Edited by Javier Magano and Joshua R Dunetz Transition Metal-Catalyzed Couplings in Process Chemistry Related Titles de Meijere, A., Br€ase, S., Oestreich, M (eds.) Hall, D G (ed.) Metal Catalyzed CrossCoupling Reactions and More Preparation and Applications in Organic Synthesis, Medicine and Materials Second, Completely Revised Edition 2014 ISBN: 978-3-527-33154-3 Zaragoza D€ orwald, F Lead Optimization for Medicinal Chemists Pharmacokinetic Properties of Functional Groups and Organic Compounds 2012 ISBN: 978-3-527-33226-7 Shioiri, T., Izawa, K., Konoike, T (eds.) Pharmaceutical Process Chemistry 2011 ISBN: 978-3-527-32650-1 Yudin, A K (ed.) Catalyzed Carbon-Heteroatom Bond Formation 2011 ISBN: 978-3-527-32428-6 Boronic Acids 2011 ISBN: 978-3-527-32598-6 Blaser, H.-U., Federsel, H.-J (eds.) Asymmetric Catalysis on Industrial Scale Challenges, Approaches and Solutions Second Edition 2010 ISBN: 978-3-527-32489-7 Dunn, P., Wells, A., Williams, M T (eds.) Green Chemistry in the Pharmaceutical Industry 2010 ISBN: 978-3-527-32418-7 Nugent, T C (ed.) Chiral Amine Synthesis Methods, Developments and Applications 2010 ISBN: 978-3-527-32509-2 Edited by Javier Magano and Joshua R Dunetz Transition Metal-Catalyzed Couplings in Process Chemistry Case Studies from the Pharmaceutical Industry The Editors Javier Magano Pfizer Inc., Chemical Research and Development Eastern Point Raod Groton, CT 06340 USA Dr Joshua R Dunetz Pfizer Inc., Chemical Research and Development Eastern Point Road Groton, CT 06340 USA All books published by Wiley-VCH are carefully produced Nevertheless, authors, editors, and publisher not warrant the information contained in these books, including this book, to be free of errors Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at # 2013 Wiley-VCH Verlag GmbH & Co KGaA, Boschstr 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages) No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers Registered names, trademarks, etc used in this book, even when not specifically marked as such, are not to be considered unprotected by law Composition Thomson Digital, Noida, India Printing and Binding Singapore Cover Design Print ISBN: ePDF ISBN: ePub ISBN: mobi ISBN: oBook ISBN: Markono Print Media Pte Ltd Formgeber, Eppelheim 978-3-527-33279-3 978-3-527-65893-0 978-3-527-65892-3 978-3-527-65891-6 978-3-527-65890-9 Printed in Singapore Printed on acid-free paper To Kari, Ana, and Sonia, for their love and support And to my parents, for their gift of a good education – Javier Magano For Cynthia, for Caitlin – Joshua R Dunetz VII Contents Foreword XV Foreword XVII Foreword XIX List of Contributors XXIII Introduction XXIX List of Abbreviations XXXIII 1.1 1.2 1.2.1 1.2.2 1.3 1.3.1 1.3.2 1.4 1.5 2.1 2.2 2.3 2.4 2.5 Copper-Catalyzed Coupling for a Green Process David J Ager and Johannes G de Vries Introduction Synthesis of Amino Acid 14 Asymmetric Hydrogenation Approach Enzymatic Approaches Copper-Catalyzed Cyclization C–N Bond Formation INDAC (1) Synthesis Sustainability 10 Summary 10 References 11 Experiences with Negishi Couplings on Technical Scale in Early Development 15 Murat Acemoglu, Markus Baenziger, Christoph M Krell, and Wolfgang Marterer Introduction 15 Synthesis of LBT613 via Pd-Catalyzed Negishi Coupling 16 Elaboration of a Negishi Coupling in the Synthesis of PDE472 19 Ni-Catalyzed Negishi Coupling with Catalytic Amounts of ZnCl2 21 Conclusions 22 References 23 VIII Contents 3.1 3.2 3.3 3.4 3.5 4.1 4.2 4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 4.4 5.1 5.2 5.3 5.4 5.5 5.6 6.1 6.2 6.3 6.3.1 6.3.2 6.3.3 6.3.4 6.3.5 Developing Palladium-Catalyzed Arylations of Carbonyl-Activated C–H Bonds 25 Carl A Busacca and Chris H Senanayake Introduction 25 Suzuki Approach to Side Chain Installation 26 Arylation of Carbonyl-Activated C–H Bonds 30 Pd Purging from API 36 Conclusions 37 References 37 Development of a Practical Synthesis of Naphthyridone p38 MAP Kinase Inhibitor MK-0913 39 John Y.L Chung Introduction 39 Medicinal Chemistry Approach to 40 Results and Discussion 42 ADC Route to 21 42 Tandem Heck–Lactamization Route to 23 47 Suzuki–Miyaura Coupling 48 Preparation of Grignard 22 for Endgame Couplings 49 Coupling of Organomagnesium 22 and Naphthyridones 19–21 50 Conclusions 54 References 54 Practical Synthesis of a Cathepsin S Inhibitor 57 Xiaohu Deng, Neelakandha S Mani, and Jimmy Liang Introduction 57 Synthetic Strategy 59 Syntheses of Building Blocks 59 Sonogashira Coupling and Initial Purification of 63 Salt Selection 65 Conclusions 70 References 70 C–N Coupling Chemistry as a Means to Achieve a Complicated Molecular Architecture: the AR-A2 Case Story 73 Hans-J€ urgen Federsel, Martin Hedberg, Fredrik R Qvarnstr€om, and Wei Tian A Novel Chemical Entity 73 Evaluation of Synthetic Pathways: Finding the Best Route 73 Enabling C–N Coupling by Defining the Reaction Space 76 First Experiences 76 Setbacks and Problem Solutions 78 Scoping Out Key Parameters for Best Reaction Performance 79 Ligand Screening 79 Finding the Best Base 80 Contents 6.3.6 6.3.7 6.3.8 6.4 6.4.1 6.4.2 6.4.3 6.5 Optimizing the Ligand/Metal Ratio 81 Temperature Effect 82 Optimizing the Catalyst Loading 82 From Synthesis to Process 83 Demonstration on Scale 83 Environmental Performance 85 Impurity Tracking 86 Concluding Remarks 88 References 88 Process Development and Scale-up of PF-03941275, a Novel Antibiotic 91 Kevin E Henegar and Timothy A Johnson Introduction 91 Medicinal Chemistry Synthesis of PF-03941275 91 Synthesis of 5-Bromo-2,4-difluorobenzaldehyde (1) 93 Synthesis of Amine 93 Miyaura Borylation Reaction 95 Suzuki–Miyaura Coupling 97 Barbituric Acid Coupling 101 Chlorination and API Isolation 101 Conclusions 104 References 104 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.1 8.2 8.3 8.4 8.4.1 8.4.2 8.4.3 8.5 9.1 9.2 9.3 9.3.1 Development of a Practical Negishi Coupling Process for the Manufacturing of BILB 1941, an HCV Polymerase Inhibitor 105 Bruce Z Lu, Guisheng Li, Frank Roschangar, Azad Hossain, Rolf Herter, Vittorio Farina, and Chris H Senanayake Introduction and Background 105 Stille Coupling 107 Suzuki Coupling 107 Negishi Coupling 109 Initial Investigation 109 Negishi Coupling Optimization 110 Negishi Coupling Process Scale-up 118 Comparison of Three Coupling Processes 119 References 119 Application of a Rhodium-Catalyzed, Asymmetric 1,4-Addition to the Kilogram-Scale Manufacture of a Pharmaceutical Intermediate 121 Alexandra Parker Introduction 121 Early Development 122 Process Optimization 126 Manufacturability 127 IX X Contents 9.3.2 9.4 9.5 9.6 Rhodium Removal 129 Process Scale-up 131 Recent Developments 133 Conclusions 133 References 134 10 Copper-Catalyzed C–N Coupling on Large Scale: An Industrial Case Study 135 Arianna Ribecai and Paolo Stabile Introduction 135 Process Development of the C–N Bond Formation 137 Choice of Catalytic System 140 Choice of Base: Inorganic Versus Organic 141 Choice of Solvent 142 Optimized Conditions for C–N Bond Formation to 142 Purging Residual Copper from 143 Conclusions 144 References 144 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 11 11.1 11.2 11.2.1 11.2.2 11.2.3 11.2.4 11.2.5 11.2.6 11.2.7 11.2.8 11.3 12 12.1 12.2 12.3 12.4 Development of a Highly Efficient Regio- and Stereoselective Heck Reaction for the Large-Scale Manufacture of an a4b2 NNR Agonist 147 Per Ryberg Introduction 147 Process Optimization 149 Selectivity in the Heck Reaction 149 Identification of Selective Conditions for the Heck Coupling 149 Investigation of the Mechanism of the Heck Step 152 Identification of a Solution to the Pd Mirror Problem 153 Development of a Backup Method for Residual Pd Removal 156 Effect of Water on the Reaction 157 Development of a Semicontinuous Process Based on Catalyst Recycling 159 Application on Large Scale 160 Conclusions 162 References 162 Commercial Development of Axitinib (AG-013736): Optimization of a Convergent Pd-Catalyzed Coupling Assembly and Solid Form Challenges 165 Robert A Singer Introduction 165 First-Generation Synthesis of Axitinib 165 Early Process Research and Development 167 Commercial Route Development 169 354 22 Large-Scale Applications of Transition Metal Removal Techniques 69 de Koning, P.D., Murtagh, L., Lawson, J.P., 70 71 72 73 74 75 76 77 78 79 80 81 82 83 Vonder Embse, R.A., Kunda, S.A., and Kong, W (2011) Org Process Res Dev., 15, 1046 de Koning, P.D., McAndrew, D., Moore, D., Moses, I.B., Boyles, D.C., Kissick, K., Stanchina, C.L., Cuthbertson, T., Kamatani, A., Rahman, L., Rodriguez, R., Urbina, A., Sandoval, A., and Rose, P.R (2011) Org Process Res Dev., 15, 1018 Daïri, K., Yao, Y., Faley, M., Tripathy, S., Rioux, E., Billot, X., Rabouin, D., Gonzalez, G., Lavallee, J.-F., and Attardo, G (2007) Org Process Res Dev., 11, 1051 Li, B., Buzon, R.A., and Zhang, Z (2007) Org Process Res Dev., 11, 951 Denni-Dischert, D., Marterer, W., B€anziger, M., Yusuff, N., Batt, D., Ramsey, T., Geng, P., Michael, W., Wang, R.-M.B., Taplin, F., Jr., Versace, R., Cesarz, D., and Perez, L.B (2006) Org Process Res Dev., 10, 70 K€ onigsberger, K., Chen, G.-P., Wu, R.R., Girgis, M.J., Prasad, K., Repic9, O., and Blacklock, T.J (2003) Org Process Res Dev., 7, 733 Jiang, X., Lee, G.T., Prasad, K., and Repic9, O (2008) Org Process Res Dev., 12, 1137 Flahive, E.J., Ewanicki, B.L., Sach, N.W., O’Neill-Slawecki, S.A., Stankovic, N.S., Yu, S., Guinness, S.M., and Dunn, J (2008) Org Process Res Dev., 12, 637 Ribecai, A., Bacchi, S., Delpogetto, M., Guelfi, S., Manzo, A.M., Perboni, A., Stabile, P., Westerduin, P., Hourdin, M., Rossi, S., Provera, S., and Turco, L (2010) Org Process Res Dev., 14, 895 Jensen, M.S., Hoerrner, R.S., Li, W., Nelson, D.P., Javadi, G.J., Dormer, P.G., Cai, D., and Larsen, R.D (2005) J Org Chem., 70, 6034 Pink, C.J., Wong, H.-t., Ferreira, F.C., and Livingston, A.G (2008) Org Process Res Dev., 12, 589 Barbaras, D., Brozio, J., Johannsen, I., and Allmendinger, T (2009) Org Process Res Dev., 13, 1068 Crudden, C.M., McEleney, K., MacQuarrie, S.L., Blanc, A., Sateesh, M., and Webb, J.D (2007) Pure Appl Chem., 79, 247 Guin o, M and Hii, K.K (2005) Tetrahedron Lett., 46, 6911 Tsukamoto, H., Suzuki, T., Sato, M., and Kondo, Y (2007) Tetrahedron Lett., 48, 8438 84 Wells, A (2006) International Symposium 85 86 87 88 89 90 91 92 on Green Chemical Processes for Pharmaceuticals and Fine Chemicals, McGill University, Canada Oshita, K., Oshima, M., Gao, Y.-h., Lee, K.-H., and Motomizu, S (2002) Anal Sci., 18, 1121 Guibal, E., Von Offenberg Sweeney, N., Zikan, M.C., Vincent, T., and Tobin, J.M (2001) Int J Biol Macromol., 28, 401 El Hankari, S., El Kadib, A., Finiels, A., Bouhaouss, A., Moreau, J.J.E., Crudden, C.M., Brunel, D., and Hesemann, P (2011) Chem Eur J., 17, 8984 Gallou, F., Koenig, K.J., Bochniak, D., Horhota, S.T., Yee, N.K., and Senanayake, C.H (2006) Org Process Res Dev., 10, 937 Nair, D., Wong, H.-T., Han, S., Vankelecom, I.F.J., White, L.S., Livingston, A.G., and Boam, A.T (2009) Org Process Res Dev., 13, 863 McEleney, K., Allen, D.P., Holliday, A.E., and Crudden, C.M (2006) Org Lett., 8, 2663 Knight, D.W., Morgan, I.R., and Proctor, A.J (2010) Tetrahedron Lett., 51, 638 For recent examples of metal removal on large scale, see (a) Mitchell, D., Cole, K.P., Pollock, P.M., Coppert, D.M., Burkholder, T.P., and Clayton, J.R., (2012) Org Process Res Dev., 16, 70 (Pd removal with SiliaBond Thiol after Buchwald–Hartwig amination); (b) Abele, S., Inauen, R., Funel, J.-A., and Weller, T., (2012) Org Process Res Dev., 16, 129 (Pd removal with citric acid and activated carbon after ester arylation); (c) Yang, Q., Ulysse, L.G., McLaws, M.D., Keefe, D.K., Haney, B.P., Zha, C., Guzzo, P.R., and Liu, S., (2012) Org Process Res Dev., 16, 499 (Pd removal via silica gel plug after carbonylation reaction); (d) Schmidt, G., Reber, S., Bolli, M.H., and Abele, S., (2012) Org Process Res Dev., 16, 595 (Cu removal with citric acid after cyanation); (e) Goodyear, A., Linghu, X., Bishop, B., Chen, C., Cleator, E., McLaughlin, M., Sheen, F.J., Stewart, G.W., Xu, Y., and Yin, J., (2012) Org Process Res Dev., 16, 605 (Pd removal with MP-TMT after Buchwald– Hartwig amination); (f) Tudhope, S.R., Bellamy, J.A., Ball, A., Rajasekar, R., Meera, H.S., Gnanadeepam, J.M., Saiganesh, R., Gibson, F., He, L., Behrens, C.H., References Underiner, G., Marfurt, J., and Favre, N., (2012) Org Process Res Dev., 16, 635 (Pd removal with silica gel bed after Tsuji–Trost reaction); (g) Fei, Z., Kong, W., Wang, H., Peng, J., Sun, F., Yin, Y., Bajwa, J., and Jiang, X., (2012) Org Process Res Dev., 16, 1436 (Zn removal with EDTAÁ4Na after aliphatic nitro reduction); (h) Betti, M., Castagnoli, G., Panico, A., Coccone, S.S., and Wiedenau, P., (2012) Org Process Res Dev., 16, 1739 (Pd removal with a combination of TMT and activated carbon after Buchwald–Hartwig amination); (i) Duan, S., Venkatraman, S., Hong, X., Huang, K., Ulysse, L., Mobele, B.I., Smith, A., Lawless, L., Locke, A., and Garipati, R., (2012) Org Process Res Dev., 16, 1787 (Cu removal with aqueous ammonia after Cu-catalyzed amination); (j) Mortensen, M.A., Guo, C., Reynolds, N.T., Wang, L., Helle, M.A., Keefe, D.K., Haney, B.P., Paul, B.J., Bruzinski, P.R., Wolf, M.A., Malinowski, N.L., and Yang, Q., (2012) Org Process Res Dev., 16, 1811 (Pd removal with Darco KB-G after Migita coupling); (k) Sperry, J.B., Farr, R.M., Levent, M., Ghosh, M., Hoagland, S.M., Varsolona, R.J., and Sutherland, K (2012) Org Process Res Dev., 16, 1854 (Pd removal with aqueous cysteine after Sonogashira coupling) 355 j357 Index a acetic anhydride 139, 173, 192, 195, 196, 204 acetonedicarboxylate 41 acid, as metal chelator 274 acrylate, as by-product 255 acyl azide 234 adapalene 322 adiabatic cooling 283 aldehyde 5, 234 alkoxycarbonylation 288 – ethoxycarbonylation 290 O-allylation 190 allyl bromide 26, 190 allyl t-butyl carbonate 191 p-allyl complex, from allyl carbonate 190 allylic alcohol 195 4-allylisoindoline 267 allylmagnesium chloride 269, 273 – as base 272 p-allylpalladium complex 189–191, 193 alumina plug 336 amidase amidation, metal-catalyzed – base particle size effect 229 – copper-catalyzed 225 – of enol triflate 225 – palladium-catalyzed 223, 225 – water effect 229 amide condensation 42, 74, 217, 218 a-amino acid amino acid arylation – copper-catalyzed – palladium-catalyzed amino acid dehydrogenase amino acid synthesis, enzymatic amino acid, unnatural 2-amino-1,3-benzothiazol-4-ol 202 aminocarbonylation 291 1-aminocyclobutanecarboxylic acid 105 2-amino-3-methylpyridine 40 4-aminopyridine 329, 330 2-aminotetralin, chiral 73 aminotetralin, racemic 74 ammonia – in Buchwald–Hartwig amination 304 – to solubilize magnesium salts 274 amphiphiles 300 angiotensin 1-converting enzyme inhibitor angiotensin II receptor antagonist 21 aniline o-anisidine 202 antibiotic – cethromycin 189, 190 – daptomycin 91 – EDP-420 189, 192, 195 – erythromycin A 189 – Ketek 189 – ketolide 189 – linezolid 91 – macrolide 189 – quinoline pyrimidine trione 91 – telithromycin 189 anti-elimination, base-induced 53 antimitotic agent 343 N-arylalkyl group, as hydride donor 79 O-arylation 207, 208 aryl group exchange 172, 258 aryllithium 254 atom economy 239 axitinib 165, 345 azadipeptide 323 azepane 239 azepanone 233 azlactone b barbituric acid 101 Bayesian reliability approach 242 Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry, First Edition Edited by Javier Magano and Joshua R Dunetz Ó 2013 Wiley-VCH Verlag GmbH & Co KGaA Published 2013 by Wiley-VCH Verlag GmbH & Co KGaA 358 j Index 9-BBN 28 benign by design 300, 308 3-benzonitriles 217 benzophenone 330 benzophenone hydrazone 314 benzophenone imine 330, 331 benzylamine 75 benzyloxy carbamate of ammonia – in Buchwald–Hartwig amination 304 benzyltriethylammonium bromide – additive for Negishi coupling 110 BF3Á2AcOH 30 BH3ÁTHF 31 bicyclolide 199 2,20 -bipyridine 110 bis-p-allylation 192–199 – stepwise 194 – tandem inter- and intramolecular 192 bisboron reagent 27 1,8-bis(dimethylamino)naphthalene 168 bis(pinacolato)diboron 96 bisulfite adduct, for aldehyde purification 93 Boc-piperazine 333 borane, in situ generation 35 boraneÁMe3N 347 borate complex 107, 317, 332 boronate ester 97, 100 boron scavenger, ethanolamine 29 boroxine 128 – effect on Rh-catalyzed asymmetric Michael reaction of boronic acid 132 borylation 108, 109 – Miyaura borylation 91, 95 2-borylsilane 27, 28 B-Raf kinase inhibitor 16, 343 bromine migration 87 4-bromoanisole 284, 285, 286, 304 4-bromobenzaldehyde dimethyl acetal 21 3-bromobenzonitrile 217 1-bromo-4-chlorobenzene 324 4-bromo-2-chloro-3-iodopyridine 47 4-bromo-1-chloroisoquinoline 16 1-bromo-3-chloropropane 59 5-bromo-2,4-difluorobenzaldehyde 93 5-bromo-2-hydroxynicotinic acid 25 bromoindole 316 4-bromoisoindoline 267 2-bromo-5-methyl-1,3,4-thiadiazole 97, 100 bromonaphthalene 322 3-bromophenyl acetic acid 217 2-bromopyridine 105, 323, 330 N-bromosuccinimide 93 bromotetralin 74 Bu2BOTf 123 Bucherer–Bergs reaction Buchwald–Hartwig amination 8, 16, 74, 76, 139, 304, 309, 314, 318, 330, 331, 333, 338 butyl acrylate 282 t-butylamine 68 t-butyl carbamate of ammonia, in Buchwald–Hartwig amination 304 i-butyl chloroformate 52 tert-butylimino-tri(pyrrolidino) phosphorane 235, 245 tert-butyl nitrite 234 N-t-butylpiperidine 40 butyl vinyl ether 344 3-butyn-1-ol 336 3-butyn-2-ol 326 c cannabinoid-1 receptor inverse agonist 217 carbamate 237 carbon acid – malonate 30 – in Pd-catalyzed coupling 30, 31 carbon footprint 10 carbon monoxide, in carbonylation reaction 287 carbonylation – under continuous-flow processing 291 – under microwave heating 287 – palladium-catalyzed 287 catalyst activation 74, 83, 129 catalyst deactivation 234 – by peroxide in THF 132 catalyst inhibition – by ligand 173 – palladium, by cyanide 222 catalyst loading – effect on residual metal content 314 catalyst recycling 160, 314 catalyst resting state 153 cathepsin K inhibitor 233, 325 cathepsin S inhibitor 57 – peptide 57 CDI 62 chelation, to heavy metals 143 chiral auxiliary – ephedrine-based 123 – oxazolidinone 234 chiral metal complex 121 chlorination 101 2-chloro-3-aminopyridine 25 4-chlorobenzylamine 59 4-chlorobenzyl bromide 217 Index 4-chlorobenzyl chloride 218 4-chloro-N-t-butylpiperidine 41, 49 a-chlorocarboxylic acid 4-chloro-3-iodopyridine 47 2-chloro-5-iodopyrimidine 322 m-chloroperoxybenzoic acid 50 N-chlorosuccinimide 101 cholecystokinin 1R receptor agonist 333 chromatography 237, 315 – on c-alumina 341 – on silica 183 cinnamic acid citric acid, to solubilize magnesium salts 274 cladinose 195, 196, 198 classical resolution 1, 74 c-Met/ALK inhibitor 340 c-Met kinase inhibitor 332 cocrystal 66 continuous-flow processing 280 copper catalyst/precatalyst – copper bronze 330 – CuBr 140 – CuBr2 140 – CuCl 9, 341 – CuI 6, 27, 58, 63, 107, 137, 140, 142, 181, 182, 185, 327, 328, 331, 337, 339, 347 – CuO 140 – Cu2O 6, 321 – Cu(OAc)2 140, 308 corticotropin-releasing factor antagonist 328, 346 COX-II selective inhibitor 341 CRF-1 antagonist 136 critical micelle concentration 299 crizotinib 340 cross-metathesis 303 crotonate imide 234 Curtius rearrangement 234, 237 cyanation – palladium-catalyzed 219–224, 323, 338 – water effect 221 cyanide, additive effect on solubility 222 cyanide scavenger, ammonium hydroxide 221 cyanohydrin 32 cyclization 25 – copper-catalyzed 1, 6, cyclopropanation 331 d DBU 141, 208, 244 D3/D2/5-HT2 receptor antagonist 335 debenzylation 74 decarboxylation 30 dechlorination 40 degassing 219, 221 – to reduce residual palladium 314 dehydroalanine design of experiments 139, 247 Dess–Martin reagent 57 desymmetrization 235 2D heteronuclear multiple-bond correlation 45 diarylborinic acid 318 diaryl ether 328, 341 diaryl ether formation 202, 207 – copper-catalyzed 315 diastereomer equilibration 101 DIBAL-H 324 dibenzylamine 68 dibromantin 93 1,3-dibromo-5,5-dimethylhydantoin 93 di-t-butyl dicarbonate 147 2,6-dichloroaniline 43 2,6-dichlorophenylacrylamide 47 4,6-dichloropyrimidine 202, 205 diene 234, 235, 239 diethyl malonate 31 diethyl oxalate 66 Differin 322 2,4-difluorobenzaldehyde 93 difluoromethylation 182 2,4-difluorophenylboronic acid 43, 48 3,5-difluorophenylboronic acid 127 1,2-dihalobenzene, in Heck coupling 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine 136 dimethyl carbonate, as solvent in RCM 239 (R,R)-2,6-dimethylmorpholine 93, 94 diphenyl pyrrolidine-2-phosphonate di(2-pyridyl)zinc 112 directed metalation 26 (ỵ)-discodermolide 317 distillation, for aldehyde purification 93 disulfide 254 divinyl carbinol 235 diyne 185 D-proline dynamic kinetic resolution 217, 222, 223 dynamic light scattering 301 e ebalzotan 73 Eco-indicator 99 10 E-factor 86 enamide 5, 223–229 enolate 42, 122 j359 360 j Index – a-arylation, palladium-catalyzed 30–36, 324 enolization – of NMP with organozinc reagent 113 enol sulfonate 223 enol triflate – isomerization 225 enzymatic resolution EP1 antagonist 318 epimerization epoxide 235, 243 Erlenmeyer reaction erythromycin A 9-oxime 190, 192, 195, 196 etching, by hydroxyde 34 ethyl acetate, to quench NMP enolate 115 ethylamine 25 ethyl p-aminocinnamate 105 ethyl benzoate 290 ethyl 2-bromo-2,2-difluoroacetate 330 ethyl carbamate of ammonia, in Buchwald–Hartwig amination 304 ethylene 249 – release during RCM 241 ethylene carbonate – as solvent 48 ethyl 3-ethoxyacrylate 43 ethylhexyl acrylate 255 N-ethyl-4-piperidone 40 ethyne surrogate 343 ethynylbenzaldehyde 59 4-ethynylbenzaldehyde 59 2-ethynylpyridine 182, 183, 185 Et2Zn 220, 221, 224 Evans aldol condensation 234 f fenleuton 326, 331 filter aid – Celite 36 – Cellflock 317 – Harbolite clay 314 – Hyflo super cel 323 – Solka-Floc 332 – Solka-Floc 40 NF 329 Fisher indole synthesis Florisil 166 fool’s gold 348 formaldehyde 325 Friedel–Crafts reaction 87 fungicidal derivative 324 g Glaser–Hay coupling 185 glycine antagonist 320 glycolic acid, to solubilize magnesium salts 274 Goldberg amidation 135 gold trichloride – catalyst in Michael reaction 307 gradient-enhanced nuclear Overhauser effect 45 green chemistry 1, 85 – twelve principles 300 Grignard reagent 21, 26, 40, 49, 112, 123, 254, 267, 322, 323, 324 – i-PrMgCl 26, 49, 112 – vinylmagnesium chloride 147 h HATU 57, 62 HCV NS5B polymerase inhibitor 105 Hayashi–Miyaura coupling 121, 122, 133 – water effect 132 Heck coupling 5, 26, 47, 147, 165, 168, 173, 192, 267, 302, 314, 344, 345 – carbopalladation step 151 – catalytic cycle 150 – double arylation product 155 – intramolecular 320 – large vessel approach under microwave heating 284 – mechanism 152 – with microwave heating 281 – open-vessel approach using MW heating 281 – oxygen effect 158 – regioisomer formation 147 – semi-continuous process 161 – solvent-free using MW heating 281 – stereoisomer formation 147 – stop-flow approach using MW heating 283 – water effect 157 Heck coupling-lactamization 48 Heck-lactamization 42, 47 hemiketal 192, 193 hepatitis C virus protease inhibitor 326 – NS3/4a protease inhibitor 267 heterocycle, N-arylation 137 heterogeneous catalyst 314 heterogeneous mixtures, in flow processes 280 hexamethyldistannane 40 n-HexLi, as alternative to n-BuLi 19 high-pressure equipment 287 high-throughput experimentation high-throughput screening 268 HIV-1 protease inhibitor 323 HOAt 62 Index homocoupling 64, 109 – in Sonogashira coupling 181, 185 homogeneous versus heterogeneous reactions 141 HPLC, chiral 217 5-HT1B receptor antagonist 73 Hugershoff benzothiazole synthesis 202 humidified drying 101 hydantoin hydantoinase hydrate 199 hydrazide 234 b-hydride elimination 121, 151 hydride transfer 78 hydroboration 28 hydrodebromination 77 hydrodehalogenation 64 hydrogenation, asymmetric 217, 314 – of enamide 5, 223 – rhodium-catalyzed – of 2-substituted indoles hydrophobically directed organic synthesis 299 hydrophobic effect 299 4-hydroxybenzoic acid 147 hydroxycarbonylation 288 N-hydroxyurea 331 i iC Kinetics software 260 imidazole 135 imidazolidinone 137 indolapril indole 1, 135 indole-6-carboxylic acid 105 indole synthesis, from o-iodoanilines 105 (S)-2-indoline carboxylic acid inertion 30, 130, 158, 170, 171, 178 – via subsurface sparging with nitrogen 185 – via vacuum and backfilling with nitrogen 185 inert support 314 infrared spectroscopy 261 iodination 48, 168, 171 6-iodoindazole 168 iodophenol 182 4-iodopyridine 346 isocyanate 234 isooctyl 3-mercaptopropionate 256, 260 k a-keto acid ketolide, tethered aromatic group 189 ketone reduction, diastereoselective 217 kinetic resolution kinetic solubility 262 Krapcho decarboxylation 31 Kumada–Corriu coupling 50, 267–273 – allylation 267 – Mg salts removal 273 – nickel-catalyzed 323, 324 – oxygen effect 272 l lactam hydrolysis 34 lactamization 40 lactic acid 329 Lewis acid, for borane generation 35 ligand – acetylacetone – amino acid – AmPhos 269 – AsPPh3 111 – bidentate 140, 255 – BINAP 77, 81, 121, 150, 211, 228, 256 – – oxidation 130 – (Ỉ)-BINAP 75, 79, 80, 97, 332 – (R)-BINAP 125, 126, 334 – BIPHEP 211 – (R,R)-2,200 -bis[(S)-1-(diphenylphosphino) ethyl]-1,100 -biferrocene – bite angle 97 – Buchwald’s biaryls 31, 205 – t-BuDavePhos 211 – (R)-t-Bu JOSIPHOS 228 – t-butyl JohnPhos 150 – cataCXium 45 – cBRIDP 304, 309 – chiral diene 125 – chiral diphosphine 125 – (S,S)-ChiraPHOS 126 – (1R,2R)-trans-cyclohexyldiamine 137, 141 – cyclohexyl JohnPhos 150 – Cy-JohnPhos 211 – DavePhos 210, 228, 269, 320, 333 – 1,2-diamine 135 – 1,3-diketone 6, – trans-(1R,2R)-N,N0 dimethylcyclohexyldiamine 137, 141 – N,N-dimethylglycine 140, 141, 142 (S,S)-DIOP 126 (S)-(ỵ)-(3,5-dioxa-4-phosphacyclohepta[2,1a;3,4-a0 ]dinaphthalen-4-yl)piperidine (S,S)-DIPAMP 126 – dippf 210, 211, 228, 269 – DMEDA 141 j361 362 j Index – DPEPhos 97, 210 – dppb 111, 191, 193, 195, 196, 211, 227, 228 – dppe 97, 111, 211, 228 – dppf 150, 211, 219, 228, 329 – dppp 111, 211, 228, 345 – dtbpf 95, 97, 210, 211, 228 – N-heterocyclic carbene 45 – IMes-HCl 46, 47 – JohnPhos 211 – JosiPhos 256 – L-proline 141 – MePhos 210, 314 – (R,R)-MeULLUPHOS 126 – NIXANTPHOS 211 – 8-OH-Qy 141 – P(t-Bu)3 31, 80, 96, 150, 205, 211, 347 – P(t-Bu)3ÁHBF4 269 – P(t-Bu)2Me 210, 211 – P(t-Bu)2Ph 99, 210, 211 – P(t-Bu)2PhÁHBF4 269 – P(p-C6H4SO3Na)3 111 – PCy3 96 – PCy3ÁHBF4 269 – PCy2(Mes) 269 – PCy2[(o-tol)indole] 269 – P(2-furyl)3 80, 97, 111, 211 – 1,10-phenanthroline 141 – phosphoramidite 4, 125 – P(i-Bu)3 96 – P(o-MeOPh)3 46, 47 – P(p-MeOPh)3 80, 99, 111 – P(neopentyl)(t-Bu)2ÁHBF4 269, 270, 273 – P(OPh)3 150 – PPh3 28, 31, 45, 46, 48, 80, 111, 148, 150, 191, 205, 211, 319, 320, 327, 331, 337, 342, 344 – P(o-tol)3 80, 150, 153, 167, 168, 211, 220, 224, 316, 346 – P(p-tol)3 107, 111, 150 – QPhos 150, 211 – RuPhos 269 – SPhos 46, 96, 150, 211, 269 – 2,20 ,6,60 -tetramethylheptane-2,5-dione – (R)-TMBTP 126 – (S)-Tol-BINAP 126 – TrixiePhos 211 – Xantphos 80, 95, 97, 150, 168, 169, 170, 173, 211, 225, 228, 255, 257 – XPhos 150, 211, 228, 269 5-lipoxygenase enzyme competitive inhibitor 253 5-lipoxygenase inhibitor 326, 339 lithiation 26, 48, 107, 109, 280 ortho-lithiation 20 – halogen directed 26 lithium bromide – additive to suppress 1,4-addition 169 lithium-bromide exchange 17, 19 losartan 328 L-selectride 217 lyophilization 65 m macrocycle 267 macrolactamization 267 macrolide, bridged 193 magnesium-bromide exchange 26 magnesium metal 49 magnesium, Rieke 254 maleic acid 21 2-mercaptopyridine 246 4-mercaptopyridine 321 mesofluidic flow 280 metalation 15, 26, 105, 254 ortho-metalation 15 metal immobilization 314 metal leaching, palladium 314 metal removal 313 – adsorption methods 330 – chromatography on alumina 315 – chromatography on silica 314 – copper 9, 136, 143, 183, 186, 313, 321, 326, 328, 330, 331, 336, 338, 341, 343, 346 – via crystallization 314 – via distillation 315 – extraction methods 316 – via filtration 314, 321 – fixed-bed adsorption 315 – gold 349 – iridium 313, 331 – iron 313, 328, 342 – magnesium 273, 324 – mercury 333, 349 – nickel 313, 323, 324 – oxidants for ligand oxidation 130 – palladium 18, 21, 30, 36, 100, 117, 156, 169, 175, 183, 206, 210, 227, 258, 273, 313, 314, 316, 317, 318, 320, 322, 324, 326, 328, 329, 331, 332, 333, 335, 336, 338, 339, 340, 341, 342, 343, 344, 345, 347, 348, 349 – – via aqueous MeOH wash 187 – platinum 349 – via recrystallization 314 – rhodium 129, 313, 334 – ruthenium 236, 313, 315, 325, 326, 331, 349 – via salt formation 321 Index – zinc 18, 21, 313, 322, 323, 338, 343 metal scavenger – N-acetylcysteine 18, 343, 344, 345 – acid-washed bentonite 348 – activated carbon 21, 36, 227, 316, 323, 326, 330, 336, 343 – activated clay 336 – active carbon 156 – additive effect 345 – alumina 314, 325 – Amberlite IRC resins 336 – ammonium formate 336 – ammonium hydroxide 186, 326, 328, 336, 338 – Aquaguard 227 – dppe 169, 337, 345 – dppp 337 – Carboraffin P 321 – carboxylate, polymer bound 348 – chitosan, cross-linked 349 – citric acid 323, 324, 330 – CUNO ZetaCarbon cartridge 143 – cysteine 129, 184, 186, 324, 325 – cysteine on silica 100 – cysteine on silica-alumina 340 – Darco G-60 36, 212, 258, 348 – Darco KB 329 – Darco KB-B 210, 212, 227, 265 – Deloxan 156 – Deloxan THP 336 – DIAION CR20 335 – diaminobenzyl resin 37 – 1,2-diaminopropane 169, 175, 345 – 1,2-diaminopropane/1,2-bis (diphenylphosphino)ethane 345 – diethylenetriamine 345 – dimethylaminoethanethiol 336 – N,N-dimethylglycine 142, 143, 346 – Divergan HM 130 – Duolite GT73 dried 344 – Duolite GT73 wet/Na2SO4 344 – Ecosorb 227 – Ecosorb C-941 318 – EDTA 18, 322, 345 – EDTAÁ2Na 18, 21, 322, 343 – EDTAÁ3Na 322 – EDTAÁ4Na 323, 339 – ethanolamine 212, 317, 344 – ethylenediamine 18, 336, 343, 345 – ethylenediamine-modified silica 316 – functional groups 315 – functionalized silica 130 – hydrogen peroxide 349 – hydrophilic resin 348 – hydrophobic resin 348 – 2-hydroxypyridine 336 – iron(IV) sulfide 348 – isothiouronium, polymer bound 348 – maleic acid 344 – 2-mercaptonicotinic acid 326 – mercaptopropyl-modified silica 316 – mesoporous molecular sieves 348 – mesoporous silica-based materials 349 – mesoporous silicate 349 – Norit A 331 – Norit A Supra 323, 338 – Panther Creek Clay/silica 60 344 – P(n-Bu)3 117, 212, 213, 328, 330, 341, 348 – phosphine-functionalized polystyrene 348 – phosphine, polymer bound 347 – phosphotungstic acid-modified alumina 316 – phosphotungstic acid-modified carbon 316 – Picachem carbon 322 – PICA P1400 carbon 324, 331 – polystyrene-bound diethanolamine 348 – potassium dihydrogen phosphate 330 – pre-packed cartridge 36 – pyridine 18 – QuadraPure 130, 143, 156 – SiliaBond Thiol 100, 156, 212, 337, 338, 339, 345 – silica 227, 314, 323, 325, 326, 328, 336, 338 – silica gel/polyamine 348 – Silicycle thiourea 212 – Si-TAAcOH 345 – Si-thiol resin 37 – Si-thiourea resin 37 – Si-triamine resin 37 – Smopex 130, 143, 156, 333 – Smopex-110 316, 333 – Smopex-234 156, 334 – sodium bisulfite 316 – solvent 143 – sulfonate, polymer bound 348 – tetrakis(hydroxymethyl)phosphonium chloride 325 – tetramethylethylenediamine 344 – thiol-modified silica 323 – thiol, polymer bound 347 – thiosalicylic acid 345 – thiourea 212, 344 – TMT (trimercaptotriazine) 316, 318, 336 – – MP-TMT 37, 130, 332, 333 – – polystyrene-bound TMT 318 – – TMT-15 318, 320 – – TMTÁNa3 320 j363 364 j Index – – TMTÁNa3 undecahydrate 318 – triamine-derived silica 316 – triethanolamine 344 – triethylamine 342 – triethylenetetramine 345 – tris(2-aminoethyl)amine) 345 – tris(hydroxymethyl)aminomethane 322, 344 – trithiocyanuric acid 212, 318 metastable zone 262 4-methoxybenzylamine 42 4-methoxybiphenyl 285 4-methoxycinnamic acid 284, 285 methyl acrylate 282, 284, 285 methylamine 147 N-methylation 25 methyl benzoate, to quench NMP enolate 117 2-methyl-3-butyn-2-ol 343 methyl-capped polyethyleneglycol 301 N-methyl-D-glucamine 320 methyl iodide, disposal 25 methyl itaconate 349 methyl 3-methoxyacrylate 43 2-methylmorpholine 61 N-methylmorpholine 93 N-methylpiperazine 74, 78 methyl propiolate 43 methyl vinyl ketone 303 mGluR5 negative allosteric modulators 181 Mg turnings 21 micellar catalysis 300 micelle, macrocircular array 302 Michael reaction 121 – on a,b-unsaturated ketones 307 – 1,3-addition byproduct 124 – arylboronic acids to a,b-unsaturated esters 123 – asymmetric 122 – – copper-catalyzed Grignard addition 123 – – rhodium-catalyzed 121, 334 – organocopper-catalyzed 308 – palladium versus rhodium catalysis 122 microfluidic flow 280 microsomal triglyceride transfer protein inhibitor 331 microwave heating 255, 279 – large vessel approach 283, 285 – multiple vessel approach 282 – sealed-vessel batch approach 282 – stop-flow approach 282 microwave heating/flow processing combination 280 MIDA boronate 133 Migita coupling 165, 168, 169, 253, 255, 321, 339 – cobalt-catalyzed 256 – copper-catalyzed 255 – iron-catalyzed 255 – mechanism 260 – nickel-catalyzed 255 Mitsunobu reaction 37, 235 Mo(CO)6, as CO source 287 monoethyl oxalate 66, 69 morpholine 60, 73 MPEG-550 308 muscarinic receptor antagonist 329 n nanofiltration – to remove palladium 348 – to remove ruthenium 349 nanomicelle 299, 307 naphthyridone 40 Negishi coupling 15–23, 50, 109–119, 305, 322, 343 – additive effect 110 – alkoxide effect in reaction rate 116 – catalyst/ligand effect 111 – catalytic in zinc 15, 21 – trans-cis isomerization in transmetalation step 113 – nickel-catalyzed 16, 21 – palladium-catalyzed 16, 19 – solvent effect 110 – stages of catalytic cycle 15 – temperature effect in by-product formation 114 – zinc waste 16 – Zn source effect 113 neopentyl 3,5-difluorophenyl boronate ester 127 neopentyl glycol boronic ester 124 neuraminidase inhibitor 324 nevirapine 25 nickel catalyst/precatalyst – NiCl2(dppe) 21 – NiCl2(dppp) 324, 325 – NiCl2(PPh3)2 324 6-nitroindazole 165 a4b2 NNR agonist 147 non-nucleoside reverse transcription inhibitor 25 nonpeptide angiotensin II receptor antagonist 328 o obatoclax 341 olefin hydrogenation 235, 238 Index – asymmetric 123 olefin migration – side reaction in RCM 237 on-demand gas delivery device 293 on-demand gas reactor 293 organocuprate 121, 307 organolithium – Bu3MgLi 254 organozinc 15, 50, 112, 305, 307, 322, 343 – methods of preparation 15 – from organolithium 15, 17, 112 – from organomagnesium 15, 112 oseltamivir 324 oxalamide 62 oxazole 342 oxidation – Pd(0) to Pd(II) 30 – Tamao-Fleming 28, 30, 31 oxime 192 Oxone 335, 344 2-oxopentanoic acid 69 p packed cartridge, of metal scavenger 315 palladium – on basic carbon 314 – on metal oxides 314 – on polymers 314 – on silicas 314 – supported 314 palladium black 151, 292, 294, 314 palladium catalyst inhibition – in Migita coupling 171 palladium catalyst/precatalyst – [PdBrP(t-Bu)3]2 334, 339 – PdBr2[P(o-tol)3]2 160 – PdCl2 28, 281, 285, 288, 320, 337, 344 – PdCl2(AmPhos)2 305 – PdCl2(dppf) 27, 43, 48, 92, 95, 97, 111, 166, 208, 254, 256, 317, 329, 340, 342 – PdCl2(dppf)ÁCH2Cl2 340 – PdCl2(dtbpf) 210, 309, 338 – PdCl2(MeCN)2 327, 331 – [PdCl(p-allyl)]2 304, 309 – PdCl2(PCy3)2 95 – PdCl2(PPh3)2 18, 20, 27, 58, 63, 92, 95, 97, 111, 181, 182, 185, 319, 322, 335, 337 – Pd(PCy3)2 111 – Pd(dba)2 75, 95, 97, 153, 227, 347 – Pd2(dba)3 28, 168, 170, 191, 193, 195, 196, 218, 219, 226, 227, 255, 257, 268, 320, 332, 333 – Pd2(dba)3ÁCHCl3 46, 47 – Pd(OAc)2 28, 31, 45, 46, 47, 48, 77, 79, 97, 107, 111, 148, 150, 167, 168, 173, 191, 205, 206, 210, 211, 220, 224, 225, 227, 256, 268, 270, 288, 314, 316, 325, 329, 342, 345, 346 – Pd[P(t-Bu)3]2 80, 111, 302, 332 – Pd(PPh3)4 17, 20, 41, 107, 109, 112, 204, 319, 323, 339, 343, 348 – Pd[P(o-tol)3] 152 – Pd[P(o-tol)3]4 220 – PEPPSI 95 – polymer-Pd(PPh3)4 111 palladium mirror 153 palladium on carbon 314 palladium staining 152 PDE-V inhibitor 322 Pearlman’s catalyst 314 PEG-600 301 perindopril phenylacetaldehyde phenylalanine ammonia lyase phenylboronic acid 286 phenyl chloroformate 50 (S)-1-phenylethylamine 75 N-phenyl triflimide 225 phosphodiesterase-4 inhibitor 333 phosphodiesterase PDE4D isoenzyme inhibitor 19, 324 phosphonium ion 258 phosphorus removal 343 phthalimide 235 pinacol acetal 100 pinacolone 324 piperazine 74 piperidine 62 p38 mitogen-activated protein kinase inhibitor 39 polyethyleneglycol 301 polymer-supported catalyst 328 potassium chloride – additive for Heck coupling 48 potassium isothiocyanate 202 potassium trifluoroborate 133 powder X-ray diffraction 153, 263 principal component analysis 244 process mass intensity 10, 85 projection to latent structure 244 i-propyl borate 48 i-propyl 2-cyano acetate 32 (R)-propylene oxide 147 protecting group 59 – acetyl 139, 192, 196 – Boc 147 – oxime 193 j365 366 j Index – phthalimide 239 – tetrahydropyran 165 – TMS 59 protecting group cleavage – acetyl 139, 195, 196 – Boc 62, 152, 338 – Cbz 314 – oxime 195, 198 – phthalimide 235 – TBS 195 – TMS 59 protodeboronation 92, 95, 107, 109, 127, 133 – water effect 97 protodemetalation 109 protodestannylation 107 Proton Sponge 168, 169, 173 pyrazole 135, 139, 142, 255, 346 – N-alkylation 59, 61, 62 – copper-catalyzed arylation 136, 137 pyridine, as solvent 53 pyridine N-oxide 40, 50 2-pyridinesulfonyl chloride 246 pyridone 138 2-pyridylboronic acid 109 2-pyridylzinc bromide 109, 112 pyrrole 135 pyrrolquinolone 336 rhodium – supported on basic carbon 314 rhodium catalyst/precatalyst – Rh(acac)[(S)-BINAP] 121 – Rh(acac)(C2H4)2 122 – {RhCl[(S)-BINAP]}2 129 – [RhCl(COD)]2 125, 129, 334 – [Rh(OH)(BINAP)]2 122 ring-closing metathesis 233–249, 267, 302, 325, 326, 331 – impurity effect 243 – olefin migration mechanism 238 – steric bulk effect 235 – temperature effect 240 robalzotan 73 ruthenium catalyst/precatalyst – 14-electron turnover species 240 – first generation for RCM 239 – Grubbs second-generation 303 – Hoveyda’s first-generation catalyst 326 – Hoveyda’s second generation catalyst 234, 239, 249, 325 – RuCl2[(S)-xylbinap][(S)-daipen] 218 – ruthenium hydride 237 – screen for RCM 239 – second generation for RCM 239 s q quinoline 190, 192 quinoline-N-oxide 25, 37 r racemase Raman spectroscopy 260 rate-limiting step 260 ReactIR 241 redox economy 59 reduction – azide to amine 217 – carbonyl 30 – carboxylic acid to alcohol 31, 35 – imine to amine 59, 75 – keto acid, asymmetric – Pd(II) to Pd(0) 32, 347 reductive amination 59, 75 reductive elimination 258, 260 regioisomer assignment – from Suzuki coupling 45 residence time – in flow processes 280 response surface methodology 242 retinoid X receptor antagonist 344 salt formation – acid screen 66 – citric acid 274 (ỵ)-di-p-toluoyl-D-tartaric acid 336 HBr 85 – HCl 236, 237, 275, 347 – hemi-maleate 21 – H3PO4 66 – lactic acid 329 – L-tartrate 64 – N-methyl-D-glucamine 320 – monooxalate 70 – oxalic acid 66 – 5-oxopyrrolidine-2-carboxylic acid 66 Sandmeyer reaction 48, 166, 168 sebacic acid 301 serine – as source of chirality Sharpless epoxidation 235 Sharpless “on water” approach 299 silane 28 silica gel 323 – filtration 196 – pad 326, 338 – plug 100, 206, 328 Index silver tetrafluoroborate – catalyst in Michael reaction 307 b-sitosterol 308 SNAr reaction 25, 165 sodium azide 217, 223 sodium borohydride 59 – for borane generation 35 sodium chloride – additive for Heck coupling in water 302 sodium hydride, large-scale use 32 sodium perborate tetrahydrate 30 sodium triacetoxyborohydride 59 Solka-Floc 314 solvate – acetone 262 – acetonitrile 101 – CH2Cl2 262 – ethanol 101 – MTBE 52 Sonogashira coupling 26, 59, 63, 181–187, 326, 331, 336, 338, 343 – cobalt-catalyzed 181 – copper-free 181 – gold-catalyzed 181 – indium-catalyzed 181 – iron-catalyzed 181 – nickel-catalyzed 181 – oxygen effect 181, 185 – palladium free 181 – ruthenium-catalyzed 181 – silver-catalyzed 181 sorafenib 165 spiking experiment 243 stannane 40, 107 Stille coupling 40, 107, 108, 119, 217 stirring – overhead versus magnetic 95 stress-activated kinase p38a inhibitor 342 styrene 269, 270 succinic acid 308 sulfide 254 sulfonamide 235, 243 sulfuration 254, 256 sulfur source – disulfur dichloride 254 – 2-ethylhexyl 3-mercaptopropionate 255 – isooctyl 3-mercaptopropionate 255 – molecular sulfur 254 – potassium thioacetate 254 – propyl 3-mercaptopropionate 255 – sodium thiocyanate/NBS 254 – thiourea 254 – triisopropylsilanethiol 253 supercritical fluid extraction – to remove ruthenium 349 supersaturation 263 supported catalyst 280 supported reagent 280 surfactant 299 – Brij 30 301, 306, 308 – Brij 35 308 – Cremophor EL 308 – Nok 308 – (polyoxoethanyl-a-tocopheryl)sebacate 301, 306 – Solutol HS 15 301, 308 – TPGS-750-M 303, 304, 306, 308 – Triton X-100 301, 308 Suzuki–Miyaura coupling 26, 27, 28, 41, 43, 48, 92, 97, 107, 119, 202, 205, 208, 213, 309, 314, 316, 317, 318, 322, 328, 332, 333, 335, 340, 341, 342 – boric acid residues 213 – under continuous flow 286 – in conventionally heated mesoscale flow reactor 286 – large vessel approach using MW heating 284 – with microwave heating 281 – open-vessel approach using MW heating 281 – rate acceleration by IPA 48 – stop-flow approach using MW heating 283 syn-elimination – thermally-induced 53 t Tamiflu 324 taranabant, asymmetric synthesis 217 telescoping 100, 256 tetraalkylammonium carboxylate, as ionic organic base tetraalkylphosphonium carboxylate, as ionic organic base tetra-n-butylammonium bromide, additive for Suzuki coupling 281 tetra-n-butylammonium chloride, additive for Heck coupling 48 tetra-n-butylammonium iodide, additive for Negishi coupling 110 tetrahydroazepine 325 tetrahydroquinoline 320 tetralin 74 tetramethylethylenediamine – additive in Negishi coupling 305, 306 j367 368 j Index – additive in organocopper Michael reaction 307, 308 1,1,3,3-tetramethylguanidine 208 THF stability – in contact with HCl 35 thioamidine 255 thioether 168, 255, 260, 321 thiophenol 254, 257 thiophenoxide 254 thymidylate synthetase inhibitor 321 thymitaq 320 TMSOTf 50 p-toluenesulfonic anhydride 226 topoisomerase II inhibitor 91 tosylate 235, 243 transition temperature 262 transmission electron microscopy 301 triazole 342 triflate 16, 18, 138, 318, 343 4-(trifluoromethyl)phenylboronic acid 202 2,4,5-trifluorophenylboronic acid 342 trimethylborate 36 trisulfide 254 Tsuji–Trost reaction 189, 190, 314 – hard nucleophile 189 – mechanism 190 – soft nucleophile 189 – water effect 198 tube-in-tube approach, to perform reactions with gases 292 type II olefin 303 u Ullmann coupling 6, 135, 328, 330, 341, 346 ultrasound 280 v vanilloid receptor-1 antagonist 201 vaniprevir 267 vascular endothelial growth factor 345 – antagonist 165 vessel fouling, by residual palladium 184 2-vinylpyridine 165, 174, 345 vinylsilane 28 vitamin E 301 w Weinreb amide 218 Williamson ether formation 190, 192 z ZnBr2 17, 114, 343 ZnCl2 20, 21, 112, 114, 322 Zn(CN)2 – as cyanide source in cyanation 219, 224, 338 – particle size effect in cyanation 220 zinc dust 305 – catalytic in cyanation 338 zinc metal, as reducing agent 171 zinc powder 305 – in organocopper-catalyzed Michael reaction 308 Zn(OTf)2 114 ... increasingly popular, chemists in industry applied them to the synthesis of many drug candidates The value of transition metal- catalyzed cross -couplings was evident in the pharmaceutical industry since... Dunetz Transition Metal- Catalyzed Couplings in Process Chemistry Case Studies from the Pharmaceutical Industry The Editors Javier Magano Pfizer Inc., Chemical Research and Development Eastern Point... Microwave Heating in Preparative Chemistry 279 Continuous-Flow Processing in Preparative Chemistry 280 Coupling Reactions Performed Using Microwave Heating or Continuous-Flow Processing 281 Suzuki–Miyaura