Radical Chain Reduction and C(sp2/sp3) Carboxylation via Formate Activation Public
Smith, Gavin (Fall 2024)
Abstract
Over the last several decades, various modes of catalysis in chemical synthesis have emerged at the forefront of synthetic organic chemistry to make carbon-carbon bond formation more efficient and selective. While single electron transformations have maintained synthetic utility for decades, the emergence of photoredox catalysis has reinvigorated the field of single electron processes by introducing mild and catalytic conditions for single electron activation of organic molecules via redox manipulations. While many photoredox methodologies have relied on highly reducing or oxidizing photocatalysts for radical formation, we utilized previous methodologies in our group to access potent reductants via mild hydrogen atom transfer processes. We have demonstrated through a polarity matched hydrogen atom transfer between an electrophilic thiyl radical and abundant formate salts, we are able to mildly generate the radical anion of carbon dioxide (CO2•−), a potent reductant (E ½ o = -2.2 V vs SCE). We demonstrate the utility of this reaction in a variety of reductive transformations including hydroarylation, defluoroalkylation, ketyl radical formation, detosylation, and radical deamination of aryl ammonium salts. Furthermore, our research shows CO2•− as a nucleophilic source of CO2 as it adds across alpha, beta-unsaturated alkenes in a 1,4-addition. In addition, formate activation with phenyl triflimide is used nickel-catalyzed cross coupling to generate aryl/vinyl carboxylic acids from their corresponding aryl/vinyl bromide precursors. Finally, we utilize computational chemistry to help elucidate the mechanistic features of a protocol for catalytic dearomatization of unactivated arenes via catalytic hydroalkylation.
Table of Contents
Chapter 1: An overview of Single Electron Transformations, the Emergence of Photoredox Catalysis, and Nickel-Catalyzed Cross-Couplings……………………………………………........................................................................1
1.1 Single Electron Transformations………………………………………………………………......................................2
1.1.1 Hydrogen Atom Abstraction……………………………………………………………….........................................2
1.1.2 Halogen Atom Abstraction………………………………………………………………….........................................4
1.1.3 The Emergence of Photoredox Catalysis……………………………………………………....................................6
1.2 An Overview of Nickel-Catalyzed Cross Couplings………………………………………......................................10
1.3 References……………………………………………………………………………………............................................11
Chapter 2: Radical Chain Reduction via the Carbon Dioxide Radical Anion (CO2•−)……..................................15
2.1: An Overview of Photoredox in the Jui Lab………………………………………………….....................................17
2.2: An Overview of the Carbon Dioxide Radical Anion………………………………………....................................19
2.2.1 Mechanistic Investigations into CO2•– as an Upconverted Reductant……………………............................20
2.2.2: Investigations into Radical Chain Generation of CO2•– …………………………………...............................25
2.2.3: Generation of CO2•– with Alternative Initiators………………………………………….................................26
2.2.4: Reductive Process Enabled by CO2•–……………………………………………………......................................29
2.3 References……………………………………………………………………………………...........................................36
Chapter 3: Hydrocarboxylation of Electron-Deficient Alkenes via the Carbon Dioxide Radical Anion (CO2•−)………………………………………………………………………….................................................................42
3.1: Discovery and Optimization of the CO2•− as a Nucleophilic Source of CO2……………...........................….44
3.2: References………………………………………………………………………………...........................................…..52
Chapter 4: Nickel/Visible-Light Catalyzed Carboxylation of C(sp2) Bromides via Formate Activation…………………………………………………………………………………..............................................……58
4.1: Incentive and Overview of C(cp2) Carboxylations……………………………...................................…………..60
4.2: Initial Investigations Using Alternative Initiators……………………………….................................………....62
4.3: Reaction Optimization Under Photochemical Conditions……………………................................……………64
4.4: Mechanistic Investigations into Phenyl Triflimide………………………………………….................................67
4.5 References……………………………………………………………………………............................................……..77
Chapter 5: Supporting Information……………………………………………….........................................…………..82
S2.4 Supporting Information………………….………………………………………….......................................………82
S2.4.1 General Information………………………………………………………………….......................................……82
S2.4.2 Optimization of Hydrodehalogenation with CO2•−…………………………….............................……….....84
S2.4.3: General Procedures………………………………………………………………….......................................……87
S2.4.4: Alternative Initiators……………………………………………………………......................................………..89
S2.4.5: Preparation of Starting Materials………………………………………………....................................………..90
S2.4.6: Preparation of Substrates from the Substrate Table……………………..............................……………….102
S2.4.7: Fluorescence Quenching Experiments………………………………………………...................................…117
S2.4.8: Transient Absorption Spectroscopy…………………………………………………...................................….118
S2.4.9: Quantum Yield Experiments…………………………………………………………........................................123
S2.4.10: Chain Length Approximation……………………………………………………….....................................…125
S2.4.11: Computational Details………………………………………………………….…......................................…..125
S2.4.12: Electrochemical Measurements………………………………………………....................................……….141
S2.4.13: References…………………………………………………………………………..........................................….143
S3.3.1 General Information……………………………………………………….........................................……………149
S3.3.2: Optimization of Carboxylation of Michael Acceptors………………….................................……………...152
S3.3.3: Preparation of Substrates………………………………………………….......................................…………...153
S3.3.4: Preparation of Products from Figure 3.5………………………....................................……………………...155
S3.3.5: Computational Details……………………………………………........................................…………………...160
S3.3.6: References…………………………………………………………...........................................…………………..161
S4.6.1 General Procedures………………………………………………….......................................…………………...164
S4.6.2 Electrochemical Measurements……………………………….....................................…………………………165
S4.6.3. Optimization Details……………………………………….......................................……………………………166
S4.6.4: Investigations into the Role of Phenyl Triflimide…………….................................………………………..170
S4.6.5: Preparation of Starting Materials……………………………....................................….………………………173
S4.6.6: Preparation of Products from Substrate Table………………..................................…………………………176
S4.6.7: References……………………………………………………………...........................................………………..189
5.1: Appendix: Spectra………………………………………………………………….........................................………193
List of Figures
Figure 1.1: Common Photoredox Catalysts Alongside their Excited State Redox Potentials and max……………………………………………………………………………………………..........................................…...7
Figure 1.2: Graphic representation of oxidative/reductive quenching cycles shared by all photoredox-catalyzed
systems alongside common stoichiometric donors and acceptors………............................................................8
Figure 1.3: Graphic representation of a Jablonski diagram (A) alongside the different energy transfer mechanisms
—Forster (B) and Dexter (C)………………………………….................................................…………...................….9
Figure 2.1: A representative catalytic cycle for thiol/formate catalyzed photoredox systems in the Jui lab…………………………………………………………………………………..................................................………..….19
Figure 2.2: Modified Catalytic Cycle Generating Electrophilic Thiyl Radical via SET……............................….....21
Figure 2.3: Factors Contributing to the Feasibility of HAT from Formate……………….............................…..…...21
Figure 2.4: Formate Catalyzed Reduction of an Aryl Chloride via Thiol Oxidation………..............................……23
Figure 2.5: HAT catalyst Screen and Control……………………………………………….....................................…....24
Figure 2.6: A Summary of Mechanistic Evidence for CO2•– Generation…………….................................…………25
Figure 2.7: The Formation of Electrophilic Radicals under Alternative Conditions…………..............................27
Figure 2.8: Alternative Initiators Screen…………………………………………………......................................…….27
Figure 2.9: Proposed Mechanistic Scenario for Aryl Chloride Reduction…………................................………….28
Figure 2.10: A Summary of Intermolecular Hydroarylation Protocols via (Hetero)aryl Radical Giese Addition………………………………………………………………………….......................................................………29
Figure 2.11: Modern Examples of Unactivated Alkene Hydroarylation with Unactivated Arenes……………………………………………………………………………................................................……………30
Figure 2.12: Solvent Screen for Hydroarylation……………………………......................................…………………31
Figure 2.13: Potential Solvent Factors Impacting Reaction Effiacy……….................................…………………..32
Figure 2.14: Cosolvent Screening for Hydroarylation……………………………....................................…………...33
Figure 3.1: Potential Reaction Mechanism for CO2 Incorporation via CO2•−…….............................……………44
Figure 3.2: Optimization/Controls for Hydrocarboxylation of Michael Acceptors…….............................………45
Figure 3.3: Optimization of Carboxylation for 1,1-Diphenylethylene……………...............................……………46
Figure 3.4: Investigations into Michael Acceptor Single Electron Reduction………................................……….48
Figure 3.5: Reduction Potential Series Demonstrating the Split Reactivity for Michael Acceptors…………………………………………………………………………………................................................…..49
Figure 3.6: Evaluation of Olefin Conjugate Addition with Different Formyl C-H Sources...............................…50
Figure 3.7: Graphic Representation of the Anomeric Effect in Formyl C-H Systems…...............................…....52
Figure 4.1: Classical Methods of Constructing Carboxylic Acids……………………….....................................…..60
Figure 4.2: Catalytic Strategies for C(sp2) Carboxylation………………………………......................................…..61
Figure 4.3: Initial Mechanistic Scenario for C(sp2) Carboxylation…………………....................................………62
Figure 4.4: Overview of Reaction Screening for Alternative Initiators…………………........................................63
Figure 4.5: Reduction Pathway and CV of Phenyl Triflimide………………………….......................................……68
Figure 4.6: Evaluation of Alternative Sulfonylating Agents…………………………….....................................……71
Figure 4.7: Nickel Photocatalyst Dependence…………………………………………........................................…….74
List of Schemes
Scheme 1.1: General Overview of Radical Philicity and Polar Effects………………................................…………..4
Scheme 1.2: Classical Example of XAT-mediated Tin cyclization in the Racemic Total Synthesis of Hirustene……………………………………………………………………………………...............................................…..5
Scheme 1.3: Generation of alpha-amino radicals under Photocatalytic Conditions for XAT from Aryl/Alkyl Halides……………………………………………………………………………...........................................................…..6
Scheme 1.4: Standard catalytic cycle for nickel-catalyzed reductive cross-electrophile coupling………………………………………………………………………………….............................................……….11
Scheme 2.1: Radical Hydroarylation and Defluoroalkylation of Olefins………..............................……………….18
Scheme 2.2: Initial hypothesis regarding the generation of CO2•– via HAT……...........................……………….19
Scheme 4.2: Reaction Pathway for CO Generation………………………………………...................................……..69
Scheme 4.3: Carbon Monoxide Recycling System…………………………………………....................................…..72
Scheme 4.4: Proposed Mechanistic Scenario………………………………………………....................................……75
List of Tables
Table 2.1: Hydroarylation Substrate Scope…………………………………………………….......................................34
Table 2.2: Alternative Reduction Scope…………………………………………………......................................………35
Table 4.1: Solvent Screen Under Photochemical Conditions……………………................................………………64
Table 4.2: Reaction Screening with Electron-Rich/Neutral Arene……………………...............................…………65
Table 4.3: HAT Catalyst Screen…………………………………………………………........................................……....66
Table 4.4: Reaction Controls……………………………………………………………........................................……….70
Table 4.5: Phenyl Triflimide Loading……………………………………………......................................………………73
Table 4.6: Substrate Scope for C(sp2) Carboxylation…………………………..................................…………………47
List of Abbreviations
3DPAFIPN 2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile
4CzIPN 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene
4CzTPN 2,3,5,6-tetrakis(carbazol-9-yl)-1,4-dicyanobenzene
AcOH acetic acid
AIBN azobisisobutyronitrile
APCI atmospheric-pressure chemical ionization
CySH cyclohexanethiol
CV cyclic voltammetry
DABCO 1,4-diazabicyclo[2.2.2]octane
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane
DFT density functional theory
DMSO dimethyl sulfoxide
DMF dimethylformamide
Et2O diethyl ether
EtOAc ethyl acetate
GCMS gas chromatography mass spectrometry
HAT hydrogen atom transfer
HMPA hexamethylphosphoramide
HPLC high performance liquid chromatography
HRMS high-resolution mass spectrometry
LCMS liquid chromatography mass spectrometry
MeCN acetonitrile
MeOH methanol
MHz mega hertz
MTBE methyl tert-butyl ether
NMR nuclear magnetic resonance
Oxidative Addition
PC photocatalyst
PCET proton-coupled electron transfer
PhSH thiophenol
PTFE polytetrafluoroethylene
PTH 10-phenylphenothiazine
RE Reductive Elimination
SCE saturated calomel electrode
SET single electron transfer
TAS transient absorption spectroscopy
TBDPS tert-Butyldiphenylsilyl
TEA triethylamine
TFE 2,2,2-trifluoroethanol
THF tetrahydrofuran
TLC thin layer chromatography
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