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Published on 30 May 2016 on http://pubs.rsc.org | doi:10.1039/9781782627913-FP001
Volume 2
Synthetic Methods in Drug Discovery
View Online
RSC Drug Discovery Series
Editor-in-Chief:
Professor David Thurston, King’s College, London, UK
Series Editors:
Professor David Rotella, Montclair State University, USA
Professor Ana Martinez, Centro de Investigaciones Biologicas-CSIC, Madrid,
Spain
Dr David Fox, Vulpine Science and Learning, UK
Advisor to the Board:

Professor Robin Ganellin, University College London, UK
Titles in the Series:

1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups
2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1
3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2
4: Accounts in Drug Discovery
5: New Frontiers in Chemical Biology
6: Animal Models for Neurodegenerative Disease
7: Neurodegeneration
8: G Protein-Coupled Receptors
9: Pharmaceutical Process Development
10: Extracellular and Intracellular Signaling
11: New Synthetic Technologies in Medicinal Chemistry
12: New Horizons in Predictive Toxicology
13: Drug Design Strategies: Quantitative Approaches
14: Neglected Diseases and Drug Discovery
15: Biomedical Imaging
16: Pharmaceutical Salts and Cocrystals
17: Polyamine Drug Discovery
18: Proteinases as Drug Targets
19: Kinase Drug Discovery
20: Drug Design Strategies: Computational Techniques and Applications
21: Designing Multi-Target Drugs
22: Nanostructured Biomaterials for Overcoming Biological Barriers
23: Physico-Chemical and Computational Approaches to Drug Discovery
24: Biomarkers for Traumatic Brain Injury
25: Drug Discovery from Natural Products
26: Anti-Inflammatory Drug Discovery
27: New Therapeutic Strategies for Type 2 Diabetes: Small Molecules
28: Drug Discovery for Psychiatric Disorders
29: Organic Chemistry of Drug Degradation
30: Computational Approaches to Nuclear Receptors
View Online
31: Traditional Chinese Medicine

32: Successful Strategies for the Discovery of Antiviral Drugs
33: Comprehensive Biomarker Discovery and Validation for Clinical
Application
34: Emerging Drugs and Targets for Parkinson’s Disease
35: Pain Therapeutics; Current and Future Treatment Paradigms

36: Biotherapeutics: Recent Developments using Chemical and Molecular
Biology
37: Inhibitors of Molecular Chaperones as Therapeutic Agents
38: Orphan Drugs and Rare Diseases
39: Ion Channel Drug Discovery
40: Macrocycles in Drug Discovery
41: Human-based Systems for Translational Research
42: Venoms to Drugs: Venom as a Source for the Development of Human
Therapeutics
43: Carbohydrates in Drug Design and Discovery
44: Drug Discovery for Schizophrenia
45: Cardiovascular and Metabolic Disease: Scientific Discoveries and New
Therapies
46: Green Chemistry Strategies for Drug Discovery
47: Fragment-Based Drug Discovery
48: Epigenetics for Drug Discovery
49: New Horizons in Predictive Drug Metabolism and Pharmacokinetics
50: Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis,
Evaluation
51: Nanomedicines: Design, Delivery and Detection
52: Synthetic Methods in Drug Discovery: Volume 1
53: Synthetic Methods in Drug Discovery: Volume 2
How to obtain future titles on publication:

A standing order plan is available for this series. A standing order will bring
delivery of each new volume immediately on publication.
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Published on 30 May 2016 on http://pubs.rsc.org | doi:10.1039/9781782627913-FP001 View Online
View Online
Synthetic Methods in Drug

Discovery
Volume 2
Edited by
David Blakemore
Pfizer, Cambridge, UK
Email: david.blakemore@pfizer.com
Paul Doyle
Peakdale Molecular Ltd, Chapel-en-le-Frith, UK
Email: paul.doyle@peakdale.co.uk
Yvette Fobian
Pfizer, Groton, CT, USA
Email: yvette.m.fobian@pfizer.com
Published on 30 May 2016 on http://pubs.rsc.org | doi:10.1039/9781782627913-FP001 View Online
RSC Drug Discovery Series No. 53
Print ISBN: 978-1-78262-786-9

Two-volume set print ISBN: 978-1-78262-787-6
PDF eISBN: 978-1-78262-791-3
EPUB eISBN: 978-1-78262-792-0
ISSN: 2041-3203
A catalogue record for this book is available from the British Library
r The Royal Society of Chemistry 2016
All rights reserved
Apart from fair dealing for the purposes of research for non-commercial purposes or for
private study, criticism or review, as permitted under the Copyright, Designs and Patents
Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not
be reproduced, stored or transmitted, in any form or by any means, without the prior
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Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon, CR0 4YY, UK
Preface
Synthetic Organic chemistry is at the heart of drug discovery. The vast

majority of top selling drugs are small molecules that started life being
synthesised in pharmaceutical chemistry laboratories. In any drug discovery
programme, a considerable number of compound series will be examined
and a large number of targets synthesised before a viable drug candidate is
identified; this is primarily because the challenges of balancing potency
against a target, identifying acceptable pharmacokinetic properties and
avoiding toxicity issues are considerable. With these challenges in mind, it is
important for the medicinal chemistry team to identify effective ways to
make new molecules as rapidly as possible. For molecules that have the right
mix of desired properties, the challenge becomes how to scale the molecule
up most effectively and with environmental sensitivity: further testing
often requires significant bulk material and the routes utilised by process
chemistry groups are often very different from those used by the medicinal
chemistry team. While the underlying drivers of the medicinal chemistry
team and process chemistry team may be different, they both rely on
identifying effective synthetic chemistry routes to make the key compounds.
While a large number of books have been published that cover synthetic
organic chemistry in significant detail, we felt that very few had taken the
perspective of what is most important to the pharmaceutical chemist. In this
book, we wanted to identify the reactions that are used routinely in the drug
discovery process as well as highlighting the current state of the art. For the
most important reactions (where there can be a bewildering number of
different methods available), we have tried to illustrate the best approaches
to use to maximise the chance of successful reaction and the challenges that
are present when they are utilised in the synthesis of molecules of relevance
to drug discovery.

Synthetic Methods in Drug Discovery: Volume 2
Edited by David Blakemore, Paul Doyle and Yvette Fobian
Published by the Royal Society of Chemistry, www.rsc.org
vii
View Online
viii Preface
Volume 2 of the book covers some of the most important pharmaceutically

relevant reactions including the use of organometallic reagents, fluorination
approaches and asymmetric methods. In addition, we have covered
reactions that are not that common currently but which have the potential to
have significant impact in the future; these include catalytic amide bond
forming reactions and Csp2–Csp3 couplings. Finally, we conclude this

volume with a look at the increasing interest in the expansion of chemical
space used in making drug-like scaffolds and highlight the current state of
the art in this area.
The authors of our chapters are highly experienced industrial chemists or
academics, and it is our hope that the reader of this book will gain an
overview of how synthetic organic chemistry impacts the drug discovery
process and a perspective on the current state of the art (and limitations) in
this key area.
David Blakemore, Paul Doyle and Yvette Fobian

Contents
Volume 1
Chapter 1 Suzuki–Miyaura Coupling 1

David Blakemore
1.1 Introduction 1
1.2 The Catalytic Cycle of the SMC 3
1.3 The Impact of the Ligand 4
1.4 Electron-rich, Sterically Hindered
Phosphine Ligands 6
1.5 N-Heterocyclic Carbene Ligands 9
1.6 The Boronate Species 10
1.7 Base and Solvent 19
1.8 Optimal Reaction Conditions 20
1.9 Examples of Process-scale SMC Reactions 23
1.10 Side Reactions in SMC Reactions 29
1.10.1 Oxidation and Homo-coupling 29
1.10.2 Protodeboronation 32
1.11 SMC Reactions of Dihalogenated
Aromatic Systems 51
1.12 SMC Reactions of Aryl Tosylates, Mesylates and
Diazonium Species 58
1.13 Generation of Vinyl, Cyclopropyl
and Benzyl Derivatives 59
1.14 Conclusion 62
References 63

ix
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x Contents
Chapter 2 Negishi Coupling 70

Chris Limberakis
2.1 Introduction 70
2.2 Mechanism 71
2.3 Formation of Organozinc Reagents 72

2.4 Applications in Drug Discovery 74
2.4.1 sp3–sp3 Carbon Bond Formation 75
2.5 Conclusion 99
References 100
Chapter 3 Hiyama Coupling 104

Lee Boulton
3.1 Introduction 104

3.2 Development of the Hiyama Coupling Reaction 105
3.3 Mechanistic Considerations 106
3.4 Fluoride-free Hiyama Coupling 109
3.5 Hiyama–Denmark Coupling 114
3.6 Summary 119
References 120
Chapter 4 Sonogashira Coupling 122

Lee Boulton

4.2 Development of the Sonogashira Reaction 123
4.3 Mechanistic Aspects of the Reaction 124
4.3.1 Typical Reaction Conditions 126
4.4 Utility of the Sonogashira Reaction 126
4.5 The Glaser–Hay Coupling Reaction 136
4.6 The Copper-free Sonogashira Coupling Reaction 136
4.7 Summary 140
Acknowledgements 141
References 141
Chapter 5 Heck Coupling 143

Alpay Dermenci and Jotham W. Coe

5.2 Intermolecular Heck Couplings 148
View Online
Contents xi
5.3 Intramolecular Heck Reactions 158

5.4 Conclusion 165
References 166
Chapter 6 Palladium- and Copper-catalysed C–N Cross-coupling

in Drug Discovery 170
Kevin D. Hesp and Julien Genovino

6.1.1 Overview of Pd-catalysed C–N Cross-coupling 172
6.1.2 Overview of Cu-catalysed C–N Cross-coupling 178
6.2 Primary and Secondary Aliphatic Amines 180
6.3 Anilines and Amino Heterocycles 197
6.4 Amides, Sulfonamides, and Other Weak
N–H Nucleophiles 207
6.5 Azoles 214
6.6 Ammonia, Hydrazine, and their Surrogates 222
6.7 Summary and Outlook 229
References 232
Chapter 7 Chan–Lam Coupling Reaction: Copper-promoted C–Element

Bond Oxidative Coupling Reaction with Boronic Acids 242
Patrick Y. S. Lam
7.1 General Introduction 242

7.2 C–N Oxidative Coupling with Arylboronic Acids 244
7.2.1 Recent C–N Oxidative Coupling with
Arylboronic Acids 244
7.2.2 Intramolecular C–N Oxidative Coupling 251
7.2.3 Recent Pharmaceutical Applications 252
7.3 C–O Oxidative Coupling with Arylboronic Acids 256
7.3.1 Intramolecular C–O Oxidative Coupling 259
7.3.2 Pharmaceutical Applications 260
7.4 C–N and C–O Oxidative Coupling with Alkenyl, Alkyl
and Alknylboronic Acids 261
7.4.1 Boron Reagents 263
7.5 Other C–Element Oxidative Coupling (C–S, C–P,
C–F, C–Cl, C–Br, C–I, C–Se, C–Te, C–F, C–C, C–H) 264
7.6 Mechanistic Studies 266
7.7 Future and Conclusions 268
References 269
View Online
xii Contents
Chapter 8 C–H Activation Approaches to Molecules 274

Elizabeth M. Beck, Antonia F. Stepan and Damien Webb

8.2 C–H Arylation 275
8.2.1 Intermolecular C(sp2)–H Arylation 277

8.2.2 Intramolecular C(sp2)–H Arylation 302
8.2.3 C(sp3)–H Arylation 305
8.3 C–H Alkenylation and Alkylation 307
8.3.1 C(sp2)–H Alkenylation and Alkylation 307
8.3.2 C–H Insertion of Carbenes and
Metal Carbenoids 314
8.4 C–H Amination 316
8.5 C–H Oxidation 330
8.6 C–H Halogenation 337
8.7 C–H Borylation 349
8.7.1 Borylation of Arene C–H Bonds 350
8.7.2 Borylation of Heteroarene C–H Bonds 356
8.7.3 Directed C–H Borylation 361
8.8 Summary and Outlook 372
References 374
Chapter 9 Palladium-catalyzed Decarboxylative Couplings 384

Christophe Linder and Nuria Rodrı́guez

9.2 Redox-neutral Decarboxylative Biaryl Syntheses 386
9.2.1 Decarboxylative Couplings with Bimetallic
Catalysts 387
9.2.2 Decarboxylative Couplings with Pd-based
Systems 399
9.3 Decarboxylative Direct Arylation Processes 402
9.4 State-of-the-Art in Decarboxylative Couplings 403
9.5 Conclusions 404
Abbreviations 405
References 405
Chapter 10 New Frontiers with Transition Metals 411

Brian S. Gerstenberger

10.2 Iron Cross-coupling Reactions 412
View Online
Contents xiii
10.3 Iron Catalysed Synthesis of Biaryl Compounds 421

10.4 Iron Catalysed Oxidative Functionalisation
of Amines 423
10.5 Nickel Transition Metal Catalysis 427
10.6 Transition Metal Catalysed C–H C(sp2)–C(sp2)
Coupling 429
10.7 Transition Metal Catalysed Direct C–H
C(sp2)–C(sp2) Coupling 433
10.8 Conclusion 439
References 439
Subject Index 443
Volume 2
Chapter 11 Lithium, Magnesium, and Copper: Contemporary

Applications of Organometallic Chemistry in the
Pharmaceutical Industry 1
Sajiv K. Nair, Benjamin N. Rocke and Scott Sutton
11.1 Introduction 1
11.2 Applications of Directed Metalation in the
Pharmaceutical Industry 2
11.2.1 ortho-Lithiation of Aromatic Systems 2
11.2.2 Union of DoM and Cross-coupling
Reactions 5
11.2.3 Examples of ortho-Lithiation Chemistry
in Drug Synthesis 7
11.2.4 Magnesiation of Pyridines and
Pyrimidines: New Generation of
Multimetallic Reagents 9
11.2.5 a-Lithiation of Saturated Azaheterocycles 16
11.2.6 Conclusion 29
11.3 Applications of i-PrMgCl LiCl 29
11.3.1 Magnesium–Halogen Exchange 32
11.3.2 1,2-Addition 35
11.3.3 Electrophilic Cyanation 37
11.3.4 Synthesis of Boronic Esters/Acids 40
11.4 Conjugate Addition and Substitution Reactions of
Organometallic Reagents 41
11.4.1 Overview of Organocuprate Chemistry 43
11.4.2 Conjugate Addition 45
View Online
xiv Contents
11.4.3 Substitution 54
11.4.4 Removal of Cu 62
11.4.5 Conclusion 64
References 65
Chapter 12 C–N Bond Formation via Hydrogen Transfer 75

Daniel C. Schmitt and Anne-Marie D. Schmitt
12.2 N-Alkylation via Hydrogen Borrowing 77
12.2.1 Synthesis of Primary, Secondary, and
Tertiary Amines 77
12.2.2 Alkylation of Weak Nitrogen Nucleophiles 82
12.2.3 Limitations and Advances 84
12.2.4 Hydrogen Transfer with Amines or
Carboxylic Acids 84
12.3 Dehydrogenative Amide Synthesis 88
12.3.1 Lactamisation of Amino Alcohols 88
12.3.2 Intermolecular Dehydrogenative Amide
Couplings 90
12.3.3 Dehydrogenative Couplings of Alcohol or
Amine Surrogates 99
12.4 Heterocycle Synthesis 103
12.4.1 Dehydrogenative Synthesis of
Heteroaromatics: Pyridines, Pyrazines,
and Pyrroles 104
12.4.2 Dehydrogenative Synthesis of Bicyclic
Heteroaromatics 106
12.4.3 Synthesis of Non-aromatic
Heterocycles 109
12.5 Summary 118
References 119
Chapter 13 Synthesis of Sulfonamides 123

Anne-Marie D. Schmitt and Daniel C. Schmitt

13.2 Synthesis from Arenes 123
13.3 Synthesis from Thiols and Aryl Amines 127
13.4 Organometallic Intermediates in the Synthesis of
Sulfonamides 130
13.4.1 Organolithium and Grignard Additions 130
13.4.2 Palladium-catalysed Synthesis of Aryl
Sulfonamides 133
View Online
Contents xv
13.5 Conclusion 136

References 136
Chapter 14 Asymmetric Methods and Their Use in the Pharmaceutical

Industry 139
Peter D. Smith, Mark A. Graham, Rachel H. Munday,

Craig S. Donald, Thomas M. McGuire and
Robert E. Kyne Jr.

14.2 Asymmetric Hydrogenation 140
14.2.1 Introduction 140
14.2.2 Alkenes 142
14.2.3 Ketones 153
14.2.4 Chiral Amine Synthesis via Asymmetric
Hydrogenation 162
14.2.5 Heterocycles 169
14.2.6 Future Directions 176
14.3 Chiral Reduction of Ketones 182
14.3.2 CBS Reagent as Reducing Agent for
Ketones 182
14.3.3 DIP-Cl Reagent as a Reducing Agent for
Ketones 194
14.4 Enantioselective Oxidation of Olefins:
Enantioselective Epoxidation and Enantioselective
Dihydroxylation 205
14.4.1 Enantioselective Epoxidation 205
14.4.2 Enantioselective Dihydroxylation 213
14.4.3 Enantioselective Epoxidation and
Dihydroxylation – Conclusions 220
14.5 Chiral Auxiliaries and Organocatalysis in Drug
Discovery 222
14.5.2 Chiral Auxiliaries 222
14.5.3 Organocatalysis 238
14.6 Chapter Conclusion 250
References 250
Chapter 15 Fluorination Approaches 263

Duncan L. Browne and Paul Richardson

15.2 Nucleophilic Reagents for Fluorination 265
View Online
xvi Contents
15.3 Electrophilic Reagents for Fluorination 266

15.4 Synthesis of Alkyl Fluorides 267
15.4.1 Nucleophilic Substitution 267
15.4.2 Deoxyfluorination of Alcohols 272
15.4.3 Decarboxylative Fluorination of
Carboxylic Acids 286

15.4.4 Direct Fluorination of Hydrocarbons 290
15.4.5 a-Fluorination of Carbonyl Compounds
and their Derivatives 293
15.5 Synthesis of Aryl Fluorides 301
15.5.1 Classical Approaches 301
15.5.2 Pd-catalysed Fluorination of Aryl Halides
and Derivatives 308
15.5.3 Fluorination of Organolithiums/Grignard
Reagents 313
15.5.4 Fluorination of Aryl Stannanes 317
15.5.5 Fluorination of Boronic Acids 318
15.5.6 Fluorination of Aryl Silanes 323
15.5.7 Pd-mediated Directed Fluorination 324
15.6 Difluoromethylation 327
15.7 Trifluoromethylation 337
References 357
Chapter 16 The Development of Csp3–Csp2 Coupling Methodology 371

Brian T. O’Neill

16.2 Catalytic Process 372
16.3 Oxidative Addition 375
16.4 Transmetallation and Reductive Elimination 376
16.5 Enhancing Reductive Elimination with Palladium
Dialkylbiarylphosphines 377
16.6 Transmetallation and Coupling of Organoboron
Species 389
16.7 Transmetallation and Coupling of
Alkoxy-Substituted Borates 397
16.8 Nickel Catalysed Processes for Csp3–Csp2
Coupling 402
16.9 Summary and Conclusion 408
References 409
View Online
Contents xvii
Chapter 17 Catalytic Amide Bond Forming Methods 413

Benjamin N. Atkinson, A. Rosie Chhatwal and
Jonathan M. J. Williams
17.1 Amidation of Carboxylic Acids 413

17.1.1 Homogeneous Metal Catalysed

Amidation of Carboxylic Acids 414
17.1.2 Heterogeneous Catalysts for the
Amidation of Carboxylic Acids 415
17.1.3 Non-metal Catalysts for the Amidation of
Carboxylic Acids 416
17.2 Transamidation 417
17.2.1 Metal Catalysed Transamidation 418
17.2.2 Non-metal Catalysed Transamidation 420
17.3 Amidation of Esters 423
17.3.1 Metal Catalysed Amidation of Esters 423
17.3.2 Non-metal Catalysed Amidation
of Esters 424
17.4 Amidation of Aldehydes (without Oxime
Intermediates) 426
17.4.1 Metal Catalysed Amidation of
Aldehydes 426
17.5 Amidation of Alcohols 430
17.5.1 Homogeneous Metal Catalysed
Amidation of Alcohols 430
17.5.2 Heterogeneous Metal Catalysed
Amidation of Alcohols 432
17.6 Amidation of Nitriles 433
17.6.1 Hydration of Nitriles to Primary Amides 433
17.6.2 Amine Addition to Nitriles 434
17.6.3 Catalysed Ritter and Ritter-type Reactions 435
17.7 Oxime/oxime Intermediates to Amides 436
17.7.1 Catalytic Aldoxime Rearrangement and
Coupling into Primary, Secondary and
Tertiary Amides 437
17.7.2 Catalytic Beckmann Rearrangements 439
17.8 Aminocarbonylations 440
17.8.1 Aminocarbonylation of C–X Bonds 440
17.8.2 Aminocarbonylation of C–H Bonds 443
17.9 Miscellaneous Amidations 446
17.10 Conclusion 448
References 448
View Online
xviii Contents
Chapter 18 Accessing Novel Molecular Motifs and Monomers 454

Subramanyam Chakrapani and Joseph S. Warmus

18.2 The Value of a Medicinal Chemistry Friendly
Building Block (Monomer) Collection 455

18.3 Development of the Pfizer Monomer Collection 459
18.3.1 Expanding the Reagent Collection Scope 459
18.3.2 Creation of a Tier 1 Monomer Collection at
Pfizer 460
18.3.3 Building a Tier 1 Monomer Set 461
18.3.4 Creation of Enabled Monomer Set for
Parallel (Library) Synthesis 463
18.4 Expanding Monomer Diversity 465
18.4.1 In situ Monomer Strategy 465
18.4.2 Expanding Diversity of Other
Limited-availability Monomer Sets 477
18.5 Utility and Accessibility of Fluorinated Monomers 489
18.5.1 The Utility of Fluorine in Medicinal
Chemistry 489
18.5.2 Fluorine Addition to Monomer Sets 490
18.6 Multi-step Library Synthesis 492
18.7 Future Directions 497
18.7.1 New Library Strategies 497
18.8 Final Thoughts 497
References 499
Subject Index 505

Published on 30 May 2016 on http://pubs.rsc.org | doi:10.1039/9781782627913-00001
CHAPTER 11
Lithium, Magnesium, and

Copper: Contemporary
Applications of Organometallic
Chemistry in the
Pharmaceutical Industry
SAJIV K. NAIR,a BENJAMIN N. ROCKEb AND SCOTT SUTTON*a
a
Pfizer Worldwide Medicinal Chemistry, 10770 Science Center Drive,
San Diego, CA 92121, USA; b Pfizer Worldwide Medicinal Chemistry,
Eastern Point Rd., Groton, CT 06340, USA
*Email: scott.sutton@pfizer.com
11.1 Introduction
During the past 20 years, the field of organometallic chemistry has expanded
dramatically marching across the periodic table to embrace transition
metals, lanthanides, post-transition metals, and now even silicon, germa-
nium, antimony and tellurium. In an industrial setting, constraints such as
speed, cost, quality and reproducibility make high yielding and simple
chemistry important, while placing emphasis on selecting green reagents
and solvents.1 Simplicity, described by Hudlicky and Natchus in their per-
spective on modern synthetic design, can be described not just by the steps
executed but especially by those avoided.2,3 In this context, the main group
metals of lithium and magnesium, and the transition metal copper, form a

1
View Online
2 Chapter 11
solid foundation of many simple, high yielding, and cost effective C–C bond
forming reactions spanning those requiring a strong base for C–H depro-
tonation (Li), those that require a hard, reactive nucleophile (Li and Mg), and
those that require a softer, more selective nucleophile (Cu). Additionally,
recent developments from both academic and industrial pioneers have
brought forth new methods and reagents with greater control when using
these classical metals. The aim of this chapter is to demonstrate, with
selected examples, how this chemistry has been applied to overcome the
hurdles of drug discovery and to offer insight into the utility of recent ad-
vances in the reactivity and selectivity of Li, Mg, and Cu intermediates. Some
limitations and potential future developments are discussed where fitting.
Examples have been selected that aim to highlight overall efficiency in the
synthesis of drug targets and that bring a rapid increase in molecular
complexity while reducing the need for precious metals.
11.2 Applications of Directed Metalation in the

Pharmaceutical Industry
11.2.1 ortho-Lithiation of Aromatic Systems
Aromatic rings are common scaffolds in pharmaceutical leads that can be
used to orient groups in specific directions in order to enhance binding
interactions in protein–ligand recognition (as well as potentially functioning
in the binding event themselves). Thus, efficient synthetic methods that
allow the introduction of highly functionalised aromatic moieties play a
crucial role in drug discovery. One such approach is directed ortho-metalation
(DoM). This reaction involves deprotonation of the aromatic ring ortho to a
heteroatom-containing directing metalation group (DMG) by a strong base
such as an alkyllithium. The ortho-lithiated intermediate is then trapped with
a suitable electrophile (Scheme 11.1).
The discovery of ortho-lithiation chemistry dates back to the late 1930’s,
when Gilman4 and Wittig5 independently reported the ortho-deprotonation
of anisole with n-BuLi and quenching with carbon dioxide. The vast scope of
DoM chemistry has recently been extensively reviewed.6 This section will
focus mainly on highlights of ortho-lithiation used in the pharmaceutical
industry.
In comparison to traditional electrophilic aromatic substitution (EAS), the
advantages of well-defined regiocontrol and the vast number of choices in
the DMGs have made DoM a very valuable method in organic synthesis.
DMG DMG DMG

Li E
R-Li E+
Scheme 11.1 Directed ortho-metalation (DoM).

View Online
Lithium, Magnesium, and Copper 3
A DMG requires a contrasting mix of properties: while it needs to co-ordinate

effectively to the strong base used (e.g., alkyllithium reagents), it also needs
to be resistant to nucleophilic attack as the base also has the potential to act
as a nucleophile. Steric hindrance and/or electronic features are usually
incorporated to resolve this dichotomy. Furthermore, DMGs should ideally
have the ability to be converted easily to other functional groups, a task that
is not trivial because they are inherently designed to withstand nucleophilic
attack.
A basic three-step mechanism has been proposed to explain the DoM
reaction (Scheme 11.2). This invokes the complex-induced proximity effect
(CIPE)7,8 wherein the alkyl lithium aggregate (RLi)n coordinates to the DMG
through an equilibrium process, and the complex thus formed places the
base in close proximity to the ortho proton leading to a coordinated ortho-
lithiated species, which then reacts with the electrophile to form the 1,2-
disubstituted arene.6,9
Based on their coordination ability, DMGs have been classified into three
groups: strong, moderate and weak. DMGs can also lower the pKa of the
adjacent proton via inductive withdrawal in some cases. Examples from
these categories, including carbon- and heteroatom-based DMGs, are shown
in Figure 11.1.6 Among the strong DMGs, the oxazoline, OTHP, and NHCO2R
(e.g., NHBoc) groups are more synthetically useful since they can be easily
converted to carboxylic acids, phenols, or anilines.
DMG DMG DMG DMG

(R-Li)n
H H Li E
(R-Li)n -RH E+
Scheme 11.2 Proposed mechanism for DoM.
Strong DMGs Moderate DMGs Weak DMGs
CONHR NHCO2R CF3 CH(OR)2

-
DMG CONR2 NHCOR OMe CH2O
-
Li OCONR2 NR2 O
N N
OSEM F
Cl N
O OTHP
O R
CH=NR SO2NR N
(CH2)nNR2 SO2t-Bu NR2 N

OSO2NR2 R
OP(O)(NMe2)2
Figure 11.1 Examples of directed metalation groups (DMGs).

View Online
4 Chapter 11
The tertiary amide group (CONR2) is a widely used DMG but it usually
requires further derivatisation10 to convert it to a reactive functional group;
however, it readily participates in intramolecular cyclisation reactions to
form lactones.11 Tertiary amides have also been converted to ketones12
through an intermediary a-amino alkoxide that plays the role of the DMG
(Scheme 11.3).
Georg and co-workers have shown that tertiary amides can be easily
converted to the corresponding aldehyde using the Schwartz reagent
Cp2Zr(H)Cl,13,14 and Snieckus and Zhao have recently reported an improved
one-pot protocol (Scheme 11.4) using Cp2ZrCl2/LiAlH(O-t-Bu)3.15
In the list of moderate DMGs, the a-amino alkoxide group is of particular
interest as it serves as a masked aldehyde conveniently effecting a one-pot
ortho-alkylation of aromatic aldehydes (Scheme 11.5).16
Of the DMGs on the list above, the O-carbamate (OCONR2) has the
strongest directing ability and so is potentially very attractive. Unfortunately,
it is also amongst the most resistant to further transformations, limiting its
effectiveness somewhat. It can be converted to the corresponding phenol
under harsh hydrolysis conditions (aq. NaOH) or by using strong reducing
agents (LiAlH4) but these conditions limit substrate scope due to functional
group tolerance. Encouragingly, Snieckus et al. have recently extended the
utility of the Schwartz reagent, Cp2Zr(H)Cl, to the reductive cleavage of the
O-carbamate DMG giving a phenol product under mild conditions that
tolerate various functional groups.17 Additionally, the O-carbamate group has
been reductively cleaved using i-PrMgCl and Ni(acac)2, which highlights
the latent potential of this DMG.18 One valuable facet of this DMG is its ability
to undergo the anionic Fries rearrangement which involves a 1,3 – O-C
migration of the carbamoyl group.19 The tertiary amide group (CONR2)
Me
O Me
CONEt2 LiO NMe2
Li CHO
MeLi, THF DMF
-70°C 25°C, 16 h
56%
Cl Cl Cl
Scheme 11.3 Synthesis of ortho-substituted ketones.
CHO CONEt2 CHO
Cp2ZrCl2 (1.4 eq) Cp2Zr(H)Cl(1.5 eq)

LiAlH(O-t-Bu)3(1.4 eq) THF
NMe2 NMe2 NMe2
THF, RT, 2 min 0.5 h, RT
81% 76%
Snieckus in-situ protocol Georg conditions
Scheme 11.4 Snieckus in situ protocol for the Georg reduction of a teriary amide.
View Online
NMe NMe
NMe H H
LiO N LiO N
CHO
Li N n-BuLi Li
C6H6, RT C6H6, RT
CHO
1. THF
-42 °C, MeI Me
2. 10% aq. HCl

67%
Scheme 11.5 One-pot ortho-alkylation of benzaldehyde.
O O
1. LDA, THF,
-70 °C NEt2 Tf O, Et N NEt2
2 3
2. MeOH
N OCONEt 2 N O DCM, 0 °C N OTf
61% H
O O
A B C N A B C N
N D N D
O
Et
Camptothecin O
OH
Scheme 11.6 Anionic Fries rearrangement reaction in the synthesis of

Camptothecin.
transferred in this fashion could then be utilised in further DoM’s yielding

diverse poly-substituted arenes. An example of the application of the anionic
Fries rearrangement reaction is illustrated in the synthesis of the A/B/C/D ring
core of the antitumor agent camptothecin (Scheme 11.6).20
11.2.2 Union of DoM and Cross-coupling Reactions

Transition metal catalysed cross-coupling reactions are ubiquitous in the
synthesis of pharmaceutical lead compounds as has been discussed in
previous chapters. The Suzuki–Miyaura coupling is a key bond forming re-
action in the pharmaceutical industry. Snieckus and co-workers have fo-
cused their research efforts toward the union of DoM and cross-coupling
reactions with a view to take advantage of the regiochemical fidelity of the
former class and the versatility of the latter. This strategy, commonly re-
ferred to as the ‘‘DoM-cross-coupling nexus,’’ enables the regioselective
introduction of a metal (B, Mg, Zn, Sn, Si) on one coupling partner or a
View Online
6 Chapter 11
Li
O LDA, B(O-i-Pr)3 O B(O-i-Pr)3
NEt2 THF, -20 °C NEt2
O O
OH
H 3C
Br
CH3 O
OH
PdCl2(dppf) NEt2
THF, H2O
88% O
Scheme 11.7 DoM-cross-coupling nexus.
DMG
DMG
Catalyst Y
+
X YH
X = hal, OTf, B(OR)2 Y = O, NR, S
Scheme 11.8 Heteroatom–aryl coupling using DoM.
leaving group (halogen, triflate) on the other using DoM. The approach is
highly effective for the synthesis of polysubstituted biaryls and heterobiaryls
(Scheme 11.7).21
The regioselective introduction of the metal (e.g., boron) or the leaving
group also allows access to biaryl ethers, anilines and sulfides via
heteroatom–aryl couplings such as the Ullmann, Buchwald–Hartwig, and
Chan–Lam methodologies (Scheme 11.8).
The ability to utilise a functional group as both a DMG for ortho-metalation
and as a coupling partner in a metal catalysed reaction is a particularly
attractive approach. The latent potential of the O-carbamate group has been
applied to the cross-coupling arena wherein this DMG plays its intended
role of introducing electrophiles at the ortho-position, but it also serves as
the leaving group in ‘‘combined’’ Suzuki–Miyaura (with organoborates)22
or Kumada–Corriu (with Grignard reagents)18 cross-coupling reactions
(Scheme 11.9).23,24
The same theme has been extended to other DMGs such as the sul-
fonamide (SO2NEt2)25 and to the weaker O-sulfamate (OSO2NEt2).22,26 Fur-
thermore, as mentioned earlier, DMG’s such as the OCONEt2 and SO2NEt2
View Online
OCONEt2 OCONEt2
1) t-BuLi,THF, -78 °C
2) Me2C=CHCHO H3C
Et2NOCO CH3 3) AcOH, 0 °C O CH3
54% H3C
Ph
PhB3O3:PhB(OH)2 (10:1)
NiCl2(PCy3)2
PCy3HBF4, K3PO4 H3C
o-xylene, 150 °C, 56% O CH3
H3C
Scheme 11.9 Latency of DMG and ‘‘combined’’ cross-coupling.
can be reductively cleaved to provide meta-substituted arenes.18,27 The scope

of this approach has been further extended to sp2–sp3 carbon–carbon bond
construction by the recent findings that aryl sulfamates28,29 and aryl car-
bamates28 undergo iron-catalysed cross coupling with primary and second-
ary alkyl Grignard reagents. Aryl and heteroaryl sulfamates were also used as
electrophilic partners in a palladium-catalysed cross-coupling with primary
and secondary aminomethyl trifluoroborates.30 Aryl sulfamates and carba-
mates also undergo nickel-catalysed amination reactions.31
11.2.3 Examples of ortho-Lithiation Chemistry in Drug

Synthesis
ortho-Lithiation chemistry has found numerous applications in medicinal
chemistry as well as in process chemistry. In addition to the commonly
utilised DMGs, substrate derived DMGs have also been used productively. An
outstanding example of the latter concept is seen in the highly convergent
synthesis of Cozaar, a non-peptide angiotensin II receptor antagonist used to
treat hypertension. With the goal of avoiding the use of trialkyltin azide and
a free radical bromination step as utilised in earlier approaches, Larsen et al.
at Merck utilised the intrinsic tetrazole group in Cozaar as a DMG to syn-
thesise a boronic acid intermediate (Scheme 11.10).32
Ortho-lithiation chemistry has also been applied in both the racemic33 and
the stereoselective synthesis34 of the anti-HIV agent efavirenz (Sustiva)
wherein the NHBoc group served as a DMG in the synthesis of a key tri-
fluoromethyl ketone intermediate (Scheme 11.11). In the asymmetric syn-
thesis, this ketone was subjected to an enantioselective alkynylation with a
cyclopropyl acetylide in the presence of (1R,2S)-N-pyrrolidinylnorephedrine
to obtain the desired framework of efavirenz. Notably, MTBE was used in
place of THF as a solvent to avoid the competitive attack of n-butyllithium on
THF at 0 1C in the DoM step.
Achmatowicz and co-workers at Amgen have reported an elegant synthesis
of the phthalazine core of one of their leading p38 MAP kinase inhibitors
Published on 30 May 2016 on http://pubs.rsc.org | doi:1
CPh3 CPh3 Cl
N NH N N N N
1. Ph3CCl N
8
N N Et3N, THF N N 1. n-BuLi, -20°C N N OH
N
2. Filter 2. B(OMe)3, -25°C
B(OH) 2 +
Et3N.HCl 3. IPA, 20% aq. NH4Cl
Cl Br
N
OH
1. Pd(OAc) 2, PPh3 (4 eq), K2CO3 N N NH
THF: diethoxymethane (1:4), H2O N N
84% (over 6 steps)
2. 0.7 M H2SO4, MeCN:H 2O(1:1)
93%
Cozaar
Scheme 11.10 Synthesis of Cozaar.
O HO OH
Cl 1. n-BuLi, TMEDA, Cl Cl
MTBE, 0°C→5°C, 2h CF3 HCl, EtOAc CF3
2. CF3CO2Et, 87%
NHBoc NHBoc NH2.HCl
-15 °C→25 °C
O
Cl
CF3 F 3C
1. aq. NaOAc,MTBE Cl
2. PMB-OH, p-TsOH(cat.) NH O
Chapter 11
MeCN, 90%
N O
H
efavirenz
OMe
Scheme 11.11 Synthesis of efavirenz.

View Online
using a DoM approach. Thus, the reaction of 4-chlorobenzoyl chloride with

tert-butylamine installed the secondary amide group CONH-t-Bu as a DMG.
After careful optimisation of the DoM, a suitable base (MeLi) and appro-
priate quenching conditions with DMF were found to yield the desired
hydroxyisoindolinone (Scheme 11.12). Treatment of this intermediate with
hydrazine hydrate yielded the 6-chlorophthalazin-1-ol in 73% overall yield

en route to the kinase inhibitor.35
In order to examine spirocyclisation as a design strategy to overcome the
metabolic liabilities of their leading calcitonin gene-related peptide (CGRP)
receptor antagonist telcagepant (MK-0974), Burgey and coworkers at Merck
utilised DoM to access a spiroazabenzoxazinone (Scheme 11.13).36 Ortho-
lithiation of Boc-protected 2-amino-6-chloropyridine and trapping of the
anion with N-benxyloxycarbonyl-4-piperidinone gave, after in situ cyclisation,
the requisite spirocyclic framework. Subsequent deprotection and dechlo-
rination under hydrogenolysis conditions gave the desired spiroazaben-
zoxazinone side chain. Attempts at carrying out the DoM-cyclisation with
a des-chloro substrate were unsuccessful, presumably due to competing
nucleophilic addition of the alkyllithium to form the corresponding
dihydropyridine.37
11.2.4 Magnesiation of Pyridines and Pyrimidines: New

Generation of Multimetallic Reagents
Pyridines and pyrimidines are very common motifs pursued by medicinal
chemists. Regioselective metalation of these heterocycles using strong bases
such as alkyllithiums, non-nucleophilic lithium dialkylamides (e.g., LDA,
LiTMP) and superbases like n-BuLi/Me2N(CH2)2OLi38,39 have been used for
selective and convenient functionalisation of these heterocycles and the
scope of this chemistry has been covered extensively in recent reviews.39–41
DMGs such as methoxy, halogens, thiomethyl and dimethylamino groups
play their anticipated roles and in many cases make the suitably substituted
heteroaromatic less susceptible to dimerisation reactions as well as
nucleophilic addition by the base (e.g., alkyl lithium).
In pyridine itself, the relative acidities around the ring are 700 : 72 : 1
[C4 : C3 : C2].42 The position next to the nitrogen is considered least acidic
because the sp2 lone pair on nitrogen has an anti-bonding interaction with
the C–Li bond.43,44 The regioselectivity obtained is consistent with this. Key
examples of regioselectivity that can be obtained with 3-substituted pyridine
are shown in the examples below (Schemes 11.14–11.16).45,46 In most cases,
the products of reaction at C4 are obtained but there are exceptions (pri-
marily through the use of chelating amine ligands). For example, metalation
of 3-fluoropyridine followed by quenching with carbon dioxide gives C4
substitution with n-BuLi in THF but the use of DABCO changes the select-
ivity to C2.43 The authors postulate that initial kinetic deprotonation
occurs at C2 (due to chelation of the lithium base to the pyridyl nitrogen)
but that this rearranges to the C4 lithiated product which is more
10
OLi
O 1. t-BuNH2, DCM O MeLi (2 eq),
0 °C→23 °C, 0.5 h DEM,THF, -10 °C N
Cl N
2. aq. NaOH (5N) H
97% Li Cl
Cl Cl
O
O OH
1. DMF, -15 °C→-10 °C aq. N2H4, AcOH N
N N
2. sat. aq. NH4Cl, -5 °C 90-100 °C
Cl N N O
73% overall yield Cl
HO
N
N
H
p38 MAP kinase inhibitor
Scheme 11.12 DoM approach to a p38 MAP kinase inhibitor.
Chapter 11
Lithium, Magnesium, and Copper

F 3C F 3C
O O
N O N O
F F
NH NH O
NH
F N F
N N NH
O N O
N
telcagepant (MK-0974)
O
O
NHBoc O O
CbzN NH HN NH
1) n-BuLi, TMEDA, THF Pd/C, H2, EtOH
N
2) N
CbzN O N
Cl
50% Cl
Scheme 11.13 DoM in the synthesis of a spiroazabenzoxazinone analog of telcagepant (MK-0974).
11
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treaty and end the war, release the volunteers, remove the
excuse for war expenditures, and then give the Filipinos the
independence which might be forced from Spain by a new treaty.
… The title of Spain being extinguished we were at liberty to
deal with the Filipinos according to American principles. The
Bacon resolution, introduced a mouth before hostilities broke
out at Manila, promised independence to the Filipinos on the
same terms that it was promised to the Cubans.
{661}
I supported this resolution and believe that its adoption
prior to the breaking out of hostilities would have prevented
bloodshed, and that its adoption at any subsequent time would
have ended hostilities. … If the Bacon resolution had been
adopted by the Senate and carried out by the President, either
at the time of the ratification of the treaty or at any time
afterwards, it would have taken the question of imperialism
out of politics and left the American people free to deal with
their domestic problems. But the resolution was defeated by
the vote of the Republican Vice-President, and from that time
to this a Republican Congress has refused to take any action
whatever in the matter.
"When hostilities broke out at Manila, Republican speakers and

Republican editors at once sought to lay the blame upon those
who had delayed the ratification of the treaty, and, during
the progress of the war, the same Republicans have accused the
opponents of imperialism of giving encouragement to the
Filipinos. …
"The Filipinos do not need any encouragement from Americans

now living. Our whole history has been an encouragement, not
only to the Filipinos, but to all who are denied a voice in
their own government. If the Republicans are prepared to
censure all who have used language calculated to make the
Filipinos hate foreign domination, let them condemn the speech
of Patrick Henry. When he uttered that passionate appeal,
'Give me liberty or give me death,' he expressed a sentiment
which still echoes in the hearts of men. Let them censure
Jefferson; of all the statesmen of history none have used
words so offensive to those who would hold their fellows in
political bondage. Let them censure Washington, who declared
that the colonists must choose between liberty and slavery.
Or, if the statute of limitations has run against the sins of
Henry and Jefferson and Washington, let them censure Lincoln,
whose Gettysburg speech will be quoted in defense of popular
government when the present advocates of force and conquest
are forgotten. … If it were possible to obliterate every word
written or spoken in defense of the principles set forth in
the Declaration of Independence, a war of conquest would still
leave its legacy of perpetual hatred, for it was God himself
who placed in every human heart the love of liberty. He never
made a race of people so low in the scale of civilization or
intelligence that it would welcome a foreign master.
"Those who would have this nation enter upon a career of

empire must, consider not only the effect of imperialism on
the Filipinos, but they must also calculate its effects upon
our own nation. We cannot repudiate the principle of
self-government in the Philippines without weakening that
principle here. …
"Our opponents, conscious of the weakness of their cause, seek

to confuse imperialism with expansion, and have even dared to
claim Jefferson as a supporter of their policy. Jefferson
spoke so freely and used language with such precision that no
one can be ignorant of his views. On one occasion he declared:
'If there be one principle more deeply rooted than any other
in the mind of every American, it is that we should have
nothing to do with conquest.' And again he said: 'Conquest is
not in our principles; it is inconsistent with our
government.' The forcible annexation of territory to be
governed by arbitrary power differs as much from the
acquisition of territory to be built up into states as a
monarchy differs from a democracy. The Democratic party does
not oppose expansion when expansion enlarges the area of the
Republic and incorporates land which can be settled by
American citizens, or adds to our population people who are
willing to become citizens and are capable of discharging
their duties as such. …
"A colonial policy means that we shall send to the Philippine

Islands a few traders, a few taskmasters and a few
officeholders and an army large enough to support the
authority of a small fraction of the people while they rule
the natives. If we have an imperial policy we must have a
great standing army as its natural and necessary complement.
The spirit which will justify the forcible annexation of the
Philippine Islands will justify the seizure of other islands
and the domination of other people, and with wars of conquest
we can expect a certain, if not rapid, growth of our military
establishment. …
"The Republican platform assumes that the Philippine Islands

will be retained under American sovereignty, and we have a
right to demand of the Republican leaders a discussion of the
future status of the Filipino. Is he to be a citizen or a
subject? Are we to bring into the body politic eight or ten
million Asiatics, so different from us in race and history
that amalgamation is impossible? Are they to share with us in
making the laws and shaping the destiny of this nation? No
Republican of prominence has been bold enough to advocate such
a proposition. The McEnery resolution, adopted by the Senate
immediately after the ratification of the treaty, expressly
negatives this idea. The Democratic platform describes the
situation when it says that the Filipinos cannot be citizens
without endangering our civilization. Who will dispute it? And
what is the alternative? If the Filipino is not to be a
citizen, shall we make him a subject? On that question the
Democratic platform speaks with equal emphasis. It declares
that the Filipino cannot be a subject without endangering our
form of government. A Republic can have no subjects. A subject
is possible only in a government resting upon force; he is
unknown in a government deriving its just powers from the
consent of the governed. "The Republican platform says that
'the largest measure of self-government consistent with their
welfare and our duties shall be secured to them (the
Filipinos) by law.' This is a strange doctrine for a
government which owes its very existence to the men who
offered their lives as a protest against government without
consent and taxation without representation. In what respect
does the position of the Republican party differ from the
position taken by the English government in 1776? Did not the
English government promise a good government to the colonists?
What king ever promised a bad government to his people? Did
not the English government promise that the colonists should
have the largest measure of self-government consistent with
their welfare and English duties? Did not the Spanish
government promise to give to the Cubans the largest measure
of self-government consistent with their welfare and Spanish
duties? The whole difference between a Monarchy and a Republic
may be summed up in one sentence. In a Monarchy the King gives
to the people what he believes to be a good government; in a
Republic the people secure for themselves what they believe to
be a good government. …
{662}
"The Republican platform promises that some measure of

self-government is to be given the Filipinos by law; but even
this pledge is not fulfilled. Nearly sixteen months elapsed
after the ratification of the treaty before the adjournment of
Congress last June, and yet no law was passed dealing with the
Philippine situation. The will of the President has been the
only law in the Philippine Islands wherever the American
authority extends. Why does the Republican party hesitate to
legislate upon the Philippine question? Because a law would
disclose the radical departure from history and precedent
contemplated by those who control the Republican party. The
storm of protest which greeted the Porto Rican bill was an
indication of what may be expected when the American people
are brought face to face with legislation upon this subject.
If the Porto Ricans, who welcomed annexation, are to be denied
the guarantees of our Constitution, what is to be the lot of
the Filipinos, who resisted our authority? If secret
influences could compel a disregard of our plain duty toward
friendly people, living near our shores, what treatment will
those same influences provide for unfriendly people 7,000
miles away? …
"Is the sunlight of full citizenship to be enjoyed by the

people of the United States, and the twilight of
semi-citizenship endured by the people of Porto Rico, while
the thick darkness of perpetual vassalage covers the
Philippines? The Porto Rico tariff law asserts the doctrine
that the operation of the Constitution is confined to the
forty-five States. The Democratic party disputes this doctrine
and denounces it as repugnant to both the letter and spirit of
our organic law. There is no place in our system of government
for the deposit of arbitrary and irresponsible power. That the
leaders of a great party should claim for any President or
Congress the right to treat millions of people as mere
'possessions' and deal with them unrestrained by the
Constitution or the bill of rights, shows how far we have
already departed from the ancient landmarks and indicates what
may be expected if this nation deliberately enters upon a
career of empire.
"The territorial form of government is temporary and

preparatory, and the chief security a citizen of a territory
has is found in the fact that he enjoys the same
constitutional guarantees and is subject to the same general
laws as the citizen of a state. Take away this security and
his rights will be violated and his interests sacrificed at
the demand of those who have political influence. This is the
evil of the colonial system, no matter by what nation it is
applied. …
"Let us consider briefly the reasons which have been given in

support of an imperialistic policy. Some say that it is our
duty to hold the Philippine Islands. But duty is not an
argument; it is a conclusion. To ascertain what our duty is,
in any emergency, we must apply well settled and generally
accepted principles. It is our duty to avoid stealing, no
matter whether the thing to be stolen is of great or little
value. It is our duty to avoid killing a human being, no
matter where the human being lives or to what race or class he
belongs. …
"It is said that we have assumed before the world obligations

which make it necessary for us to permanently maintain a
government in the Philippine Islands. I reply, first, that the
highest obligation of this nation is to be true to itself. No
obligation to any particular nations, or to all the nations
combined, can require the abandonment of our theory of
government, and the substitution of doctrines against which
our whole national life has been a protest. And, second, that
our obligation to the Filipinos, who inhabit the islands, is
greater than any obligation which we can owe to foreigners who
have a temporary residence in the Philippines or desire to
trade there. It is argued by some that the Filipinos are
incapable of self-government and that, therefore, we owe it to
the world to take control of them. Admiral Dewey, in an
official report to the Navy Department, declared the Filipinos
more capable of self-government than the Cubans, and said that
he based his opinion upon a knowledge of both races. …
"Republicans ask, 'Shall we haul down the flag that floats

over our dead in the Philippines?' The same question might
have been asked when the American flag floated over
Chapultepec and waved over the dead who fell there; but the
tourist who visits the City of Mexico finds there a national
cemetery owned by the United States and cared for by an
American citizen. Our flag still floats over our dead, but
when the treaty with Mexico was signed American authority
withdrew to the Rio Grande, and I venture the opinion that
during the last fifty years the people of Mexico have made
more progress under the stimulus of independence and
self-government than they would have made under a carpet-bag
government held in place by bayonets. The United States and
Mexico, friendly republics, are each stronger and happier than
they would have been had the former been cursed and the latter
crushed by an imperialistic policy disguised as 'benevolent
assimilation.'
"'Can we not govern colonies?', we are asked. The question is

not what we can do, but what we ought to do. This nation can
do whatever it desires to do, but it must accept
responsibility for what it does. If the Constitution stands in
the way, the people can amend the Constitution. I repeat, the
nation can do whatever it desires to do, but it cannot avoid
the natural and legitimate results of its own conduct. …
"Some argue that American rule in the Philippine Islands will

result in the better education of the Filipinos. Be not
deceived. If we expect to maintain a colonial policy, we shall
not find it to our advantage to educate the people. The
educated Filipinos are now in revolt against us, and the most
ignorant ones have made the least resistance to our
domination. If we are to govern them without their consent and
give them no voice in determining the taxes which they must
pay, we dare not educate them, lest they learn to read the
Declaration of Independence and Constitution of the United
States and mock us for our inconsistency. The principal
arguments, however, advanced by those who enter upon a defense
of imperialism are:
"First—That we must improve the present opportunity to become

a world power and enter into international politics.
{663}
"Second—That our commercial interests in the Philippine

Islands and in the Orient make it necessary for us to hold the
islands permanently.
"Third—That the spread of the Christian religion will be

facilitated by a colonial policy.
"Fourth—That there is no honorable retreat from the position

which the nation has taken.
"The first argument is addressed to the nation's pride and the

second to the nation's pocket-book. The third is intended for
the church member and the fourth for the partisan. It is
sufficient answer to the first argument to say that for more
than a century this nation has been a world power. For ten
decades it has been the most potent influence in the world.
Not only has it been a world power, but it has done more to
affect the politics of the human race than all the other
nations of the world combined. Because our Declaration of
Independence was promulgated others have been promulgated.
Because the patriots of 1776 fought for liberty, others have
fought for it. Because our Constitution was adopted, other
constitutions have been adopted. The growth of the principle
of self-government, planted on American soil, has been the
overshadowing political fact of the nineteenth century. It has
made this nation conspicuous among the nations and given it a
place in history such as no other nation has ever enjoyed.
Nothing has been able to check the onward march of this idea.
I am not willing that this nation shall cast aside the
omnipotent weapon of truth to seize again the weapons of
physical warfare. I would not exchange the glory of this
Republic for the glory of all the empires that have risen and
fallen since time began.
"The permanent chairman of the last Republican National

Convention presented the pecuniary argument in all its
baldness when he said: 'We make no hypocritical pretense of
being interested in the Philippines solely on account of
others. While we regard the welfare of those people as a
sacred trust, we regard the welfare of the American people
first. We see our duty to ourselves as well as to others. We
believe in trade expansion. By every legitimate means within
the province of government and constitution we mean to
stimulate the expansion of our trade and open new markets.'
This is the commercial argument. It is based upon the theory
that war can be rightly waged for pecuniary advantage, and
that it is profitable to purchase trade by force and violence.
… The Democratic party is in favor of the expansion of trade.
It would extend our trade by every legitimate and peaceful
means; but it is not willing to make merchandise of human
blood. But a war of conquest is as unwise as it is
unrighteous. A harbor and coaling station in the Philippines
would answer every trade and military necessity, and such a
concession could have been secured at any time without
difficulty.
"It is not necessary to own people in order to trade with

them. We carry on trade to-day with every part of the world,
and our commerce has expanded more rapidly than the commerce
of any European empire. We do not own Japan or China, but we
trade with their people. We have not absorbed the republics of
Central and South America, but we trade with them. It has not
been necessary to have any political connection with Canada or
the nations of Europe in order to trade with them. Trade
cannot be permanently profitable unless it is voluntary. …
"Imperialism would be profitable to the army contractors; it

would be profitable to the ship-owners, who would carry live
soldiers to the Philippines and bring dead soldiers back; it
would be profitable to those who would seize upon the
franchises, and it would be profitable to the officials whose
salaries would be fixed here and paid over there; but to the
farmer, to the laboring man and to the vast majority of those
engaged in other occupations it would bring expenditure
without return and risk without reward.
"The pecuniary argument, though more effective with certain

classes, is not likely to be used so often or presented with
so much enthusiasm as the religious argument. If what has been
termed the 'gunpowder gospel' were urged against the Filipinos
only, it would be a sufficient answer to say that a majority
of the Filipinos are now members of one branch of the
Christian church; but the principle involved is one of much
wider application and challenges serious consideration. The
religious argument varies in positiveness, from a passive
belief that Providence delivered the Filipinos into our hands
for their good and our glory, to the exultation of the
minister who said that we ought to 'thrash the natives
(Filipinos) until they understand who we are,' and that 'every
bullet sent, every cannon shot and every flag waved, means
righteousness.' … If true Christianity consists in carrying
out in our daily lives the teachings of Christ, who will say
that we are commanded to civilize with dynamite and proselyte
with the sword? …
"Love, not force, was the weapon of the Nazarene; sacrifice

for others, not the exploitation of them, was His method of
reaching the human heart. A missionary recently told me that
the Stars and Stripes once saved his life because his
assailant recognized our flag as a flag that had no blood upon
it. Let it be known that our missionaries are seeking souls
instead of sovereignty; let it be known that instead of being
the advance guard of conquering armies, they are going forth
to help and uplift, having their loins girt about with truth
and their feet shod with the preparation of the gospel of
peace, wearing the breastplate of righteousness and carrying
the sword of the spirit; let it be known that they are
citizens of a nation which respects the rights of the citizens
of other nations as carefully as it protects the rights of its
own citizens, and the welcome given to our missionaries will
be more cordial than the welcome extended to the missionaries
of any other nation.
"The argument made by some that it was unfortunate for the

nation that it had anything to do with the Philippine Islands,
but that the naval victory at Manila made the permanent
acquisition of those islands necessary, is also unsound. We
won a naval victory at Santiago, but that did not compel us to
hold Cuba. The shedding of American blood in the Philippine
Islands does not make it imperative that we should retain
possession forever. American blood was shed at San Juan Hill
and El Caney, and yet the President has promised the Cubans
independence. The fact that the American flag floats over
Manila does not compel us to exercise perpetual sovereignty
over the islands; the American flag waves over Havana to-day,
but the President has promised to haul it down when the flag
of the Cuban Republic is ready to rise in its place. Better a
thousand times that our flag in the Orient give way to a flag
representing the idea of self-government than that the flag of
this Republic should become the flag of an empire.
{664}
"There is an easy, honest, honorable solution of the

Philippine question. It is set forth in the Democratic
platform, and it is submitted with confidence to the American
people. This plan I unreservedly indorse. If elected, I will
convene congress in extraordinary session as soon as
inaugurated and recommend an immediate declaration of the
nation's purpose, first, to establish a stable form of
government in the Philippine Islands, just as we are now
establishing a stable form of government in Cuba; second, to
give independence to the Cubans; third, to protect the
Filipinos from outside interference while they work out their
destiny, just as we have protected the republics of Central
and South America, and are, by the Monroe doctrine, pledged to
protect Cuba."
UNITED STATES OF AMERICA: A. D. 1900.

The Republican candidate on the same subject.
The answer of the party controlling the government to the

impeachment of its policy of colonial acquisition, and
especially of its conduct in the Philippine Islands, was given
by Mr. McKinley, in a letter of acceptance, addressed,
September 8, to the committee which gave him formal notice of
his renomination by the Republican convention. After
rehearsing at considerable length the events which preceded,
attended and followed the capture of Manila, he continued:
"Would not our adversaries have sent Dewey's fleet to Manila

to capture and destroy the Spanish sea power there, or,
dispatching it there, would they have withdrawn it after the
destruction of the Spanish fleet; and, if the latter, whither
would they have directed it to sail? Where could it have gone?
What port in the Orient was opened to it? Do our adversaries
condemn the expedition under the command of General Merritt to
strengthen Dewey in the distant ocean and assist in our
triumph over Spain, with which nation we were at war? Was it
not our highest duty to strike Spain at every vulnerable
point, that the war might be successfully concluded at the
earliest practicable moment? And was it not our duty to
protect the lives and property of those who came within our
control by the fortunes of war? Could we have come away at any
time between May 1, 1898, and the conclusion of peace without a
stain upon our good name? Could we have come away without
dishonor at any time after the ratification of the peace
treaty by the Senate of the United States? There has been no
time since the destruction of the enemy's fleet when we could
or should have left the Philippine Archipelago. After the
treaty of peace was ratified, no power but Congress could
surrender our sovereignty or alienate a foot of the territory
thus acquired. The Congress has not seen fit to do the one or
the other, and the President had no authority to do either, if
he had been so inclined, which he was not. So long as the
sovereignty remains in us it is the duty of the Executive,
whoever he may be, to uphold that sovereignty, and if it be
attacked to suppress its assailants. Would our political
adversaries do less?
"It has been asserted that there would have been no fighting
in the Philippines if Congress had declared its purpose to
give independence to the Tagal insurgents. The insurgents did
not wait for the action of Congress. They assumed the
offensive; they opened fire on our Army. Those who assert our
responsibility for the beginning of the conflict have
forgotten that, before the treaty was ratified in the Senate,
and while it was being debated in that body and while the
Bacon resolution was under discussion, on February 4, 1899,
the insurgents attacked the American Army, after being
previously advised that the American forces were under orders
not to fire upon them except in defense. The papers found in
the recently captured archives of the insurgents demonstrate
that this attack had been carefully planned for weeks before
it occurred. This unprovoked assault upon our soldiers at a
time when the Senate was deliberating upon the treaty shows
that no action on our part, except surrender and abandonment,
would have prevented the fighting, and leaves no doubt in any
fair mind of where the responsibility rests for the shedding
of American blood.
"With all the exaggerated phrase-making of this electoral

contest, we are in danger of being diverted from the real
contention. We are in agreement with all of those who
supported the war with Spain and also with those who counseled
the ratification of the treaty of peace. Upon these two great
essential steps there can be no issue and out of these came
all of our responsibilities. If others would shirk the
obligations imposed by the war and the treaty, we must decline
to act further with them, and here the issue was made. It is our
purpose to establish in the Philippines a government suitable
to the wants and conditions of the inhabitants and to prepare
them for self-government when they are ready for it and as
rapidly as they are ready for it. That I am aiming to do under
my Constitutional authority, and will continue to do until
Congress shall determine the political status of the
inhabitants of the archipelago.
"Are our opponents against the treaty? If so, they must be

reminded that it could not have been ratified in the Senate
but for their assistance. The Senate which ratified the treaty
and the Congress which added its sanction by a large
approbation comprised Senators and Representatives of the
people of all parties. Would our opponents surrender to the
insurgents, abandon our sovereignty or cede it to them? If
that be not their purpose, then it should be promptly
disclaimed, for only evil can result from the hopes raised by
our opponents in the minds of the Filipinos, that with their
success at the polls in November there will be a withdrawal of
our Army and of American sovereignty over the archipelago; the
complete independence of the Tagalog people recognized and the
powers of government over all the other people of the
archipelago conferred upon the Tagalog leaders. The effect of
a belief in the minds of the insurgents that this will be done
has already prolonged the rebellion and increases the
necessity for the continuance of a large army. It is now
delaying full peace in the archipelago and the establishment
of civil governments and has influenced many of the insurgents
against accepting the liberal terms of amnesty offered by
General MacArthur under my direction. But for these false
hopes, a considerable reduction could have been had in our
military establishment in the Philippines, and the realization
of a stable government would be already at hand.
{665}
"The American people are asked by our opponents to yield the

sovereignty of the United States in the Philippines to a small
fraction of the population, a single tribe out of 80 or more
inhabiting the archipelago, a faction which wantonly attacked
the American troops in Manila while in rightful possession
under the protocol with Spain, awaiting the ratification of
the treaty of peace by the Senate, and which has since been in
active, open rebellion against the United States. We are asked
to transfer our sovereignty to a small minority in the
islands, without consulting the majority, and to abandon the
largest portion of the population, which has been loyal to us,
to the cruelties of the guerrilla insurgent bands. More, than
this, we are asked to protect this minority in establishing a
government, and to this end repress all opposition of the
majority. We are required to set up a stable government in the
interest of those who have assailed our sovereignty and fired
upon our soldiers, and then maintain it at any cost or
sacrifice against its enemies within and against those having
ambitious designs from without. This would require an army and
navy far larger than is now maintained in the Philippines and
still more in excess of what will be necessary with the full
recognition of our sovereignty. A military support of
authority not our own, as thus proposed, is the very essence
of militarism, which our opponents in their platform oppose,
but which by their policy would of necessity be established in
its most offensive form.
"The American people will not make the murderers of our

soldiers the agents of the Republic to convey the blessings of
liberty and order to the Philippines. They will not make them
the builders of the new commonwealth. Such a course would be a
betrayal of our sacred obligations to the peaceful Filipinos
and would place at the mercy of dangerous adventurers the
lives and property of the natives and foreigners. It would
make possible and easy the commission of such atrocities as
were secretly planned to be executed on the 22d of February,
1899, in the city of Manila, when only the vigilance of our
Army prevented the attempt to assassinate our soldiers and all
foreigners and pillage and destroy the city and its
surroundings. In short, the proposition of those opposed to us
is to continue all the obligations in the Philippines which
now rest upon the Government, only changing the relation from
principal, which now exists, to that of surety. Our
responsibility is to remain, but our power is to be
diminished. Our obligation is to be no less, but our title is
to be surrendered to another power, which is without
experience or training or the ability to maintain a stable
government at home and absolutely helpless to perform its
international obligations with the rest of the world. To this
we are opposed. We should not yield our title while our
obligations last. In the language of our platform, 'Our
authority should not be less than our responsibility,' and our
present responsibility is to establish our authority in every
part of the islands.
"No government can so certainly preserve the peace, restore

public order, establish law, justice and stable conditions as
ours. Neither Congress nor the Executive can establish a
stable government in these islands except under our right of
sovereignty, our authority and our flag. And this we are
doing. We could not do it as a protectorate power so
completely or so successfully as we are doing it now. As the
sovereign power, we can initiate action and shape means to
ends and guide the Filipinos to self-development and
self-government. As a protectorate power we could not initiate
action, but would be compelled to follow and uphold a people
with no capacity yet to go alone. In the one case we can
protect both ourselves and the Filipinos from being involved
in dangerous complications; in the other we could not protect
even the Filipinos until after their trouble had come. Beside,
if we cannot establish any government of our own without the
consent of the governed, as our opponents contend, then we
could not establish a stable government for them or make ours
a protectorate without the like consent, and neither the
majority of the people or a minority of the people have
invited us to assume it. We could not maintain a protectorate
even with the consent of the governed without giving
provocation for conflicts and possibly costly wars. Our rights
in the Philippines are now free from outside interference and
will continue so in our present relation. They would not be
thus free in any other relation. We will not give up our own
to guarantee another sovereignty.
"Our title is good. Our peace commissioners believed they were

receiving a good title when they concluded the treaty. The
Executive believed it was a good title when he submitted it to
the Senate of the United States for its ratification. The Senate
believed it was a good title when they gave it their
Constitutional assent, and the Congress seems not to have
doubted its completeness when they appropriated $20,000,000
provided by the treaty. If any who favored its ratification
believed it gave us a bad title, they were not sincere. Our
title is practically identical with that under which we hold
our territory acquired since the beginning of the government,
and under which we have exercised full sovereignty and
established government for the inhabitants. It is worthy of
note that no one outside of the United States disputes the
fulness and integrity of the cession. What then is the real
issue on this subject? Whether it is paramount to any other or
not, it is whether we shall be responsible for the government
of the Philippines with the sovereignty and authority which
enable us to guide them to regulated liberty, law, safety and
progress, or whether we shall be responsible for the forcible
and arbitrary government of a minority without sovereignty and
authority on our part and with only the embarrassment of a
protectorate which draws us into their troubles without the
power of preventing them. There were those who two years ago
were rushing us on to war with Spain who are unwilling now to
accept its clear consequence, as there are those among us who
advocated the ratification of the treaty of pence, but now
protest against its obligations. Nations which go to war must
be prepared to accept its resultant obligations, and when they
make treaties must keep them.
{666}
"Those who profess to distrust the liberal and honorable

purposes of the Administration in its treatment of the
Philippines are not justified. Imperialism has no place in its
creed or conduct. Freedom is a rock upon which the Republican
party was builded and now rests. Liberty is the great
Republican doctrine for which the people went to war and for
which 1,000,000 lives were offered and billions of dollars
expended to make it a lawful legacy of all without the consent
of master or slave. There is a strain of ill-conceived
hypocrisy in the anxiety to extend the Constitutional
guarantees to the people of the Philippines while their
nullification is openly advocated at home. Our opponents may
distrust themselves, but they have no right to discredit the
good faith and patriotism of the majority of the people, who
are opposing them; they may fear the worst form of imperialism
with the helpless Filipinos in their hands, but if they do, it
is because they have parted with the spirit and faith of the
fathers and have lost the virility of the founders of the
party which they profess to represent.
"The Republican party does not have to assert its devotion to

the Declaration of Independence. That immortal instrument of
the fathers remained unexecuted until the people under the
lead of the Republican party in the awful clash of battle
turned its promises into fulfillment. It wrote into the
Constitution the amendments guaranteeing political equality to
American citizenship and it has never broken them or counseled
others in breaking them. It will not be guided in its conduct by
one set of principles at home and another set in the new
territory belonging to the United States. If our opponents
would only practice as well as preach the doctrines of Abraham
Lincoln there would be no fear for the safety of our
institutions at home or their rightful influence in any
territory over which our flag floats.
"Empire has been expelled from Porto Rico and the Philippines
by American freemen. The flag of the Republic now floats over
these islands as an emblem of rightful sovereignty. Will the
Republic stay and dispense to their inhabitants the blessings
of liberty, education and free institutions, or steal away,
leaving them to anarchy or imperialism? The American question
is between duty and desertion—the American verdict will be for
duty and against desertion, for the Republic against both
anarchy and imperialism."
UNITED STATES OF AMERICA: A. D. 1900 (June).

Revenues and expenditures of the government for the
fiscal year ended June 30, 1900.
The revenues of the Government from all sources (by

warrants) for the fiscal year ended June 30. 1900, were:
From internal revenue.

$295,327,926.76
From customs.
233,164,871.16
From profits on coinage, bullion deposits, etc.
9,992,374.09
From District of Columbia.
4,008,722.77
From fees-consular, letters patents, and land.
3,291.716.68
From sales of public lands.
2,836.882.98
From tax on national banks.
1.998.554.00
From navy pension, navy hospital, clothing,
and deposit funds.
1,621.558.52
From sales of Indian lands.
1,384,663.49
From payment of interest by Pacific railways.
1,173,466.43
From miscellaneous.
997,375.68
From sales of Government property.
779,522.78
From customs fees, fines, penalties, etc.
675,706.95
From immigrant fund.
537,404.81
From deposits for surveying public lands.
273,247.19
From sales of ordnance material.
257,265.56
From Soldiers' Home, permanent fund.
247,926.62
From tax on seal skins, and rent of seal islands.
225,676.47
From license fees, Territory of Alaska.
157,234.94
From trust funds, Department of State.
152,794.56
From depredations on public lands.
76,307.58
From Spanish indemnity.
57,000.00
From sales of lands and buildings
3,842,737.68
From part payment Central Pacific
Railroad indebtedness.

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Synthetic methods in drug discovery

Successful Drug Discovery Volume 2 1st Edition Janos

Synthetic biology Volume 2 Maxim Ryadnov

Allosterism in drug discovery Dario Doller

Computational Methods for GPCR Drug Discovery 1st

Small Molecule Drug Discovery: Methods, Molecules and

Heterocyclic chemistry in drug discovery 1st Edition Li

Antidotes to Toxins and Drugs From Natural Sources to

Open Access Databases and Datasets for Drug Discovery

RSC Drug Discovery Series

Advisor to the Board:

Titles in the Series:

31: Traditional Chinese Medicine

35: Pain Therapeutics; Current and Future Treatment Paradigms

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Synthetic Methods in Drug

RSC Drug Discovery Series No. 53

Print ISBN: 978-1-78262-786-9

r The Royal Society of Chemistry 2016

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Synthetic Organic chemistry is at the heart of drug discovery. The vast

RSC Drug Discovery Series No. 53

Volume 2 of the book covers some of the most important pharmaceutically

forming reactions and Csp2–Csp3 couplings. Finally, we conclude this

David Blakemore, Paul Doyle and Yvette Fobian

Chapter 1 Suzuki–Miyaura Coupling 1

RSC Drug Discovery Series No. 53

Chapter 2 Negishi Coupling 70

2.3 Formation of Organozinc Reagents 72

Chapter 3 Hiyama Coupling 104

3.1 Introduction 104

Chapter 4 Sonogashira Coupling 122

4.1 Introduction 122

Chapter 5 Heck Coupling 143

5.1 Introduction 143

5.3 Intramolecular Heck Reactions 158

Chapter 6 Palladium- and Copper-catalysed C–N Cross-coupling

6.1 Introduction 170

Chapter 7 Chan–Lam Coupling Reaction: Copper-promoted C–Element

7.1 General Introduction 242

Chapter 8 C–H Activation Approaches to Molecules 274

8.1 Introduction 274

8.2.1 Intermolecular C(sp2)–H Arylation 277

Chapter 9 Palladium-catalyzed Decarboxylative Couplings 384

9.1 Introduction 384

Chapter 10 New Frontiers with Transition Metals 411

10.1 Introduction 411

10.3 Iron Catalysed Synthesis of Biaryl Compounds 421

Subject Index 443

Chapter 11 Lithium, Magnesium, and Copper: Contemporary

Chapter 12 C–N Bond Formation via Hydrogen Transfer 75

Chapter 13 Synthesis of Sulfonamides 123

13.1 Introduction 123

13.5 Conclusion 136

Chapter 14 Asymmetric Methods and Their Use in the Pharmaceutical

Peter D. Smith, Mark A. Graham, Rachel H. Munday,

14.1 Introduction 139

Chapter 15 Fluorination Approaches 263

15.1 Introduction 263