of zebras stampeded by our camp the first morning, a
couple of giraffes were looking us over from a hill top, and a
rhinoceros went through the camp and stole a smoked ham.
Pa is so scared he stays in his tent most of the time and shivers. He
says he has got chills and fever, but I can tell when a man’s heart
comes up in his mouth, and chokes him.
I told him this morning that if he showed the white feather now it was
all off with him, and the Hagenbach’s would leave him in Africa to be
adopted by a tribe. Pa said, “You watch me when we get to catching
animals. I will make any animal that crosses my path think he has
run into a live wire.”
Well, I hope Pa will not be a coward.
CHAPTER XII.
All Kinds of Climates in South Africa—Pa Hires Men to Capture Wild
Animals—The Boy and His Pa Capture Some Tigers and a Big Lion
—They Have a Narrow Escape from a Rhinoceros.
I don’t know whether I like the climate of South Africa or not, but you
can have any kind of climate you are looking for, from the Alaska
kind to the tropical kind, the same day.
I think it is the climate that makes all the animals so mad. One
minute a lion or a tiger may be lolling with his tongue out, fighting
flies and scratching fleas, and the next minute there are icicles on his
moustache, and he has to crawl into a hole in the ground to keep
from freezing.
These natives beat me. They do not wear any clothes except a doily,
made of bark or grass, over their loins, and from the doily, above and
below, their skin is bare, and they ought to be arrested for disorderly
conduct and exposure, but their skin is thick and warty like a
rhinoceros, and when it freezes it looks like pickled pigs’ feet.
One man we have hired to help capture animals is a native chief with
sixty wives, and he has brought them all to camp with him, and we
have to feed them, and it is rumored the women all have their caps
set for Pa, if the husband dies, and Pa is afraid they will kill their old
man and select Pa to fill the vacancy, that being the unwritten law
that a man’s wives can select a husband.
Gee, if I had to be a stepson to all those sixty senegambians that
look like monkeys in the face and when on dress parade like oxen, I
should die, or they would, if I could find chloroform enough to go
around.
Well, Pa is trying his best to save the life of that husband of the sixty
wives, and every time one of the wives pats Pa on the back or
chucks him under the chin he has a chill, and I know he will do
something desperate if they get after him in flocks.
I suppose I ought not to have done it, but I told one of the wives who
understands a little English that Pa liked to be hugged and
squeezed, and held on the girls’ laps, so when we get through work
at night and sit around the camp fire they take turns holding Pa on
their laps, and he thinks one of the women broke one of his ribs
hugging him, cause they are strong as giants, and have a terrible
squeeze.
I told one of them she could make herself solid with Pa if she could
get him a nice long snake, so she went off into the jungle alone and
came back dragging a snake more than twenty feet long, and put it
in Pa’s tent when he was asleep. When Pa woke up in the morning
and found the snake coiled upon his blanket he threw a fit and went
to the doctor and got some medicine for chills and fever, and we put
the snake into a cage to sell to a menagerie.

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List of Contributors xiii

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

2 Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms 61

3 Functionalization of Five-membered Heterocycles with Two Heteroatoms 109

3.4 Alkynylation 134

4 Transition Metal-Catalyzed C–H Functionalization of Indole Benzenoid Ring 155

5 Transition Metal-Catalyzed C2 and C3 Functionalization of Indoles 193

5.2.1 Arylation of Indoles 194

6 C(sp2)–H Functionalization of Indolines at the C7-Position 251

List of Contributors xiii

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

2 Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms 61

3 Functionalization of Five-membered Heterocycles with Two Heteroatoms 109

4 Transition Metal-Catalyzed C–H Functionalization of Indole Benzenoid Ring 155

5 Transition Metal-Catalyzed C2 and C3 Functionalization of Indoles 193

6 C(sp2)–H Functionalization of Indolines at the C7-Position 251

8 Functionalization of Pyridines, Quinolines, and Isoquinolines 357

10 Functionalization of Chromenes and Their Derivatives 435

11 Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles 485

12 Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles 543

13 C–H Functionalization of Saturated Heterocycles Beyond the C2 Position 567

14 Asymmetric Functionalization of C–H Bonds in Heterocycles 609

15 Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases 631

16 C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides 657

17 Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals 683

18 Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products 703

Stellios Arseniyadis University of Rennes, CNRS

Jung Min Joo Vikash Kumar

Tharmalingam Punniyamurthy Nathalal Parekh Road, Matunga

Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

1.2 Electrophilic C–H Bond Activation and Concerted Metalation Deprotonation

Hg(OAc)2 in nitrobenzene, 150 °C: 57% 43%

Hg(CIO4)2 in 60% HClO4, 23 °C: 11% 89%

ArH + HgX 2  [π complex ]  [σ complex ]+ [X− ] → arylmercury product

1.2.2 Modern Concerted Metalation Deprotonation

X Pd (cat.) R Suzuki-Miyaura reaction

X Pd (cat.) R Mizoroki-Heck reaction

1.2.3 Classic Electrophilic C–H Activation

1.2.3.1 Electrophilic Auration of Arenes

1.2.3.2 The Shilov Reaction

AMLA (ambiphilic metal ligand activation) TSs

1.2.3.3 Post-Shilov Electrophilic Activation

CH4 + 2 H2SO4 → CH3OSO3H + 2 H2O + SO2

1.3 Oxidative Addition

1.3.1 Stoichiometric Oxidative Addition of C–H Bonds

1.3.2 Mechanistic Pathways and the Oxidative Addition Continuum

M − R + R' − H → M − R' + R-H (R, R'=hydrocarbyl or H)

1.3.3 Catalytic Reactions Proceeding via Oxidative Addition

Up She Went with the Inventor Steering, and Pa Hanging On

Pa Gave a “Honk, Honk” Like an Auto, But the Lion Wasn’t

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ArH + HgX 2 [π complex ] [σ complex ]+ [X− ] → arylmercury product