Green Techniques for Organic Synthesis and Medicinal Chemistry

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 This edition first published 2018 © 2018 John Wiley & Sons Ltd All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions The right of Wei Zhang and Berkeley W Cue to be identified as the authors of the editorial material in this work has been asserted in accordance with law Registered Office(s) John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office 9600 Garsington Road, Oxford, OX4 2DQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com Wiley also publishes its books in a variety of electronic formats and by print-on-demand Some content that appears in standard print versions of this book may not be available in other formats Limit of Liability/Disclaimer of Warranty In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make This work is sold with the understanding that the publisher is not engaged in rendering professional services The advice and strategies contained herein may not be suitable for your situation You should consult with a specialist where appropriate Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages Library of Congress Cataloging-in-Publication Data Names: Zhang, Wei, 1961– editor | Cue, Berkeley W., editor Title: Green techniques for organic synthesis and medicinal chemistry / edited by Wei Zhang, Berkeley W Cue, Jr Description: Second edition | Hoboken, NJ : John Wiley & Sons, 2018 | Includes index | Identifiers: LCCN 2017043086 (print) | LCCN 2017047560 (ebook) | ISBN 9781119288176 (pdf ) | ISBN 9781119288589 (epub) | ISBN 9781119288169 (cloth) Subjects: LCSH: Pharmaceutical chemistry | Green chemistry Classification: LCC RS403 (ebook) | LCC RS403 G74 2018 (print) | DDC 615.1/9–dc23 LC record available at https://lccn.loc.gov/2017043086 Cover Design: Wiley Cover Images: (top) © blueclue/Getty Images; (bottom) © funnyangel/Shutterstock Set in 10/12pt WarnockPro by Aptara Inc., New Delhi, India 10 v Contents List of Contributors xvii Foreword xxi Preface xxiii Part I  1.1 1.2 1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.4 1.4.1 1.4.2 1.4.3 1.4.4 1.4.5 1.5 1.6 1.7 1.7.1 1.7.2 1.7.3 1.7.4 1.7.5  2.1 2.1.1 General Topics in Green Chemistry Green Chemistry Metrics Frank Roschangar and Juan Colberg Business Case Historical Context Metrics, Awards, and Barriers Mass-Based Metrics Life-Cycle Assessment Green Analytical Chemistry (GAC) Awards Barriers Metrics Unification Via Green Aspiration Level Standardizing Metrics 10 Defining Analysis Starting Points 10 Considering Drug Manufacturing Complexity 11 Green Aspiration Level (GAL) 11 Relative Process Greenness (RPG) 11 Green Scorecard 12 Supply Chain 14 Outlook and Opportunities 15 Industry-Wide Adaption 15 Integration with LCA 15 Application of GAL to Supply Chain 15 Transformation-Type–Based GAL 15 Opportunities for Government 16 References 17 Green Solvents 21 Janet L Scott and Helen F Sneddon Introduction 21 The Need for Greener Alternatives for Chlorinated Solvents 21 vi Contents 2.1.2 2.1.3 2.2 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.3.6 2.3.7 2.3.8 2.3.9 2.4 The Need for Greener Alternatives for Dipolar Aprotic Solvents Scope 23 Solvent Selection Guides and Tools 23 Greener Molecular Solvents 24 Carbonates 24 γ-Valerolactone 25 Dimethylisosorbide 27 Butanol 27 Ethyl Lactate and Lactic Acid 28 Glycerol and Glycerol Derivatives 29 Cyrene 31 2-Methyl Tetrahydrofuran 32 Cyclopentyl Methyl Ether 32 Opportunities, Challenges, and Future Developments 34 References 34  Green Analytical Chemistry 43 Paul Ferguson and Douglas Raynie Introduction 43 Analytical Method Assessment 44 Case Studies 46 Sample Preparation 47 Sample Preparation Focusing on Liquid Approaches 47 Sample Preparation Using Solid Supports 49 Techniques and Methods 50 Liquid Chromatography 50 Gas Chromatography 57 Supercritical Fluid Chromatography 58 Spectroscopy 60 Process Analytical Technology 60 Biopharmaceutical Analysis 62 Biopharmaceutical Sample Preparation 63 Chromatographic and Electrophoretic Separation 63 PAT for Biopharmaceuticals 65 Conclusions 65 Acknowledgments 66 References 66 3.1 3.1.1 3.1.2 3.2 3.2.1 3.2.2 3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.4 3.5 3.5.1 3.5.2 3.5.3 3.6  4.1 4.2 4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.4 4.4.1 23 Green Engineering 71 Christopher L Kitchens and Lindsay Soh Introduction: Green Engineering Misconceptions and Realizations 12 Principles of Green Engineering 72 Green Chemistry Metrics Applied to Engineering 73 Maleic Anhydride Production Example 74 Level Green Chemistry Metrics 74 Level Green Chemistry Metrics 78 Level Green Chemistry Metrics 80 Use of Green Solvents in the Chemical Industry 80 Waste Prevention 80 71 Contents 4.4.2 4.4.3 4.4.4 4.4.5 4.4.6 4.4.7 4.5 4.6 Inherently Non-Hazardous 81 Renewable Rather Than Depleting 83 Design for Commercial After-Life 84 Separation and Purification to Minimize Energy Consumption and Materials Use 84 Integration and Interconnectivity with Available Energy and Materials Flows 85 Conserve Complexity 85 Presidential Green Chemistry Awards 86 Opportunities and Outlook 87 References 87  Greening of Consumer Cleaning Products 91 David C Long History of Green Consumer Cleaning Products 91 Cleaning Products Before 1990: Great Cleaners but Not Green 91 The Birth of Green Cleaning Products: Green but Didn’t Clean 92 Early Entries in Green Cleaning 93 Green Cleaning Can Provide Better Cleaning: The Historical Influence of Major Manufacturers Drivers for Greener Products 94 Consumers 94 Governmental Regulations and Non-Governmental Organizations 95 Environmentally Preferable Purchasing Programs 96 Major Retailers 97 Development of Green Cleaning Criteria and Eco-Labeling 98 History and Background 98 Green Seal 100 ECOLOGO 100 EPA’s Design for the Environment/Safer Choice 101 GreenList® 101 Development of Greener Ingredients for Cleaners 102 Background 102 Surfactants 102 Solvents 104 Chelants 105 Oxidizers 107 Colorants and Dyes 108 Fragrances 108 Disinfectants and Preservatives 109 The Future of Green Cleaning 111 Acknowledgments 112 References 112 5.1 5.1.1 5.1.2 5.1.3 5.1.4 5.2 5.2.1 5.2.2 5.2.3 5.2.4 5.3 5.3.1 5.3.2 5.3.3 5.3.4 5.3.5 5.4 5.4.1 5.4.2 5.4.3 5.4.4 5.4.5 5.4.6 5.4.7 5.4.8 5.5  6.1 6.2 6.2.1 6.2.2 6.2.3 6.2.4 Innovation with Non-Covalent Derivatization John C Warner and Emily Stoler Introduction 117 NCD Overview 118 NCD Definitions 118 NCD Design 118 NCD Preparation 119 NCD Characterization 120 117 93 vii viii Contents 6.3 6.3.1 6.3.2 6.3.3 6.3.4 6.3.5 6.4 Pharmaceutical NCDs 121 API Solubility 121 API Bioavailability 122 API Stability 122 API Additional Performance Enhancements 122 API NCD Future 123 Environmental and Green Chemistry Benefits 123 References 123 Part II  7.1 7.2 7.2.1 7.2.2 7.2.3 7.3 7.3.1 7.4 7.4.1 7.5 7.6  8.1 8.2 8.2.1 8.3 8.4 8.4.1 8.4.2 8.4.3 8.4.4 8.4.5 8.4.6 8.4.7 8.4.8 8.4.9 8.5  9.1 9.2 Green Catalysts 131 Catalytic C-H Bond Cleavage for Heterocyclic Compounds 133 Zhanxiang Liu and Yuhong Zhang Introduction 133 Synthesis of Nitrogen Heterocycles 133 Synthesis of Five-Membered N-Heterocycles 133 Synthesis of Six-Membered N-Heterocycles 140 Synthesis of Other N-Heterocycles 143 Synthesis of Oxygen-Containing Heterocycles 144 Synthesis of Furan 144 Synthesis of Sulfur-Containing Heterocycles 148 Synthesis of Dibenzothiophenes 148 Medium-Sized Heterocyclic Compounds 150 Conclusion 152 References 152 Biocatalysis 161 James Lalonde Introduction 161 Enzymes for Biocatalysis 162 Practical Aspects of Using Enzymes in Drug Manufacture 163 Advances in Enzyme Engineering and Directed Evolution 164 Biocatalytic Synthesis of Pharmaceuticals: Case Studies of Highly Efficient Pharmaceutical Syntheses 165 Atorvastatin 165 Synthesis of Beta-Lactam Antibiotics 168 Pregabalin 169 Sitagliptin, Glasdegib, and Dexamphetamine 170 Simvastatin 172 Sulopenem and Montelukast 173 Boceprevir and Telaprevir 175 Esomeprazole 176 Synthesis of Drug Metabolites 177 Summary and Future Outlook 178 References 180 Practical Asymmetric Organocatalysis 185 Wen-Zhao Zhang, Samik Nanda, and Sanzhong Luo Introduction 185 Aminocatalysis 185 Contents 9.3 9.4 9.5 9.6 9.7 9.8 9.9 Brønsted Acid Catalysis 191 Brønsted Base Catalysis 193 Hydrogen-Bonding Catalysis 197 Phase-Transfer Catalysis 202 Lewis Acid, Lewis Base, and N-Heterocyclic Carbene Catalysis 204 Large-Scale Reaction (>100-Gram Reaction) 207 Conclusion 209 References 209  Fluorous Catalysis 219 L´aszl´o T Mika and Istv´an T Horv´ath Introduction and the Principles of Fluorous Catalysis 219 Ligands for Fluorous Transition Metal Catalysts 224 Synthetic Application of Fluorous Catalysis 225 Hydroformylation 225 Hydrogenation 229 Hydrosylilation 232 Cross-Coupling Reactions 236 Hydroboration 243 Oxidation 243 Esterification, Transesterification, and Acetylation 248 Other Metal Catalyzed Carbon-Carbon Bond–Forming Reactions Fluorous Organocatalysis 256 Other Applications of Fluorous Catalysis 259 References 259 10.1 10.2 10.3 10.3.1 10.3.2 10.3.3 10.3.4 10.3.5 10.3.6 10.3.7 10.3.8 10.4 10.5  11.1 11.1.1 11.1.2 11.2 11.2.1 11.2.2 11.2.3 11.2.4 11.3 11.3.1 11.3.2 11.3.3 11.3.4 11.3.5 11.4 11.4.1 11.4.2 11.4.3 11.4.4 11.4.5 11.4.6 Solid-Supported Catalysis 269 Sukanta Bhattacharyya and Basudeb Basu Introduction 269 General Introduction 269 The Impact of Solid-Phase Organic Synthesis on Green Chemistry Immobilized Palladium Catalysts 270 Suzuki Reactions 270 Mizoroki–Heck Reactions in Water 273 Sonogashira Reactions in Water 274 Tsuji–Trost Reactions in Water 276 Immobilized Rhodium Catalysts 276 Introduction 276 Rhodium(II) Carbenoid Chemistry 277 Rhodium(I)-Catalyzed Addition Reactions 278 Rhodium-Catalyzed Hydrogenation Reactions 278 Rhodium-Catalyzed Carbonylation Reactions 278 Immobilized Ruthenium Catalysts 279 Introduction 279 Ruthenium-Catalyzed Metathesis Reactions 279 Ruthenium-Catalyzed Transfer Hydrogenation 280 Ruthenium-Catalyzed Epoxidation 282 Ruthenium-Catalyzed Cyclopropanation Reactions 282 Ruthenium-Catalyzed Halogenation Reactions 283 250 269 ix x Contents 11.5 11.5.1 11.5.2 11.5.3 11.6 Other Immobilized Catalysts 284 Immobilized Cobalt Catalysts 284 Immobilized Copper Catalysts 285 Immobilized Iridium Catalysts 285 Conclusions 286 References 287  Asymmetric Organocatalysis in Aqueous Media 291 Kartick C Bhowmick and Tanmoy Chanda Introduction 291 Carbon-Carbon Bond-Formation Reactions 292 Aldol Reactions 292 1,4-Conjugate Addition Reactions 305 Mannich Reactions 310 Diels-Alder Reactions 311 Miscellaneous C-C Bond-Forming Reactions 312 Reactions Other than C-C Bond Formation 313 Conclusion 314 References 314 12.1 12.2 12.2.1 12.2.2 12.2.3 12.2.4 12.2.5 12.3 12.4 Part III  13.1 13.2 13.2.1 13.2.2 13.2.3 13.2.4 13.2.5 13.2.6  14.1 14.2 14.3 14.3.1 14.3.2 14.3.3 14.3.4 14.3.5 14.4 14.4.1 14.4.2 14.5 14.6 14.6.1 Green Synthetic Techniques 325 Solvent-Free Synthesis 327 Kendra Leahy Denlinger and James Mack Introduction 327 Ball Milling 328 Types of Ball Mills 329 Kinetics and Thermodynamics of Solvent-Free Reactions Hard-Soft Acid-Base Theory 333 Stereoselectivity 334 Catalysis 334 Isolation Techniques 336 References 339 Ultrasonic Reactions 343 Rodrigo Cella and H´elio A Stefani Introduction 343 How Does Cavitation Work? 343 Aldol/Condensation Reactions 345 Aldol Reaction 345 Mukaiyama Aldol Reaction 345 Knoevenagel Reaction 346 Claisen-Schmidt Reaction 349 Mannich Reaction 350 1,4-Addition 351 Michael Additions 351 Baylis-Hillman Reaction 353 Heterocycles Synthesis 353 Coupling Reactions 356 Heck Cross-Coupling Reaction 356 330  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 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 Josiphos® 170 Juglone 399–400 306 k kaempferol 550 β-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 β-lactam antibiotics 433 lactic acid 28–9 lactones, synthesis of 147 lanthanide(III) bis(perfluorooctansulfonyl)amides 249 453 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 Li2 CO3 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 51–2 Index liquid-liquid extraction (LLE) 48 liquiritin 551 low thermal-mass (LTM) chromatography 58 L-proline 299, 345, 428 LUF5771 416 α-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 M2 CO3 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 11 C-carbonylation of aryl halides 453 in peptide chemistry 456 and quantitative formation of γ-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 NH4 OAc-HOAc system 349 NH-1,2,3-triazoles, solid-supported synthesis of 484 Index 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-β-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 α-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 β-lactam from chiral amino alkyl isonitriles 433 of α-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 Brønsted 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 309 Index 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 Patern`o, Emanuele 374, 390 Patern`o-Băuchi 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 Pd2 (dba)3 /Hmbpa (Methyl 4,6-O-benzylidene-3-deoxy-3(diphenylphosphino)-α-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 α-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 2β-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-π-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-4carboxamide 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 373 Index 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 277–8 Index 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-1carboxylic 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)-3methoxyphenoxy)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 β-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 480 Index of trans 3-alkyl-substituted β-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 α-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) 57 Index 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 ([Et3 NH][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 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 v γ-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 B12 327 vitamin D 359 VOC, see volatile organic compounds 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 Zoloft 603, 609 zwitterionic surfactants 103 331, 333 .. .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 Chemistry and Material Science, Nanjing Normal University, Nanjing, China xix xxi Foreword This second edition of Green Techniques for Organic Synthesis and Medicinal Chemistry by Cue and. .. prescription for drug makers: Update the plants The Wall Street Journal, September  Cue, B W (2012) Green chemistry strategies for medicinal chemists In Green Techniques for Organic Synthesis and Medicinal