Microwave Assisted Intramolecular Dehydrogenative Dehydro-Diels Alder Approach To Substituted Benzofused Heterocycles by Justin T. Proto B.S. Chemistry, University of North Carolina, Chapel Hill, 2007 Submitted to the Graduate Faculty of the Kenneth P. Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Master of Science University of Pittsburgh 2016 UNIVERSITY OF PITTSBURGH DIETRICH SCHOOL OF ARTS AND SCIENCES This thesis was presented by Justin T. Proto It was defended on April 14, 2016 and approved by Dr. Seth Horne, Associate Professor, Department of Chemistry Dr. Paul Floreancig, Professor, Department of Chemistry Thesis Director: Dr. Kay Brummond, Professor, Department of Chemistry UNIVERSITY OF PITTSBURGH [NAME OF THE SCHOOL] ii Copyright © by Justin T. Proto 2016 Copyright © by [Author’s name] [year] iii Micrwave Assisted Intramolecular Dehydrogenative Dehydro-Diels Alder Approach To Substituted Benzofused Heterocycles Justin T. Proto, M.S. University of Pittsburgh, 2016 ABSTRACT [TITLE OF THE THESIS/DISSERTATION] The emergence of benzo[b]thiophenes and benzo[b]furans as biologically useful [Author’s Name], [M.A./M.S./PhD] scaffolds is of growing attention in medicine as natural products and pharmaceutical drugs. The University of Pittsburgh, [year] means to produce these synthetic cores quickly and from economic starting materials has garnered much attention. Much of the current methodology is focused on formation of the heterocyclic ring annulation from benzene derivatives. However, the mechanistic restraints of this chemistry narrows the substitutional scope of the resulting benzo-fused heterocycles. Presented here is a simple methodology to produce uniquely substituted benzo[b]thiophenes and benzo[b]furans via the intramolecular dehydro-Diels-Alder reaction induced by microwave heating. Starting from aromatic heterocycles and focusing on a strategy of benzene annulation from heterocyclic-diene alkynyl-dienophile pairs forming tricyclic fused heterocycles were readily synthesized. The allowance of major product selection was demonstrated by solvent choice during heating; fully aromatic heterocycles were favored when PhNO2 was chosen, in as little as 10% by volume. The use of DMF favored the formation of dihydroheterocycles. The reaction showed a tolerance of terminal alkyne substitution and generally produced good yields. iv TABLE OF CONTENTS ABBREVIATIONS .................................................................................................................. XIII PREFACE ................................................................................................................................. XIV 1.0 INTRODUCTION ........................................................................................................ 1 1.1 BENZO[B]THIOPHENE APPLICATION IN DRUG LEADS AND NATURAL PRODUCTS ..................................................................................................... 2 1.2 BENZO[B]FURAN APPLICATION IN DRUG LEADS AND NATURAL PRODUCTS ........................................................................................................................ 10 2.0 BENZO[B]THIOPHENE AND BENZO[B]FURAN SYNTHETIC CONSTRUCTION METHODS ................................................................................................ 19 2.1 BENZO[B]THIOPHENE SYNTHETIC CONSTRUCTION METHODS .. 19 2.2 BENZO[B]FURAN SYNTHETIC CONSTRUCTION METHODS ............ 33 3.0 MICROWAVE-ASSISTED DEHYDROGENATIVE DEHYDRO-DIELS- ALDER REACTION TO BENZOFUSED HETEROCYCLES. ............................................ 43 CONCLUSION ........................................................................................................................... 62 APPENDIX A .............................................................................................................................. 63 A.1 CHEMICAL CHARACTERIZATION CHECKLIST .................................. 63 A.2 GENERAL METHODS .................................................................................... 65 A.3 COMPOUND SYNTHESIS .............................................................................. 67 v A.4 COMPOUND 1H AND 13C NMR SPECTRA ............................................... 113 BIBLIOGRAPHY ..................................................................................................................... 187 vi LIST OF TABLES Table 1 Exploration of solvent role in product determination on (E)-3-(thiophen-3-yl)allyl 3- phenylpropiolate ........................................................................................................................... 52 Table 2 Summary of results in opt. aromatic annulation conditions ............................................ 57 Table 3 Summary of results with DMF as reaction solvent.......................................................... 60 Table 4 Chemical characterization checklist ................................................................................ 64 vii LIST OF FIGURES Figure 1 Raloxifene® ..................................................................................................................... 2 Figure 2 Antimitotic 2-(4’-methoxyphenyl)-3-(3’,4’,5’-trimethoxybenzoyl)-6-methoxybenzo[b] thiophene ......................................................................................................................................... 2 Figure 3 Antifungal Sertaconazole ................................................................................................. 3 Figure 4 Antithrombitic (E)-3-(3-(4-chlorophenoxy)-5,6-bis((4-(phenylthio)benzyl)oxy)benzo[b] thiophen-2-yl)-2-(pyridin-4-yl)acrylic acid .................................................................................... 3 Figure 5 SSRI (S)-1-((R)-4-(4-methoxybenzo[b]thiophen-2-yl)-2,2-dimethylpiperidin-1-yl)-3- ((2-methyl-1H-indol-4-yl)oxy)propan-2-ol .................................................................................... 4 Figure 6 SSRI 1-(benzo[b]thiophen-3-yl)-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-1-ol .... 4 Figure 7 Rho kinase inhibitor 4-(5-(1-aminobutyl)-3-methylbenzo[b]thiophen-2-yl)pyrimidin-2- amine ............................................................................................................................................... 5 Figure 8 Histamine H3 antagonist (4-cyclobutylpiperazin-1-yl)(3-(piperidin-1-yl-methyl)benzo [b]thiophen-5-yl)methanone ........................................................................................................... 5 Figure 9 5-LO inhibitor 3-(4-fluorophenyl)-6-((4-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-1H- 1,2,3-triazol-1-yl)methyl)benzo[b]thiophene-2-carboxamide ........................................................ 6 Figure 10 Anti-inflammatory Zileuton ........................................................................................... 6 Figure 11 Dopamine D3 receptor antagonist N-(4-(piperazin-1-yl)butyl)benzo[b]thiophene-2- carboxamide .................................................................................................................................... 7 viii Figure 12 PGD2 antagonist (Z)-7-((1R,2R,3S,5S)-2-(5-hydroxybenzo[b]thiophene-3-carbox amido)-6,6-dimethylbicyclo[3.1.1]heptan-3-yl)hept-5-enoic acid ................................................. 7 Figure 13 Anticoagulant 6-((4-methoxybenzyl)oxy)benzo[b]thiophene-2-carboximidamide ....... 8 Figure 14 Echinothiophene ............................................................................................................. 9 Figure 15 Bryoanthrathiophene ...................................................................................................... 9 Figure 16 Ramelteon ..................................................................................................................... 10 Figure 17 Tasimelteon .................................................................................................................. 10 Figure 18 MT1/MT2 antagonist N-(2-(5-methoxy-2-arylbenzofuran-3-yl)ethyl)acetamide ........ 11 Figure 19 Hepatitis C NS5B allosteric inhibitor (4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-fluorophenyl)boronic acid . 11 Figure 20 Protein Tyrosine Phosphatase inhibitor 3-((3-chlorophenyl)ethynyl)-2-(4-(2-(cyclo propylamino)-2-oxoethoxy)phenyl)-6-hydroxybenzofuran-5-carboxylic acid ............................ 12 Figure 21 fXIa allosteric inhibitor sodium 6-ethoxy-3-(ethoxycarbonyl)-2-(((3-(ethoxycarbonyl)- 2-(((3-(ethoxycarbonyl)-6-methoxy-2-methylbenzofuran-5-yl)oxy)methyl)-6-methoxy benzo furan-5-yl)oxy)methyl)benzofuran-7-sulfonate ............................................................................ 13 Figure 22 Antimitotic N-((7S)-10-(hydroxymethyl)-1,2,3-trimethoxy-6,7-dihydro-5H-benzo[6,7] cyclohepta[1,2-f]benzofuran-7-yl)acetamide ................................................................................ 14 Figure 23 Cytotoxic ((2R,3S)-5-(6-acetyl-5-hydroxybenzofuran-2-yl)-2-(3-hydroxy-4-methoxy phenyl)-3,4-dihydro-2H-pyran-3-yl)methyl acetate ..................................................................... 15 Figure 24 Anti-inflammatory 2-(5-(3-hydroxypropyl)benzofuran-2-yl)-5-methoxyphenol ........ 16 Figure 25 Antitubercular (E)-3-(7-methoxybenzofuran-5-yl)acrylaldehyde ................................ 17 Figure 26 HIF-1 inhibitor Moracin O ........................................................................................... 17 ix Figure 27 Pd catalyzed