Transition-Metal-Catalyzed C-H

Functionalization of Heterocycles
Punniyamurthy T.
Visit to download the full and correct content document:
https://ebookmass.com/product/transition-metal-catalyzed-c-h-functionalization-of-het
erocycles-punniyamurthy-t/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

Transition Metal-Catalyzed Benzofuran Synthesis 1st

Edition Xiao-Feng Wu

https://ebookmass.com/product/transition-metal-catalyzed-
benzofuran-synthesis-1st-edition-xiao-feng-wu/

Strategies for Palladium-Catalyzed Non-Directed and

Directed C-H Bond Functionalization 1st Edition Edition
Anant R. Kapdi And Debabrata Maiti (Eds.)

https://ebookmass.com/product/strategies-for-palladium-catalyzed-
non-directed-and-directed-c-h-bond-functionalization-1st-edition-
edition-anant-r-kapdi-and-debabrata-maiti-eds/

Metal-Catalyzed Asymmetric Hydrogenation. Evolution and

Prospect Montserrat Diéguez

https://ebookmass.com/product/metal-catalyzed-asymmetric-
hydrogenation-evolution-and-prospect-montserrat-dieguez/

Metal and Nonmetal Assisted Synthesis of Six-Membered

Heterocycles Navjeet Kaur

https://ebookmass.com/product/metal-and-nonmetal-assisted-
synthesis-of-six-membered-heterocycles-navjeet-kaur/
Mechanical Design: Theory and Applications T. H. C.
Childs

https://ebookmass.com/product/mechanical-design-theory-and-
applications-t-h-c-childs/

Transition Metal Oxides for Electrochemical Energy

Storage Jagjit Nanda

https://ebookmass.com/product/transition-metal-oxides-for-
electrochemical-energy-storage-jagjit-nanda/

Photochemistry of Heterocycles Maurizio D’Auria

https://ebookmass.com/product/photochemistry-of-heterocycles-
maurizio-dauria/

N-Sulfonated-N-Heterocycles: Synthesis, Chemistry, and

Biological Applications Galal H. Elgemeie

https://ebookmass.com/product/n-sulfonated-n-heterocycles-
synthesis-chemistry-and-biological-applications-galal-h-elgemeie/

Marx, Uno and the Critique of Economics: Towards an Ex-

Capitalist Transition 1st Edition Thomas T. Sekine

https://ebookmass.com/product/marx-uno-and-the-critique-of-
economics-towards-an-ex-capitalist-transition-1st-edition-thomas-
t-sekine/
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
© 2023 John Wiley & Sons, Inc.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means,
electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material
from this title is available at http://www.wiley.com/go/permissions.

The right of Tharmalingam Punniyamurthy, Anil Kumar to be identified as the author(s) of the editorial material in this work has been asserted
in accordance with law.

Registered Office
John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA

For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com.

Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions
of this book may not be available in other formats.

Trademarks: Wiley and the Wiley logo are trademarks or registered trademarks of John Wiley & Sons, Inc. and/or its affiliates in the United
States and other countries and may not be used without written permission. All other trademarks are the property of their respective owners.
John Wiley & Sons, Inc. is not associated with any product or vendor mentioned in this book.

Limit of Liability/Disclaimer of Warranty

In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to
the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package
insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or
indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this
work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically
disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No
warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that
an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that
the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may
make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies
contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be
aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the
publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental,
consequential, or other damages.

A catalogue record for this book is available from the Library of Congress

Hardback ISBN: 9781119774136; Set ISBN: 9781394180974 (Volume 1); ePub ISBN: 9781119774150;
ePDF ISBN: 9781119774143; oBook ISBN: 9781119774167

Cover image: © zhengshun tang/Getty Images; Courtesy of Tharmalingam Punniyamurthy and Anil Kumar
Cover design by Wiley

Set in 9.5/12.5pt STIX Two Text by Integra Software Services Pvt. Ltd, Pondicherry, India
 v

Contents

List of Contributors 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
4.1 Introduction 155
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 C5 Functionalization 170
4.3.1 C5 Arylation 171
4.3.2 C5 Selenylation 173
4.4 C6 Functionalization 174
4.4.1 C6 Arylation 174
4.5 C7 Functionalization 174
4.5.1 C7 Alkylation 175
4.5.2 C7 Arylation 176
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
5.1 Introduction 193
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 Introduction 251
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
7.1 Introduction 319
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
7.2.2.1 Copper Catalysis 326
7.2.2.2 Nickel Catalysis 326
7.2.2.3 Cobalt Catalysis 328
7.2.2.4 Palladium Catalysis 328
7.2.2.5 Rhodium Catalysis 329
7.2.3 Alkynylation 330
7.2.3.1 Copper-Mediated Reactions 330
7.2.3.2 Nickel Catalysis 330
7.2.3.3 Palladium Catalysis 331
7.2.4 Arylation 333
7.2.4.1 Copper Catalysis 333
7.2.4.2 Nickel Catalysis 334
7.2.4.3 Cobalt Catalysis 337
7.2.4.4 Iron Catalysis 337
7.2.4.5 Palladium Catalysis 337
7.2.4.6 Rhodium Catalysis 340
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
7.4.1 Copper Catalysis 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
7.5.1 Copper Catalysis 347
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:

List of Contributors xiii

Preface xvii

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

Tariq M. Bhatti, Eileen Yasmin, Akshai Kumar, and Alan S. Goldman

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

B. Prabagar and Zhuangzhi Shi

3 Functionalization of Five-membered Heterocycles with Two Heteroatoms 109

Jung Min Joo

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

Vikash Kumar, Rajaram Maayuri, Lusina Mantry, and Parthasarathy Gandeepan

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

Pinki Sihag, Meledath Sudhakaran Keerthana, and Masilamani Jeganmohan

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

Neeraj Kumar Mishra and In Su Kim

7 Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms 319
Tanumay Sarkar, Subhradeep Kar, Prabhat Kumar Maharana, Tariq. A. Shah, and Tharmalingam Punniyamurthy

Volume 2:
List of Contributors xiii

8 Functionalization of Pyridines, Quinolines, and Isoquinolines 357

Jun Zhou and Bing-Feng Shi

9 Transition Metal-catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives 393
Christian Bruneau and Rafael Gramage-Doria

10 Functionalization of Chromenes and Their Derivatives 435

Laura Cunningham, Sundaravel Vivek Kumar, and Patrick J. Guiry
xii Brief Contents

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

Rajeev Sakhuja and Anil Kumar

12 Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles 543

Neha Jha and Manmohan Kapur

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

Amalia-Sofia Piticari, Natalia Larionova, and James A. Bull

14 Asymmetric Functionalization of C–H Bonds in Heterocycles 609

Olena Kuleshova and Laurean Ilies

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

Yong Liang and Stanislaw F. Wnuk

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

Morgane de Robichon, Juba Ghouilem, Angélique Ferry, and Samir Messaoudi

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

Harshita Shet and Anant R. Kapdi

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

François Richard, Elias Selmi-Higashi, and Stellios Arseniyadis

Index 727
 xiii

List of Contributors

Stellios Arseniyadis 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
Department of Chemistry
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
Indian Institute of Technology Guwahati
Guwahati 781039, India Bing-Feng Shi
Department of Chemistry
François Richard Zhejiang University
Queen Mary University of London 38 Zheda Rd., Hangzhou 310027, China
Department of Chemistry
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
Department of Chemistry
Tanumay Sarkar Indian Institute of Technology Madras
Department of Chemistry Chennai 600036, India
Indian Institute of Technology Guwahati
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
Department of Chemistry
Mile End Road, London, E1 4NS, UK Eileen Yasmin
Department of Chemistry
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
 1.2 Electrophilic C–H Bond Activation and Concerted Metalation Deprotonation 3

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
4 1 Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization

dissociates in concert. They left open the possibility that proton transfer may occur through a cyclic TS or to the 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.
Another random document with
no related content on Scribd:
Toledo (Crónica de), 131.

Toledo (D. Francisco de), 406.

Toledo (Juan el Viejo de), 290.

Tomás (Álvaro), 510.

Toribio (S.), 72.

Toro (Arcediano de), 346.

Torquemada (Juan de), 314.

Torre (Alfonso de la), 331.

Torre (Bachiller de la), 430.

Torre (Fernando de la), 335.

Torrella (Gaspar), 466.

Torrella (Jerónimo), 464.

Torrellas (Pedro), 335.

Torres Naharro (Bartolomé de), 515.

Tovar (Fr. Luis de), 509.

Tractado de la vida y estado de la perfeccion, 484.

Tristan de leonis (Libro del esforçado cauallero

don), 496.

Τroyana (Crónica), 255.

Tungano (Libro del caballero don), 509.

Turpin (Crónica latina del seudo), 147.

Turranius Gracilis, 31.

Uligia (Fr. Gombaldo de), 273.

Urrea (D. Pedro Manuel de), 528.

Urríes (Mosén Ugo de), 404.

Valera (Mosén Diego de), 411.

Valerio (S.), 98.

Valladolid (Alfonso de), 217 y 236.

Valladolid (Juan de), 335.

Vargas (Fr. Alonso de), 257.

Vaticana (Cancioneiro da), 204.

Vázquez de Tapia (Hernán), 522.

Vega (Fr. Pedro de la), 511.

Velasco (D. Antonio de), 512.

Verague (Pedro de), 261.

Vergel de consolación, 275 y 466.

Vespasiano (Istoria del noble), 430.

Viana (Príncipe Carlos de), 340.

Vicente (Gil), 497.

Victoriano y Molón (Lorenzo), 470.

Villalpando (Mosén Juan de), 335.

Villena (D. Enrique de), 288.

Vincencio, 107.

Vinones (Fr. Juan Bautista de), 507.

Viñoles (Narcis), 511.

Vivero (D. Luis de), 512.

Vives (Juan Luis), 536.

Vocabulario catalán y alemán, 499.

Yuçuf (Historia de), 228.

Zacuto (Abraham), 464.

Zadik-ben-Zadik, 112.

Zamora (Alfonso de), 540.

Zamora (Juan Gil de), 209.

 ERRATAS

PÁGINA LÍNEA DICE DEBE

DECIR

61 15 dodne
donde

65 rótulo popular erudita popular y

erudita

73 7 venementi
vehementi

119 22 101 110

129 4 Beitrâge
Beiträge

129 38 antiquissime
antiquissimi

144 36 métr. poét.

metr. poet.

160 14 romanos
romeros

163 2 Vikins
Vikings

214 39 Saviesa
 Saviesa, según la

opinión corriente,

aunque propiamente
no
fué D. Jaime su

autor.

222 36 libre
libro

274 35 (1300)
(1390)

294 15 Terencio, Peno

Terencio Peno

303 20 1498
1398

312 29 Jun
Juan

314 37 Herberg
Herbera y

380 5 Osuna
Osma

400 34 Zamburda
Zambardo

420 22 1913
1915

422 31 bulas
buhas
 423 38 pestíferas las
pestíferas

463 6 1913
1915
 OBRAS DE D. JULIO CEJADOR Y FRAUCA

Gramática Griega, según el sistema histórico

comparado. Pesetas 15—Herederos de Juan Gili:
Cortes, 581, Barcelona.

La Lengua de Cervantes.—Gramática y
Diccionario de la lengua castellana en el
"Ingenioso Hidalgo Don Quijote de la Mancha".—
Tomo I: Gramática. En España, pesetas 10.—
Tomo II: Diccionario y Comentarios. Pesetas 25.
—Jubera Hermanos, Campomanes, 10, Madrid.

Cabos sueltos, Literatura y lingüística. Pesetas 5.

—Perlado, Páez y C.ª, Sucesores de Hernando,
Arenal 11, Madrid.

Nuevo método teórico-práctico para aprender

la Lengua Latina.—Primer curso: Tomo I, Libro
de clase; tomo II, Libro de casa. Pesetas 12.—
Segundo curso: Tomo I, Libro de clase; tomo II,
Libro de casa. Pesetas 12.—Perlado, Páez y C.ª,
Sucesores de Hernando, Arenal, 11, Madrid.
El Lenguaje.—Serie de estudios, de los que van ya
publicados los tomos siguientes:

Tomo I: Introducción á la Ciencia del Lenguaje.

—Segunda edición, enteramente refundida y
aumentada. Pesetas 6.

Tomo II: Los Gérmenes del Lenguaje.—Estudio

físico, fisiológico y psicológico de las voces del
lenguaje, como base para la investigación de sus
orígenes.—En España, pesetas 10.—Jubera
Hermanos, Campomanes, 10, Madrid.

Tomo III: Embriogenia del Lenguaje.—Su

estructura y formación primitivas, sacadas del
estudio comparativo de los elementos
demostrativos de las lenguas.—En España,
pesetas 12.—Jubera Hermanos, Campomanes,
10, Madrid.

Tomo IV: Tesoro de la Lengua Castellana,

Origen y vida del Lenguaje. Pesetas 12.—
Tomo A, Ε, I, O, U. Perlado, Páez y C.ª, Arenal,
11, Madrid.

Tomo V: Tesoro de la Lengua Castellana, etc.,

etc. Tomo R.
Tomo VI: Tesoro de la Lengua Castellana, etc.,
etc. Tomo N, Ñ.

Tomo VII: Tesoro de la Lengua Castellana, etc.,

etc. Tomo L.

Tomo VIII: Tesoro de la Lengua Castellana.—

Silbantes. Primera parte.

Tomo IX: Tesoro de la Lengua Castellana.—

Silbantes. Segunda parte.

Tomo X: Tesoro de la Lengua Castellana.—

Silbantes. Tercera parte.

Tomo XI: Tesoro de la Lengua Castellana.—

Silbantes. Cuarta parte.

Tomo XII: Tesoro de la Lengua Castellana.—

Labiales. (Β. P.). Primera parte.

Tomo XIII: Tesoro de la Lengua Castellana.—

Labiales. (Β. P.). Segunda parte (en prensa).

Oro y oropel, novela. Pesetas 3.—Perlado, Páez y

C.ª, Arenal, 11, Madrid.

Pasavolantes, colección de artículos. Pesetas 3.—

Jubera Hermanos, Campomanes, 10, Madrid.
Mirando á Loyola, novela. Pesetas 3,50.
—"Renacimiento", San Marcos, 42, Madrid.

Arcipreste de Hita, edición, prólogo y comentario:

dos tomos. Pesetas 6.— Paseo de Recoletos, 25,
"La Lectura".

Rojas, "La Celestina", edición, prólogo y

comentario: dos tomos. Pesetas 6.—Paseo de
Recoletos, 25, "La Lectura".

El Lazarillo de Tormes, edición, prólogo y

comentario: un tomo. Pesetas 3.—Paseo de
Recoletos, 25, "La Lectura".

Mateo Alemán, Guzmán de Alfarache, edición y

prólogo: dos tomos. "Renacimiento".

Lorenzo Gracián, El Criticón, edición y prólogo:

dos tomos. "Renacimiento".

¡De la tierra...!, colección de artículos. Pesetas 3.

—Jubera Hermanos, Campomanes, 10, Madrid.

Trazas del amor, novela.—J. Ratés, plaza de San

Javier, 6, Madrid.

Epítome de Literatura Latina. Pesetas 3.—

Victoriano Suárez, Preciados, 48, Madrid.
En prensa: Historia de la Lengua y Literatura
Castellana, t. II.

Diálogos sobre el nacimiento del Castellano.

*** END OF THE PROJECT GUTENBERG EBOOK HISTORIA DE
LA LENGUA Y LITERATURA CASTELLANA, TOMO 1 ***

Updated editions will replace the previous one—the old editions

will be renamed.

Creating the works from print editions not protected by U.S.

copyright law means that no one owns a United States copyright
in these works, so the Foundation (and you!) can copy and
distribute it in the United States without permission and without
paying copyright royalties. Special rules, set forth in the General
Terms of Use part of this license, apply to copying and
distributing Project Gutenberg™ electronic works to protect the
PROJECT GUTENBERG™ concept and trademark. Project
Gutenberg is a registered trademark, and may not be used if
you charge for an eBook, except by following the terms of the
trademark license, including paying royalties for use of the
Project Gutenberg trademark. If you do not charge anything for
copies of this eBook, complying with the trademark license is
very easy. You may use this eBook for nearly any purpose such
as creation of derivative works, reports, performances and
research. Project Gutenberg eBooks may be modified and
printed and given away—you may do practically ANYTHING in
the United States with eBooks not protected by U.S. copyright
law. Redistribution is subject to the trademark license, especially
commercial redistribution.

START: FULL LICENSE

THE FULL PROJECT GUTENBERG LICENSE
 PLEASE READ THIS BEFORE YOU DISTRIBUTE OR USE
THIS WORK

To protect the Project Gutenberg™ mission of promoting the

free distribution of electronic works, by using or distributing this
work (or any other work associated in any way with the phrase
“Project Gutenberg”), you agree to comply with all the terms of
the Full Project Gutenberg™ License available with this file or
online at www.gutenberg.org/license.

Section 1. General Terms of Use and

Redistributing Project Gutenberg™
electronic works
1.A. By reading or using any part of this Project Gutenberg™
electronic work, you indicate that you have read, understand,
agree to and accept all the terms of this license and intellectual
property (trademark/copyright) agreement. If you do not agree to
abide by all the terms of this agreement, you must cease using
and return or destroy all copies of Project Gutenberg™
electronic works in your possession. If you paid a fee for
obtaining a copy of or access to a Project Gutenberg™
electronic work and you do not agree to be bound by the terms
of this agreement, you may obtain a refund from the person or
entity to whom you paid the fee as set forth in paragraph 1.E.8.

1.B. “Project Gutenberg” is a registered trademark. It may only

be used on or associated in any way with an electronic work by
people who agree to be bound by the terms of this agreement.
There are a few things that you can do with most Project
Gutenberg™ electronic works even without complying with the
full terms of this agreement. See paragraph 1.C below. There
are a lot of things you can do with Project Gutenberg™
electronic works if you follow the terms of this agreement and
help preserve free future access to Project Gutenberg™
electronic works. See paragraph 1.E below.
1.C. The Project Gutenberg Literary Archive Foundation (“the
Foundation” or PGLAF), owns a compilation copyright in the
collection of Project Gutenberg™ electronic works. Nearly all the
individual works in the collection are in the public domain in the
United States. If an individual work is unprotected by copyright
law in the United States and you are located in the United
States, we do not claim a right to prevent you from copying,
distributing, performing, displaying or creating derivative works
based on the work as long as all references to Project
Gutenberg are removed. Of course, we hope that you will
support the Project Gutenberg™ mission of promoting free
access to electronic works by freely sharing Project
Gutenberg™ works in compliance with the terms of this
agreement for keeping the Project Gutenberg™ name
associated with the work. You can easily comply with the terms
of this agreement by keeping this work in the same format with
its attached full Project Gutenberg™ License when you share it
without charge with others.

1.D. The copyright laws of the place where you are located also
govern what you can do with this work. Copyright laws in most
countries are in a constant state of change. If you are outside
the United States, check the laws of your country in addition to
the terms of this agreement before downloading, copying,
displaying, performing, distributing or creating derivative works
based on this work or any other Project Gutenberg™ work. The
Foundation makes no representations concerning the copyright
status of any work in any country other than the United States.

1.E. Unless you have removed all references to Project

Gutenberg:

1.E.1. The following sentence, with active links to, or other

immediate access to, the full Project Gutenberg™ License must
appear prominently whenever any copy of a Project
Gutenberg™ work (any work on which the phrase “Project
Gutenberg” appears, or with which the phrase “Project
Gutenberg” is associated) is accessed, displayed, performed,
viewed, copied or distributed:

This eBook is for the use of anyone anywhere in the

United States and most other parts of the world at no cost
and with almost no restrictions whatsoever. You may copy
it, give it away or re-use it under the terms of the Project
Gutenberg License included with this eBook or online at
www.gutenberg.org. If you are not located in the United
States, you will have to check the laws of the country
where you are located before using this eBook.

1.E.2. If an individual Project Gutenberg™ electronic work is

derived from texts not protected by U.S. copyright law (does not
contain a notice indicating that it is posted with permission of the
copyright holder), the work can be copied and distributed to
anyone in the United States without paying any fees or charges.
If you are redistributing or providing access to a work with the
phrase “Project Gutenberg” associated with or appearing on the
work, you must comply either with the requirements of
paragraphs 1.E.1 through 1.E.7 or obtain permission for the use
of the work and the Project Gutenberg™ trademark as set forth
in paragraphs 1.E.8 or 1.E.9.

1.E.3. If an individual Project Gutenberg™ electronic work is

posted with the permission of the copyright holder, your use and
distribution must comply with both paragraphs 1.E.1 through
1.E.7 and any additional terms imposed by the copyright holder.
Additional terms will be linked to the Project Gutenberg™
License for all works posted with the permission of the copyright
holder found at the beginning of this work.

1.E.4. Do not unlink or detach or remove the full Project

Gutenberg™ License terms from this work, or any files
containing a part of this work or any other work associated with
Project Gutenberg™.
 1.E.5. Do not copy, display, perform, distribute or redistribute
this electronic work, or any part of this electronic work, without
prominently displaying the sentence set forth in paragraph 1.E.1
with active links or immediate access to the full terms of the
Project Gutenberg™ License.

1.E.6. You may convert to and distribute this work in any binary,
compressed, marked up, nonproprietary or proprietary form,
including any word processing or hypertext form. However, if
you provide access to or distribute copies of a Project
Gutenberg™ work in a format other than “Plain Vanilla ASCII” or
other format used in the official version posted on the official
Project Gutenberg™ website (www.gutenberg.org), you must, at
no additional cost, fee or expense to the user, provide a copy, a
means of exporting a copy, or a means of obtaining a copy upon
request, of the work in its original “Plain Vanilla ASCII” or other
form. Any alternate format must include the full Project
Gutenberg™ License as specified in paragraph 1.E.1.

1.E.7. Do not charge a fee for access to, viewing, displaying,

performing, copying or distributing any Project Gutenberg™
works unless you comply with paragraph 1.E.8 or 1.E.9.

1.E.8. You may charge a reasonable fee for copies of or

providing access to or distributing Project Gutenberg™
electronic works provided that:

• You pay a royalty fee of 20% of the gross profits you derive from
the use of Project Gutenberg™ works calculated using the
method you already use to calculate your applicable taxes. The
fee is owed to the owner of the Project Gutenberg™ trademark,
but he has agreed to donate royalties under this paragraph to
the Project Gutenberg Literary Archive Foundation. Royalty
payments must be paid within 60 days following each date on
which you prepare (or are legally required to prepare) your
periodic tax returns. Royalty payments should be clearly marked
as such and sent to the Project Gutenberg Literary Archive
 Foundation at the address specified in Section 4, “Information
about donations to the Project Gutenberg Literary Archive
Foundation.”

• You provide a full refund of any money paid by a user who

notifies you in writing (or by e-mail) within 30 days of receipt that
s/he does not agree to the terms of the full Project Gutenberg™
License. You must require such a user to return or destroy all
copies of the works possessed in a physical medium and
discontinue all use of and all access to other copies of Project
Gutenberg™ works.

• You provide, in accordance with paragraph 1.F.3, a full refund of

any money paid for a work or a replacement copy, if a defect in
the electronic work is discovered and reported to you within 90
days of receipt of the work.

• You comply with all other terms of this agreement for free
distribution of Project Gutenberg™ works.

1.E.9. If you wish to charge a fee or distribute a Project

Gutenberg™ electronic work or group of works on different
terms than are set forth in this agreement, you must obtain
permission in writing from the Project Gutenberg Literary
Archive Foundation, the manager of the Project Gutenberg™
trademark. Contact the Foundation as set forth in Section 3
below.

1.F.

1.F.1. Project Gutenberg volunteers and employees expend

considerable effort to identify, do copyright research on,
transcribe and proofread works not protected by U.S. copyright
law in creating the Project Gutenberg™ collection. Despite
these efforts, Project Gutenberg™ electronic works, and the
medium on which they may be stored, may contain “Defects,”
such as, but not limited to, incomplete, inaccurate or corrupt
data, transcription errors, a copyright or other intellectual
property infringement, a defective or damaged disk or other
medium, a computer virus, or computer codes that damage or
cannot be read by your equipment.

1.F.2. LIMITED WARRANTY, DISCLAIMER OF DAMAGES -

Except for the “Right of Replacement or Refund” described in
paragraph 1.F.3, the Project Gutenberg Literary Archive
Foundation, the owner of the Project Gutenberg™ trademark,
and any other party distributing a Project Gutenberg™ electronic
work under this agreement, disclaim all liability to you for
damages, costs and expenses, including legal fees. YOU
AGREE THAT YOU HAVE NO REMEDIES FOR NEGLIGENCE,
STRICT LIABILITY, BREACH OF WARRANTY OR BREACH
OF CONTRACT EXCEPT THOSE PROVIDED IN PARAGRAPH
1.F.3. YOU AGREE THAT THE FOUNDATION, THE
TRADEMARK OWNER, AND ANY DISTRIBUTOR UNDER
THIS AGREEMENT WILL NOT BE LIABLE TO YOU FOR
ACTUAL, DIRECT, INDIRECT, CONSEQUENTIAL, PUNITIVE
OR INCIDENTAL DAMAGES EVEN IF YOU GIVE NOTICE OF
THE POSSIBILITY OF SUCH DAMAGE.

1.F.3. LIMITED RIGHT OF REPLACEMENT OR REFUND - If

you discover a defect in this electronic work within 90 days of
receiving it, you can receive a refund of the money (if any) you
paid for it by sending a written explanation to the person you
received the work from. If you received the work on a physical
medium, you must return the medium with your written
explanation. The person or entity that provided you with the
defective work may elect to provide a replacement copy in lieu
of a refund. If you received the work electronically, the person or
entity providing it to you may choose to give you a second
opportunity to receive the work electronically in lieu of a refund.
If the second copy is also defective, you may demand a refund
in writing without further opportunities to fix the problem.

1.F.4. Except for the limited right of replacement or refund set

forth in paragraph 1.F.3, this work is provided to you ‘AS-IS’,