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C–H Functionalization Through Nucleophilic and Radical Addition to the Aromatic Π-System

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C–H Functionalization Through Nucleophilic and Radical Addition to the Aromatic Π-System C–H Functionalization Through Nucleophilic and Radical Addition to the Aromatic π-System The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation D'Amato, Erica. 2017. C–H Functionalization Through Nucleophilic and Radical Addition to the Aromatic π-System. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:42061473 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA C–H Functionalization through Nucleophilic and Radical Addition to the Aromatic !-System A dissertation presented by Erica D’Amato to The Department of Chemistry and Chemical Biology in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Chemistry Harvard University Cambridge, Massachusetts June 2017 © 2017 Erica D’Amato All rights reserved. Dissertation Advisor: Professor Tobias Ritter Erica D’Amato C–H Functionalization through Nucleophilic and Radical Addition to the Aromatic !-System Abstract Electrophilic, nucleophilic or radical addition to the aromatic !-system is an approach to aromatic C–H functionalization that bypasses the difficult C–H metalation step typical of modern C–H activation chemistry. !-Addition strategies can provide enhanced reactivity, complementary selectivity and improved practicality for aromatic C–H functionalization. This dissertation describes two strategies for aromatic C–H functionalization that proceed through an addition to the aromatic !-system, either by a nucleophile or a radical. First, an aromatic C–H hydroxylation protocol in which the arene is activated through "6- coordination to an iridium(III) complex is described. "6-Coordination of the arene increases its electrophilicity and allows for nucleophilic attack on the aromatic !-system, even for electron-rich arenes. The use of oxygen nucleophiles for C–H functionalization with "6-arene complexes is reported for the first time. High positional selectivity of hydroxylation at the site of least electron density is observed. Through investigation of intermediate "5-cyclohexadienyl adducts and arene exchange reactions, incorporation of arene !-activation into a catalytic cycle for C–H functionalization is evaluated. Second, a direct radical aromatic C–H amination reaction with a dramatic improvement in substrate scope compared to prior art is reported. Addition of the ammoniumyl radical, derived from a cationic hydroxylamine derivative, to the aromatic !-system is proposed for the amination reaction, which is fast, practical, scalable, and tolerant of air and moisture. An iron(II) salt accelerates the reaction but is not necessary for full conversion when the reaction is conducted in hexafluoroisopropanol (HFIP). Factors that rationalize the expansion of the substrate scope are presented: hydrogen bonding by the solvent HFIP to anions of cationic species results in their enhanced reactivity. iii TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................................................. iv! NOTE ........................................................................................................................................................... vi! ACKNOWLEDGMENTS .......................................................................................................................... vii! LIST OF ABBREVIATIONS ...................................................................................................................... ix! 1. INTRODUCTION .....................................................................................................................................1! 1.1. Aromatic C–H functionalization........................................................................................................1! 1.1.1. Aromatic C–H functionalization through C–H -bond activation ..........................................2! 1.1.2. Aromatic C–H functionalization through -addition ............................................................11! 1.2. 6-Arene complexes for aromatic C–H functionalization .............................................................16! 1.2.1. Stoichiometric C–H functionalization with 6-arene complexes ..........................................18! 1.2.2. Toward catalytic C–H functionalization with 6-arene complexes .......................................20! 1.3. Radical addition for aromatic C–H functionalization ......................................................................23! 1.3.1. Mechanistic features of radical addition to arenes ..................................................................24! 1.3.2. Reactions that proceed through radical addition to arenes ......................................................26! 1.4. Aromatic C–H hydroxylation ..........................................................................................................29! 1.4.1. Aromatic C–H hydroxylation through -bond activation .....................................................30! 1.4.2. Aromatic C–H hydroxylation through -addition .................................................................32! 1.5. Aromatic C–H amination .................................................................................................................36! 1.5.1. Aromatic C–H amination through -bond activation ............................................................37! 1.5.2. Aromatic C–H amination through -addition .......................................................................40! 1.6. Summary of introduction .................................................................................................................48! 2. SELECTIVE AROMATIC C–H HYDROXYLATION ENABLED BY 6-COORDINATION TO IRIDIUM(III) ...............................................................................................................................................49! 2.1. 6-Coordination for C–H functionalization ...................................................................................49! 6 2.2. Discovery of a C–H hydroxylation reaction using [( -arene)IrCp*](BF4)2 .................................52! 2.3. Mechanistic insight into C–O bond formation ................................................................................54! 6 2.4. Formation of C–N bonds using [( -arene)IrCp*](BF4)2 ..............................................................56! 2.5. Toward a catalytic reaction ..............................................................................................................57! 2.6. Conclusions and outlook .................................................................................................................58! iv 3. RADICAL AROMATIC C–H AMINATION IN HEXAFLUOROISOPROPANOL ............................61! 3.1. Radical addition for aromatic C–H functionalization ......................................................................61! 3.2. HFIP as a superior solvent for radical C–H amination ....................................................................62! 3.3. Substrate scope of C–H amination in HFIP .....................................................................................66! 3.4. Conclusions and outlook .................................................................................................................67! 4. CONCLUSION ........................................................................................................................................69! 5. EXPERIMENTAL ...................................................................................................................................70! 5.1. Materials and methods .....................................................................................................................70! 5.1.1. Solvents ...................................................................................................................................70! 5.1.2. Chromatography ......................................................................................................................70! 5.1.3. Spectroscopy and instruments .................................................................................................70! 5.1.4. Starting materials .....................................................................................................................71! 5.1.5. Computational details ..............................................................................................................71! 5.2. Experimental details for chapter 2 ...................................................................................................72! 5.2.1. Compound synthesis and characterization ..............................................................................72! 5.2.2. Mechanistic experiments .........................................................................................................90! 5.2.3. X-ray crystallography ..............................................................................................................93! 5.3. Experimental details for chapter 3 ...................................................................................................95! 5.2.1. Compound synthesis and characterization ..............................................................................95!
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