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Novel Aryne-Mediated Synthetic Methodologies Anton Vladimirovich Dubrovskiy Iowa State University Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2012 Novel aryne-mediated synthetic methodologies Anton Vladimirovich Dubrovskiy Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Organic Chemistry Commons Recommended Citation Dubrovskiy, Anton Vladimirovich, "Novel aryne-mediated synthetic methodologies" (2012). Graduate Theses and Dissertations. 12656. https://lib.dr.iastate.edu/etd/12656 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Novel aryne-mediated synthetic methodologies by Anton Vladimirovich Dubrovskiy A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Organic Chemistry Program of Study Committee: Richard C. Larock, Co-Major Professor Malika Jeffries-EL, Co-Major Professor Aaron Sadow Yan Zhao Thomas J. Greenbowe Iowa State University Ames, Iowa 2012 Copyright © Anton Vladimirovich Dubrovskiy, 2012. All rights reserved. ii To chemistry iii TABLE OF CONTENTS LIST OF ABBREVIATIONS .............................................................................................. vii CHAPTER 1. DISSERTATION ORGANIZATION ...........................................................1 CHAPTER 2. USE OF ARYNES FOR THE SYNTHESIS OF 5-MEMBERED RING HETEROCYCLES ..................................................................................................................6 2.1. Scope of the Review ...........................................................................................................6 2.2. Synthesis of 5-Membered Ring-containing Heterocycles ..................................................8 2.2.1. Benzotriazoles ......................................................................................................8 2.2.2. Benzisoxazolines ..................................................................................................9 2.2.3. Benzisoxazoles ...................................................................................................12 2.2.4. 1H-Indazoles ......................................................................................................14 2.2.5. 2H-Indazoles ......................................................................................................20 2.2.6. Pyrido[1,2-b]indazoles .......................................................................................21 2.2.7. Pyrido[2,1-a]isoindoles, Indolizino[3,4,5-ab]isoindoles, and Related Heterocycles .................................................................................................................23 2.2.8. Benzofurans and Dihydrobenzofurans ...............................................................26 2.2.9. Indoles, Indole-indolones, Pyrroloindolones, Isatins, Indolines, and Indolin-3-ones ..............................................................................................................28 2.2.10. Iminoisobenzofurans and Iminoisoindolines ...................................................35 2.2.11. Carbazoles and Dibenzofurans ........................................................................38 iv 2.3. Conclusions .......................................................................................................................39 2.4. References .........................................................................................................................40 CHAPTER 3. SYNTHESIS OF BENZISOXAZOLES BY THE [3 + 2] CYCLOADDITION OF IN SITU GENERATED NITRILE OXIDES AND ARYNES .......................................................................................................................44 3.1. Abstract .............................................................................................................................44 3.2. Introduction .......................................................................................................................44 3.3. Results and Discussion .....................................................................................................46 3.4. Conclusions .......................................................................................................................61 3.5. Acknowledgement ............................................................................................................62 3.6. Experimental .....................................................................................................................62 Synthesis of the starting chlorooximes .....................................................................................62 Synthesis of the benzisoxazoles ................................................................................................68 3.7. References .........................................................................................................................83 CHAPTER 4. INTERMOLECULAR C-O ADDITION OF CARBOXYLIC ACIDS TO ARYNES: SYNTHESIS OF o-HYDROXYARYL KETONES, XANTHONES, 4-CHROMANONES, AND FLAVONES ............................................................................88 4.1. Abstract .............................................................................................................................88 4.2. Introduction .......................................................................................................................88 4.3. Results and Discussion .....................................................................................................89 4.3.1. Synthesis of o-Hydroxyaryl Ketones .................................................................89 v 4.3.2. Synthesis of Xanthones ......................................................................................97 4.3.3. Synthesis of 4-Chromanones and Flavones .....................................................102 4.3.4. Final Mechanistic Considerations ....................................................................115 4.4. Conclusions .....................................................................................................................118 4.5. Acknowledgement ..........................................................................................................119 4.6. Experimental ...................................................................................................................119 Reaction of carboxylic acids with arynes ..............................................................................120 Reaction of 2-alkenoic acids with arynes ..............................................................................128 Reaction of 2-alkynoic acids with arynes ..............................................................................135 4.7. References .......................................................................................................................138 CHAPTER 5. SYNTHESIS OF o-(DIMETHYLAMINO)ARYL KETONES, ACRIDONES, ACRIDINIUM SALTS, AND 1H-INDAZOLES BY THE REACTION OF HYDRAZONES AND ARYNES ...........................................................144 5.1. Abstract ...........................................................................................................................144 5.2. Introduction .....................................................................................................................144 5.3. Results and Discussion ...................................................................................................145 5.3.1. Ketimine generation and Subsequent transformations ....................................145 5.3.2. Synthesis of Aminoaryl Ketones .....................................................................148 5.3.3. Synthesis of N-Methylacridones ......................................................................161 5.3.4. Synthesis of Acridinium Salts ..........................................................................168 5.3.5. Synthesis of 1H-Indazoles from Hydrazones ..................................................171 vi 5.3.6. Synthesis of 1H-Indazoles by the Chlorination and Subsequent Cyclization of ortho-Aminoaryl Ketimines ..................................................................................180 5.4. Conclusions .....................................................................................................................183 5.5. Acknowledgement ..........................................................................................................184 5.6. Experimental ...................................................................................................................184 Synthesis of the starting hydrazones ......................................................................................185 Synthesis of aminoaryl ketimines and derivatives .................................................................200 Synthesis of the aminoaryl ketones ........................................................................................204 Synthesis of the acridones ......................................................................................................220 Synthesis of acridinium salts ..................................................................................................228
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