New and efficient approaches to functionalization via metal catalyzed and photo induced transformations

The CHOH region in the 13C NMR spectrum of the carboborative ring contraction product S1-A-D.. Favorskii, Wagner-Meerwein, pinacol, and Wolff rearrangements.17 With the availability and

NEW AND EFFICIENT APPROACHES TO FUNCTIONALIZATION VIA

METAL-CATALYZED AND PHOTO-INDUCED TRANSFORMATIONS

by

VU TRAN NGUYEN, M Eng

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

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 Oleg V 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 John C.-G 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

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

NEW AND EFFICIENT APPROACHES TO FUNCTIONALIZATION VIA

METAL-CATALYZED AND PHOTO-INDUCED TRANSFORMATIONS

Vu Tran Nguyen, Ph.D

The University of Texas at San Antonio, 2020

Supervising Professor: Oleg V Larionov, Ph.D

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

TABLE OF CONTENTS

ACKNOWLEDGEMENTS iv

ABSTRACT vi

TABLE OF CONTENTS vii

LIST OF FIGURES xiii

CHAPTER I INTRODUCTION 1

CHAPTER II PHOTO-INDUCED RING CONTRACTION 7

INTRODUCTION 8

EXPERIMENTAL DESIGN 9

RESULTS AND DISCUSSIONS 12

MECHANISTIC INVESTIGATION 15

CONCLUSION 21

GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS 21

CHAPTER III SULFOLENE SYNTHESIS AND TRANSITION METAL – CATALYZED DIENYLATION USING SULFOLENE 49

CHAPTER III.1 SULFOLENE SYNTHESIS 50

INTRODUCTION 50

EXPERIMENTAL DESIGN 51

RESULTS AND DISCUSSIONS 53

CONCLUSION 54

GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS 54

CHAPTER III.2 PALLADIUM-CATALYZED DIENYLATION 58

INTRODUCTION 58

EXPERIMENTAL DESIGN 60

RESULTS AND DISCUSSIONS 61

CONCLUSION 66

GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS 66

CHAPTER III.3 NICKEL-CATALYZED DIENYLATION 85

INTRODUCTION 85

EXPERIMENTAL DESIGN 85

RESULTS AND DISCUSSIONS 87

CONCLUSION 88

GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS 88

CHAPTER IV ACRIDINE-CATALYZED DECARBOXYLATION AND FUNCTIONALIZATION OF CARBOXYLIC ACIDS 92

CHAPTER IV.1 DECARBOXYLATIVE OLEFINATION 93

INTRODUCTION 93

EXPERIMENTAL DESIGN 96

RESULTS AND DISCUSSIONS 99

CONCLUSION 116

GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS 116

CHAPTER IV.2 DECARBOXYLATIVE AMINATION 165

INTRODUCTION 165

EXPERIMENTAL DESIGN 167

RESULTS AND DISCUSSIONS 169

CONCLUSION 178

GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS 178

CHAPTER IV.3 DECARBOXYLATIVE SULFONYLATION 234

INTRODUCTION 234

EXPERIMENTAL DESIGN 234

CHAPTER V FUNCTIONALIZATION OF ARYL HALIDES 236

CHAPTER V.1 BORYLATION OF ARYL HALIDES 237

INTRODUCTION 237

EXPERIMENTAL DESIGN 238

RESULTS AND DISCUSSIONS 239

CONCLUSION 244

GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS 244

CHAPTER V.2 SULFONE SYNTHESIS 257

INTRODUCTION 257

EXPERIMENTAL DESIGN 259

RESULTS AND DISCUSSIONS 260

CONCLUSION 268

GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS 268

CHAPTER VI DIMERIZATION OF QUINOLINES 286

INTRODUCTION 287

EXPERIMENTAL DESIGN 287

RESULTS AND DISCUSSIONS 288

CONCLUSION 293

GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS 293

APPENDIX A Copyright Clearance 301

APPENDIX B Copies of 1 H and 13 CNMR Spectra for Chapter II 307

APPENDIX C Copies of 1 H and 13 CNMR Spectra for Chapter III 365

APPENDIX D Copies of 1 H and 13 CNMR Spectra for Chapter IV.1 422

APPENDIX E Copies of 1 H and 13 CNMR Spectra for Chapter IV.2 533

APPENDIX F Copies of 1 H and 13 CNMR Spectra for Chapter V.1 666

APPENDIX H Copies of 1 H and 13 CNMR Spectra for Chapter VI 729

APPENDIX G Copies of 1 H and 13 CNMR Spectra for Chapter V.2 758

REFERENCES 797 VITA

LIST OF TABLES Chapter II

Table II.1.Optimization for photoinduced carboborative ring contraction 10

Table II.2 Photoinduced carboborative ring contraction in the presence of different photosensitizers 11

Table II.3 Scope of the Photoinduced Carboborative Ring Contraction 12

Table II.4 Scope of the Photoinduced Carboborative Ring Contraction of Terpenoids 14

Chapter III Table III.1 Optimization of the 3-sulfolene synthesis from 1,3-dienes 52

Table III.2 Synthesis of 3-sulfolenes from 1,3-dienes 53

Table III.3 Optimization of Reaction Conditions 61

Table III.4 Scope of the Reaction with Sulfolene 5 62

Table III 5 Scope of the Reaction with Substituted Sulfolenes 64

Table III.6 Optimization tables for Ni-catalyzed dienylation 86

Chapter IV Table IV.1 Reaction conditions for dehydrodecarboxylation 97

Table IV.2 Reaction conditions for cooperative chemoenzymatic LACo process 98

Table IV.3 Reaction conditions for interrogation of the decarboxylation-on-cobaloxime mechanism 106

Table IV 4 Production of carbon dioxide and hydrogen during dehydrodecarboxylation of

palmitic acid 107

Table IV 5 Acridine-catalyzed reaction of palmitic acid with TEMPO 111

Table IV 6 Reaction conditions for the direct decarboxylative alkylation (DDA) of anilines

Table V 1 Photoinduced Dual C–H/C–X Borylation of Iodobenzene in Other Solvents 239

Table V 2 Reaction conditions for the sulfone synthesis 259 Chapter VI

Table VI 1 Reaction Conditions for the Synthesis of ortho-Methylene-Bridged

N-Heterobiaryls 288

LIST OF FIGURES Chapter I

Figure I.1 Comparison of contemporary and prior art in decarboxylative functionalization 1

Figure I.2 Borylation of aryl halides under ultra-violet conditions 3

Figure I.3 Two approaches to N-heterocyclic sulfones 3

Figure I.4 General formation of alkyl radicals and application of newly-formed radicals in useful transformations 4

Figure I.5 New and efficient transformations using alkenes as starting materials 5

Chapter II Figure II.1 Photoinduced Carboborative Ring Contraction 9

Figure II.2 Structural Diversification of the Carboborative Ring Contraction Products 15

Figure II 3 Reaction of limonene and triethylborane 16

Figure II 4 Stereochemical assignment of diastereomers of alcohol S1 17

Figure II 5 The CH(OH) region in the 13C NMR spectrum of the carboborative ring contraction product S1-A-D 19

Figure II 6 The CH(OH) range in the 13C NMR spectrum of the reduction product S1-A-D with the (S)-CBS catalyst 19

Figure II 7 The CH(OH) region in the 13C NMR spectrum of the reduction product S1-A-D with the (R)-CBS catalyst 20

Figure II 8 Summary of ring contraction mechanism 20

Figure II.9 Stereochemical Assignment of the C6-Stereocenter in Alcohol 23 by the Mosher

ester method 38

Figure II.10 Stereochemical Assignment of the C10-Stereocenter in Alcohol 30 by the

Mosher ester method 42

Figure II.11 Stereochemical Assignment of the C10-Stereocenter by the Mosher ester method

47

Chapter III

Figure III.1 Sulfolane and 3-sulfolene in organic and medicinal chemistry 50

Figure III.2 Synthesis of sulfolenes from 1,3-dienes 51

Figure III 3 A Synthetic approaches to conjugated dienes and polyenes 58

Figure III.4 Synthesis of conjugated dienes and polyenes using sulfolenes and proposed

catalytic cycle 59

Figure III.5 Mechanistic Experiments 65

Figure III 6 Scope of Ni-catalyzed dienylation reaction 88

Chapter IV

Figure IV.1 Catalytic dehydrodecarboxylation of carboxylic acids 95

Figure IV.2 Scope of photoinduced dehydrodecarboxylation 100

Figure IV 3 Cooperative chemoenzymatic LACo process and polymerization of plant

oil-derived alkenes 102

Figure IV 4 Decarboxylation-on-cobaloxime mechanism 104

Figure IV 5 Radical trapping experiments with TEMPO and the influence of varied initial

catalyst loading on the photoinduced dehydrodecarboxylation reaction 108

Figure IV 6 EPR spectrum of acridinyl radical HA 112

Figure IV 7 HRMS (A) and EPR (B) studies of the photoinduced reaction of cobaloxime C1 with dihydroacridine H2A 113

Figure IV 8 Dehydrodecarboxylation using n-octylcobaloxime as catalyst 114

Figure IV 9 Mechanism of the acridine/cobaloxime dual catalytic photoinduced dehydrodecarboxylation reaction 115

Figure IV 10 Decarboxylative N-alkylation of anilines 166

Figure IV 11 Scope of the direct decarboxylative N-alkylation 170

Figure IV 12 N-Alkylation of heteroaromatic amines 171

Figure IV 13 N-Alkylation of natural products and drugs 172

Figure IV 14 N-Trideuteromethylation by DDA with AcOH-d4 173

Figure IV 15 One-step access to N-arylpyrrolidine by DDA with acid 99 174

Figure IV 16 Radical trapping experiments with TEMPO as well as radical ring-opening and ring-closing experiments with cyclopropylacetic acid and 6-heptenoic acid 174

Figure IV 17 Evaluation of involvement of alkyl carbocations in the DDA reaction 175

Figure IV 18 EPR of Cu(hfac)2 in the presence of aniline 176

Figure IV 19 EPR spectra of Cu(hfac)2 in the presence of aniline with combined total concentration of 10 mM in benzene at room temperature 176

Figure IV 20 Job plot of the Cu(hfac)2–aniline system at 3265.94 G 176

Figure IV 21 Mechanistic studies of the DDA reaction 177

Chapter V Figure V 1 Photoinduced 1,2- and 1,3-Selective Dual C–H/C–X Borylation Reaction of Haloarenes 238

Figure V 2 Electrophilic borylation of the intermediate ArBpin 240

Figure V 3 Plausible Reaction Pathways for the Photoinduced Dual C–H/C–X-Borylation 241

Figure V 4 Scope of the Photoinduced 1,2 and 1,3-Selective Dual C–H/C–X-Borylation Reaction of Haloarenes 242

Figure V 5 Applications and synthesis of N-heterocyclic sulfones and sulfides a Biomedical applications of N-heterocyclic sulfones b Synthetic strategies toward N-heterocyclic sulfones 258

Figure V 6 Scope of the persulfate-initiated sulfone synthesis 261

Figure V 7 Chemodivergent access to sulfones and sulfides 263

Figure V 8 Kinetic profile of reaction of 4-haloquinolines with p-toluenesulfinate 264

Figure V 9 Oxidation of sulfinate by persulfate 265

Figure V 10 Reaction mechanism for catalytic sulfone formation with sulfinic acids 265

Figure V 11 Mechanism of formation of symmetrical sulfones and sulfides 267

Chapter VI

Figure VI 1 Direct Synthesis of ortho-Methylene-Bridged Heterobiaryls from

N-Heterocycles 287

Figure VI 2 Organocatalytic Synthesis of ortho-Methylene-Bridged N-Heterobiaryls 289

Figure VI 3 Synthesis of 4,4'-Methylene-Bridged N-Heterobiaryls 290

Figure VI 4 Synthesis of 2-Alkylquinolines and 2-Alkylisoquinolines 290

Figure VI 5 Intermediates in the Reaction of Methylmagnesium Chloride with Isoquinoline 291

Figure VI 6 Reaction between 1-d 1-isoquinoline with 25 mol% MgH2 after 2 h 292

Figure VI 7 Reaction between 1-d 1-isoquinoline with 25 mol% MgH2 after 21 h 292

Figure VI 8 Oxidation of the methylene group in diquinolinylmethanes 16 and 17 293

CHAPTER I INTRODUCTION

Functionalization has emerged as an attractive strategy for the diversification of compounds especially in drug development and materials science It describes the action or process of introducing a functional group into (part of) a molecule in order to alter the chemical behavior of the molecule Functionalization delivers crucial benefits including vast chemical libraries, step-reducing behavior, a means of accessing synthetically challenging compounds, and saving costs

Indeed, functionalization allows for the generation of chemical libraries and natural products alike By only one or two simple transformations from the lead compounds, other analogous compounds can be prepared and tested for their metabolism or efficacy Late-stage functionalization has the potential to modulate the pharmacokinetic and pharmacodynamic properties without the need for developing or redesigning synthetic methods and restarting synthesis It allows for the rapid exploration of structure-activity relationships (SAR) and directed improvement of on-target potency.1

Figure I.1 Comparison of contemporary and prior art in decarboxylative functionalization

Late-stage functionalization encourages chemists to synthesize the target compounds in a shorter and more efficient manner The work of Ackermann and co-workers from AstraZeneca is a typical example.2By the development of cobalt-catalyzed C–H methylation, they have accessed

20 drug analogues in a one-step manner, thus they can eliminate more than 100 unwanted synthetic steps As a result, more time, resources, and labor can be saved as well as less waste is generated Another example is the radical cross-coupling reaction (RCC) between alkenyl zinc and redox-active esters developed by Baran and colleagues.3 This protocol enabled the syntheses

of fifteen different natural products wherein the number of steps for the syntheses was decreased

and the overall yields were enhanced For instance, the steroidal product 1 was obtained after

only two steps in comparison with the previous tedious 7-step synthetic route (Figure I.1)

Nowadays, chemists not only strive to access valuable and precious compounds using abundant and inexpensive materials but also to consider environmental aspects of new methodologies in order to minimize the environmental impact Additionally, new catalytic approaches have emerged that allow for construction of challenging carbon‒carbon and carbon‒heteroatom bonds Furthermore, new methodologies in the fields of photocatalysis, transition metal catalysis, radical chemistry, and redox chemistry have found applications in organic synthesis

Aryl halides are one of the most common classes of compounds since they are present in a number of transition-metal-catalyzed cross-coupling reactions including Stille, Heck, Kumuda, Negishi, and Suzuki coupling.4 It is well established that these types of reactions involve the use

of significant amounts of heavy or precious metals Some of them require harsh conditions, high temperatures, or expensive and proprietary ligands These drawbacks may prevent some of these transformations from industrial applications In addition, from the viewpoint of green chemistry, heavy metal waste is also harmful to the environment The development of protocols using aryl halides, which utilize milder conditions and often do not rely on transition metals, have attracted continuous interest

Organoboron compounds are an essential class of reagents that are used in many organic transformations, including Chan-Lam and Suzuki-Miyaura cross-coupling reactions.5 The preparation of this class compound often begins with aryl halides or pseudo-halides employing precious transition-metals such as palladium, iridium, rhodium as catalysts Thanks to recent developments in photochemistry, aryl halides have become widely used as reagents in coupling reactions without using metal catalysts Our group has had experience in the synthesis of areneboronic acids from the corresponding aryl halides under ultraviolet conditions (Figure I.2).6With the exciting results in hand, we put more effort into investigating the nature of borylation reaction in different types of solvents and shifting the necessary wavelength for reaction to visible range using photocatalysts Details of the development of new 1,2- and 1,3- regioselective diborylation reaction and the use of phenothiazines as photocatalysts to make the reaction

working under visible conditions will be discussed more in this dissertation (vide infra)

Figure I.2 Borylation of aryl halides under ultra-violet conditions

Another valuable and useful class of products from aryl halides are sulfones N-Heterocyclic sulfones have key roles in medicinal and agricultural chemistry,7 organic synthesis,8 and materials science.9 Two approaches are typically used to synthesize N-heterocyclic sulfones (Figure I.3) Both approaches have some unsolved drawbacks including poor step economy,10environmental and toxicological liabilities of thiols, side reactions, harsh conditions, and lower yields In addition, the use of transition metals as catalysts is another limitation of the second approach The discovery and development of a methodology to make sulfones from N-heteroaryl halides and sulfinate salts will be presented in this dissertation

Figure I.3 Two approaches to N-heterocyclic sulfones.

Carboxylic acids are abundant industrial and bioderived feedstocks.11 For example, long-chain fatty acids are key constituents of glycerol triesters, triglycerides that are the main components of vegetable and algal oils.12 Decarboxylative generation of alkyl radicals has emerged as a practical platform for the development of new carbon-carbon and carbon‒heteroatom bonds The

most common way is the conversion of carboxylic acids into redox-active esters of N-hydroxy

phthalimide or hypervalent iodine (III) compounds However, these approaches have poor step economy and atom economy since they require the formation and isolation of redox-active derivatives as well as generation of large amounts of waste Thus, direct decarboxylative reactions are attractive from the synthetic perspective

Recently, we discovered that the acridine can facilitate the formation of alkyl radicals in

decarboxylative reactions via a photoinduced proton-coupled electron transfer (PCET) process in

the acridine‒carboxylic acid hydrogen bond complex The presence of acridine radicals is confirmed by EPR studies and their characterization will be presented in this dissertation The generated radicals can participate in a series of useful transformations producing valuable products including alkenes, amines, alcohol, sulfonamides (Figure I.4) The discovery and extension of applications of decarboxylative protocol for functionalization will be presented in a separate chapter

Figure I.4 General formation of alkyl radicals and application of newly-formed radicals in

useful transformations

Alkenes are key synthetic intermediates and commodity chemicals in the industrial production of polymers, adhesives, detergents, surfactants, and plasticizers.13 Alkenes involve in a series of

useful transformation to construct of new C−C, C−O, and C−N bonds en route to active

pharmaceutical ingredients, biological probes, and advanced functional materials.14 Even though alkenes are naturally abundant, many methods to prepare alkenes have been explored and developed recently For example, mono alkenes can also be easily accessed by some regio- and enantioselective synthetic methods such as Heck-type reactions or the Diels-Alder cycloaddition.15 However, the synthesis of 1,3-dienes is still challenging especially the control of stereoselectivity The direct Heck arylation reactions of 1,3-diens yielded mixtures of regio- and stereoisomers and suffered from low yields and narrow scope.16 The preparation requires two subsequent alkenylation reactions or unstable dienylation reagents to achieve the target products

An efficient way to prepare 1,3-dienes remains elusively Herein, the new and efficient way to

make arylated 1,3-diens from corresponding 1,3-dienes via sulfolene intermediates will be

discussed The synthesis of sulfolenes will also be included and compared with the typical methods Moreover, the palladium-catalyzed dienylation reaction can be further modified to replace the precious palladium with a more inexpensive nickel catalyst Some interesting results

in the optimization steps will be listed

Figure I.5 New and efficient transformations using alkenes as starting materials.

Ring contraction reactions are among the most interesting and useful strategic transformations to prepare complex carbocyclic and heterocyclic molecules From the more abundant and large

rings, the less accessible smaller and densely substituted ones can be constructed using known reactions, e.g Favorskii, Wagner-Meerwein, pinacol, and Wolff rearrangements.17 With the availability and easy preparation of cyclohexene motifs, we aim to use them as precursors for the formation of less readily accessible five-membered carbocycles and heterocycles.18 We envisioned that cyclohexenes undergo photosensitized isomerization to strained and highly

reactive E-isomers that readily participate in a variety of reactions, e.g., additions of alcohol and

cycloadditions.19 More details about the carboborative ring contraction including mechanism investigation will be discussed in one chapter of this dissertation

CHAPTER II PHOTO-INDUCED RING CONTRACTION

Six-membered carbocyclic and heterocyclic alkenes are readily available and abundant resources since they are represented in secondary metabolites such as terpenes and alkaloids or can be prepared in one-step Diels-Alder cycloaddition Herein, a new and efficient photoinduced carboborative ring contraction of such cyclohexene motifs is reported In comparison with other ring contraction reactions, carboborative ring contraction results in an appendage of an additional side chain with a new stereocenter The products can be prepared regio-and stereoselectively and feature multiple stereocenters, including contiguous quaternary carbons The synthetic utility of the reaction has been further demonstrated by converting the intermediate organoboranes to alcohols, amines, and alkenes The mechanism of this reaction was further investigated, and we

figure out that the dynamical asymmetry is the key factor in the stereoselectivity of this ring

contraction The dynamic trajectories suggest that the inversion and retention products are formed from the same transition state, and the trajectories accurately account for the experimental product ratios

All products in this chapter were prepared by me with the assistance of Ms Hang Dang and Mr

Dat Nguyen in purification The X-ray crystal of compound 21 was grown by Hang Dang and

analyzed by Dr Hadi Arman For mechanism clarification, some experimental results using CBS catalysts of Dr Shengfei Jin and density functional theory calculations results of the group of Dr Daniel Singleton will be mentioned briefly

Reprinted with permission from: Jin, S.; Nguyen, V.T.; Dang, H.T.; Nguyen, D.P.; Arman, H.D.; Larionov, O.V Photoinduced carboborative ring contraction enables regio-and stereoselective

synthesis of multiply substituted five-membered carbocycles and heterocycles J Am Chem

Soc 2017, 139, 1365–11368 Copyright (2017) American Chemical Society

Reprinted in part with permission from: Roytman, V.A.; Jin, S., Nguyen, V.T.; Nguyen, V.D.; Haug, G.C.; Larionov, O.V.; Singleton, D.A Bond Memory in Dynamically-Determined

Stereoselectivity J Am Chem Soc 2020, 142, 85-88 Copyright (2020) American Chemical

Society

INTRODUCTION

Ring contraction reactions are among the most useful strategic transformations for the construction of complex carbocyclic and heterocyclic molecules Favorskii, Wagner-Meerwein, pinacol, and Wolff rearrangements, as well as ring contraction reactions mediated by hypervalent iodine and selenium reagents, allow for efficient construction of densely substituted and less accessible smaller cyclic systems from the more abundant larger ones with predictable and high stereoselectivity.1

Six-membered ring is widely represented among secondary metabolites, e.g., terpenes and alkaloids Cyclohexene motif can also be easily accessed by a number of regio- and enantioselective synthetic methods, e.g., the Diels-Alder cycloaddition.2 The abundance and synthetic accessibility of the unsaturated six-membered ring system make it an excellent precursor to the less readily accessible five-membered carbocycles and heterocycles.3 In addition, structural alteration, including ring system modification, plays an important role in medicinal chemistry of natural products, since it can lead to improved activity, metabolic stability, and target specificity.4

Photochemical activation enables the generation of chemical intermediates that are not accessible

from the ground states, e.g., E-cyclohexenes,5 and triplet aryl cations,6 whose reactivity is distinctively different from the thermally-generated species

Cyclohexenes undergo photosensitized isomerization to strained and highly reactive E-isomers

that readily participate in a variety of reactions, e.g., additions of alcohols and cycloadditions.7Experimental and computational evidence indicates that the more stable chair conformation is

responsible for the reactivity observed for E-cyclohexene.8,9 Despite the high angular strain

within the ring, the reactions of E-cyclohexenes E-1 can be remarkably stereoselective.19,8

We report herein an efficient photoinduced carboborative ring contraction that enables a

regioselective synthesis of multiply substituted cyclopentanes 2 (Figure II 1) The reaction

proceeds under mild conditions in the absence of additives and catalysts In contrast to most other ring contraction processes, the photoinduced carboborative ring contraction results in an

appendage of an additional side chain with a new stereocenter The structure of the products 3

can be further diversified via conversion of the boryl group in the side chain to other functional

groups A number of secondary metabolites were readily converted to functionalized cyclopentanes with two new stereocenters, including quaternary all-carbon stereocenters

Figure II.1 Photoinduced carboborative ring contraction

EXPERIMENTAL DESIGN

Although earlier observations of the photoinduced reaction between cyclohexenes and

trialkylboranes suggested that syn-carboboration with retention of the cyclohexane ring took

place,10 we observed a clean and efficient carboborative ring contraction that, after oxidation,

resulted in isolation of alcohol 4 as the sole product from the UV-induced ( = 254 nm) reaction

of 1-methylcyclohexene and triethylborane (Table II.1)

Specifically, the earlier reports by Nozaki10 indicated that the photochemical reaction between

cyclohexenes and trialkylboranes produced cis-2-alkylcyclohexanols, i.e., products of the

carboboration with retention of the six-membered ring Our experiments with a variety of cyclohexenes and trialkylboranes and under a variety of conditions, on the other hand, showed that the products of the carboborative ring contraction were formed With the limited spectroscopic information provided in Refs 10a,b, it was of interest to compare our 1H NMR

spectrum for the product of the reaction of cyclohexene with tributylborane (alcohol 14) with

that of the product obtained by Nozaki et al, since the 1H NMR spectrum of their product was

shown in Figure 1 in Ref 10b Comparison of their 1H NMR spectrum with that of alcohol 14

shows that the multiplet signal of the CH proton in the CH–OH group appears in both spectra

between 3.10 and 3.55 ppm (3.40–3.55 ppm for alcohol 14, and ~3.10–3.55 ppm in the spectrum

from Ref 10b in CCl4) In contrast, the multiplet signal of the CH proton in the CH–OH group of

cis-2-butylcyclohexanol appears significantly more downfield, at 3.95–4.00 ppm in CCl4

Taken together, our experimental results and the comparison of the available spectroscopic data suggest that the products of the photochemical reaction of cyclohexenes with trialkylboranes observed by Nozaki et al were the products of the carboborative ring contraction

Table II.1.Optimization for photoinduced carboborative ring contraction a

Further investigation showed that xylene isomers were superior to other aromatic hydrocarbons

as photosensitizers, with p-xylene delivering a higher yield of alcohol 4 than m-, and o-xylenes

(91% for p-xylene, 82% for o-xylene, and 71% for m-xylene) The reaction proceeded faster and

with higher yields in more polar solvents, e.g., in alcohols, with ethanol as the optimal solvent Other suitable solvents included dioxane, and tetrahydrofuran The photochemical quantum yield

for the formation of alcohol 4 was 0.26 The organoborane intermediate corresponding to

product 4 was observed by means of NMR spectroscopy, indicating that the carboborative ring

contraction is a photoinduced process that takes place before the oxidative work-up

Table II.2 Photoinduced carboborative ring contraction in the presence of different

a Reaction conditions: 1-methylcyclohexene (1 mmol), Et 3 B (2 mmol) ArCO 2 R (0.2

mmol), solvent (5 mL), 25 o C, UV lamp, 36 h b Determined by 1 H NMR spectroscopy

with 1,4-dimethoxybenzene as an internal standard added to the reaction mixture after

completion of the experiment

Interestingly, the reaction can also be carried out with a catalytic photosensitizer (Table II.2) Among photosensitizers evaluated,11 ethyl benzoate (20 mol%) was found superior, delivering

product 4 in 95% yield at 254 nm (in tetrahydrofuran) and 300 nm (in ethanol)

RESULTS AND DISCUSSIONS

The scope of the reactants was next examined (Table II 3) A number of boranes bearing primary and secondary alkyl groups were reacted with 1-methylcyclohexene under the optimal conditions

Table II.3 Scope of the photoinduced carboborative ring contractiona

9-methoxy-9-borabicyclo[3.3.1]-nonane (9-BBN-OMe) also proved to be a suitable reacting

partner, and the diol 12 was isolated after oxidation in 63% yield

Other unsaturated six-membered carbocycles and heterocycles were studied as well

Cyclohexene produced the corresponding alcohols 13 and 14 in 98 and 90% yields, indicating

that cyclohexenes with the unsubstituted C=C bond can also be used in the photoinduced

carboborative rearrangement reaction 1-tert-Butylcyclohexene also produced the sterically

hindered alcohol 15 in 51% yield Experiments with unsaturated six-membered oxygen and nitrogen heterocycles afforded tetrahydrofuran 16 and pyrrolidine 17 While tetrahydrofuran 16 was isolated as a single diastereomer, the diastereomeric ratio was 10:1 for pyrrolidine 17

Terpenoids have important applications in medicine, agriculture, organic synthesis, as well as flavor and fragrance industries.13 We were, therefore, interested in examining the generality of the photoinduced carboborative ring contraction reaction with several readily available

terpenoids and their derivatives (Table II 4) Terpinolene (18) produced the five-membered ring

product 19 with >20:1 stereoselectivity (R,R)-Carveol (20) afforded product 21 in a high yield

and with 7–10 : 1 stereoselectivity The minor diastereomer had the opposite configuration at the

carbon atom of the alcohol stereocenter in the side chain Alcohol 21 can be further purified by recrystallization to >20:1 d.r The stereochemical assignment of the carveol product 21 was confirmed by X-ray crystallography Similarly, TBS ether of carveol 22 afforded alcohols 23 and

24 in 63 and 58% yields, respectively The syntheses of products 21 and 23 were readily carried out on gram scales Interestingly, the all-carbon quaternary stereocenter in 21-24 was formed

with very high stereoselectivity, as, in each case, the same configuration was observed for this

stereocenter Carvone-derived tertiary alcohol 25 gave rise to product 26 with two adjacent

quaternary stereocenters in the newly-formed stereochemical triad indicating that carboborative ring contraction can be used for construction of molecules with contiguous quaternary stereocenters.14 In addition, nerol oxide and valencene were readily converted to tetrahydrofuran

28 and 6/5-fused bicyclic alcohol 30 in 52 and 74% yields

Table II.4 Scope of the Photoinduced Carboborative Ring Contraction of Terpenoids a

a Reaction conditions: terpenoid (1 mmol), trialkylborane (1–1.5 mmol), EtOH (5 mL), p-xylene

(2 mL), UV (254 nm), then H2O2, NaOH, or Na2CO3·1.5H2O2 b Yield of pure diastereomer 21

after recrystallization The minor diastereomer has the opposite configuration of the CH(OH) stereocenter in the side chain

The C–B bond in organoboranes can be readily converted to a variety of functional groups.12,15

For example, the photoinduced carboborative ring contraction of carveol 20 and its TBS ether 22

was followed by a reaction with 2-methyl-2-nitrosopropane dimer16 resulting in the formation of

E-alkenes 31 and 32 that were isolated as single isomers in 68 and 70% yields (Figure II 2)

Further, 4-alkoxyphenol 33 was readily prepared by a photoinduced carboborative ring

contraction of 1-methylcyclohexene, followed by treatment with benzoquinone

Figure II.2 Structural diversification of the carboborative ring contraction products

Interestingly, although the formation of 2-alkylhydroquinones had previously been reported for a reaction of trialkylboranes with benzoquinone,17 O-alkylation product 33 was isolated as a major

product in this case, in line with the reactivity pattern previously observed for sterically hindered

secondary B-alkylcatecholboranes.18 In addition, amination19 of the

1-methylcyclohexene-derived organoborane intermediate with hydroxylamine-O-sulfonic acid afforded amine 34

MECHANISTIC INVESTIGATION

1-Methylcyclohexene reacted 1.9 times faster than cyclohexene This result, in addition to the higher reaction rates in more polar solvents,6 may indicate that polar intermediates are involved

in the photoinduced carboborative ring contraction process Existing experimental evidence

shows that the protonation of the C=C bond in E-cyclohexenes occurs stereoselectively from the outside face of the E-cyclohexene ring leading to an equatorial C–H bond in the resulting

cyclohexyl cation.8 The trialkylborane addition from the outside face of E-cyclohexene will

result in dipolar intermediate I (Figure II.1)

Initially, we proposed that the migration of the endocyclic C3 atom to C1 can be accompanied by

a migration of one of the alkyl groups R from boron to C2 position Our experimental data

indicate that the migration of the C3 atom to C1 results in the trans-configuration of the

borylalkyl group (C2) with respect to the equatorially oriented substituent at C4 in the

rearrangement product 3 A similar ring contraction step was proposed to explain the

stereoselection in the terminal step of the Prins-pinacol rearrangement of allylic diol-derived acetals.20 The migration of the alkyl group R from boron to C2 position can proceed with inversion or retention of the configuration at C2 Experimentally, the observed configuration at

C2 in the major product 3 corresponds to the inversion pathway, while the minor product 3' can

be formed by the retention pathway

Further investigation pointed out an unusual observation is that the two rearrangement steps are stereochemically linked, but not completely so That is, if the bond to C3 lost in the ring-contraction step is viewed as the “leaving group” and the migrating boron–alkyl is the

“nucleophile”, the combination of steps converting Z-1 to 2 occurs with preferential, but not

exclusive, inversion of configuration at C2 If the two migrations occurred simultaneously, stereospecific inversion would be expected, as in any SN2 step If the ring-contraction step were complete before the boron–alkyl migration, equal inversion and retention might be expected The high stereoselectivity but absence of SN2-like stereospecificity then appears inconsistent with either a concerted or a two-step process

Figure II 3 Reaction of limonene and triethylborane

In fact, the reaction of limonene (35) with triethylborane produces four diastereomeric organoborane intermediates 36-I, 36-R, 36-I, 36-R that upon stereospecific oxidation with hydrogen peroxide afford alcohols S1-A-D (see below for experiment results)

The ratio of diastereomers S1-A-D was determined by integration of the signals in the 80−82

ppm range that correspond to the CH(OH) carbon The CH(OH) stereocenter in the major

diastereomer of S1-A was determined to be S by means of the Mosher ester analysis, using the

protocol developed by Hoye.21

In order to further assign the stereochemical configurations of the newly-formed stereocenters,

we oxidized the diastereomeric mixture of alcohols S1-A-D to ketone S2 that was formed as a 4 :

1 mixture of ketone diastereomers S2-1 and S2-2 X-ray crystallographic analysis and NMR

spectroscopy were previously used to determine the relative stereochemistry in the

five-membered ring system of carboborative ring contraction products In all cases,

trans-configuration was observed for the two substituents in the five-membered ring of the major

diastereomer, and the relative configurations of diastereomers S2-1 and S2-2 were assigned

accordingly

Figure II 4 Stereochemical assignment of diastereomers of alcohol S1

In order to assign signals corresponding to the CH(OH) carbon in the 13C NMR spectrum of B-D, the ketone mixture S2-1/S2-2 was subjected to the enantioselective CBS-catalyzed

S1-reduction22 that proceeds according to the stereochemical model shown in Figure II 4

Specifically, the reduction affords the (R)-alcohol with the CBS catalyst, while the alcohol product is favored with the (R)-CBS catalyst Additionally, given the proximity of the

(S)-quaternary -stereocenter in ketones S2, the selectivities were expected to be higher for one diastereomer of ketone S2 and lower for the other with each enantiomer of the CBS catalyst,

resulting in the matched and mismatched selectivity ratios The information obtained from the

analysis of the 13C NMR data for both enantiomers of the CBS catalyst thus allows for assigning

the signals in the 80−82 ppm range to the four diastereomers of alcohol S1

When the S2-1 and S2-2 mixture was subjected to the reduction with catecholborane in the

presence of the (S)-CBS catalyst, the diastereomers corresponding to the signals at 80.6 and 81.0

ppm were formed in a 1 : 1 ratio (Figure II.4 and Figure II 6) The diastereomers with signals at 81.7 and 81.3 ppm were formed in 19.4 : 1 ratio Conversely, a 5.6 : 1 ratio was observed for the

diastereomers with signals at 80.6 and 81.0 ppm with the (R)-CBS catalyst (Figure II 4 and

Figure II 7), while the diastereomers with signals at 81.7 and 81.3 ppm were formed with a 1 :

1.6 ratio The ratios of the mismatched to matched reductions were 3.2 : 1 for the (S)-CBS catalyst, and 5 : 1 for the (R)-CBS catalyst, suggesting that the diastereomers with signals at 80.6

and 81.0 ppm are produced from the major ketone diastereomer S2-1, while the diastereomers with signals at 81.7 and 81.3 ppm are produced from the minor diastereomer S2-2 The results of

the CBS reduction experiments combined with the Mosher ester analysis of the major

diastereomer of alcohol S1 allow for the assignment of the four signals in the 80−82 ppm range

as shown in Figure II 4, thus enabling determination of the ratios of alcohols S1-A-D and by

corollary, due to the aforementioned stereospecificity of the organoborane oxidation, the ratios of

organoboranes 36-I, 36-R, 37-I, 37-R

Figure II 5 The CH(OH) region in the 13C NMR spectrum of the carboborative ring contraction

product S1-A-D

Figure II 6 The CH(OH) range in the 13C NMR spectrum of the reduction product S1-A-D with

the (S)-CBS catalyst

Figure II 7 The CH(OH) region in the 13C NMR spectrum of the reduction product S1-A-D

with the (R)-CBS catalyst

With these results in hand, we engaged in a collaboration with the group of Singleton to gain insights into the mechanism Interestingly, our results suggested that the inversion and retention products are formed from the same intermediate and the trajectories accurately account for the experimental product ratios The unusual origin of the selectivity is the dynamically retained non-equivalence of newly formed versus pre-existing bonds after the first bond migration

Figure II 8 Summary of ring contraction mechanism

CONCLUSION

In conclusion, this paper describes a regio- and stereoselective photoinduced carboborative ring contraction The operationally simple reaction produces substituted five-membered carbocycles and heterocycles on gram scales, and it can be used for structural modification of natural products containing a cyclohexene ring and in natural product synthesis The organoborane

intermediates 3 can further serve as precursors to alcohols, amines, and E-alkenes Density

functional theory calculations indicate that the ring contraction is a step-wise process wherein the stereoselectivity is controlled by dynamic asymmetry

GENERAL PROCEDURES AND CHARACTERIZATION OF PRODUCTS

GENERAL INFORMATION

Materials: Acetonitrile and methanol were dried over 3 Å molecular sieves Anhydrous dichloromethane, toluene, and diethyl ether were collected under argon from an LC Technologies solvent purification system, having been passed through two columns packed with molecular sieves Anhydrous tetrahydrofuran was distilled from sodium/benzophenone ketyl under the atmosphere of nitrogen and collected fresh immediately before use Solutions of triethylborane and tributylborane in tetrahydrofuran, as well as 9-methoxy-9-borabicyclo[3.3.1]nonane were used as received from commercial sources (Acros, MilliporeSigma) Other trialkylboranes were prepared by hydroboration of alkenes with borane-tetrahydrofuran complex.23 rac-2-Cyclopropyl-4-methyl-3,6-dihydro-2H-pyran,24 methyl 5-

methyl-3,6-dihydropyridine-1(2H)-carboxylate,25

(1S,2S,5R)-1,2-dimethyl-5-(prop-1-en-2-yl)cyclohexan-1-ol (25)26 was prepared according to the literature procedures (S,S)-Carveol was

prepared from (S)-carvone as described for (R,R)-carveol (20) Benzoquinone was sublimed,

stored at –20 C, and handled in a glovebox All other chemicals were used as commercially available

Experimental equipment: The photochemical reactions were conducted in quartz test-tubes

(10, 20, and 95 mL capacity, Quartz Scientific, Inc.) in a Rayonet RPR-100 photochemical reactor equipped with 16 Ushio 8W T5 UV-C lamps ( = 254 nm) with the fan on The chamber temperature was 25 C The reaction test-tubes were placed ~2 cm from the UV lamps

Glovebox work was carried out in a nitrogen-filled LC Technology Solutions LCPW-220 glovebox

Purification: Column chromatography was performed using CombiFlash Rf-200

(Teledyne-Isco) automated flash chromatography system, as well as manually Thin layer chromatography was carried out on silica gel-coated glass plates (Merck Kieselgel 60 F254) Plates were visualized under ultraviolet light (254 nm) and using a potassium permanganate stain

Characterization: 1H, 13C, 11B, and 19F NMR spectra were recorded at 500 MHz or 300 MHz (1H), 125 MHz or 75 MHz (13C), 470 MHz or 282 MHz (19 F), and 160 MHz (11B) on an Agilent Inova 500 or 300, and Bruker AVANCE III 500 instruments in CDCl3 or other specified deuterated solvents with and without tetramethylsilane (TMS) as an internal standard at 25 C, unless specified otherwise Chemical shifts () are reported in parts per million (ppm) from tetramethylsilane (1H and 13C), BF3OEt2 (11B), and CFCl3 (19F) Coupling constants (J) are in

Hz Proton multiplicity is assigned using the following abbreviations: singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint.), septet (sept.), multiplet (m), broad (br)

Infrared measurements were carried out neat on a Bruker Vector 22 FT-IR spectrometer fitted with a Specac diamond attenuated total reflectance (ATR) module

GENERAL PROCEDURES

General procedure for the photoinduced carboborative ring contraction (GP1)

p-Xylene (2 mL) and ethanol (5 mL) were placed in a quartz test-tube equipped with a stirbar

Argon was bubbled through a glass pipet reaching to the bottom of the test-tube while vigorous stirring was maintained for 10 min Cycloalkene (1 mmol, 1 equiv.) and trialkylborane (1 mmol,

1 equiv.) were then added, and the test-tube was sealed with a rubber septum The solution was stirred for 5 min, and the septum on the quartz test-tube was additionally secured with Parafilm®tape to minimize exposure of the solution to air The reaction mixture was irradiated without stirring at 25 °C for the specified time in a Rayonet RPR-100 photochemical reactor

General procedure for the oxidative work-up with hydrogen peroxide (GP2)

A flask equipped with a stirbar was purged with argon, and the reaction mixture obtained in GP1 was quickly poured into the flask Sodium hydroxide (1 mL, 3 equiv., 3M aqueous solution) and hydrogen peroxide (0.3 mL, 3 equiv., 30% aqueous solution) were added, and the reaction mixture was stirred at 50 °C for 1 h The reaction mixture was extracted with EtOAc (3 × 15 mL) The organic phases were combined, dried over anhydrous Na2SO4 and concentrated under

reduced pressure The crude product was purified by flash chromatography on silica gel (EtOAc/hexane) to give the desired alcohol

General procedure for preparation of trialkylboranes (GP3)

A pressure tube was purged with argon and charged with alkene (14 mmol, 2.8 equiv.) THF complex (5 mL of 1M solution in THF, 5 mmol, 1 equiv.) was added then dropwise at 0 C

Borane-The mixture was stirred at room temperature (for products 6, 7, and 8) or 50 °C (for products 9,

10, and 11) for 16 h The alkene consumption was monitored by 1H NMR in CDCl3, and the trialkylborane formed was used as synthesized without purification

General procedure for the oxidative work-up with sodium percarbonate (GP4)

A flask equipped with a stirbar was purged with argon, and the reaction mixture obtained in GP1 was quickly poured into the flask Sodium percarbonate (314 mg, 2 equiv.) and water (1 mL) were added, and the reaction mixture was stirred at 50 °C for 1 h The reaction mixture was extracted with EtOAc (3 × 15 mL) The organic phases were combined, dried over anhydrous

Na2SO4 and concentrated under reduced pressure The crude product was purified by flash chromatography on silica gel (EtOAc/hexane) to give the desired alcohol

Calculation of the photochemical quantum yield

The photon flux of the photochemical reactor was determined using the azoxybenzene chemical actinometer system.[27]

Incident photon flux in 45 min: 0.86 mmol photons

Amount of alcohol 4 formed in 45 min: 0.22 mmol

 = 0.22/0.86 = 0.26

PRODUCTION CHARACTERIZATION

1-(1-Methylcyclopentyl)propan-1-ol (4)

According to GP1, a stirred mixture of p-xylene (2 mL) and ethanol (5 mL) was degassed with

Ar for 10 min in a quartz test-tube 1-Methylcyclohexene (96 mg, 1 mmol) and triethylborane (1

mL, 1M solution in THF, 1 mmol, 1 equiv.) were then added The solution was irradiated at 25

°C for 14 h in a Rayonet RPR-100 photochemical reactor The reaction mixture was oxidized with hydrogen peroxide (0.3 mL, 3 equiv., 30% aqueous solution) and sodium hydroxide (1 mL,

3 equiv., 3M aqueous solution) at 50 °C for 1 h according to GP2 The reaction mixture was then extracted with EtOAc (3 × 15 mL) The organic phases were combined, dried over anhydrous

Na2SO4 and concentrated under reduced pressure The crude product was purified by flash

chromatography on silica gel (EtOAc/hexane, 1 : 10 v/v) to give alcohol 4 (130 mg, 91%) as a

colorless oil

1H NMR (300 MHz, CDCl3): 3.14 (1 H, dd, J = 10.3, 2.0 Hz), 1.70 (1 H, br s), 1.61–1.20 (10 H, m), 0.96 (3 H, t, J = 7.4 Hz), 0.85 (3 H, s) ppm – 13C NMR (75 MHz, CDCl3): 81.7, 47.3, 37.2, 36.9, 25.6, 25.0, 24.9, 21.2, 11.7 ppm – IR: 3390, 2953, 2871, 1453, 1376, 1307, 1240, 1101, 1017, 969, 922 cm-1 – HRMS calcd for

C9H17O: 141.1279, found 141.1281 [M–H+]

1-(1-Methylcyclopentyl)pentan-1-ol (5)

According to GP1, a stirred mixture of p-xylene (2 mL) and ethanol (5 mL) was degassed with

Ar for 10 min in a quartz test-tube 1-Methylcyclohexene (96 mg, 1 mmol) and tributylborane (1

mL, 1M solution in diethyl ether, 1 mmol, 1 equiv.) were then added The solution was irradiated

at 25 °C for 14 h in a Rayonet RPR-100 photochemical reactor The reaction mixture was oxidized with hydrogen peroxide (0.3 mL, 3 equiv., 30% aqueous solution) and sodium hydroxide (1 mL, 3 equiv., 3M aqueous solution) at 50 °C for 1 h according to GP2 The reaction mixture was then extracted with EtOAc (3 × 15 mL) The organic phases were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure The crude product was

purified by flash chromatography on silica gel (EtOAc/hexane, 1 : 20 v/v) to give alcohol 5 (155

mg, 91%) as a colorless oil

1H NMR (500 MHz, CDCl3): 3.26 (1 H, dd, J = 9.7, 1.6 Hz), 1.68–1.23

(15 H, m), 0.96–0.85 (6 H, m) ppm – 13C NMR (125 MHz, CDCl3): 80.1, 47.3, 37.3, 37.0, 32.6, 29.4, 25.1, 25.0, 22.9, 21.3, 14.2 ppm – IR: 3377,