Metal-Catalyzed & Photo-Induced Functionalization: New Approaches, Vu Nguyen (UTSA)

NEW AND EFFICIENT APPROACHES TO FUNCTIONALIZATION VIA METAL- CATALYZED AND PHOTO-INDUCED TRANSFORMATIONS by VU TRAN NGUYEN, M. DISSERTATION Presented to the Graduate Faculty of The University of Texas at San Antonio in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY IN CHEMISTRY COMMITTEE MEMBERS: Oleg V. Hyunsoo Han, Ph. THE UNIVERSITY OF TEXAS AT SAN ANTONIO College of Science Department of Chemistry December 2020 DEDICATION To my wife and my dear daughter who always believe in me.

To my parents who provide me with constant inspiration. ACKNOWLEDGEMENTS First and foremost, I have to thank my family who has supported me not only through graduate school but through life thus far. Their concern and encouragement are what kept me going every moment in my life. I owe my deepest gratitude to my wife for her silent sacrifice to my little family.

I owe my mother, who inspired me and let me know about the beautiful world of chemistry. Secondly, I need to thank Dr. Larionov for his constant encouragement and support to push me to become better. Without him motivating me, I would never have the achievement today.

I learned from him the way of thinking and developing a project. I hope that I can continue to grow and advance as I finish my career at UTSA. I want to also acknowledge my committee members, Dr. Hyunsoo Han, Dr.

Francis Yoshimoto, and Dr. Zhao, for all the time and effort you all have made to help me become a well-rounded chemist. You all have been key to my professional development by always being ready to question me to help me achieve all the critical milestones of graduate school. Thank you for always encouraging me to do better.

I would like to thank the Department of Chemistry at the University of Texas at San Antonio for the constant support and continued dedication to providing opportunities for success. There is not one faculty member who I have not interacted with, asked advice, or been evaluated by. I would also like to thank all the professors that took part in teaching me during my education at UTSA. I would like to thank my lab members for all the years we have spent together.

Without your support, I know that I also would not have been nearly successful as today. Special thanks to Anh Vo, who gave me an opportunity to join the group of Dr. Larionov and begun my career here at UTSA. All are owed thanks (not limited too or in any specific order): David Stephens, Bhuwan Chhetri, Johant Lakey-Beitia, John Doyle, Jessica Burch, Victoria Soto, Adelphe Mfuh, Shengfei Jin, Xianwei Sui, Graham Haug, Brett Schneider, Oscar Garcia, Carsten Flores-Hansen, Dat Nguyen, Hang Dang, Viet Nguyen, Ngan Vuong, Hoang Pham, Trang Le, Dat Le, Tiffany Nguyen, Tu Ho.

I want to thank various agencies and foundations for supporting our work at the lab of Dr. Larionov: the Max and Minnie Tomerlin Voelcker Fund, the Welch Foundation, the National Institute of General Medical Sciences, and the University of Texas at San Antonio. I also want to iv thank Dr. Judith Walmsley for her generous donation to my awards at UTSA: Abrams and Walmsley awards.

These awards helped me focus on science and get some achievements so far. “This Master’s Thesis/Recital Document or Doctoral Dissertation was produced in accordance with guidelines which permit the inclusion as part of the Master’s Thesis/Recital Document or Doctoral Dissertation the text of an original paper, or papers, submitted for publication. The Master’s Thesis/Recital Document or Doctoral Dissertation must still conform to all other requirements explained in the “Guide for the Preparation of a Master’s Thesis/Recital Document 6 or Doctoral Dissertation at The University of Texas at San Antonio.” It must include a comprehensive abstract, a full introduction and literature review, and a final overall conclusion. Additional material (procedural and design data as well as descriptions of equipment) must be provided in sufficient detail to allow a clear and precise judgment to be made of the importance and originality of the research reported.

It is acceptable for this Master’s Thesis/Recital Document or Doctoral Dissertation to include as chapters authentic copies of papers already published, provided these meet type size, margin, and legibility requirements. In such cases, connecting texts, which provide logical bridges between different manuscripts, are mandatory. Where the student is not the sole author of a manuscript, the student is required to make an explicit statement in the introductory material to that manuscript describing the student’s contribution to the work and acknowledging the contribution of the other author(s). The approvals of the Supervising Committee which precede all other material in the Master’s Thesis/Recital Document or Doctoral Dissertation attest to the accuracy of this statement.” December 2020 v NEW AND EFFICIENT APPROACHES TO FUNCTIONALIZATION VIA METAL- CATALYZED AND PHOTO-INDUCED TRANSFORMATIONS Vu Tran Nguyen, Ph.

The University of Texas at San Antonio, 2020 Supervising Professor: Oleg V. Functionalization has emerged as an attractive strategy for the diversification of compounds especially in drug development and materials science. The recent emerging trend in chemical functionalization is not only to access challenging and valuable compounds using abundant and inexpensive materials but also to consider environmental aspects of new methodologies. New methodologies in the fields of photocatalysis, transition metal catalysis, radical chemistry, and redox chemistry have found applications in functionalization.

Herein, new and efficient approaches to functionalization of common aryl halides, abundant carboxylic acids, and readily available alkenes via metal-catalyzed or photoinduced transformations will be discussed. Specifically, the focus will be on the following transformations: conversion of aryl halides to borylated compounds and corresponding sulfones, as well as conversion of carboxylic acids to amines, alkenes, and other important compounds. Alkenes take part in discrete carboborative ring contractions or challenging dienes syntheses. In some cases, discussion of the mechanistic investigations and density functional theory calculations will be included to provide insights into the reaction details.

Some ongoing works with preliminary results in decarboxylation and dienylation will be briefly discussed. vi TABLE OF CONTENTS ACKNOWLEDGEMENTS. vi TABLE OF CONTENTS. vii LIST OF FIGURES.

PHOTO-INDUCED RING CONTRACTION. 9 RESULTS AND DISCUSSIONS. 21 GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS. SULFOLENE SYNTHESIS AND TRANSITION METAL – CATALYZED DIENYLATION USING SULFOLENE.

51 RESULTS AND DISCUSSIONS. 54 GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS. 54 vii CHAPTER III. PALLADIUM-CATALYZED DIENYLATION.

60 RESULTS AND DISCUSSIONS. 66 GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS. NICKEL-CATALYZED DIENYLATION. 85 RESULTS AND DISCUSSIONS.

88 GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS. ACRIDINE-CATALYZED DECARBOXYLATION AND FUNCTIONALIZATION OF CARBOXYLIC ACIDS. 96 RESULTS AND DISCUSSIONS. 116 GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS.

116 viii CHAPTER IV. 167 RESULTS AND DISCUSSIONS. 178 GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS. FUNCTIONALIZATION OF ARYL HALIDES.

BORYLATION OF ARYL HALIDES. 238 RESULTS AND DISCUSSIONS. 244 GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS. 259 RESULTS AND DISCUSSIONS.

268 GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS. DIMERIZATION OF QUINOLINES. 287 RESULTS AND DISCUSSIONS. 293 GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS.

Copies of 1H and 13CNMR Spectra for Chapter II. Copies of 1H and 13CNMR Spectra for Chapter III. Copies of 1H and 13CNMR Spectra for Chapter IV. Copies of 1H and 13CNMR Spectra for Chapter IV.

Copies of 1H and 13CNMR Spectra for Chapter V. Copies of 1H and 13CNMR Spectra for Chapter VI. Copies of 1H and 13CNMR Spectra for Chapter V. 797 VITA x LIST OF TABLES Chapter II Table II.Optimization for photoinduced carboborative ring contraction.

Photoinduced carboborative ring contraction in the presence of different photosensitizers. Scope of the Photoinduced Carboborative Ring Contraction. Scope of the Photoinduced Carboborative Ring Contraction of Terpenoids. 14 Chapter III Table III.

Optimization of the 3-sulfolene synthesis from 1,3-dienes. Synthesis of 3-sulfolenes from 1,3-dienes. Optimization of Reaction Conditions. Scope of the Reaction with Sulfolene 5.

Scope of the Reaction with Substituted Sulfolenes. Optimization tables for Ni-catalyzed dienylation. 86 Chapter IV Table IV. Reaction conditions for dehydrodecarboxylation.

Reaction conditions for cooperative chemoenzymatic LACo process. Reaction conditions for interrogation of the decarboxylation-on-cobaloxime mechanism. 106 xi Table IV. Production of carbon dioxide and hydrogen during dehydrodecarboxylation of palmitic acid.

Acridine-catalyzed reaction of palmitic acid with TEMPO. Reaction conditions for the direct decarboxylative alkylation (DDA) of anilines. DDA reaction performance with other photocatalysts with and without added DIPEA. Reaction Conditions for the Photocatalytic Direct Decarboxylative Sulfonylamidation.

Photoinduced Dual C–H/C–X Borylation of Iodobenzene in Other Solvents. Reaction conditions for the sulfone synthesis. 259 Chapter VI Table VI. Reaction Conditions for the Synthesis of ortho-Methylene-Bridged N- Heterobiaryls.

288 xii LIST OF FIGURES Chapter I Figure I. Comparison of contemporary and prior art in decarboxylative functionalization. Borylation of aryl halides under ultra-violet conditions. Two approaches to N-heterocyclic sulfones.

General formation of alkyl radicals and application of newly-formed radicals in useful transformations. New and efficient transformations using alkenes as starting materials. 5 Chapter II Figure II. Photoinduced Carboborative Ring Contraction.

Structural Diversification of the Carboborative Ring Contraction Products. Reaction of limonene and triethylborane. Stereochemical assignment of diastereomers of alcohol S1. The CH(OH) region in the 13C NMR spectrum of the carboborative ring contraction product S1-A-D.

The CH(OH) range in the 13C NMR spectrum of the reduction product S1-A-D with the (S)-CBS catalyst. The CH(OH) region in the 13C NMR spectrum of the reduction product S1-A-D with the (R)-CBS catalyst. Summary of ring contraction mechanism. 20 xiii Figure II.

Stereochemical Assignment of the C6-Stereocenter in Alcohol 23 by the Mosher ester method. Stereochemical Assignment of the C10-Stereocenter in Alcohol 30 by the Mosher ester method. Stereochemical Assignment of the C10-Stereocenter by the Mosher ester method. 47 Chapter III Figure III.

Sulfolane and 3-sulfolene in organic and medicinal chemistry. Synthesis of sulfolenes from 1,3-dienes. Synthetic approaches to conjugated dienes and polyenes. Synthesis of conjugated dienes and polyenes using sulfolenes and proposed catalytic cycle.

Scope of Ni-catalyzed dienylation reaction. 88 Chapter IV Figure IV. Catalytic dehydrodecarboxylation of carboxylic acids. Scope of photoinduced dehydrodecarboxylation.

Cooperative chemoenzymatic LACo process and polymerization of plant oil- derived alkenes. Decarboxylation-on-cobaloxime mechanism. 104 xiv Figure IV. Radical trapping experiments with TEMPO and the influence of varied initial catalyst loading on the photoinduced dehydrodecarboxylation reaction.

EPR spectrum of acridinyl radical HA. HRMS (A) and EPR (B) studies of the photoinduced reaction of cobaloxime C1 with dihydroacridine H2A. Dehydrodecarboxylation using n-octylcobaloxime as catalyst. Mechanism of the acridine/cobaloxime dual catalytic photoinduced dehydrodecarboxylation reaction.

Decarboxylative N-alkylation of anilines. Scope of the direct decarboxylative N-alkylation. N-Alkylation of heteroaromatic amines. N-Alkylation of natural products and drugs.

N-Trideuteromethylation by DDA with AcOH-d4. One-step access to N-arylpyrrolidine by DDA with acid 99. Radical trapping experiments with TEMPO as well as radical ring-opening and ring-closing experiments with cyclopropylacetic acid and 6-heptenoic acid. Evaluation of involvement of alkyl carbocations in the DDA reaction.

EPR of Cu(hfac)2 in the presence of aniline. EPR spectra of Cu(hfac)2 in the presence of aniline with combined total concentration of 10 mM in benzene at room temperature. 176 xv Figure IV. Job plot of the Cu(hfac)2–aniline system at 3265.

Mechanistic studies of the DDA reaction. Photoinduced 1,2- and 1,3-Selective Dual C–H/C–X Borylation Reaction of Haloarenes. Electrophilic borylation of the intermediate ArBpin. Plausible Reaction Pathways for the Photoinduced Dual C–H/C–X-Borylation.

Scope of the Photoinduced 1,2 and 1,3-Selective Dual C–H/C–X-Borylation Reaction of Haloarenes. Applications and synthesis of N-heterocyclic sulfones and sulfides. Biomedical applications of N-heterocyclic sulfones. Synthetic strategies toward N-heterocyclic sulfones.

Scope of the persulfate-initiated sulfone synthesis. Chemodivergent access to sulfones and sulfides. Kinetic profile of reaction of 4-haloquinolines with p-toluenesulfinate. Oxidation of sulfinate by persulfate.

Reaction mechanism for catalytic sulfone formation with sulfinic acids. Mechanism of formation of symmetrical sulfones and sulfides. 267 xvi Chapter VI Figure VI. Direct Synthesis of ortho-Methylene-Bridged N-Heterobiaryls from N- Heterocycles.

Organocatalytic Synthesis of ortho-Methylene-Bridged N-Heterobiaryls. Synthesis of 4,4'-Methylene-Bridged N-Heterobiaryls. Synthesis of 2-Alkylquinolines and 2-Alkylisoquinolines .