1,2-Oxaborines: Synthesis, Properties, and Reactivity Author: Nicole Anne Nava Persistent link: http://hdl.handle.net/2345/bc-ir:107626 This work is posted on eScholarship@BC, Boston College University Libraries. Boston College Electronic Thesis or Dissertation, 2017 Copyright is held by the author, with all rights reserved, unless otherwise noted. 1,2-Oxaborines: Synthesis, Properties, and Reactivity Nicole Anne Nava A thesis submitted to the Faculty of the department of Chemistry in partial fulfillment of the requirements for the degree of Master of Science Boston College Morrissey College of Arts and Sciences Graduate School December 2017 © Copyright 2017 Nicole Anne Nava 1,2-Oxaborines: Synthesis, Properties, and Reactivity Nicole Anne Nava Advisor: Professor Shih-Yuan Liu Despite extensive research in B–N-containing aromatic systems (most notably 1,2- azaborines) for their potential use in biomedicine and materials science, development of their oxygen counterparts, 1,2-oxaborines, remains underdeveloped. Presented herein is a straightforward route to access 1,2-oxaborines via a ring-closing metathesis strategy. Attempts to utilize the 1,2-oxaborine as a 1,3-diene in the Diels–Alder cycloaddition for potential application as a 4C + 1O synthon are also presented. Lastly, investigations regarding the aromaticity of the B–O heterocycles is probed using computations and isothermal reaction calorimetry. TABLE OF CONTENTS Table of Contents ..................................................................................................................... iv List of Tables .............................................................................................................................. v List of Figures ............................................................................................................................ vi List of Schemes ....................................................................................................................... vii List of Abbreviations………………………………………………………………………………………ix Acknowledgements ................................................................................................................. xi Introduction ............................................................................................................................... 1 1.0 Chapter 1 ........................................................................................................................... 3 1.1 First Reports of CC/BN Isosterism ........................................................................................... 3 1.2 Pioneering Studies in Azaborine Chemistry ........................................................................ 5 1.3 Advances in Azaborine Synthesis............................................................................................. 7 1.4 Elaboration of the Azaborine Core ....................................................................................... 10 1.4.1 Functionalization Reactions of 1,2-Azaborines ............................................................... 10 1.4.2 Applications of 1,2-Azaborines in Organic Synthesis. .................................................. 14 2.0 Chapter 2 ........................................................................................................................ 19 2.1 Initial Methods for the Synthesis of 1,2-Oxaborines ...................................................... 19 2.2 Advancements in Oxaborine Syntheses .............................................................................. 22 2.2.1 Reactivity Investigations of 1,2-Oxaborines Enabled by the Ashe Synthesis ..... 22 2.2.2 Martin and Co-workers' Route to Oxaborines ................................................................. 24 2.2.3 Yorimitsu's Nickel-Catalyzed Boron-Insertion of Benzofurans ................................ 25 2.3 Liu Group Efforts Towards the Isolation and Study of Monocyclic 1,2-Oxaborines 28 2.3.1 Diels-Alder Cycloaddition of 1,2-Oxaborines ................................................................... 31 2.4 Progress Towards the Resonance Stabilization Energy Determination of 1,2- Oxaborines .................................................................................................................................... 34 2.5 Conclusions ................................................................................................................................... 38 3.0 Chapter 3: Experimental..…………………………………………………………………………….40 iv LIST OF TABLES Table 1.1 Physical Properties of Isosteric N2O and CO2 Pair Table 1.2 Nucleophilic Addition to B–Cl-1,2-Azaborine Table 1.3 Dienophile Scope of Diels-Alder Reaction with N–TBS-B–Me-1,2-Azaborine Table 2.1 Catalyst Screen for Oxidation to 1,2-Oxaborine Table 2.2 Calculated Thermodynamic Parameters for 1,2-Oxaborine Cycloaddition at 298 K Using Maleic Anhydride as the Dienophile Table 2.3 Calculated Thermodynamic Parameters for 1,2-Oxaborine Cycloaddition at 298 K Using Methyl Acrylate as the Dienophile Table 2.4 Lewis Acid Screen for Diels-Alder Cycloaddition Table 2.5 Homogeneous Hydrogenation Catalyst Screen Table 2.6 Computationally Determined Heats of Hydrogenation v LIST OF FIGURES Figure 1.1 Isolated Azaborine Isomers Figure 1.2 Thermodynamic Parameters for Diels-Alder Reaction Involving 1,2- Azaborines Figure 2.1 Proposed Mechanism for Nickel-Catalyzed Boron-Insertion Figure 2.2 BN Heterocycles Utilized for Resonance Stabilization Energy Determination vi LIST OF SCHEMES Scheme 1.1 Dewar’s Synthesis of 9,10-azaboraphenanthrenes Scheme 1.2 Pioneering Strategies to Access Monocyclic 1,2-Azaborines Scheme 1.3 Ashe’s Initial Synthetic Route to 1,2-Azaborines Scheme 1.4 Ashe’s Ring-Expansion Protocol Towards the Synthesis of 1,2-Azaborines Scheme 1.5 Contributions from Liu Group Using Versatile B–Cl Intermediate Scheme 1.6 Protecting Group-Free Strategy to Versatile B–OBu Moiety Scheme 1.7 Electrophilic Aromatic Substitution of 1,2-Azaborines Scheme 1.8 Electrophilic Aromatic Substitution at C5 Scheme 1.9 Rhodium-Catalyzed Boron Arylation of 1,2-Azaborines Scheme 1.10 C6-Borylation of Parental 1,2-Azaborine Scheme 1.11 Thermal Diels-Alder Cycloaddition of 1,2-Azaborines Scheme 1.12 Reversible Cycloaddition Using Methyl Acrylate as Dienophile Scheme 2.1 Formation of 1,2-Oxaborine by Rearrangement of Diboronic Acid Scheme 2.2 Dewar’s Synthetic Strategy to Access 9,10-boroxarophenanthrene Scheme 2.3 Isolation of First Monocyclic 1,2-Oxaborine Scheme 2.4 Demethylation Strategy for the Synthhesis of Benzofused 1,2-Oxaborines Scheme 2.5 Dolle’s Downstream Functionalization of Benzofused 1,2-Oxaborines Scheme 2.6 Ashe’s Route to Generate Minimally-Substituted 1,2-Oxaborines Scheme 2.7 Generation of Phenyl Boroxine from 1,2-Oxaborine Precursor Scheme 2.8 1,2-Oxaborine Formation via 1,1-Insertion Mechanism Scheme 2.9 Nickel-Catalyzed Boron-Atom Insertion of Benzofurans vii Scheme 2.10 Functionalization of Boronate Esters and 1,2-Oxaborines Scheme 2.11 Liu’s Initial Route to Access 1,2-Oxaborines Scheme 2.12 Liu’s Revised Synthesis to Access 1,2-Oxaborines Scheme 2.13 Proposed Cycloaddition Reaction Using 1,2-Oxaborines as 1,3-Dienes Scheme 2.14 Proposed Mechanism for the Generation of B–Ph Boroxine Scheme 2.15 Proposed Route to Synthesize Enol Ether Isomer for Calorimetry Studies Scheme 2.16 Isomerization to Enol Ether Isomer Using Metal Hydride viii LIST OF ABBREVIATIONS BCl3 boron trichloride BIPHEP 2,2’-Bis(diphenylphosphino)biphenyl br broad Bu n-butyl CH2Cl2 dichloromethane COD 1,5-cyclooctadiene d doublet D debye DART direct analysis in real time dd doublet of doublets DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DIBAL-H diisobutylaluminum hydride DMAD dimethyl acetylenedicarboxylate DMSO dimethyl sulfoxide dq doublet of quartets dtbpy 4,4’-Di-tert-butyl-2,2’-dipyridyl equiv equivalents Et2O diethyl ether Et3N triethylamine h hour(s) ix H2 hydrogen gas IPr 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) (iPr)2NH diisopropylamine KHMDS Potassium bis(trimethylsilyl)amide m multiplet MeOH methanol n-BuLi n-butyllithium NMR nuclear magnetic resonance spectroscopy PCy3 tricyclohexylphosphine Ph phenyl PPh3 triphenylphosphine PV pressure vessel Py pyridine q quartet RSE resonance stabilization energy RT room temperature s singlet t triplet THF tetrahydrofuran TMSCl trimethylsilyl chloride x ACKNOWLEDGEMENTS First and foremost, I would like to thank my adviser, Professor Liu, for providing the opportunity to join his research group and pursue a new, rather unexplored area of chemistry. His understanding and guidance has allowed me to grow as a scientist, and recognize additional areas I hope to improve. I would also like to thank all members of the Liu group, with additional appreciation for Dr. Jacob Ishibashi and Zachary Giustra, who routinely provided advice on executing experiments. Additionally, Yuanzhe Zhang, has made my time in the Liu group enjoyable with his light-hearted demeanor and sense of humor. I would like to acknowledge Professor Morken and Professor Byers for serving on my thesis committee. Special thanks are due to Professor Liu and Professor Morken who have greatly aided in my transition from graduate school to a career. Prior to beginning graduate studies, my time in the lab of Professor Suzanne Blum was instrumental in solidifying my desire to pursue research. Professor Blum has since remained an invaluable mentor and provided unwavering support in both my academic and professional pursuits. Also while in the Blum lab,