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Anodic Electrochemistry: Controlling the Reactivity of Radical Cation Intermediates Robert John Perkins Washington University in St

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Anodic Electrochemistry: Controlling the Reactivity of Radical Cation Intermediates Robert John Perkins Washington University in St Washington University in St. Louis Washington University Open Scholarship Arts & Sciences Electronic Theses and Dissertations Arts & Sciences Summer 8-15-2016 Anodic Electrochemistry: Controlling the Reactivity of Radical Cation Intermediates Robert John Perkins Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/art_sci_etds Recommended Citation Perkins, Robert John, "Anodic Electrochemistry: Controlling the Reactivity of Radical Cation Intermediates" (2016). Arts & Sciences Electronic Theses and Dissertations. 883. https://openscholarship.wustl.edu/art_sci_etds/883 This Dissertation is brought to you for free and open access by the Arts & Sciences at Washington University Open Scholarship. It has been accepted for inclusion in Arts & Sciences Electronic Theses and Dissertations by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN ST. LOUIS Department of Chemistry Dissertation Examination Committee: Kevin Moeller, Chair Vladimir Birman Marcus Foston Garland Marshall John-Stephen Taylor Anodic Electrochemistry: Controlling the Reactivity of Radical Cation Intermediates by Robert John Perkins A dissertation presented to the Graduate School of Arts & Sciences of Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 2016 St. Louis, Missouri Table of Contents List of Figures iv List of Schemes v List of Tables vi List of Abbreviations vi Acknowledgments ix Abstract x Chapter 1: Introduction 1 1.1 Basic Concepts in Organic Electrochemistry 1 1.1.1 Basics of an Electrochemical Reaction 1 1.1.2. Constant Potential versus Constant Current Electrolysis 3 1.1.3 Divided versus Undivided Cells 6 1.1.4 The Electrochemical Double Layer 6 1.2 Intramolecular Anodic Olefin Coupling Reactions 7 1.3 References 11 Chapter 2: Controlling the Course of a Radical Cation-Derived Reaction with the Use of a Second Nucleophile 12 2.1 Approaching the Problem: Tethering a Second Nucleophile 17 2.1.1 Synthesizing Tethered Alcohol Enol Ethers 18 2.1.2 Tethered Alcohol Enol Ethers in Simple Anodic Oxidations 19 2.1.3 Mechanistic Study 21 2.2 Controlling the Electrolysis Pathway with the Second Nucleophile 22 2.2.1 Substrate Synthesis 22 2.2.2 Initial Electrolysis Studies 25 2.2.3 Optimizing the Electrolysis: Reversibility of Alcohol Trapping 26 2.3 Conclusions 29 2.4 References 29 2.5 Experimental 31 Chapter 3: Expanding the Scope of Tethered Alcohol Enol Ether Electrolysis Substrates 51 3.1 New Efficient Synthesis of Tethered Alcohol Enol Ethers 53 3.1.1 Literature Precedent for “Michael-like” Additions to Ketal-Protected Enones 54 3.1.2 Developing a “Michael-like” Addition of Grignards to Ketal-Protected Enones 56 3.1.3 Reintroducing the Methyl Groups 59 3.1.4 Generalizing the “Michael-like” Additions of Grignards to Ketal-Protected Enones 62 3.2 Electrolysis Studies 65 3.2.1 Initial Studies: Solubility Problems and Initial Results 65 3.2.2 Solving Solubility Problems and Insight into the Electrolysis of 3.4 69 3.3 Conclusions 77 ii 3.4 References 77 3.5 Experimental 79 Chapter 4: Anodic Couplings of Carboxylic Acids to Electron-rich Olefins and the Importance of the Second Oxidation 102 4.1 Kolbe Decarboxylation versus Lactone Formation 102 4.2 Initial Cyclization Studies 104 4.3 Anodic Coupling of Carboxylic Acids to Styrenes 104 4.4 Conclusions 114 4.5 References 116 4.6 Experimental 117 Chapter 5: Lignin as a Sustainable Feedstock for Synthetic Building Blocks 165 5.1 Introduction 165 5.2 Structure and Diassembly of Lignin 166 5.2.1 Structural Motifs in Lignin 166 5.2.2 Disassembly of Lignin into Monomers for Synthetic Processing 167 5.3 Processing Lignin-Derived Monomers into Synthetic Building Blocks 169 5.3.1 Small Molecule Building Blocks Derived from Syringealdehyde 170 5.3.2 Small Molecule Building Blocks Derived from Cinnamyl Alcohol Methyl Ether 172 5.3.3 Electrochemical Proessing of Lignin-Derived Substrates 175 5.4 Lignin-Based Synthesis of Natural Product Scaffold 178 5.4.1 Indanone Synthesis 178 5.4.2 Dibenzodiazepine Synthesis 179 5.4.3 Anthraquinone Synthesis 181 5.5 Conclusions 182 5.6 References 182 5.7 Experimental 184 iii List of Figures Figure 1-1: Electrolysis Schematic. 2 Figure 1-2: Constant Potential Electrolysis. 4 Figure 1-3: Constant Current Electrolysis. 5 Figure 1-4: Constant Current Electrolysis Potential Control with Varying Current Density 5 Figure 1-5: Electrochemical Double Layer 7 Figure 1-6: Chemical Versus Electrochemical Oxidation. 7 Figure 2-1: Polycyclic Natural Products 14 Figure 3-1: Structure of natural product Artemisolide 52 Figure 3-2: Tethered alcohol enol ether for the formation of a 5-7-5 tricyclic ring system 53 Figure 3-3: Spectrum of the crude product resulting from oxidation of 3.4, with coumarin internal standard. 71 Figure 4-1: Radical cation stabilization by an o-methoxy substitutent 114 Figure 5-1: Lignin Structure 166 Figure 5-2: Aromatic electron-rich natural product scaffolds 167 Figure 5-3: Isolated solvolysis products from birch sawdust 168 Figure 5-4: Isolated solvolysis products from cedar sawdust 169 iv List of Schemes Scheme 1-1: Electrochemical Umpolong Reaction. 8 Scheme 1-2: General Anodic Olefin Coupling Reaction Mechanism 9 Scheme 1-3: Anodic Olefin Coupling Reactions in Total Synthesis 10 Scheme 2-1: Failed anodic cyclization reactions 13 Scheme 2-2: “Work-around” methods for furan/enol ether 7-membered ring formation 15 Scheme 2-3: Ring expansion route to 7-membered ring 16 Scheme 2-4: A plan for avoiding elimination reactions 18 Scheme 2-5: Copper coupling for the synthesis of tethered alcohol enol ethers 19 Scheme 2-6: Electrolysis of tethered alcohol enol ether substrates 20 Scheme 2-7: Tethered alcohol enol ether mechanistic study product distribution 21 Scheme 2-8: Initial palladium coupling-based route to enol ether 2.24 23 Scheme 2-9: Vinyl anion-based route to enol ether 2.24 24 Scheme 2-10: Acid-based decomposition of enol ether 2.24 25 Scheme 2-11: Initial electrolysis with tethered alcohol enol ether 2.24 26 Scheme 2-12: Competition study 27 Scheme 2-13: Optimized electrolysis with tethered alcohol enol ether at low temperature 29 Scheme 3-1: Revisited: Failed 7-membered ring furan-enol ether anodic coupling 52 Scheme 3-2: Initial synthesis of tethered alcohol enol ether 3.4 54 Scheme 3-3: Proposed “Michael-like” addition of an alkyl anion equivalent to a ketal 54 Scheme 3-4: Literature precedent for alkyl anion addition to ketal-protected enones 55 Scheme 3-5: Evolution of Grignard addition workup 58 Scheme 3-6: Enone protection with an epoxide 60 Scheme 3-7: New synthesis of enol ether 3.4 61 Scheme 3-8: Expanding the scope of “Michael-like” Grignard additions to ketals and acetals 64 Scheme 3-9: Initial electrolysis studies 66 Scheme 3-10: Electrolysis of enol ether 3.6 68 Scheme 3-11: Products seen in electrolysis of enol ether 3.4 72 Scheme 3-12: Possible pathways to furan oxidation product 3.19 74 Scheme 3-13: Proposed route to conformationally constrained electrolysis substrate 76 Scheme 4-1: The Kolbe electrolysis 102 Scheme 4-2: Intramolecular anodic coupling of a carboxylic acid and olefin 103 Scheme 4-3: Anodic coupling of a carboxylic acid to a styrene with a slow second oxidation 110 Scheme 4-4: Predicted relative rates of single-electron oxidation based on resonance stabilization of the resulting cation 113 Scheme 5-1: Synthetic manipulation of syringealdehyde 170 Scheme 5-2: Isoquinoline alkaloid synthesis 172 Scheme 5-3: Synthetic manipulation of sinapyl alcohol methyl ether 173 Scheme 5-4: Proposed mechanism of solvolytic cleave of lignin to methyl ether 174 v Scheme 5-5: Benzimidazole and benzothiazole synthesis with electrochemically recycled CAN 176 Scheme 5-6: Direct electrochemical cyclizations 177 Scheme 5-7: Hydrogenation with electrochemically generated hydrogen gas 177 Scheme 5-8: Indanone synthesis 178 Scheme 5-9: Dibenzodiazepine synthesis 180 Scheme 5-10: Anthraquinone synthesis 181 List of Tables Table 4-1: Anodic coupling of carboxylic acids to ketene dithioacetals 105 Table 4-2: Extension of carboxylic acid couplings with electron-rich olefins to vinyl sulfides and enol ethers 106 Table 4-3: Extension to styrene trapping groups 107 Table 4-4: Effect of methoxy substituents on anodic couplings of carboxylic acids with styrenes 111 Table 4-5: Effect of methoxy substitutens on anodic couplings of alcohols with styrenes in C-glycoside synthesis 115 List of Abbreviations A ampere Ac acetyl Bn benzyl Bu butyl nBu butyl tBu 1,1-dimethylethyl dba dibenzylideneacetone dppf 1,1’-bis(diphenylphosphino)ferrocene DCM dichloromethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIBAL diisobutylaluminum hydride DMAP 4-(dimethylamino)pyridine DMF dimethyl formamide DMSO dimethyl sulfoxide E voltage EDTA ethylenediaminetetraacetic acid Ep/2 half-peak height ESI electrospray ionization Et ethyl F faraday g gram vi hr hour HMDS bis(trimethylsilyl)amide HMPA hexamethylphosphoramide HR-MS high resolution mass spectrometry IR infrared L liter LAH lithium aluminum hydride LDA lithium diisopropylamide M mole per liter mCPBA 3-chloroperbenzoic acid Me methyl mol mole Ms methanesulfonyl n quantified charge NBS N-bromosuccinimide NMR nuclear magnetic resonance Ph phenyl PPA polyphosphoric acid PPTS pyridinium p-toluenesulfonate iPr 1-methylethyl Rf retention factor Rn variable functional group RSM recovered starting material RVC reticulated vitreous carbon s second T temperature TBAF tetrabutylammonium fluoride TBS tert-butyldimethylsilyl TEA triethylamine TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxy Tf trifluoromethanesulfonyl TFA trifluoroacetic acid TIPS triisopropylsilyl TMS trimethylsilyl THF tetrahydrofuran Ts 4-methylbenzylsulfonyl V volt X variable atom or group Y variable atom or group vii Acknowledgments Kevin Moeller secured funding for and guided this research.
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