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Transition Metal‑Catalyzed Radical Functionalization of Alkenes with Alcohols and Formamide Derivatives

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Transition Metal‑Catalyzed Radical Functionalization of Alkenes with Alcohols and Formamide Derivatives This document is downloaded from DR‑NTU (https://dr.ntu.edu.sg) Nanyang Technological University, Singapore. Transition metal‑catalyzed radical functionalization of alkenes with alcohols and formamide derivatives Cheng, Jun Kee 2016 Cheng, J. K. (2016). Transition metal‑catalyzed radical functionalization of alkenes with alcohols and formamide derivatives. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/69209 https://doi.org/10.32657/10356/69209 Downloaded on 04 Oct 2021 15:36:58 SGT ALCOHOLS T .M. - CATALYZED RADICAL FUNCTIONALIZATION OF ALKENES WITH & FORMAMIDE S TRANSITION METAL-CATALYZED RADICAL FUNCTIONALIZATION OF ALKENES WITH ALCOHOLS AND FORMAMIDE DERIVATIVES CJK CHENG JUN KEE 2016 SCHOOL OF PHYSICAL AND MATHEMATICAL SCIENCES 2016 TRANSITION METAL-CATALYZED RADICAL FUNCTIONALIZATION OF ALKENES WITH ALCOHOLS AND FORMAMIDE DERIVATIVES CHENG JUN KEE School of Physical and Mathematical Sciences A thesis submitted to the Nanyang Technological University in partial fulfillment of the requirement for the degree of Doctor of Philosophy 2016 ACKNOWLEDGEMENTS Without the never-wavering encouragement and assistance of many parties in all ways, I would not have come thus far to present this dissertation. I would therefore, like to take this opportunity to convey my ‘vote of thanks’. First and foremost, I am obliged to my supervisor, Professor Loh Teck Peng who kindly offered me a position in his research group in 2012. His constant encouragement and invaluable guidance all along my tenure as a PhD student are greatly appreciated. Special mention goes to Ms Chen Xiao Ping, Ms Florence Ng Pei Fan and Ms Celine Hum Wei Mei who always tend to my relentless enquiries in administrative and academic matters. I am especially grateful to all who provided me with prompt technical and analytical supports to complete this thesis work (Ms Goh Ee Ling, Mr Derek Ong for NMR, Ms Zhu Wen Wei and Ms Joanne Pui for mass spectroscopy, Dr Li Yongxin and Dr Rakesh Ganguly for X-ray analysis). Thanks a ton to my colleagues and friends in CBC for being benevolent presence during my stay. I am hugely indebted to Dr Sreekumar Pankajakshan and Dr Chua Sin Siu for untiring moral supports as well as constructive advice when I almost gave up. My special thanks to Dr Jackson Koh Peng Fei, Wang Wee Jian, Wong Zhen Zhou, Tan Yu Jia and Dr Teo Kim Hoon for the supports that came in all forms and loving friendship that enabled me to endure the difficult times. Last but never the least, this thesis is dedicated to my parents who selflessly nurture and provide me with everything I need. Thanks to my jovial brothers, Kai Xian and Kai Jie who never fail to cheer me and back me up. Thank you, Shen Liang for walking me through this journey. Words cannot begin to describe the unconditional love you guys shower me with. i TABLE OF CONTENTS ACKNOWLEDGEMENTS ........................................................................... i TABLE OF CONTENTS ............................................................................... ii LIST OF ABBREVIATIONS ........................................................................ iv SUMMARY ................................................................................................... viii CHAPTER 1 GENERAL INTRODUCTION ........................................... 1 1.1 Difunctionalization of alkenes ................................................................. 2 1.2 Radical functionalization of alkenes ........................................................ 3 1.3 Oxyarylation of alkenes ........................................................................... 5 1.4 Oxycarbonylation of alkenes ................................................................... 9 1.5 Oxyalkylation of alkenes ......................................................................... 14 1.6 Conclusion ............................................................................................... 28 CHAPTER 2 COPPER- OR COBALT-CATALYZED DIRECT COUPLING OF sp3 α-CARBON OF ALCOHOLS WITH ALKENES AND HYDROPEROXIDES ................................................ 30 2.1 Introduction ........................................................................................... 31 2.2 Results and discussion .......................................................................... 48 2.3 Conclusion ............................................................................................ 58 2.4 Experimental section ............................................................................. 59 CHAPTER 3 IRON-CATALYZED PEROXIDATION- AMINOCARBONYLATION OF ALKENES WITH HYDROPEROXIDES AND FORMAMIDES VIA FORMYL C(sp2)-H FUNCTIONALIZATION ........................................................ 79 3.1 Introduction ........................................................................................... 80 3.2 Results and discussion .......................................................................... 94 3.3 Conclusion ............................................................................................ 101 ii 3.4 Experimental section ............................................................................. 102 CHAPTER 4 IRON-CATALYZED AMINOCARBONYLATION OF ENAMIDES WITH FORMAMIDES FOR EXPEDIENT SYNTHESIS OF N-ACYL ENAMINE AMIDES .................................. 117 4.1 Introduction ........................................................................................... 118 4.2 Results and discussion .......................................................................... 130 4.3 Conclusion ............................................................................................ 142 4.4 Experimental section ............................................................................. 143 LIST OF PUBLICATIONS ..................................................................... 155 iii LIST OF ABBREVIATIONS δ chemical shift °C degree centigrade Ac acetyl acac acetylacetonate Ac2O acetic anhydride AcOH acetic acid 1-Ad 1-adamantane Ar aryl atm atmosphere Bn benzyl BnBr benzyl bromide bs broad singlet CFL compact fluorescent lamp cod 1,5-cyclooctadiene Cy cyclohexane d doublet DABCO (1,4-diazabicyclo[2.2.2]octane) DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane ddt doublet of doublets of triplets DIAD diisopropyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMF N,N-dimethylformamide dr diastereomeric ratio iv dt doublet of triplets DTBP di-tert-butyl peroxide ESI electrospray ionization Et ethyl Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol EWG electron-withdrawing group h hour HIR hypervalent iodine reagent HIV human immunodeficiency virus HRMS high resolution mass spectrometry hv photoirradiation Hz Hertz IAd N,N’-Bis(adamantyl)imidazole-2-ylidene iPr isopropyl iPrOH isopropanol J coupling constant KHMDS potassium bis(trimethylsilyl)amide LED light-emitting diode MHz megahertz nPr n-propyl nBu n-butyl nBuBr n-butyl bromide nHex n-hexane NHPI N-hydroxyphthalimide v pc phthalocyanine TMHD (2,2,6,6-tetramethyl-3,5-heptanedionate) m multiplet MAP mitogen-activated protein MeNO2 nitromethane m-NO2BzOH 3-nitrobenzoic acid m.p. melting point NMR nuclear magnetic resonance NHC N-heterocyclic carbene OAc acetate OTf triflate PCy3 tricyclohexylphosphine PhCF3 trifluoromethylbenzene PhCl chlorobenzene Phe phenylalanine PIDA (diacetoxyiodo)benzene PivOH pivalic acid PINO phthalimide N-Oxyl Radical PPh3 triphenylphosphine PRE persistent radical effect p-TsOH p-toluenesulfonic acid Py pyridine q quartet (rac)-BINAP (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene rt room temperature rr regioisomeric ratio vi s singlet SET single-electron-transfer SOMO singly occupied molecular orbital t triplet td triplet of doublets TFAcac trifluoroacetylacetonate t-AmOH 2-methyl-2-butyl alcohol TBHP tert-butyl hydroperoxide TBPB tert-butyl peroxybenzoate tBu tert-butyl TEA/NEt3 triethylamine TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl TFA trifluoroacetate THC transfer hydrogenative coupling THF tetrahydrofuran TLC thin layer chromatography TMEDA tetramethylethylenediamine TMS trimethylsilyl vii SUMMARY Alkene functionalization is an important class of reaction which builds up molecular complexity in a rapid and efficient manner on the ubiquitous chemical feedstock. In complementary to transition metal-mediated approach, radical-mediated carbofunctionalization of alkene has recently received commendable attention, which features the addition of carbon-centered radical to the alkene double bond, a strategy endowed by high propensity of carbon radical to add to unsaturated system as well as broad functional group tolerance. This thesis describes the direct functionalization of alkenes with alcohols and formamide derivatives, which proceeds through the addition of radicals derived from respective coupling partner to the alkene acceptor. Following the generation of radical adduct, the latter could couple with an oxygen-centered radical to give carbooxgenation product or undergo SET oxidation step. Thereof, the thus-formed carbocation intermediate could trap an oxygen nucleophile or undergo elimination process to restore the alkenyl functionality. In Chapter 1, recent developments in radical-mediated intermolecular carbooxygenation of alkene and the mechanistic details are discussed with highlights on the oxyarylation, oxycarbonylation and oxylkylation reaction. In Chapter 2, a novel copper- or cobalt- catalyzed oxyalkylation of 1,3-enynes and arylalkenes with alcohols was introduced.
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