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A New Method for Synthesis of Aziridine 2-Phosphonates and Their Biological Activities

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A New Method for Synthesis of Aziridine 2-Phosphonates and Their Biological Activities A NEW METHOD FOR SYNTHESIS OF AZIRIDINE 2-PHOSPHONATES AND THEIR BIOLOGICAL ACTIVITIES A THESIS SUBMITTED TO THE GRADUATE SCHOOL OF NATURAL AND APPLIED SCIENCES OF MIDDLE EAST TECHNICAL UNIVERSITY BY HAKAN BAB İZ IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN CHEMISTRY SEPTEMBER 2010 Approval of the thesis: A NEW METHOD FOR SYNTHESIS OF AZIRIDINE 2-PHOSPHONATES AND THEIR BIOLOGICAL ACTIVITIES submitted by HAKAN BAB İZ in partial fulfillment of the requirements for the degree of Master of Science in Chemistry Department, Middle East Technical University by, Prof. Dr. Canan Özgen _____________________ Dean, Graduate School of Natural and Applied Sciences Prof. Dr. İlker Özkan _____________________ Head of Department, Chemistry Prof. Dr. Özdemir Do ğan ______________________ Supervisor, Chemistry Dept., METU Examining Committee Members: Prof. Dr. Ayhan S. Demir ______________________ Chemistry Dept., METU Prof. Dr. Özdemir Do ğan ______________________ Chemistry Dept., METU Prof. Dr. Cihangir Tanyeli ______________________ Chemistry Dept., METU Prof. Dr. Metin Zora ______________________ Chemistry Dept., METU Assoc. Prof. Dr. Adnan Bulut ______________________ Chemistry Dept., Kırıkkale Üniv. Date: 17.09.2010 I hereby declare that all information in this document has been obtained and presented in accordance with academic rules and ethical conduct. I also declare that, as required by these rules and conduct, I have fully cited and referenced all material and results that are not original to this work. Name, Last name : Hakan Babiz Signature : iii ABSTRACT SYNTHESIS OF AZIRIDINE 2-PHOSPHONATES AND THEIR BIOLOGICAL ACTIVITIES Babiz, Hakan M.S., Department of Chemistry Supervisor: Prof. Dr. Özdemir Do ğan September 2010, 74 pages A systematic study was carried out for the synthesis of aziridine 2-phosphonates by using two methods. First method is the classical Gabriel-Cromwell reaction and the second one is the modified version of Gabriel-Cromwell reaction which was developed in this thesis. In the first method, vinyl phosphonate was used as the starting material, then it was brominated to get 1,2-dibromoethyl phosphonate. HBr elimination from this compound, then reaction with different primary amines gave desired aziridinyl phosphonates in good yields. In the second method, easily available acetyl phosphonate was used as the starting material which was reacted with DBU and tosyl chloride to get α-tosylated vinyl phosphonate. Reaction of this compound with the same amines gave aziridinyl phosphonates in good yields, as well. Biological activities of all newly synthesized compounds were studied against different bacteria. Key words: Aziridinyl phosphonates, Gabriel-Cromwell reaction, biological activity. iv ÖZ AZ İRİDİNE 2-FOSFONATLARIN SENTEZ İ VE B İYOLOJ İK AKT İVİTELER İ Babiz, Hakan Yüksek Lisans, Kimya Bölümü Tez Yöneticisi: Prof. Dr. Özdemir Do ğan Eylül 2010, 74 sayfa Aziridin 2-fosfonatların sentezi için iki ayrı yöntem kullanılarak sistematik bir çalı şma yapılmı ştır. Birinci yöntem klasik Gabriel-Cromwell tepkimesi ve ikinci yöntem bu tez kapsamında geli ştirilmi ş olan modifiye Gabriel-Cromwell tepkimesidir. Birinci yöntemde ba şlangıç maddesi olarak vinil fosfonat kullanılmı ş ve bu maddenin bromlanmasıyla 1,2-dibromoetil fosfonat elde edilmi ştir. Bu bile şikten HBr ayrılması sonra farklı birinci derece aminlerle tepkimesiyle beklenen aziridinil fosfonatlar iyi verimlerle elde edilmi ştir. İkinci yöntemde ise bulunması daha kolay asetil fosfonat ba şlangıç maddesi olarak kullanılmı ştır. Bu bile şiğin DBU ve tosil klorür ile tepkimesinden α-tosillenmi ş vinil fosfonat elde edilmi ştir. Bu bile şiğin aynı aminlerle tepkimesinden de beklenen aziridinil fosfonatlar yine iyi verimlerle elde edilmi ştir. Sentezlenen tüm yeni bile şiklerin biyolojik aktiviteleri farklı bakteriler üzerinde çalı şılmı ştır. Anahtar kelimeler: aziridinil fosfonatlar, Gabriel-Cromwell reaksiyonu, biyolojik aktivite. v To my dear parents... vi ACKNOWLEDGEMENTS I would like to express my greatest appreciations to my supervisor Prof. Dr. Özdemir Do ğan for his patience, guidance, advice, criticism, encouragements throughout this study. I would also thank to Assoc. Prof. Dr. Adnan Bulut for his encouragement support, help and interesting scientific discussions. Moreover, I want to thank to my labmates Şerife Özdemir, Akın İnce, Muhammet İş çi, Gül Şenyurt and Serkan Tan for their friendship. I would like to thank to Assoc. Prof. Dr. Ay şegül Çetin Gözen and Assist. Prof. Dr. Songül Budak for biological activity tests. I would like to thank to all organic group members for their friendship. In addition, I would like to thank to Seda Karayılan and Zehra Uzuno ğlu for obtaining NMR spectra. Finally, I owe great thanks to my parents for their endless love, support, patience and absolute belief in me. vii TABLE OF CONTENTS ABSTRACT ............................................................................................................... iv ÖZ ................................................................................................................................ v ACKNOWLEDGEMENTS ....................................................................................... vii TABLE OF CONTENTS ......................................................................................... viii LIST OF TABLES .................................................................................................... xii LIST OF FIGURES .................................................................................................. xiii LIST OF SCHEMES .................................................................................................. xv LIST OF ABBREVIATIONS .................................................................................. xvii CHAPTERS 1. INTRODUCTION ................................................................................................... 1 1.1 Properties of aziridines .................................................................................. 2 1.1.1 Structure of aziridines ............................................................................ 2 1.1.2 Acidity of aziridines ............................................................................... 3 1.1.3 Spectroscopic Properties of aziridines ................................................... 3 1.2 Synthetic Methods for Aziridines .................................................................. 4 1.2.1 Addition to Alkenes ............................................................................... 4 1.2.1.1 Addition of Nitrenes and Nitrenoids to Alkenes ............................ 4 1.2.1.2 Aziridines by Addition-Elimination Processes ............................... 5 1.2.2 Addition to Imines ................................................................................. 6 1.2.2.1 Carbene Methodology..................................................................... 6 1.2.2.2 Aza-Darzens and Analogous Reactions .......................................... 7 1.2.2.3 Ylide-mediated aziridination .......................................................... 8 1.2.3 Addition to Azirines ............................................................................... 8 viii 1.2.4 Aziridines through Cyclization .............................................................. 9 1.2.4.1 From Epoxides ................................................................................ 9 1.2.4.2 From 1,2-Aminoalcohols and 1,2-Aminohalides ......................... 10 1.2.4.3 From 1,2-Azidoalcohols ............................................................... 11 1.3 Aziridine 2-phosphonates ............................................................................ 12 1.3.1 Synthesis of Aziridine 2-Phosphonates ................................................ 13 1.3.1.1 Ring Closure by Nucleophilic Substitution .................................. 13 1.3.1.2 Aziridination using Nitrenes ......................................................... 16 1.3.1.3 Aziridination using Carbenoids .................................................... 18 1.3.1.4 Reduction of 2 H Azirine-2-Phosphonates .................................... 18 1.4 Aim of the work .......................................................................................... 19 2. RESULTS AND DISCUSSION ............................................................................ 20 2.1 Synthesis of aziridines ................................................................................. 20 2.1.1 Synthesis of aziridines starting from α-tosylated vinyl phosphonate .. 20 2.1.1.1 Synthesis of α-tosylated vinyl phosphonate ................................. 20 2.1.1.1.1 Mechanism of Michaelis-Arbuzov reaction .............................. 21 2.1.1.1.2 Synthesis of α-tosylated vinyl phosphonate .............................. 22 2.1.1.1.3 Synthesis of aziridine 2-phosphonate derivatives ...................... 23 2.1.2 One-pot synthesis of aziridine 2-phosphonate ..................................... 28 2.1.3 Synthesis of aziridines starting from 1,2-dibromoethyl phosphonate via Gabriel-Cromwell reaction ................................................................................. 29 2.1.3.1 Synthesis of starting material 1,2-dibromoethyl phosphonate ..... 30 2.1.3.2 Synthesis of aziridine derivatives ................................................. 30 2.1.4 Synthesis of N-H aziridine 2-phosphonate by benzyl cleavage ........... 32 2.1.5 Comparision of two
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