Acetic Anhydride 139, 173, 192, 195, 196, 204

j357

Index

a 2-amino-3-methylpyridine 40 acetic anhydride 139, 173, 192, 195, 196, 204 4-aminopyridine 329, 330 acetonedicarboxylate 41 2-aminotetralin, chiral 73 acid, as metal chelator 274 aminotetralin, racemic 74 acrylate, as by-product 255 ammonia acyl azide 234 – in Buchwald–Hartwig amination 304 adapalene 322 – to solubilize magnesium salts 274 adiabatic cooling 283 amphiphiles 300 aldehyde 5, 234 angiotensin 1-converting enzyme inhibitor 1 alkoxycarbonylation 288 angiotensin II receptor antagonist 21 – ethoxycarbonylation 290 aniline 2 O-allylation 190 o-anisidine 202 allyl bromide 26, 190 antibiotic allyl t-butyl carbonate 191 – cethromycin 189, 190 p-allyl complex, from allyl carbonate 190 – daptomycin 91 allylic alcohol 195 – EDP-420 189, 192, 195 4-allylisoindoline 267 – erythromycin A 189 allylmagnesium chloride 269, 273 – Ketek 189 – as base 272 – ketolide 189 p-allylpalladium complex 189–191, 193 – linezolid 91 alumina plug 336 – macrolide 189 amidase 5 – quinoline pyrimidine trione 91 amidation, metal-catalyzed – telithromycin 189 – base particle size effect 229 anti-elimination, base-induced 53 – copper-catalyzed 225 antimitotic agent 343 – of enol triﬂate 225 N-arylalkyl group, as hydride donor 79 – palladium-catalyzed 223, 225 O-arylation 207, 208 – water effect 229 aryl group exchange 172, 258 amide condensation 42, 74, 217, 218 aryllithium 254 a-amino acid 4 atom economy 239 amino acid arylation axitinib 165, 345 – copper-catalyzed 8 azadipeptide 323 – palladium-catalyzed 8 azepane 239 amino acid dehydrogenase 5 azepanone 233 amino acid synthesis, enzymatic 8 azlactone 5 amino acid, unnatural 5 2-amino-1,3-benzothiazol-4-ol 202 b aminocarbonylation 291 barbituric acid 101 1-aminocyclobutanecarboxylic acid 105 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. 358j Index

9-BBN 28 Bu2BOTf 123 benign by design 300, 308 Bucherer–Bergs reaction 5 3-benzonitriles 217 Buchwald–Hartwig amination 8, 16, 74, 76, benzophenone 330 139, 304, 309, 314, 318, 330, 331, 333, 338 benzophenone hydrazone 314 butyl acrylate 282 benzophenone imine 330, 331 t-butylamine 68 benzylamine 75 t-butyl carbamate of ammonia, in benzyloxy carbamate of ammonia Buchwald–Hartwig amination 304 – in Buchwald–Hartwig amination 304 i-butyl chloroformate 52 benzyltriethylammonium bromide tert-butylimino-tri(pyrrolidino) – additive for Negishi coupling 110 phosphorane 235, 245 BF3 2AcOH 30 tert-butyl nitrite 234 BH3THF 31 N-t-butylpiperidine 40 bicyclolide 199 butyl vinyl ether 344 2,20-bipyridine 110 3-butyn-1-ol 336 bis-p-allylation 192–199 3-butyn-2-ol 326 – stepwise 194 – tandem inter- and intramolecular 192 c bisboron reagent 27 cannabinoid-1 receptor inverse agonist 217 1,8-bis(dimethylamino)naphthalene 168 carbamate 237 bis(pinacolato)diboron 96 carbon acid bisulfite adduct, for aldehyde purification 93 – malonate 30 Boc-piperazine 333 – in Pd-catalyzed coupling 30, 31 borane, in situ generation 35 carbon footprint 10 boraneMe3N 347 carbon monoxide, in carbonylation borate complex 107, 317, 332 reaction 287 boronate ester 97, 100 carbonylation boron scavenger, ethanolamine 29 – under continuous-flow processing 291 boroxine 128 – under microwave heating 287 – effect on Rh-catalyzed asymmetric Michael – palladium-catalyzed 287 reaction of boronic acid 132 catalyst activation 74, 83, 129 borylation 108, 109 catalyst deactivation 234 – Miyaura borylation 91, 95 – by peroxide in THF 132 2-borylsilane 27, 28 catalyst inhibition B-Raf kinase inhibitor 16, 343 – by ligand 173 bromine migration 87 – palladium, by cyanide 222 4-bromoanisole 284, 285, 286, 304 catalyst loading 4-bromobenzaldehyde dimethyl acetal 21 – effect on residual metal content 314 3-bromobenzonitrile 217 catalyst recycling 160, 314 1-bromo-4-chlorobenzene 324 catalyst resting state 153 4-bromo-2-chloro-3-iodopyridine 47 cathepsin K inhibitor 233, 325 4-bromo-1-chloroisoquinoline 16 cathepsin S inhibitor 57 1-bromo-3-chloropropane 59 – peptide 57 5-bromo-2,4-difluorobenzaldehyde 93 CDI 62 5-bromo-2-hydroxynicotinic acid 25 chelation, to heavy metals 143 bromoindole 316 chiral auxiliary 4-bromoisoindoline 267 – ephedrine-based 123 2-bromo-5-methyl-1,3,4-thiadiazole 97, 100 – oxazolidinone 234 bromonaphthalene 322 chiral metal complex 121 3-bromophenyl acetic acid 217 chlorination 101 2-bromopyridine 105, 323, 330 2-chloro-3-aminopyridine 25 N-bromosuccinimide 93 4-chlorobenzylamine 59 bromotetralin 74 4-chlorobenzyl bromide 217 Index j359 4-chlorobenzyl chloride 218 decarboxylation 30 4-chloro-N-t-butylpiperidine 41, 49 dechlorination 40 a-chlorocarboxylic acid 2 degassing 219, 221 4-chloro-3-iodopyridine 47 – to reduce residual palladium 314 2-chloro-5-iodopyrimidine 322 dehydroalanine 5 m-chloroperoxybenzoic acid 50 design of experiments 139, 247 N-chlorosuccinimide 101 Dess–Martin reagent 57 cholecystokinin 1R receptor agonist 333 desymmetrization 235 chromatography 237, 315 2D heteronuclear multiple-bond – on c-alumina 341 correlation 45 – on silica 183 diarylborinic acid 318 cinnamic acid 5 diaryl ether 328, 341 citric acid, to solubilize magnesium salts 274 diaryl ether formation 202, 207 cladinose 195, 196, 198 – copper-catalyzed 315 classical resolution 1, 74 diastereomer equilibration 101 c-Met/ALK inhibitor 340 DIBAL-H 324 c-Met kinase inhibitor 332 dibenzylamine 68 cocrystal 66 dibromantin 93 continuous-flow processing 280 1,3-dibromo-5,5-dimethylhydantoin 93 copper catalyst/precatalyst di-t-butyl dicarbonate 147 – copper bronze 330 2,6-dichloroaniline 43 – CuBr 140 2,6-dichlorophenylacrylamide 47 – CuBr2 140 4,6-dichloropyrimidine 202, 205 – CuCl 9, 341 diene 234, 235, 239 – CuI 6, 27, 58, 63, 107, 137, 140, 142, 181, 182, diethyl malonate 31 185, 327, 328, 331, 337, 339, 347 diethyl oxalate 66 – CuO 140 Differin 322 – Cu2O 6, 321 2,4-difluorobenzaldehyde 93 – Cu(OAc)2 140, 308 difluoromethylation 182 corticotropin-releasing factor antagonist 2,4-difluorophenylboronic acid 43, 48 328, 346 3,5-difluorophenylboronic acid 127 COX-II selective inhibitor 341 1,2-dihalobenzene, in Heck coupling 5 CRF-1 antagonist 136 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine 136 critical micelle concentration 299 dimethyl carbonate, as solvent in RCM 239 crizotinib 340 (R,R)-2,6-dimethylmorpholine 93, 94 cross-metathesis 303 diphenyl pyrrolidine-2-phosphonate 6 crotonate imide 234 di(2-pyridyl)zinc 112 Curtius rearrangement 234, 237 directed metalation 26 cyanation (þ)-discodermolide 317 – palladium-catalyzed 219–224, 323, 338 distillation, for aldehyde purification 93 – water effect 221 disulfide 254 cyanide, additive effect on solubility 222 divinyl carbinol 235 cyanide scavenger, ammonium diyne 185 hydroxide 221 D-proline 2 cyanohydrin 32 dynamic kinetic resolution 217, 222, 223 cyclization 25 dynamic light scattering 301 – copper-catalyzed 1, 6, 8 cyclopropanation 331 e ebalzotan 73 d Eco-indicator 99 10 DBU 141, 208, 244 E-factor 86 – D3/D2/5-HT2 receptor antagonist 335 enamide 5, 223 229 debenzylation 74 enolate 42, 122 360j Index – a-arylation, palladium-catalyzed 30–36, 324 glycolic acid, to solubilize magnesium enolization salts 274 – of NMP with organozinc reagent 113 Goldberg amidation 135 enol sulfonate 223 gold trichloride enol triflate – catalyst in Michael reaction 307 – isomerization 225 gradient-enhanced nuclear Overhauser enzymatic resolution 1 effect 45 EP1 antagonist 318 green chemistry 1, 85 epimerization 5 – twelve principles 300 epoxide 235, 243 Grignard reagent 21, 26, 40, 49, 112, 123, 254, Erlenmeyer reaction 5 267, 322, 323, 324 erythromycin A 9-oxime 190, 192, 195, 196 – i-PrMgCl 26, 49, 112 etching, by hydroxyde 34 – vinylmagnesium chloride 147 ethyl acetate, to quench NMP enolate 115 ethylamine 25 h ethyl p-aminocinnamate 105 HATU 57, 62 ethyl benzoate 290 HCV NS5B polymerase inhibitor 105 ethyl 2-bromo-2,2-difluoroacetate 330 Hayashi–Miyaura coupling 121, 122, 133 ethyl carbamate of ammonia, in – water effect 132 Buchwald–Hartwig amination 304 Heck coupling 5, 26, 47, 147, 165, 168, 173, ethylene 249 192, 267, 302, 314, 344, 345 – release during RCM 241 – carbopalladation step 151 ethylene carbonate – catalytic cycle 150 – as solvent 48 – double arylation product 155 ethyl 3-ethoxyacrylate 43 – intramolecular 320 ethylhexyl acrylate 255 – large vessel approach under microwave N-ethyl-4-piperidone 40 heating 284 ethyne surrogate 343 – mechanism 152 ethynylbenzaldehyde 59 – with microwave heating 281 4-ethynylbenzaldehyde 59 – open-vessel approach using MW heating 281 2-ethynylpyridine 182, 183, 185 – oxygen effect 158 Et2Zn 220, 221, 224 – regioisomer formation 147 Evans aldol condensation 234 – semi-continuous process 161 – solvent-free using MW heating 281 f – stereoisomer formation 147 fenleuton 326, 331 – stop-flow approach using MW heating 283 filter aid – water effect 157 – Celite 36 Heck coupling-lactamization 48 – Cellflock 317 Heck-lactamization 42, 47 – Harbolite clay 314 hemiketal 192, 193 – Hyflo super cel 323 hepatitis C virus protease inhibitor 326 – Solka-Floc 332 – NS3/4a protease inhibitor 267 – Solka-Floc 40 NF 329 heterocycle, N-arylation 137 Fisher indole synthesis 1 heterogeneous catalyst 314 Florisil 166 heterogeneous mixtures, in flow fools gold 348 processes 280 formaldehyde 325 hexamethyldistannane 40 Friedel–Crafts reaction 87 n-HexLi, as alternative to n-BuLi 19 fungicidal derivative 324 high-pressure equipment 287 high-throughput experimentation 7 g high-throughput screening 268 Glaser–Hay coupling 185 HIV-1 protease inhibitor 323 glycine antagonist 320 HOAt 62 Index j361 homocoupling 64, 109 ketone reduction, diastereoselective 217 – in Sonogashira coupling 181, 185 kinetic resolution 2 homogeneous versus heterogeneous kinetic solubility 262 reactions 141 Krapcho decarboxylation 31 HPLC, chiral 217 Kumada–Corriu coupling 50, 267–273 5-HT1B receptor antagonist 73 – allylation 267 Hugershoff benzothiazole synthesis 202 – Mg salts removal 273 humidified drying 101 – nickel-catalyzed 323, 324 hydantoin 5 – oxygen effect 272 hydantoinase 5 hydrate 199 l hydrazide 234 lactam hydrolysis 34 b-hydride elimination 121, 151 lactamization 40 hydride transfer 78 lactic acid 329 hydroboration 28 Lewis acid, for borane generation 35 hydrodebromination 77 ligand hydrodehalogenation 64 – acetylacetone 6 hydrogenation, asymmetric 217, 314 – amino acid 8 – of enamide 5, 223 – AmPhos 269 – rhodium-catalyzed 2 – AsPPh3 111 – of 2-substituted indoles 2 – bidentate 140, 255 hydrophobically directed organic – BINAP 77, 81, 121, 150, 211, 228, 256 synthesis 299 ––oxidation 130 hydrophobic effect 299 – ()-BINAP 75, 79, 80, 97, 332 4-hydroxybenzoic acid 147 – (R)-BINAP 125, 126, 334 hydroxycarbonylation 288 – BIPHEP 211 N-hydroxyurea 331 – (R,R)-2,200-bis[(S)-1-(diphenylphosphino) ethyl]-1,100-biferrocene 2 i – bite angle 97 iC Kinetics software 260 – Buchwalds biaryls 31, 205 imidazole 135 – t-BuDavePhos 211 imidazolidinone 137 – (R)-t-Bu JOSIPHOS 228 indolapril 1 – t-butyl JohnPhos 150 indole 1, 135 – cataCXium 45 indole-6-carboxylic acid 105 – cBRIDP 304, 309 indole synthesis, from o-iodoanilines 105 – chiral diene 125 (S)-2-indoline carboxylic acid 1 – chiral diphosphine 125 inertion 30, 130, 158, 170, 171, 178 – (S,S)-ChiraPHOS 126 – via subsurface sparging with nitrogen 185 – (1R,2R)-trans-cyclohexyldiamine 137, 141 – via vacuum and backfilling with – cyclohexyl JohnPhos 150 nitrogen 185 – Cy-JohnPhos 211 inert support 314 – DavePhos 210, 228, 269, 320, 333 infrared spectroscopy 261 – 1,2-diamine 135 iodination 48, 168, 171 – 1,3-diketone 6, 8 6-iodoindazole 168 – trans-(1R,2R)-N,N0- iodophenol 182 dimethylcyclohexyldiamine 137, 141 4-iodopyridine 346 – N,N-dimethylglycine 140, 141, 142 isocyanate 234 – (S,S)-DIOP 126 isooctyl 3-mercaptopropionate 256, 260 – (S)-(þ)-(3,5-dioxa-4-phosphacyclohepta[2,1- a;3,4-a0]dinaphthalen-4-yl)piperidine 3 k – (S,S)-DIPAMP 126 a-keto acid 5 – dippf 210, 211, 228, 269 ketolide, tethered aromatic group 189 – DMEDA 141 362j Index – DPEPhos 97, 210 ortho-lithiation 20 – dppb 111, 191, 193, 195, 196, 211, 227, 228 – halogen directed 26 – dppe 97, 111, 211, 228 lithium bromide – dppf 150, 211, 219, 228, 329 – additive to suppress 1,4-addition 169 – dppp 111, 211, 228, 345 lithium-bromide exchange 17, 19 – dtbpf 95, 97, 210, 211, 228 losartan 328 – N-heterocyclic carbene 45 L-selectride 217 – IMes-HCl 46, 47 lyophilization 65 – JohnPhos 211 – JosiPhos 256 m – L-proline 141 macrocycle 267 – MePhos 210, 314 macrolactamization 267 – (R,R)-MeULLUPHOS 126 macrolide, bridged 193 – NIXANTPHOS 211 magnesium-bromide exchange 26 – 8-OH-Qy 141 magnesium metal 49 – P(t-Bu)3 31, 80, 96, 150, 205, 211, 347 magnesium, Rieke 254 – P(t-Bu)3HBF4 269 maleic acid 21 – P(t-Bu)2Me 210, 211 2-mercaptopyridine 246 – P(t-Bu)2Ph 99, 210, 211 4-mercaptopyridine 321 – P(t-Bu)2PhHBF4 269 mesofluidic flow 280 – P(p-C6H4SO3Na)3 111 metalation 15, 26, 105, 254 – PCy3 96 ortho-metalation 15 – PCy3 HBF4 269 metal immobilization 314 – PCy2(Mes) 269 metal leaching, palladium 314 – PCy2[(o-tol)indole] 269 metal removal 313 – – P(2-furyl)3 80, 97, 111, 211 adsorption methods 330 – 1,10-phenanthroline 141 – chromatography on alumina 315 – phosphoramidite 4, 125 – chromatography on silica 314 – P(i-Bu)3 96 – copper 9, 136, 143, 183, 186, 313, 321, 326, – P(o-MeOPh)3 46, 47 328, 330, 331, 336, 338, 341, 343, 346 – P(p-MeOPh)3 80, 99, 111 – via crystallization 314 – P(neopentyl)(t-Bu)2HBF4 269, 270, 273 – via distillation 315 – – P(OPh)3 150 extraction methods 316 – – fi PPh3 28, 31, 45, 46, 48, 80, 111, 148, 150, via ltration 314, 321 191, 205, 211, 319, 320, 327, 331, 337, – fixed-bed adsorption 315 342, 344 – gold 349 – – P(o-tol)3 80, 150, 153, 167, 168, 211, 220, 224, iridium 313, 331 316, 346 – iron 313, 328, 342 – P(p-tol)3 107, 111, 150 – magnesium 273, 324 – QPhos 150, 211 – mercury 333, 349 – RuPhos 269 – nickel 313, 323, 324 – SPhos 46, 96, 150, 211, 269 – oxidants for ligand oxidation 130 – 2,20,6,60-tetramethylheptane-2,5-dione 6 – palladium 18, 21, 30, 36, 100, 117, 156, 169, – (R)-TMBTP 126 175, 183, 206, 210, 227, 258, 273, 313, 314, – (S)-Tol-BINAP 126 316, 317, 318, 320, 322, 324, 326, 328, 329, – TrixiePhos 211 331, 332, 333, 335, 336, 338, 339, 340, 341, – Xantphos 80, 95, 97, 150, 168, 169, 170, 173, 342, 343, 344, 345, 347, 348, 349 211, 225, 228, 255, 257 –– via aqueous MeOH wash 187 – XPhos 150, 211, 228, 269 – platinum 349 5-lipoxygenase enzyme competitive – via recrystallization 314 inhibitor 253 – rhodium 129, 313, 334 5-lipoxygenase inhibitor 326, 339 – ruthenium 236, 313, 315, 325, 326, 331, 349 lithiation 26, 48, 107, 109, 280 – via salt formation 321 Index j363 – zinc 18, 21, 313, 322, 323, 338, 343 – hydrophobic resin 348 metal scavenger – 2-hydroxypyridine 336 – N-acetylcysteine 18, 343, 344, 345 – iron(IV) sulfide 348 – acid-washed bentonite 348 – isothiouronium, polymer bound 348 – activated carbon 21, 36, 227, 316, 323, 326, – maleic acid 344 330, 336, 343 – 2-mercaptonicotinic acid 326 – activated clay 336 – mercaptopropyl-modified silica 316 – active carbon 156 – mesoporous molecular sieves 348 – additive effect 345 – mesoporous silica-based materials 349 – alumina 314, 325 – mesoporous silicate 349 – Amberlite IRC resins 336 – Norit A 331 – ammonium formate 336 – Norit A Supra 323, 338 – ammoniumhydroxide 186,326,328,336,338 – Panther Creek Clay/silica 60 344 – Aquaguard 227 – P(n-Bu)3 117, 212, 213, 328, 330, 341, 348 – dppe 169, 337, 345 – phosphine-functionalized polystyrene 348 – dppp 337 – phosphine, polymer bound 347 – Carboraffin P 321 – phosphotungstic acid-modified – carboxylate, polymer bound 348 alumina 316 – chitosan, cross-linked 349 – phosphotungstic acid-modified carbon 316 – citric acid 323, 324, 330 – Picachem carbon 322 – CUNO ZetaCarbon cartridge 143 – PICA P1400 carbon 324, 331 – cysteine 129, 184, 186, 324, 325 – polystyrene-bound diethanolamine 348 – cysteine on silica 100 – potassium dihydrogen phosphate 330 – cysteine on silica-alumina 340 – pre-packed cartridge 36 – Darco G-60 36, 212, 258, 348 – pyridine 18 – Darco KB 329 – QuadraPure 130, 143, 156 – Darco KB-B 210, 212, 227, 265 – SiliaBond Thiol 100, 156, 212, 337, 338, – Deloxan 156 339, 345 – Deloxan THP 336 – silica 227, 314, 323, 325, 326, 328, 336, 338 – DIAION CR20 335 – silica gel/polyamine 348 – diaminobenzyl resin 37 – Silicycle thiourea 212 – 1,2-diaminopropane 169, 175, 345 – Si-TAAcOH 345 – 1,2-diaminopropane/1,2-bis – Si-thiol resin 37 (diphenylphosphino)ethane 345 – Si-thiourea resin 37 – diethylenetriamine 345 – Si-triamine resin 37 – dimethylaminoethanethiol 336 – Smopex 130, 143, 156, 333 – N,N-dimethylglycine 142, 143, 346 – Smopex-110 316, 333 – Divergan HM 130 – Smopex-234 156, 334 – Duolite GT73 dried 344 – sodium bisulfite 316 – Duolite GT73 wet/Na2SO4 344 – solvent 143 – Ecosorb 227 – sulfonate, polymer bound 348 – Ecosorb C-941 318 – tetrakis(hydroxymethyl)phosphonium – EDTA 18, 322, 345 chloride 325 – EDTA2Na 18, 21, 322, 343 – tetramethylethylenediamine 344 – EDTA3Na 322 – thiol-modified silica 323 – EDTA4Na 323, 339 – thiol, polymer bound 347 – ethanolamine 212, 317, 344 – thiosalicylic acid 345 – ethylenediamine 18, 336, 343, 345 – thiourea 212, 344 – ethylenediamine-modified silica 316 – TMT (trimercaptotriazine) 316, 318, 336 – functional groups 315 ––MP-TMT 37, 130, 332, 333 – functionalized silica 130 ––polystyrene-bound TMT 318 – hydrogen peroxide 349 ––TMT-15 318, 320 – –– hydrophilic resin 348 TMT Na3 320 364j Index –– – TMT Na3 undecahydrate 318 cobalt-catalyzed 256 – triamine-derived silica 316 – copper-catalyzed 255 – triethanolamine 344 – iron-catalyzed 255 – triethylamine 342 – mechanism 260 – triethylenetetramine 345 – nickel-catalyzed 255 – tris(2-aminoethyl)amine) 345 Mitsunobu reaction 37, 235 – tris(hydroxymethyl)aminomethane 322, 344 Mo(CO)6, as CO source 287 – trithiocyanuric acid 212, 318 monoethyl oxalate 66, 69 metastable zone 262 morpholine 60, 73 4-methoxybenzylamine 42 MPEG-550 308 4-methoxybiphenyl 285 muscarinic receptor antagonist 329 4-methoxycinnamic acid 284, 285 methyl acrylate 282, 284, 285 n methylamine 147 nanofiltration N-methylation 25 – to remove palladium 348 methyl benzoate, to quench NMP enolate 117 – to remove ruthenium 349 2-methyl-3-butyn-2-ol 343 nanomicelle 299, 307 methyl-capped polyethyleneglycol 301 naphthyridone 40 N-methyl-D-glucamine 320 Negishi coupling 15–23, 50, 109–119, 305, methyl iodide, disposal 25 322, 343 methyl itaconate 349 – additive effect 110 methyl 3-methoxyacrylate 43 – alkoxide effect in reaction rate 116 2-methylmorpholine 61 – catalyst/ligand effect 111 N-methylmorpholine 93 – catalytic in zinc 15, 21 N-methylpiperazine 74, 78 – trans-cis isomerization in transmetalation methyl propiolate 43 step 113 methyl vinyl ketone 303 – nickel-catalyzed 16, 21 mGluR5 negative allosteric modulators 181 – palladium-catalyzed 16, 19 Mg turnings 21 – solvent effect 110 micellar catalysis 300 – stages of catalytic cycle 15 micelle, macrocircular array 302 – temperature effect in by-product Michael reaction 121 formation 114 – on a,b-unsaturated ketones 307 – zinc waste 16 – 1,3-addition byproduct 124 – Zn source effect 113 – arylboronic acids to a,b-unsaturated esters 123 neopentyl 3,5-difluorophenyl boronate – asymmetric 122 ester 127 –– copper-catalyzed Grignard addition 123 neopentyl glycol boronic ester 124 –– rhodium-catalyzed 121, 334 neuraminidase inhibitor 324 – organocopper-catalyzed 308 nevirapine 25 – palladium versus rhodium catalysis 122 nickel catalyst/precatalyst fl fl – micro uidic ow 280 NiCl2(dppe) 21 microsomal triglyceride transfer protein – NiCl2(dppp) 324, 325 inhibitor 331 – NiCl2(PPh3)2 324 microwave heating 255, 279 6-nitroindazole 165 – large vessel approach 283, 285 a4b2 NNR agonist 147 – multiple vessel approach 282 non-nucleoside reverse transcription – sealed-vessel batch approach 282 inhibitor 25 – stop-flow approach 282 nonpeptide angiotensin II receptor microwave heating/flow processing antagonist 328 combination 280 MIDA boronate 133 o Migita coupling 165, 168, 169, 253, 255, obatoclax 341 321, 339 olefin hydrogenation 235, 238 Index j365 – – asymmetric 123 Pd(OAc)2 28, 31, 45, 46, 47, 48, 77, 79, 97, olefin migration 107, 111, 148, 150, 167, 168, 173, 191, 205, – side reaction in RCM 237 206, 210, 211, 220, 224, 225, 227, 256, 268, on-demand gas delivery device 293 270, 288, 314, 316, 325, 329, 342, 345, 346 on-demand gas reactor 293 – Pd[P(t-Bu)3]2 80, 111, 302, 332 organocuprate 121, 307 – Pd(PPh3)4 17, 20, 41, 107, 109, 112, 204, 319, organolithium 323, 339, 343, 348 – – Bu3MgLi 254 Pd[P(o-tol)3] 152 organozinc 15, 50, 112, 305, 307, 322, 343 – Pd[P(o-tol)3]4 220 – methods of preparation 15 – PEPPSI 95 – – from organolithium 15, 17, 112 polymer-Pd(PPh3)4 111 – from organomagnesium 15, 112 palladium mirror 153 oseltamivir 324 palladium on carbon 314 oxalamide 62 palladium staining 152 oxazole 342 PDE-V inhibitor 322 oxidation Pearlmans catalyst 314 – Pd(0) to Pd(II) 30 PEG-600 301 – Tamao-Fleming 28, 30, 31 perindopril 1 oxime 192 phenylacetaldehyde 5 Oxone 335, 344 phenylalanine ammonia lyase 5 2-oxopentanoic acid 69 phenylboronic acid 286 phenyl chloroformate 50 p (S)-1-phenylethylamine 75 packed cartridge, of metal scavenger 315 N-phenyl triflimide 225 palladium phosphodiesterase-4 inhibitor 333 – on basic carbon 314 phosphodiesterase PDE4D isoenzyme – on metal oxides 314 inhibitor 19, 324 – on polymers 314 phosphonium ion 258 – on silicas 314 phosphorus removal 343 – supported 314 phthalimide 235 palladium black 151, 292, 294, 314 pinacol acetal 100 palladium catalyst inhibition pinacolone 324 – in Migita coupling 171 piperazine 74 palladium catalyst/precatalyst piperidine 62 – [PdBrP(t-Bu)3]2 334, 339 p38 mitogen-activated protein kinase – PdBr2[P(o-tol)3]2 160 inhibitor 39 – PdCl2 28, 281, 285, 288, 320, 337, 344 polyethyleneglycol 301 – PdCl2(AmPhos)2 305 polymer-supported catalyst 328 – PdCl2(dppf) 27, 43, 48, 92, 95, 97, 111, 166, potassium chloride 208, 254, 256, 317, 329, 340, 342 – additive for Heck coupling 48 – PdCl2(dppf) CH2Cl2 340 potassium isothiocyanate 202 – PdCl2(dtbpf) 210, 309, 338 potassium trifluoroborate 133 – PdCl2(MeCN)2 327, 331 powder X-ray diffraction 153, 263 – [PdCl(p-allyl)]2 304, 309 principal component analysis 244 – PdCl2(PCy3)2 95 process mass intensity 10, 85 – PdCl2(PPh3)2 18, 20, 27, 58, 63, 92, 95, 97, projection to latent structure 244 111, 181, 182, 185, 319, 322, 335, 337 i-propyl borate 48 – Pd(PCy3)2 111 i-propyl 2-cyano acetate 32 – Pd(dba)2 75, 95, 97, 153, 227, 347 (R)-propylene oxide 147 – Pd2(dba)3 28, 168, 170, 191, 193, 195, protecting group 59 196, 218, 219, 226, 227, 255, 257, 268, – acetyl 139, 192, 196 320, 332, 333 – Boc 147 – – Pd2(dba)3 CHCl3 46, 47 oxime 193 366j Index – phthalimide 239 rhodium – tetrahydropyran 165 – supported on basic carbon 314 – TMS 59 rhodium catalyst/precatalyst 4 protecting group cleavage – Rh(acac)[(S)-BINAP] 121 – acetyl 139, 195, 196 – Rh(acac)(C2H4)2 122 – Boc 62, 152, 338 – {RhCl[(S)-BINAP]}2 129 – Cbz 314 – [RhCl(COD)]2 125, 129, 334 – – oxime 195, 198 [Rh(OH)(BINAP)]2 122 – phthalimide 235 ring-closing metathesis 233–249, 267, 302, – TBS 195 325, 326, 331 – TMS 59 – impurity effect 243 protodeboronation 92, 95, 107, 109, 127, 133 – olefin migration mechanism 238 – water effect 97 – steric bulk effect 235 protodemetalation 109 – temperature effect 240 protodestannylation 107 robalzotan 73 Proton Sponge 168, 169, 173 ruthenium catalyst/precatalyst pyrazole 135, 139, 142, 255, 346 – 14-electron turnover species 240 – N-alkylation 59, 61, 62 – first generation for RCM 239 – copper-catalyzed arylation 136, 137 – Grubbs second-generation 303 pyridine, as solvent 53 – Hoveydas first-generation catalyst 326 pyridine N-oxide 40, 50 – Hoveydas second generation catalyst 234, 2-pyridinesulfonyl chloride 246 239, 249, 325 – pyridone 138 RuCl2[(S)-xylbinap][(S)-daipen] 218 2-pyridylboronic acid 109 – ruthenium hydride 237 2-pyridylzinc bromide 109, 112 – screen for RCM 239 pyrrole 135 – second generation for RCM 239 pyrrolquinolone 336 s q salt formation quinoline 190, 192 – acid screen 66 quinoline-N-oxide 25, 37 – citric acid 274 – (þ)-di-p-toluoyl-D-tartaric acid 336 r – HBr 85 racemase 5 – HCl 236, 237, 275, 347 Raman spectroscopy 260 – hemi-maleate 21 rate-limiting step 260 – H3PO4 66 ReactIR 241 – lactic acid 329 redox economy 59 – L-tartrate 64 reduction – N-methyl-D-glucamine 320 – azide to amine 217 – monooxalate 70 – carbonyl 30 – oxalic acid 66 – carboxylic acid to alcohol 31, 35 – 5-oxopyrrolidine-2-carboxylic acid 66 – imine to amine 59, 75 Sandmeyer reaction 48, 166, 168 – keto acid, asymmetric 2 sebacic acid 301 – Pd(II) to Pd(0) 32, 347 serine reductive amination 59, 75 – as source of chirality 5 reductive elimination 258, 260 Sharpless epoxidation 235 regioisomer assignment Sharpless on water approach 299 – from Suzuki coupling 45 silane 28 residence time silica gel 323 – in flow processes 280 – filtration 196 response surface methodology 242 – pad 326, 338 retinoid X receptor antagonist 344 – plug 100, 206, 328 Index j367 silver tetrafluoroborate supercritical fluid extraction – catalyst in Michael reaction 307 – to remove ruthenium 349 b-sitosterol 308 supersaturation 263 SNAr reaction 25, 165 supported catalyst 280 sodium azide 217, 223 supported reagent 280 sodium borohydride 59 surfactant 299 – for borane generation 35 – Brij 30 301, 306, 308 sodium chloride – Brij 35 308 – additive for Heck coupling in water 302 – Cremophor EL 308 sodium hydride, large-scale use 32 – Nok 308 sodium perborate tetrahydrate 30 – (polyoxoethanyl-a-tocopheryl)sebacate sodium triacetoxyborohydride 59 301, 306 Solka-Floc 314 – Solutol HS 15 301, 308 solvate – TPGS-750-M 303, 304, 306, 308 – acetone 262 – Triton X-100 301, 308 – acetonitrile 101 Suzuki–Miyaura coupling 26, 27, 28, 41, 43, – CH2Cl2 262 48, 92, 97, 107, 119, 202, 205, 208, 213, 309, – ethanol 101 314, 316, 317, 318, 322, 328, 332, 333, – MTBE 52 335, 340, 341, 342 Sonogashira coupling 26, 59, 63, 181–187, – boric acid residues 213 326, 331, 336, 338, 343 – under continuous flow 286 – cobalt-catalyzed 181 – in conventionally heated mesoscale flow – copper-free 181 reactor 286 – gold-catalyzed 181 – large vessel approach using MW – indium-catalyzed 181 heating 284 – iron-catalyzed 181 – with microwave heating 281 – nickel-catalyzed 181 – open-vessel approach using MW – oxygen effect 181, 185 heating 281 – palladium free 181 – rate acceleration by IPA 48 – ruthenium-catalyzed 181 – stop-flow approach using MW – silver-catalyzed 181 heating 283 sorafenib 165 syn-elimination spiking experiment 243 – thermally-induced 53 stannane 40, 107 Stille coupling 40, 107, 108, 119, 217 t stirring Tamiflu 324 – overhead versus magnetic 95 taranabant, asymmetric synthesis 217 stress-activated kinase p38a inhibitor 342 telescoping 100, 256 styrene 269, 270 tetraalkylammonium carboxylate, as ionic succinic acid 308 organic base 6 sulfide 254 tetraalkylphosphonium carboxylate, as ionic sulfonamide 235, 243 organic base 6 sulfuration 254, 256 tetra-n-butylammonium bromide, additive for sulfur source Suzuki coupling 281 – disulfur dichloride 254 tetra-n-butylammonium chloride, additive for – 2-ethylhexyl 3-mercaptopropionate 255 Heck coupling 48 – isooctyl 3-mercaptopropionate 255 tetra-n-butylammonium iodide, additive for – molecular sulfur 254 Negishi coupling 110 – potassium thioacetate 254 tetrahydroazepine 325 – propyl 3-mercaptopropionate 255 tetrahydroquinoline 320 – sodium thiocyanate/NBS 254 tetralin 74 – thiourea 254 tetramethylethylenediamine – triisopropylsilanethiol 253 – additive in Negishi coupling 305, 306 368j Index – additive in organocopper Michael u reaction 307, 308 Ullmann coupling 6, 135, 328, 330, 1,1,3,3-tetramethylguanidine 208 341, 346 THF stability ultrasound 280 – in contact with HCl 35 thioamidine 255 v thioether 168, 255, 260, 321 vanilloid receptor-1 antagonist 201 thiophenol 254, 257 vaniprevir 267 thiophenoxide 254 vascular endothelial growth factor 345 thymidylate synthetase inhibitor 321 – antagonist 165 thymitaq 320 vessel fouling, by residual palladium 184 TMSOTf 50 2-vinylpyridine 165, 174, 345 p-toluenesulfonic anhydride 226 vinylsilane 28 topoisomerase II inhibitor 91 vitamin E 301 tosylate 235, 243 transition temperature 262 w transmission electron microscopy 301 Weinreb amide 218 triazole 342 Williamson ether formation 190, 192 triflate 16, 18, 138, 318, 343 4-(trifluoromethyl)phenylboronic z acid 202 ZnBr2 17, 114, 343 2,4,5-trifluorophenylboronic ZnCl2 20, 21, 112, 114, 322 acid 342 Zn(CN)2 trimethylborate 36 – as cyanide source in cyanation 219, fi trisul de 254 224, 338 – Tsuji Trost reaction 189, 190, 314 – particle size effect in cyanation 220 – hard nucleophile 189 zinc dust 305 – mechanism 190 – catalytic in cyanation 338 – soft nucleophile 189 zinc metal, as reducing agent 171 – water effect 198 zinc powder 305 tube-in-tube approach, to perform reactions – in organocopper-catalyzed Michael with gases 292 reaction 308 type II olefin 303 Zn(OTf)2 114