Heterocyclic Chemistry Short Course - Part A
Albert Padwa, Instructor

Table of Contents


Session IA Chemistry of Heteroaromatics

General Considerations Common Five and Six Ring Heteroaromatics  2
Methods of Drug Synthesis  4
Nomenclature  5
Indicated Hydrogen Rule  8
Fused Rings  9
pi-Deficient Heteroaromatics  11
pi-Excessive Heteroaromatics  13
Synthesis of Heteroaromatics  15
Cyclization Reactions for Heterocyclic Synthesis  16
Synthetic Aspects of 5-Ring Heteroaromatics 17 Paal-Knorr Furan Synthesis  17
Five Top Methods to Synthesize Furans  18
Radical Cyclization for Furan Synthesis  20
Five Top Methods to Synthesize Pyrroles  22
Thiophene Ring Synthesis  25
Five Top Methods to Synthesize Oxazoles  27
Five Top Methods to Synthesize Isoxazoles  28
Five Top Methods to Synthesize Pyrazoles  30
Five Top Methods to Synthesize Imidazoles  33
Use of Tosmic Reagent for Heterocyclic Synthesis  26
Five Top Methods to Synthesize Thiazoles  39
Five Top Methods to Synthesize Isothiazoles  41
Five Top Methods to Synthesize Indoles  43
Synthesis of 3-Indoles via Tin Mediated Cyclization  45
Buchwald Zirconium Benzyne Complex for Indoles  46
Reductive N-Heterocyclization of Nitroarenes  48
Use of Pyridynes for Heterocyclic Synthesis  50
Chemical Behavior of 5-Ring Heteroaromatics  51 Electrophilic Substitution  51
Furan Cationic Substitutions  51
Ring Opening Reactions of Furans  52
Indole Lithiates for Alkaloid Synthesis  53
Cycloaddition of Furans and Pyrroles  54
4+2-Cycloadditions of Heteroaromatics  56
Tandem Diels-Alder Retro Reaction of Oxazoles  58
Oxazole Cycloadditions  59
Diels-Alder of Thiazole Derivatives  60
Intramolecular Kondrateva Pyridine Synthesis  61
Synthetic Aspects of 6-Ring Heteroaromatics  62 Five Top Methods to Synthesize Pyridines  63
Quinoline Synthesis  65
Five Top Methods to Synthesize Quinolines  66
Isoquinoline Synthesis  68
Five Top Methods to Synthesize Isoquinolines  69
Bischler Napieralski Method  71
Pictet-Spengler Tetrahydroisoquinoline Synthesis  72
Pictet Spengler Cyclization  73
Methods to Generate Iminium Ions  74
Acyl Iminium Activation  75
Mannich Reaction using Pyrroles  77
Benzal Aminoacetal Isoquinoline Synthesis  78
Chemical Behavior of 6-Ring Heteroaromatics  81 Inverse Electron Demand Reactions of Pyridazines  82
Triazines and Tetrazine Cycloadditions  83
Hetero Diels-Alder Reactions  86
Inverse Electron Demand Diels-Alder Reactions of Triazines  89
Electrophilic and Nucleophilic Reactions of Pyridines  90
Synthesis of Thieno Fused Quinolines  91
Suzuki Reaction for Heterocycles  92
Metallation/Cross Coupling for Polycondensed Heteroaromatics  94
Intramolecular Aza-Wittig Reaction  96
Oxazoles and Imidazolinones via an Intramolecular Aza-Wittig Reaction  98
Application of Heck Reaction for Heterocyclic Synthesis  100
Intramolecular Heck Cyclizations  102
Five-Membered Ring Formation  105
Heck Reaction with Organotin Compounds  108
Six-Membered Ring Formation  111
Synthesis of Medium and Large Rings  113
Pd-Catalyzed Rearrangement Followed by an Intramolecular Heck Reaction  115
Multiple Cyclizations  116
Regio and Stereocontrol of Heck Reaction  118
Session IIA Heterocycles as Vehicles for Organic Synthesis Use of Heteroaromatics in Synthesis  124 Thiophene Desulfurization  124
Furan as a 1,4-Dicarbonyl Source  125
Furan Hydrolysis and Oxidation  126
Oxidation of Furylcarbinols to Hydropyranones  127
Generation of 3-Oxidopyrylium Ylide  129
Use of Oxazoles in Alkaloid Synthesis  130
Unmasking of the Isoxazole Ring  132
Pyrrole Nitrogen Extrusion  133
Benzotriazole Chemistry  135
2,3-Dihydro-4-Pyridones as Synthetic Intermediates  143
N-Alkyl Acyl Pyridinium Salts for Alkaloid Synthesis  148
Heteroaromatics as Latent Anions  151
Use of Oxazolines in Synthesis  152
Activating Groups for Indole Lithiation  153
2-Lithio Thiazoles for Aza-Sugar Synthesis  154
Metalation and Electrophilic Substitution Reactions  156
Aldehyde Based Syntheses Using Thiazoles  157
Metalation of Aryloxazolines  158
Meyers Oxazoline Biaryl Synthesis  159
Oxazolium Salts as Precursors to o-Quinomethanes  168
Dihydrothiazoles and Dihydrooxazoles as Latent Anions  169
1,3-Dithianes as Acyl Anion Equivalents  169
Use of Heterocycles for Alkene Synthesis  171
Chemistry of N-Nitroso Oxazolidones  172
1,2,3-Selenadiazoles for Alkyne Synthesis  174
Vinyl Vicinal Tricarbonyl for Heterocyclic Synthesis  175
Chemistry of 3-Sulfolenes  176
Extrusion of SO2 from Dihydrobenzo[c]thiophene Dioxides  177
Session IIIA Cycloaddition and Cyclization Processes Diels-Alder Chemistry  179 Imino Diels-Alder Reactions  180
Imines as Dienophiles  180
Lewis Acid Catalyzed Reactions of Imines  181
Oxime Ethers as Dienophiles  182
Vinylsulfonylimines as Azadienes  184
N-Sulfonyl-1-aza-1,3-butadiene Diels-Alder  185
Preparation of N-Sulfonyl-1-aza-butadiene  187
Intramolecular Imino 4+2 Cycloadditions  188
N-Acyl Azadienes  189
Use of Benzyne for Heterocyclic Synthesis  190
Cycloaddition of Vinyl Isocyanates  192
Intramolecular Heck Reaction  193
Indole 2,3-Quinodimethane Strategy  194
Intramolecular Azadiene Cycloadditions  195
Diels-Alder Reactions of Isoquinolium Salts  196
Nitroso Compounds as Dienophiles  197
N-Sulfinyl Carbamate Cycloadditions  199
N-Sulfinylsulfonamides  200
a-Pyrone as Butadiene Equivalents  201
Diels-Alder of Heterodienophiles  204
Intramolecular 4+2 Cycloaddition of Heterodienes  205
Thiocarbonyl Dienophiles  206
Dipolar-Cycloaddition Chemistry  207 Frontier MO Theory  207
Classification of Dipoles  208
Nitrones - Preparation and Regiochem Considerations  209
Use of Nitrones in Synthesis  210
Nitro Alkene Cycloadditions  212
Tandem Nitro Alkene Cycloadditions  213
Nitrile Oxides for Mixed Aldol Chemistry  214
Synthetic Applications of the INOC Reaction  216
Nitrile Ylides  219
Azomethine Ylides  220
Aza Allyl Anion Cycloadditions  224
Carbonyl Ylides  225
Thiocarbonyl Ylides  228
Azide Dipolar Cycloaddition  229
Nitrile Imines  230
Diazo Compounds  231
Hetero Hydrogen Atom Insertions  237
Azomethine Imines  238
Mesoionic Species  239
3+2 Annulation via Allenylsilanes  240
Cycloreversion Chemistry  241
Session IVA Reactive Intermediates in Heterocyclic Chemistry 2+2-Cycloaddition Reactions  242 Intramolecular 2+2-Ketene Cycloadditions  242
Staudinger Reaction  244
Cyano Cloro Ketene for b-Lactam Synthesis  248
Other Methods for b-Lactam Synthesis  249
Heterocyclic Synthesis via Olefin Metathesis  250
Paterno Buchi Reaction  251
Intramolecular Vinylogous Amide Photocycloaddition  252
Photocyclization of N-Aryl Enamines to Indolines  253
Chloroacetamide Photocyclization  256
Photochemical 2+2 Methods  258
Photochemical and Thermal Transformations with Heterocycles 259 Photodesilylation of Iminium Ions  259
Electron Transfer-Radical Cation Chemistry  262
Heterocyclic Phototranspositions  263
Dimroth Rearrangement  269
van Alphen-Huttel Rearangement of 3H-Pyrazoles  273
Thermally Induced Heterocyclic Rearrangements  274
Sigmatropic Processes Using Heterocycles  275 Ketene Routes Using Pyrroles  275
Ammonium Ylide Rearrangements  275
1,3-Sigmatropic Rearrangements  276
Cyclopropyl Iminium Shifts  276
Applications of the Schmidt Reaction  278
3,3-Sigmatropic Rearrangements  281
Aza-Claisen Rearrangement  282
Ireland-Claisen Rearrangment with Heterocycles  283
Aza-Cope Rearrangement  284
Overman 3,3-Sigmatropic Shift for Alkaloids  284
Hetero-Cope for Indole Synthesis  286
Tetrathiafulvene Mediated Radical Crossover  288
Ugi Reaction for Heterocyclic Synthesis  289
Passerini Reaction for Heterocyclic Synthesis  291
Methods to Generate Nitrene Intermediates  292
Use of Nitrenes in Heterocyclic Synthesis  293
Vinyl Nitrene Cyclizations  294
Synthesis of Aziridines  295 Aziridines from Iodoazides  296
Aziridines from Photolysis of Triazolines  297
1-Vinyl Aziridines from Triazoline Decomposition  300
Aziridinium Salts in Synthesis  301
Developments in Aziridine Chemistry  303
Azomethine Ylide Formation from Aziridines  304
Photochemistry of Aziridines  305
Session VA Special Topics in Heterocyclic Chemistry Epoxide Chemistry  306 Asymmetric Epoxidation  306
Epoxidation of Alkenes by Peroxycarboxylic Acids  309
Synthesis of Epoxides Using Sulfur Ylides  311
Epoxidation of Alkenes Mediated by Dioxiranes  313
Epoxides from Halohydrins and 1,2-Glycols  314
b-Lactam Chemistry  315 Cycloaddition Reactions  317
Passerini Reaction  318
b-Lactams in Antibiotic Synthesis  319
Five Ring Heteroaromatics Revisted  320 Oxazole Synthesis  321
Synthesis of Isoxazoles  323
Preparation and Chemistry of Imidazoles  326
Pyrazole Chemistry  331
Synthesis and Chemistry of Thiazoles  333
Reactivity of Pyridines and their Benzo Derivatives  338 Friedel Craft Reaction of Pyridines  339
Chemistry of Pyridine N-Oxides  342
Variation of the Hantzsch Synthesis  346
Enamine-Oxazinone Route to Prepare Pyridines  347
Seven Membered Ring Heterocycles  348 Ring Expansion of Cylic Enamines  349
Cope Rearrangements as a Method  352
1-Photolysis of Heterocyclic N-Oxides  353
1,2 Diazepines via Reaction of Pyrylium Salts  354
Beckman Rearrangement of Cyclohexanone Oximes  355
Photolysis of Aryl Azides  359
Photoisomerizations to Generate Seven Membered Rings  360
1,7-Electrocyclizations to Benzoxepins  361
Concluding Remarks

Use of Computer Database for Searching the Heterocyclic Literature

Why a Short Course in
Heterocyclic Chemistry?
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Heterocyclic Computer
Database - "Chemkey"
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Part B
Table of Contents
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Albert Padwa chemap@emory.edu