global sustainability (the impact of local cultures) || index
TRANSCRIPT
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