355

aAbstraction of

hydride 288hydrogen 45, 51single electrons 48

Acetalshydrolysis 28, 44oxidation 26, 338preparation 64, 342reaction with Grignard reagents 27reduction 342

Acetoacetic esters, see 3-Oxo carboxylic acidderivatives

Acetone, pKa 144Acetonitrile, pKa 144Acetophenone, pKa 144Acetylacetone, pKa 144Acetyl cation, IR spectrum 22Acetylene, alkylation 347Acetylenes, see AlkynesAcetyl halides, IR spectra 22Acetyl nitrate 53Acid–base theory 144C,H-Acidic compounds, see Active hydrogen

compoundsAcridines 267, 268, 346Acridinones 248Acrolein, N-alkylation with 11Acrylamides

cyclization 317as dienophiles 4

Acrylatesarylation 287, 290, 297, 299, 300cyclization 311, 312Heck reaction 290, 297, 299, 300metalation 172, 173, 196preparation 187, 251, 265reaction with amides 244

reaction with nitromethane 347stability 265

Acrylic acid, dianion 172, 196Activating groups

in deprotonation of C(sp3), H-groups 147in ortho-metalation 177

Active hydrogen compoundsacidity 144, 147, 148alkylation 94, 148, 346arylation 293dimerization 89, 195

2-(Acylamino)ethyl electrophiles 85, 86Acylation of

alcohols 261–266, 271–275, 336–339amines 262–271, 342, 343amino acids 263, 264, 269, 270amino alcohols 262, 264, 268, 271, 274anilines 266–268phenols 272–274thiols 275

Acyl carbanions (RC(=O)M) 173–175, 196Acyl cyanides, IR 22Acyl fluorides 21, 22Acylium ions 21, 22Acyl lithium compounds (RC(=O)Li)

173–175, 196Acylpalladium complexes 280, 282, 300Acylsilanes

cyclization 324reaction with allylic carbanions 151

N-Acylsulfonamides, metalation 186, 188Adamantyl cation 249Addition to double bonds, see AlkenesAddition–elimination mechanism 60, 61Air, oxidation by 45–51, 292, 338Alcohols

acidity 144, 146O-acylation 261–266, 271–275, 336–339C-alkylation 160, 169, 184, 185

Index

Side Reactions in Organic Synthesis. Florencio Zaragoza D�rwaldCopyright � 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-31021-5

356

O-alkylation 81, 83, 84, 91, 93, 113, 114,239–243, 349

autoxidation 47base-labile 271carbocations from 93, 232, 249carbonylation 173conversion to halides 73, 91fragmentation 36, 38, 116, 239metalation 169Oppenauer oxidation 170preparation 97–124, 150–182problematic 271–275reaction with epoxides 113, 114rearrangement 36, 38sterically deactivated 271sulfonylation 339

Aldehydesautoxidation 46, 47reduction by SET 201

Aldol addition 154Aliphatic electrophilic substitution 36Aliphatic nucleophilic substitution 59, 143,

229mechanisms 59

Alkaloids 5, 7Alkanes

autoxidation 45–47fragmentation 36pKa 161

Alkenesaddition of

alcohols 311, 314amides 244amines 314, 345arenes 287cuprates 150, 159enolates 29, 193nitrile oxides 318nitromethane 347organolithium compounds 165,

168–170, 179, 190, 202, 322, 323, 326organopalladium compounds 285–287,

297–301oxygen 45, 51radicals 317, 323, 326silanes 312stannanes 296sulfonamides 300thiols 312

captodative 42cyclopropanation 64dihydroxylation 4, 39epoxidation 39

hydroboration 203hydrogenation 295metalation 158, 171–173, 184, 189, 190,

199as neighboring groups 90, 92preparation by

dimerization of halides 77, 78, 89b-elimination 63, 67, 68, 184–190, 230,

240, 241, 245, 285retro-Diels–Alder reaction 37

push-pull 42stability 38, 39, 42, 43strained 38, 39, 185

Alkenylboronic acids 283, 294Alkoxides, see AlcoholsAlkoxybenzyl derivatives, stability 42(Alkoxymethyl)phosphonium salts 166Alkoxyvinyl carbanions 172, 173, 184, 189,

190tert-Alkylamines

N-acylation 263, 264, 267, 268, 270N-alkylation 233, 234, 238preparation 61, 231, 232

Alkylation of fluoride 229–231, 253Alkylation of heteroatoms 229C-Alkylation of

alcohols 160, 169, 184, 185alkenes 285, 286alkynes 108, 152–154, 160, 171, 184, 191,

347amides 155, 156, 158, 163, 319, 347amines 162, 164arenes 64carbamates 164, 167, 168, 180, 186, 190,

194carbanions 143–182carboxylic acids 153carboxylic esters 148, 153–156, 159, 169,

185, 187, 192, 193, 198, 324, 328cyanide 42, 64, 73, 74, 119, 120, 349dithioacetals 83, 105, 160, 167enolates 64, 148, 153–160, 198, 347ethers 165, 166, 182, 200ketones 13, 42, 64, 154, 157–159, 193, 311,

324nitriles 66, 148, 155, 169nitroalkanes 62, 148, 187, 193, 347phenols 241, 242sulfones 64, 98, 185, 310, 347sulfonic esters 70thioethers 156, 160, 187, 198

C-Alkylation vs O-alkylation 13, 241, 311,324, 327

Index

357

N-Alkylation ofamides 11, 243–248, 252amidines 250amines 14, 85, 89, 90, 91, 94–96, 109–112,

231–238, 344–346anilines 232, 234–238benzothiazoles 85, 349carbamates 95, 248, 249carbazoles 238guanidines 250imides 246, 247sulfonamides 251, 252, 300ureas 248, 249

N-Alkylation vs O-alkylation 11–13,243–249

O-Alkylation ofalcohols 81, 83, 84, 91, 93, 113, 114,

239–243, 349amides 11–13, 243carboxylates 251imides 85, 247ketones 13, 311, 324, 327phenols 66, 85, 113, 241–243

S-Alkylation, of thiols 76, 82, 84, 90, 95,115–117, 324, 348

tert-Alkyl esters 240, 265, 271–273Alkyl fluorides

preparation 121–124, 229–231, 253reactivity 66–69, 93, 94

Alkyl groups, effect on cyclization 317, 318Alkyl halides

metalation 170, 171, 183–185, 190–193problematic 66–69, 72–97, 236, 240, 241,

245, 266Alkyl iodides

cross-coupling 285preparation 69, 121–124

Alkyl nitrates 52, 53Alkyl sulfonates 70, 73–75Alkyl tresylates 67Alkyl triflates, base-induced fragmentation

70, 71Alkynes

addition of nucleophiles to 312–314alkylation 108, 152–154, 160, 171, 184,

191, 347arylation 290, 292cyclization 312, 314detonation 53hydrozirconation 104metalation 159, 160, 171, 191oxidative dimerization 292pKa 144, 161

Allenesaddition of alcohols to 314cyclization 312, 314formation 153, 171, 172, 184, 289metalation 172

Allyl cyanide 155Allyl ethers, metalation 166Allylic

alcohols, homologation 173arylation 295carbanions 38, 104, 150–155, 167, 168, 171electrophiles 66, 75, 88, 93, 231–238, 242,

247, 248, 319enolates 153–155rearrangement 93–97, 104, 150–155, 319

p-Allylpalladium complexes 94–96, 111, 114,282

Allyl silanes 107, 109Allyl stannanes 107, 109, 322, 342Aluminum phenolates, as Lewis acids 154Ambergris 7Ambident nucleophiles; see C-Alkylation vs

O-Alkylation, N-Alkylation vs O-alkylation,Amides, Ketones, Nitroalkanes, Phenols, etc

Amidesalcoholysis 41C-alkylation 155, 156, 158, 163, 319, 347N-alkylation 11, 243–248, 252O-alkylation 11–13, 243, 247cyclization 315–317N-dealkylation 66deprotonation 155, 243–246hydrolysis 40, 41, 336metalation 148, 155, 156, 158, 163, 164,

174, 186, 195preferred conformation 315

AmidinesN-alkylation 250metalation 164

Aminalsalkylation 346formation 312oxidation 26

Amination, of arenes 346Amine N-oxides

deprotonation 162formation 14, 15fragmentation 63

AminesN-acylation 262–271, 342, 343C-alkylation 162, 164N-alkylation 14, 85, 89, 90, 91, 94–96,

109–112, 231–238, 344–346

Index

N-arylation 346N-benzylation 42, 61, 77, 78, 233, 235,

237, 238, 345dealkylation 66, 200IR spectrum 21metalation 162, 164, 180, 181, 200, 343nitrogen inversion 14nucleophilicity 24oxidation 14, 25problematic 267–271protection, as enamines 43quaternization 14, 24

a-Amino acidsN-acylation of 263, 264, 269, 270acylation with 262–265a-alkylation 198N-alkylation 111, 232, 233, 245,

345O-alkylation 251–253conversion to a-chloro acids 91conversion to morpholinones 111unprotected, acylation of 269unprotected, acylation with 262–265

b-Amino acids, fragmentation 37Amino acrylates 43, 172Amino alcohols

N-acylation 264, 268, 271O-acylation 262, 274O-alkylation 239preparation 109–112

Aminobenzyl derivatives, stability 42b-Amino carbanions 1862-Aminoindoles, autoxidation 49Amino ketones 5, 42Aminolysis of carboxylic esters 264, 343Aminomethyl phenols 41, 42a-Amino nitriles, N-acylation 269Aminophenols

N-acylation 268, 271, 274O-acylation 271, 274N-alkylation 238O-alkylation 243

Aminopyridines 48, 164Aminopyrroles, autoxidation 49Ammonia

reaction with halides 77, 91reaction with epoxides 109

Ammonium salts, see Quaternary ammoniumsalts

Analysis, retrosynthetic 3Anchimeric assistance (Neighboring group

participation) 64, 90–93Anemonine 43

Anglecompression 317distortion 21, 35–40

Anilinesacylation 266–268alkylation 232, 234–238

AnisolepKa 161metalation 176

Anomeric effect 20Anthranilic acid derivatives 235, 236Anthraquinones 51, 79Antiaromatic carbanions 196, 197Anti conformation 18–20Antioxidants 47, 48Arenes

metalation 175–182, 194oxidation 45–51palladation 281, 287vinylation 283, 286, 287, 294, 295,

297–300Aromatic carbanions 175Aromatic vs benzylic deprotonation 180Aromatic nucleophilic substitution 72, 346Aromatization, oxidative 51Arylamines, see AnilinesArylation of enones 295Aryl group exchange 293Aryl halides

arylation 282–284, 287–289, 293, 296–298deprotonation 177–180halogen–metal exchange 174, 177,

191–193homocoupling 287–291hydrodehalogenation 287vinylation 283, 285

Arynes 177, 178Ascorbic acid 47Aspartic acid, C-alkylation 155, 156Asymmetric, see Diastereoselective,

EnantioselectiveAutoxidation 45–517-Azanorbornenes, ring opening 283Azetidines, ring opening 66, 345Azide

nucleophilic displacement of 66reaction with epoxides 117, 118

Azidesdisplacement of azide 66formation 73–75, 84, 117, 118stability 53

Azidoacetonitrile 53Aziridines, deprotonation 165

Index358

Azirines 165Azo compounds 53

bBaeyer strain 319Baldwin’s rules 4, 309Barbier reaction 280Base-labile carboxylic esters 271Basicity

effect of hyperconjugation on 23vs nucleophilicity 147

Baylis–Hillman reaction 155Benzamides, deprotonation 163Benzene

pKa 161metalation 175

Benzhydryl derivatives 76, 77, 232, 252Benzimidazoles

N-acylation 262formation 237

Benzocyclobutenes 190, 298, 299Benzocyclopropenes 190Benzoic acid

dianion of 179pKa 144vinylation 287

Benzophenones 300Benzoquinones, Diels–Alder reaction 40Benzothiazoles, N-alkylation 85, 349Benzoylation, see AcylationBenzpinacol (1,1,2,2-tetraphenyl-1,2-

ethanediol) 36Benzyl alcohols, dianions 169Benzylamines, metalation 180, 181Benzylation, see AlkylationBenzyl halides

dimerization 77, 78reactivity 67, 75–79, 86sterically demanding 77

Benzyl hydroperoxides 46Benzylic

carbanions 105, 151, 152, 180electrophiles 67, 75–79, 86

Benzylic vs aromatic metalation 180Benzyloxycarbonyl group, hydrogenolysis 37Bernthsen acridine synthesis 267BHT 48Biaryls 283, 284, 289, 292, 293, 296–298Bicyclic amines, basicity 24Boc group

chelate formation 1641,2-migration 194

C–C Bond cleavage 35–39, 42, 116, 239, 299

Bond energies 46r-Bonds, hyperconjugation 17Borane, reduction of epoxides 101Boranes

addition to double bonds 203adducts with amines 181, 162, 343cross-coupling 285reaction with epoxides 104transmetalation 203

a-Boron, electrophiles with 81Boron enolates 182Boronic acid esters 283, 296Boronic acids

cross-coupling with 283, 292, 294, 296,297

homocoupling 291, 292hydrolysis 292, 296oxidation 292

Boron trihalides 69, 122Bridgehead enolates 157, 158Bridgehead positions

alkenes at 39carbanions at 157nucleophilic substitution at 62

Bromides, preparation fromalcohols 73epoxides 121fluorides 69sulfonates 73

4-Bromobutylamines, cyclization 3181-Bromo-4-chlorobutane, metalation 191Bromochloromethane 794-Bromocyclopentene 922-Bromoethanol 11Bromofluoromethane 79Bromoiodomethane 79Bromonitromethane 82, 83Brook rearrangement 105, 151, 1741,3-Butadienes 39, 43tert-Butyl carbamates

chelate formation 1641,2-migration 194

tert-Butyl esters, see tert-Alkyl esterstert-Butyl ethers 239, 241tert-Butyl ketones 86Butyllithium, see Organolithium

compoundstert-Butyllithium 148tert-Butyl radicals 62

cCaptodative effect 42, 43, 195Carbamates

Index 359

C-alkylation 164, 167, 168, 180, 186, 190,194

N-alkylation 95, 248, 249Carbanions

acyl 173–175alkylation 143–182allylic 38, 104, 150–155, 167, 168, 171amide-derived 155, 156aromatic 175benzylic 105, 151, 152, 180bridgehead 157configurational stability 197cyclization 190–193dimerization 50, 176, 178, 179, 195, 196formyl 173generation 143–149a-halogen 159, 170, 171, 183–185, 189,

201b-halogen 177–180, 184, 185, 188a-heteroatom 161imidoyl 173–175with leaving groups in b position 184a-nitrogen 162–165, 194, 200b-nitrogen 178–180, 186–188oxidation 50, 157, 164, 167, 195, 292a-oxygen 165–170, 184, 194, 200b-oxygen 184–186, 190propargylic 150–155, 159, 160, 171rearrangement 160, 161, 166, 193, 194stability 182a-sulfur 165–170, 187, 198b-sulfur 187tautomers of carbenes 183, 196vinylic 171–173, 183, 184, 189, 190, 199,

201, 202Carbazoles, N-alkylation 238Carbene complexes 294Carbenes 183, 184, 196Carbocations

formation 59, 60, 62, 320–323Friedel–Crafts alkylation with 64, 69, 93,

313rearrangement 69, 252, 320, 322

Carbohydrates, O-tritylation 59Carbon monoxide, reaction with

alcoholates 173organolithium compounds 173, 174organopalladium complexes 291

Carbon tetrachloride 83, 84Carbonylation, see Carbon monoxideCarboxylate dianions 158Carboxylic acids

acidity 144, 146

C-acylation 159C-alkylation 153O-alkylation 251decarboxylation 159, 266dianions 153, 158, 159, 179, 196preparation 47, 173, 181, 184, 189problematic 261

Carboxylic estersacidolysis 41C-alkylation 148, 153–156, 159, 169, 185,

187, 192, 193, 198, 324, 328aminolysis 264halogenation 84, 179metalation 153–156, 167–169, 173, 185,

187, 192, 196, 198preferred conformation 315preparation 251–254transesterification 240, 266, 274, 275

Catalysis byenantiomerically pure complexes 4, 36,

111, 114enantiomerically pure nucleophiles 337enzymes 334–336, 338, 339palladium 111, 114, 235, 236, 245,

279–301Cesium carboxylates 251Cesium hydroxide 232, 233, 344, 345Cesium fluoride 229, 233, 251, 284Chain reactions 45, 60–62Chain structure, in cyclizations 315Chelate formation

organolithium compounds 162–170,177–181, 186, 194

organopalladium compounds 281, 300Chiral auxiliaries 4, 36, 111, 114, 158, 168,

194, 198, 337Chloroacetic acid, dianion 159Chloroacetonitrile 87Chlorobenzene, metalation 178Chlorocyclohexane, conformation 20Chloroform 83, 84a-Chloro Grignard compounds 201Chlorohydrins (2-chloroethanols)

cyclization 59, 170, 171, 318preparation 121–124, 171

1-Chloro-6-iodohexane, metalation 191Chloromethylation 24Chloromethyl methyl ether 44, 793-Chloroperbenzoic acid 392-Chlorotetrahydropyran 20Chlorovinyl carbanions 172, 184, 188, 189,

2024-Chromanones, deprotonation 186

Index360

Chromium complexes, metalation 176Chrysanthemic acid 64Cine- vs ipso-substitution 294Cinnamyl derivatives

alkylation with 93, 150, 234, 235, 245, 284metalation 150, 171, 202reduction 95

Cis–trans isomerization 199, 201, 202Clustering 44Combustion 52Configuration, effect on stability 189, 190Configurational stability of

enolates 197, 198Grignard reagents 200–202organocopper compounds 202, 203organolithium compounds 199–200organomercury compounds 198organozinc compounds 202, 203

Conformationamides and esters 315effects of hyperconjugation on 19

Conjugation 42, 75Contraction of rings 109Convergent synthesis 2Cope rearrangement 5Coupling constants 23Cross-coupling 282–301Crotonic acid derivatives 153, 154Crowded molecules 35, 77, 233, 239, 242,

261–272, 296Cumulenes, see AllenesCuprates, see Organocopper compoundsCurcumine 48Curtin–Hammett principle 13Cyanide, reaction with epoxides 119Cyanides, see NitrilesCyanoacetic acid esters, C-alkylation 148Cyanohydrins, O-acylation 272Cyclic substrates, Sn2 at 74, 75Cyclization 309–328

Baldwin’s rules 309of carbanions 190–193

Cycloalkanes, heats of combustion 319Cycloalkenes, epoxidation 39Cycloalkylmethyl carbocations 320Cyclobutanes

formation 43, 315, 320, 325fragmentation 8, 36, 37, 39ring expansion 320

Cyclobutanols, fragmentation 36Cyclobutenediones, as starting material 7Cyclobutenes, formation 185, 326Cyclobutenone 197

Cyclobutylmethylcarbanions 325carbocations 320radicals 8, 325

Cyclohexane, autoxidation 46Cyclohexanes, conformation 20Cyclohexanones 149, 311Cyclohexene, epoxidation 39Cyclohexylmethyl carbocation 320Cyclometalation, Pd-complexes 298Cyclooctene, epoxidation 39Cyclopalladation 281, 298Cyclopentadiene

formation 36pKa 161

Cyclopentadienyl cation 196Cyclopentanones 311Cyclopentylmethyl carbocation 320Cyclopentenediones 196Cyclopropane, pKa 161Cyclopropanes

preparation 157, 158, 167, 168, 170, 192,252, 320–324

pyrolysis 36ring opening 36, 51, 320, 322, 325

Cyclopropenes 172, 197Cyclopropyl ketones 324Cyclopropyl sulfonates, Sn2 74, 75Cyclopropylidenes 39Cyclopropylmethyl

carbanions 322carbocations 314radicals 322, 323

Cycloreversion 36, 37Cysteine, O-alkylation 252

dD (bond dissociation enthalpy) 46Darkening of arenes 49DAST 230DBU, N-alkylation 250Dealkylation of

amines 66, 200pyridines 39

Dearomatization 163Decalins 5Decarboxylation 159, 266Deflagration 52Dehalogenation 68, 95, 287–291Dehydrogenation 51Design of a synthesis 2Detonations 52Diacids 334

Index 361

Dialkylamino acids 265Diamides, hydrolysis 336Diamines

monoalkylation 234, 344, 345monoacylation 342, 343monosulfonylation 342–344

Diaminobenzenes, monoalkylation 345Diaminopurines, acylation 270Dianions 158–160Diarylamines

N-acylation 267, 268preparation 177

Diastereoselectiveallylation of amines 94–96, 111deprotonation 26, 156, 164, 186dihydroxylation 4, 39esterification 337, 338Michael addition 29reduction of acetals 342Sn2¢ reaction 94–97

Diazenes, preferred conformation 201,1-Diazides 84Diazo alkanes 53, 180, 181, 252Diazocarboxylic acid derivatives 11, 239Diazomethane 53, 180, 181Diazonium salts 282Dibromodifluoromethane 841,2-Dibromoethane 84, 85, 98, 348Dibromomethane 791,3-Dicarbonyl compounds 42, 157–159Dicarboxylic acids 3341,2-Dichloroethane

alkylation with 84, 243, 348deprotonation 184

1,2-Dichloroethenedeprotonation 189preferred configuration 19

Dichloromethane, reaction with amines 24Dicyclopentadiene, thermolysis 37Diels–Alder reaction

of enones 29of furans 4, 318intramolecular 158, 316, 318of o-quinodimethanes 78, 79

Diesters, monosaponification 334, 335, 338Diethylaminosulfur trifluoride (DAST) 230Difluorodiazene, conformation 201,2-Difluoroethane, conformation 181,1-Difluoroethene, metalation 172, 189Difluoronitromethane, pKa 147Dihalides

cyclization 192as electrophiles 79, 84, 85, 153, 243, 348

formation 66halogen–metal exchange 174, 183–185,

190–192, 348monofunctionalization 85, 193, 241, 243,

246, 250, 284, 348Dihalomethanes, nucleophilic substitution

at 24, 79Dihydrobenzopyrans 313Dihydrofurans 314, 324Dihydropyrans 327Dihydropyridines 39, 62Dihydropyrroles 314Dihydroxybenzenes, monoalkylation 340,

341Dihydroxylation of alkenes 4, 39Diisobutylaluminum hydride 101, 102Dimerization of

alkenes 43allyl cyanide 155a-halo esters 89imidazolinones 195isonitriles 174nitroalkanes 195organometallic compounds 50, 176–179,

195, 196phenols 48

Dimethoxymethane, hydrolysis 44N,N-Dimethylacetamide

deprotonation in water 145pKa 144

Dimethyl azodicarboxylate 53N,N-Dimethylbenzylamine, metalation 180,

181N,N-Dimethylformamide, metalation 174Dimethyl sulfide, pKa 161Dinitriles, hydrolysis 336Dinitromethane, pKa 144Diols

fragmentation 36monoacylation 273, 336–339monoalkylation 59, 241, 242, 340, 341preparation 4, 39

1,3-Dioxanesoxidation 338reduction 342

Diphenylamine, N-acylation 268Diphenylmethane, pKa 161Diradicals 38, 51Disconnection 3Dithioacetals

C-alkylation 83, 105, 160, 167deprotonation 27, 160, 167enantiomerically pure 335

Index362

Dithiocarbamates 168Double bond–no bond resonance 44

eElectrochemical generation of radicals 60Electrocyclization 51Electron-withdrawing groups, effect on

acidity 146, 147nucleophilic substitutions 86

Electrophilesallylic 66, 75, 88, 93, 231–238, 242, 247,

248, 319benzylic 67, 75–79, 86a-boron 81with a-electron-withdrawing groups 82, 86a-halogen 79b-halogen 84, 85a-nitro 82, 83propargylic 93–97, 232, 235, 247a-silicon and a-tin 80, 81structure 21

a-Elimination 161, 183b-Elimination 61, 63, 67, 68

decomposition of carbanions 165,184–190

preparation of acrylates 265preparation of strained alkenes 39, 185

Elimination–addition mechanism 60, 61Enamines

metalation 172, 173preparation 43, 327

Enantiomerically pure bases 158, 168, 194,198

Enantioselectivealkylation of carbanions 198deprotonation 158, 167, 168, 194Diels–Alder reaction 4esterification 337–339saponification 334–336

Enantiotopic groups, differentiation334–336, 337–339

Ene reaction 316Energetic materials 52Energies of hyperconjugation 18Enolates

C-acylation 173C-alkylation 64, 148, 153–160, 198, 347configurational stability 197, 198formation 148, 149C-halogenation 84kinetic/thermodynamic 148, 149oxidative dimerization 157, 195

Enolatization as side reaction 161

Enol esters 274, 283, 338Enol ethers

arylation 286formation 311hydrosilylation 312metalation 172, 184, 190as nucleophiles 93

Enonesarylation 295conjugate addition 29, 150, 173, 311, 326Diels–Alder reaction 29

Entropy, cyclizations 319Enynes

deprotonation 160, 172, 189formation 284transformations 314, 326

Enzymesmonoacylations with 338monosaponifications with 334–336

Epichlorohydrin 105, 109, 115Epoxides

formation 39, 51, 59, 170, 171, 318metalation 166reaction with

alcohols 113, 114amides 245amines 109–112aminophenols 238azide 117, 118borohydride 101, 102carbon nucleophiles 98, 103–109cyanide 119, 120guanidine 250halides 121–124hydride 100–103iodide 98, 121–124LiAlH4 100, 101organometallic reagents 98, 103–109phenolates 98pyrazole 73thiols 115–117trifluoroacetamides 245

reactivity vs sulfonates 98, 101, 105, 120,122, 124

rearrangement 99, 103–109, 117, 123Epoxy ketones, fragmentation 116Epoxy nitriles 327Equilibration of enolates 148, 149Equilibrium acidities 144, 147, 161Esterases 334, 335, 338Esterification, enantioselective 337–339Esters, see Carboxylic estersEthane, conformation 18

Index 363

Ethanes, fragmentation 36Ethene

pKa 161IR spectrum 21

Etherscleavage 165, 166macrocyclic 319metalation 165, 166, 182, 200preparation 113, 114, 239–243, 311, 313,

314, 318, 328, 340–342, 349Wittig rearrangement 161, 165, 166, 193,

194Ethoxyquin 48Ethyl acetate, pKa 144Ethylamine, conformation 19Ethylbenzene, metalation 152Ethyl derivatives, hyperconjugation in 18Ethylene, see EtheneEthylenediamine, monosulfonylation 344Ethylene dichloride, see 1,2-DichloroethaneEthynylbenzene, see Phenylacetylene2-Ethynylpyridine, metalation 196Expansion of rings 320Explosives 52

fFerrocenes 36, 176Flash vacuum pyrolysis 36Fluorene, pKa 161Fluoride

alkylation 229–231, 253as base 68, 251, 284as leaving group 66–69, 88, 93, 94reaction with epoxides 121–124

Fluorine, effect onacidity 147nucleophilic substitution 87

Fluoroalkanes, pKa 147Fluoroarenes, metalation 177–180Forbidden cyclizations 309Forbidden rearrangements 161Formaldehyde 21, 152Formamides, metalation 174Formamidines, metalation 164Formates, metalated (ROC(=O)M) 173Formyl groups, metalation 173Fragmentations 36, 116Free radicals, see RadicalsFree radical substitution 60–62Friedel–Crafts alkylation 64, 69, 93,

313Fritsch–Buttenberg–Wiechell rearrangement

183

Fumaric acid derivativesDiels–Alder reaction 318preparation 268

Functional groupsconjugation 42, 75hyperconjugation 42, 18incompatibility 41

3-Furanones 311Furans

Diels–Alder reaction 4, 318metalation 176preparation 314vinylation 287

Furazanes (1,2,5-oxadiazoles) 53

gGas-phase ionization potentials 49, 50Gauche conformation 18–20gem-Dialkyl effect 317, 318Geminal effect 44Glucose, tritylation 59Glycosides, oxidative cleavage 28Glycosylation 85Glycosyl halides, hydrolysis 28Good leaving groups 62Grignard reagents, see CarbanionsGrovenstein–Zimmerman rearrangement

193, 194Guanidines, N-alkylation 250

hHalide ions, reaction with epoxides 121Halides, see Alkyl halides, Aryl halidesHaloacetic acid derivatives 87, 159, 243, 247,

286, 317x-Haloalkylamines

alkylation with 236, 237, 345cyclization 318, 328

Haloalkyl imines, cyclization 326, 327Haloalkyl ketones, cyclization 324, 327Halo arenes

amination 346cross-coupling 282–301deprotonation 177–179homocoupling 287–290reduction 287–291

a-Haloboronic esters 81, 822-Haloethanols, see Halohydrinsa-Halogen carbanions 159, 170, 171,

183–185, 189, 201b-Halogen carbanions 177–180, 184, 185,

188Halogen dance 177

Index364

Halogen–metal exchangearyl halides 174, 177, 191–193dihalides 174, 183–185, 190–192, 348

Halohydrins (2-haloethanols)alkylation with 11, 91cyclization 59, 170, 171, 318formation 121–124, 171

Halo ketonesnucleophilic substitution at 86, 87Pd-catalyzed cross-coupling 291, 292preparation 159, 171

Halomalonic acid derivatives 893-(Halomethyl)acrylates 323Halo nitro compounds 62, 82, 83a-Halo organometallic compounds 159, 170,

171, 183–185, 189, 201b-Halo organometallic compounds 177–180,

184, 185, 1883-Halopropyl ketones 324Halopyridines, amination 346Halo sulfones 87a-Halosulfoxides 88, 201, 202, 292Halo thioethers 88, 91, 92, 348Hammett principle 9Hard and soft acids and bases 9Heck reaction 285Henderson–Hasselbalch equation 145Heteroarenes

metalation 176, 180, 193, 195ring opening 159, 160, 176

Heteroatomsacylation 261–275alkylation 229–254

Heterocycles, formation 327Hexafluoro-2-butyne 231Hexanitrobenzene 53HMX 521H NMR, orthoamides 22Homoallylic

alcoholates, fragmentation 38carbanions 323, 325, 326carbocations 252, 320, 322, 323radicals 323

Homocoupling ofaryl halides 287boronic acid derivatives 291organometallic compounds 195, 291

Homolytic bond cleavage 8, 35–39, 46, 68,317, 323, 325, 326

HSAB 9Hydrazines, conformation 19Hydrazoic acid (HN3), pKa 144Hydrazones

metalation 171oxidation 252

Hydrideabstraction 288reaction with epoxides 100

Hydride complexes 285, 288Hydrobenzoin (1,2-diphenylethane-1,2-diol)

monoacylation 336monoalkylation 340

Hydroboration 203Hydrocarbons, fragmentation 36Hydrogen abstraction 45Hydrogenation 295Hydrogen fluoride 121–124, 229, 230

pKa 144Hydrogen halides, reaction with epoxides

121Hydrogen iodide 69Hydrogenolysis of cyclobutanes 37Hydrogen peroxide

conformation 20formation 47oxidation of amines 15

Hydrolysis ofacetals 28, 44amides 41, 336boronic acids 296carboxylic esters 334, 335lactams 40

Hydroperoxides 45–51, 287Hydroperoxyl 45Hydroquinones

monoalkylation 85, 341as radical scavengers 265as reducing agents 289

Hydrosilylation 312Hydroxy acids

acylation of 272acylation with 262, 263C-alkylation 155O-alkylation 239

Hydroxybenzoic acid, alkylation 241, 243,251

Hydroxybenzyl derivatives, stability 42N-(2-Hydroxyethyl)amides 41Hydroxylamines, preparation 1772-(Hydroxymethyl)benzoic acid derivatives

41(Hydroxymethyl)phenol 42a-Hydroxy nitriles, acylation 272Hydroxyphosphonates 1673-Hydroxypropionitriles 119Hydroxy thiols, acylation 275

Index 365

Hydrozirconation 104Hyperconjugation 17, 19Hypochlorites, conformation 19

iImidates (imino ethers) 11–13, 243, 247Imidazoles

N-alkylation 62, 66arylation 300formation 236, 237

Imidazolinones, dimerization 195Imides

N-alkylation 246, 247O-alkylation 85, 247

Imidoyl carbanions (RN=CMR) 173–175Imines

cyclization 312, 327formation 165metalation 174, 327

Imino ethers 11–13, 243, 247Incompatible functional groups 41Indazoles 77Indenes 168

pKa 161Indium 153, 166, 171Indoles

C-alkylation 66, 165autoxidation 49metalation 165N-methylation 49as neighboring group 91preparation 314C-vinylation 287

Indolines, N-acylation 268Indolizines, C-arylation 284Infrared spectra 21, 22Inhibitors of

autoxidation 37, 47, 48radical-mediated polymerization 265

Initiators 45C–H Insertion 183, 184Inversion (Walden) 59, 60Iodide, as reducing reagent 79, 124Iodoarenes

cross-coupling 290, 295, 296, 298–300deiodination 290deprotonation 177

a-Iodo ketones, formation 171Iodonium salts, cross-coupling 282Ionic liquids 230Ipso- vs cine-substitution 294Iridium complexes 232Iron complexes 36, 176, 274

IR spectroscopy 21, 22Isatins 174Isochromanes 287, 313Isoindoles 313Isomerization of

2-aminoethyl esters 41amino ketones 42epoxides 99, 104, 123

Isonitrilescyclization 314from epoxides and cyanide 119, 120metalation 164reaction with organolithium compounds

174, 175Isoquinolines

formation 290, 313metalation 176

Isoxazolidines 318

kKetals, see AcetalsKetene acetals

addition to enones 29reaction with epoxides 109

Ketenes, formation 188Ketene silyl acetals 109Keto carboxylic acid derivatives, see 3-Oxo

carboxylic acid derivativesKetones

C-acylation 173aldol addition 154C-alkylation 13, 42, 154, 157–159, 193,

311, 324O-alkylation 13, 311, 324, 327arylation 293, 295autoxidation 51formation 71, 169, 173–175, 181, 194fragmentation 37, 116with a-leaving groups 72, 86–90, 116metalation 148, 149, 154, 157–159,

193oxidation 293problematic 196, 197reaction

with allylic carbanions 150–155with arylpalladium complexes 281

rearrangement 37, 42Kinetic acidity 144Kinetic enolate formation 148, 149Kinetic resolution 198Kinetics of

deprotonation 144enolate formation 148, 149

Index366

lLactams

C-alkylation 148, 347N-alkylation 11, 12, 244, 246O-alkylation 11–13formation 12, 315–317hydrolysis 40

b-Lactamsalkylation 12, 246hydrolysis 40

Lactonesformation 311, 315, 318, 328structure 21

Lanthanide salts, catalysts forepoxide opening 110, 111monoacylation 336

LDA 148, 149Least nuclear motion principle 145, 180Leaving groups 62Lewis acids and bases 9, 10Ligands, enantiomerically pure 4, 36, 111,

114, 158, 168, 194, 198, 337Linear synthesis 2Lipases 335, 338Lithiation, see MetalationLithium alkoxides, reactivity 240Lithium amide bases 148, 149Lone electron pairs, hyperconjugation 19Lycopodine 5

mMacrocyclization 320Magnesium amide bases 175Maleic acid derivatives 238, 266Maleimides

Diels–Alder reaction 40preparation 238

Malic acid, C-alkylation 155, 156Malonic esters

C-alkylation 94, 328monosaponification 334, 335

Malonodinitrile 44alkylation 66pKa 144

Mannich basesreaction with thiols 61thermal decomposition 41

Mannich reaction 5MCPBA 39Mechanisms

Heck reaction 285nucleophilic substitution 59Pd-mediated cross-coupling 282

Menschutkin reaction, see Quaternaryammonium salts

Mercaptans, see Thiols2-Mercaptoethanols, acylation 275Mercury(II) acetate, as oxidant 26Mesylates 70, 71Metalation of

alcohols 169alkenes 158, 171–173, 184, 189, 190, 199alkyl halides 170, 171, 183–185, 190–193alkynes 159, 160, 171, 191amides 148, 155, 156, 158, 163, 164, 174,

186, 195amines 162, 164, 180, 181, 200, 343anisole 176arenes 175–182benzene 175benzylic positions 152, 180–182carbamates 164, 167, 168, 179, 180, 186,

190, 194carboxylic acids 153, 158, 159, 179, 196carboxylic esters 153–156, 167–169, 173,

185, 187, 192, 196, 198dithioacetals 27, 160, 167enol ethers 172, 184, 190ethers 165, 166, 182, 200ferrocene 176formamides 174formamidines 164furans 176imines 174, 327indoles 165isoquinoline 176ketones 148, 149, 154, 157–159, 193nitriles 155, 169, 173nitro compounds 148, 177, 179, 187, 193,

195nitrones 174phosphine oxides 185, 186, 200pyridines 175, 176, 195sulfonamides 164, 165sulfonates 70, 71sulfones 64, 98, 185, 310, 347thiocarbamates 168, 200thioethers 156, 160, 187, 198thiophenes 176, 180, 193toluene 180

Methane, pKa 161Methanesulfonates, see MesylatesMethanesulfonyl azide 53Methanol

dianion 169pKa 144

Index 367

Methoxytoluene, metalation 181Methylation, see Alkylation

reagents for 63Methyl azide 53Methylenecyclopropanes 39Methyl ethers, deprotonation 165Methyl hypochlorite 19Methyl hypofluorite 19Methyl nitrate 53Methyl phenyl sulfone, pKa 147Methylpyridines, metalation 195Michael addition 29, 64, 179, 191, 295, 347Michael-type addition of

amides 11, 244amines 345thiols 61

Mitsunobu reaction 11, 85, 242, 247Monoacylation of

arenes 333diamines 342diols 273, 336–339

Monoalkylation ofC,H-acidic compounds 346amines 231, 342carbanions 346diamines 234, 238, 342diols 59, 241, 242, 340, 341

Monoderivatization ofdicarboxylic acids 334dihalides 85, 193, 241, 243, 246, 250, 284,

348Monotetrahydropyranylation 342Morpholinones 111

nNatural products 4–7NBS, cleavage of glycosides 28Negishi reaction 282, 285Neighboring group participation 64, 90–93Neopentyl derivatives 73, 74, 254Neopentylmagnesium bromide 193Nitramine 52Nitrates 52, 53Nitrile oxides 318Nitriles

C-alkylation 66, 148, 155, 169formation

from alcohols 42from alkyl bromides 349from amides 66from epoxides 119, 120from nitroalkanes 64from organometallic reagents 152

from sulfonates 73, 74hydrolysis 336metalation 155, 169, 173

Nitroalkanesalkylation with 62–64, 96C-alkylation 62, 148, 187, 193, 347O-alkylation 148dimerization 195displacement of nitro group 62–64, 96,

187a-halo 82, 83pKa 144, 147stability 52, 53

Nitroalkenes 296N-Nitroamines 52Nitroanilines

N-acylation 268N-alkylation 236, 237

Nitroarenesmetalation 177, 179reaction with organometallic compounds

167, 177stability 52, 53

Nitrobenzene 53Nitrobenzenesulfonamides 252Nitrobenzenesulfonates 71, 72Nitrobenzyl halides

dimerization 77, 78nucleophilic substitutions 61, 76–78

b-Nitro carbanions 187Nitrocumyl chloride 61a-Nitro electrophiles 82, 832-Nitroethanols, O-acylation 272a-Nitrogen carbanions 162–165, 194, 200b-Nitrogen carbanions 178–180, 186–188Nitro groups

displacement 62–64, 96elimination 187

Nitromethanealkylation of 347alkylation with 63pKa 144stability 53

Nitrones, metalation 174N-Nitrosoamines 83, 164Nitrosoarenes 177NMR 22, 23No-bond resonance, see HyperconjugationNorbornanes 92Norbornene

epoxidation 39Heck reaction 298, 299

Norbornenes 92

Index368

Nuclear magnetic resonance 22, 23Nucleophilic catalysis 337Nucleophilic substitution

at aliphatic carbon 59, 143, 229at allylic carbon 93–97at benzylic carbon 61, 67, 75–79, 86intramolecular 59, 310, 311, 318, 319, 324,

327at propargylic carbon 93–97, 232at tertiary carbon 59, 61, 62, 86, 90

Nucleophilicityof amines 24vs basicity 147effect of hyperconjugation on 23of enolates 148of phosphites 24

oOctogen 52Olefins, see AlkenesOligo(ethylene glycol) 340Oligomerization

of acrylates 265of difunctional compounds 41of Michael acceptors 347as side reaction of cyclizations 327

Oligothiophenes 49, 50Oppenauer oxidation 170Organoaluminum compounds

configurational stability 198reaction with epoxides 103–109

Organoboron compounds, see BoranesOrganocopper compounds

alkylation 97, 98configurational stability 202, 203reaction with epoxides 106, 107Sn2¢ reaction 97vinylation 97

Organolithium compoundsconfigurational stability 168, 186, 189,

190, 197–200formation, mechanism 197reaction

with alkenes 165, 168–170, 179, 190,202, 322, 323, 326

with carbon monoxide 173with epoxides 103–109with isonitriles 174

Organomagnesium compounds, seeCarbanionsconfigurational stability 200

Organomercury compounds 198, 199Organometallic compounds, see Carbanions

Organopalladium compounds 279–281Organoselenium compounds 63Organosilicon compounds, see SilanesOrganotin compounds, see StannanesOrganotin hydrides 8, 68, 103, 317, 325, 326Organotitanium compounds 107, 108Organozinc compounds

alkylation 97, 106, 150, 151, 171, 203, 285configurational stability 202, 203cross-coupling 285homocoupling 292

Organozirconium compounds 104, 161Orthoamides 26, 346Orthocarbonates, hydrolysis 44Orthoesters

hydrolysis 44preparation 83, 84reaction with Grignard reagents 27

Orthoformates 44Ortho-metalation 175–182Osmium tetroxide 4Oxadiazoles 537-Oxanorbornenes 4Oxidation

of acetals 26, 338of alcohols 47of aldehydes 47of alkenes 4, 39, 45, 51of amines 15, 26of arenes 48–50of boronic acid derivatives 291, 292of carbanions 50, 157, 164, 167, 195, 292of dihydropyridines 39of dithioacetals 167of enolates 51, 157, 291of ketones 51, 293of orthoamides 26of palladium complexes 280, 291of phenols 47, 48potentials 49, 50rates 25by SET 48

Oxidative coupling 287, 292Oxidative dealkylation 39Oxidative dimerization 48, 50, 176–179, 195,

196, 292Oxide ion, as leaving group 185Oxiranes, see Epoxides3-Oxo carboxylic acid derivatives

C-alkylation 159conversion to enamines 43dianions 159esterification 266

Index 369

Oxy-Cope rearrangement 5Oxygen 45–51a-Oxygen carbanions 165–170, 184, 194, 200b-Oxygen carbanions 184–186, 190Ozone, oxidation of acetals 26Ozonides 53

pPalladacycles 281, 298Palladium catalysis 279–301

N-alkylation 345allylic substitution 94–96, 103, 111, 114,

235, 236, 245N-arylation 346cross-coupling 282Heck reaction 285homocoupling 287, 291hydrogenation 295

Palladium complexesas catalysts 282–301oxidation 280preparation 279–281reactivity 279stability 279, 293, 298, 300thermolysis 280, 298

Payne rearrangement 117, 123Pentaerythrityl derivatives 52, 73Pentanitrotoluene 53Perchlorates 53Peroxides 20, 53, 284, 287Peroxyl radicals 46PETN 52Phenacyl esters 236, 243, 253Phenacyl halides 14, 86, 87Phenol, pKa 144Phenols

O-acylation 272–274alkylation 66, 85, 113, 241–243autoxidation 47, 48from boronic acids 292oxidative dimerization 48

Phenylacetylenecross-coupling 290, 292pKa 144

Phosphinamides (R2P(=O)NR2) 162Phosphine oxides

formation 65, 242metalation 185, 186, 200

Phosphinesaryl group exchange 293formation 67as leaving group 66as Lewis base 106

as ligands 111, 114quaternization 293

Phosphites 24, 83Phosphonium salts

dealkylation 65, 66, 95dearylation 293pKa 161

Photochemistry 60–62, 315[2 + 2] Photocycloaddition 315Phthalimides 85, 89, 348Picric acid

O-alkylation 241pKa 144

Pictet–Spengler reaction 312, 313Pig liver esterase 335Piperazines 234, 345Pitzer strain 319pKa 144, 161Polarizability 9Polyamines 345, 346Poly(ethylene glycol), monoalkylation 340Polyhydroxybenzenes, monoalkylation 85,

340, 341Polymerization, inhibition 265Polynitroarenes 52, 53Poor leaving groups 62Potassium fluoride 68, 229, 230Precapnelladiene 7Principle of least nuclear motion 145, 180Problematic

alcohols 271–275alkyl halides 66–69, 72–97, 236, 240, 241,

245, 266amines 267–271benzyl halides 77–79boron derivatives 81carboxylic acids 261dienes 39, 40, 43electrophiles 59thiols 275

Propargylation ofamines 232anilines 235imides 247malonates 94

Propargyliccarbanions 150–155, 171dianions 159, 160electrophiles 93–97, 232, 235, 247halides, metalation 191

S-Propargyl xanthates 253, 254[1.1.1]Propellane 323, 324Propene, pKa 161

Index370

Propiolic acid derivatives 196Propionitrile, deprotonation in water 145Protective-group-free strategies 262Protoanemonine 43Protodemetalation 296Pseudomonas lipase 338Pteridines, N-alkylation 238Purines 270Push-pull alkenes 42Pyramidal inversion 144-Pyranones, deprotonation 186Pyrans 20, 64Pyrazoles 73, 74Pyridine, ionization potential 50Pyridines

addition of radicals to 36formation 39metalation 175, 176, 195

Pyridinium salts, reduction 60Pyridones 10Pyrimidine-2,4-diones, deprotonation 173Pyrroles

autoxidation 49metalation 172

Pyrrolidinespreparation 312, 324quaternization 14

PyrrolidinonesC-alkylation 347N-alkylation 246formation 12, 311

qQuaternary ammonium salts

dealkylation 95pKa 161preparation 14, 24, 231

Quinine derivatives, as catalysts 337o-Quinodimethanes 51, 78, 79Quinuclidine N-oxide 187Quinuclidines, quaternization 24

rRacemization, see Configurational stabilityRadical clocks 325Radicals

addition to alkenes 317, 323, 326addition to pyridines 36formation 8, 36, 45–51, 60–62, 317, 323,

325, 326rearrangement 8, 322, 326

Ranunculin 43Rate constants, see Relative rates

Rates of deprotonation 26Rates of oxidation 25Reactive rotamer effect 317Rearrangement

of aldols 37allylic 93–97, 104, 150–155, 319of amino ketones 42of carbanions 160, 161, 166, 193, 194of carbocations 69, 252, 320, 322of cyclopropanes 36of 1,3-dienes 39, 40of epoxides 99, 103–109, 117, 123of radicals 8, 322, 326oxy-Cope 5

Reduction ofacetals 342aryl halides 287–291azides 118epoxides 100–103

Relative rates ofcyclization 327, 328deprotonation 26, 144epoxidation 39oxidation 25Sn1 67, 74, 80, 82, 86, 92Sn2 72, 74, 76, 79, 81, 82, 87, 88, 92

Resolution, kinetic 198Retro-Aldol addition 37Retro-Diels–Alder reaction 37Retro-Mannich reaction 37, 41Retrosynthetic analysis 3Rhodium complexes 11Rhodococcus rhodochrous 336Ring contraction 109Ring expansion 320Ring formation 309–328Ring opening of epoxides 97–124Ring size, effect on cyclization 319, 327Rotational barriers 17–19, 315

sSamarium iodide 103, 162, 174, 175Saponification, enantioselective 334–336Scavengers 47, 48Schiff bases, see IminesSchotten–Baumann procedure 269Serine 73, 74, 263SET

bond cleavage 38nucleophilic substitution by 60–62oxidation by 48, 167, 195

Shapiro reaction 171Shikimic acid 4

Index 371

Shock sensitivity 52, 532,3-Sigmatropic rearrangements 193Silanes

Brook rearrangement 174, 175formation 64, 158, 171, 172, 179, 181, 190,

194, 200nucleophilic substitution at a-halo 80reaction with epoxides 109

a-Silicon, electrophiles with 80Silver salts, protection of polyols 339, 340Silyl enol ethers 149Silyl ethers 117–120Silyl ketene acetals 29, 109, 347Single electron transfer, see SETSoft acids and bases 9Soft enolization 182Solubility of starting materials 340Solvent cage 61Solvents, effect on

Pd-catalyzed reactions 290, 293, 296pKa 144substitutions 60, 66

Sonogashira reaction 282, 284, 290Sparteine 168, 194, 199Spectroscopic properties 21–23Spiro compounds 8, 40Stability

of carbanions 182of organic compounds 35toward oxygen 45

Stannanesallylation of 152, 284allylation with 109, 322cross-coupling 282–284, 289, 294, 296,

297, 300formation 193substitution at a-halo 80transmetalation 143, 159, 198, 200

Stereoelectronic effects 17Stereoselective, see Diastereoselective,

EnantioselectiveSteric crowding, effects on

acylation 261, 267, 271alkylation 72–77, 233cross-coupling 296Heck reaction 296nucleophilic substitution 72stability 36, 38, 239

Stevens rearrangement 161, 193, 194Stilbenes 77, 78, 283, 286, 300Stille reaction 282–284, 289, 294, 296, 297,

300Strained bonds 35, 38, 39

Strained rings 36, 185, 319–327Strain energy 319Structure, effect of hyperconjugation on 17,

21Substitution, aliphatic nucleophilic 59, 143,

229Substructures, recognition of 3Succinic acid derivatives 155, 156, 158Succinimide, N-alkylation 247Sulfenes 70Sulfides, see ThioethersSulfinates

S-alkylation 96displacement 64, 70, 71, 165

Sulfonamidesaddition to alkenes 300N-alkylation 251, 252, 300hydrolysis 252metalation 164, 165pKa 251as protective group 252

Sulfonates (Sulfonic acid esters)as leaving group 70–72metalation 70preparation 339reactivity vs epoxides 98, 101, 105, 120,

122, 124Sulfones

C-alkylation of 64, 98, 185, 310, 347displacement of sulfinate 63, 64, 70, 71,

165pKa 147

Sulfonium saltsalkylation with 60, 62, 63, 76cross-coupling 282dealkylation 95deprotonation 26

Sulfonyl azides 53Sulfoxides

deprotonation 177, 178a-halo 201, 292sulfur–metal exchange 178, 197,

201, 202a-Sulfur carbanions 165–170, 187, 198b-Sulfur carbanions 187Sultones (cyclic sulfonates) 70Superoxide 45Suzuki reaction 282, 283, 292–297Symbiosis 44Symmetric substrates,

monofunctionalization 333–349Synkamin (vitamine K5) 48Synthesis design 2

Index372

tTartaric acid derivatives 263, 273TBAF 229, 230c-Terpinene 48Tertiary alcohols

acylation 265, 272alkylation of 114, 239–241, 311, 314, 318alkylation with 93, 249carbonylation 173formation 39, 71, 72, 101, 105–124, 153,

157, 159, 174, 186, 200fragmentation 36–38, 116

Tertiary aminesdealkylation 66, 200formation 231–238oxidation 15, 26quaternization 14, 24

Tertiary halidespreparation 93, 122solvolysis 67, 74, 80, 86substitution 59, 61, 62, 82, 86, 90

Tetrabutylammonium fluoride 229, 230Tetrachlorocarbon 83, 84Tetra(dimethylamino)ethene 289Tetrafluorohydrazine, conformation 20Tetrahydrofuran, cleavage by Lewis acids 104Tetrahydrofurans

as hydrogen donors 183, 184preparation 311

Tetrahydroisoquinolines 313Tetrahydropyrans 20, 319Tetrahydropyranyl ethers 342Tetrahydrothiophenes 312Tetraline, autoxidation 46Tetramethylammonium, pKa 161Tetramethylethylenediamine (TMEDA) 1752,2,6,6-Tetramethylpiperidines 234Tetrazoles, stability 52, 53Tetryl 52TFA, amides of 245Thermal elimination 63Thermodynamic (equilibrium) acidity

144–146Thermodynamic enolate formation 148, 149Thiazoles, N-alkylation 85, 349Thiiranes 168Thioacetals, see DithioacetalsThioamides 163Thiocarbamates 168, 200a-Thio carbanions 165–170, 200b-Thio carbanions 187Thiocyanate, as nucleophile 76, 89Thioethers

formation 76, 82, 84, 90, 95, 115–117, 324,348

metalation 156, 160, 187, 198as neighboring group 92

Thioketals, see DithioacetalsThiol esters

cross-coupling 282formation 275metalation 168

Thiolsacylation 275alkylation 76, 82, 84, 90, 95, 115–117, 324,

348Thiophenes

arylation 289metalation 176, 180, 193oxidation 49, 50

Thiophenols, see ThiolsTHP ethers 342a-Tin, electrophiles with 80Titanium alcoholates 100, 108, 110, 114,

116–118, 123Titanium tetrachloride 109, 121Titanocenes 102, 103TNT 52, 53Tocopherol 48Toluene

pKa 161metalation 180

Tosylates, see SulfonatesTosyl cyanide 152Tosylhydrazones 171Transesterification 240, 266, 274, 275Transition metal complexes 9, 45, 279Transmetalation 161Tresylates 67Trialkyloxonium salts 12Triarylphosphine dihalides 230Triazacyclononane, monoalkylation 346Tributyltin hydride 8, 68, 103, 317, 325, 326Trichloroacetamides, cyclization 317Trichloroacetimidates 932,2,2-Trichloroethyl derivatives 87, 88Trichloromethylbenzene 83Trichloromethyl groups 83, 84, 87, 88Triethylaluminum 104, 106, 108Triethyl orthoformate 44, 84Triflates 71, 73, 75, 88, 92, 289Trifluoroacetamides 245Trifluoroacetic acid 265Trifluoroethanesulfonates (tresylates) 672,2,2-Trifluoroethyl derivatives 87, 88, 233Trifluoromethane, pKa 147

Index 373

Trifluoromethylarenes, metalation 177Trifluoromethyl groups

effect on Sn2 rates 87, 88, 92formation 230, 231

Trifluoromethyl ketones 21, 22, 150Trimethylaluminum 108Trimethylsilyl azide 117, 118Trimethylsilyl cyanide 119, 1202,4,6-Trinitrobenzoic acid 2652,4,6-Trinitrotoluene 52Triphenylmethane, pKa 161Triphenylmethyl, see TritylTriphenylphosphine difluoride 230Triplet oxygen 45–512,4,6-Tris(trifluoromethyl)benzoic acid 265N-Tritylamides, N-alkylation 244Tritylamines

acylation 267alkylation 233

Tritylation 59, 340Trityl esters 271Tropane derivatives 14

uUnprotected amino/hydroxy acids 262–265,

268–270, 272Ureas

N-alkylation 248, 249deprotonation 164, 248

Urethanes, see CarbamatesUV radiation 45

vVinyl azide 53Vinylboronic acids 283, 294

O-Vinyl carbamates 189Vinyl chlorides, metalation 189Vinyl epoxides 95, 97, 103–105, 108, 109,

114, 119, 120Vinyl ethers 274, 283, 338Vinylic carbanions 171–173, 183, 184, 189,

190, 199, 201, 202Vinylidenes 183, 196, 201Vinyl iodides 189, 286Vinylpyridine, as Michael acceptor 347Vinylsilanes, preparation 172, 190Vinylstannanes 284, 294Vitamine C (ascorbic acid) 47Vitamine E (tocopherol) 48Vitamine K5 (synkamin) 48

wWacker reaction 292Wagner–Meerwein rearrangement 320Walden inversion 59, 60Water

pKa 144as solvent 279, 280

Williamson ether synthesis 81, 239–243,349

Wittig rearrangement 161, 165, 166, 193, 194Workup of reactions 1

xXanthates, O-alkylation with 254

zZeolites 336, 337Z group, hydrogenolytic cleavage 37Zinc, see Organozinc compounds

Index374