MICROWAVE ASSISTED ORGANIC SYNTHESIS
CONTENTS 1 THEORETICAL ASPECTS OF MICROWAVE DIELECTRIC HEATING 1 1 1 INTRODUCTION 1 1 1 1 MICROWAVE RADIATION FREQUENCIES AVAILABLE FOR DIELECTRIC HEATING 2 1 2 THEORETICAL BASIS OF DIELECTRIC HEATING 4 1 2 1 RELAXATION TIMES OF SOLVENTS 4 1 2 2 LOSS TANGENTS 7 1 3 DIELECTRIC PROPERTIES OF SOLIDS 14 1 4 COMPARISON OF MICROWAVE AND CONVENTIONAL HEATING 18 1 5 ACKNOWLEDGEMENT 21 1 6 REFERENCES 21 2 MICROWAVE ACCELERATED METAL CATALYSIS ORGANIC TRANSFORMATIONS AT WARP SPEED 23 2 1 INTRODUCTION 23 2 2 STILLE COUPLINGS 24 2 3 SUZUKI COUPLINGS 25 2 4 NEGISHI COUPLINGS 29 2 5 HECK COUPLINGS 29 2 6 CYANATION AND SONOGASHIRA REACTIONS 31 2 7 CARBON HETEROATOM COUPLING REACTIONS 32 2 8 ASYMMETRIC MOLYBDENUM CATALYSED ALLYLIC ALKYLATIONS 34 2 9 CARBONYLATIVE COUPLINGS 35 2 9 1 MOLYBDENUM HEXACARBONYL AS A SOLID CO RELEASING REAGENT 36 2 9 2 FORMAMIDES AS LIQUID CO RELEASING REAGENTS 38 2 10 OUTLOOK 41 2 11 ACKNOWLEDGEMENT 41 2 12 REFERENCES 41 3 HETEROCYCLIC CHEMISTRY USING MICROWAVE ASSISTED APPROACHES 44 3 1 INTRODUCTION 44 3 2 FIVE MEMBERED SYSTEMS WITH ONE HETEROATOM 45 3 2 1 FURANS AND BENZOFURANS 45 3 2 2 PYRROLES INDOLES AND INDOLIZINES 46 3 2 3 THIOPHENES 47 3 3 FIVE MEMBERED SYSTEMS WITH TWO HETEROATOMS 48 3 3 1 IMIDAZOLES PYRAZOLES AND BENZIMIDAZOLES 48 3 3 2 OXAZOLES ISOXAZOLES THIAZOLES BENZOXAZOLES AND BENZOTHIAZOLES 51 3 4 FIVE MEMBERED RING SYSTEMS WITH MORE THAN TWO HETEROATOMS 53 3 4 1 TRIAZOLES 53 3 4 2 OXADIAZOLES 54 3 4 3 TETRAZOLES 56 3 5 SIX MEMBERED HETEROCYCLES CONTAINING ONE HETEROATOM 57 3 5 1 PYRIDINES QUINOLINES ISOQUINOLINES AND FUSED RING ANALOGUES 57 3 5 2 BENZOPYRANS 59 3 6 SIX MEMBERED HETEROCYCLES CONTAINING AT LEAST TWO HETEROATOMS 61 3 6 1 PYRIMIDINES AND QUINAZOLINES 61 3 6 2 TRIAZINES AND TETRAZINES 63 3 7 SEVEN MEMBERED HETEROCYCLES CONTAINING AT LEAST TWO HETEROATOMS 1 4 AND 1 5 BENZODIAZEPINES 63 3 8 POLYCYCLIC HETEROCYCLES 65 3 8 1 FUSED RING HETEROCYCLES 65 3 8 2 FUSED HETEROCYCLES SHARING AT LEAST ONE HETEROATOM 68 3 9 CONCLUSION 70 3 10 REFERENCES 71 4 MICROWAVE ASSISTED REDUCTIONS 75 4 1 INTRODUCTION 75 4 2 REDUCTION OF CARBON CARBON MULTIPLE BONDS 76 4 2 1 C C MULTIPLE BOND REDUCTION USING TRANSFER HYDROGENATION 76 4 2 2 C C MULTIPLE BOND REDUCTION USING OTHER METHODS 79 4 3 REDUCTION OF CARBONYL GROUPS 80 4 3 1 CARBONYL REDUCTION USING BOROHYDRIDES 81 4 3 2 CARBONYL REDUCTION UNDER MEERWEIN PONNDORF VERLEY CONDITIONS 82 4 3 3 CARBONYL REDUCTION BY TRANSFER HYDROGENATION 83 4 3 4 CARBONYL REDUCTION BY THE CANNIZZARO REACTION 84 4 3 5 CARBONYL REDUCTION USING OTHER METHODS 86 4 4 REDUCTION OF NITROGEN FUNCTIONAL GROUPS 87 4 4 1 REDUCTION OF IMINES 87 4 4 2 REDUCTION OF NITRO GROUPS 90 4 4 3 REDUCTION OF HYDRAZONES AND HYDRAZIDES 93 4 5 HYDRODEHALOGENATION 95 4 6 CONCLUSIONS 98 4 7 REFERENCES 98 5 SPEED AND EF CIENCY IN THE PRODUCTION OF DIVERSE STRUCTURES MICROWAVE ASSISTED MULTI COMPONENT REACTIONS 102 5 1 BACKGROUND 102 5 1 1 INTRODUCTION 102 5 1 2 DESIGNING THE METHOD 102 5 1 3 BENE TS WITH MULTI COMPONENT REACTIONS 103 5 1 4 MULTI COMPONENT VERSUS ONE POT SYNTHESIS 103 5 2 MULTI COMPONENT REACTIONS 105 5 2 1 HANTZSCH REACTION 105 5 2 2 BIGINELLI REACTION 107 5 2 3 UGI REACTION 107 5 2 4 KINDLER REACTION 109 5 2 5 GEWALD SYNTHESIS OF 2 ACYL AMINO THIOPHENES 110 5 2 6 MANNICH REACTION 111 5 2 7 BORONIC MANNICH REACTION 111 5 2 8 PAUSON KHAND REACTION 112 5 2 9 WITTIG REACTION 112 5 2 10 AZA DIELS ALDER REACTION 114 5 3 VERSATILE REAGENTS IN MULTI COMPONENT REACTIONS 114 5 3 1 TRIPHENYLPHOSPHORANYLIDENE ETHENONE 114 5 3 2 N N DIMETHYLFORMAMIDE DIETHYL ACETAL 115 5 3 3 N N DIMETHYLFORMAMIDE DIETHYL ACETAL ON SOLID SUPPORT 116 5 4 MISCELLANEOUS PRODUCTS 117 5 4 1 IMIDAZOLES 117 5 4 2 SUBSTITUTED IMIDAZOLES 118 5 4 3 IMIDAZO PYRIDINES 119 5 4 4 1 2 4 TRIAZINE 120 5 4 5 INDOLIZINES 121 5 4 6 SUBSTITUTED PRALINES 122 5 4 7 QUINOLINES 122 5 4 8 QUINAZOLIN 4 3H ONES 123 5 4 9 SUBSTITUTED PYRROLES 124 5 4 10 INDOLES 125 5 4 11 SPIROINDOLES 125 5 4 12 AMINO PHOSPHONATES 126 5 4 13 6 CYANO 5 8 DIHYDROPYRIDO 2 3 D PYRIMIDIN 4 3H ONES 127 5 4 14 MULTI COMPONENT REACTIONS USING ISATOIC ANHYDRIDE 127 5 4 15 PYRIDO 2 3 D PYRIMIDINES 128 5 5 SUMMARY 129 5 6 REFERENCES 129 6 INTEGRATING MICROWAVE ASSISTED SYNTHESIS AND SOLID SUPPORTED REAGENTS 133 6 1 INTRODUCTION 133 6 2 MICROWAVE HEATING OF REACTIONS 134 6 2 1 HEATING A HETEROGENEOUS SAMPLE POLYMER CONSIDERATIONS 134 6 2 2 HEATING A POLYMER SOLVENT A BINARY PHASE SYSTEM 135 6 2 3 MIGRATION OF THE REACTING SPECIES 138 6 2 4 REACTION HEATING SOLVENT CONSIDERATIONS 139 6 3 MICROWAVE REACTIONS WITH POLYMER SUPPORTED REAGENTS 141 6 3 1 POLYMER DRYING 142 6 3 2 REDUCTIVE AMINATIONS 142 6 3 3 THE HENRY REACTION 143 6 3 4 ALKYLATION REACTIONS 143 6 3 5 O ALKYLATIONS OF CARBOXYLIC ACIDS 144 6 3 6 WITTIG REACTIONS 146 6 3 7 ACYLATION REACTIONS 147 6 3 8 PREPARATION OF ISOCYANIDES 149 6 3 9 SYNTHESIS OF THIOAMIDES 150 6 3 10 ESTERI CATION OF ALCOHOLS USING HETEROGENEOUS ACID CATALYST 152 6 3 11 CHEMOSELECTIVE BROMOMETHOXYLATION 153 6 3 12 BECKMANN REARRANGEMENT 153 6 3 13 HYDROGENATION OF ELECTRON DE CIENT ALKENES 155 6 3 14 HECK REACTIONS 156 6 3 15 KETONE KETONE REARRANGEMENTS USING POLYMER SUPPORTED ALCL3 157 6 3 16 SYNTHESIS OF 1 3 4 OXADIAZOLES USING POLYMER SUPPORTED BURGESS REAGENT 157 6 3 17 PREPARATION OF A SUBSTITUTED 2 AMINO 1 3 4 OXADIAZOLE LIBRARY 159 6 3 18 SYNTHESIS OF THIOHYDANTOINS 160 6 3 19 HYDROLYSIS OF SUCROSE TO FRUCTOSE 161 6 3 20 MICROWAVE PROMOTED ENZYMATIC REACTIONS 161 6 3 21 SPECTROSCOPIC ESTIMATION OF POLYMER SUPPORTED FUNCTIONAL GROUPS 164 6 3 22 THE SYNTHESIS OF PLICAMINE 164 6 3 23 MICROWAVE ASSISTED SCAVENGING REACTIONS 167 6 4 CONCLUSION 169 6 5 REFERENCES 170 7 MICROWAVE ASSISTED SOLID PHASE SYNTHESIS 177 7 1 COMBINATORIAL CHEMISTRY AND SOLID PHASE ORGANIC SYNTHESIS 177 7 2 MICROWAVE CHEMISTRY AND SOLID PHASE ORGANIC SYNTHESIS 178 7 2 1 MICROWAVE DIELECTRIC HEATING 179 7 2 2 SOLVENTS 179 7 2 3 THERMAL AND MECHANICAL STABILITY OF POLYMER SUPPORTS 180 7 2 4 EQUIPMENT 183 7 3 LITERATURE SURVEY 184 7 3 1 PEPTIDE SYNTHESIS AND RELATED EXAMPLES 184 7 3 2 RESIN FUNCTIONALISATION 188 7 3 3 TRANSITION METAL CATALYSIS 193 7 3 4 SUBSTITUTION REACTIONS 196 7 3 5 MULTI COMPONENT CHEMISTRY 201 7 3 6 CONDENSATION REACTIONS 204 7 3 7 REARRANGEMENTS 206 7 3 8 CLEAVAGE REACTIONS 208 7 3 9 MISCELLANEOUS 212 7 3 10 CASE STUDY PYRAZINONE DIELS ALDER CHEMISTRY 216 7 4 OTHER TYPES OF SUPPORTS 218 7 5 CONCLUSION 219 7 6 REFERENCES 219 8 TIMESAVINGS ASSOCIATED WITH MICROWAVE ASSISTED SYNTHESIS A QUANTITATIVE APPROACH 222 8 1 INTRODUCTION 222 8 2 TIMESAVINGS ASSOCIATED WITH MICROWAVE ASSISTED SYNTHESIS 222 8 3 ACCELERATION OF COMBINATORIAL LIBRARY DESIGN AND DEVELOPMENT STAGES 224 8 3 1 THE CONTEST 226 8 3 2 THE THERMAL APPROACH 227 8 3 3 THE MICROWAVE APPROACH 229 8 4 NEW ADVANCES IN MICROWAVE TECHNOLOGY 230 8 5 REFERENCES 235 9 SCALE UP OF MICROWAVE ASSISTED ORGANIC SYNTHESIS 237 9 1 INTRODUCTION 237 9 2 MECHANISMS AND EFFECTS OF MICROWAVE HEATING 239 9 3 APPROACHES TO MICROWAVE ASSISTED ORGANIC CHEMISTRY 242 9 3 1 SOLVENT FREE METHODS 243 9 3 2 SCALE UP OF SOLVENT FREE METHODS 244 9 3 3 ADVANTAGES AND DISADVANTAGES OF SOLVENT FREE METHODS 247 9 3 4 METHODS EMPLOYING SOLVENTS 248 9 3 5 SCALE UP OF METHODS EMPLOYING SOLVENTS 251 9 3 6 ADVANTAGES AND DISADVANTAGES OF METHODS UTILISING SOLVENTS 259 9 4 SAFETY 262 9 5 TANDEM TECHNOLOGIES INVOLVING MICROWAVES 263 9 6 CONCLUDING REMARKS 265 9 7 REFERENCES 266