New Synthetic Strategies towards Indolizines and Pyrroles Dissertation zur Erlangung des Grades Doktor der Naturwissenschaften vorgelegt am Fachbereich Chemie, Pharmazie und Geowissenschaften der Johannes Gutenberg-Universität Mainz von Murat Kücükdisli geboren in Düzce, Türkei Mainz 2015 Datum der mündlichen Prüfung: 28.04.2015 Dekan: 1. Berichterstatter: Prof. Dr. Till Opatz 2. Berichterstatter: To my family ACKNOWLEDGEMENTS v Table of Contents ACKNOWLEDGEMENTS ............................................................................................... V LIST OF ABBREVIATIONS ........................................................................................... IX 1 INTRODUCTION ....................................................................................................... 1 1.1 Nitrogen Containing Heteroaromatic Compounds .................................. 1 1.2 Indolizines .................................................................................................... 2 1.2.1 Synthesis of Indolizines ............................................................................. 4 1.2.1.1 Annulation of Pyridines .................................................................. 4 1.2.1.2 Annulation of Pyrroles .................................................................. 10 1.3 Pyrroles ....................................................................................................... 14 1.3.1 Synthesis of Pyrroles ............................................................................... 15 2 MOTIVATION .......................................................................................................... 23 3 RESULTS AND DISCUSSION ................................................................................ 27 3.1 Indolizines .................................................................................................. 27 3.1.1 Decoration of the Pyrrole Unit ................................................................ 27 3.1.1.1 Initial Findings .............................................................................. 27 3.1.1.2 Reaction Optimization .................................................................. 31 3.1.1.3 Substrate Scope ............................................................................. 33 3.1.1.4 Mechanisms and Limitations ........................................................ 36 3.1.2 2-Aminoindolizines ................................................................................. 38 3.1.2.1 Initial Findings .............................................................................. 38 3.1.2.2 Reaction Optimization .................................................................. 42 3.1.2.3 Substrate Scope Studies ................................................................ 43 3.1.2.4 Limitations .................................................................................... 47 3.1.3 Decoration of the Pyridine Unit............................................................... 48 3.1.3.1 Initial Findings .............................................................................. 51 3.1.3.2 Reaction Optimization .................................................................. 52 3.1.3.3 Substrate Scope Studies ................................................................ 55 3.2 Pyrroles ....................................................................................................... 60 3.2.1 Pyrrole-2-carbonitriles ............................................................................. 61 3.2.2 2,4-Disubstituted Pyrroles ....................................................................... 63 3.2.3 2,3,5-Trisubstituted Pyrroles ................................................................... 67 3.2.4 Pyrrole-2-carboxamides........................................................................... 70 3.2.5 2,2’-Bipyrroles ......................................................................................... 72 4 CONCLUSION AND OUTLOOK ........................................................................... 75 vii CONTENT 5 EXPERIMENTAL SECTION ................................................................................. 81 5.1 General Experimental Methods ............................................................... 81 5.2 Annulation of pyridines ............................................................................ 82 5.2.1 Synthesis of Indolizines from Pyridinium Ylides ................................... 82 5.2.2 Synthesis of 2-Aminoindolizines .......................................................... 115 5.3 Annulation of Pyrroles ............................................................................ 135 5.3.1 Synthesis of Indolizines from Pyrroles ................................................. 135 5.4 Synthesis of Pyrroles ............................................................................... 154 5.4.1 Synthesis of Pyrrole-2-carbonitriles ...................................................... 154 5.4.2 Synthesis of 2,4-Disubstituted Pyrroles ................................................ 160 5.4.3 Synthesis of 2,3,5-Trisubstituted Pyrroles ............................................ 166 5.4.4 Synthesis of Pyrrole-2-carboxamides.................................................... 171 5.4.5 Synthesis of 2,2’-Bipyrroles .................................................................. 177 6 REFERENCES ........................................................................................................ 179 APPENDIX A: NMR SPECTRA ................................................................................... 193 APPENDIX B: X-RAY DATA ....................................................................................... 248 ERKLÄRUNG ................................................................................................................. 265 viii LIST OF ABBREVIATIONS Ac Acetyl Bt Benzotriazole COSY Correlation spectroscopy Cp Cyclopentadienyl anion DCM Dichloromethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DEAD Diethyl acetylenedicarboxylate DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DNA Deoxyribonucleic acid EDG Electron-donating group ESI Electrospray ionization esp Espionate; α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid EWG Electron-withdrawing group FDA Food and drug administration GC Gas chromatography HMBC Heteronuclear multiband coherence HRMS High resolution mass spectrometry HSQC Heteronuclear single quantum coherence Hz Hertz IBCF Isobutyl chloroformate IR Infrared KHMDS Potassium hexamethyldisilazane LC Liquid chromatography LDA Lithium diisopropylamide LED Light-emitting diode ix LIST OF ABBREVIATIONS MS Mass spectrometry NMM N-Methylmorpholine NMR Nuclear magnetic resonance NOESY Nuclear Overhauser effect spectroscopy oct Octanoate PDE Phosphodiesterase ppm Parts per million REWG Removable electron-withdrawing group RNA ribonucleic acid rt Room temperature TBAB Tetrabutylammonium bromide TBAI Tetrabutylammonium iodide Tc Thiophene-2-carboxylate TEA Triethylamine Tf Triflyl; trifluoromethanesulfonyl THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilyl TOF Time-of-flight Ts Tosyl x 1 Introduction 1.1 Nitrogen Containing Heteroaromatic Compounds Nitrogen heterocycles are the most common molecular scaffolds that can be found in nature. They can be considered as vital structures for the chemistry of living organisms.1 For example, pyrimidine and purine which are the building blocks of DNA and RNA are two important mono- and bicyclic heteroaromatic compounds.2 Besides, three of the twenty proteinogenic amino acids; namely histidine, tryptophan, and proline contain N-heterocyclic motifs (Figure 1). Imidazole and indole are two N-heteroaromatic structures that are found in the former two, respectively.1 Figure 1. Amino acids with N-heterocycles When considering the existence of N-heterocycles in nature, it is inevitable that medicinal chemists pay special attention to this class of compounds. A recently published report3 analyzed that 59% of unique small-molecule drugs approved by the Food and Drug Agency (FDA) in the United States contains at least one nitrogen heterocycle. While the majority of N-heterocycles are five- and six-membered rings, around 40% of them are aromatic. Figure 2 shows the top five aromatic and non-aromatic N-heterocycles. Figure 2. Common aromatic and non-aromatic N-heterocycles in small-molecule drugs Pyridine and piperidine are the most common structures among aromatic and non-aromatic N-heterocyclic compounds, respectively. In addition to their pharmaceutical use, nitrogen 1 1 INTRODUCTION containing heteroaromatic compounds have many applications in materials science as well.4- 7 1.2 Indolizines Indolizine is a bicyclic heteroaromatic compound and analogue of indole. It can also be described as a fused heterocycle which is the combination of an electron-deficient pyridine and an electron-excessive pyrrole by overlapping of two C-N bonds from each ring (Figure 3).8 Figure 3. Structure of the indolizine This fully conjugated 10-system was first described by Angeli in 1890.9 Twenty-two years later, the first synthesis of the unsubstituted indolizine was accomplished by Scholtz.10 Since its discovery, indolizine had been called pyrrocoline, pyrrole[1,2-a]pyridine, pyrindole, and pyrrodine. The term indolizine was first suggested by Tschitschibabin and has been used by German and Japanese scientists.11 Although the non-fused indolizines have not been found in nature,12