UNIVERSITY OF OKLAHOMA GRADUATE COLLEGE SYNTHESIS OF NITROGEN HETEROCYCLES VIA TRANSITION METAL CATALYZED REDUCTIVE CYCLIZATIONS OF NITROAROMATICS A Dissertation SUBMITTED TO THE GRADUATE FACULTY in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY By David K. O Dell Norman, Oklahoma 2003 UMI Number: 3109054 INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. UMI UMI Microform 3109054 Copyright 2004 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 Copyright DAVID K. O DELL 2003 Ail Rights Reserved SYNTHESIS OF NITROGEN HETEROCYCLES VIA TRANSITION METAL CATALYZED REDUCTIVE CYCLIZATIONS OF NITROAROMATICS A Dissertation APPROVED FOR THE DEPARTMENT OF CHEMISTRY AND BIOCHEMISTRY BY Kenneth M. Nicholas, chair Ronald L. Halterman I/- Vadim A. Soloshonok Richm-d W. Taylor I Michael H. Engel ACKNOWLEDGEMENTS I would like to thank my wife Sijy for her unwavering support and affection. I would also like to thank my parents John O'Dell and Marlene Steele, my deceased step­ parents Jim Steele and Laurie O'Dell, all for never discouraging my curiosity as a child. I owe a large debt of gratitude to all my teachers. At Wilson High School, Ronald Gunter allowed me to "mix things up" during class, and never discouraged me despite occasional exothermic reactions and the frequent disappearance of chemicals. At East Central University, Professor Daniel Mclnnes who provided me with my first exposure to modem organic chemistry through sweat stained shirts and chalk stained hands. At MIT Scott Virgil taught me how to do chromatography. At the University of Oklahoma the late Professor Roland Lehr, who unfortunately was unable to see me complete my studies, helped me through many difficult cume problems. Professor Nicholas for allowing me to work in his laboratory and supporting me when nothing seemed to work (I guess we didn't need the title of my initial studies: 'The chemistry of tar'). Of course I would like to thank my committee for their participation in the entire process. Susan Alguindigue for her help with NMR experiments and some of the nice figures contained herein. I appreciate the support from the OU Graduate Alumni Fellowship. I would also like to thank all the people I met while at OU, especially the Nicholas lab: Russell, Radhey, Manoj, Nick, Andrea, Masa, Jerome, Kirk, Pei, Quincai, and anyone else who helped along the way. IV Wer genug gelernt hat, hat nichts gelemt. Elias Canetti TABLE OF CONTENTS Page Chapter 1 INTRODUCTION AND BACKGROUND 1.1 Synthesis of Amines in Organic Chemistry 1 1.1.1 Classical Amination Methods I 1.1.2 Modem Amination Methods 4 1.1.2.1 Allylic Amination 8 1.3 The Reduction of Aromatic Nitro Groups in Organic Chemistry 21 1.3.1 Classical Methods 21 1.3.2 Reductive Carbonylation 22 1.3.3 Reduction of Aromatic Nitro Groups in the Synthesis of Nitrogen Heterocycles 24 1.4 Project Objectives 29 Chapter 2 SYNTHESIS AND REDUCTIVE CYCLIZATION OF MODEL COMPOUNDS: TOWARDS THE SYNTHESIS OF 6-MEMBERED NITROGEN HETEROCYCLES 2.1 Introduction and Background 31 2.1.1 Classical 4-Quinolone Syntheses 32 2.1.2 Modem Methods in 4-Quinolone Synthesis 34 2.2 Results and Discussion 38 VI 2.2.1 Preparation and Cyclization of 2-Nitro a-Methyl Styrene 38 2.2.2 Implications of the Cyclization of 2-Nitro a-Methyl Styrene 40 2.2.3 Preparation and Cyclization of 2-Nitro Enones 43 2.2.4 Preparation and Cyclization of Aromatic Nitro Compounds with Pendant Propargyl Groups 47 2.3 Summary and Conclusions 48 Chapter 3 SYNTHESIS AND REDUCTIVE CYCLIZATION OF O-NITRO BAYLIS-HILLMAN ADDUCES 3.1 Introduction 49 3.1.1 The Baylis-Hillman Reaction 50 3.1.2 0-Nitro Baylis-Hillman Adducts in Heterocyclic Chemistry 50 3.2 Results and Discussion 52 3.2.1 Preparation of Baylis-Hillman Adducts 52 3.2.2 Cyclization of o-Nitro Baylis-Hillman Adducts 54 3.2.3 Possible Mechanisms for the Formation of Products from Reductive Cyclization of Baylis-Hillman Adducts 61 Vll 3.2.4 Attempts at Preparation of Potential Intermediates in the Reductive Cyclization of o-Nitro Baylis-Hillman Adducts 63 3.3 Summary and Conclusions 65 Chapter 4 SYNTHESIS AND CYCLIZATION OF DERIVATIVES OF BAYLIS-HILLMAN ADDUCTS 4.1 Introduction 66 4.2 Attempted Oxidation of Baylis-Hillman Adducts 67 4.3 Synthesis and Cyclization of Baylis-Hillman Acetates: A New Synthesis of 3-Substituted Quinolines 70 4.4 Other Methods fro Preparing 3-Carboalkoxy Quinolines 84 4.5 Synthesis and Cyclization of Other Derivatives Of Baylis-Hillman Adducts: Carboxylic Acid, TMS Ether, and Trifluoroacetate 86 4.6 Attempts to Synthesize 4 -CF3 Quinolines 91 4.7 Mechanistic Experiments 96 4.7.1 Attempts to Understand the Active Organometallic Species 96 Vlll 4.7.2 Attempted Synthesis of Potential Organic Intermediates 99 4.8 Proposed Mechanisms 102 4.8.1 Potential Mechanisms For Nitro Reduction 102 4.8.2 Potential Mechanisms For Quinoline Formation 106 4.9 Summary and Conclusions 108 Chapter 5 SYNTHESIS OF IH-INDAZOLES FROM 2-NlTRO KETOXIMES 5.1 Introduction 110 5.2 Results and Discussion 114 5.2.1 Initial Results 114 5.2.2 Synthesis of 2-Nitro Ketoximes 117 5.2.3 Synthesis of IH-lndazoles 124 5.3 The Significance of the Synthesis of IH- Indazoles from 2-Nitro Ketoximes 126 5.4 Potential Mechanisms for Indazole Formation 130 5.5 Summary 132 Chapter 6 PROJECT SUMMARY AND FUTURE DIRECTIONS 6.1 Project Summary 133 6.2 Future Directions 138 IX 6.2.1 Organometallic/Inorganic Chemistry 138 6.2.2 Organic Chemistry 140 Chapter 7 EXPERIMENTAL 7.1 General Considerations 143 7.2 Stile Couplings 144 7.3 Synthesis of 4-Quinolone 82 148 7.4 Organocerium Mediated Addition of Grignards to 2-Nitro Benzaldehyde 149 7.5 Synthesis of Baylis-Hillman Adducts 150 7.6 Cyclization of Baylis-Hillman Adducts 155 7.7 Alternative Preparation of 99 159 7.8 Preparation of Baylis-Hillman Acetates 161 7.9 Cyclization of Baylis-Hillman Acetates: Synthesis of 3-Substituted Quinolines 164 7.10 Preparation of Other Derivatives of Baylis- Hillman Adducts Acid (131), Trifluoroacetate (132), and TMS Ether (133) 167 7.11 Preparation of Ketone 140 169 7.12 Preparation of 2-Nitro Ketoximes 169 7.13 Synthesis of 1-H Indazoles 175 7.14 Details of X-Ray Data for 176 178 7.15 Calculation of AG for Rotamers of 99 189 7.16 Method of Internal Standard 192 REFERENCES 193 XI LIST OF SCHEMES Page Scheme 1.1 Classical Syntheses of Alkylamines 2 Scheme 1.2 A One-Pot Reductive Amination 3 Scheme 1.3 Schverdina-Kotscheschow Amination 4 Scheme 1.4 Hydroamination of Alkynes in Synthesis 5 Scheme 1.5 Hydroboration/Amination 5 Scheme 1.6 Amines from Alcohols via Sulfamate Esters 6 Scheme 1.7 Asymmetric Aziridination 7 Scheme 1.8 Asymmetric Hydroamination 8 Scheme 1.9 Enders Asymmetric Amination with Allyl Fe Complexes 9 Scheme 1.10 Asymmetric Pd-Catalyzed Allylic Amination 9 Scheme 1.11 Sharpless-Kresze Amination 10 Scheme 1.12 Allylic Amination by Mo Oxaziridine Complexes 11 Scheme 1.13 Mo-Catalyzed Allylic Amination 12 Scheme 1.14 Hetero-Diels Alder Reaction of Nitrosobenzene with 2,3 Dimethylbutadiene 13 Scheme 1.15 Proposed Catalytic Cycle for Mo-Catalyzed Allylic Amination 13 Scheme 1.16 Allylic Amination Catalyzed by Fe Salts 14 Scheme 1.17 Allylic Amination with 2,4 Dinitrophenyl Hydroxylamine 15 Scheme 1.18 Carbazole Production from 2-Nitrobiphenyl, a Probe for Nitrenes 18 Scheme 1.19 Cenini's Allylic Amination of Cyclohexene 19 Scheme 1.20 Asymmetric Allylic Amination by Metal Bound Nitrenes 20 Scheme 1.21 Intermediates in the Reduction of Aromatic Nitro Compounds 22 Scheme 1.22 Selected Reactions of Aromatic Nitro Groups with Metal Carbonyls 23 Scheme 1.23 A Reissert Indole Synthesis 25 Xll Scheme 1.24 Selected Heterocycles Synthesized by the Reductive Cyclization of Nitroaromatics with Tervalent Phosphorous Reagents 26 Scheme 1.25 Synthesis of Nitrogen Heterocycles via the Reductive Carbonylation of Nitroaromatics 28 Scheme 1.26 Substrates Selected for Reductive Cyclization 29 Scheme 1.27 Heterocycles Synthesized through Reductive Cyclization of Nitroaromatics Catalyzed by Cp-M Carbonyls 30 Scheme 2.1 Classical Quinolone Syntheses 33 Scheme 2.2 Dieckmann Cyclization Strategy for 4-Quinolones 34 Scheme 2.3 Sneickus's Route to 4-Quinolones 35 Scheme 2.4 Grohe's Ciprofloxacin Synthesis 36 Scheme 2.5 Carbonylative Pd-Catalyzed Quinolone Synthesis 37 Scheme 2.6 Synthesis of Skatole 74 from 2-Nitrostyrene 73 39 Scheme 2.7 Cenini's Mechanistic Probe in Reductive Cyclization of 2- Nitrostyrene 41 Scheme 2.8 Watanabe's Labeling Experiment 42 Scheme 2.9 Deuterium Loss from 3-Methyl Indole Under Watanabe's Conditions 42 Scheme 2.10 Synthesis of 3-Methylquinolone 82 45 Scheme 2.11 Attempted Intramolecular Amination/Heck Reaction Sequence 46 Scheme 2.12 Synthesis and Cyclization of Propargyl Alcohols 48 Scheme 3.1 The Baylis-Hillman Reaction 50 Scheme 3.2 Baylis-Hillman Adducts as Precursors to Nitrogen Heterocycles 51 Scheme 3.3 Cyclization of Baylis-Hillman Adduct 8 8 54 Scheme