Heterocyclic
Chemistry Short Course - Part A
Albert
Padwa, Instructor
Table
of Contents
Introduction
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
Albert Padwa chemap@emory.edu
