Green Techniques for Organic Synthesis and Medicinal Chemistry

Green Techniques for Organic Synthesis and Medicinal Chemistry
Edited by
Wei Zhang
Department of Chemistry
University of Massachusetts–Boston
Massachusetts
USA
Berkeley W. Cue
BWC Pharma Consulting
Nottingham, New Hampshire
USA
Second Edition
v
Contents
List of Contributors xvii
Foreword xxi
Preface xxiii
Part I General Topics in Green Chemistry 1
? Green Chemistry Metrics 3
Frank Roschangar and Juan Colberg
1.1 Business Case 3
1.2 Historical Context 3
1.3 Metrics, Awards, and Barriers 4
1.3.1 Mass-Based Metrics 4
1.3.2 Life-Cycle Assessment 6
1.3.3 Green Analytical Chemistry (GAC) 7
1.3.4 Awards 7
1.3.5 Barriers 9
1.4 Metrics Unification Via Green Aspiration Level 9
1.4.1 Standardizing Metrics 10
1.4.2 Defining Analysis Starting Points 10
1.4.3 Considering Drug Manufacturing Complexity 11
1.4.4 Green Aspiration Level (GAL) 11
1.4.5 Relative Process Greenness (RPG) 11
1.5 Green Scorecard 12
1.6 Supply Chain 14
1.7 Outlook and Opportunities 15
1.7.1 Industry-Wide Adaption 15
1.7.2 Integration with LCA 15
1.7.3 Application of GAL to Supply Chain 15
1.7.4 Transformation-Type–Based GAL 15
1.7.5 Opportunities for Government 16
References 17
? Green Solvents 21
Janet L. Scott and Helen F. Sneddon
2.1 Introduction 21
2.1.1 The Need for Greener Alternatives for Chlorinated Solvents 21vi Contents
2.1.2 The Need for Greener Alternatives for Dipolar Aprotic Solvents 23
2.1.3 Scope 23
2.2 Solvent Selection Guides and Tools 23
2.3 Greener Molecular Solvents 24
2.3.1 Carbonates 24
2.3.2 ?-Valerolactone 25
2.3.3 Dimethylisosorbide 27
2.3.4 Butanol 27
2.3.5 Ethyl Lactate and Lactic Acid 28
2.3.6 Glycerol and Glycerol Derivatives 29
2.3.7 Cyrene 31
2.3.8 2-Methyl Tetrahydrofuran 32
2.3.9 Cyclopentyl Methyl Ether 32
2.4 Opportunities, Challenges, and Future Developments 34
References 34
? Green Analytical Chemistry 43
Paul Ferguson and Douglas Raynie
3.1 Introduction 43
3.1.1 Analytical Method Assessment 44
3.1.2 Case Studies 46
3.2 Sample Preparation 47
3.2.1 Sample Preparation Focusing on Liquid Approaches 47
3.2.2 Sample Preparation Using Solid Supports 49
3.3 Techniques and Methods 50
3.3.1 Liquid Chromatography 50
3.3.2 Gas Chromatography 57
3.3.3 Supercritical Fluid Chromatography 58
3.3.4 Spectroscopy 60
3.4 Process Analytical Technology 60
3.5 Biopharmaceutical Analysis 62
3.5.1 Biopharmaceutical Sample Preparation 63
3.5.2 Chromatographic and Electrophoretic Separation 63
3.5.3 PAT for Biopharmaceuticals 65
3.6 Conclusions 65
Acknowledgments 66
References 66
? Green Engineering 71
Christopher L. Kitchens and Lindsay Soh
4.1 Introduction: Green Engineering Misconceptions and Realizations 71
4.2 12 Principles of Green Engineering 72
4.3 Green Chemistry Metrics Applied to Engineering 73
4.3.1 Maleic Anhydride Production Example 74
4.3.2 Level 1 Green Chemistry Metrics 74
4.3.3 Level 2 Green Chemistry Metrics 78
4.3.4 Level 3 Green Chemistry Metrics 80
4.4 Use of Green Solvents in the Chemical Industry 80
4.4.1 Waste Prevention 80Contents vii
4.4.2 Inherently Non-Hazardous 81
4.4.3 Renewable Rather Than Depleting 83
4.4.4 Design for Commercial After-Life 84
4.4.5 Separation and Purification to Minimize Energy Consumption and Materials Use 84
4.4.6 Integration and Interconnectivity with Available Energy and Materials Flows 85
4.4.7 Conserve Complexity 85
4.5 Presidential Green Chemistry Awards 86
4.6 Opportunities and Outlook 87
References 87
? Greening of Consumer Cleaning Products 91
David C. Long
5.1 History of Green Consumer Cleaning Products 91
5.1.1 Cleaning Products Before 1990: Great Cleaners but Not Green 91
5.1.2 The Birth of Green Cleaning Products: Green but Didn’t Clean 92
5.1.3 Early Entries in Green Cleaning 93
5.1.4 Green Cleaning Can Provide Better Cleaning: The Historical Influence of Major Manufacturers 93
5.2 Drivers for Greener Products 94
5.2.1 Consumers 94
5.2.2 Governmental Regulations and Non-Governmental Organizations 95
5.2.3 Environmentally Preferable Purchasing Programs 96
5.2.4 Major Retailers 97
5.3 Development of Green Cleaning Criteria and Eco-Labeling 98
5.3.1 History and Background 98
5.3.2 Green Seal 100
5.3.3 ECOLOGO 100
5.3.4 EPA’s Design for the Environment/Safer Choice 101
5.3.5 GreenList® 101
5.4 Development of Greener Ingredients for Cleaners 102
5.4.1 Background 102
5.4.2 Surfactants 102
5.4.3 Solvents 104
5.4.4 Chelants 105
5.4.5 Oxidizers 107
5.4.6 Colorants and Dyes 108
5.4.7 Fragrances 108
5.4.8 Disinfectants and Preservatives 109
5.5 The Future of Green Cleaning 111
Acknowledgments 112
References 112
? Innovation with Non-Covalent Derivatization 117
John C. Warner and Emily Stoler
6.1 Introduction 117
6.2 NCD Overview 118
6.2.1 NCD Definitions 118
6.2.2 NCD Design 118
6.2.3 NCD Preparation 119
6.2.4 NCD Characterization 120viii Contents
6.3 Pharmaceutical NCDs 121
6.3.1 API Solubility 121
6.3.2 API Bioavailability 122
6.3.3 API Stability 122
6.3.4 API Additional Performance Enhancements 122
6.3.5 API NCD Future 123
6.4 Environmental and Green Chemistry Benefits 123
References 123
Part II Green Catalysts 131
? Catalytic C-H Bond Cleavage for Heterocyclic Compounds 133
Zhanxiang Liu and Yuhong Zhang
7.1 Introduction 133
7.2 Synthesis of Nitrogen Heterocycles 133
7.2.1 Synthesis of Five-Membered N-Heterocycles 133
7.2.2 Synthesis of Six-Membered N-Heterocycles 140
7.2.3 Synthesis of Other N-Heterocycles 143
7.3 Synthesis of Oxygen-Containing Heterocycles 144
7.3.1 Synthesis of Furan 144
7.4 Synthesis of Sulfur-Containing Heterocycles 148
7.4.1 Synthesis of Dibenzothiophenes 148
7.5 Medium-Sized Heterocyclic Compounds 150
7.6 Conclusion 152
References 152
? Biocatalysis 161
James Lalonde
8.1 Introduction 161
8.2 Enzymes for Biocatalysis 162
8.2.1 Practical Aspects of Using Enzymes in Drug Manufacture 163
8.3 Advances in Enzyme Engineering and Directed Evolution 164
8.4 Biocatalytic Synthesis of Pharmaceuticals: Case Studies of Highly Efficient Pharmaceutical
Syntheses 165
8.4.1 Atorvastatin 165
8.4.2 Synthesis of Beta-Lactam Antibiotics 168
8.4.3 Pregabalin 169
8.4.4 Sitagliptin, Glasdegib, and Dexamphetamine 170
8.4.5 Simvastatin 172
8.4.6 Sulopenem and Montelukast 173
8.4.7 Boceprevir and Telaprevir 175
8.4.8 Esomeprazole 176
8.4.9 Synthesis of Drug Metabolites 177
8.5 Summary and Future Outlook 178
References 180
? Practical Asymmetric Organocatalysis 185
Wen-Zhao Zhang, Samik Nanda, and Sanzhong Luo
9.1 Introduction 185
9.2 Aminocatalysis 185Contents ix
9.3 Br?nsted Acid Catalysis 191
9.4 Br?nsted Base Catalysis 193
9.5 Hydrogen-Bonding Catalysis 197
9.6 Phase-Transfer Catalysis 202
9.7 Lewis Acid, Lewis Base, and N-Heterocyclic Carbene Catalysis 204
9.8 Large-Scale Reaction (>100-Gram Reaction) 207
9.9 Conclusion 209
References 209
?? Fluorous Catalysis 219
Laszl ´ o T. Mika and Istv ´ an T. Horv ´ ath ´
10.1 Introduction and the Principles of Fluorous Catalysis 219
10.2 Ligands for Fluorous Transition Metal Catalysts 224
10.3 Synthetic Application of Fluorous Catalysis 225
10.3.1 Hydroformylation 225
10.3.2 Hydrogenation 229
10.3.3 Hydrosylilation 232
10.3.4 Cross-Coupling Reactions 236
10.3.5 Hydroboration 243
10.3.6 Oxidation 243
10.3.7 Esterification, Transesterification, and Acetylation 248
10.3.8 Other Metal Catalyzed Carbon-Carbon Bond–Forming Reactions 250
10.4 Fluorous Organocatalysis 256
10.5 Other Applications of Fluorous Catalysis 259
References 259
?? Solid-Supported Catalysis 269
Sukanta Bhattacharyya and Basudeb Basu
11.1 Introduction 269
11.1.1 General Introduction 269
11.1.2 The Impact of Solid-Phase Organic Synthesis on Green Chemistry 269
11.2 Immobilized Palladium Catalysts 270
11.2.1 Suzuki Reactions 270
11.2.2 Mizoroki–Heck Reactions in Water 273
11.2.3 Sonogashira Reactions in Water 274
11.2.4 Tsuji–Trost Reactions in Water 276
11.3 Immobilized Rhodium Catalysts 276
11.3.1 Introduction 276
11.3.2 Rhodium(II) Carbenoid Chemistry 277
11.3.3 Rhodium(I)-Catalyzed Addition Reactions 278
11.3.4 Rhodium-Catalyzed Hydrogenation Reactions 278
11.3.5 Rhodium-Catalyzed Carbonylation Reactions 278
11.4 Immobilized Ruthenium Catalysts 279
11.4.1 Introduction 279
11.4.2 Ruthenium-Catalyzed Metathesis Reactions 279
11.4.3 Ruthenium-Catalyzed Transfer Hydrogenation 280
11.4.4 Ruthenium-Catalyzed Epoxidation 282
11.4.5 Ruthenium-Catalyzed Cyclopropanation Reactions 282
11.4.6 Ruthenium-Catalyzed Halogenation Reactions 283x Contents
11.5 Other Immobilized Catalysts 284
11.5.1 Immobilized Cobalt Catalysts 284
11.5.2 Immobilized Copper Catalysts 285
11.5.3 Immobilized Iridium Catalysts 285
11.6 Conclusions 286
References 287
?? Asymmetric Organocatalysis in Aqueous Media 291
Kartick C. Bhowmick and Tanmoy Chanda
12.1 Introduction 291
12.2 Carbon-Carbon Bond-Formation Reactions 292
12.2.1 Aldol Reactions 292
12.2.2 1,4-Conjugate Addition Reactions 305
12.2.3 Mannich Reactions 310
12.2.4 Diels-Alder Reactions 311
12.2.5 Miscellaneous C-C Bond-Forming Reactions 312
12.3 Reactions Other than C-C Bond Formation 313
12.4 Conclusion 314
References 314
Part III Green Synthetic Techniques 325
?? Solvent-Free Synthesis 327
Kendra Leahy Denlinger and James Mack
13.1 Introduction 327
13.2 Ball Milling 328
13.2.1 Types of Ball Mills 329
13.2.2 Kinetics and Thermodynamics of Solvent-Free Reactions 330
13.2.3 Hard-Soft Acid-Base Theory 333
13.2.4 Stereoselectivity 334
13.2.5 Catalysis 334
13.2.6 Isolation Techniques 336
References 339
?? Ultrasonic Reactions 343
Rodrigo Cella and Helio A. Stefani ´
14.1 Introduction 343
14.2 How Does Cavitation Work? 343
14.3 Aldol/Condensation Reactions 345
14.3.1 Aldol Reaction 345
14.3.2 Mukaiyama Aldol Reaction 345
14.3.3 Knoevenagel Reaction 346
14.3.4 Claisen-Schmidt Reaction 349
14.3.5 Mannich Reaction 350
14.4 1,4-Addition 351
14.4.1 Michael Additions 351
14.4.2 Baylis-Hillman Reaction 353
14.5 Heterocycles Synthesis 353
14.6 Coupling Reactions 356
14.6.1 Heck Cross-Coupling Reaction 356Contents xi
14.6.2 Sonogashira Reaction 357
14.6.3 Stille Cross-Coupling 357
14.6.4 Suzuki Cross-Coupling 359
14.7 Wittig Reaction 361
14.8 Diels-Alder Reaction 362
14.9 Miscellaneous 365
14.10 Conclusions 366
References 366
?? Photochemical Synthesis 373
Stefano Protti, Maurizio Fagnoni, and Angelo Albini
15.1 Introduction 373
15.2 Synthesis and Rearrangement of Open-Chain Compounds 376
15.2.1 Reactions of Olefins 376
15.2.2 Ar-H Functionalization 380
15.2.3 Miscellaneous 380
15.3 Synthesis of Three- and Four-Membered Rings 382
15.3.1 Synthesis of Three-Membered Rings 383
15.3.2 Synthesis of Four-Membered Rings 385
15.4 Synthesis of Five-, Six- (and Larger)-Membered Rings 391
15.4.1 Synthesis of Five-Membered Rings 391
15.4.2 Synthesis of Six-Membered Rings 394
15.4.3 Synthesis of Larger Rings 397
15.5 Oxygenation and Oxidation 398
15.6 Conclusions 400
Acknowledgments 401
References 401
?? Pot Economy Synthesis 407
Wenbin Yi, Xin Zeng, and Song Gao
16.1 Introduction 407
16.2 Multicomponent Reactions 407
16.2.1 The Grieco Reaction 408
16.2.2 The Petasis Reaction 409
16.2.3 The Sonogashira-Type Reaction 410
16.2.4 The Ugi/Knevengagel/Click Reaction 411
16.2.5 MCR involving Aza-Diels-Alder Reaction 412
16.2.6 MCR Involving Fluorination and Trifluoromethylation 412
16.2.7 Other Kinds of Reactions 413
16.3 One-Pot and Multi-Step Reactions 415
16.3.1 Two-Step Reaction Sequences 416
16.3.2 Three-Step Reaction Sequences 418
16.3.3 More Than Three-Step Reaction Sequences 421
16.4 One-Pot Asymmetric Synthesis 424
16.4.1 Transition-Metal Catalysis 424
16.4.2 Organocatalysis 427
16.4.3 Chiral Pool-Based One-Pot Synthesis 431
16.5 Outlook 434
References 434xii Contents
?? Microwave-Assisted Organic Synthesis: Overview of Recent Applications 441
Nandini Sharma, Upendra K. Sharma, and Erik V. Van der Eycken
17.1 Introduction 441
17.1.1 Microwave-Assisted MCR Synthesis of N-Containing Heterocycles 442
17.1.2 Coupling Reactions 445
17.2 C-H Functionalization 449
17.2.1 Metal-Catalyzed C-H Functionalization 449
17.2.2 Metal-free C-H Functionalization 451
17.2.3 Oxidative C-H Functionalization 451
17.3 Insertion Reactions 452
17.3.1 Carbon Dioxide Insertion 452
17.3.2 Carbon Monoxide Insertion 453
17.3.3 Isonitrile Insertion 453
17.4 Reduction 453
17.4.1 Microwave-Assisted Hydrogenation of Alkynes and Alkenes 454
17.4.2 Reduction of Carbonyl Groups 454
17.5 Synthesis of Peptides and Related Fine Chemicals 455
17.6 Newer Developments 459
17.6.1 SiC Reactors and Continuous Flow Synthesis 459
17.6.2 Nanomaterial Synthesis 460
17.7 Summary 461
References 461
?? Solid-Supported Synthesis 469
Indrajeet J. Barve and Chung-Ming Sun
Abbreviations 469
18.1 Introduction 471
18.2 Techniques of Solid-Phase Supported Synthesis 472
18.2.1 Recent Advances in Linkers for Solid-Supported Synthesis 472
18.3 Solid-Phase Supported Heterocyclic Chemistry 476
18.3.1 Solid-Phase Synthesis of Nitrogen Heterocycles 476
18.3.2 Solid-Phase Synthesis of Oxygen Heterocycles 484
18.3.3 Solid-Phase Synthesis of Heterocycles with More Heteroatom 485
18.4 Solid-Supported Synthesis of Natural Products 486
18.5 Solid-Supported Organometallic Chemistry 491
18.6 Solid-Phase Synthesis of Peptides 493
18.7 Solid-Phase Supported Stereoselective Synthesis 494
18.8 Interdisciplinary Solid-Supported Synthesis 499
18.8.1 Microwave-Assisted Solid-Phase Synthesis 499
18.8.2 Solid-Phase Supported Reagents in Organic Synthesis 502
References 505
?? Light Fluorous Synthesis 509
Wei Zhang
19.1 Introduction 509
19.2 “Heavy” Versus “Light” Fluorous Chemistry 509
19.3 The Green Chemistry Aspects of Fluorous Synthesis 510
19.3.1 Fluorous Solid-Phase Extraction (F-SPE) to Reduce Waste 510
19.3.2 Recycling Techniques 510Contents xiii
19.3.3 Monitoring Reactions 510
19.3.4 Fluorous Linker-Facilitated Synthesis 511
19.3.5 Microwave-Assisted Synthesis 511
19.3.6 Multicomponent Reactions 511
19.3.7 Reactions and Separations in Aqueous Media 511
19.4 Fluorous Techniques for Discovery Chemistry 511
19.4.1 Fluorous Ligands for Metal Catalysis 511
19.4.2 Fluorous Organocatalysis 514
19.4.3 Fluorous Reagents 516
19.4.4 Fluorous Scavengers 518
19.4.5 Fluorous Linkers 520
19.4.6 Fluorous Mixture Synthesis (FMS) 528
19.5 Conclusions 533
References 533
Part IV Green Techniques and Strategies in the Pharmaceutical Industry 539
?? Ionic Liquids in Pharmaceutical Industry 541
Julia L. Shamshina, Paula Berton, Hui Wang, Xiaosi Zhou, Gabriela Gurau, and Robin D. Rogers
Abbreviations 541
20.1 Introduction 543
20.2 Finding the Right Role for ILs in the Pharmaceutical Industry 544
20.2.1 Use of ILs as Solvents in the Synthesis of Drugs or Drug Intermediates 544
20.2.2 Use of ILs for Pharmaceutical Crystallization 546
20.2.3 Use of ILs in Pharmaceutical Separations 547
20.2.4 Use of ILs for the Extraction of Drugs From Natural Products 551
20.2.5 Use of ILs for Drug Delivery 552
20.2.6 Use of ILs for Drug Detection 553
20.2.7 ILs as Pharmaceutical Ingredients 554
20.2.8 ILs in Membrane Transport 566
20.3 Conclusions and Prospects 567
References 568
?? Green Technologies and Approaches in the Manufacture of Biologics 579
Sa V. Ho and Kristi L. Budzinski
21.1 Introduction 579
21.2 Characteristics of Biologics 580
21.3 Manufacture of Therapeutic Biologics 581
21.3.1 General Characteristics of Conventional Biologics Manufacturing 581
21.3.2 Process and Analytical Technologies 583
21.3.3 Manufacturing Facilities 586
21.4 Environmental Metrics Development and Impact Analysis 587
21.4.1 Mass-Based Metrics 587
21.4.2 Energy-Based Metrics 589
21.4.3 Life-Cycle Assessment 591
21.5 Some Future Directions 592
21.6 Conclusions 594
Acknowledgments 594
References 594xiv Contents
?? Benchmarking Green Chemistry Adoption by “Big Pharma” and Generics Manufacturers 601
Vesela R. Veleva and Berkeley W. Cue
22.1 Introduction 601
22.2 Literature Review 602
22.3 Pharmaceutical Industry Overview and Green Chemistry Drivers 604
22.3.1 Cost Savings 605
22.3.2 Improved Reputation 605
22.3.3 Environmental Impacts of Pharmaceuticals 605
22.3.4 Legislation 606
22.3.5 Customer Demands 606
22.3.6 Investor Pressures 607
22.3.7 Attracting and Retaining Talent 607
22.4 Benchmarking Industry Adoption of Green Chemistry 607
22.4.1 Methods 607
22.4.2 Innovative Pharmaceutical Companies 608
22.4.3 Generic Pharmaceutical Companies 608
22.5 Results and Discussion 610
22.6 Conclusion 616
References 616
?? Green Process Chemistry in the Pharmaceutical Industry: Case Studies Update (????–????) 621
Joseph M. Fortunak, Ji Zhang, Frederick E. Nytko III, and Tiffany N. Ellison
23.1 Introduction 621
23.2 Pharmaceutical Patents Driving Innovation 622
23.3 A Caution About Drug Manufacturing Costs 623
23.4 Process Evolution by Multiple Route Discovery Efforts—Dolutegravir 624
23.5 The Impact of Competition on Process Evolution—Tenofovir Disoproxil Fumarate 628
23.5.1 Tenofovir Disoproxil Fumarate: The Cumulative Impact of Incremental Process Improvements 632
23.6 Simeprevir (Olysio/Sovriad) and Analogues: Chiral Phase-Transfer Catalyst-Promoted Optical
Alpha-Amino Acid Synthesis: A Metal-free Process 633
23.7 Vaniprevir (MK 7009), Simeprevir (TMC435), and Danoprevir: Ring-Closing Metathesis (RCM)
for Macrocyclic Lactam Synthesis: Now a Commercial Reality 635
23.8 Daclatasvir (BMS-790052, Daklinza), and Ledipasvir (GS-5885): Palladium Catalyzed
Cross-Coupling for Greening a Process 638
23.9 Sitagliptin (Januvia) and Ponatinib (Iclusig): Greening the Process by Telescoping Multiple Steps
Together 639
23.10 Febuxostat (Uloric): Greening the Process via Metal Catalyzed C-H Activation: A Prospect 641
23.11 Conclusions 644
References 644
?? Greener Pharmaceutical Science Through Collaboration: The ACS GCI
Pharmaceutical Roundtable 649
Julie B. Manley and Michael E. Kopach
24.1 Introduction 649
24.2 Establishing Pre-Competitive Collaborations 650
24.2.1 Background 650
24.2.2 Mission and Membership 651
24.2.3 Strategic Priorities 652
24.3 Informing and Influencing the Research Agenda 654Contents xv
24.3.1 Key Research Areas 654
24.3.2 Research Grants 656
24.4 Developing Tools 661
24.4.1 Process Mass Intensity 661
24.4.2 Solvent Guide 662
24.4.3 Reagent Guide 662
24.4.4 Electronic Lab Notebooks 663
24.4.5 Continuous Processing Business Cases 664
24.5 Educating Leaders 666
24.5.1 Articles of Interest 667
24.5.2 Influencing Editorial Policy 667
24.5.3 Future Scientists 667
24.6 Collaborating Globally 668
24.6.1 Internal Collaboration 668
24.6.2 External Collaboration 668
24.7 Future Opportunities 669
24.7.1 Analytical Chemistry 669
24.7.2 Animal Health Products 669
24.7.3 Generic Manufacturing 670
24.7.4 Drug Delivery Formulation 670
24.8 Success Factors 671
24.8.1 Unique Value Proposition 671
24.8.2 Degree of Commonality 671
24.8.3 Critical Mass 671
24.8.4 Financial Investment 672
24.8.5 In-Kind Contribution 672
24.8.6 Leadership 672
References 673
Index 675???
Index
a
Abbreviated New Drug Application (ANDA)
615–616
absorption 22, 45, 79, 82, 373–4, 387, 398, 507, 514,
541, 555, 560, 566
Absorption, Distribution, Metabolism, and Excretion
(ADME) 541, 560
ABT-341 423
accelerated hydrogen peroxide (AHP) 110–11
accidents 603
acesulfamate 558
acesulfame 567
acetaldehyde 167–8, 295, 423, 482, 496–8
acetaminophen 547
acetic acid 29, 38, 45, 57, 81, 92, 105–6, 198, 353, 355,
408–9, 426, 442, 449, 451, 460, 469, 471, 482,
488–9, 496–8, 501
acetone 27, 45, 55, 125, 166, 186, 220, 231, 256, 258–9,
268, 298, 303, 310, 336, 345, 384–7, 394, 428, 510
acetone, aldol reactions of 258
acetonitrile 23, 45, 47, 51–2, 54–5, 59, 68, 235–6, 248,
338, 349, 378, 391, 395, 397–8, 400, 549
acetophenone 238, 384, 454
acetylation 248–50
of 2-phenylethanol 249
acetylcodeine 549
acetylene dicarboxylicesters asdipolarophiles 425
acetylsalicylate 560
acetylsalicylic acid 547, 558
AChE 411
acid–base neutralization 587
acroloylferrocene 352
ACS Green Chemistry Institute Pharmaceutical Round
Table (GCI PR) 23, 586
Actavis plc 611
activation reactions 141, 441
active pharmaceutical ingredients (APIs) 21, 543, 555
additional performance enhancements 122
bioavailability of 122
biocatalytic routes to 162
cocrystals of 122
greenness of 21
liquid salt forms of 556
as NCD 123
solubility of 121–2
“spring and parachute” model of 122
stability of 122
acyclovir 560
acylation 250–1
acyl chloride 477, 486
AD, see adefovir dipivoxil
adamantane 250, 270
based NHC–palladium polymer 271
1,4-addition 351–3
addition reactions 305–6
adefovir dipivoxil (AD) 546, 549
adrenosterone 389
affinity chromatography (AC) 582
Aglaia plant genus 391
agrochemicals 133, 152, 412, 442
AIBN, see 2,2?-azobisazobutyronitrile
albendazole 546–8
alcohol dehydrogenases 173
aldehydes 375
aldolases 163, 167–8
aldol reactions 292, 345
asymmetric, in water 293–303
4-hydroxyproline organocatalysts for 302
linear amino acid based organocatalysts for 305
Mukaiyama 345–6
organocatalysts for 292–305
aliphatic aldehydes 426
Green Techniques for Organic Synthesis and Medicinal Chemistry, Second Edition. Edited by Wei Zhang and Berkeley W. Cue.
© 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd.??? Index
alkene 375
alkylation 251–3
fluorous-biphase 251
Pd-catalyzed asymmetric allylic 252
alkylbenzenes 356
alkylimidazolium salts 546
alkyl polyglucosides (APGs) 103
allergic reactions 164
allylation 251
allylphenols 378
allyltrimethylsilane 378
alumina 281, 284
supported cobalt catalysts 284
aluminium-trichloride 251
Alzheimer’s disease (AD) 385, 411
American Chemical Society (ACS) 96, 101–2, 601
?-methylstyrene 408
Amgen 417, 586
amino acid 389
Fmoc 482
?-amino acid 334
?-amino-carbonyl 350
Aaminocarbonylation 453
aminocatalysis 185–91
aldol reaction 185–9
chiral aminocatalysts 186, 188, 190
Mannich reaction in 190
of Michael addition 190–1
pathways 186
proline-catalyzed Mannich reaction 189
synthesis of Wieland–Miescher and Hajos–Parrish
189
aminomethylphenol derivatives 409
4-aminophenol 547
aminophenols 409
3-aminopropylated-MCM-48, 273
3-aminopropyl triethoxysilane 279
2-aminopyridines 520
2-aminothiazole 121
aminotris (methylene phosphonic acid) (ATMP)
106
ammonium chloride 110–11, 355
amorphous compounds 555
amoxicillin 161, 168–9
amphiphilic organocatalysts 297, 301–2
ampicillin 168, 565–6
AMVI, see analytical method volume intensity
analgesics 558
analytical method volume intensity (AMVI) 46
Anastas, Paul 96, 601
anesthetics 558–9, 567
anilides 137
anion-exchange method 552–3
anionic antibiotics 565
anionic surfactants 103
anisoles 250–1, 378
anthraquinone 400
antiarrhythmic drugs 558
antibacterials 558
anticancer activity 565
anticrystal engineering 558
anticrystal engineering approach 556–7
antidepressants 548
antifreeze glycopeptides 456
antifungals 418
antihelminthic neotuberostemonines 397
antimalarial compounds 551
Antimycin A3b 489, 491
apigenin 550
API-ILs 556–60
antimicrobial properties of 565
anti-proliferative effects of 565–6
appropriate selection of ions 556–8
design approach 566
examples 557–8
immobilized onto silica 564
modulating ionicity of 560–3
pharmaceutical activity assessment of 564–6
as pharmaceuticals strategies 561
prodrug 563
solubility of a drug through 566
water solubility of 560
API supported ionic liquid phases (API-SILPs) 564
Apotex 612
aprepitant 409
aquatic organisms 27, 92, 103
arene–alkene meta-photocycloaddition reaction 397
Ar-ethynyl-TAA 357
Ar-H functionalization 380
Arkon Consultants and NuPro Technologies, Inc. 87
aromatic aldehydes 186, 246, 258, 295, 297, 299,
345–51, 451
artemisinin 551
arylacetylenes 365
arylalkanoic acids 549
arylation 251–3
of indoles with aryl-halides 252
aryl halides 239, 270, 272Index ???
3-aryl-1,2,3-oxadiazoles 364
arylpiperazinylbutyl derivatives, solid-supported
synthesis of 481
?-arylpropionic acid derivatives, synthesis of 378
aryl stannanes 239
ascaridol 399
Aspen Pharmaceutical 612
Aspergillus 418
aspirin 552, 558
astemizole 178
AstraZeneca 81, 610
asymmetric aldol reactions
asymmetric aldol addition 257
in water 293–300, 303
asymmetric allylic alkylation 251
asymmetric catalysis 204
asymmetric Michael addition reaction 203, 257, 309,
430
catalyzed by Br?nsted base catalyst 195
of cyclic ketones 307
of cyclohexanone 307
of ketones 306
of thioacetic acid, thiophenol, and thiol 198
in water media 306–8
asymmetric Michael/transamination/cyclization
process 429
asymmetric organocatalytic oxidation reactions 257
asymmetric polyene Heck cyclization 425
asymmetric synthesis 161, 256, 424–34
asymmetric transfer hydrogenation 280
atenolol 550
atom economy 73–4, 168, 172, 269, 407, 458, 509, 603
atorvastatin 165–8
chemoenzymatic routes to 166
Pfizer’s process to 167–8
aza-Diels–Alder reaction 363, 412
tetrahydroquinolines, synthesis of 364
azalactones 202
aza-Michael reaction 352
aza-Povarov 363–4
azasugar 395
azepinones, synthesis of 151
azide–alkyne cycloaddition 285, 334–5, 421, 443, 456
azide–alkyne (click reaction) for diastereoselective
synthesis 421
azides 138, 142, 276, 411, 443
2-azidobenzoic acid 477
2-azidoethanol 415
2,2?-azobisazobutyronitrile (AIBN) 282
azodicarboxylate 428
azole antifungals 418
azomethine ylide 394, 421
b
Bacillus megaterium 178
Baeyer–Villiger mono-oxygenase (BVMO) 176
Baeyer–Villiger oxidation 247, 249, 545
ball milling 328–38
diagrams of motion in 332
functionalized polymer resins in 338
types of ball mills 329, 332
Bartoli-indole synthesis 483
batch microwave reactors 443, 459
Baylis-Hillman reactions 353
benchmarking 601–16
benign solvents 59, 445
benzaldehyde 31, 40, 135, 345, 386
benzalkonium 556–9
benzalkonium chloride 104
benzene, benzoylation of 250
benzene 1,2-diamine 520
benzene reaction 74
benzethonium 558–9
benzimidazolinopiperazinones 495
solid-supported synthesis of 482–3
benzo[b]phosphole 415
1,5-benzodiazepinic rings 354
1,3-benzodioxole isocyanide 426
benzofurans 484–5
benzoin esters 384
benzophenone 358, 360, 376–7
benzophenones 358, 360
benzoquinone 363
1,2-benzothiazines 150
benzothiazoles 26, 149
synthesis of 149
benzotriazoles
based activators 456
benzotriazoles, synthesis of 139
benzoxazine 191
benzoxazole 26
benzoylnitromethane 415
1-benzyl-3-methylimidazolium chloride [C7H7mim]Cl
551
beta-lactam antibiotics 168–9
BET bromodomain inhibitor 521
biaryl derivatives 491
biaryl ethenes 360??? Index
biaryl moieties 308
bicalutamide 122
bifunctional organocatalysts 296
Biginelli, Pietro 355
Biginelli reactions 355
big pharma 604, 606, 612–13
Biltricide, see praziquantel
bimetallic catalysts 274
bimetallic copolymers 271
Bim-Oct 552–3
BimSi(OEt)3Cl or OimSi(OEt)3Cl 552–3
BINAP 232
bioaccumulation 46, 55, 78–9
bioaccumulation factor (BAF) 26, 35, 58–9
bioactivation 22
bioactive palominol, synthesis of 393
bioactive triquinane sequiterpene (±)-?9(12)-capnellene
384
bioactivity 580
bio-based glycerol and glycerol derivatives 29–31
acetals and ketals 31
hydrogen-bonding capacity of 30–1
physicochemical properties of 30
range of reactions 30
biocatalysis
biocatalytic routes to API 162
enzymes for 162–4
of pharmaceuticals 165–78
for synthesis of pharmaceutical intermediates
163
biocatalysts, use in chemical manufacturing 164
biodegradation 55, 79
bioethanol 54
biologics 579, 605
characteristics of 580–1
environmental impact considerations for 587–92
future prospects 592–4
manufacturing facilities for 586–7
manufacturing of 579, 581–7
process analytical technology (PAT) for 585–6
process technologies for 583–5
therapeutic 581–7
biopharmaceutical analysis 62–5. See also biologics
chromatographic and electrophoretic separation
63–5
sample preparation 63
Biopharmaceutical benchmarks 2014 579
biopharmaceutical industry 604
bioprocessing 579–81, 585, 587
biosensors 554
biphasic catalysis 509, 511
biphasic systems 219, 545, 551
bipolar disorder 419
bis-butenolide 400
bis(2-methoxyethyl) ammonium
bis(trifluoromethylsulfonyl)imide 551
bis-NHC–palladium polymer 270
bisoprolol 549
[bis(trifluoroacetoxy)iodo]benzene 449
Biyouyanagi (H. chinense L. var. salicifolium) 386
biyouyanagin A 386
B3LYP/6-31+G(d) density functional theory 331
BNCT, see boron neutron capture therapy
Boc 456, 473, 475
boceprevir 175–6
bone marrow 580
borate ester–mediated amidation reactions 33
boronic acid 361, 410
boronic acids 278
boron neutron capture therapy (BNCT) 433
borosilicate 460
BPy-PMO 285–6
breast cancer 110, 579–80
Bbrivudine 546
bromobenzene 270, 357
4-bromobenzyl bromide 361
bromoiodoarene 414
2-bromo-2-nitropropane-1,3-diol (bromopol) 109
Br?nsted acid catalysis 191–3
asymmetric Friedel-Crafts reaction catalyzed by
193
asymmetric Mannich reaction by 193
asymmetric reduction of quinolines by 192
enamides catalyzed by 192
pathway 191
Br?nsted base catalysis 193–6
asymmetric Michael addition catalyst by 194–6
asymmetric Phospha-Michael addition catalyzed by
196
pathway 194
BTPP, see tert-butylimino-tri(pyrrolidino)phosphorane
Buchi, George 374, 390 ¨
Buchwald-Hartwig reactions 449
buspirone 178
butanol 27
butenolide 400
1-butyl-3-methylimidazolium dimethyl phosphate
([C4mim][DMP]) 549Index ???
1-butyl-3-methylimidazolium ibuprofenate
([C4mim][Ibu]) 552
1-butyl-3-methylimidazolium trifluoroacetate
([C4mim][TFA]) 546
?-butyrolactone 26
BVDU (Brivudin, Zostex, Zerpex, Zonavir) 446
BVMO, see Baeyer–Villiger mono-oxygenase
byproducts 377
c
CAE, see coacervative extraction
CALB, see Candida antarctica
California Green Chemistry Initiative 606
camptothecin 391
Candida antarctica (CALB) 335
Candida infections 418
capillary electrophoresis (CE) 65, 549
capillary electrophoresis-enhanced chemiluminescence
(CE-ECL) 549
capillary gel electrophoresis (CGE) 65
capillary zone electrophoresis (CZE) 65, 549–50
Capnella imbricata 384
carbamates 488
carbamazepine 122
carbazoles, synthesis of 138
carbenes 204, 207
carbohydrates 103, 166
carbonates 24–5
cyclic 24
dialkyl 24
dimethyl 24–5
metal mediated reactions 24
carbon-carbon bond-formation reactions 292,
312–13, 392, 422, 445–9
diastereoselective and enantioselective 351
carbon-carbon bond-forming reactions, metal
catalyzed 250–6
carbon-carbon bonds 250–6
carbon dioxide 48–9, 84–5
carbon dioxide insertion chemistry 452
carbon footprint 587, 603, 606, 616
carbon monoxide 225, 452
insertion chemistry 453
carbon tetrachloride 21
carbonyl-alkene cycloaddition 374
?-carboranyl-?-acyloxy-amides 433
carboxylic acid 119–20, 188–9
cascade reaction 407
castanospermine 393
catalysis 334–6
catalyst/product separation 20
catecholborane 243
cationic surfactants 103
cavitation 343–5
Cbz 489, 520
C?CAT catalytic system 453
C-C coupling 237
CE, see capillary electrophoresis
CE-ECL, see capillary electrophoresis-enhanced
chemiluminescence
cellulose 25–6, 31, 59, 549
cephalexin 161, 168–9
cephalosporins 433
cephalotoxine 397
cetylpyridinium 558–9
cetyltrimethylammonium bromide (CTAB) 283
C60 fullerene 362
CGE, see capillary gel electrophoresis
chalcones 349–50
chelants 105–7
chemical engineering 44, 356
chemical processing industry 80
chemoenzymatic processes 169
chemoselectivity 164, 230
ChemSusChem 21
chiral amine-polyoxometalate (CA-POM) hybrids
188
chiral analysis 59
chiral Br?nsted acid catalysts 191, 391
chiral Br?nsted base catalysts 194
chiral dihydropyrones 313
chiral drugs 550
chiral hydrogen-bonding catalysts 197, 201
chiral imidazolidinones 311
chiral ionic liquids (CILs) 314
chiral Lewis acid 206
chiral metal complexes 291
chiral phase-transfer catalysts 203
chiral pool-based one-pot synthesis 431–4
chiral resolution 122, 162
chiral separations 550
chloramphenicol 550
chlorinated hydrocarbon solvents 104
chlorinated solvents 21–2
greener alternatives for 21–2
chlorinated waste 22
chlorine bleach 107, 110
chlorine demand 107??? Index
4?-chloroacetanilide 547
chloroacetic acid 426
2-chloroacrylonitrile 416
chloroform 21–2, 547
6-chlorohexanol 503
4-chloro-3-nitrocoumarin 391
chlorophenols 92, 378
chlorpheniramine 550
cholesterol 166, 172, 297, 380
chromanoid scaffolds 431
chromatographic analysis 46, 549
chromatographic purification 584
chromatography 336
chromium 108
cinacalcet 417
Cinchona alkaloids 193–5, 197–203
cinchonidine 208
cinnamaldehydes 205, 429
cinnarizinne 566
circulating (micro)reactors 374
circulatory disorders 388
13-cis-retinoic acid 379
Claisen-Schmidt reactions 349–50
click chemistry 334
click reactions 285, 411–12
climate change 99, 592
clinoptilolite (CP) 346
Clorox® Bleach 94, 107
cloud point extraction (CPE) 48
Cl
2PdL29a catalyst 238
CM, see cross metathesis
[C4mim]Cl-salt aqueous biphasic system 551
CMR, see cross-metathesis reaction
C-N coupling 448–9
coacervates 48
coacervative extraction (CAE) 48
coacervative liquids 48
cobalt catalysts 284–5
cobalt catalysts, immobilized 284–5
cobalt-catalyzed C-H annulation reactions 148
cocrystals 118–20, 122
of API 122
in chiral resolution of APIs 122
of 1:1 danazol:vanillin 122
definition 118
glutaric acid 122
stability to hydration 122
cofactor recycling systems 178
Colawet MA-80, 557–8
Co-L31e catalyst 244
Collaborative Innovation Project Group 110
colloids 555
colorants 108
column chromatography 336
combinatorial chemistry 409, 413, 471
communication 111–12
competitive absorption 374
computational chemistry 112
computational toxicology 112
condensation reactions 345–51
conductor-like screening model for real solvents
(COSMO-RS) 550
1,4-conjugate addition reactions 305–10
conjugate additions 203–5
conjugated dienes 232, 375, 398
consumer pressure 96
Consumer Product Safety Act of 1972 93
continuous chromatography 584
continuous processes 585
copper (I) catalyst 389
copper catalysts, immobilized 285
copper-catalyzed azide–alkyne cycloaddition (CuAAC)
reaction 335, 443, 456
copper-catalyzed 1,7-enyne
trifluoromethylation/bicyclization reaction 416
copper-catalyzed Henry reactions 254–5
copper-free Sonogashira reactions 24
cosmetics 27
COSMO-RS, see conductor-like screening model for
real solvents
cost index (CI) 73
cotton 387
coumarin-3-carboxamides with 1,2,3-triazole moiety,
synthesis of 411
coumarin-pyrrole-isoquinoline-fused pentacyclic
compounds 391
coumarins, synthesis of 146–7
coupling reactions 30–2, 356–61
of amines 490
C-N coupling 448–9
C-S coupling 448
Diels-Alder reaction 362–5
Heck 445–7
Heck and Suzuki 30
Heck cross-coupling reaction 356–7
Hiyama cross-coupling reaction 491
isonitrile insertion/C-O cross-coupling reaction
453Index ???
ligand-free Suzuki 28
microwave-assisted 445–9
palladium-catalyzed carbonylative Negishi
cross-coupling reactions 453
Sonagashira cross-coupling reactions 31
Sonogashira 447–8
Stille cross-coupling 357
Suzuki cross-coupling reaction 359–61
Suzuki reaction 447
Wittig reaction 361–2
CP, see clinoptilolite
CPE, see cloud point extraction
CPME, see cyclopentyl methyl ether
cross-coupling reactions 27, 31–2
cross-linking 282, 461
cross metathesis (CM) 279
cross-metathesis reactions (CMR) 254
cryogenic conditions 167
C-S coupling 448
CTAB, see cetyltrimethylammonium bromide
Cu-catalyzed azide–alkyne Huisgen
[3+2]-cycloaddition reaction 443
Cu-catalyzed Ullmann coupling 449
CuI nanoparticles 357
cumene hydroperoxide 176
?-cuparenone 392
Curie, Jacques 343
Curie, Pierre 343
current manufacturing guidelines (c-GMPs) 612
cyclic carbonates 24
cyclic enones 352
cycloaddition 416
cycloalkane 248
cyclobutane ring, intramolecular formation of 387–9
cyclobutanes 382
cyclodextrin 317, 319
?-cyclodextrin (?-CD) 550
cyclodextrin complexes 357
?-cyclodextrin modified with epichlorohydrin
(?-CDEpi) 554
cycloheptanoindole 398
1,3-cyclohexanedione derivative 393
cyclohexanone 176, 189, 194
cyclohexene 229–30
cyclohexenone 244, 351
cyclooctene 245
cyclopalladated ferrocenylimines 359
cyclopenta[b]benzofurans 391
cyclopentadiene 32, 205–6
cyclopentyl methyl ether (CPME) 32–4, 202
cyclopropanation reactions 277–8, 282–3
cyclopropanes 282, 383–4, 429
CYP102A1 (P450-BM3) 178
CYP3A4 enzymes 178
cyrene 31
cytochrome P450 enzymes 177
cyclopropanation 179
drug metabolites from 177–9
engineered 179
cytotoxic activity 391, 396
cytotoxicity 552, 565
Cytovene 609
CZE, see capillary zone electrophoresis
d
danazol 122
Dane salt 169
D-camphor sulfonic acid (D-CSA) 299–300
DCE, see 1,2-dichloroethane
D-CSA, see D-camphor sulfonic acid
decanoic acid 563
decarboxylative cross-couplings 449
degradation 48, 51, 59, 79, 122
dehydroaminoacids 230
dehydrocavidine 551
7-dehydrocholesterol 380
dendrimers 298–9
density functional theory 331
2-deoxy-D-ribose 5-phosphate aldolase (DERA) 167
DERA, see 2-deoxy-D-ribose 5-phosphate aldolase
dermatitis 111
design for degradation (DfD) 603
Design for the Environment (DfE)/Safer Choice
Program 96, 101
destabilization 375
destruxin E, solid-supported synthesis of 489–92
dexametasone 552
dexamphetamine 161, 170–1
DfE program, see Design for the Environment/Safer
Choice Program
diabetes 170, 395, 418, 423
dialkylethers 220
?,?-diamino acid 195
1,5-diaminoanthraquinones 408
diarylprolinol ether catalyst 313
diazoketones 389, 393
?-diazoketones 393
diazolidinyl urea 109??? Index
diazomethane 168
diazonamide A 398
dibenzo[b,d]azepines 151
dibenzothiophenes, synthesis of 148–9
dichloroethane 334
1,2-dichloroethane (DCE) 334
dichloromethane (DCM) 22, 549
dicyanonaphthalene 395
didecyldimethylammonium 557
Diels-Alder reactions 205–7, 254–6, 292, 311–12,
331, 397
of N-oxides and cycopenta-1,3-diene 255
dienes 232, 256, 345
diethylamine 57
diethylenetriamine penta (methylene phosphonic acid)
(DTPMP)) 106
diethylenetriaminepentaacetic acid (DTPA) 106
diethyl ether 22, 32–4, 389
diethyl malonate 252, 431
diethyl tartrate 176
differential scanning calorimetry (DSC) 120–1
2,6-difluorobenzyl azide 416
1,2-difurylalkene 400
2,3-dihydrobenzo[f][1,2,5]thiadiazepin-4(5H)-one
1,1-dioxides, solid-supported synthesis of 485
3,4-dihydro-2H-pyran 408
dihydrolevoglucosenone, see cyrene
2,3-dihydronaphtho[1,2-b]furans 145
dihydropyrano[2,3-c] pyrazole 475
dihydropyrimidinones 355
2,4-diketones 352
2,5-diketopiperazines 432
dimethyl carbonate 24
dimethylformamide (DMF) HS-GC-MS method
549
dimethylisosorbide (DMI) 27
boiling point of 27
neat 27
solubilizing properties of 27
stability of 27
dimethylol dimethyl (DMDM) hydantoin 109
dimethyl sulfoxide (DMSO) 23, 549
diosgenin-based amphiphilic organocatalyst 297
dioxolane 395
dipeptide 298
dipeptidyl peptidase 4 (DPP-4) 418
diphyllobothrium latum 421
dipolar aprotics 23
disinfectants 110–11
disodium benzophenondisulfonate 377
DISSOLVINE 106
1,4-disubstituted 1,2,3-triazoles 354
1,4-divinyl benzene (DVB) 282
2D-LC 64
DMDM, see dimethylol dimethyl hydantoin
DMI, see dimethylisosorbide
DMSO, see dimethyl sulfoxide
docusate 556–7, 565
1-dodecyl-3-methylimidazolium chloride 565
domino reaction 407
double salt ionic liquids (DSIL) 547
downstream process (DSP) 581
DPP-4, see dipeptidyl peptidase 4
D-proline 345
dragmacidin E 398
drug metabolites, synthesis of 177–8
DSC, see differential scanning calorimetry
DSIL, see double salt ionic liquids
DSP, see downstream process
DTPA, see diethylenetriaminepentaacetic acid
DTPMP, see diethylenetriamine penta (methylene
phosphonic acid)
dual functional liquid salts 559–60
DVB, see 1,4-divinyl benzene
dyes 108
e
(E)-2-(benzo[d]thiazole-2-yl)-3-heteroarylacrylonitriles 349
Eckert, Charles 87
ECL, see electrochemiluminescence sensor
eco-labeling 98–100
eco-label certification 100
ISO 14020/14024 guiding principles 98–9
ECOLOGO® program 100–1
Eco Options program, 2006 97
EDTA, see ethylenediaminetetraacetic acid tetra
E-factor 73–5, 78, 80, 587–8, 603, 615
electrochemiluminescence (ECL) sensor 554
electrophilic lactonization reaction, solid-supported
synthesis in 485
electrospray ionisation (ESI) 61
Eli Lilly 586
ELISA, see enzyme-linked immunosorbent assay
antibody based testing
Elliman’s solid-phase organic synthesis 473Index ???
Emergency Planning and Community Right-to-Know
Act (EPCRA) 96
EMLA® cream 567
endo/exo isomers 391
energy-based metrics 589–91
enol silyl ether moiety 395
EntrestoTM 123
Environmentally Preferable Purchasing Program, 1999
96–7
Environmental Protection Agency (EPA) 606
EPA method 550, 47
EPA method 610, 47
Safer Chemical Ingredients List 110
“Safer Detergents Stewardship Initiative” 103
Toxic Release Inventory (TRI) 46
enzyme engineering 164–5
enzyme-linked immunosorbent assay (ELISA) antibody
based testing 164
EPA, see Environmental Protection Agency
EPCRA, see Emergency Planning and Community
Right-to-Know Act
epoxidation 282
Eschenmoser-type condensation 418
e-series glycol ethers 104
ESI, see electrospray ionisation
esomeprazole 176
esterification 248–50
in biphasic system 249
ethanol 54
ethyl cyanoacetate 346
ethylenediaminetetraacetic acid tetra (EDTA) 105–6
ethylene glycol ether 105
ethyl glyoxalate 415
ethyl lactate 28–9
melamine-Pd catalyst mediated Suzuki-Miyaura
cross-coupling in 28
as a solvent in Cu-catalyzed oxidative coupling 28
1-ethyl-3-methylimidazolium acetate ([C2mim][OAc])
547
ethyl-S-lactate solvents 105
etodolac 567
Etodolac-Lidocaine Topical Patch 567
etomidate 547
Etter, Margaret 118
Euphorbiaceae plant family 388
excited-state-intramolecular proton transfer (ESIPT)
391
E/Z isomerization, photoinduced 379
f
failure mode and effect analysis (FMEA) 74
fault tree analysis (FTA) 74
FBS, see fluorous-biphase systems
FDASIA, see Food and Drug Administration Safety and
Innovation Act
fenofibrate 547
fexofenadine (Allegra) 177
five-membered rings
formation by ring contraction/enlargement 392–4
synthesis of 391–4
flash chromatography 57
flavanoid scaffold 431
flavonol 391
Flos Genkwa 550
fluoren-9-ylmethyloxycarbonyl (Fmoc) 456
fluorinated cyclohexenones 412
fluorinated dihydroquinolinone 413
fluorinated isoquinolines 413
fluorination 412–13
fluorous benzaldehyde 520
fluorous-biphase allylation 252
fluorous-biphase Prins reaction 251
fluorous-biphase systems (FBS) 220, 246
fluorous bis(oxazolines) 254
fluorous Boc 520
fluorous catalysis
in acetylation 248–50
in esterification 248–50
fluorous-biphase concept in 220–2
fluorous transition metal catalysts 224–5
in hydroboration–oxidation reaction 243
in hydroformylation reaction 225–9
in hydrogenation 229–32
in hydrosilylation reaction 232–6
in oxidation reactions 243–8
principles of 219–24
in transesterification reactions 248–50
in transition metal catalyzed cross-coupling
reactions 236–43
fluorous catalyst 221–3
fluorous distannoxane catalyst 249
fluorous DMSO 518–19
fluorous HPLC (F-HPLC) 528
fluorous ligands for metal catalysis 512–14
fluorous linkers 520–8
fluorous mixture synthesis (FMS) 528–33
fluorous nanoparticles, Pd-based 242??? Index
fluorous organocatalysis 256–9, 514–16
fluorous organocatalysts 256–8, 431–2, 511–16
fluorous phosphines 222–3
ligands of 224
fluorous phosphite ligands 225
fluorous (S)-pyrroldine sulfonamide 256
fluorous reagents 516–18
fluorous reverse-phase silica gels 242
fluorous safety-catch linkers 520
fluorous scavengers 518–20
fluorous (Rf) silyl 528
fluorous synthesis
of an imidazo[1,2-a]pyridine derivative
521
components of a 560-member mappicine library
529
for discovery chemistry 511–33
of drug-like molecules and nature product analogs,
diastereomers, and enantiomers 529–33
fluorous linker-facilitated synthesis 511
fluorous solid-phase extraction (F-SPE) to reduce
waste 510
green chemistry aspects of 510–11
heavy versus light 509–10
monitoring reactions 510
of quinoxalinone 520
recycling techniques 510
fluorous-tagged aryl stannanes 239
fluorous transition metal catalysts 224–5
FMEA, see failure mode and effect analysis
Fmoc-amino acids 482
FMS, see fluorous mixture synthesis
Food and Drug Administration Safety and Innovation
Act (FDASIA) 615
fragrances 108–9
Friedel-Crafts acylations 249–50
with acyl-chloride 250
of veratrole 250
Friedel-Crafts reactions 192, 545
Fritsch Pulverisette 6, 332
frustrated Lewis pairs (FLP)-catalyzed hydrogenations
455
FTA, see fault tree analysis
fumaric esters 352
functionalized polymer resins 337
furan, synthesis of 144–5
furan-2(5H)-one derivatives, solid-supported synthesis
of 485–6
furfural 32
g
GAC, see green analytical chemistry
Ga-catalyzed Mannich reaction 351
gas chromatography 57–8
gastrointestinal stromal tumor (GIST) 417
GC3 Innovation Project Group 111
G-CON Manufacturing 587
GDUFA, see Generic Drug User Fee Amendment
GE Healthcare Life Sciences’ KUBio FlexFactory
platform 587
gem-difluoromethylenes 413
GEN, see Global Ecolabeling Network
Genentech 586
Generally Regarded as Safe (GRAS) List 111, 558
GeneratoR of Agro-based Sustainable Solvents
(GRASS) 29
Generic Drug User Fee Amendment (GDUFA)
615
Generic Pharmaceutical Association (GPhA) 606
generic pharmaceutical industry 604, 608–10
Gewald reaction 419
GHS, see Globally Harmonized System
Gilead Sciences 610
Ginkgo Biloba 388
GIST, see gastrointestinal stromal tumor
glasdegib 162, 171–2
GlaxoSmithKline (GSK) 81, 327, 586, 609
Global Ecolabeling Network (GEN) 98–9
Globally Harmonized System (GHS) 82
glycerol 83
glycerol carbonate 24
glycol ethers 104–5
glycosidases 395
glycyrrhizic acid 551
glyoxal 109
GPhA, see Generic Pharmaceutical Association
Grandisol 387
GRAS, see Generally Regarded as Safe List
GRASS, see GeneratoR of Agro-based Sustainable
Solvents
green analytical chemistry (GAC)
case studies 46–7
comparison of green profiles 46–7
critical review of 44
principles of 43
relative eluting strengths of solvent mixtures 56
sample preparation and analytical measurement
options 44–5, 47–50
techniques and methods 50–60Index ???
green aspiration level (GAL) 9–10, 11
application to supply chain 15
drug manufacturing complexity and 11
green chemistry with 16
Green Scorecard and 13
industry-wide adaption 15
LCA, integration with 15
process starting materials, definition for 10–11
relative process greenness and 11
standardizing metrics 10
transformation-type-based 15
green chemistry 601–2
benchmarking industry adoption of 607–17
cost of implementing 614–15
customer demands 606
literature review 602–4
opportunities 615
principles of 603
green chemistry metrics
awards 7–8
barriers 9
GAC 7
government adoption of 16
Green Scorecard 12
historical context of 3–4
industries and 3, 14
life-cycle assessment 6–7, 15
mass-based 4–5, 6
supply chain 14
unification via green aspiration level 9
Green Chemistry 21
Green Chemistry Institute (ACS/GCI) Green
Chemistry Formulators’ Roundtable 102, 111
green chemistry metrics
components 73
E-factor 75
energy-based metrics 589–91
exposure assessment 79
level 1, 74–8
level 2, 78–80
level 3, 80
maleic anhydride production example 74
mass-based metrics 587–9
reaction mass efficiency (RME) metric 74
risk and hazard assessment 78–9
green chemistry (GC) program 607
green consumer cleaning products
birth of 92
chelants 105–7
chemical selection in consumer cleaning products
96
colorants and dyes 108
consumers and 94–5
Design for the Environment (DfE) Program
101
drivers and 94–7
early products 93–4
eco-labeling 98–100
ECOLOGO® program 100–1
fragrances 108–9
future of 111–12
general requirements for chemicals 102
government regulations and non-governmental
organizations, role of 95–6
Greenlist® 101
Green Seal standards 100
major retailers of 97–8
oxidants or oxidizers 107
solvents 104–5
surfactants 102–4
green engineering
green chemistry metrics in 73–80
life-cycle considerations for 86
misconceptions and realizations 71–2
principles of 72
greener alternatives
for chlorinated solvents 21–3
for dipolar aprotics 23
greener molecular solvents
bio-based glycerol and glycerol derivatives 29–31
carbonates 24–5
cyclopentyl methyl ether (CPME) 32–4
cyrene 31
dimethylisosorbide (DMI) 27
ethyl lactate 28–9
lactic acid 28–9
2-methyl tetrahydrofuran (2-MeTHF) 32
n-butanol 27
opportunities, challenges, and future developments
34
?-valerolactone 25–7
Greenlist® process 94, 101
green procurement programs 97
Green Reaction Conditions, 1998 87
Green Scorecard 12
GAL and 13
rating matrix for RPG for 12
Green Seal standards 100??? Index
green solvents, application of
bio-based products 83
in conserving complexity of a process 85–6
for EHS and life-cycle impacts 81–2
as fertilizers 84
mass/energy integration 85
in reactions and separations processes 81
renewable solvents 83–4
in separations processes 84–5
waste prevention 80–1
Grieco three-component reaction 408–9
Grignard reactions 32, 34
griseofulvin 547
Grubbs catalyst 253
Grubbs-Hoveyda catalysts 253–4, 279–80
GVL, see ?-valerolactone
h
Hajos-Parrish-Eder-Sauer-Wiechert reaction 207, 256
halohydrin dehalogenase (HHDH) 166
hamigerans 396
Hantzsch-type mechanism 443
Hantzsch-type reaction 28
hard-soft acid-base (HSAB) theory 333–4
1H-benzotriazoles 353
HCOOH/KI catalytic system 452
Heck and Suzuki coupling reactions 30
Heck cross-coupling reaction 356–7
Heck isomerization–Fischer indolization–alkylation
(HIFIA) synthesis 443
Heck isomerization–Fischer indolization (HIFI)
synthesis 443
Heck reactions 236–9, 243, 445–7
of 2,3-dihydrofurane and 4-chloropentyl-triflate
238
of iodobenzene and methyl-acrylate 239
palladium complexes for 237
HEDP, see 1-hydroxyethylidene diphosphonic acid
helium 57–8
Henry reactions 254
herbertenolide 392
heterocycles synthesis 353–5
heterogeneous catalysts 446
heterogeneous sonochemistry 344
1-hexadecyl-3-methylimidazolium chloride 565
hexanoic acid 563
hexetidinium 558–9
1-hexyl-2,3-dimethylimidazolium dazolium
dihydrogen phosphate ([bnmim]H2PO4) 346
HIFI, see Heck isomerization–Fischer indolization
synthesis
HIFIA, see Heck isomerization–Fischer
indolization–alkylation synthesis
high performance liquid chromatography (HPLC)
51–2, 586
high through-put (HTP) screening 164–5
Hippophae rhamnoides 550
Hiyama cross-coupling reaction 491
HLB, see hydrophilic-lipophilic balance
HMG-CoA reductase inhibitor 394
Home Depot 97–8
homogeneous catalytic reactions 219
homogeneous sonochemistry 344
Hospira 611
“hot spot” theory 344
HPLC, see high performance liquid chromatography
HSAB, see hard-soft acid-base theory
HTP, see high through-put screening
Huisgen 1,3-dipolar cycloaddition 354
4-hydoxyproline catalysts 300–5
hydrazides 473, 475
hydrazine-derived heterocycles 473
?-hydrazinocarboxylic acids 410
hydroboration 243–4
hydroformylation 225–9
of 1-alkenes 229
catalysts for 228
first fluorous 228
of propylene 225
rhodium-catalyzed, of 1-octene 228–30
hydrogen 58
hydrogenation 229–32
fluorous ligands for 231
of 1-octene 231
of 4-octyne 231
of styrene 232
hydrogen bonding 118–19
hydrogen-bonding catalysis 197–202
asymmetric intramolecular [2+2]
photocycloaddition catalyzed by 202
asymmetric Strecker reaction catalyzed by 198
Michael addition reaction 198–201
pathway of 197
symmetric Michael addition catalyzed by 202
hydrogen peroxide-based bleaches 107
hydrophilic interaction chromatography (HILIC) 54,
59
hydrophilic-lipophilic balance (HLB) 553Index ???
hydroxy and acid group–modified catalysts 303–5
1-hydroxyethylidene diphosphonic acid (HEDP) 106
1-hydroxyethyl-3-methylimidazolium chloride
[C2OHmim]Cl 551
hydroxy group–protected catalysts 300–3
with polymer support 303
hydroxylactams, solid-supported synthesis of 484
4-hydroxy-L-proline 302
5-hydroxy-1,4-naphthoquinone 399
hydroxy-o-quinodimethanes 397
4-hydroxyproline-based catalysts 305–10
ionic liquid–type 309
modified 308–9
modified with polymer support 309
hydroxyquinoline-2-carboxylic acid derivate 429
Hypericum genus 386
i
IBISS, see InBioSynSolv
ibuprofen 381, 556
ibuprofenate 557
ideal recoverable catalyst 219
IFRA, see International Fragrance Association
IL, see ionic liquids
ILs, see ionic liquids
imatinib 417
imidazole 480
imidazolidinyl urea 109
4-imino-?-lactam derivatives, synthesis of 144
immobilized cobalt catalysts 284–5
immobilized copper catalysts 285
immobilized iridium catalysts 285–6
immobilized palladium catalysts 270–6
immobilized rhodium catalysts 276–9
immobilized ruthenium catalysts 279–84
InBioSynSolv (IBISS) 29
indazole, synthesis of 138–9
indole 382
infrared (IR) spectroscopy 60, 120
in silico design strategies 83–4
insulin-regulated aminopeptidase (IRAP) inhibitors
459–60
intermolecular formation of a cyclobutane ring 385–7
International Consortium for Innovation and Quality
in Pharmaceutical Development (IQ) 603
International Fragrance Association (IFRA) 108
intramolecular formation of a cyclobutane ring 387–9
ionic-catalyzed Knoevenagel condensation 346
ionic liquids (ILs) 48
ADME (absorption, distribution, metabolism, and
excretion) for 560
1-allyl-3-ethylimidazolium tetrafluoroborate
([aeim][BF4]) 546
in analysis of separation efficiency 548
of antibacterial quaternary ammonium cations 556
based silica sorbent 551
in chromatographic analysis 549
in chromatographic separations 548–9
for continuous pharma manufacturing 547–50
definition 544
in determination of flavonoids 550
as drug carriers 552–3
for drug detection 553–4
for extraction of drugs from natural products 551
formation of biphasic systems 545
in headspace gas chromatography (HSGC) 549
in high performance liquid chromatography (HPLC)
548–9
in HS-GC analysis of residual solvents 549
hydrophilic 547
hydrophobic 547
IL-APIs 556–60
imidazolium 553
imidazolium-based 546, 549
for isolation of pharmaceutically active shikimic acid
551
as matrix media 549
in membrane transport 566–7
miscible 546–7
for pharmaceutical crystallization 546–7
as pharmaceutical ingredients 554–6
phosphonium and ammonium-based 565
protic (PILs) 551
in purification of several APIs 547
room temperature (RTIL) 545–6
salicylate 558
solubility of model drugs in 546
as solvents in synthesis of drugs or drug
intermediates 544–6
structure 544
sulfonic acid-functionalized 551
in synthesis of 5?-O-monoesters of
1-?-D-arabinofuranosylcytosine 545
tuammoniumheptane salicylate 566
as a tunable hydrophilic–lipophilic carrier 553
ionic liquid–tagged organocatalysts 309
IRAP, see insulin-regulated aminopeptidase inhibitors
iridium catalysts, immobilized 285–6??? Index
isatins, synthesis of 136–7
isobenzofuranones, synthesis of 145–6
isochromenes, synthesis of 147–8
isocoumarins, synthesis of 146–7
ISO Eco-Labels 99
isofagomine 395
isoindolin-1-ones, synthesis of 134
isoniazid 121
isonitrile 520
isonitrile insertion/C-O cross-coupling reaction 453
isopropanol 388, 400
isopropylmyristate (IPM) 552
isoquinoline, synthesis of 140–1
isoquinolinium 412
isoquinolinones, synthesis of 141–2
isorhamnetin 550
itraconazole 547, 566
j
Januvia® 170
Johnson & Johnson 586, 609
Jorgensen–Hayashi catalyst 429
Jorgensen–Hayashi organocatalysts 306
Josiphos® 170
Juglone 399–400
k
kaempferol 550
?-ketoesters 352
ketone reductase (KRED) 166–7, 173
montelukast 174
reduction 173–5
ketones 375
ketoprofen 549
Knoevenagel condensation 346–9
of ethyl cianoacetate and aromatic aldehydes
347
green protocol for 346
of malonitrile and aromatic aldehydes 348
Knoevenagel–Michael cyclization 355
Knoevenagel/Ugi/click reaction 411–12
KRED, see ketone reductase
l?
-lactam antibiotics 433
lactic acid 28–9
lactones, synthesis of 147
lanthanide(III) bis(perfluorooctansulfonyl)amides
249
large-scale reaction 207–9
of 6-cyanoindole derivatives 209
of Wieland–Miescher and Hajos–Parrish ketones
208
L29e-modified Pd catalyst 238
Lennox-Gastaut syndrome 416
levulinic acid 32
Lewis acid catalysis 204–7
Lewis base catalysis 204–7
Li
2CO3 334
lidocaine 542
lidocainium 557–9
lidocainium acetylsalicylate 558
lidocainium chloride 564
lidocainium salicylate 562
life-cycle assessment (LCA) approach 587, 591–2
ligand-free catalysis 335
ligand-free Suzuki coupling reactions 28
ligands
bipyridine 286
diphenylphosphine 271
exchange of the catalyst species 228
fluorous 511–14
fluorous phosphine 224
fluorous phosphite 225
fluorous-tagged 241
for HIV protease inhibitor 376
N-, O-, S-, and Si-containing 226–7
Phosphine-phosphite 502
linear amino acid catalysts 305
linkers for solid-phase organic synthesis (SPOS)
472–5
linoleic acid 563
Liotta, Charlie 87
lipase hydrolytic ester resolution 170
lipophilic decylsulfate 566
lipopolysaccharides (LPS) 164
Lipshutz, Bruce 87
liquid chromatography 63
acetone as solvent in 55
dichloromethane mixtures in 55
green acids and bases used in 57
methanol as solvent in 55
popularity 50
propylene carbonate-ethanol mixtures in 54–5
reduction in mobile-phase volume 50–1
solvent selection in 52–7
sustainability of 50
temperature, importance of 51–2Index ???
liquid-liquid extraction (LLE) 48
liquiritin 551
low thermal-mass (LTM) chromatography 58
L-proline 299, 345, 428
LUF5771 416
?-Lycorine 428
Lyrica® 169
Lysobactin (Katanosin B) 487
m
mAb production, characteristics of 582–3
MacMillan’s imidazolidinone catalyst 190
macrocyclic peptide 495
macrocyclic peptidomimetics, solid-phase parallel
synthesis of 493–4
maleic acid, sunlight-photocatalyzed alkylation of
377
maleic anhydride (MA) 74
malononitrile 346
Mannia Fragrans 392
Mannich reactions 310–11, 350–1
mannostatin A 393
MASPOS, see microwave-assisted solid-phase organic
synthesis
mass-based metrics 587–9
mass spectrometry 62
MCM-41 279–80
MCM-48 273
M
2CO3 333
MCR, see multicomponent reaction
Med-Immune 586
medium-sized heterocyclic compounds 150–1
MEKC, see micellar electrokinetic chromatography
Meldrum’s acid 346, 411
Menshutkin reaction 31
mercaptoethanol 482
Merck 586, 609
Merrifield, Bruce 336
Merrifield resins 278, 336–7, 480
Merrilactone A, synthesis of 385
1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole
(MSNT) 483
metal-catalyzed C-H functionalization 449–51
metal-free C-H functionalization 451
metal-organic frameworks (MOFs) synthesis 460
metathesis 253–4
methamphetamine hydrochloride (MA×HCl) 554
methanol 54, 360, 455
methopholine 382
methotrexate 552
1-methoxyethyl-3-methylimidazolium
methanesulfonate ([moemim][MeSO3]) 546
1-methoxyethyl-3-methylimidazolium trifluoroacetate
([moemim][TFA]) 546
methyl 2-(dimethylamino)acrylate 416
methyl-glucoside acetals, hydrogenolysis of 33
1-methylisoquinoline 391
methyl 3-methoxyacrylate 416
methyl phenyldiazoacetate (MPDA) 277
2-methylpropanal 426
2-methyl tetrahydrofuran (2-MeTHF) 32
methyltrimethoxysilane (TMOS/MTMOS) 552
metoprolol 549
micellar electrokinetic chromatography (MEKC) 65,
548
Michael additions 351–3
to nitroalkenes 352
Michael addition/Thorpe-Ziegler reaction 475
Michael-Henry cascade reaction 201
microbubbles 344
microfluidics 51
microwave-assisted organic synthesis (MAOS) 441,
511
of 1-alkyl-3-benzylindoles 443
in carbon dioxide insertion chemistry 452
in carbon monoxide insertion chemistry 453
catalytic reactions 441
C-H functionalizations by 449–52
continuous flow synthesis 441, 459–60
of cotinine and iso-cotinine analogs 445
coupling reactions 445–9
covalent grafting of an amino acid 458
decarboxylative cross-couplings 449
direct arylation of 2,6-diarylated
imidazo[2,1-b][1,3,4]thiadiazoles 450
direct C-H acylation under palladium-catalysis
449–50
domino Heck/borylation of acrylamides 447
hydrogenation of alkynes and alkenes 454
in isocyanide insertion chemistry 453
isoquinazolin-1-ones, Pd-catalyzed synthesis of
454
Leu-Enkephalin using SAM1 Linker, synthesis of
457
ligand-free Heck coupling of 5-iodo-2?-deoxyuridine
with acrylates 446
mild deprotection of Alloc and allyl esters 458
of N-containing heterocycles 442–5??? Index
microwave-assisted organic synthesis (MAOS)
(Continued)
Ni-C catalyzed synthesis of 2,4,5-trisubstituted
imidazoles 444
palladium catalysis under 450
in Pd-catalyzed carbonylation of
2-bromobenzaldehyde derivatives 453
in Pd-free aminocarbonylation of N-tosylhydrazones
453
of peptides and related fine chemicals 455–8
of 2-pyrrolin-5-one derivative 443
for reduction of carbonyl groups 454–5
in reduction of organic compounds 453–5
regioselective C-5 arylation 451
Sonogshira couplings 447–8
Suzuki reaction 447
three-component access to 2-pyrrolin-5-ones 443
three-component scaffold formation of IRAP hit
460
three-component sequence towards susbstituted
indoles 444
of 1,2,3-triazoles 444
use of copper-assistance in 450
microwave-assisted solid-phase organic synthesis
(MASPOS) 499–502
microwave-assisted SPPS (MW-SPSS) 456
microwave heating 30, 456–7, 461
C-H functionalizations by 449
in Pd-mediated 11C-carbonylation of aryl halides
453
in peptide chemistry 456
and quantitative formation of ?-valerolactone 455
in Suzuki reaction 447
in synthesis of simple organic molecules 441
microwave irradiation 448
Mitsunobu alkylation with glycoaldehyde dimethyl
acetal 482
Mizoroki–Heck reaction 445–7. See also Heck
reactions
Mizoroki–Heck reactions 271–3
palladium catalyst for 273–4
using MCM-Silica–anchored Pd catalyst 273–4
in water 273–4
Mn-based catalyst 245
mobile-phase additives 55
5-monosubstituted tetrazoles 425
montelukast 173–4
Morita-Baylis-Hillman reaction 353
mouse antinociception assays 564
Mukaiyama adol reaction 205
Mukaiyama aldol reactions 345–6
multicomponent reactions (MCRs) 407, 511
of aspidosperma alkaloids 414
of benzo[b]phosphole oxides 415
of bioactive indoles 414
of fluorinated cyclohexenones 413
of fluoroalkenes and difluoromethylenes 414
Grieco three-component reaction 408–9
MCR involving aza-Diels–Alder reaction 412
MCR involving fluorination and trifluoromethylation
412–13
Petasis reaction 409–10
Sonogashira reaction 410–11
Ugi/Knevengagel/cick reaction 411–12
multidimensional chromatography 64
multiwall carbon nanotubes (MWCNTs) 554
MWCNT, see multiwall carbon nanotubes
Mylan 611
n N
-alkenyl-substituted maleimides 397
N-alkylation reactions 545
N-aminoacyl-N-phenyl-hydrazines 410
nanomaterial synthesis 460
naphthoquinone derivatives 399
naproxen 547
NATO Advanced Research Workshop: Green
Industrial Applications of Ionic Liquids 544
natural products, solid-supported synthesis of
486–91
N-bromosuccinimide 24
n-butanol 27
n-butyl ether 549
1-n-butylimidazolium tetrafluoroborate ([Hbim]BF4)
355
n-butyltellurides alkynes 360
N-containing heteroaromatics 442
N-containing heterocycles, microwave-assisted
synthesis of 442–5
near-infrared spectroscopy (NIR) 60–3
NEMI database 46
neolone 110
new temperature programme rate 58
N-heterocyclic carbene catalysis 204–7
N-heterocyclic carbenes (NHCs) 270
n-hexane 388
NH4OAc-HOAc system 349
NH-1,2,3-triazoles, solid-supported synthesis of 484Index ???
NH-1,2,3-triazoles containing dipeptide,
solid-supported synthesis of 485
N-(hydroxyethyl)-ethylenediaminetriacetic acid
(HEDTA) 106
NIR, see near-infrared spectroscopy
nitrilotriacetic acid (NTA) 105
nitroalkenes 352
nitrogen-containing heterocyles 421
nitrogen heterocycles, synthesis of 476–84
benzotriazoles 139
carbazoles 138
4-imino-?-lactam derivatives 144
indazole 138–9
indoles 137–8
isatins 136–7
isoindolin-1-ones 134
isoquinoline 140–1
isoquinolinones 141–2
phenanthridines 141
phenazines 142–3
phthalimides 136
pyridines 140
pyrroles 133–4
pyrrolidines 137
pyrrolidones 135–6
quinolinones 141–2
nitromethane 352
4-nitrophenol 547
nitrothiazolo[3,2-c] pyrimidines derivatives 445
NMe-IB-01212 487–8
N-methyl morpholine (NMM) 190
N-methylpiperazine 421
N-methylpyrrolidinone (NMP) 23
N-methyl-2-pyrrolidone (NMP) 549
N,N-bisdiethylterephthalamide 122
N,N?-bis(3,5-di-tert-butylsalicylidene)-(R,R)-
cyclohexane-1,2-diamine 426
N,N-dimethylacetamide (DMA) 23, 83
N,N-dimethylethanolammonium octanoate 551
N,N-dimethylformamide (DMF) 23, 83
NOBIN-prolinamide organocatalyst 293
noncovalent derivatives (NCDs) 117
characterization technique 120–1
coformers 119
definitions 118
design ideas 118–19
environmental and green chemistry benefits of
123
formation of 123
as a mechanism for pollution prevention 123
novel 120
pharmaceutical 121–3
preparation 119–20
noncovalent derivatization 123
nonylphenol ethoxylate 104
normal-phase chromatography 54
Norrish type II reaction 384
Novartis 609
Novozym 435, 545
N-phenoxyacetamides, rhodium(III)-catalyzed
redox-neutral coupling of 145
N-propargylation 421
NSAID biphenylacetic acid 460
NSF/GGI 355 Greener Chemicals and Processes
Information Standard 616
NS3 protease inhibitors 175
NTA, see nitrilotriacetic acid
nuclear magnetic resonance (NMR) imaging 61–2,
120
nuclear quadrupole resonance (NQR) 120
nucleoside chemistry 546
nuevamine aza-analogues 412
o
1-octadecyl-3-methylimidazolium chloride 565
1-octadecyl-3-methylimidazolium
hexafluorophosphate 565
1-octadecyl-3-methylimidazolium
tris(pentafluoroethyl)trifluorophosphate 565
octadecylsulfate 566
Office of Pollution Prevention and Toxics (OPPT) 95
olanzapine 419
oleate 566
olefins
epoxidation 282
metathesis 253
moiety 376
reactions of 376–80
use of electron-rich 378
oleic acid 563
oligonucleotide synthesis 425
omeprazole 549
one-pot asymmetric synthesis 424–34
of ABT-341, 425
of ?-acyloxy amide from amino acids 434
chiral pool-based 431–4
of diketopiperazines from chiral amino acid 433
of hydroquinoline-2-carboxylates 430??? Index
one-pot asymmetric synthesis (Continued)
of ?-lactam from chiral amino alkyl isonitriles 433
of ?-lycorane catalyzed by thiourea-quinine 429
Michael/Mannich/lactamization reaction 431
of morpholin-2-one from chiral amino acids 433
of nitrocyclopropanes catalyzed by diphenylproline
429
of optically active hydroquinoline-2-carboxylates
429
organocatalysis 427–31
of pyrroline catalyzed by [Ru]-prophyrine 426
of quaternary 3-nitrochromane 432
of renin inhibitor catalyzed by proline 428
of six contiguous stereocenters 431
of spirooxindoles catalyzed by fluorous
organocatalyst 432
of tetrahydropyrans catalyzed by diphenylproline
430
of tetrazole catalyzed by [Al]-Salen 427
one-pot enantioselective double Michael addition 427
one-pot reactions 407–8, 415–24
of aryl bromide with piperazine 418
of bioactive peptide 420
of cinacalcet 419–20
cinacalcet, synthesis of 417
of 2,6-difluorobenzyl azide with 416
2-fluoro-1,3-dicarbonyls-initiated 416
HF elimination and rearrangement in 416
of N-cyanomethyl amide 419
of olanzapine 421
of oseltamivir 423–4
of posaconazole intermediate 418
of praziquantel 421–2
pyridines, synthesis of 416–17
of pyridinone-3-yl-benzimidazol-2-ones 422
of rufinamide 416
of sitagliptin precursor 419
sunitinib, synthesis of 417–18
three-step reaction sequences 418–21
of triazolobenzodiazepines 421
online LC 62
open-chain compounds 376–82
Organic Process Research and Development (OPRD)
21
Organization for Economic Co-operation and
Development (OECD) 95
organocatalysis 427–31
assymetric, in aqueous media 271–94
in asymmetric epoxidation in water 314
catalysts used in 185
fluorous 256–9
organocatalytic asymmetric reduction 258
organocatalytic epoxidation 258
in synthesis of substituted dihydropyran in water
313
organocatalysts
amphiphilic 297, 301–2
arene-based 297
in asymmetric aldol reaction in water 304
in asymmetric aldol reactions in water 293–303
in asymmetric epoxidation in water 314
bifunctional 296
Br?nsted bases as 193
in a cascade reaction in water 313
in C-C bond-forming reactions 314
chiral amino sulfonamide as 189
chiral bispidine-based amine 310
chiral diamine 306
cinchonidine as 208
for 1,4-conjugate addition reactions 309–10
cyclopropanation reaction and 313
in cyclopropanation reaction in water 314
diamine-containing bifunctional 306
for Diels-Alder reactions 311–12
di(methylimidazole)prolinol silyl ether 307
in a domino reaction in water 312
ethylene diamine-derived 299
fluorous 256–8, 431–2, 511–14
fluorous containing (S)-pyrrolidine sulphonamide
306
formation of bifunctional 308
hydrogen-bonding 200
hydroxyl and acid group-modified 303–4
hydroxyl phthalimide-linked triazolepyrrolidine
307
4-hydroxy-L-proline based 300
4-hydroxyproline based 302, 309
4-hydroxyproline–based 309
ionic liquid–tagged 309
ionic liquid tagged 4-hydroxyproline 302
Jorgensen-Hayashi 306
large-scale aldol reaction catalyzed by 208
linear amino acid based 305
for Mannich reactions 311
modified 4-hydroxyproline 304
modified L-proline 293
modified proline 307–8
polymer-supported 309Index ???
polymer-supported 4-hydroxyproline 304
polystyrene-supported 303
prolinamide 307
prolinamide based 187
proline and hydroxyproline-based 310
proline-derived dipeptide as 190
protonated (S)-prolinamide 298
P-spiro amino-pahosphonium salt as 202
pyrrolidine-based chiral amine 307
pyrrolidine-based thiourea bifunctional
enamine-based 308
pyrrolidine–oxyimides 308
pyrrolidine-thiourea–based 306
recyclable 307
reusable ionic liquid–type 309
siloxy-L-serine 311
siloxytetrazole 311
in synthesis of oxyaminated products in water 314
TBDPS-substituted siloxyproline 301
4-tert-butyldimethylsiloxy substituted 311
thiourea 298
thiourea-based 200
of trans-4-(2,2-diphenylacetoxy) group 302
used in large-scale reaction 208
water-compatible 308
organocatalytic asymmetric Diels-Alder reaction
363
organocatalytic domino/cascade reactions 431
organocatalyzed Mannich Reaction 351
organometallic chemistry on solid-support 491–2
oseltamivir phosphate (Tamiflu®) 423
1,2,3-oxadiazoles, sonochemical synthesis of 364–5
oxetane 391
oxidants or oxidizers 107
oxidation reactions 243–8
of aldehydes to acids 247
of cycloalkanes 248
of functionalized olefins 246
of sulfides 248
oxidative C-H functionalization 451–2
8-oxoprotoberberine derivative, synthesis of 378
oxyamination reactions 313
oxygenated organic liquids 399
oxygenation reactions 399
oxygen-containing heterocycles, synthesis of
coumarins 146–7
furan 144–5
isobenzofuranones 145–6
isochromenes 147–8
isocoumarins 146–7
lactones 147
oxygen heterocycles, solid-supported synthesis of
484–5
oxytrifluoromethylation of 1,7-enzymes 417
p
palladium-catalyzed 2-arylation of oxazole derivatives
24
palladium-catalyzed carbonylative Negishi
cross-coupling reactions 453
palladium-catalyzed C-H olefination 145
palladium-catalyzed Heck-reaction 236
palladium(II)-catalyzed sequential C(sp3)-H
monoarylation/amidation 143
palladium–lanthanide copolymers 271
palladium perfluorooctanesulfonate [Pd(OPf)2] 241
p-(amino methyl) benzoic acid (PAMBA) moiety 483
p-aminophenol 553
p-anisidine 311, 351
papaverine 551
parabens 110
paracetamol 553
Parkinson’s disease 385
partitioning 84
Passerini reaction 426, 433
Paterno, Emanuele 374, 390 `
Paterno-B ` uchi reaction 390–1 ¨
in synthesis of merrilactone 390
Pd- and Cu-catalyzed N-arylation 449
Pd-based hybrid metal catalyst 237
[Pd]-BINAP 425–6
Pd-1,3-bis(diphenylphosphino)propane (Pd-DPPP)
catalysts 545
Pd-catalyzed arylation reactions 33
Pd/C-catalyzed hydrogenation 455
Pd
2(dba)3/Hmbpa (Methyl
4,6-O-benzylidene-3-deoxy-3-
(diphenylphosphino)-?-D-altropyranoside)
446
PDUFA, see Prescription Drug User Fee Act
PEG, see polyethylene glycol
PEGA800 (polyethylene glycol dimethyl acrylamide)
resin 483
penicillin acylase 169
peptide synthesis, solid-supported 493–4
perfluoroalkyl-tagged bis(dihydrooxazole)copper
complexes 254
perfluorophenyl catalyst 294??? Index
perfluorosulfonyl benzaldehydes 520–1
permissible exposure limit (PEL) 73
Petasis-borono-Mannich reactions 30–1, 410
Petasis reaction 409–10
Pfizer 81, 586, 609, 614
pharmaceutical activity assessment of ILs 564–6
pharmaceutical industry 21, 32, 34
attracting and retaining talent 607
biocatalysis and 161
biopharmaceutical industry 604
choice of solvent 21
cost savings 605
customer demands 606
environmental impacts of pharmaceuticals 605–6
generic 604
innovative 604
investor pressures 607
legislation 606
NCDs 121–3
products of Biginelli reaction in 355
reputation 605
pharmaceutical NCDs 121–3
Ibuprofen–menthol 121
Pharmaceutical Roundtable 586, 601
pharmaceuticals, environmental impacts of 605–6
pharmaceuticals in the environment (PIEs) 123, 606,
616
phase separation 233, 235–6
phase-transfer catalysis 202–4
asymmetric alkylation catalyzed by 204
asymmetric conjugate addition catalyzed by 204
asymmetric epoxidation reaction catalyzed by 203
asymmetric umpolung reaction of imines by 204
phase transfer catalysts (PTCs) 202–4
phenanthridines, synthesis of 141
phenazines, synthesis of 142–3
phenylboronic acid 241
1-phenylcyclohexene 408
1,4-phenylenebis-(phenylmethanone) 358
1-phenylethanol 335
pheromones 383, 430
phosphine ligands 26, 228, 230–1
phosphonium 202, 259
phosphonium chloride 259
phosphoric acid 57, 191
phosphorus 222–5
photocatalyzed/photosensitized C-H functionalization
376
photochemical electrocyclic reactions 379–80
photochemical synthesis 373–401
of aminoacid 389
of antihelmintic ascaridol 399
Ar-H functionalization 380
of ?-arylpropionic acid derivatives 378
of azasugar inhibitors 395
of bioactive cardenolide ouabagenin 390
of bioactive compound 394
of bioactive juglone 399
of bis-butenolide 400
of biyouyanagin A 386
of chlorolissoclimide 381
cyclobutane ring, intramolecular formation of
387–9
E/Z isomerization in 379
five-membered rings, synthesis of 391–4
from “green chemistry” point of view 374
of 2?-hydroxysolanascone 389
of ibuprofen 381
of indole 382
involving organic compounds 375
larger rings, synthesis of 397–8
limitations of 374
of lineatin 386
mechanistic studies 373–4
of methopholine 382
olefins, reactions of 376–80
oxa-di-?-methane rearrangement, (ODPM) 383
of oxetanes 389–90
photochemical preparation of compound 398
photocyclization of triptolide 396
photoinduced rearrangement of pyridinium salt
393
photolysis of 5-chloro-N-phenyl-1H-pyrazole-4-
carboxamide derivative 394
photoredox catalyzed cycloaddition 394
in preparation of alicyclic compounds 380–1
reasons for not using 373
of rhodopeptin 385
six-membered rings, synthesis of 394–7
sunlight-photocatalyzed alkylation of maleic acid
377
of terebic acid 377
of tetracyclic compound 398
of tetracyclic lycopodium alkaloid magellanine 384
of tetrahydroisoquinoline 378
of three- and four-membered rings 382–91
three-membered rings, synthesis of 383–4
photochemistry 373Index ???
photocycloaddition 389
photodecarbonylation reaction 392
photo-Favorskii rearrangement 381
photogenerated singlet oxygen 398
photoinduced electron transfer (PET) reaction 395
photolysis 384, 391, 393–4
photosensitization 375
photo-Wolff rearrangement 389
phthalimides, synthesis of 136
phytoalexins 388
4-picoline 24
Pictet–Spengler reaction 412
piezoelectric materials 343
PIL, see protic ILs (PILs)
pincer complex 283, 285
piperazine 275
piperazinones, solid-supported synthesis of 481
planetary ball mills 329, 331
Plataforma Solar de Almeria (PSA) 387
platinum nanoparticles 554
1-[(5-(p-nitrophenyl) furfurylidene) amino] hydantoin
sodium 552
polarity 30, 49, 54–5, 336
Pollution Prevention Act (PPA) 95–6
Polton, Tom 606
polyacrylic acid 105
polyaniline (PANI) 274
polycyclic compound 201, 421
polyethylene glycol (PEG) 120, 272, 553
polyketides 425
polymer-immobilized peptido triazole, solid-supported
synthesis of 484
polymer resins 336–8
polymer-supported scandium catalyst 408
polymorphism 554–5
polyoxyethylene sorbitan monooleate (Tween-80)
552
polyoxymethylene urea 109
polyquinane sesquiterpenoids 383
polystyrene-based organic polymers 281
polystyrene resin (PS-type resin) 232, 271, 277, 282
polystyrene-supported triphenylphosphine 338
poly-2,4,6–triallyloxy-1,3,5-triazine 281
posaconazole 418
potassium aryltrifluoroborate 360
potassium carbonate 334
powder X-ray diffraction (PXRD) 120
Practice Greenhealth 606
praziquantel 421
praziquantel (PZQ) 122, 421
pregabalin 169–70
visible-light photoredox catalyzed synthesis of 377
preparative chromatography 59
Prescription Drug User Fee Act (PDUFA) 615
preservatives 109–10
Presidential Green Chemistry Challenge Awards
86–7, 101
previtamin D3 379–81
primaquine 566
Princer type palladium complexes 237
procainium 558–9
procainiumamide 558–9
process analytical technology (PAT) 47, 585–6
applications 62
for biopharmaceuticals 65
control strategy in 61
monitoring and controlling of pharmaceutical
crystallisation processes 61–2
on-line process monitoring 62
quality by design (QbD) approaches 60
sample measurement approaches 61
process integration 85
process research and development (PR&D) 21
Proctor & Gamble (P&G) 93–4, 111
product improvement 98, 101
productivity 161, 164–5, 167–8
product selectivity 219, 228
prolinamide-based organocatalysts 187
proline-based dipeptides 298
proline catalysts 292–3, 305–10
acid group–modified 293–8
acid group–modified, with dendrimer and polymer
support 298–9
conjugate 299–300
ionic liquid–type 309
modified 306–8
modified with polymer support 309
proline-cholesterol 297
proline thioamide 298
promoters 350
propantheline 558
propranolol 178, 549–30
propylene glycol n-butyl ether 105
ProSARTM 174
protease inhibitor (PI) 175–6, 376
protecting groups 172, 458
protective linkers 520
protein microspheres 353??? Index
protic ILs (PILs) 551
p-series glycol ethers 105
Psidium guajava 389
p-toluenesulfonate 558
p-toluenesulfonic acid (PTSA) 354
p-toluensulfonic acid 384
purchasing decisions 75
pyrazinamide 121
pyrazole rings 354
pyridine 416
pyridine catalyzed Knoevenagel condensation 346
pyridine derivatives, synthesis of 409
pyridines, synthesis of 140
pyridinium perchlorate 393
pyridinium salts 393, 395
pyridinopyrimidin-4-ones 450
pyrmetazole 176
pyrroles 133–4, 393
pyrrolidines 137, 412
pyrrolidine triazoles 306
pyrrolidones, synthesis of 135–6
pyrrolo[de]phenanthridine 428
q
qPCR, see quantitative polymerase chain reaction
8Q-peptide (8QSer) 456
quality control 550
quantitative analysis 549, 554
quantitative polymerase chain reaction (qPCR) 586
quartz halogen lamps 398
quaternium-15 109
quercetin 124, 550, 554
quinazolin-4-ones 450
quinoline derivatives 281, 535, 545
quinolines 192, 284
quinolinones, synthesis of 141–2
quinone 74
quinonoid compounds 399
r
radical reactions 344, 528
Raman spectroscopy 60, 120, 331
Ranbaxy Laboratories 612
ranitidine 557
ranitidine hydrochloride 556
Rasta resin 271
rate acceleration 291, 455
rate enhancement 34, 447
rational design 29, 174, 407
raw materials 71–3, 91–4, 96–7, 99
REACH, see Registration, Evaluation, and
Authorization of Chemicals Regulation
reaction efficiency 141
reaction kinetics 79, 441
reaction monitoring 37, 41–2
reaction rates 229, 232–2, 246, 24241
reaction times 168, 235, 356, 441
real-time analysis 61, 510
recombinant protein, manufacturing process of a 582
redox processes 375
‘reduce, replace, recycle’ maxim 50
reflective spectroscopy 60
regioisomers 141
Registration, Evaluation, and Authorization of
Chemicals Regulation, (REACH) 83, 96, 100
renewable feedstocks 603
renewable resources 21, 23, 28, 32, 103
renin–angiotensin–aldosterone system (RAAS) 428
renin inhibitors 428
research and development (R&D) 604
Research Institute for Fragrance Materials (RIFM)
108
residence time 459
resin-bound triazene 477
resin IRA-96 346
resin solvation 338
Resource Conservation and Recovery Act (RCRA) 46
resource consumption 86
resource efficiency 602
retro aza- Michael/aza -Michael mechanism 171–2
Retsch mixer mill 329–30
Retsch MM400 mixer mill 331–2
reversed-phase chromatography (RPLC) 54
rhodium catalysis of C-H activation 144
rhodium catalysts
in carbonylation reactions 278–9
C-H functionalization and 151, 277
in hydrogenation reactions 278
immobilized 276–9
Rh(III)-catalyzed C-H activation/cyclo-addition of
benzamides and methylenecyclopropanes 150
rhodium-catalyzed carbonylation reactions 278–9
rhodium-catalyzed hydrogenation reactions 278
rhodium-catalyzed sp2-C-H bond functionalization
24
rhodium(I)-catalyzed addition reactions 278
rhodium(II) carbenoid chemistry 277
rhodium(II) carbenoids 277–8Index ???
rhodopeptins 385
RIFM, see Research Institute for Fragrance Materials
ring-closing metathesis (RCM) 30
ring-opening/closing metathesis (ROM/RCM) 279
ring-opening metathesis polymerization (ROMP) 279
rink resin 477
Ritonavir 554
Robinson annulation process 416
rocaglamides 391
Roche 609
Ron Brown Award for Corporate Leadership 101
Rose Bengal photosensitized oxygenation 399
Royal Society of Chemistry 602
(3R,4S,5R)-3,4,5-trihydroxycyclohex-1-ene-1-
carboxylic acid 551
RTILs, see ionic liquids
Ru-based catalysts 253
Ru-BINAP catalysts 232
Rubrolide A 400
rufinamide 416
ruthenium catalysts 279–84
in cyclopropanation reactions 282–3
in epoxidation 282
in halogenation reactions 283–4
in metathesis reactions 279–80
ruthenium(II)-phenyloxazoline catalyst 282–3
Ru(xantphos)arene catalyst 454
ruthenium-catalyzed cyclopropanation reactions
282–3
ruthenium-catalyzed transfer hydrogenation 280–2
ruthenium N-heterocyclic catalysts 279, 281
ruthenium trichloride 283
rutin 554
s
saccharin 122, 567
safety-catch linkers 520–1
salicylaldehyde 409, 411
salicylaldehydes 411
salicylic acid 547, 558
salt formation 562
sample preparation 47–50
sample preparation in GAC
cloud point extraction (CPE) 48
coacervative extraction (CAE) 48
ionic liquids (ILs) 48
liquid–liquid extraction (LLE) 48
process analytical technology (PAT) approach 47
solid–liquid extraction 47–8
solid-phase extraction (SPE) 49
solid-phase microextraction (SPME) 50
statistical design, use of 47
stir-bar sorptive extraction 50
sub- or supercritical water extraction 48–9
supercritical fluid extraction (SFE) 49
Sandoz Pharmaceutical 611
sandramycin 429
Sanofi 81, 586, 609, 611
SBA-15 silica 279–80
S.C. Johnson & Son (S.C. Johnson) 94
scaffolds 140, 162, 197
scaling up 459
Schiff bases 270, 274, 425
schizophrenia 419
S-[3-(chloro-2-hydroxypropyl)trimethylammonium]
[bis((trifluoromethyl)sulfonyl) imide]
(S-[CHTA][NTf2]) 50
screening 119
SDG, see solvent drop grinding
(S)-diphenylprolinol TMS ether 429
SDS, see sodium dodecyl sulfate
SelectfluorTM 413
selenium-based catalyst 247
Sensitox 400
SFE, see supercritical fluid extraction
SFLP, see supported fluorous liquid phase catalysis
side reactions 166, 356
silica 273, 365, 427
silicon carbide (SiC) reactors 459–60
silver salts 360
silvestrol 392
simvastatin 172–3
Singulair® 173
sitagliptin 161, 170–2, 418–19
six-membered rings 394–7
six-membered rings, synthesis of 394–7
size-exclusion chromatography (SEC) 64
skin permeability 552
smple protonated (S)-prolinamide organocatalyst 298
sodium borohydride 167, 473
sodium docusate 564
sodium dodecyl sulfate (SDS) 549
sodium hydroxymethylglycinate 109
SOLARIS plant 387
solar light 377, 387
sol-gel method 552
solid catalysts 447
solid fluorous catalysts (SFC) 221??? Index
solid–liquid extraction 47–8
solid–liquid separation 220
solid-phase extraction (SPE) 49
solid-phase microextraction (SPME) 50
solid-phase organic synthesis (SPOS) 269–70, 471–2
advances in linkers for 472–5
in alkane metathesis 493
in alkylation 480
of Antimycin A3b 489
of arylpiperazinylbutyl derivatives 481
of arylpiperazinylbutyl derivatives of
4,5-dihydro-12,4,-triazine-6(1H)-ones 480
of benzimidazolinopiperazinones 482–3, 495–6
of chalcones 492
of C-mannosylated glycopeptide on the Sieber amide
resin 493
in coupling of polymer-attached amines with
4,5-disubstituted o-fluoronitrobenzenes 482
of 3-deazapurine derivatives 476
of destruxin E 489–92
of 2,3-dihydrobenzo[f][1,2,5]thiadiazepin-4(5H)-one
1,1-dioxides 485–6
of dihydroquinoxaline-2-ones 499–501
of dithianes and dithiolanes 503
in dithioacetalization of aldehydes and ketones
503
of diverse indoles 483–4
in electrophilic lactonization reaction 485
Elliman’s solid-phase organic synthesis 473
of esterification of (4-(hydroxymethyl)-3-
methoxyphenoxy)acetic acid (HMPB) 488
of furan-2(5H)-one derivatives 485–6
of glycopeptide 494
of heterocycles with more heteroatom 485–6
heterocyclic chemistry 476–86
in Hiyama reactions 491–2
of 1H-pyrazolo[3,4-d]pyrimidines 479
in hydrolysis of imine 480
of hydroxylactams 484
of indazole derivatives using triazenes 477–8
of intermediates 474
of Lysobactin (Katanosin B) 487, 489
of macrocyclic peptide 495
of macrocyclic peptidomimetics 493–4
Merrifield’s solid-phase peptide synthesis 471–2
microwave-assisted solid-phase organic synthesis
(MASPOS) 499–502
in Mitsunobu alkylation with glycoaldehyde dimethyl
acetal 482
model hydrazones on solid-support 472–3
morphological changes in osteoclast-like
multinuclear cells (OCLs) 490
of natural products 486–91
of NH-1,2,3-triazoles 484
of NH-1,2,3-triazoles containing dipeptide 485
of nicotinoyl amino acid derivatives 495
of nitrogen heterocycles 476–84
of N-methylated cyclic peptide NMe-IB-01212
487–8
organometallic chemistry 491–2
in oxidation 480, 485
of oxygen heterocycles 484–5
of peptides 493–4
phosphine–phosphite (P-OP) ligands for 501–2
of piperazinones 481
of polymer-bound dihydropyrano[2,3-c]pyrazoles
475
of polymer-immobilized peptido triazole 484
of polymer-supported air-stable Pd–NHC complex
503
of polymer-supported free functionalized indoles
483
of polymer-supported peptide hydrazides 475
in preparation of ?-phenylpropiophenone derivatives
491
in preparation of polymer-supported Pd–NHC
complexes 504
of quinoxalines 501–2
of quinoxalinones 501
reagents in organic synthesis 502–4
of spiroisoxazolinodiketopiperazine 487
of spiroisoxazolinodiketopiperazines 486
of (1S,5S)-6-oxa-3,8-diazabicyclo[3.2.1]octane
497–8
stereoselective synthesis 494–9
of substituted benzofuran 485
of substituted guanidines 499–500
of substituted xanthines 480
in sulfonylation of amine 486
of teixobactin 488, 490
of 1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ones
481
of tetrahydrobenzopyrazino-thiadiazinone dioxides
496
of tetrahydroisoquinolines 476, 478
of tetrasubstituted pyrrolo[2,3-d] pyrimidines
476–7
of 1,3,7,8-tetrasubstituted xanthine derivatives 480Index ???
of trans 3-alkyl-substituted ?-lactams 498
of triazolobenzodiazepinones 479
of trisubstituted imidazo[4,5-c] pyridines 476
of trisubstituted triazolobenzodiazepinones
477
of uracil- and coumarin-fused spirooxindole
derivatives 503–4
of uracil fused spiroxindole 504
solid-phase peptide synthesis (SPPS) 33, 455
solid-phase synthesis 476–84
solid-phase synthesis (SPS) 471–2
solid-state structure 558
solid-supported catalysis 269–86
catalysts and ligands used in 270–6
impact on green chemistry 269–70
solid-supported heterocyclic chemistry 476–86
solid-supported reagents (SSRs) 502–4
solubility switch technique 222
soluble polymers 308, 499
solution-phase peptide synthesis 458
solvent drop grinding (SDG) 120
solvent-free Biginelli reaction 355
solvent-free reactions 81, 236, 330
solvent-free synthesis 327–38
catalysis 334–6
isolation techniques 336–8
kinetics and thermodynamics of 330–3
stereoselectivity in 334
solvents 104–5
chlorinated 22
of concern 22
cyclic carbonate 24
greenness of 81
recycling of 328
resin solvation by 338
selection guides and tools 23–4
Sonagashira cross-coupling reactions 31
of 2-halo-3-alkyl imidazo[4,5-b]pyridines (I, Br, Cl)
448
sonication 344
sonocatalysis 344
sonochemical Diels–Alder reaction 362–3
sonochemical Suzuki reaction 359
sonochemical Wittig reaction 362
sonochemistry 343–4
definition 343
Sonogashira coupling 241–3
of aryl bromides and chlorides 243
of aryl bromides and terminal alkynes 242
palladium catalyst for 275–6
in water 274–6
Sonogashira cross-coupling reaction 357
Sonogashira reactions 241–3, 410–11, 448, 503
MW-assisted Sonogshira couplings 447–8
sorbitan laurate (Span-20) 552
source reduction 96
soy 105
spectroscopy 60
SPEX SamplePrep 8000M mixer/mill 329–30
spiroisoxazolinodiketopiperazines, solid-supported
synthesis of 486–7
spirooxindole derivatives 503
SPPS, see solid-phase peptide synthesis
SPS, see solid-phase synthesis
SSR, see solid-supported reagents
STADA Arzneimittel AG 612
stakeholders 602, 605
STAO, see surfactant type asymmetric organocatalyst
Staudinger–aza-Wittig reaction 452
staurosporines 393
stavudine 546
stearic acid 563
Stemona alkaloids 427
Stemonaceae plants 427
step economy 434, 509
stereoselective oxidative addition of halogens 334
stereoselective synthesis, solid-phase supported
494–9
stereoselectivity in solution chemistry 334
Stille coupling 239–40
of alkyl bromides and aryl stannanes 239
procedure of 240
Stille cross-coupling 357
synthesis of benzophenones by 358
Stille reaction 239–40
stir-bar sorptive extraction 50
“stop-and-go” approach to synthesis 415
Strecker reaction 197–8
structural diversity 427, 431
styrene 232, 408
derivatives 283
?-styrylbutyltelluride 360
sub- or supercritical water extraction 48–9
5-substituted tetrazoles 425
sucrose 552
sulfacetamide 556–8
sulfamic acid 350
sulfonamides, synthesis of 149–50??? Index
sulfur-containing heterocycles, synthesis of
benzothiazoles 149
dibenzothiophenes 148–9
sulfonamide 149–50
sulopenem 173–5
Sunitinib (SU11248) 417–18
sunlight 374, 377, 399–400
supercritical carbon dioxide (sc-CO2) 48, 232, 543,
550
supercritical fluid chromatography (SFC) 52, 58–9,
64–5
supercritical fluid extraction (SFE) 49
supercritical fluids (SCF) 23, 564
supercritical water 49
supported aqueous phase (SAP) catalysis 221
supported fluorous liquid phase (SFLP) catalysis 221
supported metal complexes 282
supported reagents 269, 286
suprofen 548
surfactants 102–4
surfactant type asymmetric organocatalyst (STAO)
309
sustainability 32, 50, 71–2, 80, 83, 87
sustainable chemistry 603
sustainable practices 592, 606
Suzuki cross-coupling reaction 359–61
of aryl telurides 360
energy-efficient surface acoustic wave in 360
1,3-enynes, synthesis of 360
in synthesis of vitamin D3 analogues 359
Suzuki–Miyaura coupling reactions 32, 238, 270–3
cross-coupling 460
organotellurium compounds in 360
Suzuki–Miyaura reaction 28, 238, 271–2, 359–60, 460
Suzuki reactions 240–1, 245, 250–4, 270–3, 278, 359,
362
MW-assisted 447
Swedish National Pharmaceutical Strategy (NPS) 606
Swern oxidation 518–19
symmetrical biaryls, synthesis of 360–1
synthetic chemistry 31, 43, 60, 243, 491, 502, 604
synthetic pharmaceuticals 543
t
tachisterol 380
Takeda Pharmaceutical 610
tandem reaction 407
targeting 65
Target Sustainable Product Index program, 2013 97
taxol 217, 391
TBAB, see tetrabutylammonium bromide
TBAHS, see tetrabutylammonium hydrogen sulfate
t-butyl 6-cyano-5-hydroxy-3-oxohexanoate 167
technology, and hazardous materials/processes 72
Teflon 221–2, 232, 254
Tegafur 121
teixobactin 488, 490
telaprevir 175–6
TEMPO 245–6, 451
TEOS, see tetraethylorthosilicate
terebic acid, photocatalyzed synthesis of 377
terfenadine (Seldane) 177
terpenes 383, 398
tert-butylimino-tri(pyrrolidino)phosphorane (BTPP)
480
testosterone 53
tetrabenazine 395
tetrabutylammonium bromide (TBAB) 349
tetrabutylammonium hydrogen sulfate (TBAHS) 496
tetrabutylphosphonium 558–9, 561
tetrabutylphosphonium salicylate 561–2
tetraethylorthosilicate (TEOS) 283
tetrafluoroborate 565
1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ones,
solid-supported synthesis of 481
tetrahydrofuran (THF) 32
tetrahydroisoquinoline, photoredox catalyzed allylation
of 378
tetrahydroisoquinolines 378
solid-supported synthesis of 476, 478
tetrahydropyran motif 430
1,2,3,4-tetrahydropyridine-containing spirooxindoles
431
tetrahydroquinolines 363, 408
tetramethoxysilane (TMOS) 552
1,1,3,3-tetramethylguanidine (TMG) 195
tetrapeptide 336–7
tetraphenylporphyrin (TPP) 400
tetraponerines 381
1,3,7,8-tetrasubstituted xanthine derivatives,
solid-supported synthesis of 480
tetrazoles 425
Teva Pharmaceuticals 611
TH, see transfer hydrogenation
thebaine 549, 554
therapeutic proteins 580
thiazoles 349, 450–1
thin-layer chromatography (TLC) 57Index ???
thiocoraline 429
thiols 194, 198–9
thiourea-based organocatalysts 200
thiourea-catalyzed double Michael reaction 428
thiourea organocatalysts 298
three-membered rings 383–4
threshold limit value (TLV) 73
throughput 58, 178, 357, 456
TIPS 301, 520
TLV, see threshold limit value
TMG, see 1,1,3,3-tetramethylguanidine
TMOS, see tetramethoxysilane
Togni’s reagent 416–17
toluene 26, 28, 34, 64, 549
total synthesis 185, 197
toxicity factor 73
Toxic Release Inventory (TRI) 46
Toxic Substances Control Act (TSCA) 79, 95,
111
traceless cleavage 486
trahertz spectroscopy 120
tramadolium 558–9
transaminases 171
trans-enyne product 335
transformation-type GAL 15–16
transesterification 248–50
transesterification reactions 248–50
transfer hydrogenation (TH) 280–1
transition-metal catalysis 424–7
transition metal catalysts 224–5
transition-metal-catalyzed C-H functionalizations
133
transition metal-catalyzed C-S cross-coupling reaction
448
transition metal-catalyzed decarboxylative couplings
449
13-trans-retinoic acid 379
trastuzumab 579–80
trialkylamines 220
triaryl amines 357
1,2,3-triazoles 414–15, 445
triazolobenzodiazepine-fused polycyclic compounds
421
tributilstannanes 357
trichloromethane 549
triethylamine 549
triethylammonium tetrafluoroborate ([Et3NH][BF4])
546
triethylborane 167
trifluoroacetic acid (TFA) 57, 355
trifluoromethylated heterocycles 416
trifluoromethylation 412–13
1-(trifluoromethyl)-4-fluoro-1,2-dihydroisoquinoline
412
Ttrifluridine 546
trifluridine 546
trimethylsilanoate 473
trimethylstannanes 357
triphenylphosphine 228, 230–1
triphenylphosphine-ligated macroreticular polystyrene
278
triple sulfa drug 121
triplet aryl cations 377
triplet states 374
triptolide 396
triquinane sequiterpene 384
trisubstituted imidazo[4,5-c] pyridines,
solid-supported synthesis of 476
1,4,5-trisubstituted 1,2,3-triazoles 415
Trypodendron lineatum Olivie 386
TSCA, see Toxic Substances Control Act, 1976
Tsuji–Trost reaction 276
tuberculosis 119
tubular reactors 459
two-in-one strategy 511
u
Ugi 4C-3CRs 433
Ugi-4CR/cyclization protocol 445
Ugi reaction (U-4CR) 421, 431, 520
UHPLC 47, 51–2, 62
UIC-94017, synthesis of 376
Ullmann coupling 449
ultrasound 30, 81, 343
aldol reaction under 345
assisted Claisen–Schmidt reaction 349–50
assisted cross-coupling reaction 358–61
assisted functionalization of alkynes 365
assisted ionic-catalyzed Knoevenagel reaction
346–9
assisted Michael Addition 351–3
assisted synthesis of nitroolefins 350
based aqueous biphasic systems 551
Baylis–Hillman reaction under 353
benzotriazoles, synthesis of 354
Biginelli reaction under 355
click chemistry under 354
condensation of o-phenylenediamine 354??? Index
ultrasound (Continued)
cross-coupling reaction between organoltellurides
under 360
doubled Stille Reaction under 358
in extraction of drugs from natural products 551
heterogeneous-catalyzed synthesis of imines under
365
homocoupling of aryl n-butyltellurides under 361
irradiation 353, 365
Mannich reaction under 350–1
mediated reaction of arylacetylenes 365
mediated Suzuki Ccoupling between
organotrifluoroborates and organotellurium 361
Mukaiyama aldol reaction under 345
organocatalyzed Diels–Alder reaction under 363
promoted palladium-catalyzed detelluration 361
pyrazole compounds, synthesis of 354
Sonogoshira coupling using Cu nanoparticle in
358
synthesis of nitroalkenes 349
tandem reaction (Wittig-Suzuki) under 362
uncatalyzed Mukaiyama reaction 345–6
unsaturated ketones 375
upstream process (USP) 581
urine samples 548
U.S. Clean Air and Clean Water Acts 46
U.S. Geological Survey (USGS) 605
U.S. National Fire Protection Association (NFPA) 46
U.S. Toxic Substances Control Act 111
USGS, see U.S. Geological Survey
USP, see upstream process
UV light 380
v?
-valerolactone (GVL) 25–7, 455
cinnamates, production of 25
from levulinic acid 25
Pd-contamination of products and 25
Pt-catalyzed hydroformylation and formylation in
25
vanadium 74
vapour pressure 48, 51
VDCC, see voltage-dependent Ca2+ channels
verapamil 178
Viagra 10, 603, 609
Vilsmeier–Haack reaction 418
viral chemotherapy 546
vitamin B
12 327
vitamin D 359
VOC, see volatile organic compounds
volatile organic compounds (VOCs) 22, 97, 100, 545
voltage-dependent Ca2+ channels (VDCC) 431
w
Wacker oxidation of polyfunctional olefins 245–6
Walmart 94, 97
sustainability program of 94
Wang resin 485, 491, 493–4
warfarin 550
Warner Babcock Institute (WBI) 117
wastewater treatment plants (WWTPs) 23, 111, 605
water 104
asymmetric aldol reactions in 293–300
copper-catalyzed azide–alkyne cycloaddition
(CuAAC) reaction in 443
domino reaction in 312
Mizoroki–Heck reactions in 273–4
Sonogashira coupling in 274–6
Tsuji–Trost reaction in 276
water/n-butanol binary azeotrope 27
water-soluble benzophenone derivative 377
wetting agents 92, 558
what if analysis (WIA) 74
Wig-L-Bug mill 329
Wilkinson’s catalyst 220–1, 230, 232, 243
Wilkinson’s complex 222, 230, 233
Wittig condensation 379
Wittig–Heck reaction 274
Wittig reactions 338, 361–2
Wittig–Suzuki reactions 274
Wolff rearrangement 389
worker safety 82
Wurtz-type products 357
x
xestoquinone 425
X-ray fluorescence (XRF) 60
XRF, see X-ray fluorescence
xylene 84, 87, 104
y
Yang reaction 389–90
Yucatan micropig (YMP) 552
z
ZantacTM 556
zeolites 564
zinc oxide with imidazole, reaction of 331, 333
Zoloft 603, 609
zwitterionic surfactants 103
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