DOCSLIB.ORG

New Synthetic Strategies Towards Indolizines and Pyrroles

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
New Synthetic Strategies Towards Indolizines and Pyrroles 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
Load more

Recommended publications
  • Part I: Nitroalkenes in the Synthesis of Heterocyclic Compounds† Cite This: RSC Adv.,2014,4, 48022 Azim Ziyaei Halimehjani,*A Irishi N
    RSC Advances REVIEW View Article Online View Journal | View Issue Part I: Nitroalkenes in the synthesis of heterocyclic compounds† Cite this: RSC Adv.,2014,4, 48022 Azim Ziyaei Halimehjani,*a Irishi N. N. Namboothiri*b and Seyyed Emad Hooshmanda The applications of nitroalkenes in the synthesis of three- to five-membered O, N and S-heterocycles, including natural products are investigated in this review. These heterocyclic compounds were synthesized from nitroalkenes with a variety of substituents at the a and b-positions and those that were part of common and medium rings via a wide variety of reactions such as Michael addition reactions, epoxidation, [3 + 2] cycloaddition and many cascade/domino/tandem reactions. In addition, the potential of nitroalkenes to take part in multi-component and cascade reactions, particularly, in diastereo- and enantioselective versions is reviewed. The high reactivity of nitroalkenes and their Received 18th August 2014 potential to coordinate with the metal catalysts as well as organocatalysts signify them as efficient Accepted 16th September 2014 precursors in synthetic organic chemistry. Also, the flexibility of the nitro group in functional group DOI: 10.1039/c4ra08828j manipulations has expanded the scope of the nitro group, in general, and nitroalkenes, in particular, in www.rsc.org/advances organic synthesis. aFaculty of Chemistry, Kharazmi University, 49 Mofateh St., Tehran, Iran. E-mail: † Dedicated to Professor Mohammad Reza Saidi on the occasion of his 70th [email protected]; Fax: +98 (21) 88820992; Tel: +98 (21) 88848949 birthday. bDepartment of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India. E-mail: [email protected] Published on 17 September 2014.
    [Show full text]
  • Total Synthesis of 1,2- Diamine Contained Alkaloids, Schizozygine, Vallesamidine and Strempeliopine (Chapter 1 and 2)
    Towards Schizozygine Type Alkaloids: Total Synthesis of (+)-Vallesamidine and (+)-Strempeliopine by Xiangyu Zhang A thesis submitted in partial fulfilment of the requirement for the degree of Doctor of Philosophy Department of Chemistry University College London Declaration I, Xiangyu Zhang, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signed: Date: i Abstract As a classic and powerful tool for carbon-carbon bond formation, the nitro-Mannich reaction has shown its versatility in drugs and natural products syntheses. The 1,2- diamine structure, a reduced moiety from nitro-Mannich adduct, is widely present in naturally occurring alkaloids and this feature suggested the potential application of nitro- mannich reaction in such alkaloids synthesis. This thesis showcases the nitro-Mannich reaction as a key strategic reaction through studies towards the total synthesis of 1,2- diamine contained alkaloids, schizozygine, vallesamidine and strempeliopine (Chapter 1 and 2). Initial studies on the schizozygine molecule (Chapter 3) generated a diastereoselective nitro-Mannich reaction on -branched nitroalkanes to synthesise complex -nitroamines with three contigurous chiral centres and syn,anti stereochemistry. This reaction was followed by a reductive cyclisation to achieve the functionalised piperidine ring C. Although the subsequent manipulation towards advanced shcizozygine intermediate was unsuccessful, the nitro-Mannich/reductive cyclisation sequence provided methodology for highly functionalised piperidine ring synthesis. A second generation route using nitro-Mannich reaction was accompanied by other nitro group chemistry, Michael addition, Tsuji-Trost allylation and nitro group reduction/C-N coupling reaction, to realise the quick and concise preparation of an A/B/C ring intermediate.
    [Show full text]
  • Conjugate Additions of Nitroalkanes to Electron-Poor Alkenes: Recent Results
    Chem. Rev. 2005, 105, 933−971 933 Conjugate Additions of Nitroalkanes to Electron-Poor Alkenes: Recent Results Roberto Ballini,* Giovanna Bosica, Dennis Fiorini, Alessandro Palmieri, and Marino Petrini* Dipartimento di Scienze Chimiche, Universita` di Camerino, via S. Agostino, 1, I-62032 Camerino, Italy Received September 30, 2004 Contents Conjugate additions using highly stabilized carban- ions are still of interest since a growing number of 1. Introduction 933 these procedures can be carried out in environmen- 2. General Aspects of the Conjugate Addition of 934 tally benign solvents such as water and using cata- Nitroalkanes lytic amounts of the basic promoter. In addition, the 2.1. Multiple Additions 934 achievement of diastereo- and enantioselective pro- 2.2. Basic Catalysts 935 cesses is no longer an exclusive domain of highly 3. New Basic Catalysts for the Conjugate Addition 936 reactive carbanionic systems working in carefully 4. Diastereoselective Conjugate Additions 936 controlled conditions3 but can be nowadays conducted 4.1. Intermolecular Additions 936 even at room temperature using easily available 4.2. Intramolecular Additions 948 substrates and suitable base/solvent combinations. 5. Asymmetric Conjugate Additions Promoted by 949 Nitroalkanes are a valuable source of stabilized Chiral Catalysis carbanions since the high electron-withdrawing power 6. Conjugate Addition−Elimination Reactions 953 of the nitro group provides an outstanding enhance- R 7. Synthetic Applications 957 ment of the hydrogen acidity at the -position (cf. pka ) 4-8 7.1. Pyrrolidines and Derivatives 957 MeNO2 10). Nitronate anions 2 that can be generated from nitroalkanes 1 using a wide range of 7.2. Lactones and Oxygenated Heterocycles 960 bases act as carbon nucleophiles with common elec- 7.3.
    [Show full text]
  • Open Sacher - Phd Dissertation.Pdf
    The Pennsylvania State University The Graduate School Eberly College of Science PROGRESS TOWARD A TOTAL SYNTHESIS OF THE LYCOPODIUM ALKALOID LYCOPLADINE H A Dissertation in Chemistry by Joshua R. Sacher © 2012 Joshua R. Sacher Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 2012 ii The dissertation of Joshua Sacher was reviewed and approved* by the following: Steven M. Weinreb Russell and Mildred Marker Professor of Natural Products Chemistry Dissertation Advisor Chair of Committee Raymond L. Funk Professor of Chemistry Gong Chen Assistant Professor of Chemistry Ryan J. Elias Frederik Sr. and Faith E. Rasmussen Career Development Professor of Food Science Barbara Garrison Shapiro Professor of Chemistry Head of the Department of Chemistry *Signatures are on file in the Graduate School iii ABSTRACT In work directed toward a total synthesis of the Lycopodium alkaloid lycopladine H (21), several strategies have been explored based on key tandem oxidative dearomatization/Diels-Alder reactions of o-quinone ketals. Both intra- and intermolecular approaches were examined, with the greatest success coming from dearomatization of bromophenol 84b followed by cycloaddition of the resulting dienone with nitroethylene to provide the bicyclo[2.2.2]octane core 203 of the natural product. The C-5 center was established via a stereoselective Henry reaction with formaldehyde to form 228, and the C-12 center was set through addition of vinyl cerium to the C-12 ketone to give 272. A novel intramolecular hydroaminomethylation of vinyl amine 272 was used to construct the 8-membered azocane ring in intermediate 322, resulting in establishment of 3 of the 4 rings present in the natural product 21 in 9 steps from known readily available compounds.
    [Show full text]
  • Synthesis of Biologically Active Compounds
    SYNTHESIS OF BIOLOGICALLY ACTIVE COMPOUNDS BY DUSHANT ANANDRAO KHOBRAGADE DIVISION OF ORGANIC CHEMISTRY: TECHNOLOGY NATIONAL CHEMICAL LABORATORY PUNE 411008, INDIA DECEMBER 2006 SYNTHESIS OF BIOLOGICALLY ACTIVE COMPOUNDS A THESIS SUBMITTED TO THE UNIVERSITY OF PUNE FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY BY DUSHANT ANANDRAO KHOBRAGADE Division of Organic Chemistry: Technology National Chemical Laboratory Pune 411008 INDIA DECEMBER 2006 CERTIFICATE This is to certify that the work incorporated in the thesis entitled “Synthesis of Biologically Active Compounds” submitted by Mr. Dushant A. Khobragade was carried out by him under my supervision at National Chemical Laboratory, Pune. Material that has been obtained from other sources is duly acknowledged in this thesis. Date: Subhash P. Chavan Research Supervisor DECLARATION I hereby declare that the thesis entitled “Synthesis of Biologically Active Compounds” submitted for Ph. D. degree to the University of Pune has been carried out at National Chemical Laboratory, under the supervision of Dr. Subhash P. Chavan. This work is original and has not been submitted in part or full by me for any degree or diploma to this or any other university. Date: Dushant A. Khobragade Division of Organic Chemistry: Technology National Chemical Laboratory Pune 411 008. Dedicated To My (late) Uncle and Grandmother Acknowledgements It gives me great pleasure to express my deep gratitude to my research guide, Dr. S. P. Chavan, for introducing me to the fascinating field of Organic Chemistry, for his inspiring guidance and never diminishing encouragement throughout my research programme. I am thankful to Dr. S. K. Kamat and Dr. U. R. Kalkote for their affection, suggestions and helping me to speed up work throughout my research programme.
    [Show full text]
  • The Case of Silodosin
    Department of Chemistry Doctorate School in Industrial Chemical - XXVII Cycle New processes for the APIs industrial production: the case of silodosin Ph. D. Thesis of Francesco CALOGERO R09773 Tutor: Prof. Daniele Passarella Cotutor: Dr. Emanuele Attolino Coordinator: Prof. Dominique Roberto Academic Year: 2013/2014 Ai miei genitori Dietro ogni problema c’è un’opportunità (Behind every problem there is an opportunity) Galileo Galilei (1564-1642) ABSTRACT This thesis is focused on the development of new synthetic processes for the production of already known Active Pharmaceutical Ingredients (APIs). The research work was performed in the laboratories of Dipharma Francis srl, a company which operates in the generic drug market. The launch of the generic version of a drug in the market often leads to lowering of product prices for both the branded product and the generic ones. For this reason, the process adopted to produce an API has to be innovative, efficient, safe and, of course, cheaper than the existing ones, in order to be competitive in the market. During my Ph.D. I worked on the synthesis of some APIs, in particular here I report the feasibility and development studies of an alternative process to produce silodosin. Silodosin is an API used as a treatment for the symptoms of Benign Prostatic Hyperplasia (BPH). In order to establish the synthetic strategy and to outline our freedom to operate, an accurate survey of the whole patent literature about silodosin has been done. During the feasibility study several synthetic approaches have been tried in order to functionalise indoline at positions 5 and 7.
    [Show full text]
  • A Review of the Synthetic Strategies Toward Dihydropyrrolo[1,2-A]Pyrazinones
    Review A Review of the Synthetic Strategies toward Dihydropyrrolo[1,2-a]Pyrazinones Pieterjan Winant 1,† , Tomas Horsten 1,† , Shaiani Maria Gil de Melo 2, Flavio Emery 2,* and Wim Dehaen 1,* 1 Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium; [email protected] (P.W.); [email protected] (T.H.) 2 Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences at Ribeirao Preto of the University of Sao Paulo, Ribeirao Preto 14040903, SP, Brazil; [email protected] * Correspondence: fl[email protected] (F.E.); [email protected] (W.D.) † Both authors contributed equally to this work. Abstract: Dihydropyrrolo[1,2-a]pyrazinone rings are a class of heterocycles present in a wide range of bioactive natural products and analogues thereof. As a direct result of their bioactivity, the synthesis of this privileged class of compounds has been extensively studied. This review provides an overview of these synthetic pathways. The literature is covered up until 2020 and is organized according to the specific strategies used to construct the scaffold: fusing a pyrazinone to an existing pyrrole, employing a pyrazinone-first strategy, an array of multicomponent reactions and some miscellaneous reactions. Keywords: pyrrole; pyrazinone; heterocycle; natural product; cycloaddition; multicomponent reaction 1. Introduction Citation: Winant, P.; Horsten, T.; Gil de Melo, S.M.; Emery,F.; Dehaen, W.A Nitrogen-containing heteroaromatic rings are valuable motifs in bioactive molecules Review of the Synthetic Strategies toward and recurrent scaffolds present in drugs [1,2]. The application of nitrogen ring systems Dihydropyrrolo[1,2-a]Pyrazinones. in drug development is related to their diverse properties, including relatively small con- Organics 2021, 2, 118–141.
    [Show full text]
  • Nitro Compounds and Their Derivatives in Organic Synthesis • Nagatoshi Nishiwaki Nitro Compounds and Their Derivatives in Organic Synthesis
    Nitro Organic Compounds Synthesis in Derivatives and Their • Nagatoshi Nishiwaki Nitro Compounds and Their Derivatives in Organic Synthesis Edited by Nagatoshi Nishiwaki Printed Edition of the Special Issue Published in Molecules www.mdpi.com/journal/molecules Nitro Compounds and Their Derivatives in Organic Synthesis Nitro Compounds and Their Derivatives in Organic Synthesis Editor Nagatoshi Nishiwaki MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade • Manchester • Tokyo • Cluj • Tianjin Editor Nagatoshi Nishiwaki Kochi University of Technology Japan Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Molecules (ISSN 1420-3049) (available at: https://www.mdpi.com/journal/molecules/special issues/nitro organic synthesis). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03943-148-9 (Hbk) ISBN 978-3-03943-149-6 (PDF) c 2020 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Editor .............................................. vii Nagatoshi Nishiwaki A Walk through Recent Nitro Chemistry Advances Reprinted from: Molecules 2020, 25, 3680, doi:10.3390/molecules25163680 .............
    [Show full text]