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Fluorination of alkyl radicals using electrophilic N-F reagents and investigation on the intramolecular… Rueda Becerril, Montserrat 2014

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FLUORINATION OF ALKYL RADICALS USING ELECTROPHILICN−F REAGENTS AND INVESTIGATION ON THEINTRAMOLECULAR CHEMOSELECTIVITY OF ALKOXYRADICALSbyMontserrat Rueda BecerrilB. Sc., Universidad Auto´noma del Estado de Me´xico, 2008a thesis submitted in partial fulfillmentof the requirements for the degree ofDOCTOR OF PHILOSOPHYinthe faculty of graduate and postdoctoral studies(Chemistry)THE UNIVERSITY OF BRITISH COLUMBIA(Vancouver)December 2014c©Montserrat Rueda Becerril, 2014AbstractThe selective fluorination of organic molecules has become increasingly important for the pharmaceu-tical and agrochemical industries, given that the presence of this atom enhances the lipophilicity andbioavailability of molecules. Despite the extensive research in fluorine chemistry, there is a paucity ofselective and safe sources of fluorine for radical reactions. I hereby present the investigation of N−Freagents as efficient fluorine atom transfer agents to alkyl radicals. Although most of the research pre-sented in this work focuses on fluorination methodologies, a study on the intramolecular chemoselectivityof alkoxy radicals is also discussed.Chapter 2 describes the exploratory work into the feasibility of transferring a fluorine atom to alkylradicals from electrophilic sources of fluorine. Diacyl peroxides and t-butylperesters were homolyzedto generate alkyl radicals in the presence of different N−F fluorine sources. Primary, secondary, andtertiary fluoroalkanes were successfully synthesized under the reaction conditions. This methodologywas successfully applied to the fluorination of a cholic acid derivative.In Chapter 3, photoredox catalysis was explored as an alternative method to generate alkyl radicalsin the context of radical fluorination. Trisbipyridylruthenium (II) and visible light were utilized to pro-mote the decarboxylative fluorination of phenoxyacetic acid derivatives. Electron-withdrawing groupson the aryl ring favoured the transformation, while electron-donating groups provided undesired prod-ucts. An estrone derivative was successfully fluorinated with our visible-light mediated methodology.Additionally, transient absorption spectroscopy studies in collaboration with the Wolf group at the Uni-versity of British Columbia, along with cyclic voltammetry experiments performed in collaboration withthe Bizzotto group at the same institution, provided evidence to support an oxidative mechanism of thephotocatalytic cycle.Chapter 4 describes a study to assess the chemoselectivity of alkoxy radical cyclizations onto silylenol ethers, when other radical pathways can occur. Cyclization of intramolecular competition substratesshowed that 5-exo cyclization of alkoxy radicals onto silyl enol ethers were preferred over 5-exo cycliza-tions onto terminal, disubstituted and trisubstituted alkenes, as well as 1,5-hydrogen atom transfer reac-tions and β-fragmentations. Silyl enol ethers as alkoxy radical acceptors strongly favour 6-exo cyclizationover 1,5-hydrogen atom transfer from an allylic position.iiPrefaceChapter 2 is based on research performed in the Sammis group with my colleagues Claire ChatalovaSazepin and Dr. Joe C. T. Leung, in collaboration with Prof. Jean-Francois Paquin Prof. Pierre Ken-nepohl and Dr. Tulin Okbino˘glu. This work was published as a communication in 2012: Rueda-Becerril,M.; Chatalova Sazepin, C.; Leung, J. C. T.; Okbino˘glu, T.; Kennepohl, P.; Paquin, J.-F.; Sammis, G. M.J. Am. Chem. Soc. 2012, 134, 4026-4029. The DFT calculations were performed by Prof. Pierre Ken-nepohl and Dr. Tulin Okbino˘glu. Substrates 152, 153 and 155 were prepared by C. Chatalova Sazepin.Substrate 156 was prepared by Dr. Joe C. T. Leung. Substrate 147 was prepared by Dr. Natalie E.Campbell. Compounds 163 and 164 were characterized by C. Chatalova Sazepin. The measurementson the lamp emission presented in Section 3.7.7 (Figure 3.13) were performed by the Paquin researchgroup in Universite´ Laval. I performed all other syntheses, characterizations and experimental work inthis chapter.Chapter 3 is based on research performed in the Sammis group published in two separate commu-nications in 2012 and 2014: Leung, J. C. T.; Chatalova Sazepin, C.; West, J. G.; Rueda-Becerril, M.;Paquin, J.-F.; Sammis, G. M. Angew. Chem. Int. Ed. 2012, 51, 10804-10807; and Rueda-Becerril,M.; Mahe´, O.; Drouin, M.; Majewski, M. B.; West, J. G.; Wolf, M. O.; Sammis, G. M.; Paquin, J.-F.J. Am. Chem. Soc. 2014, 136, 2637-2641. The transient absorption spectroscopy (TAS) experimentswere performed by Dr. Marek Majewski from the Wolf research group at UBC. The measurement ofthe oxidation potentials of Selectfluor R© and phenoxyacetic acid (257) using cyclic voltametry (CV) wasperformed with the help of Dr. Jannu´ R. Casanova Moreno from the Bizzotto research group at UBC.Fluoroethers 262 and 272 were synthesized and characterized by Dr. Olivier Mahe´ from the Paquingroup at Universite´ Laval. I performed all other syntheses, characterizations and experimental work inthis chapter.Chapter 4 is based on research performed in the Sammis group in collaboration with my colleaguesDr. Joe C. T. Leung and Christine R. Dunbar. The results were published as a full article in 2011:Rueda-Becerril, M.; Leung, J. C. T.; Dunbar, C. R.; Sammis, G. M. J. Org. Chem. 2011, 76, 7720-7729. Compounds 337 and 337 were synthesized by me but were characterized by Dr. Joe C. T. Leung.Competition substrate type E was synthesized and radically cyclized by C. R. Dunbar. I performed allother syntheses, characterizations and experimental work presented in this chapter.iiiTable of ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iiPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iiiTable of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ivList of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viiiList of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ixList of Schemes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvList of Abbreviations and Symbols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xviAcknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxDedication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxii1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 General properties and reactivity of radicals . . . . . . . . . . . . . . . . . . . . . . . 21.1.1 Carbon radical generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.1.2 Carbon radical reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.1.2.1 Tandem radical reactions: building molecular complexity . . . . . . 61.1.3 Oxygen-centered radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81.2 Fluorine atom transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101.2.1 Fluorine: history and traditional sources . . . . . . . . . . . . . . . . . . . . . 101.2.2 Naturally occurring organofluorines and the effect of fluorine in bioactive molecules 111.2.3 Traditional sources of fluorine in organic synthesis . . . . . . . . . . . . . . . 151.2.3.1 Electrophilic sources of fluorine . . . . . . . . . . . . . . . . . . . . 161.2.3.2 Mechanism of N−F reagents: SN2 vs SET . . . . . . . . . . . . . . 211.2.4 The fluorination of radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24ivTable of Contents2 Fluorine transfer to alkyl radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262.1 Radical sources of fluorine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262.1.1 Elemental fluorine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272.1.2 Trifluoromethyl hypofluorite . . . . . . . . . . . . . . . . . . . . . . . . . . . 312.1.3 Xenon difluoride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342.2 Proposed radical fluorination using N-F reagents . . . . . . . . . . . . . . . . . . . . 382.2.1 N−F bond dissociation energy calculations . . . . . . . . . . . . . . . . . . . 392.3 Initial studies: lauroyl peroxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412.3.1 Lauroyl peroxide fluorination optimization studies . . . . . . . . . . . . . . . 442.3.1.1 Thermolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442.3.1.2 Photolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452.4 Alkylboranes as radical precursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472.5 t-Butylperesters as alkyl radical precursors . . . . . . . . . . . . . . . . . . . . . . . . 492.5.1 Fluoroalkane standards synthesis . . . . . . . . . . . . . . . . . . . . . . . . . 522.5.2 Perester fluorination optimization . . . . . . . . . . . . . . . . . . . . . . . . 532.6 Large molecule targets: the synthesis of cholic fluoroalkane 159 . . . . . . . . . . . . 582.7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622.8 Experimentals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622.8.1 General experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622.8.2 Synthesis of fluoroalkane standards . . . . . . . . . . . . . . . . . . . . . . . 632.8.2.1 General fluoroalkane synthesis procedure . . . . . . . . . . . . . . . 632.8.3 Quantification utilizing gas chromatography . . . . . . . . . . . . . . . . . . . 652.8.4 Synthesis of acids 150 and 164. . . . . . . . . . . . . . . . . . . . . . . . . . 662.8.5 Synthesis of t-butylperesters . . . . . . . . . . . . . . . . . . . . . . . . . . . 692.8.5.1 General t-butyl perester synthesis procedure . . . . . . . . . . . . . 692.8.6 General fluorination procedure . . . . . . . . . . . . . . . . . . . . . . . . . . 702.8.7 Synthesis of fluoride 159 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722.8.7.1 1H NMR yield determination of fluoroalkane 159 . . . . . . . . . . 783 Direct C-F bond formation using photoredox catalysis . . . . . . . . . . . . . . . . . . . 803.1 Visible-light photoredox catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803.1.1 Tris(bipyridine)ruthenium(II) ([Ru(bpy)3]2+) photoredox properties . . . . . . 803.1.2 Application of ruthenium (II) photoredox catalysis to organic synthesis . . . . 823.1.2.1 Photoredox C−H bond formation . . . . . . . . . . . . . . . . . . . 833.1.2.2 Photoredox C−C bond formation . . . . . . . . . . . . . . . . . . . 873.2 Initial studies: photocatalytic halogen exchange . . . . . . . . . . . . . . . . . . . . . 983.3 Decarboxylative fluorination precedents and proposed visible-light photoredox approach 1003.4 Catalytic photoredox decarboxylative fluorination . . . . . . . . . . . . . . . . . . . . 1023.4.1 Synthesis of phenoxyacetic acids . . . . . . . . . . . . . . . . . . . . . . . . . 1053.4.2 Catalytic photoredox decarboxylative fluorination scope . . . . . . . . . . . . 106vTable of Contents3.4.3 Photoredox fluorination of estrone derivative . . . . . . . . . . . . . . . . . . 1103.5 Mechanistic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1123.5.1 Transient absorption spectroscopy studies . . . . . . . . . . . . . . . . . . . . 1133.5.2 Cyclic voltammetry studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1183.7 Experimentals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1183.7.1 General experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1183.7.2 General synthesis aryloxy acids . . . . . . . . . . . . . . . . . . . . . . . . . 1193.7.3 NMR-scale catalytic photoredox decarboxylative fluorination studies . . . . . . 1223.7.4 General photoredox decarboxylative fluorination procedure . . . . . . . . . . . 1233.7.5 Comparative photofluorodecarboxylation experiments . . . . . . . . . . . . . 1263.7.6 Cyclic voltametry studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1283.7.7 Lamp emission measurements . . . . . . . . . . . . . . . . . . . . . . . . . . 1284 Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation . . . . . . . . . . . . . . . . . . . . . 1294.1 Generation of alkoxy radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1304.2 Reactivity of alkoxy radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1314.3 Electrophilicity and nucleophilicity of radicals . . . . . . . . . . . . . . . . . . . . . . 1344.4 Reaction rates of oxygen-centered radicals . . . . . . . . . . . . . . . . . . . . . . . . 1364.5 Silyl enol ethers as radical reactive partners . . . . . . . . . . . . . . . . . . . . . . . 1384.6 Competition studies using silyl enol ethers as radical acceptors . . . . . . . . . . . . . 1404.6.1 Synthesis of competition substrates . . . . . . . . . . . . . . . . . . . . . . . 1414.6.1.1 Synthesis of competition substrate 332 . . . . . . . . . . . . . . . . 1414.6.1.2 Synthesis of competition substrate 340 . . . . . . . . . . . . . . . . 1424.6.1.3 Synthesis of competition substrates 348 and 349 . . . . . . . . . . . 1434.6.1.4 Synthesis of competition substrate 325 . . . . . . . . . . . . . . . . 1444.6.1.5 Synthesis of competition substrate 360 . . . . . . . . . . . . . . . . 1454.6.1.6 Synthesis of competition substrate 367 . . . . . . . . . . . . . . . . 1464.6.1.7 Synthesis of competition substrate 372 . . . . . . . . . . . . . . . . 1474.6.2 Competing 5-exo alkoxy radical cyclization onto silyl enol ether and onto sub-stituted alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1484.6.3 Competing 1,5-HAT and alkoxy radical cyclization onto silyl enol ethers . . . 1524.6.4 Alkoxy radical chemoselectivity study summary . . . . . . . . . . . . . . . . 1554.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1574.8 Experimentals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1574.8.1 General methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1574.8.2 Detailed synthesis of cyclizations precursors . . . . . . . . . . . . . . . . . . 1584.8.2.1 Synthesis of competition substrate 332 procedure . . . . . . . . . . 1584.8.2.2 Synthesis of competition substrate 340 procedure . . . . . . . . . . 160viTable of Contents4.8.2.3 Synthesis of competition substrates 348 and 349 procedure . . . . . 1634.8.2.4 Synthesis of competition substrates 325 procedure . . . . . . . . . . 1674.8.2.5 Synthesis of competition substrates 360 procedure . . . . . . . . . . 1694.8.2.6 Synthesis of competition substrates 367 procedure . . . . . . . . . . 1724.8.2.7 Synthesis of competition substrates 372 procedure . . . . . . . . . . 1754.8.3 General radical cyclization procedure . . . . . . . . . . . . . . . . . . . . . . 1774.8.4 Cyclization products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1774.8.5 NMR analysis of the reaction mixtures . . . . . . . . . . . . . . . . . . . . . . 1794.8.5.1 Analysis of competition substrate 332 . . . . . . . . . . . . . . . . . 1794.8.5.2 Analysis of competition substrate 340 . . . . . . . . . . . . . . . . . 1804.8.5.3 Analysis of competition substrates 348 and 349 . . . . . . . . . . . 1814.8.5.4 Analysis of competition substrate 325 . . . . . . . . . . . . . . . . . 1824.8.5.5 Analysis of competition substrate 360 . . . . . . . . . . . . . . . . . 1834.8.5.6 Analysis of competition substrate 367 . . . . . . . . . . . . . . . . . 1844.8.5.7 Analysis of competition substrate 372 . . . . . . . . . . . . . . . . . 1855 Conclusions and future work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1865.1 Chapter 2: conclusions and future work . . . . . . . . . . . . . . . . . . . . . . . . . 1875.2 Chapter 3: conclusions and future work . . . . . . . . . . . . . . . . . . . . . . . . . 1915.3 Chapter 4: conclusions and future work . . . . . . . . . . . . . . . . . . . . . . . . . 194Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195Appendix A Selected spectra for Chapter 2 . . . . . . . . . . . . . . . . . . . . . . . . . . 208Appendix B Selected spectra for Chapter 3 . . . . . . . . . . . . . . . . . . . . . . . . . . 219Appendix C Selected spectra for Chapter 4 . . . . . . . . . . . . . . . . . . . . . . . . . . 233viiList of TablesTable 1.1 Relevant bond dissociation energies . . . . . . . . . . . . . . . . . . . . . . . . 3Table 1.2 Fried and Sabo’s test of the activity in rat liver of 45 and 46 . . . . . . . . . . . 15Table 2.1 DFT calculated properties of the N−F bond of NFSI, Selectfluor R©and NFPY . 40Table 2.2 Lauroyl peroxide themolysis-fluorination: fluorine source, time and solvent opti-mization study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Table 2.3 Optimization of the fluorination conditions for perester 139 . . . . . . . . . . . 54Table 2.4 Optimization of the fluorination conditions of 151 . . . . . . . . . . . . . . . . 56Table 2.5 Optimization of the fluorination conditions of 152 . . . . . . . . . . . . . . . . 57Table 2.6 Optimization of the fluorination conditions of 158 . . . . . . . . . . . . . . . . 60Table 3.1 Halide exchange using visible-light promoted photoredox catalysis . . . . . . . 99Table 3.2 Photoredox decarboxylative fluorination control experiments . . . . . . . . . . 105Table 3.3 Optimization photoredox decarboxylative fluorination reaction conditions for sub-strate 267 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106Table 3.4 Optimization of photoredox decarboxylative fluorination reaction conditions forsubstrate 290 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111Table 4.1 Selected absolute carbon and alkoxy radical rate constants . . . . . . . . . . . . 137Table 4.2 Alkoxy radical selectivity twards cyclization onto silyl enol ether summary . . . 156Table 5.1 Fluorine atom transfer to alkyl radicals, results summary . . . . . . . . . . . . . 188Table 5.2 Catalytic photoredox decarboxylative fluorination, results summary . . . . . . . 192viiiList of FiguresFigure 1.1 Reactive intermediates in organic chemistry: carbanion, carbon free radical, car-bocation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Figure 1.2 General radical chain reaction mechanism . . . . . . . . . . . . . . . . . . . . 4Figure 1.3 Carbon radical precursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Figure 1.4 Selected reactivity modes of carbon radicals . . . . . . . . . . . . . . . . . . . 6Figure 1.5 Types of oxygen-centered radicals . . . . . . . . . . . . . . . . . . . . . . . . 8Figure 1.6 Selected acyloxy radical precursors . . . . . . . . . . . . . . . . . . . . . . . 9Figure 1.7 Some abiogenic naturally occurring organofluorindes . . . . . . . . . . . . . . 12Figure 1.8 Some biogenic naturally occurring organofluorindes . . . . . . . . . . . . . . 12Figure 1.9 Selected commercially available fluorine containing pharmaceuticals . . . . . . 14Figure 1.10 Selected organic sources of fluoride ion (F–) . . . . . . . . . . . . . . . . . . . 16Figure 1.11 Representative N−F electrophilic sources of fluorine . . . . . . . . . . . . . . 18Figure 1.12 Possible mechanistic pathways for nucleophiles reacting with electrophilic sourcesof fluorine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Figure 1.13 Ionic vs radical fluorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Figure 2.1 Thermodynamic data for the fluorination of alkanes with F2 . . . . . . . . . . 27Figure 2.2 Mechanism of the acid catalyzed fluorination of alkenes with xenon difluoride . 35Figure 2.3 Previously proposed mechanism for fluorination using electrophilic N−F reagentsand our proposed mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39Figure 2.4 Selected electrophilic sources of fluorines for DFT calculations . . . . . . . . . 39Figure 2.5 Lauroyl peroxide, common radical initiator . . . . . . . . . . . . . . . . . . . 42Figure 2.6 Crude 1H NMRspectrum of the first fluorine atom transfer from NFSI to lauroylperoxide under thermal conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Figure 2.7 Leffler’s carboxy-inversion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Figure 2.8 Alkylboranes autoxidation mechanism: SH2 initiation step . . . . . . . . . . . 49Figure 2.9 Alkylboranes autoxidation mechanism . . . . . . . . . . . . . . . . . . . . . . 50Figure 2.10 Quantification of fluoroalkane 159 utilizing 1H NMR analysis, trial 1 . . . . . 78Figure 2.11 Quantification of fluoroalkane 159 utilizing 1H NMR analysis, trials 2 and 3 . . 79Figure 3.1 Tris(bipyridine)ruthenium(II) ([Ru(bpy)3]2+) photocatalyst . . . . . . . . . . . 81ixList of FiguresFigure 3.2 Simplified molecular orbital representation of [Ru(bpy)3]2+ photochemistry . . 81Figure 3.3 Photoexcitation, oxidative and reductive quenching cycles for [Ru(bpy)3]2+ . . 82Figure 3.4 Photocatalytic [2 + 2] enone cycloaddition scope . . . . . . . . . . . . . . . . 92Figure 3.5 Proposed halogen exchange utilizing a visible-light mediated photoredox process 98Figure 3.6 Absorption spectra of phenoxyacetic acid (257), Selectfluor R© (59) and [Ru(bpy)3]Cl2 inH2O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103Figure 3.7 Proposed oxidation of phenoxyacetic acids via visible-light photoredox catalysis 103Figure 3.8 Photoexcitation, oxidative and reductive quenching cycles for [Ru(bpy)3]2+ . . 113Figure 3.9 Excited state difference spectra . . . . . . . . . . . . . . . . . . . . . . . . . . 115Figure 3.10 Redox pairs in the photocatalytic decarboxylative fluorination reaction . . . . . 116Figure 3.11 Cyclic voltammetry of phenoxyacetic acid (257) . . . . . . . . . . . . . . . . 117Figure 3.12 Cyclic voltammetry of Selectfluor R© . . . . . . . . . . . . . . . . . . . . . . . 117Figure 3.13 Measured emission of 500 W lamp . . . . . . . . . . . . . . . . . . . . . . . . 128Figure 4.1 Selected alkoxy radical precursors . . . . . . . . . . . . . . . . . . . . . . . . 130Figure 4.2 Alkoxy radical modes of reactivity . . . . . . . . . . . . . . . . . . . . . . . . 132Figure 4.3 Polar effects in radical substitution . . . . . . . . . . . . . . . . . . . . . . . . 135Figure 4.4 SOMO interactions with HOMO and LUMO . . . . . . . . . . . . . . . . . . 135Figure 4.5 Electrophilic vs nucleophilic radicals . . . . . . . . . . . . . . . . . . . . . . . 136Figure 4.6 Designed competition substrates . . . . . . . . . . . . . . . . . . . . . . . . . 140Figure 4.7 1HNMR analysis of the crude reaction mixture of the cyclization of competitionsubstrate 332 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179Figure 4.8 1HNMR analysis of the crude reaction mixture of the cyclization of competitionsubstrate 340 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180Figure 4.9 1HNMR analysis of the crude reaction mixture of the cyclization of competitionsubstrate 348 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181Figure 4.10 1HNMR analysis of the crude reaction mixture of the cyclization of competitionsubstrate 349 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182Figure 4.11 1HNMR analysis of the crude reaction mixture of the cyclization of competitionsubstrate 325 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183Figure 4.12 1HNMR analysis of the crude reaction mixture of the cyclization of competitionsubstrate 360 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183Figure 4.13 1HNMR analysis of the crude reaction mixture of the cyclization of competitionsubstrate 367 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184Figure 4.14 1HNMR analysis of the crude reaction mixture of the cyclization of competitionsubstrate 372 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185Figure 5.1 Studies performed in thesis work . . . . . . . . . . . . . . . . . . . . . . . . . 186Figure 5.2 Possible fluorine atom transfer mechanisms . . . . . . . . . . . . . . . . . . . 189Figure 5.3 Proposed photoredox decarboxylative fluorination mechanism . . . . . . . . . 191xList of FiguresFigure 5.4 Alternative photo catalysts with stronger oxidation potentials for the transitionof Ru(III) to Ru(II) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194xiList of SchemesScheme 1.1 Mode of action of AIBN as a radical initiator . . . . . . . . . . . . . . . . . . 4Scheme 1.2 High complexity generation via the use of free radicals: Parker’s synthesis ofcodeine and morphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Scheme 1.3 Radical decarboxylation of acyloxy radicals . . . . . . . . . . . . . . . . . . 8Scheme 1.4 Synthesis of cubane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Scheme 1.5 Acyloxy-radical mediated Barton decarboxylation . . . . . . . . . . . . . . . 10Scheme 1.6 Fluorocitrate biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Scheme 1.7 Barton’s use of CF3OF as an electrophilic fluorinating reagent . . . . . . . . . 17Scheme 1.8 Purrington’s synthesis of fluoromalonates using 53 . . . . . . . . . . . . . . . 18Scheme 1.9 Umemoto’s synthesis of α-fluoroketones using 64 . . . . . . . . . . . . . . . 19Scheme 1.10 Barnette’s use of 55 to fluorinate phenyl magnesium bromide . . . . . . . . . 19Scheme 1.11 DesMarteau’s use of 56 in the fluorination of α-carbonylic positions . . . . . 19Scheme 1.12 Differding’s electrophilic fluorination using of 57 . . . . . . . . . . . . . . . 20Scheme 1.13 Bank’s electrophilic fluorination of androsterone derivative using 59, Selectfluor R© 21Scheme 1.14 Reaction of 2-naphthol (75) with NFPY 76 . . . . . . . . . . . . . . . . . . . 22Scheme 1.15 Citronellic ester enolate fluorination probe . . . . . . . . . . . . . . . . . . . 23Scheme 1.16 Cyclopropane radical clock probe for electrophilic fluorination . . . . . . . . 24Scheme 2.1 Radical perfluorination mechanism of ethane with F2 . . . . . . . . . . . . . 28Scheme 2.2 Radical perfluorination mechanism of ethane with F2 . . . . . . . . . . . . . 29Scheme 2.3 Radical mechanism for the fluorination of sym-dichlorodifluoroethylene andchloroform with F2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Scheme 2.4 Selective fluorination of carboxylic acid salts 97 with F2 . . . . . . . . . . . . 31Scheme 2.5 Fluorination of ethene with trifluoromethyl hypofluorite . . . . . . . . . . . . 32Scheme 2.6 Fluorination of 1,1-diphenylethene with trifluoromethyl hypofluorite . . . . . 33Scheme 2.7 Acid catalyzed fluorination of alkenes with xenon difluoride . . . . . . . . . . 34Scheme 2.8 Fluorination of enol 114 utilizing xenon difluoride . . . . . . . . . . . . . . . 35Scheme 2.9 Xenon difluoride reactivity towards aromatic ketones . . . . . . . . . . . . . 36Scheme 2.10 Xenon difluoride reactivity towards aromatic aldehydes . . . . . . . . . . . . 36Scheme 2.11 Decarboxylative halogenation reactions . . . . . . . . . . . . . . . . . . . . . 37Scheme 2.12 Xenon difluoride luorodecarboxylation reaction mechanism . . . . . . . . . . 37xiiList of SchemesScheme 2.13 Thermally or photochemically initiated diacylperoxide decomposition . . . . 41Scheme 2.14 Thermolysis and fluorination of lauroyl peroxide using NFSI . . . . . . . . . 42Scheme 2.15 Fluorination of 1,3,5-trimethoxybenzene by NFSI under thermal conditions . 43Scheme 2.16 Synthesis of fluoroalkane standard 121 . . . . . . . . . . . . . . . . . . . . . 44Scheme 2.17 Alkyl radical generation via alkylborane reaction with O2 . . . . . . . . . . . 47Scheme 2.18 Hydroboration of 1-octene . . . . . . . . . . . . . . . . . . . . . . . . . . . 47Scheme 2.19 Fluorination of trialkylborane 131 with NFSI . . . . . . . . . . . . . . . . . . 48Scheme 2.20 Hydroboration of styrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Scheme 2.21 Fluorination of trialkylborane 135 with NFSI . . . . . . . . . . . . . . . . . . 48Scheme 2.22 Thermal decomposition of t-butylperester . . . . . . . . . . . . . . . . . . . 50Scheme 2.23 Synthesis of 4-phenylbutyric acid t-butylperester . . . . . . . . . . . . . . . . 51Scheme 2.24 Fluorination of t-butylperester 139 . . . . . . . . . . . . . . . . . . . . . . . 51Scheme 2.25 Synthesis of fluoroalkane standard 140 . . . . . . . . . . . . . . . . . . . . . 52Scheme 2.26 Synthesis of fluoroalkane standard 146 . . . . . . . . . . . . . . . . . . . . . 52Scheme 2.27 Synthesis of fluoroalkane standard 148 . . . . . . . . . . . . . . . . . . . . . 53Scheme 2.28 Synthesis of secondary t-butylperester 151 . . . . . . . . . . . . . . . . . . . 55Scheme 2.29 Fluorination of t-butylperester 153 . . . . . . . . . . . . . . . . . . . . . . . 57Scheme 2.30 Summary of the fluorination results obtained using t-butylperesters as radicalprecursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58Scheme 2.31 Synthesis of t-butylperester derived from cholic acid . . . . . . . . . . . . . . 59Scheme 2.32 Undesired elimination pathway for fluoroalkane 159 . . . . . . . . . . . . . . 61Scheme 3.1 Reduction of phenacylsulphonium salts through visible-light photocatalysis . 83Scheme 3.2 Reduction of electron poor alkyl bromides . . . . . . . . . . . . . . . . . . . 83Scheme 3.3 Reduction of electron poor alkenes through photoredox catalysis . . . . . . . 84Scheme 3.4 Fukuzimi’s photocatalytic reduction of phenacyl halides . . . . . . . . . . . . 85Scheme 3.5 Photocatalytic Meerwein-Pondorf-Verley . . . . . . . . . . . . . . . . . . . . 86Scheme 3.6 Stephenson’s tin-free reductive dehalogenation . . . . . . . . . . . . . . . . . 87Scheme 3.7 Reductive dimerization of benzyl bromide . . . . . . . . . . . . . . . . . . . 87Scheme 3.8 Photoredox-catalyzed Pschorr reaction . . . . . . . . . . . . . . . . . . . . . 88Scheme 3.9 Photocatalytic debromination of 1,2-dibromides . . . . . . . . . . . . . . . . 89Scheme 3.10 Organo-/photocatalytic enantioselective α-alkylation of aldehydes . . . . . . 90Scheme 3.11 Visible-light photocatalytic [2 + 2] enone cycloadditions . . . . . . . . . . . 91Scheme 3.12 Crossed intermolecular photocatalytic [2 + 2] enone cycloadditions . . . . . . 93Scheme 3.13 Photocatalytic [2 + 2] enone cycloadditions with cleavable redox auxiliaries . 94Scheme 3.14 Visible light photoredox catalytic radical cyclizations . . . . . . . . . . . . . 95Scheme 3.15 Intramolecular radical addition to indoles and pyrroles . . . . . . . . . . . . . 96Scheme 3.16 Photoredox and NHC dual catalysis for the asymmetric α-acylation of tertiaryamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Scheme 3.17 Possible side reaction between NFSI and DIPEA . . . . . . . . . . . . . . . . 100xiiiList of SchemesScheme 3.18 Silver-catalyzed decarboxylative fluorination of aliphatic carboxylic acids. . . 101Scheme 3.19 Photo-fluorodecarboxylation of 2-aryloxy and 2-aryl carboxylic acids . . . . . 101Scheme 3.20 Photo-fluorodecarboxylation mechanism . . . . . . . . . . . . . . . . . . . . 102Scheme 3.21 Initial studies on the photoredox decarboxylative fluorination of phenoxyaceticacids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104Scheme 3.22 Synthesis of phenoxyacetic acid substrates . . . . . . . . . . . . . . . . . . . 105Scheme 3.23 Catalytic photoredox decarboxylative fluorination scope . . . . . . . . . . . . 108Scheme 3.24 Synthesis of alkoxyacetic acid 279 . . . . . . . . . . . . . . . . . . . . . . . 109Scheme 3.25 Visible-light photocatalytic mediated decarboxylative decarboxylation of alkoxy-acetic acid 280 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109Scheme 3.26 Visible-light photocatalytic mediated decarboxylative decarboxylation ofα-fluoroaceticacid 281 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109Scheme 3.27 Synthesis of α-fluoroacetic acid 285 . . . . . . . . . . . . . . . . . . . . . . 110Scheme 3.28 Visible-light photocatalytic mediated decarboxylative decarboxylation ofα-fluoroaceticacid 281 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110Scheme 3.29 Synthesis of estrone derivative 289 . . . . . . . . . . . . . . . . . . . . . . . 111Scheme 4.1 Tributyltinhydride mediated generation of alkoxy radicals fromN-alkoxy-phthalimide292 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131Scheme 4.2 5-exo and 6-endo cyclizations of alkoxy radical 296 . . . . . . . . . . . . . . 132Scheme 4.3 Total synthesis of (+)-allo-muscarine . . . . . . . . . . . . . . . . . . . . . . 133Scheme 4.4 1,5-Hydrogen atom transfer performed by an alkoxy radical . . . . . . . . . . 133Scheme 4.5 Barton’s alkoxy radical 1,5-HAT . . . . . . . . . . . . . . . . . . . . . . . . 133Scheme 4.6 First reported alkoxy radical intramolecular 5-exo cyclization . . . . . . . . . 134Scheme 4.7 Competing 6-exo cyclization and 1,5-HAT reaction pathways of 5-hexen-1-ylradical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Scheme 4.8 Alkoxy radical cyclizations to form tetrahydropyrans . . . . . . . . . . . . . . 139Scheme 4.9 Alkoxy radical cyclizations onto silyl enol ethers . . . . . . . . . . . . . . . . 139Scheme 4.10 Synthesis of alcohol 330 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Scheme 4.11 Synthesis of competition substrate 332 . . . . . . . . . . . . . . . . . . . . . 141Scheme 4.12 Synthesis of N-alkoxyphthalimide 337 . . . . . . . . . . . . . . . . . . . . . 142Scheme 4.13 Synthesis of competition substrate 340 . . . . . . . . . . . . . . . . . . . . . 143Scheme 4.14 Synthesis of N-alkoxyphthalimide 346 . . . . . . . . . . . . . . . . . . . . . 143Scheme 4.15 Synthesis of competition substrates 348 and 349 . . . . . . . . . . . . . . . . 144Scheme 4.16 Synthesis of alcohol 353 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145Scheme 4.17 Synthesis of N-alkoxyphthalimide 325 . . . . . . . . . . . . . . . . . . . . . 145Scheme 4.18 Synthesis of N-alkoxyphthalimide 357 . . . . . . . . . . . . . . . . . . . . . 146Scheme 4.19 Synthesis of competition substrates 360 . . . . . . . . . . . . . . . . . . . . 146Scheme 4.20 Synthesis of alcohol 365 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147Scheme 4.21 Synthesis of competition substrates 360 . . . . . . . . . . . . . . . . . . . . 147xivList of SchemesScheme 4.22 Synthesis of alcohol 370 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148Scheme 4.23 Synthesis of competition substrates 360 . . . . . . . . . . . . . . . . . . . . 148Scheme 4.24 Comparison of literature cyclization rates with competing cyclization substrate 149Scheme 4.25 Substrates type A: alkoxy radicals competing 5-exo cyclizations . . . . . . . . 150Scheme 4.26 Competing 5-exo cyclization of alkoxy radicals onto a silyl enol ether and aterminal alkene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Scheme 4.27 Competing 5-exo cyclization of alkoxy radicals onto a silyl enol ether and atrans dialkyl-substituted alkene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151Scheme 4.28 Competing 5-exo cyclization of alkoxy radicals onto a silyl enol ether (cis andtrans enriched) and a trialkyl-substituted alkene . . . . . . . . . . . . . . . . . . . . . 152Scheme 4.29 Substrates type B: alkoxy radicals 6-exo cyclization competing with 1,5-HAT 153Scheme 4.30 Competing 6-exo cyclization of alkoxy radicals onto a silyl enol ether and 1,5-HAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153Scheme 4.31 Competing 6-exo cyclization of alkoxy radicals onto a silyl enol ether and 1,5-HAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154Scheme 4.32 Substrates type C: alkoxy radicals 5-exo cyclization competing with 1,5-HAT 154Scheme 4.33 Competing 5-exo cyclization of alkoxy radicals onto a silyl enol ether and 1,5-HAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154Scheme 4.34 Competing 5-exo cyclization of alkoxy radicals onto a silyl enol ether and 1,5-HAT from a benzylic position . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155Scheme 5.1 Pinacol rearrangement mechanistic study . . . . . . . . . . . . . . . . . . . . 190Scheme 5.2 Proposed synthesis of di- and trifluoromethyl ethers through catalytic photore-dox decarboxylative fluorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193Scheme 5.3 Tandem radical 1,5-HAT, 5-exo cyclization and fluorine atom transfer reaction 194xvList of Abbreviations and SymbolsA˚ angstromAIBN azobisisobutyronitrileBDE bond dissociation energyBNAH 1-benzyl-1,4-dihydronicotinamidebpy 2,2′-bypyridine◦C degree CelsiusCSA (1S)-(+)-10-camphorsulfonic acidCT charge transferCV cyclic voltametryDAST diethylaminosulfur trifluorideDBU 1,8-diazabicyclo(5.4.0)undec-7-eneDCC dicyclohexylcarbodiimideDFT density functional theoryDIAD diisopropylazodicarboxylateDIBAL diisobutylaluminum hydrideDIPEA diisopropylethylamineDMAP 4-dimethylaminopyridineDMF N,N-dimethylformamideDMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinoneDMS dimethylsulfidexviList of Abbreviations and Symbolsd doubletE1/2 half wave potentialeq. equationequiv. equivalentsESI electron spray ionizationESR electron spin resonanceEPR electron paramagnetic resonanceEWG electron withdrawing groupFCC flash column chromatographyGC gas chromatographyHAT hydrogen atom transferHRMS high resolution mass spectraHOMO highest occupied molecular orbitalHz HertzIR infraredISC intersystem crossingk reaction rate coefficient of rate constantKHMDS potassium bis(trimethylsilyl)amideL literLDA lithium diisopropylamideLRMS low resolution mass spectraLUMO lowest occupied molecular orbitalµ microm multiplet or meterM molarity or parent massmCPBA meta-chloroperbenzoic acidxviiList of Abbreviations and SymbolsmDNB meta-dinitrobenzeneMLCT metal-to-ligand charge transferMO molecular orbitalm. p. melting pointmin minuteNFPY N-fluoropyridinium saltNFSI N-fluorobenzensulfonimideNHC N-heterocyclic carbeneNHSI bisbenzenesulfonimideNMO N-methylmorpholin-N-oxideNMR nuclear magnetic resonanceOCR oxygen-centered radicalp picoPPHF pyridinium poly(hydrogen fluoride), Olah’s reagentppm parts per millionr2 correlation coefficientSCE saturated calomel electrodeSEE silyl enol etherSET single electron transferSH2 homolytic bimolecular substitutionSN1 unimolecular nucleophilic substitutionSN2 bimolecular nucleophilic substitutionSOMO singly occupied molecular orbitalτ half lifetimet triplett tertxviiiList of Abbreviations and SymbolsTAS transient absorption spectroscopyTAS-F tris(dimethylamino)sulphonium difluorotrimethylsiliconateTBAF tetrabutylammonium fluorideTBHP t-butylhydroperoxideTBS t-butyldimethylsilylTEDA triethylenediamideTEMPO 2,2,6,6-tetramethylpiperidonooxyTEOA triethanolamineTES triethylsilylTf trifluoromethylTHF tetrahydrofuranTHP tetrahydropyranTLC thin layer chromatographyTMB 1,3,5-trimethoxybenzeneTPAP tetrabutylammonium perruthenateUV ultravioletxixAcknowledgmentsMore people than I can fit in two pages havemade this thesis manuscript andmy graduate studies possible.To all of them I am forever grateful. I would specially like to thank my supervisor Prof. Glenn M.Sammis, for his relentless support since day one, throughout my graduate studies and up until the finaledit of this thesis. Glenn, from you I learned to persevere despite the difficulties one may encounter inthe path, to always stay positive and to try to analyze results and situations from different points of view.Thanks for your patience, your trust and your contagious enthusiasm towards research and chemistry. Iam fortunate to have you as my mentor.Thank you to the members of my committee, Prof. Gregory Dake, Prof. Marco Ciufolini and Prof.Keng Chou. Particularly Prof. Dake, thank you for reading my thesis and providing useful and construc-tive comments during its edition.Financial support was provided by the people of Me´xico through CONACyT (National Council ofScience and Technology), who funded four years of my graduate studies, as well as UBC through aEstella Laird fellowship that funded two years of my studies. Gracias.My research was possible thanks to the great technical team working at the Chemistry Department.Special thanks to Maria Ezhova at the NMR facility, Marshall Lapawa at the mass spectrometry facility,John Ellis and all the personnel at Chem Stores. Sheri Harbour, infinite thanks for your tireless work,guidance and countless letters since the moment I arrived in the department. You have been key in mylegal stay in this country. I admire your efficiency and incomparable organizational skills. As a teachingassistant, I had the fortune to be surrounded with hard working and kind people. Thanks to Dr. BrianCliff and Dr. Christine Rogers for helping me help the students. Also thanks to Anne Thomas and BenHerring, who make everything in their power to make the labs run smoothly and invariably succeed. We(the TAs) would live weekly nightmares if it wasn’t for all your work.Thanks to past and present Sammis group members: Maria, Jay, Hai, Joe, Natalie, Claire, Wei, Meru,Kayli, Christine, Cameron, Julian, Jason. Kayli, thanks for your sympathy, selfless help, love and shelter.Special thanks to Maria, for being my example of a strong woman in science and the world; to Jay forxxAcknowledgmentskeeping it real and teaching me the ways of the lab (and the canadian slang) in my first year; and to mydear Claire for injecting life and flavour to our days and nights in the lab, for blasting music and singingalong, and for never giving up on me despite my mood swings.I want to thank my family. I have missed you immensely but you should know I always kept you closeto my heart and in my mind. Thanks mom for life, for Mafalda, for teaching me empathy and patience,for all those nights I kept you up too late, for pushing me to find my own path and letting me go when Ifinally decided to make full use of my wings. Dad, thanks for your ethics, for the Beatles, for teachingme to be happy with what I have and accept things as they come, for your full support in any activity oradventure I ever wanted to pursue, and for always being there no matter what. Little bro, I am so proudof you. Thank you for being my friend and mischief partner all my life, for showing me to be fearless(by example), for Muse and Jordan, for your sincere laughter and your honest opinions. To my grandma,grandpa, aunts, uncles and countless cousins, your support was always invaluable.To my Vancouver family, my support system, my ever-loving and always-present friends: Niusha,Emmanuel, Paloma, Jannu, Roxana, Javier, Ben, Carmen, Freya, Jonas, Kaitlin... THANKYOU. I couldnot have done this without you here to put me back on my feet whenever I fell down. My dear latinidos,you truly made me feel at home despite the 5,000 km distance. Emmanuel, you are one of the morekind hearted people I know. Thank you for your unconditional friendship and never-faltering support,for the memorable flights, for NYC and SFO. You helped me survive my transition to independence,kept me sanely insane and made me look at things with different eyes. TQM mantito. Siempre. Jannu,I will always admire your ability to logically and objectively dissect any topic. Thank you for all thesleep-depriving talks, for Benedetti and Silvio, for the spoke key, the vitamin D and for knowing how toshout rebeldı´a. Niushita, your empathy and positive attitude are utterly contagious. Thanks for helpingme step out of my bubble to see from another perspective and understand that everyday is beautiful andthere is always a good side to any situation. Palomita causha pe, I miss you, and our movie nights andour trips to new places full of surprises. Thanks for Portland, Les Mis, the mind stimulating discussionsand the never ending fun. Jayitos x 3, thanks for the Settlers nights, the hospitality at “El jacalito”, forteaching me new peruvian words and for sharing my constant ranting over the years. Rodrigo, better latethan never... but seriously, what took you so long? Thanks for Corta´zar, coffee, and for that big heartof yours that seems to have no limits. Benny, thanks for the biking adventures, the cross-words and theintense (though sometimes pointless) discussions. Do´nde esta´ la biblioteca?Unceded Coast Salish TerritoriesOctober 1st, 2014xxiA mi tı´a Mago,who taught me to not be afraidof being an independent woman.xxiiChapter 1IntroductionAnd if you find her poor, Ithaca has not defrauded you. With thegreat wisdom you have gained, with so much experience, You mustsurely have understood what Ithacas mean.1— K. P. Kavafis (Constantine P. Cavafy)The driving force of any scientific investigation is reaching a better understanding of nature. Thesteps and pathways taken to achieve this understanding vary depending on the field and topic underscrutiny. In the case of synthetic organic chemistry, its study occurs in two major fields: total synthesisand methodology development. Total synthesis targets the construction of a complex molecule, typicallya natural product, from relatively simple starting materials.1 Synthetic organic methodology focuses onthe discovery and development of new reactions, as well as the optimization and better understanding ofknown transformations. These two branches of organic chemistry are not independent from one another.The synthesis of a complex molecule can encourage the development of new methodologies. At thesame time, the constant development of new synthetic organic methods enables the successful assembleof complex molecular frameworks. Synthetic organic chemistry has a direct impact in society, as manyof the final products may in time become part of our everyday lives in the form of pharmaceuticals, dyes,perfumes, flavour enhancing products, and new materials.The Sammis group focuses on synthetic methodology development and we are particularly interestedin radical processes of elements in the first row of the p block of the periodic table, excluding neon. Ourinterest derives from the great versatility radicals present in organic synthesis. Radical reactions oftenhave orthogonal reactivity to traditional two-electron processes, enable new reactivities, and they havethe potential to rapidly construct molecular complexity through tandem reactions.In this work I present my contribution to radical chemistry methodology, which includes the use ofcarbon radical intermediates to safely generate organic fluoroalkanes, as well as the study of the chemos-1Chapter 1. Introductionelectivity of oxygen-centered radicals (OCRs). The following section will provide an overview on theproperties of carbon radicals, the use of oxygen centered radicals as carbon radical precursors, and whatinspired us to develop safe radical-mediated fluorination methodologies.1.1 General properties and reactivity of radicalsRadicals are reactive intermediates that contain an unpaired electron in their molecular structure. Re-active intermediates are defined as short-lived, highly-energetic and highly-reactive species that cannotbe isolated but may be detected through spectroscopic methods. Although carbon radicals are the mostextensively studied type of radicals, any molecule containing an unpaired electron is defined as a radical,regardless of the atom where the unpaired electron is located.Carbon reactive intermediates in two-electron reactions, such as carbanions and carbocations, aregenerated from a heterolytic scission of a covalent bond to carbon (Figure 1.1). Carbon radicals areformed through the homolytic cleavage of a covalent carbon bond, and through this process two neutralspecies are generated.R RRRRRR RRCarbanion CarbocationCarbonFree RadicalIonic RadicalFigure 1.1. Reactive intermediates in organic chemistry: carbanion, carbon free radical, carbocation.The discovery in 1900 of a trivalent carbon containing seven valence electrons by M. Gomberg sig-nified the birth of radical organic chemistry.2 Despite his explicit wish to “reserve the field for” himself,the chemistry of carbon free radicals has been so extensively studied since this landmark discovery thatour understanding of their properties and applications has transformed them in one of the most usefuland versatile intermediates in synthetic organic chemistry.3,4The ease of formation of organic radicals is dictated by their intrinsic stability. The bond dissociationenergy (BDE) of covalent bonds is a good quantitative indication of how stable a radical is upon homo-lysis; the lower the BDE, the easier a radical can be formed. In consequence, effects that help stabilize agiven radical will be reflected in a lower BDE of the bond that will generate this radical upon homolysis.For instance, we observe in Table 1.1 that the BDE of C−H bonds is inversely proportional to the carbonsubstitution as more substituents on carbon helps stabilize the carbon radical formed. Also, allylic and2Chapter 1. Introductionbenzylic C−H bonds have a lower BDE because allylic and benzylic radicals can be stabilized throughresonance.Table 1.1. Relevant bond dissociation energies.5(kcal mol−1) (kcal mol−1) (kcal mol−1)HydrocarbonsCH3−H 105 CH2−CH−H 111 C6H5−H 113CH3CH2−H 101 H2C−CHCH2−H 88 C6H5CH2−H 90(CH3)2CH−H 98 HC−−C−H 133 Ph3C−H 81(CH3)3CH2−H 96 CH−−CCH2−H 89 C4H4CH−H 78HalogensCH3−F 110 H−F 136 F−F 38CH3−Cl 84 H−Cl 103 Cl−Cl 58CH3−Br 70 H−Br 88 Br−Br 46CH3−I 57 H−I 71 I−I 36O−X bondsHO−H 119 CH3O−H 105 CF3O−H 119HO2−H 88 HO−OH 50a CH3O−OH 45t-BuO−H 106 t-BuO−OH 55 t-BuO−Ot-Bu 39AcO−OAc 34 lauroyl peroxide 30 BzO−OBz 31RO−NO 41 RO−NO2 41 BzO−NO 34HO−SH 71 CH3O−SH 56 ± 8 CH3O−SCH3 53 ± 10HO−F 51 CH3O−F 47 CF3O−F 48HO−Cl 56 CH3O−Cl 48 CF3O−Cl 52N−X bondsCH3N−N−CH3 53 i-PrN−N−iPr 47 t-Bu-N−N-t-Bu 44FN−O 56 O2N−F 53 H2N−F 69Metal hydride sources(CH3)3Si−H 95 (CH3)3Ge−H 87 (CH3)3Sn−H 78ba In the gas phase; b same BDE as tBu3SnH.Radical reactions are also mechanistically different from two-electron, or polar, organic reactions.Radicals react through a chain reaction mechanism that involves three stages: initiation, propagation andtermination (Figure 1.2). In the initiation step, a covalent bond is homolytically cleaved to generate atleast one radical species. In the propagation steps, a radical reacts with a non-radical species to generateat least one new radical. A termination step occurs any time two radical species combine to generate anon-radical species.3Chapter 1. IntroductionInitiationPropagationTerminationA A 2AB C+A C+A BA A+C A+A COverall ReactionA AC C2A2CA C+A CB C+ +A BA A A CFigure 1.2. General radical chain reaction mechanism.1.1.1 Carbon radical generationCarbon-carbon bonds are homolytically cleaved at temperatures well over 300 ◦C.3 Temperatures below150 ◦C can only be used when the BDEs are between ∼ 30− 40 kcal mol−1. To start a radical reactioninvolving the homolysis of C−C bonds at low temperatures then, the use of radical initiators has beenimplemented. These molecules have low BDEs and their function is not to participate in the transfor-mation, but to initiate the radical chain reaction that will lead to the desired products. Common radicalinitiators include peroxides, diacylperoxides, and azo compounds. Radical initiators are typically usedin substoichiometric amounts only (∼ 1− 5 mol %). A widely used azo radical initiator is azobisisobu-tyronitrile (AIBN, 1), which readily decomposes through the homolytic cleavage of the azo C−N bondat 65 ◦C. The BDE of this C−N bond is 31 kcal mol−1 and it generates an isobutyronitryl radical alongwith one N2 molecule (Scheme 1.1).3 The isobutyronitryl radical then participates in the initiation of theradical chain reaction.N NCNNCNC+ N221Scheme 1.1. Mode of action of AIBN (1) as a radical initiator.Contrary to radical initiators, which are not incorporated in the product, radical precursors aremolecules containing a functional group that can be homolytically cleaved by the action of heat, light oranother radical, and that will be part of the final products of the reaction. Several functional groups can4Chapter 1. Introductionserve as precursors to carbon radicals. For instance, alkyl halides (4) generate carbon radicals directlyupon treatment with a radical initiator. Carbon radicals can also be generated through the trapping ofunsaturated molecules, like alkenes and alkynes. Other useful carbon radical precursors depicted inFigure 1.3 are diacyl peroxides (3), xanthates (5), alkyl peresters (6), and pyridinethiones (7). In eachcase, the bond that gets homolytically cleaved has the lowest BDE and can be selectively cleaved withoutperturbing other bonds within the molecule.RR XRO SCH3SROOO ROROOOR'X = Cl, Br, IR OONSN NRR234567Figure 1.3. Carbon radical precursors.1.1.2 Carbon radical reactivityCarbon radicals display different modes of reactivity upon their generation. They can undergo radicalsubstitution (SH2), inter- and intramolecular addition to double or triple bonds, intramolecular grouptransfer such as 1,5-hydrogen atom transfer (1,5-HAT), rearrangement reactions, radical fragmentation,and disproportionation among others. The modes of reactivity of carbon radicals relevant to this workare illustrated in Figure 1.4.The first reaction depicted is a radical substitution, which consists in the formation of a new σ-bond between a free radical and a neutral molecule at the expense of one of the σ-bonds of the neutralmolecule. Radicals can also undergo additions to pi bonds, where a radical forms a new σ-bond with oneatom of the unsaturated system through the homolytic cleavage of the pi bond. These types of additionsare among the most common radical reactions in organic synthesis and are a powerful method to rapidlyincrease molecular complexity. Atom transfer reactions are well known in carbon radical chemistry and5Chapter 1. IntroductionRadical Substitution (SH2)Radical Addition to π-bonds1,5-Hydrogen Atom Transfer (1,5-HAT)Br Br 2 BrH3C H+Br CH3+H BrBr Br++CH3Br BrCH3PhPhRPhPhRR nn = 1 or 2RintermolecularintramolecularnRadical FragmentationRHRHR OO Ea = 6.5 kcal mol-1rate ~ 109 s-1 at 60 °CR + CO2O CH3 +OFigure 1.4. Selected reactivity modes of carbon radicals.highly valued in organic synthesis as means of remote functionalization. In atom transfer reactions, acarbon radical abstracts an atom located five or six positions away. Another mode of radical reactivity isa radical fragmentation, where a new pi bond is formed at the expense of the homolysis of one of the σbonds of the atom α to the one bearing a radical.It is important to point out that after each one of these reactions occur, another carbon radical istypically formed. The radical resulting from the first reaction can further react in any of the modesdescribed (SH2, addition to pi bonds, 1,5-HAT, β-fragmentation) in what is typically called a tandem orcascade reaction.1.1.2.1 Tandem radical reactions: building molecular complexityTandem radical reactions are powerful tools to rapidly build complex molecular frameworks. For in-stance, in Parker’s synthesis of (±)-codeine (10, Scheme 1.2) and (±)-morphine (11),6 the advanced6Chapter 1. Introductionintermediate 8 undergoes a number of subsequent radical reaction upon its treatment with tributyltinhy-dride and AIBN in benzene at 130 ◦C in a sealed tube. The initial C−Br bond homolysis generates thetransient radical 12, which subsequently undergoes a regio- and stereoselective 5-exo-trig cyclizationto generate radical 13. A consecutive 6-endo-trig radical cyclization yields radical 14, which under-goes a β-elimination to afford the highly complex tetracyclic alcohol 9. Further synthetic steps from 9yielded (±)-codeine (10) and (±)-morphine (11), but the key construction of the molecular frameworkwas successfully accomplished in one step through a radical tandem process. This total synthesis ex-ample illustrates how remarkably functional group tolerant and chemoselective radical reactions can be,when they are strategically planned.Bu3SnH, AIBNC6H6, 130 °C(sealed tube)35%ONTsHOOSPh ONTsHOOSPh OHOOSPhHNTsOHOOHNTsOHOORHNHR = CH3, codeine       H, morphineONTsHOOSPhBr8 9 101112 13 14Scheme 1.2. High complexity generation via the use of free radicals: Parker’s synthesis of codeine andmorphine.67Chapter 1. Introduction1.1.3 Oxygen-centered radicalsRadicals are not restricted to carbon atoms. When an unpaired electron is situated at an oxygen atom,it is classified as an oxygen-centered radical (OCR). Figure 1.5 depicts various types of OCRs, suchas the hydroxyl radical (15), alkoxy radicals (16), alkylperoxy radicals (17), acyloxy radicals (18) andacylperoxy radicals (19).OH OR ORO OOROORO15 16 17 18 19Figure 1.5. Types of oxygen-centered radicals.A general description of acyloxy radicals (18) is presented in this section, as they are used as in-termediates to generate carbon radicals through decarboxylative processes in Chapter 2. Alkoxy radicalproperties and reactivity will be discussed in more detail in the introductory section of Chapter 4.Acyloxy radicals (18, Figure 1.5) are oxygen-centered radical species analogous to carboxylates thatportray a free radical instead of a negative charge delocalized on the O−C−O system. With the rate ofradical decarboxylation determined to be in the order of 1−7×109 s−1, depending on the alkyl chain ap-pended to the acyloxy radical,7–9 and with CO2 having a heat of extrusion∆H0ex = −2.5 kcal mol−1,10acyloxy radicals will rapidly lose carbon dioxide to cleanly generate alkyl radicals (Scheme 1.3).11 Un-surprisingly, acyloxy radicals have half lifetimes of only τ< 10−9 s.8+R COOR OO HHτ < 10-9 s-120 21Scheme 1.3. Radical decarboxylation of acyloxy radicals.The homolysis of the O−O bond in diacyl peroxides and peroxyesters,12–14 readily generates acyloxyradicals. They can also be accessed through the homolytic cleavage of the N−O bond of thiohydroxa-mates,15 as well as the electrochemical oxidation of carboxylic acids16 and metal-mediated oxidation ofcarboxylic salts (Figure 1.6).8Chapter 1. IntroductionR OR O R ONOOROOR'OOROOSR OHOR OOe- [M]Figure 1.6. Selected acyloxy radical precursors.Acyloxy radicals have found their primary use in organic synthesis as effective intermediates to re-move carboxylic acid groups from any given molecule. For instance, in Eaton and Cole’s 13-step syn-thesis of the hydrocarbon cubane,17,18 two carboxylic acid moieties were removed through radical de-carboxylation via the thermolysis of t-butylperesters, first to go from acid 23 to acetal 24 (Scheme 1.4),and to complete the synthesis from acid 25 to cubane (26).1) SOCl22) (CH3)3COOH,     Pyridine3) Cumene,      152 °COOBrBrOOBrHO2COOBr1) SOCl22) (CH3)3COOH,     Pyridine3) Cumene,      152 °CCO2HCubane22 23 242526Scheme 1.4. Synthesis of cubane.18One of the most widely used acyloxy-radical mediated reactions is the Barton decarboxylation,15,19,20which utilizes thiohydroxamates (27, Scheme 1.5) as acyloxy radical precursors and the classic AIBN/tri-butyltin hydride system to initiate the reaction. In this transformation, the in situ generated tributyltinradical forms a σ-bond with the sulfur of the thione at the expense of the sulfur-carbon double bond. Anew C−N pi-bond is created and the N−O σ bond is homolytically cleaved to generate radical 20. Rapiddecarboxylation of the acyloxy radical will in turn form an alkyl radical (21) that can trap a hydrogen9Chapter 1. Introductionatom from tributyltin hydride to yield the corresponding alkane (28). The non-radical adduct (29) isstable and unreactive under the reaction conditions.AIBN, Bu3SnHC6H6, 80 °CONROSONROSBu3SnONROSSnBu3+RR CH3 + CO2Bu3Sn H2720 2128 29Scheme 1.5. Acyloxy-radical mediated Barton decarboxylation. 15,191.2 Fluorine atom transferAtom transfers from suitable reagents to organic radicals are one of the most common strategies to ter-minate a radical chain processes. Among the most common trapping reagents for carbon radicals arehalogens. Carbon radicals can safely and effectively homolytically abstract an atom from molecularchlorine, bromine and iodine to yield the corresponding halogenated compound. Unlike its fellow halo-gens, molecular fluorine cannot be safely and easily utilized in the same way to perform an atom transferand selectively synthesize monofluoro compounds. In this section, a brief account on the history of fluo-rine, along with naturally occurring molecules containing it, and non-radical sources of fluorine will bedescribed. Also, the fluorination mechanism using electrophilic sources of fluorine will be discussed.1.2.1 Fluorine: history and traditional sourcesThe name le fluor — from the latin noun fluo meaning “stream or flow of water” — derives from thefluorine containing mineral fluorspar, which was used as a flux in iron smelting to decrease the viscosityof slags. As early as the 17th century, it was know that treatment of fluorospar with sulphuric acidreleased a gas that etched glass.21 This acid was fluoric acid. In 1810, french physicist Andre´-MarieAmpe`re suggested that fluoric acid was composed of hydrogen and an unknown element with similarcharacteristics to chlorine.22In 1886, french chemist Henri Moissan successfully isolated fluorine (F2).23–25 Moissan’s electro-lysis of a mixture of potassium hydrogen difluoride and hydrogen fluoride at -50 ◦C utilizing a platinum10Chapter 1. Introductionelectrode, allowed him to succeed where so many prominent 19th century chemists had failed. Thisimpressive accomplishment earned him the Nobel Prize in Chemistry in 1906.26–28The foundations of fluorocarbon chemistry were laid in 1890 by F. Swarts, a Belgian chemist who,for approximately 25 to 30 years, was practically the only chemist in the field reporting on the systematicdevelopment of routes to synthesize polyfluorinated compounds.22 Throughout the 20th century, severalremarkable achievements in synthetic organofluorine chemistry that propelled its development occurred,such as the discovery of freons and their refrigerant properties in the 1930s,29 the serendipitous syn-thesis of polytetrafluoroethene with the ensuing proliferation of fluorinated polymers in 1938,30 and theintroduction of fluorinated non-flammable anaesthetics in the 1950s.31Despite these great achievements, the development of organofluorine chemistry has always beenslower compared to that of its fellow halogens.32 The incorporation of fluorine into organic frameworksis challenging due to several factors, including low nucleophilicity of fluoride (F–) in polar protic solvents,the low selectivity along with the explosive and exothermic reactivity of atomic fluorine (F•), and thelack of safe electrophilic sources of fluorine (F+).33These reasons make the discovery of safe electrophilic sources of fluorine in in the late 1980’s andearly 1990’s one of the most important milestones in modern synthetic organofluorine chemistry. Thedevelopment of a variety of electrophilic sources of fluorine of the types R2NF and R3N+FA–,34–37 leadto a rapid expansion of methodologies using these “F+” reagents to access fluorinated compounds thatwere previously unattainable.381.2.2 Naturally occurring organofluorines and the effect of fluorine in bioactivemoleculesDespite being the most abundant halogen and the 13th most abundant element in the Earth’s crust,39 only30 out of the the approximately 3,700 naturally occurring organohalogen compounds known containfluorine.40 Over 50% of these naturally occurring fluorocarbons are abiogenic and have been detected involcanic emissions and thermal springs, such as the different fluoroalkenes, fluoroalkanes and fluorinesubstituted aromatic compounds shown in Figure 1.7.40The remaining natural organofluorines correspond mostly to fluorocarboxylic acids.40 The low num-ber of biogenical organofluorines can be largely attributed to the insolubility of the fluorine-containingminerals, which renders fluorine biologically unavailable.39 Additionally, the oxidation potential of fluo-rine (2 F– −−⇀↽− F2+2 e–,−3.06 V) precludes the existence of an enzyme capable of oxidatively includingfluorine in biogenic molecules.4111Chapter 1. IntroductionFFFF FFFF3C FFFCl FF ClHCHF3 CFCl3 CFCl2CF2Cl CF2Cl2CF3CF2CF2HF FFFFClFigure 1.7. Some abiogenic naturally occurring organofluorindes.The most abundant biogenic organofluoride is fluoroacetate (30, Figure 1.8). It was first discoveredin 1943 by Marais to be present in the South African plant “gifblar”, Dichapetalum cymosum, and wasdetermined that it was responsible for the toxicity of the plant.39,40 Since that discovery, countless plantsfrom different parts of the globe have been known to contain this toxin. Excellent reviews on naturallyoccurring organofluorides have been published by Harper39,42 and Gribble.40The majority of these naturally occurring organofluorides are carboxylic acids. Several fluorine-substituted fatty acids have been isolated from seeds of the Sierra Leona shrub Dichapetalum toxicarium,such as 18-fluorooleic acid (Figure 1.8, 31), 16-fluoropalmitic acid (33) and 10-fluorodecanoic acid (34).Other types of fatty acid derivatives were also obtained, such as diol 36 derived from fluorooleic acid31.40OO-FfluoroacetateOOH18-fluorooleic acidFNH2OH OOHF4-fluorothreonineOOHF16-fluoropalmitic acidOOHF10-fluorodecanoic acidFOOHOHOHHOOC COOHHO COOHFfluorocitrate303132333435 36Figure 1.8. Some biogenic naturally occurring organofluorindes.12Chapter 1. IntroductionFluorocitrate (32) has been found to be present in low concentration in tea leaves (< 30 ppm) andoatmeal (< 62 ppm).40 This highly toxic compound is known to be a metabolite formed through theso called “suicide synthesis”, through the condensation of oxaloacetate (37) and fluoroacetyl-CoA (38)via the action of the enzyme citrate synthase in the citric-acid cycle.39 The high toxicity of fluoroacetate(30) might derive from its metabolization into (2R, 3R)-2-fluorocitrate after it bioaccumulates in theplants. Interestingly, this is the only stereoisomer produced biosynthetically, and also the only toxicone, as the other three steroisomers are nontoxic.39 Sharma, Kun and Kristen proved that fluorocitrate32 “irreversibly inhibits bidirectional citrate transport”,43 which is responsible for mitochondrial energygeneration at a cellular level. This was one of the early reports on the effect the presence of fluorine hasin biologically active molecules.HO2C CO2HHO CO2HFHO2C CO2HOFSCoAOHR HScitratesynthaseinversion at C-2+HS37 38 32Scheme 1.6. Fluorocitrate biosynthesis.39Despite the paucity of fluorinated natural products that could inspire the synthesis of new molecules,the production of fluorine-containing medicinal and agrochemical compounds has steadily increasedover time.44 In 1970, only 2% of the commercially available pharmaceuticals incorporated some formof fluorine. Isanbor and O’Hagan estimated that by 2006, between 20% and 25% of the pharmaceu-tical compounds contain at least one fluorine atom in their structure.45 Some examples of prominentfluorinated drugs are shown in Figure 1.9: the antidepressant Prozac (39), cholesterol-lowering Lipi-tor (40), antibiotic Ciprobay (41), anti-cancer agents 5-fluorouracyl (5-FU, 42) and ZD9331 (43), andanti-psychotic Rispiridone (44).45–49The properties inherent to fluorine, such as high electronegativity and small size, have a signifi-cant impact in the biological properties of a molecule and on its behaviour in a biological setting. Thepresence of fluorine can modify the binding of the molecules to enzymes or receptors, their transport, ab-sorption, and eventual metabolization to be excreted from the biological system.48 The aforementionedfluorocitrate is an excellent example how the presence of a single fluorine atom in a molecule modifiesits bioactivity.4313Chapter 1. IntroductionFFFONHH ClProzacOO-OHOHNFNHO1/2 Ca2+ NNHNOOHOFHClLipitor CiprobayNHNHFOO5-fluorouracylNNHNOFNHOO OHZD9331 RispiridoneNNNONOFN NHN39 40 4142 43 44Figure 1.9. Selected commercially available fluorine containing pharmaceuticals..An early report that indisputably showed the dramatic impact fluorine could have in the properties ofa bioactive molecule was published by Fried and Sabo in 1954. An initial investigation showed that thepresence of a halogen at position 9 in 9α-halo-17α-hydroxycortisone acetate (45) and 9α-halocortisone(46), improved the activity of the compound in a glycogen assay.50 In entries 1 − 3 of Table 1.2, Friedand Sabo’s results from their first study show that the incorporation of a halogen to hydroxycortisoneand cortisone affects its activity in their glycogen assay, where chlorine has the largest effect in bothcases with almost a four fold increase in activity. They identified a trend of increased activity inverselyproportional to the size of the halogen substituent. Shortly after, the authors published another studywhere the fluorine substituted compounds, missing in the previous report, were synthesized and theiractivity probed. As shown in entry 4 of Table 1.2, a 10.7 and 9.2 fold increase was observed in theactivity of the fluoro-substituted steroids 45 and 46 respectively.51Over the next decades, the number of fluorinated compounds for medicinal and agrochemical pur-poses increased at a very fast rate. Their demand became one of the main driving forces for fluorinechemists to develop new, more efficient, and safer methodologies and reagents to introduce fluorine intomolecules.14Chapter 1. IntroductionTable 1.2. Fried and Sabo’s test of the activity in rat liver of 45 and 46.50,51OOHOHOXOOHH45OOHOXOOHH46Entry Halogen (X) Activity in rat liver, glycogen assay. Cortisone acetate = 11 Cl 4.0 ± 0.6 3.5 ± 0.42 Br 0.28 ± 0.004 0.54 ± 0.0083 I ∼ 0.1 unknown4 F 10.7 ± 2.3 9.2 ± 2.71.2.3 Traditional sources of fluorine in organic synthesisFluorine prevails in the earth’s crust in stable mineral form, mainly as fluorite, cryolite and fluorapatite.To make it useful in organic synthesis, it is necessary to extract it from these minerals and manufactureit into reagents that will enable the controlled fluorination of organic substances.It has been known for centuries that the treatment of fluorite with sulfuric acid liberates hydroflu-oric acid (HF). Strong hydrogen bonding exists within HF molecules, and of HF with H2O moleculeswhen in solution. HF is highly toxic upon inhalation, contact with the skin, and is corrosive especiallywhen in aqueous solution.21 It has to be handled with care and the use of plastic equipment is highlyrecommended, since it can also etch glass.Hydrogen bonding accounts for the low reactivity of fluoride (F–) with organic molecules comparedto its chlorine and bromine counterparts. This characteristic renders sources of fluoride as highly hygro-scopic. The nucleophilicity of fluoride can be dramatically increased when no moisture is present in thereagents used.Some traditional sources of F– are silver (I) fluoride (AgF), alkali metal fluorides (NaF, KF, CsF),52all of which are sparingly soluble in organic solvents. The need of more reactive, more selective, andmore soluble sources of F– has lead to the development of a great variety of fluoride reagents.53 Forinstance, to increases the solubility by use of a more lipophilic counter ion, tetrabutylammonium flu-oride (TBAF, 47 in Figure 1.10) and tris(dimethylamino)-sulphonium (TAS-F, 48, Figure 1.10) weredeveloped. A useful reagent for the transformation of oxygenated and sulfur-containing substrates intofluorides is diethylaminosulfur trifluoride (DAST, 49 in Figure 1.10), which generates F– in situ and15Chapter 1. Introductionselectively converts alcohols, amino alcohols, aldehydes, ketones, sulfides, and thiocarbonyls to deoxo-/desulfo- mono and difluorinated fluoroalkanes.54 Fluorohydrates of several amino containing com-pounds have been also used to lower the acidity of HF and as a safe yet sufficiently reactive sourceof fluoride ion. The most commonly used base/HF systems are triethylamine tris(hydrogenfluoride) andpyridinium poly(hydrogen fluoride) (PPHF, Olah’s reagent, 50 in Figure 1.10).33TBAFNHDAST PPHFN+ F-NSFF FSN NNSiFFTAS-FF47 48 49 50Figure 1.10. Selected organic sources of fluoride ion (F–).1.2.3.1 Electrophilic sources of fluorineThe fluorination of electron rich sites was for decades a long standing challenge in organic fluorinechemistry. A direct conversion fromC−H to C−F was not possible using exclusively HF or F– chemistry.The high electronegativity of the fluorine atom constituted the main barrier towards the formation of“F+” sources, as typically any bond to fluorine is polarized towards this atom, conferring it a permanentpartially negative charge.Fluorine (F2) is a source of electrophilic fluorine. Unfortunately, unlike other halogens whose di-atomic molecules can easily react with Lewis bases in an electrophilic fashion, pure F2 reacts violentlywith any trace of organic matter. The ease of formation of atomic fluorine made the study of the elec-trophilic reactivity of F2 impractical, unsafe and nearly impossible for the better part of the first 60years of the 20th century. The development of alternative sources of electrophilic fluorine was thus ofparamount importance to fluorine chemistry.In 1968, Barton was the first to use the term “electrophilic fluorination” to designate the reactionof electron rich sites with electron poor fluorine. He employed fluoroxytrifluoromethane (CF3OF), firstsynthesized by Cady and Kellog in 1948,55 to fluorinate double bonds and observed that the fluorinationoccurred at the most nucleophilic site of the olefin (Scheme 1.7).56 In his report, it is noted that the reac-tivity of CF3OF resembles that of Cl2 or Br2 and referred to these type of compounds as “pseudo halogen”derivatives of fluorine. Previous to Barton’s investigation, two studies from the Cady group reported onthe reactivity of trifluoromethyl fluoride both with inorganic reagents,57 and organic compounds.58 Inthe reactivity study with organic compounds, the findings described the reaction of CF3OF under ul-16Chapter 1. Introductiontraviolet (UV) light or spark induced conditions, which precluded the observation of any electrophilicbehaviour from the hypofluorite.CF3OFOHHHOFHHH+51 52Scheme 1.7. Barton’s use of CF3OF as an electrophilic fluorinating reagent.56After this discovery, a large number of studies on the reactivity and uses of CF3OF in organic syn-thesis were published. However, as fluoroxytrifluoromethane stopped being commercially available inthe late 1970’s, the number of publication of the chemistry of this reagent decreased dramatically.59Fluoroxytrifluoromethane exhibits an electrophilic behaviour due to the presence of highly electronwithdrawing groups (EWGs) directly attached to the fluorine atom. The presence of EWGs helps reversethe polarization of the O−F, typically inclined towards F, and confers a partially positive character tothe fluorine atom. The inversion of the normal bond polarization is one of the main keys towards thedevelopment of efficient electrophilic fluorinating reagents.Other chemists identified this characteristic as the key feature of fluoroxytrifluoromethane, and pur-sued the development of reagents with similar electronic characteristics. Soon, electrophilic reagentslike perchloryl fluoride (FClO3), xenon difluoride (XeF2), and a variety of perfluoroacyl hypoflurites(F3C(O)OF and RfC−(O)OF,60 where Rf = perfluoroalkyl) joined trifluoromethyl hypofluorite (CF3OF)in the list of available electrophilic fluorinating reagents.52Hypofluorites, FClO3, and XeF2 are more selective than F2 in electrophilic fluorination. However,thermal instability, and in some cases the high cost and toxicity, have precluded their widespread use aselectrophilic sources of fluorine in an industrial scale.Since the late 1970’s and all through the 1980’s decade, continuous efforts were made towards findingN−F sources of electrophilic fluorine.38 The constant investigation lead to the synthesis of new reagents,of the type R2NF and R3N+FA–, which efficiently performed the fluorination of carbanions and other highelectron density species (Figure 1.11).17Chapter 1. IntroductionNFOTfF3CSNFSCF3O OOOSNFSO OOONFNNClFBF4BF4OTfN OFSNOOFR SNFOO53 54 55 5657 58 59 60Figure 1.11. Representative N−F electrophilic sources of fluorine.In 1983, Purrington and Jones reported the synthesis of 1-fluoro-2-pyridone (53), through the treat-ment of 2-trimethylsilyloxypyridine with a mixture of F2 and N2 in FCCl3 at -78◦C. The authors high-light that no special precautions need to be taken either for the preparation or for the later use of theresulting white solid. The reactivity of 53 was tested by reacting it with a series of substituted mal-onates in toluene (Scheme 1.8). The corresponding fluoromalonates (62) were isolated, albeit in modestyields.61 This reaction set the precedent for what would be a highly prolific use of N−F reagents aselectrophilic sources of fluorine.+EtO OEtO OEtO OEtO OF+N O16 hToluene, r.t.R RR = Ph, 39 % yieldN OF5361 62 63Scheme 1.8. Purrington’s synthesis of fluoromalonates using 53.61Later, in 1986, Umemoto, Kuwada and Tomita reported the synthesis and applications of the firstisolable N-fluoropyridinium reagent (NFPY, 54, Figure 1.11).34 Several N-fluoropyridinium triflateswere prepared, with a variety of substitution patterns on the aromatic ring. In this first report, the expo-sure of these N−F salts to a silylenol ether (Scheme 1.9, 65) afforded the corresponding α-fluoroketone(66).34 A more extensive study on the effect of the counter ion and substitution at the aromatic ringin NFPYs, revealed that these characteristics had a significant effect on the reactivity, selectivity andstability of these reagents.6218Chapter 1. Introduction+X = OTf,    7 h,  87 % yield        BF4, 72 h,  traceNFXOSiMe3OFCH2Cl2, r.t.64 65 66Scheme 1.9. Umemoto’s synthesis of α-fluoroketones using 64.34Another type of N−F reagents are the neutral N-fluorosulfonimides. The first report on the synthesisand use of an N-fluorosulfonimide dates back to 1984, when Barnette prepared sulfonimides with differ-ent alkyl substitution patterns, analogous to 55 in Figure 1.11, and demonstrated their electrophilic prop-erties by reacting them with ester enolates, Grignard reagents, electron rich aromatics such as naphthol,and enolates.63 A representative example is shown in Scheme 1.10, where phenylmagnesium bromide(67) is treated with 55 in diethylether to yield phenylfluoride (68) in 50% yield, determined by 19F NMR.+Et2O, r.t.50 % yieldMgBr FSNFOO5567 68Scheme 1.10. Barnette’s use of 55 to fluorinate phenyl magnesium bromide.63In 1991, DesMarteau and Resnati reported their discovery of N-fluorobis[(trifluoromethyl)-sulfonyl]imide (Figure 1.11, 56) and its successful use to fluorinate the lithium enolates of esters, amides and ke-tones in good yields.35 A representative example is presented in Scheme 1.11, where the lithium enolateof amide 69 is formed using lithium diisopropylamide (LDA) in tetrahydrofuran, and is then treated with56 to successfully generate 70 in 87% yield. The authors also report the fluorination in high yields ofdiverse 1,3-dicarbonylic compounds utilizing the same fluorinating reagent. The presence of two sul-fonyl groups, compared to Barnette’s system with only one, dramatically increases its activity towards anucleophilic attack, reacting even with some olefines.64 DesMarteau’s discovery was key to identifyingthe structural characteristics of safe and stable electrophilic sources of fluorine.19Chapter 1. Introduction+LDATHF87% yieldNONOFF3CO2S NFSO2CF369 56 70Scheme 1.11. DesMarteau’s use of 56 in the fluorination of α-carbonylic positions.35Also in early 1991, two months before DesMarteau’s initial report on 56, Differding and Ofner de-scribed the synthesis of a sable, crystalline, electrophilic fluorinating reagent: N-fluorobis-(phenylsulfonyl)imide (NFSI, 57).36 Unlike 56, NFSI became a popular reagent to perform electrophilic fluorination andsoon became commercially available. 57 is not only highly stable and safe to use, but also reactive enoughto fluorinate aromatics, enol ethers, and carbanions. For instance, when anisol 71 is treated with NFSIneat at 150 ◦C, a quantitative transformation to fluoroanisol 72 with ortho/meta/para ratios of 58 : 5 : 37(Scheme 1.12).+150 °C, 5 hPhO2S NFSO2PhOCH3 OCH3F~ 100% yield71 57 72Scheme 1.12. Differding’s electrophilic fluorination using of 57.36The first report on the synthesis of N-fluoroquinuclidinium fluoride (58, Figure 1.11) was done byBanks et al. in 1988.65,66 The treatment of quinuclidine in trichlorofluoromethane with F2 at -35 to -84◦C was initially intended to synthesize 4-fluoroquinuclidine, but instead 58 was isolated as a white solidin 86% yield. 58 is highly hygroscopic, and was observed to undergo a 10% weight increase over 40min. N-fluoroquinuclidinium fluoride’s electrophilic properties were tested by performing fluorinationsof diethylmalonates, isopropylnitrate, Grignard reagents, arylsilanes and enamines.Four years later, in 1992, Banks and co-workers reported the synthesis and applications of 1-alkyl-4-fluoro-1,4-diazobicyclo [2.2.2]octane salts.37 This new family of reagents derives from triethylenedi-amide (TEDA) and their members contain two quaternary nitrogens, which permits the tuning of thereagent’s reactivity through the change of the alkyl substituent at nitrogen 1 without compromising itsstability. Selectfluor R© (59) was one of the salts prepared by Banks in 1992; it proved to be so safe andreliable that it was soon patented and became commercially available. As shown in Scheme 1.13, thefluorination of the androsterone enol diacetate (73) was performed utilizing Selectfluor R© in acetonitrileat 25 ◦C to yield 74 in excellent yield and high diastereoselectivity.20Chapter 1. Introduction+CH3CN, 25 °C2 h90% yield,  95α:5βNNClFBF4BF4AcOOAcHHHAcOOHHHF73 59 74Scheme 1.13. Bank’s electrophilic fluorination of androsterone derivative using Selectfluor R© (59).37In time, Selectfluor R© turned into the most widely used reagent to perform electrophilic fluorinationreactions. It has since been used in large scale reactions and the industrial preparation of various drugs.67Several reviews have been published on its preparation, mechanism, versatile uses and limitations.68–701.2.3.2 Mechanism of N−F reagents: SN2 vs SETIt remains a subject of debate whether fluorination with N−F type electrophilic sources of fluorine (seeFigure 1.11) proceeds via an bimolecular nucleophilic substitution (SN2) or an single electron trans-fer (SET).70 There is experimental evidence supporting both the SN2 mechanism,71,72 and the SETmechanism.62,73 It has even been suggested by Banks that there is a “substrate-dependent mechanisticcontinuum [SN2 ←→ fully developed SET process]” that governs these reactions.68The two possible mechanisms proposed for the fluorination of nucleophiles with N−F electrophilicsources of fluorine are depicted in Figure 1.12.72 The first mechanism invokes a typical SN2 reactionwhere the nucleophile simply donates electron density into the antibonding sigma orbital (σ∗N−F) ofthe N−F bond, breaking it and simultaneously forming a new fluorine−nucleophile bond. The secondmechanistic possibility involves a SET from the nucleophile to the N−F fluorinating reagent. The newlyformed radical then proceeds to abstract the fluorine atom from the radical anion.X F + NüSN2SETX F Nüδ+ δ-X F + NuNu F + XFigure 1.12. Possiblemechanistic pathways for nucleophiles reactingwith electrophilic sources of fluorine.72Umemoto and co-workers claimed in 1990 that their fluorination reactions using NFPYs could beexplained by a one-electron transfer mechanism facilitated by the initial formation of a charge transfer(CT) pi-complex between the pyridinium salts and the substrate (see Scheme 1.14). They based this21Chapter 1. Introductionassertion on the difference in reactivity these salts display towards Grignard reagents and organolithiumreagents, as the former generates the expected fluorination product while the latter does not.62 Theyinterpret these results as evidence in support of the SETmechanism since it had been previously reportedthat Grignard reagents display a one-electron transfer mechanism.74 Furthermore, the appearance of anorange colour upon the treatment of 2-naphthol (75, Scheme 1.14) with 3,5-dichloro-1-fluoropyridiniumtriflate (76), which disappears as the fluorination to generate 77 and 78 proceeds, is attributed to theformation of the proposed CT pi-complex between 75 and 76 that facilitates the SET in the mechanism.62N11%FCl ClOTf+OHOH+OF84%F FN FN FOHOHOHFH N FN FOHOHF-H+F-H+-H+π-complexπ-complex75 76 77 78Scheme 1.14. Reaction of 2-naphthol (75) with NFPY 76.Not everyone in the scientific community was convinced all electrophilic N−F sources of fluorinereacted through an SET mechanism. In 1991, Differding and co-workers were the first to recur to aradical clock to monitor the presence of radicals as intermediates in the reaction (Scheme 1.15).72 Theytreated citronellic ester 79 with potassium bis(trimethylsilyl)amide (KHMDS) to generate the enolate,and then added different electrophilic sources of fluorine. An SN2 mechanism would exclusively gen-erate monofluoroester 80 and possibly difluoroester 81. They envisioned that if the reaction proceededvia an SET mechanism, the radical generated in the α-carbonylic position, would immediately add in-tramolecularly to the trisubstituted alkene and form either or both cyclopentanes 82 and 83. Of all the22Chapter 1. Introductionelectrophilic sources of fluorine they used, including XeF2, SelectfluorR©(59) and NFSI (57), the onlyone which lead to the formation of cyclopentane 83 was XeF2. These results suggested that 59 and 57react via a SN2 mechanism and not through an SET process.721) KHMDS, THF,    -78 °C2) X-F,      -78 °C→r. t.OOOOOOOOF F FFOOHX = NFSI, XeF2        Selectfluor7980 8182 83Scheme 1.15. Citronellic ester enolate fluorination probe.However, these results have to be analyzed with caution. The SET pathway can be discarded basedon the experiment shown in Scheme 1.15 only if the rate of 5-exo radical cyclization is faster than recom-bination with atomic fluorine. The rate constant of cyclization of 5-hexenyl radical has been measuredto be approximately 10× 105 s−1,75 and the rate constant of reaction of atomic fluorine with the solventhas been measured to be 1 × 1011 s−1by laser flash photolysis.76 Atomic fluorine reacts so fast, thatthe recombination with the formed radical would outcompete the cyclization by five orders of magni-tude. The fact that neither cyclopentanes 82 nor 83 were observed by Differding and co-workers doesnot necessarily mean a SET process is not operating.In a different radical clock experiment, Wong and co-workers engineered methyl vinyl ether 84 andused it as a probe to detect the presence of radical intermediates in the electrophilic fluorination ofenol ethers with different fluorinating reagents. The results showed that when methyl vinyl ether 84was treated with NFSI and methanol (Scheme 1.16), the fluorinated acetal 85, expected from an ionicmechanism pathway, was isolated in 40% yield, along with the rearranged α,β-unsaturated aldehyde86 in 5% yield. Under the same conditions, Selectfluor R© yields exclusively acetal 85 in 45% yield,and NFPY show no reactivity at all. This suggests that a SET mechanism occurs when NFSI is used,but not when Selectfluor R© acts as the source of fluorine.77 It is interesting that comparable yields areobtained both with Selectfluor R© and NFSI, and yet no rearranged product 86 is observed in the case ofSelectfluor R©.23Chapter 1. IntroductionOCH31) R2N-F reagent,    CH3NO2, r. t., 6 h2) MeOH soln. in    CH3NO2FOCH3OCH3+CHOOCH340% 5%NFSI45% 0%Selectfluor0% 0%NFPY+ -OTf84 85 86Scheme 1.16. Cyclopropane radical clock probe for electrophilic fluorination.Once again, the results should be interpreted with caution. Radical cyclopropane opening has beencalculated to be 1.2×1011 s−1at 20 ◦C,78 but the reaction of atomic fluorine is close to the diffusion rateand might outcompete even a reaction as fast as cyclopropane ring opening. Moreover, in a separate ex-periment by the same group, it was observed that 2,2,6,6-tetramethylpiperidonooxy (TEMPO), a knownradical scavenger, reacts with Selectfluor R© possibly through a homolytic cleavage of the N−F bond.77Thus, an SET mechanism for Selectfluor R© cannot be discarded.1.2.4 The fluorination of radicalsDespite the great accomplishments in the development of electrophilic sources of fluorine, safe sources ofatomic fluorine for selective fluorination were scarce and remained an unsolved problem in both radicaland fluorine chemistry (Figure 1.13).R FR+ R-FF- F+RFigure 1.13. Ionic vs radical fluorination.The generation of atomic fluorine is undesirable since it reacts neither selectively nor controllably.Atomic fluorine is highly oxidizing and will react with any trace of organic matter in an exothermic,explosive and uncontrolled manner. An ideal solution to this problem would be the development of aradical mediated process that avoided the generation of atomic fluorine while still allowing the fluorineatom to participate in radical processes.24Chapter 1. IntroductionBefore 2011, few sources of atomic fluorine were known, xenon difluoride XeF2 and molecularfluorine F2 among them. We recognized the paucity of safe atomic fluorine sources and decided toaddress the problem, keeping always in mind the premise of avoiding the generation of atomic fluorineat any given point in the reaction.In Chapter 2, our discovery of the radical character of N−F fluorine sources, such as NFSI (57) andSelectfluor R© (59), along with their use as fluorine atom transfer agents to alkyl radicals is described.Chapter 3 describes the development of a new visible-light photocatalytic decarboxylative fluorina-tion reaction to generate C−F bonds, and its application to synthesize fluoromethyl ethers. Spectroscopicand electrochemical data to support the proposed reaction mechanism is also discussed.Chapter 4 outlines the properties, generation and reactivity of alkoxy radicals (carbon radical pre-cursors through tandem reactions), with the subsequent description of our study of the chemoselectivityof alkoxy radicals towards 5-exo and 6-exo cyclizations, β-fragmentations and 1,5-HAT.Finally in Chapter 5 the conclusions for each one of the three different projects that encompass thisthesis work will be presented, along with a future derived from the presented investigations.25Chapter 2Fluorine transfer to alkyl radicals...the study of fluorinated compounds still holds many surprises.— Prof. H. Moissan (1900)Professor Moissan. The whole world has admired the greatexperimental skill with which you have isolated and studied fluorine- that savage beast among the elements.— Prof. P. Klason (1906)Fluorine containing molecules display remarkable properties that have been exploited in the fields ofnew materials, pharmaceuticals, agrochemicals and multiple other commodities. The constant improve-ment and the development of new fluorinated molecules requires the design of more efficient, versatileand selective fluorine-installing methodologies.In this chapter, our investigation on the safe transfer of atomic fluorine to alkyl radicals utilizing N−Freagents is presented. Our objective was to merge fluorine and radical chemistry to generate a selectivefluorination orthogonal to existing methodologies.2.1 Radical sources of fluorineAs mentioned in Section 1.2.4, a long standing problem in organic fluorine chemistry is the lack of safeand controllable sources of atomic fluorine for selective fluorination. In this section, three sources ofradical fluorine will be described: molecular fluorine (F2), xenon difluoride (XeF2) and trifluoromethylhypofluorite (CF3OF). The fluorination mechanism and utilization in organic synthesis of the three willalso be reviewed.26Chapter 2. Fluorine transfer to alkyl radicals2.1.1 Elemental fluorineMolecular fluorine (F2) is a pale yellow gas with a stinging smell that has a boiling point of -188◦C and amelting point of -218.6 ◦C.21 The current industrial method used to manufacture F2 is the electrochemi-cal oxidation of a molten mixture of KF · 2HF at 90 ◦C. This is a slight modification to the method usedby Moissan in 1886 to isolate F2 for the first time (Section 1.2).24Molecular fluorine reacts with hydrocarbons exothermically (Figure 2.1) due to the high heats offormation of C−F and H−F bonds (approximately 108.91 kcal mol−1,79 and 133.75 kcal mol−1 re-spectively).33 As it was observed by the pioneers in fluorine chemistry, the interaction of fluorine withhydrocarbons can be violent and explosive.80 Direct fluorination of hydrocarbons utilizing F2 is non se-lective, and typically the products correspond to compounds where the carbon backbones are saturatedwith fluorine atoms. It has been proposed that perfluorination of hydrocarbons proceeds in most casesthrough a radical mechanism (Figure 2.1).80–83F2 2F+R-H F2 H-F+ FR-H+RInitiation+R F2 R-F+R R-F+ F+ FPropagationH-F+R+R R-RTerminationFR+R-H R-FOverall reactionF2 H-F+ΔH25  (Kcal mol-1)37.673.90-33.77-69.05-108.91-83.74-102.82(2.1)(2.2)(2.3)(2.4)(2.5)(2.6)(2.7)Figure 2.1. Thermodynamic data for the fluorination of alkanes with F2.84The energy required to dissociate F2 into two fluorine atoms (Figure 2.1, eq. 2.1) is only 37.67kcal mol−1,85 however this dissociation occurs in less than 1% at room temperature.84 This has put inquestion whether the process in eq. 2.1 is actually the initiation step of the chain reaction mechanism. Analternative initiation step has been proposed byMiller whereby a C−H bond reacts with F2 to generate analkyl radical, hydrogen fluoride and atomic fluorine (Figure 2.1, eq. 2.2).86,87 The radicals thus generated27Chapter 2. Fluorine transfer to alkyl radicalscan then propagate the reaction (Figure 2.1, eq. 2.3 and eq. 2.4) to form highly fluorinated molecules,or recombine in a termination step (Figure 2.1, eq. 2.5 and eq. 2.6).Fluorine’s reactivity was first studied by Moissan after he successfully isolated F2. However, it wasnot until a generation later that Bigelow’s use of nitrogen to dilute fluorine gas allowed the use of F2 ina more controlled manner.88 The dilution of F2 effectively disperses the heat generated by the formationof C−F and H−F bonds.The investigations byBigelow and co-workers on the treatment of ethane with F2 in the gas phase81,89,90revealed that multiple fluorinated products were generated, including tetrafluorocarbon, fluoroform andperfluoroethane (Scheme 2.1 87, 88, 89). Bigelow’s studies also demonstrated that the ratio of ethane tofluorine, not surprisingly, affected the ratio of these products: highly fluorinated products were favouredat higher ratios of fluorine to ethane. Initially, a classical ionic mechanism was proposed to explain theformation of the various products, but was later revised and changed to a radical chain reaction mecha-nism.80+ F+CH3CH2 F2 +CH3CH2-F FCH3CH2CH3-CH3F2CF4+ FFCH2CH3 FCH2CH2CH3-CH3-HF-HF+FCH2CH2 F2 +FCH2CH2F FMechanism+ FFCH2CH2F CF3CF3+ CF3H + CF3-CF3(2.8)(2.9)(2.10)(2.11)(2.12)87 88 89Scheme 2.1. Radical perfluorination mechanism of ethane with F2.80In the first step of the proposed reaction mechanism, atomic fluorine rapidly reacts with ethane togenerate an ethyl radical and an HF molecule, as seen in eq. 2.8 of Scheme 2.1. The activation energyfor hydrogen abstraction is quite low, which allows for the initiation of the radical chain reaction andfavours the subsequent radical propagation reactions. The ethyl radical can then react with F2 to generatefluoroethane concomitantly with atomic fluorine (eq. 2.9, Scheme 2.1). Fuoroethane can react with F• toform a new fluoroethyl radical and HF (eq. 2.10). This sequence can continue until all the C−H bondsfrom ethane have been replaced for C−F bonds to form 89 (eq. 2.11 − 2.12). The generation of 87 and88 derives from the thermal homolytic cleavage of the C−C bond of ethane, in a process similar to thatobserved in hydrocarbon cracking (C−CBDE = 95 kcal mol−1).9128Chapter 2. Fluorine transfer to alkyl radicalsBigelow and co-workers also investigated the fluorination of methane with fluoride.82 The authorsproposed radical mechanisms to rationalize their findings.80 As Scheme 2.2 shows, the sequential radicalabstraction of hydrogen from methane to generate the corresponding radical, followed by fluorine atomtrapping from F2 explains the formation of 90, 91, 88 and 87 (eq. 2.13− 2.20). When the reaction mix-ture was fractionally distilled to separate its components, perfluoroethane (89) and perfluoropropane (92)where also isolated. The formation of 89 results from the termination step depicted in eq. 2.21 wheretwo trifluoromethyl radicals combine. In the case of 92, it can be explained through the recombinationof a trifluoromethyl radical with a difluoromethyl radical (eq. 2.22) followed by hydrogen abstractionfrom pentafluoroethane by atomic fluorine (eq. 2.23) and ensuing radical recombination of the pentaflu-oroethyl and methyl radicals (eq. 2.24).+ F+CH3 F2 + FCH3CH4F2CH3F+ FCH3F FCH2CH4-HF-HF+FCH2 F2 + FMechanism+ FCH2F2 F2CH+ CF2H2 + CF3H(2.13)(2.14)(2.15)(2.16)(2.17)+ CF4 + CF3CF3 + CF3CF2CF3-HF+F2CH F2 + F+ FCF3H CF3(2.18)(2.19)-HF+F3C F2 + F (2.20)+ (2.21)F3C F3C+F3C F2CH CF3CF2H (2.22)+ (2.23)CF3CF2H+ (2.24)F3CF2C F3CF F3CF2C-HF909091918888878789899292Scheme 2.2. Radical perfluorination mechanism of ethane with F2.80Miller and co-workers conducted extensive studies on the fluorination of unsaturated systems andtheir corresponding reaction mechanism.86,87,92 One of this experiments confirmed the ability of a fluo-rine radical to abstract a hydrogen atom from a hydrocarbon, and consisted in reacting sym-dichlorodifluo-29Chapter 2. Fluorine transfer to alkyl radicalsroethylene (93) with chloroform (94) at -75 ◦C (Scheme 2.3).92 As chloroform does not react with F2 atlow temperature, F2 first reacts with olefin 93 to generate atomic fluorine and the corresponding carbonradical (eq. 2.25). The atomic fluorine then abstracts a hydrogen from chloroform, to generate HF andthe trichloromethyl radical (eq. 2.26). The isolated products, chlorofluorocarbons 95 and 96, are theresult of the radical recombination reactions shown in eq. 2.27 and eq. 2.28.+ F2+Mechanism(2.25)(2.27)FClClFFCl ClFFClFFClClClCl+ClClHClF2CFCl3-75 °CFCl ClF+ F-HF(2.26)ClClHClF + FFClClFFFClClFF+ClClClFCl ClFF ClClCl+ (2.28)FCl ClFFFCl ClFF93 9495959696Scheme 2.3. Radical mechanism for the fluorination of sym-dichlorodifluoroethylene and chloroform withF2.92It is important to note that although a radical mechanism is widely accepted in this type of gas phaseperfluorination reactions, the use of non-polar solvents and low temperatures permits selective C−Hsubstitution by molecular fluorine, which can only be explained through an ionic pathway.93–95Selective radical fluorination utilizing molecular fluorine has been difficult to achieve. Reports on thesuccessful selective fluorination of carboxylic acids were done as early as 1933 by Bockemu¨lcer, wherehe obtained β- and γ-fluoro derivatives from the liquid fluorination of n-butyric acid with molecularfluorine.96 Over a decade later, Miller and Prober explored the fluorination of acetyl fluoride with F2in the gas phase at 100 ◦C,97 and reported the generation of monofluorinated and difluorinated esters(formed upon reaction work-up) in a 6:1 ratio. Only traces of the ethyl trifluoroacetate were observed.An example of selective fluorination that is particularly interesting for this work was reported byGrakauskas in 1969.98 In his study, Grakauskas describes the effect of fluorine on carboxylic acid saltsdissolved in water (Scheme 2.4). All the alkali carboxylates (97) investigated exhibited the same be-haviour, decarboxylation followed by fluorination yielded the mono- and difluorinated compounds 9830Chapter 2. Fluorine transfer to alkyl radicalsand 99 in up to 40% yield. Monocarboxylic salts were also investigated, but unfortunately their reactionwith fluorine yielded multiple fluorinated products. The fluorination of aromatic carboxylic acids wasbriefly investigated; no products were successfully isolated. Grakauskas suggests that the mechanism ofthe decarboxylative fluorination proceeds via a Hunsdiecker-type mechanism, involving the formation ofa hypofluorite intermediate (Scheme 2.4), as had been previously reported by Cady and Kellog.55 De-spite the previous evidence suggested hypofluorites decomposed through a free-radical mechanism,99 theauthor favours an ionic pathway to explain the formation of the fluoride products 98 and 99 due to thehighly polar solvent used in the reaction conditions. It is more likely the decomposition of the transienthypofluorite occurs through a radical pathway, as suggested by Rozen and coworkers (Scheme 2.4).60,100F2/N2NaOH(aq) H2O, 0-5 °CO OONa NaOn HOFOn+F Fnn = 1, 2, 3, 4, 7, 8MechanismR O NaOF F+R OOF-CO2F+R R Fhypofluorite97 98 99Scheme 2.4. Selective fluorination of carboxylic acid salts 97 with F2.98In 1985, Scherer and coworkers provided electron paramagnetic resonance (EPR) evidence to supportthe radical mechanism proposed for fluorination using molecular fluorine.101 The detection of an alkylradical upon the treatment of an alkene with F2 unambiguously proves that a radical mechanism is inoperation.2.1.2 Trifluoromethyl hypofluoriteHypofluorites are molecules containing an O−F functional group bonded to an inorganic or organicfragment. While many stable inorganic hypofluorites are known, they are rarely used in synthetic ap-plications. Organic hypofluorites, on the other hand, are stable as long as the carbon chain attached tothe O−F functionality is partially or fully substituted with fluorine. The chemistry and application oforganohypofluorites were widely studied in the second half of the 20th century.59,102–105 This section willparticularly focus on the radical mediated reactions of trifluoromethylhypofluorite (CF3OF).Trifluoromethylhypofluorite (100) is a toxic gas with a boiling point of -95 ◦C.106 It was fist syn-thesized by Kellogg and Cady in 1948 via the catalytic fluorination of methanol vapour with molecular31Chapter 2. Fluorine transfer to alkyl radicalsfluorine in the presence of a “catalytic copper ribbon coated with fluorides of silver”.55 It has also beensynthesized from carbon dioxide, carbon monoxide, and carbonyl fluoride treated with F2 and catalyticsilver (II) fluoride, as well as through the direct fluorination of potassium cyanide with molecular fluorineat 55 ◦C.106The reactivity of trifluoromethyl hypofluorite is a consequence of the weak O−F bond (BDEO−F =44.8 ± 0.8 kcal mol−1);107 both homolytic and heterolytic modes of reactivity have been observed for100, so it can react as both an electrophilic and a radical source of fluorine. This reagent can be consideredan elemental fluorine analogue.Trifluoromethyl hypofluorite does not react upon mixing with methane, chloroform or carbon tetra-chloride, but it readily reacts under vigorous conditions, such as UV light irradiation or heating. Allisonand Cady described in 1959 that 100 reacts violently with ethene, acetylene and cyclopropane to yieldcarbon, carbon monoxide and hydrogen fluoride.58 Dilution of the reactants with N2 resulted in a con-trol addition of fluoride and trifluoromethoxy, in the case of ethene, across the double bond to yieldtrifluoromethyl 2-fluoroethyl ether 102 (Scheme 2.5). At the time, the mechanism was suggested to oc-cur through a radical pathway, but conclusive evidence to support this statement was not provided untildecades later.108 It was suggested that initial homolytic scission of the O−F of hypofluorite 100 wouldgenerate a trifluoromethoxy radical and a fluorine radical (Scheme 2.5). The latter would then add to thedouble bond of ethene and form a carbon radical. Final recombination of this carbon radical with thetrimethoxy radical would yield ether 102.+MechanismF3CO F +F3CO FHH HH+N22 C +CO 4 HFUV lightF3CO FH2C CH2hν CF3O F CF3O HHF+101 100102102Scheme 2.5. Fluorination of ethene with trifluoromethyl hypofluorite.58Trifluoromethyl hypofluorite reacts with styrene derivatives to form addition and addition-eliminationproducts, as reported by Patrick and shown in Scheme 2.6 for 1,1-diphenylethene.109 Later studies byLevy and Sterling, suggested a radical-ionic mechanism to explain the formation of 104—108. In themechanism section of Scheme 2.6 we can see that the formation of trifluoromethylether 104 and 1,2-32Chapter 2. Fluorine transfer to alkyl radicalsdifluoride 105 derives from the radical addition of atomic fluorine to the terminal end of the olefin.Although the authors acknowledge that the newly formed radicals can undergo free-radical chain reac-tions, they also suggest that a SET can occur from the carbon radical to the trifluoromethoxy radical togenerate a carbocation and trifluoromethoxide. When the molecules stay in close proximity within thesolvent cage, nucleophilic attack of trifluoromethoxide on the carbocation generate 104. If, however, tri-fluoromethoxide decomposes into COF2 and F–, then 105 forms upon nucleophilic attack of fluoride tothe benzylic carbocation. Olefin 106 can be formed instead if the benzylic carbocation loses a H+. Thistrisubstituted alkene can undergo a second CF3OF addition to generate 108. The head-to-tail dimericproduct 107 was also found in the reaction mixture.MechanismF3CO F+Freon-11-78 °CPhPhPhPhOCF3FPhPhFF+PhPh+ FPh PhPhPh+ F9% 11% 7% 8%+15%PhPhOCF3FFPhCF3OF + PhFOCF3PhFOCF3Ph PhPhSETPhFPhCOF2 ++ Fcage -H+103 100104104105105106106 107 108Scheme 2.6. Fluorination of 1,1-diphenylethene with trifluoromethyl hypofluorite.110Levy and Sterling proposed a radical-ionic mechanism based on the data they obtained by performinga Hammett analysis. The study revealed the ρ value to be−2.48±0.09 for σ constants and−2.18±0.06for σ+ constants.110 Despite the fact that a study reported by Johri and Differding, which comparedthe reactivity of CF3OCl and 100, suggested a radical mechanism was in operation,111 the authors be-lieved their “results exclude a free-radical chain reaction”. They considered the values found for ρ were“consistent with cationic intermediates rather than with the attack of a free radical on the alkene bond”.However, the low dipole moment (µ = 0.30 ± 0.02 Da)112 and the also low BDE of the O−F bond inCF3OF deterred them from from proposing a fully ionic mechanism.This radical-ionic mechanism was fairly accepted until Navarrini, Tortelli and co-workers publishedin 1995 incontrovertible evidence supporting the radical mechanism of the reaction between CF3OF anddouble bonds. Their EPR studies on the addition of CF3OF to perfluoro olefins,108,113 which detected thegenerated radicals spectroscopically, as well as their determination of the rate constants for the addition33Chapter 2. Fluorine transfer to alkyl radicalsof CF3OF to chloro fluoro alkenes,114 left no room for doubt that trifluoromethyl hypofluorite reactsthrough a radical mechanism.2.1.3 Xenon difluorideThe first noble gas compound ever prepared was reported by Neil Bartlett in 1962, while working at theUniversity of British Columbia.115 This landmark discovery inspired the work of many groups around theglobe who pushed the limits of nobel gas chemistry. Claassen, Seling, and Malm reported the synthesisof lower molecular weight xenon-fluoride compounds, such as XeF4.116 These authors also report thegeneration of “lower” xenon fluorides upon treatment of XeF4 with excess F2, likely XeF2. Nowadays,xenon difluoride is commercially available, though a common method to prepare it consists on sunlightirradiation of a 1:1 mixture of xenon and fluoride in a pyrex or quartz reactor, which yields up to 99% ofpure XeF2 on a gram scale.117,118Xenon difluoride (XeF2, 109) is a colourless crystalline solid (m. p. 129◦C) that can be easily trans-ferred and manipulated with standard laboratory equipment.119 The first bond dissociation energy forXeF2 has been determined to be 60.37 ± 0.5 kcal mol−1,120 a value that suggests this bond can be ho-molytically cleaved.76 Xenon difluoride can be considered an F2 surrogate, with the advantage that it canbe used quite safely under appropriate conditions. The use of xenon difluoride in synthesis representeda significant step towards safe sources of radical fluorine to conduct selective fluorination.As other radical and electrophilic sources of fluorine, XeF2 reacts with alkenes to generate vicinaland geminal alkyl fluorides, as was demonstrated by Shieh, Yang and Chernick two years after it wasfirst synthesized.121 Almost a decade later, Zupan and Pollak improved the XeF2 mediated fluorination ofolefins by adding a catalytic amount of acid to the reaction (Scheme 2.7).122 The products of the reactionof olefin 110 with XeF2 when R = H or CH3 are difluoride 111 as the major product (65-95% yields)and ketone 112 (rearranged product). When R = F, 111 is also the major product and although no ketonewas observed, the product of the addition of trifluoroacetate 113 was detected in small amounts.Xe F+PhPhPhPhFFPhOH+ PhOCOCF3+ FFRHF orCF3CO2H R65 – 95%PhRPhRR = H, CH3, F110 109 111 112 113Scheme 2.7. Acid catalyzed fluorination of alkenes with xenon difluoride.122The fluorination mechanism of phenyl substituted alkenes with XeF2 has been subject to debate.Starverb and co-workers conducted a study where they evaluated the correlation of ionization potentials34Chapter 2. Fluorine transfer to alkyl radicalsof different olefins to their relative rates of reaction towards fluorination with XeF2.123 It was observedthat reactions occurred faster when the alkene had a lower ionization potential, which would suggest anSET process is involved in the mechanism. The addition of catalytic amounts of acid also accelerates thereaction, which is attributed to a coordination between the acid and XeF2 (Figure 2.2) that would enhancethe electrophilicity of xenon difluoride and promote the formation of radical cation intermediates. Theauthors were unable to determine whether an ionic or radical mechanism is in operation.Xe F+PhPhPhPh FFHHFδ+ δ-Xe FHFPhPhFδ+ δ-HHHHHPhPhHH-XeSETPhFHFPh HHF2XeF103 109 105Figure 2.2. Mechanism of the acid catalyzed fluorination of alkenes with xenon difluoride.123Xenon difluoride can also selectively fluorinate enolates. For instance, exposure of estrone-derivedenol diacetate 114 to XeF2 in a dichloromethane solution at ambient temperature for 17 h, yields 115almost quantitatively and with good diastereoselectivity.124 The modified steroid 115 is important for itshigh affinity with the estrone receptor, which confers it the potential to be used in estrogen-responsivetumour studies. Although the fluorination was performed also with other reagents (CsSO4F, N2/F2,CF3OF), XeF2 provided the highest yields in all cases.Xe FF25 °C, 17 hCH2Cl2AcOOAcHHHAcOOHHHF99% yield; α/β = 9:1114109115Scheme 2.8. Fluorination of enol 114 utilizing xenon difluoride.124In 1989, Stavbert, Sket, Zajc and Zupan observed that when 1-indanone was subjected to xenondifluoride conditions, instead of the expected α fluorinated product, a rearrangement lead to the formationof 2,2-difluorochromane.125 Further investigation showed that the reaction of XeF2 with various aromaticketones, such as 116 (Scheme 2.9),126 consistently yielded the rearranged difluoroethers product (117).35Chapter 2. Fluorine transfer to alkyl radicalsXe F+ FHFCH2Cl2OXX = CH3, CH2F, ArRORXF F116 109 117Scheme 2.9. Xenon difluoride reactivity towards aromatic ketones. 126A similar study conducted by Stavber, Koren and Zupan in substituted aromatic aldehydes confirmedthe reactivity previously reported for the aromatic ketones (Scheme 2.10). The presence of electronwithdrawing groups in the aromatic ring (such as 118 shown in Scheme 2.10), afforded the correspondingrearranged products in yields ranging from 68% to 86%.127 No aldehydes with electron donating groupsin the aromatic ring are reported. The proposed mechanism to explain the transformation suggests theinitial addition of HF to the carbonyl group to form a fluorohydrine intermediate. Subsequent addition ofthe newly formed alcohol to XeF2,128 followed by rearrangement of the unstable RO−XeF intermediateresults in the formation of the difluoromethoxy products.Xe F+ FHFCH2Cl2OHF3COCF2HF3C86% yield118 109 119Scheme 2.10. Xenon difluoride reactivity towards aromatic aldehydes. 127Patrick, Johri and White first reported on the reactivity of carboxylic acids with xenon difluoride in1983.129 Analogous to the Borodin-Hunsdiecker130–132 and Kochi133 reactions, they observed that thetreatment of a carboxylic acid with XeF2 and a catalytic amount of hydrofluoric acid in dichloromethaneyielded the corresponding fluoroalkane (Scheme 2.11) in good to excellent yields (54 − 84%). Theirreaction scope includes primary, secondary and tertiary aliphatic acids, and it is compatible with methoxyand ketone groups present in the molecule, although the presence of unprotected hydroxyl groups resultsin complex product mixtures. Benzoic acid does not undergo fluorodecarboxylation, but yields smallamounts of benzoyl fluoride instead.129Patrick and co-workers later investigated the reaction mechanism involved in their newly found de-carboxylative fluorination reaction.134,135 Considering that Eisenberg and DesMarteau had previouslyreported the isolation of xenon (II) fluoride trifluoroacetate (CF3CO2XeF) derived from the reaction ofxenon difluoride and trifluoroacetic acid,136 Patrick proposes the formation of a xenon ester as the first36Chapter 2. Fluorine transfer to alkyl radicalsX2OORXRAgBorodin-Hunsdiecker reactionCCl4OOHRXRKochi reactionX = Br, ClPb(AcO)4,MXOOHRFRPatrick's decarboxylative fluorination reactionC6H6XeF2, HFCH2Cl2X = Br, Cl, IScheme 2.11. Decarboxylative halogenation reactions.129–131,133step of the reaction (Scheme 2.12, eq. 2.29). Despite initial evidence suggesting that primary and sec-ondary carboxylic acids reacted through an ionic mechanism (Scheme 2.12, eq. 2.30),134 further mech-anistic studies revealed that these react through a radical pathway.135 Trapping of the resulting primaryradical though an intramolecular cyclization onto a double bond, as well as spectroscopic detection of theprimary radical through electron spin resonance (ESR), strongly supported that the reaction of primarycarboxylic acids proceeds through a radical pathway. In this study, the mechanism of tertiary substratesremains radical and for secondary substrates is not clearly elucidated (Scheme 2.12, eq. 2.31 − 2.34).ROOH R OOXeFXe FF HFδ+ δ-+ + HFR OOXeF+ F-F- CO2 + Xe ++R FSN2 mechanismF-Radical mechanismR OOXeFCO2 + Xe+R F+ Xe+ XeR F R+R R F+ F-++ XeF2R R FF-Xe F(2.30)(2.31)(2.33)(2.32)(2.34)(2.29)Scheme 2.12. Xenon difluoride luorodecarboxylation reaction mechanism.134,13537Chapter 2. Fluorine transfer to alkyl radicalsThe radical clock experiment by Differding, which was discussed in Section 1.2.3.2, further sup-ported a radical mechanism for the reaction of XeF2 with enolates (Scheme 1.15).72 Xenon difluoridewas the only fluorine source that generated cyclopentane 83 upon its reaction with the enolate of ester79, suggesting a radical 5-exo cyclization occurs after an SET between the enolate and XeF2 takes place.One of the deterrents to the more extensive use of XeF2 is its high oxidation potential, determined tobe E = +0.19 V at pH of 1.6 using a glassy carbon electrode.137 Another factor that prevents the use ofXeF2 in organic synthesis is its expense. The cost of this reagent can be a restricting factor specially ifthe fluorination reactions are to be performed in large scale. For instance, xenon difluoride ($ 79.0 USDper gram) is almost ten times more expensive than Selectfluor R©($ 9.0 USD per gram), one of the mostused electrophilic sources of fluorine.2.2 Proposed radical fluorination using N-F reagentsThe paucity of safe sources of atomic fluorine to perform selective fluorination, along with the progres-sive increase of importance, impact and value of fluorinated molecules in pharmaceutical and agrochem-ical products, prompted us to investigate alternative and safe sources of fluorine compatible with radicalprocesses.Since one of the mechanisms proposed for the fluorination using electrophilic N−F reagents involvesthe generation of radicals through an SET process (Figure 1.12), we deemed these reagents as suitablecandidates to explore a new type of radical reactivity. When our investigation started, N−F reagents, suchas Selectfluor R©(59), NFSI (57) and NFPYs, were exclusively utilized as ionic, electrophilic sources offluorine. Mechanistically, the fluorination seemed feasible if a carbon radical species was used to forma C−F bond through a homolytic bimolecular substitution (SH2) reaction (Figure 2.3). We hypothe-sized that the N−F bond of electrophilic sources of fluorine could be used as a fluorine radical trap,provided these bonds had a suitable BDE. The treatment of N−F electrophilic sources of fluorine withany independently generated radical R• would lead to the formation of the corresponding fluoride R−F.38Chapter 2. Fluorine transfer to alkyl radicalsX F + Nu SET X F + Nu + XPreviously proposed SET mechanismX F + R FOur hypothesisRNu FX +SET ordirect atom transferFigure 2.3. Previously proposed mechanism70 for fluorination using electrophilic N−F reagents and ourproposed mechanism.2.2.1 N−F bond dissociation energy calculationsWe began the investigation by calculating the BDE of the N−F bond present in three different types offluorinating reagents: Selectfluor R©(59, Figure 2.4), NFSI (57) and NFPYs 64. We collaborated withthe Kennepohl group at UBC to investigate the N−F bond properties of these electrophilic sources offluorine.NSO2PhFNFSINNFClSelectfluorNFNFPYPhO2S57 59 64Figure 2.4. Selected electrophilic sources of fluorines for DFT calculations.Prof. Kennepohl and Tulin Okbino˘glu performed all the density functional theory (DFT) calculationsusing the quantum chemistry program ORCA. The results of the DFT calculations are summarized inTable 2.1, where DN-F corresponds to the bond dissociation energy of the N−F bond and is reported inkcal mol−1.138From Table 2.1, we can see that the change of dielectric constant in the media has little to no effect onthe bond dissociation energy (DN-F) for all three molecules. The calculations also show that the fluorineatom in Selectfluor R© is more positively charged (qF), and consequently more electrophilic, compared tothe fluorine of NFSI, as a consequence of the formally cationic nitrogen bonded to it.Homolytic bond dissociation energies for NFSI and Selectfluor R© are relatively close to one another,and they fall into the energy range of BDEs of species that can react through radical mechanism. NFPYhas a higher bond dissociation energy than the other twomolecules, likely because the homolytic cleavageof the N−F bond would generate a radical in an sp2 hybridized atom.39Chapter2.FluorinetransfertoalkylradicalsTable 2.1. DFT calculated properties of the N−F bond of NFSI, Selectfluor R©and NFPY a.NFSI b Selectfluor R© b,c NFPY b,cNSO2PhFPhO2SNNFClNFSolventrNF BONF DNF qF rNF (pm) BONF DNF qF rNF (pm) BONF DNF qF(pm) (kcal/mol) (pm) (kcal/mol) (pm) (kcal/mol)Hexane 143.8 0.839 63.4 -0.14 141.4 0.986 61.0 0.00 137.5 0.933 76.1 -0.02THF 143.8 0.837 63.3 -0.14 141.9 0.966 61.7 -0.02 137.8 0.922 75.4 -0.05CH3CN 143.7 0.839 63.2 -0.14 142.1 0.956 60.9 -0.03 137.8 0.915 75.1 -0.06H2O 143.7 0.831 63.5 -0.14 142.2 0.956 62.2 -0.03 137.9 0.914 75.3 -0.06a All DFT calculations were performed by Prof. Kennepohl and Tulin Okbino˘glu. For each species, the N−F bond distance (rNF in pm), Mayer bond order(BONF), and bond dissociation energy (DNF in kcal/mol) are computed in four different solvents: hexane, tetrahydrofuran, acetonitrile, and water. In addition,the Loewdin charge on the fluorine atom (qF) is given. b Performed using ORCA. molecular geometries were optimized using the COSMO salvation modelas implemented in ORCA with solvents varying from n-hexane to acetonitrile. c Computational results from the cationic reagents without counter ions areshown in this table. Results with appropriate counter ions differ slightly due to ion pairing effects, which do not affect the overall conclusions herein.40Chapter 2. Fluorine transfer to alkyl radicalsCommon bond dissociation energies for molecules that are known to react via a radical mechanism( Table 1.1) are typically lower than 90 kcal mol−1. Diatomic halogens display low BDEs, Cl2 being thehighest with 58 kcal mol−1. Methyl halides, except for methyl fluoride, have BDEs of 84 kcal mol−1, 70kcal mol−1 and 56 kcal mol−1 for CH3−Cl, CH3−Br and CH3−I respectively. Classic radical hydridesources, such as trimethylsilane, trimethylgermane and tributyltin hydride, show BDEs of 90 kcalmol−1,82 kcal mol−1 and 74 kcal mol−1.The calculated BDE values of 59, 57 and 64 (61 kcal mol−1, 63 kcal mol−1and 75 kcal mol−1)fall precisely on the range of bond energies that have the potential to react through a radical mechanismwith most alkyl radicals. Based on these calculations, 59, 57 and 64 have the potential to enable radicaltransformations that had so far been inconceivable. With these encouraging results in hand, we proceededto put the theory to the test in the laboratory.2.3 Initial studies: lauroyl peroxideDiacyl peroxides are known to decompose under thermal and photochemical conditions through thehomolytic scission of the oxygen-oxygen bond (Scheme 2.13).139 After the O−O bond is cleaved, thenewly generated acyloxy radical can rapidly undergo decarboxylation, but may also suffer recombina-tion or perform a hydrogen atom abstraction from the solvent depending on the reaction conditions.140,141Even though ab initio calculations suggest higher values,142 studies on the kinetics of thermal decom-position of diacylperoxides have estimated a BDE of 30 ± 1 kcal mol−1 for unbranched alkyldiacylperoxides.143,144OOROROOORORO-2 CO22 RΔacyloxy radicalsdiacyl peroxideScheme 2.13. Thermally or photochemically initiated diacylperoxide decomposition.We began our experimental investigation with one of the most commonly used free radical initiators:lauroyl peroxide (120, Figure 2.5). This long chain diacyl peroxide is not only a highly efficient radicalinitiator, but also a great source of reactive long chain alkyl radicals itself.141 Lauroyl peroxide rateconstant of decomposition (kd) varies depending on the temperature; at 40 ◦C the rate has been reportedto be kd = 4.9× 10−7 s−1, while at 85 ◦C the rate is three orders of magnitude faster (kd = 3.8× 10−4s−1).41Chapter 2. Fluorine transfer to alkyl radicalsOOOOlauroyl peroxide120Figure 2.5. Lauroyl peroxide, common radical initiator.Lauroyl peroxide’s long alkyl chains render it soluble in non-polar solvents. We decided to performour first trial using benzene-d6 as the solvent, because it effectively dissolves lauroyl peroxide and hydro-gen abstraction from the solvent is minimized. From the three electrophilic fluorinating agents of whichthe N−F bond energy was calculated (Figure 2.4), the only one that presented good solubility in benzenewas NFSI.The first trial consisted in the reaction of lauroyl peroxide with 5.0 equiv. of NFSI at 90 ◦C indeuterated benzene (Scheme 2.14). 1H NMR spectroscopic analysis of the crude reaction mixture wasperformed without any work-up or purification, and the appearance of a doublet of triplets (dt) at 4.25ppm (see Figure 2.6), characteristic of the desired fluoroundecane (121) was observed. The chemicalshift signal is consistent with the presence of a highly electron withdrawing group. Further evidence thatcorroborates the identity of this dt signal at 4.15 ppm was obtained from a fluorine-19 decoupled hydro-gen nuclear magnetic resonance (1H {19F} NMR) experiment. When the frequency of 19F is saturated,the pair of triplets (t) coalesce into one single triplet. This constitutes the first example of an electrophilicsource of fluorine effectively serving as a fluorine atom transfer agent in the presence of an alkyl radical.OOOO9 9 C6D6, 80 °C 9OO9F9 18+NFSI+120 121 122 12357Scheme 2.14. Thermolysis and fluorination of lauroyl peroxide using NFSI.The signals in the 0.5 ppm to 1.75 ppm range of the 1H NMR spectrum account for the alkyl com-ponents of the unreacted starting material 120, ester 122 and likely also from n-docosane (123), productfrom the recombination of the two undecyl radicals generated upon the double decarboxylation of lau-royl peroxide. These types of products were previously observed following the thermal decompositionof lauroyl peroxide by Guillet and Gilmer.141 They reasoned that the formation of disproportionation42Chapter 2. Fluorine transfer to alkyl radicalsand recombination products after the homolytic scission of the O−O bond in lauroyl peroxide was aconsequence of the proximity of the newly formed radicals within the “solvent cage”.145012345678ppm0.8930.9141.2701.2871.3492.0502.0752.1002.1892.2142.2393.2323.2553.2793.3023.5643.5743.5763.5793.5873.5943.6094.0324.0534.0584.0734.0804.1024.1914.2114.2316.7166.7416.7456.7636.7686.8416.8456.8496.8636.8706.8766.8906.8966.9037.1607.8117.8167.8407.9527.9597.9807.985Figure 2.6. Crude 1H NMRspectrum of the first fluorine atom transfer from NFSI to lauroyl peroxide underthermal conditions.Efforts to purify fluoroalkane 121 using flash column chromatography (FCC) proved unsuccessful.The low polarity of starting material (120) and products (121, 122, 123, etc.) made this mixture insepa-rable using the typical silica-gel stationary phase as all the components travelled equally fast through thecolumn regardless of the solvent used (petroleum ether, pentanes or hexanes). Furthermore, the reactantand products were difficult to visualize by thin layer chromatography (TLC) using UV light or differentstains.The use of 1,3,5-trimethoxybenzene (TMB) as internal standard proved ineffective; fluorination ofthe aromatic ring was observed when TMB (124) was added to the reaction mixture, and also when itwas treated with NFSI under the reaction conditions (Scheme 2.15). We decided to explored the use ofgas chromatography (GC) as an alternative quantification method.C6D6, 80 °CNFSIOCH3OCH3H3COOCH3OCH3H3COFn124 125Scheme 2.15. Fluorination of 1,3,5-trimethoxybenzene by NFSI under thermal conditions.43Chapter 2. Fluorine transfer to alkyl radicalsA de novo sample of fluoroalkane 121 was required to perform the GC quantification. This wasprepared in three steps from 1-undecanol (127) as shown in Scheme 2.16. An initial SN2 displacementof iodide 126 with sodium acetate ,146 followed by basic hydrolysis yielded alcohol 127 in 92% yieldover two steps. The synthesis of 121 from alcohol 127 was achieved by the use of a similar reagentto DAST, dimethylaminosulfur trifluoride 128, which upon formation of a O−S bond generates F– insitu to ultimately form the fluoroalkane via an SN2 reaction.147 Since purification of fluoroalkane 121was unsuccessful through FCC, Kugelrohr distillation was used instead. A detailed description of thecalibration curves and sample preparation, as well as the yield calculation procedure can be consulted inSection 2.8.3.OHCH2Cl2, 0 °CNSFFF9F9I91) AcONa    DMF, 110 °C2) NaOH, MeOH92 % yieldover two steps126 127 121128Scheme 2.16. Synthesis of fluoroalkane standard 121.2.3.1 Lauroyl peroxide fluorination optimization studies2.3.1.1 ThermolysisOptimization of the thermal fluorination of lauroyl peroxide with electrophilic sources of fluorine wasconducted through the change of variables such as electrophilic fluorine source, solvent and reactiontime. The quantification was performed using GC and the results derived from these condition screeningexercise are presented in Table 2.2.Five electrophilic sources of fluorine were investigated: NFSI (57), Selectfluor R© (59), the triflate(TfO−)N-fluoropyridinium salt (64), the trifluoroborate N-fluoropyridinium salt, and the 2,4,6-trimethyltrifluoroborate N-fluoropyridinium salt. All NFPY salts and Selectfluor R© were unable to perform the flu-orination of undecyl radical in benzene (entries 1−4, Table 2.2). Since poor solubility of Selectfluor R© inbenzene could be negatively affecting the fluorine atom transfer from Selectfluor R© to the generated radi-cal, several polar solvents were investigated. The results shown in entries 4−12 of Table 2.2 indicate thatregardless of the solvent utilized, the desired fluoroalkane 121 is not obtained when Selectfluor R© is usedas the fluorine source. The next variable to optimize was the reaction time. The reaction was monitoredevery two hours, and the results showed that the highest yield (24%) was achieved after only 2.3 h (en-44Chapter 2. Fluorine transfer to alkyl radicalstries 13 − 17, Table 2.2). It appears that product 121 is reacting under the reaction conditions, thoughnot to a great extent, since the highest yield was recorded at 2 h and longer reactions times resulted inslightly decreased yields.Table 2.2. Lauroyl peroxide themolysis-fluorination: fluorine source, time and solvent optimization study.OOOO9 9N-F reagentC14H30Solvent, 80 °CF9120 121Entry Fluorine source Solvent Time (h) 121, % yield a1 NFPY TfO– C6H6 13.8 02 NFPY BF–4 C6H6 13.8 03 2,4,6-trimethyl NFPY BF–4 C6H6 13.75 04 Selectfluor R© C6H6 13.0 05 Selectfluor R© Toluene 13.0 06 Selectfluor R© Dioxane 13.0 07 Selectfluor R© Et2O 13.0 08 Selectfluor R© THF 13.0 09 Selectfluor R© Acetone 13.0 010 Selectfluor R© CH3CN 13.0 011 Selectfluor R© CH3OH 13.0 012 Selectfluor R© AcOEt 13.0 013 NFSI C6D6 13.5 2214 NFSI C6H6 2.3 2415 NFSI C6H6 4.0 1716 NFSI C6H6 6.0 1817 NFSI C6H6 8.4 18a Quantified via gas chromatography.2.3.1.2 PhotolysisDiacyl peroxides are known to undergo not only homolytic O−O bond scission but also heterolytic pro-cesses, such as the Leffler carboxy inversion depicted in Figure 2.7,148,149 when subjected to thermolysis.While this type of carbonyl inversion rearrangements are favoured by secondary and tertiary diacylper-oxides,150 the use polar solvents, and acid catalysis,148,151,152 the inversion has also been observed innon-polar media153 and could not be entirely discarded as a possible reaction pathway for lauroyl perox-ide under our thermal reaction conditions.45Chapter 2. Fluorine transfer to alkyl radicalsOOR'OROOOR'OROO R'OR CO2O R'OOROORR'OFigure 2.7. Leffler’s carboxy-inversion.14It has been demonstrated by EPR studies that direct photolysis of acyl peroxides cleanly generatesalkyl radicals139,154 without the formation of carboxy-inversion products.13 To corroborate that an alkylradical was the species participating in the fluorine atom transfer, the use of NFSI to fluorinate alkylradicals under photolytic conditions was investigated.A Rayonet photoreactor was used to determine the optimal conditions to photolyze lauroyl peroxide.Initially, a 0.21 m solution of lauroyl peroxide in benzene was irradiated with 350 nm light for 4 h, but novisible change was observed in the 1HNMR spectra. Irradiation for an additional 15 hwith the same lightalso did not prompt the decomposition of lauroyl peroxide. The irradiation of a second solution of lauroylperoxide in benzene with 300 nm light effectively homolyzed the diacyl peroxide, and consumption ofthe lauroyl peroxide was observed in the 1H NMR spectra. As a control experiment, a solution of NFSI indeuterated benzene was also irradiated with UV light. Neither 350 nm nor 300 nm light had a significanteffect on the fluorinating agent even after 4 h irradiation periods.Despite the use of an internal ventilation system in the photoreactor, it was observed that the tem-perature inside the sample compartment is 65 ◦C during irradiation. To discard thermal decompositionof lauroyl peroxide derived from this instrumental condition, two samples containing a 0.21 m solutionof lauroyl peroxide were irradiated with 300 nm light, but one was covered with aluminum foil. Thecomparison of the 1H NMR spectra of the two samples shows that the triplet at 2.04 ppm, correspondingto the methylene α to the carbonylic position in lauroyl peroxide, diminishes after 4 h of irradiation inthe uncovered sample but remains unchanged in the sample covered with aluminum foil. This evidencestrongly supports the conclusion that 300 nm UV light homolytically cleaves the O−O bond in lauroylperoxide, not the heat generated inside the photoreactor. Alkyl radicals are generated as a consequenceof this process.46Chapter 2. Fluorine transfer to alkyl radicalsThe optimization of the fluorination reaction under photolytic conditions was then optimized. Lau-royl peroxide was subjected to 300 nm light irradiation in the presence of NFSI in C6D6 (0.3 m solution).Quantification of the photolysis reaction was achieved via gas chromatography, utilizing tetradecane asinternal standard. The irradiation of lauroyl peroxide with 300 nm light for 3.8 h yielded an average of34% of fluoroalkane 121, determined by gas chromatography.While diacyl peroxides are good radical precursors, their challenging synthesis and ambient tem-perature instability,13,152 limits their use in synthesis as versatile radical precursors. Consequently, wedecided to explore the use of other alkyl radical precursors to perform fluorine atom transfers. Theinvestigation of alkylboranes and t-butylperesters as radical precursors is is discussed in the followingsections.2.4 Alkylboranes as radical precursorsAlkylboranes have been extensively used as effective low temperature radical initiators.3 Molecular oxy-gen (O2) in its triplet form reacts with boron to generate alkyl radicals, as illustrated in Scheme 2.17.155,156Alkylboranes, particularly triethylborane, have been used to generate radicals at temperatures as low as-78 ◦C, which makes them ideal radical initiators for thermally unstable substrates or in stereoselectivereactions. Moreover, they can be accessed from any terminal alkenes through a hydroboration reaction.alkylboraneRB O2+RR RBRR O+O-78 °CScheme 2.17. Alkyl radical generation via alkylborane reaction with O2.Knowing that alkyl radicals were prone to fluorinate using our new methodology conditions, tri-octylborane borane was synthesized to be used as a radical precursor. Treatment of 1-octene (129) withdimethylsulfide borane complex (DMS, 130) in dichloromethane at ambient temperature for 18 h af-forded trioctylborane 131 in a quantitative yield. This was confirmed by 1H NMR spectroscopy with theappearance of a triplet at 3.88 ppm and the disappearance of the signals corresponding to the terminalalkene between 5.5 ppm to 6.0 ppm.(CH3)2S⋅BH3CH2Cl2+r. t.B3129 130 131Scheme 2.18. Hydroboration of 1-octene.47Chapter 2. Fluorine transfer to alkyl radicalsThe freshly prepared borane 131 was then used to generate alkyl radicals in the presence of a fluorinesource. The reaction was executed by adding a solution of tryoctylborane in C6D6 to a solution of NFSIalso in C6D6 at 40◦C (Scheme 2.19). After 18 h of constant stirring, the 1H NMR analysis showedtwo small triplets below 4.0 ppm, but no signal corresponding to the desired fluoroalkane 132 could beobserved by 19F NMR.O2+C6D640 °C → r. t.B3NFSI F131 57 132Scheme 2.19. Fluorination of trialkylborane 131 with NFSI.Several attempts were made to synthesize a trialkylborane bearing a UV active functional group thatwould allow for the reaction to be monitored via TLC. Styrene was the initial choice. The treatment of133 with 130 in dichloromethane at 0 ◦C, afforded 135 (Scheme 2.20).CH2Cl2+0 °C 3B(CH3)2S⋅BH3133 130 135Scheme 2.20. Hydroboration of styrene.Trialkylborane 135 was used to perform some fluorination tests. When a degassed C6D6 solutionof 135 and NFSI was sparged with air for 10 min(Scheme 2.21), no fluoride 136 was detected by either1H NMR or 19F NMR spectroscopy. The reaction mixture was left to stir open to air for 24 h and 36h without positive results. Sparging the solution with air for 45 min also did not yield fluoroalkane 136.O2+C6D6r. t.NFSI3B F135 57 136Scheme 2.21. Fluorination of trialkylborane 135 with NFSI.Unfortunately the ease of decomposition of alkylboranes surpasses their synthetic accessibility. Theunstable nature of alkylboranes is a common problem, as it has been accurately noted by Ollivier andRenaud.157 They comment on the lack of reproducibility of results from experiments involving the tri-ethylborane/oxygen system and state that it is a recurrent problem. Ollivier and Renaud suggest the useof freshly prepared triethylborane and warn against utilizing any commercially available trialkylborane.48Chapter 2. Fluorine transfer to alkyl radicalsThe tendency of organoboranes to rapidly oxidize in the presence of O2 to form alkylboranes ac-counts for the formation of undesired products resulting from different reaction pathways. Althoughhard evidence has not been provided to definitely support a mechanism for the initiation step,158 a SH2has been proposed and is generally accepted. As shown in Figure 2.8, triplet oxygen initially attacksboron. A B−R bond is then homolytically cleaved to generate a B−O2 bond and an alkyl radical R•.+ B + RO ORRR BRROOSH2Figure 2.8. Alkylboranes autoxidation mechanism: SH2 initiation step.The subsequent steps in the mechanism of autoxidation of trialkylboranes are widely accepted andhave been confirmed by ESR and nuclear magnetic resonance (NMR) studies.157,159,160 As depicted inFigure 2.9, the alkyl radical (R•) generated through an SH2 reaction (eq. 2.35) also reacts with oxygento generate a peroxyl radical (ROO•, eq. 2.36), which further propagates the reaction through an SH2reaction (eq. 2.37) to furnish monoperoxyborane (ROOBR2) and another alkyl radical. The rate constantof homolytic substitution of tributylpeoxyl radical at the boron centre has been measured to be kp = 2.0×106 m−1s−1.160 Peroxyl radical (ROO•) can also react with monoperoxyborane to form diperoxyboraneand release an alkyl radical (eq. 2.38), or with itself in a termination step to generate stable non-radicalproducts (eq. 2.39). Monoperoxyborane can react with oxygen, to generate diperoxyborane (eq. 2.40),or with another molecule of trialkylborane (eq. 2.41). The product of the latter is a dialkylborinate,which can also react with O2 and generate trialkylborate, which is highly stable (eq. 2.42).The presence of such a wide variety of reactive species derived from the autoxidation of the trialkyl-borane, may have prevented the fluorine atom transfer reaction from NFSI to the alkyl radical, despitethe large excess of fluorinating reagent utilized. For the desired fluorination to proceed successfully,the reaction of the alkyl radical R• with NFSI would need to outcompete any other reaction of thisradical with either O2 or proxy radical ROO•, and also the disproportionation pathway. In light of thesefindings, we decided not to pursue the use of trialkylboranes as radical precursors any further, and shiftedour attention instead to a different type of peroxides that will be discussed in the next section.2.5 t-Butylperesters as alkyl radical precursorsOne of the major problems with lauroyl peroxide, and diacylperoxides in general, was the multiple re-combination products that could be observed upon thermolysis (Scheme 2.14, 122 and 123). A solutionto this problem could be the use of a radical precursor that upon homolysis would generate radicals lessprone to recombine.49Chapter 2. Fluorine transfer to alkyl radicalsRi+R3B O2Initiation +R2BOO R+R O2 RBOOSH2+ROO R3B +ROOBR2 RPropagationkp+ROOBR2 O2 (ROO)2BR+ROOBR2 R3B 2(RO)BR2kp = 2.0 x 106 M-1 s-1 at 30 °C, for R = n-Bu+ROBR2 O2 (RO)3BFurtherreactions+ROO ROOBR2 +(ROO)2BR R2ROO   (or R  )Termination Stable non-radical products(2.35)(2.36)(2.37)(2.38)(2.40)(2.41)(2.42)(2.39)Figure 2.9. Alkylboranes autoxidation mechanism.We decided to investigate the generation of alkyl radicals from t-butylperesters, which are knownto decompose thermally via the cleavage of the O−O bond present in their structure (Scheme 2.22).Upon this homolysis, an acyloxy radical (similar to diacylperesters, Scheme 2.13) and a highly reactivet-butoxy (alkoxy) radical are generated. The acyloxy radical fragment liberates carbon dioxide withconcomitant generation of the desired alkyl radical. The alkoxy radical fragment can undergo a homolyticbimolecular substitution to abstract a hydrogen atom and generate t-butanol, or a β-fragmentation to formacetone and a methyl radical, as shown in Scheme 2.22.R OOOR OOOΔR-CO2OO++ CH3Scheme 2.22. Thermal decomposition of t-butylperester.The first perester synthesized was 4-phenylbutyric acid t-butylperester (Scheme 2.23). Treatment of4-phenylbutyric acid (137) with dicyclohexylcarbodiimide (DCC) and a catalytic amount of 4-dimethyl-50Chapter 2. Fluorine transfer to alkyl radicalsaminopyridine (DMAP) in dichloromethane at 0 ◦C, yielded perester 139 in 96% yield as a pale yellowoil. The compound showed great stability to ambient conditions.CH2Cl2, 0 °COHO+DCC, DMAPOHOOOO96 %137 138 139Scheme 2.23. Synthesis of 4-phenylbutyric acid t-butylperester.With 139 in hand, we started to investigate its reactivity under our new radical fluorination system.Gratifyingly, the treatment of this perester with NFSI in degassed C6D6 at 120◦C for 2 h (Scheme 2.24),yielded the desired fluoroalkane 140. Along with 140, a significant amount of acetone (δ 1.61 ppm)and toluene (δ 2.11 ppm), as well as traces of an unidentified alkene, were observed in the spectra. Thepresence of acetone derives from the β-fragmentation of the t-butoxy radical formed upon homolyticcleavage of the O−O bond of 139. This would also generate a methyl radical, which can add to benzeneto generate toluene (142). Toluene can also be explained by the fragmentation of the 4-phenylpropylradical, which liberates ethene and a tolyl radical. The high temperatures at which the reaction takes placealso make it possible that the elimination product from 140 is being generated, which could correspondto the trace alkene peaks observed.C6D6, 120 °CNFSIOOOF+O+CH3139 140 141 142Scheme 2.24. Fluorination of t-butylperester 139.The next challenge, as with the lauroyl peroxide fluorination, was the separation and quantification ofthe products. I proceeded then to scale up the reaction shown in Scheme 2.24, and purify the crude mix-ture using flash column chromatography to obtain fluoroalkane 140. Disappointingly, the high volatilityof fluoroalkane 140 made its isolation difficult and low yields were recorded.Since flash column chromatography purification did not provide satisfactory results and the quan-tification of the products was not reliable, once again gas chromatography was chosen to quantify thegenerated fluoroalkane. Analogous to the quantification of the lauroyl peroxide fluorination products, itwas necessary to synthesize the corresponding fluoroalkanes through an alternative methodology.51Chapter 2. Fluorine transfer to alkyl radicals2.5.1 Fluoroalkane standards synthesisThe synthesis of the original sample of fluoroalkane 140 started with the reduction of carboxylic acid 143,utilizing lithium aluminum hydride in tetrahydrofuran (THF) at -10 ◦C, to provide alcohol 144 in 78%yield (Scheme 2.25).161 Treatment of alcohol 144 with dimethylaminosulfur trifluoride and purificationby Kugelrohr distillation provided fluoroalkane 140.147CH2Cl2, 0 °CNSFFFLiAlH4THF, -10 °COHOOH F78 % yield143 144 140128Scheme 2.25. Synthesis of fluoroalkane standard 140.With fluoroalkane 140 in hand, the corresponding calibration curve standards were prepared withvariable fluoroalkane concentrations and a constant amount of tetradecane (C14H30) as internal standard.The internal standard retention time remained 5.96min, while the retention time of fluoroalkane 140was4.45min. The calibration curve was constructed with samples ranging from 1.23×10−3m to 3.0×10−2m.The resulting curve had a correlation coefficient of r2 = 0.9967.The original sample of 146 was prepared through Ley oxidation of 144, followed by addition ofmethylmagnesium bromide to aldehyde 144 to form secondary alcohol 145 in 13% yield over 2 steps(Scheme 2.26). Treatment of alcohol 145 with dimethylaminosulfur trifluoride, followed by purificationvia Kugelrohr distillation, afforded the desired fluoroalkane 146.147CH2Cl2, 0 °CNSFFFOH1) NMO, TPAP,    CH2Cl2, 0 °C→r.t.2) CH3MgBr,    Et2O, -10 °COH F144 145 146128Scheme 2.26. Synthesis of fluoroalkane standard 146.The calibration curve standards of fluoroalkane 146 were prepared varying the concentration of thefluoroalkane and keeping the amount of internal standard (tetradecane, C14H30) constant. The retentiontime of fluoroalkane 146 under the gas chromatography conditions was 4.73 min. For the calibration,52Chapter 2. Fluorine transfer to alkyl radicalsthe concentrations ranged from 1.23× 10−3m to 3.0× 10−2m, and it displayed a correlation coefficientr2 = 0.9940.To access fluoride 148, the synthesis started from the secondary alcohol 147 (Scheme 2.27). Thisalcohol had been previously synthesized by my laboratory colleague N. E. Campbell through the additionof methyl magnesium bromide to benzaldehyde. Treatment of 147 with fluorinating reagent 128 indichloromethane at 0 ◦C, followed by purification via Kugelrohr distillation, yielded a pure originalsample of 148.147CH2Cl2, 0 °CNSFFFOH F147 148128Scheme 2.27. Synthesis of fluoroalkane standard 148.The calibration curve for fluoroalkane 148 was constructed from calibration curve standards con-taining a constant amount of internal standard (tetradecane, C14H30) and a variable concentration offluoroalkane. The retention time for 148 under the GC conditions used was 3.77 min, while concen-tration of the standards ranged from 1.23 × 10−3m to 3.0 × 10−2m. The constructed calibration curvepresented a correlation coefficient of r2 = 0.9956.The one other fluoroalkane that was used in this study for GC quantifications was 154. This substratewas also synthesized by N. E. Campbell through a similar route as 146. The synthesis of the originalsample of 154 is included in Section 2.8.2 as was reported by the our group in 2012.138With the calibration curves constructed for quantification purposes, I proceeded to investigate thedifferent reaction conditions of our fluorination reaction with t-butyl peresters as radical precursors, todetermine the optimized conditions for the selective fluorination of alkyl radicals.2.5.2 Perester fluorination optimizationBoth photolytic and thermal conditions were probed to generate alkyl radicals from perester 139. 350nmUV light irradiation did not cleave the O−O bond in the perester and no product was observed by gaschromatography analysis (entries 1 − 4, Table 2.3). Shorter wavelengths were not investigated to avoidthe use of quartz glassware. Neither the change from deuterated benzene to deuterated toluene, nor theincrease in the reaction time (from 15.8 h to 25.0 h) yielded the desired fluoroalkane under the photolysisconditions. The use of microwaves to initiate the homolysis of the perester in benzene (entry 5) was also53Chapter 2. Fluorine transfer to alkyl radicalsunsuccessful. Changing the source of fluorine to Selectfluor R© (entry 6), provided no fluoroalkane 140after 13:30 h at 110 ◦C. In the end, the treatment of t-butylperester 139 with NFSI in benzene at 110◦C afforded 140 in 24% yield (entry 7, Table 2.3). This yield is the average of three different trials underthe same reaction conditions.Table 2.3. Optimization of the fluorination conditions for perester 139.Solvent110 °C or hνOOOFN-F reagentC14H30139 140Entry Fluorine source Temp. (◦C)/hν Solvent Time (h) 140, % yielda1 NFSI UV light C6D6 15.8 02 NFSI UV light C6D6 25.0 03 NFSI UV light Toluene−d8 15.8 04 NFSI UV light Toluene−d8 25.0 05 NFSI Microwave C6D6 0.75 06 Selectfluor R© 110 C6D6 13.5 07 NFSI 110 C6D6 13.0 24ba Quantified via gas chromatography.b Average of 3 experiments performed under the same conditions.Our attention was then directed to the fluorination of secondary radicals. The synthesis of the sec-ondary radical precursor was performed through the esterification of 4-phenylbutyric acid 137. Initialtreatment with thionyl chloride in methanol at 0 ◦C, followed by methylation at −78 ◦C utilizing LDAand iodomethane, provided ester 149 in 86% isolated yield over two steps (Scheme 2.28). Hydrolysisof the latter with a 2.0 m solution of sodium hydroxide in methanol, and subsequent treatment of theresulting acid (150) with t-butylhydroperoxide and dicyclohexylcarbodiimide in dichloromethane at 0◦C, readily accessed perester 151.Perester 151 was initially subjected to the fluorination conditions that worked best for 151 (5.0 equiv.of NFSI in benzene at 110 ◦C), under which the desired product was obtained in 54% yield (entry 1 ofTable 2.4). A complete optimization of the reaction was then performed. The fluorination reaction of 151was monitored at different times (Table 2.4, entries 1−3). GC analysis showed that the optimal reactiontime for this reaction was between 16 − 20 min. The decrease of the yield after ∼ 30 min suggeststhat the fluoroalkane 146 generated is being depleted under the reaction conditions, possibly through anelimination reaction.54Chapter 2. Fluorine transfer to alkyl radicalsOOO86%1) SOCl2,     CH3OH, 0 °C2) LDA,     THF, -78 °C,    then CH3IOHOOCH3O86 %t-BuOOH, DCC,DMAPCH2Cl2, 0 °CNaOH(aq), CH3OH, 0 °COHO83%137 149150151Scheme 2.28. Synthesis of secondary t-butylperester 151.Continuing with the optimization, we explored the use of solvents different to benzene, a knowncarcinogen. The results showed that acetonitrile and toluene provide comparable yields of fluoroalkane146 to the ones recorded in benzene (Table 2.4, entries 4 and 5). The use of ethyl acetate (entry 6)yielded appreciable amounts of the desired fluoroalkane (74% yield), while acetone, methanol and watersignificantly decrease the fluoroalkane yields (55%, 45% and 43% respectively, entries 7 − 9). Thelast three solvents probed were dioxane, diethyl ether, and tetrahydrofuran. The yields in these solventswere poor (20%, 11% and 7% respectively, entries 10 − 12), which is in accordance with the facileabstraction of the hydrogens α to the oxygen. The next variable explored was the type of fluorine source.Regretably, neither the use of Selectfluor R©, nor any of the N-fluoropyridinium salts NFPY yielded thedesired fluoroalkane (Table 2.4, entries 13− 16), likely due to the poor solubility of these N−F reagentsin benzene. NFSI was the only effective fluorine transfer agent under our optimized conditions. Finally,a last screening exercise to determine which was the optimal number of equivalents of NFSI required forthis reaction was performed. In Table 2.4, entries 18 − 20, the results show that decreasing the numberof NFSI equivalents has a direct impact on the yield of fluoride 146. We determined that 5.0 equivalentsof NFSI was the optimal value. With the reaction conditions optimized, perester 151 was subjected tofluorination utilizing 5.0 equivalents of NFSI in benzene at 110 ◦C for a period of 20 min, which yieldedfluoroalkane 146 in 98% (averaged of three experiments performed separately to ensure reproducibility).55Chapter 2. Fluorine transfer to alkyl radicalsTable 2.4. Optimization of the fluorination conditions of 151.C6D6, 110 °COOOFNFSIC14H30151 146Entry Solvent Fluorine source NFSI equiv. Time (min) 146, % yielda1 C6D6 NFSI 5.0 8 542 C6D6 NFSI 5.0 16 883 C6D6 NFSI 5.0 29 654 CD3CN NFSI 5.0 16 895 Toluene−d8 NFSI 5.0 16 846 AcOEt NFSI 5.0 16 747 Acetone−d6 NFSI 5.0 16 558 Methanol−d4 NFSI 5.0 16 459 D2O NFSI 5.0 16 4310 Dioxane NFSI 5.0 16 2011 Et2O NFSI 5.0 16 1112 THF NFSI 5.0 16 713 C6D6 SelectfluorR© 5.0 16 014 C6D6 NFPY BF–4 5.0 16 015 C6D6 NFPY TfO– 5.0 16 016 C6D6 2,4,6-trimethyl NFPY BF–4 5.0 16 017 C6D6 NFSI 1.0 16 6818 C6D6 NFSI 2.0 16 8319 C6D6 NFSI 3.0 16 8620 C6D6 NFSI 4.0 16 8521 C6D6 NFSI 5.0 20 98ba Quantified via gas chromatography. b Average of 3 experiments performed under the same conditions.The next substrate we investigated was t-butylperester 152, which would generate a benzylic radi-cal upon thermal homolysis. This substrate was particularly interesting to us since it is known that ametabolic pathway of Cytochrome P450 targets the oxidation of the benzylic position of different drugs.This metabolic pathway is blocked when a fluorine atom is present instead of a hydrogen in this position.At this stage, the project was formally joined by my colleague Claire Chatalova Sazepin, who per-formed the synthesis and characterization of perester 152. I received a sample of secondary perester152 and performed its fluorination utilizing the optimized conditions for perester 151. A time optimiza-tion was the only one performed for this substrate (Table 2.5). GC analysis showed that reaction timeslower than 13 min (entries 1− 2), afforded fluoroalkane 148 in ∼ 36%. After 15 min, the yield slightlyimproved to 42% (entry 3). Longer reaction times (30 min, entry 4) depleted the reaction yield, likely56Chapter 2. Fluorine transfer to alkyl radicalsdue to degradation of the generated fluoroalkane 148 under the reaction conditions. The average yieldwas determined to be 40%. Later in the investigation, the project was also joined by our colleague J.C. T. Leung. He performed optimization studies on perester 152 utilizing acetonitrile as the solvent andachieved a yield of 45% after 5 min.138Table 2.5. Optimization of the fluorination conditions of 152.C6D6, 110 °COOOFNFSIC14H30152 148Entry Time (min) 148, % yield a1 7.6 362 12 373 15 424 30 265 16 40 ba Quantified via gas chromatography.b Average of 3 experiments performed under the same conditions.Investigation of the reactivity of a tertiary perester under our fluorination reaction conditions wasappealing to us because tertiary fluoroalkanes are challenging targets to achieve via a simple SN2 dis-placement for steric reasons. Radical mediated processes have no restriction towards the use of tertiaryradicals to perform substitution reactions. We expected to provide an alternative method for the fluori-nation at sterically encumbered positions.Once again, our team work allowed access to tertiary perester 153, which proved to be a difficultsubstrate to synthesize due to its ease of decomposition. My colleague C. Chatalova Sazepin completedthe synthesis of perester 153, and I subjected the sample to the established fluorination conditions, whichafforded a yield above 99% by GC. Several trials confirmed the reproducibility of the method and anaverage yield of 98% for fluoroalkane 154 was determined (Scheme 2.29).C6D6, 110 °COOONFSIC14H30F98%153 154Scheme 2.29. Fluorination of t-butylperester 153. The yield was quantified via gas chromatography, and itreflects the average of 3 experiments performed under the same conditions..57Chapter 2. Fluorine transfer to alkyl radicalsOther peresters were synthesized, studied and optimized by C. Chatalova Sazepin and J. C. T. Le-ung. A summary of the results obtained utilizing t-butylperesters as radical precursors is shown inScheme 2.30.138 Simultaneously, I pursued larger molecular targets in order to prove the practicalityof this methodology in the context of late stage synthesis and not only in small substrates. The results ofmy investigation will be presented in Section 2.6.Solvent, 110 °Ct-Butylperester FluoroalkaneOOOR3R2NFSIFF F FNOOFR1FR3R2R1O F24%98% (benzene)86% (acetonitrile) * 98%57% *44% (benzene) **57% (acetonitrile) **45% **  * Optimized by C. Chatalova Sazepin.** Optimized by J. C. T. Leung.140 146 154 148155 156Scheme 2.30. Summary of the fluorination results obtained using t-butylperesters as radical precursors.1382.6 Large molecule targets: the synthesis of cholic fluoroalkane 159To illustrate the utility of our methodology in the context of a natural product or late stage synthesis,we investigated the fluorination of cholic acid (157), a bile acid produced in the liver from cholesterol.Initial trials to directly synthesize the t-butylperester of cholic acid without protecting groups provedunsuccessful, so further transformations were performed to accomplish the synthesis of an appropriateradical precursor.The preparation of the secondary t-butylperester 158 is summarized in Scheme 2.31. It started withthe protection of the three hydroxyl groups present in cholic acid (157) as methyl esters, under sodiumhydride and methyl iodide conditions. Subsequent treatment of the resulting permethylated cholic acidwith thionylchloride in methanol, afforded the corresponding methyl ester. The resulting ester was sub-jected to α-methylation using LDA and methyl iodide. Saponification followed by DCC coupling of the58Chapter 2. Fluorine transfer to alkyl radicalsresulting acid with t-butylhydroperoxide provided 158 as white flake-shaped crystals. This perester wasstable at ambient temperature in its solid form, but rapidly decomposed in solution. To minimize decom-position, this particular substrate had to be immediately purified through flash column chromatographyutilizing low boiling point solvents, namely petroleum ether and diethyl ether, to facilitate the solventremotion at reduced pressure and ambient temperature. The overall yield of the synthesis was 9% ofperester 158 over 5 steps.1) NaH, CH3I, THF, 0°C2) SOCl2, CH3OH, 0 °C3) LDA, CH3I, THF, -78 °C4) NaOH, CH3OH5) TBHP, DCC, DMP, CH2Cl2HOHOHOHOOHHHHOHOOOOHHHOCholic acid157 158Scheme 2.31. Synthesis of t-butylperester derived from cholic acid.The first exploratory fluorination reaction of t-butylperester 158 was performed under the previouslyestablished reaction reaction conditions (5.0 equivalents of NFSI, 0.2 m solution of 158 in deuteratedbenzene at 110 ◦C over 1 h). 1H NMR as well as low resolution mass spectra (LRMS) analysis of thecrude reaction mixture provided evidence of the generation of 159, as early as 20 min into the reaction,even if only in small amounts.Optimization of the fluorination reaction conditions for this particular substrate ensued, utilizing1H NMR spectroscopic analysis as the quantifying method of choice and CF3CO2Et as internal standard(Table 2.6). The reaction wasmonitored at different reaction times, and after 4min and 13min (Table 2.6,entries 1 and 2) no fluoroalkane 159 was observed by 1H NMR. Modifying the concentration from 0.21m to 0.10m showed that fluoroalkane 159was being generated after 5min, 10min and 31min (Table 2.6,entries 3 − 5), albeit in low yields. Longer reaction times yielded no fluoroalkane 159 (entries 6 and7). Decreasing the concentration to 0.05 m provided only a slight improvement in the reaction yield(Table 2.6, entries 8 − 11). These results were important because they show that while 159 was beingformed under the reaction conditions, it was simultaneously being consumed or degraded through anundesired pathway under the reaction conditions.59Chapter 2. Fluorine transfer to alkyl radicalsTable 2.6. Optimization of the fluorination conditions of 158.NFSISolvent, 110 °COHOOOOHHHOHOOHHHFO158 159Entry Temp. (◦C) Solvent Conc. (m) NFSI equiv. Time (min) 159, % yield a1 110 C6D6 0.21 5.0 4 02 110 C6D6 0.21 5.0 13 03 110 C6D6 0.10 5.0 5 34 110 C6D6 0.10 5.0 10 65 110 C6D6 0.10 5.0 31 96 110 C6D6 0.10 5.0 45 07 110 C6D6 0.10 5.0 62 08 130 C6D6 0.05 5.0 6 129 130 C6D6 0.05 5.0 10 1410 130 C6D6 0.05 5.0 14 1211 110 C6D6 0.05 5.0 13 612 110 C6D6 0.05 2.0 20 3213 110 C6D6 0.05 2.0 25 2814 110 C6D6 0.05 2.0 30 2515 110 CD3CN 0.10 1.0 65 3116 110 CD3CN 0.10 2.0 65 7017 110 CD3CN 0.10 3.0 65 69b18 110 CD3CN 0.10 4.0 65 4319 130 CD3CN 0.10 3.0 17 4420 130 CD3CN 0.10 3.0 31 72a Quantified via 1H NMR utilizing CF3CO2Et as internal standard.b Average of 3 experiments performed underthe same conditions.A TLC analysis of the reaction mixtures of these different reactions showed the presence of a sec-ondary product. Flash column chromatography purification of these reaction mixtures allowed the iso-lation of a small amount of this secondary product enough to perform a mass spectroscopy analysis.LRMS showed that the product had a molecular ion of [M +Na]+ = 441 (m/z), which corresponds to159 minus HF (Scheme 2.32, 160). It would appear that an elimination reaction takes place at longerreaction times under the reaction conditions.60Chapter 2. Fluorine transfer to alkyl radicalsC6H6, 110 °COHOFOHHHOHOOHHHOHOOHHHorNSO2PhPhO2SH[M + Na] = 441 m/z159 160161Scheme 2.32. Undesired elimination pathway for fluoroalkane 159.My colleague J. C. T. Leung had earlier determined that after the fluorination reaction takes place, thebisbenzenesulfonimidyl fragment gives rise to bisbenzenesulfonimide (NHSI, 161), which could act as abase in the elimination reaction. Addition of up to 2.0 equiv. of pivalic acid to suppress the eliminationreaction had no effect on the yield of 159.The next variable explored was the number of equivalent of NFSI in the reaction. When a 0.05 m so-lution of 158 in benzene was treated with only 2.0 equiv. of NFSI, 159 was generated in 32% after 20min (Table 2.6, entry 12). Longer reaction times (25 min and 30 min) showed a decrease in the yield(entries 13 and 14). Previous experiments had demonstrated that acetonitrile was a suitable candidateto substitute benzene in our fluorination reaction (see Table 2.4, entry 4). Hence, a 0.1 m solution ofthe substrate in acetonitrile was heated to 110 ◦C for 1 h, while simultaneously varying the number ofequivalents of NFSI. The yields observed ranged from 31% to 71% (Table 2.6, entries 15 − 18), withthe best results recorded when 2.0 and 3.0 equivalents of NFSI were used. Notably, the generation ofby-product 160 was effectively minimized under the acetonitrile conditions. A final temperature investi-gation revealed that even though similar yields were obtained 130 ◦C in half the reaction time (72% yield,Table 2.6, entries 20), larger amounts of the undesired product 160 were also observed. The optimizedtemperature was kept at 110 ◦C. The reaction was performed several times to ensure reproducibility.The average yield was established to be 69% (Table 2.6, entry 17), determined through 1H NMR analy-sis utilizing CF3CO2Et as internal standard.The final task now was to isolate 159. All the optimization reactions had been performed so far ina 0.1 mmol scale. We decided to use a 0.5 mmol scale reaction to perform the isolation of the desiredfluoroalkane. The fluorination of 158 was then performed with 3.0 equiv. of NFSI in acetonitrile at110 ◦C for 1.0 h. The solvent was removed by reduced pressure rotary evaporation. Purification of theresulting fluoroalkane was performed using flash column chromatography with a hexanes/ethyl acetate61Chapter 2. Fluorine transfer to alkyl radicalsgradient, yielded 159 in 24% yield. Considering the 1H NMR yield was determined to be 69% under thesame reaction conditions, it was surprising that we were able to obtain an isolated yield of only 24%.The use of an automated Biotage column purification system, again using a hexanes/ethyl acetateas the elution system provided a yield of 22%. Subsequent purification trials utilizing basified silica inthe automated Biotage column with a hexanes/ethyl acetate/triethylamine gradient yielded 24% of 159.Changing the stationary phase from silica to alumina resulted in the lose of the product. However, theuse of Florisil R© utilizing a 4:1 hexanes/ethyl acetate eluent system resulted in an isolated yield of 51%.The use of the Biotage automated column (previously previously treated with triethylamine) witha gradient of hexanes/ethyl acetate was ultimately used by my colleague J. C. T. Leung to achieve anisolated yield of 54% of fluoroalkane 159.2.7 ConclusionWe have successfully demonstrated that electrophilic N−F sources of fluorine can be used as fluorineatom sources in selective fluorination via radical processes. More importantly, our contribution openedup the field of fluorination through radical mechanisms for the scientific community to perform furtherexplorations. Indeed, immediately after our initial report different research groups have utilized N−Freagents as fluorine atom sources in various radical reactions.162–165 Our methodology nicely comple-ments the already existing polar methodologies to generate C−F bonds utilizing mild reaction conditions.Diacyl peroxides as well as t-butylperesters were effectively utilized as alkyl radical precursors un-der thermal and photochemical conditions. The generated radicals included primary, secondary andtertiary carbon species, which in the presence of N-fluorobenzensulfonimide provided the correspond-ing monofluoralkanes in a selective and safe manner. The yields ranged from ∼ 25% to > 95% yielddepending on the substitution pattern. The use of t-butylperesters minimized the radical recombinationobserved in diacyl peroxides. Additionally, the effective generation and isolation of cholic acid derivative159, illustrated the applicability of this methodology in late stage and natural product synthesis. More-over, it was demonstrated that the fluorination reaction can proceed in solvents other than benzene, suchas acetonitrile and toluene.2.8 Experimentals2.8.1 General experimentalAll reactions were performed under nitrogen atmosphere in flame-dried glassware unless otherwisenoted. Benzene and dichloromethane were obtained from a MBRAUN MB-SPS solvent purification62Chapter 2. Fluorine transfer to alkyl radicalssystem. All other solvents were used without further purification. Preparatory TLC was performed onAnaltech GF UV254 pre-coated silica gel plates (20×20 cm, 2000 µm). Automated flash chromatogra-phy was performed on a Biotage Isolera Four. All chemicals were purchased from commercial sourcesand used as received.Infrared (IR) spectra were obtained using a ThermoNicolet 4700 FT-IR spectrometer. Proton nuclearmagnetic resonance (1H NMR) spectra were recorded using a Bruker AV-300 or AV-400 spectrometer.Fluorine nuclear magnetic resonance (19F NMR) spectra were recorded using a Bruker AV-300. Car-bon nuclear magnetic resonance (13C NMR) spectra were recorded using a Bruker AV-300 or AV-400spectrometer. Chemical shifts are reported in parts per million (ppm) and are referenced to the center-line of deuterochloroform (7.27 ppm 1H NMR; 77.0 ppm 13C NMR), benzene-d6 (7.16 ppm 1H NMR;128.1 ppm 13C NMR), or acetonitrile-d3 . Fluorine NMR (19F NMR) spectra were calibrated relativeto NFSI. High resolution mass spectra (HRMS) were recorded on either a Waters or Micromass LCTspectrometer.GC analyses were performed using a Varian CP-3800 Gas Chromatograph, equipped with an au-tosampler (10 µL syringe, 5.0 µL injection). GC-FID analysis: temperature-gradient oven (start at 80◦C for 1 min, then gradient from 80 ◦C to 300 ◦C at 30 ◦C/min), 250 ◦C injector temperature, 1.0mL/min flow, He carrier gas, FactorFourTM Capillary Column VF-5ms (30 m x 0.25 mm, 0.25 µm),300 ◦C front detector temperature.Photochemical experiments were performed in a Rayonet Photochemical Reactor, using RayonetPhotochemical Reactor Lamps of 3000 A˚ for homogenic irradiation of the samples. The internal tem-perature was maintained within a 40-60 ◦C range with the aid of an integrated mechanical ventilationsystem.2.8.2 Synthesis of fluoroalkane standards2.8.2.1 General fluoroalkane synthesis procedure.147R OHCH2Cl2, 0 °CR'R FR'NSFFFTo a 0.33 M solution of the corresponding alcohol (1.0 equiv.) in dry dichloromethane at 0 ◦C, wasadded dimethylaminosulfur trifluoride (1.05 equiv.) in one portion using a plastic needleless syringe.The resulting solution was stirred for 30 min at 0 ◦C, allowed to warm to ambient temperature, and63Chapter 2. Fluorine transfer to alkyl radicalspoured over approx. 25 g of crushed ice. Once the ice melted, the organic phase was separated and theaqueous phase was extracted with dichloromethane (3 x 10 mL). The combined organic extracts werewashed with brine (10 mL), dried over Na2SO4, and filtered. The solvent was then removed by rotaryevaporation. Kugelrohr distillation afforded the corresponding fluoride.The fluoroalkane standards were utilized as authentic samples for NMR spectroscopy comparisonand for GC calibration curves.F1211-Fluoroundecane (121). 1-Undecanol (176 mg, 1.02 mmol) was subjected to the general fluo-roalkane standard synthesis procedure. Kugelrohr distillation (10 mmHg) afforded fluoride 121 as aclear colorless oil (73 mg, 0.42 mmol) in 28% yield. The compound obtained matched literature char-acterization data.166F140(3-Fluoropropyl)benzene (140). 3-Phenylpropan-1-ol (205 mg, 1.51 mmol) was subjected to thegeneral fluoroalkane standard synthesis procedure. Kugelrohr distillation (40 mmHg) afforded fluoride140 as a clear colorless oil (28 mg, 0.20 mmol) in 13% yield. 19F NMR (282 MHz): δ -180.8 ppm. Thecompound obtained matched literature characterization data.166F146(3-Fluorobutyl)benzene (146). 4-Phenylbutan-2-ol (91 mg, 0.61 mmol) was subjected to the gen-eral fluoroalkane standard synthesis procedure. Kugelrohr distillation (30 mmHg) afforded fluoride 146as a clear colorless oil in a quantitative yield. 19F NMR (282 MHz): δ -139.7, -174.5 ppm. The com-pound obtained matched literature characterization data.167,16864Chapter 2. Fluorine transfer to alkyl radicalsF154(3-Fluoro-3-methylbutyl)benzene (154). 2-Methyl-4-phenylbutan-2-ol (0.986 g, 6.00 mmol) wassubjected to the general fluoroalkane standard synthesis procedure. Distillation at reduced pressure, fol-lowed by flash chromatography (100% hexanes) yielded fluoride 154 in a 2% yield. Theminor impuritiesobserved derive from elimination. The compound obtained matched literature characterization data.169F148(1-Fluoroethyl)benzene (148). 1-Phenylethanol (127 mg, 1.04 mmol) was subjected to the generalfluoroalkane standard synthesis procedure. Kugelrohr distillation (20-30 mmHg) afforded fluoride 148as a clear colorless oil (57 mg, 0.46 mmol) in 44% yield. 19F NMR (282 MHz): δ -167.5 ppm. Thecompound obtained matched literature characterization data.1702.8.3 Quantification utilizing gas chromatographyCalibration curve construction: To quantify, it was necessary to construct calibration curves. Thecalibration standard solutions are prepared with a varying, known concentration of analyte (fluoroalkane)and a constant amount of the internal standard (tetradecane, C14H30). The curves were constructed using6 standards with concentrations ranging from 1.25 × 10−3m to 3.0 × 10−2m. The construction of thecalibration curves was performed by plotting the ratio of the internal standard to analyte as a functionof the analyte concentration. The same amount of internal standard added to the calibration standardsis added to the blank and the reaction mixture. Upon analysis of the sample, the concentration wascalculated using the ratio of analyte to internal standard, which is then extrapolated in the previouslyconstructed calibration curve plot. The internal standard and all fluoroalkanes showed clearly resolvedunder the GC conditions used.Sample preparation: To perform the analysis of the reaction mixture by GC, each reaction wasstirred for at least 5 min and then filtered through celite (washed with∼ 0.2 mL of C6D6) to remove anysolids. The filtrate was then diluted (0.1 mL of filtrate in 0.9 mL of C6H6), and the resulting solution65Chapter 2. Fluorine transfer to alkyl radicalswas homogenized using a vortex apparatus. The samples were then run on the GC using an automatedsyringe for the injection (0.5 µL injected per run).Reaction Analysis: Calibration curves were prepared between the internal standard (tetradecane,C14H30) and independently prepared alkyl fluorides. Each calibration curve consisted of 5 to 6 datapoints, with alkyl fluoride concentrations ranging from 0.00125 m to 0.03 m. A constant 0.01 m con-centration of tetradecane was maintained in all samples. In all cases, the correlation coefficient (r2)was greater than 0.99. The concentration of fluoride product was calculated using the regression equa-tions obtained from the calibration curve. The conversions were calculated based on the known initialconcentration of radical precursor added to each trial. For lauroyl peroxide, the yields are based on theformation of two undecyl radicals for every molecule of lauroyl peroxide.To confirm the accuracy of the yields, an additional method of yield quantification was examined.Separate calibration curves were prepared between the internal standard and the radical precursor (i.e.lauroyl peroxide or perester). As before, each calibration curve consisted of 5 to 6 data points, with radicalprecursor concentrations ranging from 0.00125 m to 0.03 m (a constant 0.01 m concentration of tetrade-cane was maintained in all samples). During GC analysis, lauroyl peroxide and the peresters underwentfragmentation and a slight variation in the distribution of products was observed during successive runs.Regardless, most of the conversions matched the prior method of analysis within ±5%.2.8.4 Synthesis of acids 150 and 164.OHO SOCl2CH3OH, 0 °COCH3OOCH3O LDA, CH3ITHF, -78 °COCH3OCH3137162162149Synthesis of methyl 2-methyl-4-phenylbutanoate (149).171,172 To a solution of 4-phenylbutyricacid (137, 3.01 g, 18.33 mmol) in 200 mL of methanol at 0 ◦C was added thionyl chloride (2.7 mL, 3.32g, 37.22mmol) over 5min. The solution was stirred for 15min at 0 ◦C, then allowed to warm to ambienttemperature. A second addition of thionyl chloride (2.7 mL, 3.32 g, 37.22 mmol) was performed, andthe reaction was left to stir for an additional 18 h. The reaction was quenched with saturated solutionof NaHCO3(aq) (15 mL). Rotary evaporation to remove the methanol was followed by extraction with66Chapter 2. Fluorine transfer to alkyl radicalsdiethyl ether (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried overNa2SO4 and filtered. The solvent was removed through rotary evaporation. The identity of the productwas confirmed by 1H NMR and was used for the following reaction without further purification.To a solution of diisopropylamine (1.8 mL, 1.29 g, 12.8 mmol) in 14.0 mL of dry tetrahydrofuranat -78 ◦C was added 1.38 M solution of n-butyllithium in hexanes (8.5 mL, 11.7 mmol). The resultingclear solution was stirred at -78 ◦C for 30 min. To this mixture was transfered via cannula a solution ofmethyl 4-phenylbutanoate 162 (1.82 g, 10.2 mmol) in 17 mL of dry THF, and the reaction was stirredfor 30 min at -78 ◦C. Methyliodide (1.9 mL, 4.33 g, 30.5 mmol) was then added in one portion and theresulting solution was stirred at ambient temperature for 18 h. The reaction was quenched with saturatedsolution of NH4Cl(aq) (15 mL), diluted with H2O (10 mL), and extracted with diethyl ether (3 x 10mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, and filtered.The solvent was then removed using rotary evaporation. Flash column chromatography purification (9:1hexanes/ethyl acetate) yielded methyl 2-methyl-4-phenylbutanoate (149) as a yellow oil (1.68 g, 8.75mmol) in 86% yield. 1H NMR (300 MHz; CDCl3): δ 7.27 (dt, J = 28.1, 6.5 Hz, 5H), 3.71 (s, 3H), 2.65(t, J = 7.9 Hz, 2H), 2.51 (t, J = 6.9 Hz, 1H), 2.05 (dd, J = 13.6, 7.7 Hz, 1H), 1.79-1.72 (m, 1H), 1.23(d, J = 7.0 Hz, 3H). 13C NMR (75 MHz; CDCl3): δ 177.1, 141.7, 128.5, 128.5, 126.0, 51.7, 39.1, 35.5,33.6, 17.2. IR (neat): 3027, 2973, 2979, 1736, 1600, 1496, 1455, 1378, 1203, 1162 cm−1. HRMS-ESI(m/z) [M+Na]+ calcd for C12H16O2Na: 215.1048. Found: 215.1054.OCH3O2.0 M NaOH(aq)CH3OH, refluxOHOCH3CH3149 150Synthesis of 2-methyl-4-pheynylbutanoic acid (150). To a 0.8 M solution of methyl 2-methyl-4-phenylbutanoate (149) (1.68 g, 8.75 mmol) in methanol, was added a 15% w/w NaOH(aq) solution (12mL, 45 mmol). The resulting reaction was heated to reflux (80 ◦C) and stirred for 18 h. The reactionwas allowed to cool to ambient temperature. The reaction was then concentrated under reduced pressureand the resulting solution was washed with diethyl ether. The organic phase was discarded, and theaqueous phase was acidified with a 10% HCl(aq) until the pH ≤ 2, then extracted with diethyl ether(3x10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, andfiltered. The solvent removed via rotary evaporation to yield 2-methyl-4-phenylbutanoic acid (150) (1.30g, 7.25 mmol) as yellow dark oil in 83% yield. 1H NMR (400 MHz; CDCl3): δ 7.35-7.23 (m, 5H), 2.7267Chapter 2. Fluorine transfer to alkyl radicals(t, J = 7.8 Hz, 2H), 2.56 (q, J = 7.0 Hz, 1H), 2.12-2.07 (m, 1H), 1.82-1.77 (m, 1H), 1.28 (d, J = 7.0 Hz,3H).OCH3O LDA, CH3ITHF, -78 °COCH3OCH3CH3 H3C149 163Synthesis of methyl 2,2-dimethyl-4-phenylbutanoate (163).173 To a solution of diisopropylamine(0.28 mL, 200 mg, 1.96 mmol) in 5.0 mL of dry tetrahydrofuran at -78 ◦C, was added a 1.38 M solutionof n-butyllithium in hexanes (1.4 mL, 1.96 mmol). The resulting solution was warmed to -10 ◦C andstirred for 20 min. The reaction mixture was then cooled back to -78 ◦C, and a solution of methyl 2-methyl-4-phenylbutanoate (149) (190 mg, 0.98 mmol) in 1.5 mL of dry tetrahydrofuran was added inone portion. The resulting solution was warmed to -10 ◦C, stirred for 20 min, and then cooled backto -78 ◦C. A mixture of methyliodide (90 µL, 1.47 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 20 µL, 1.96 mmol) in 5.0 mLof dry tetrahydrofuran was cooled to -78 ◦C andthen added drop wise over 2 min. The reaction mixture was allowed to warm to ambient temperatureand stirred for an additional 45 min. The reaction was quenched with a saturated solution of NH4Cl(aq)(15 mL) and extracted with diethyl ether (3x15 mL). The combined organic extracts were washed withbrine (10 mL), dried over Na2SO4, and filtered. The solvent was then removed by rotary evaporation.Flash column chromatography purification (10:1 hexanes/ethyl a cetate) yielded methyl 2,2-dimethyl-4-phenylbutanoate (163) as a clear colorless oil (24 mg, 0.12 mmol) in 12% yield. 1H NMR (300 MHz;CDCl3): δ 7.33-7.18 (m, 5H), 3.70 (s, 3H), 2.56 (dt, J = 8.0, 4.3 Hz, 2H), 1.87 (dt, J = 8.1, 4.3 Hz,2H), 1.27 (s, 6H). 13C NMR (75 MHz; CDCl3): δ 170.8, 142.4, 128.5, 128.5, 125.9, 51.9, 42.9, 42.5,31.7, 25.4, 10.0. IR (neat): 3027, 2970, 2950, 1732, 1497, 1474, 1455, 1434, 1257, 1193, 1174 cm−1.HRMS-ESI (m/z) [M+Na]+ calcd for C13H18O2Na: 229.1204. Found: 229.1203.OCH3O2.0 M NaOH(aq)CH3OH, refluxOHOCH3CH3 H3CH3C163 164Synthesis of 2,2-dimethyl-4-phenylbutanoic acid (164). To a 0.8M solution ofmethyl 2,2-dimethyl-4-phenylbutanoate (163) (24 mg, 0.12 mmol) in methanol, was added a 15% w/w NaOH(aq) solution(0.16 mL, 0.58 mmol). The resulting reaction was heated to reflux (80 ◦C) and stirred for 18 h. The68Chapter 2. Fluorine transfer to alkyl radicalsreaction was allowed to cool to ambient temperature. The reaction was concentrated under reduced pres-sure and the resulting solution was washed with diethyl ether. The organic phase was discarded, and theaqueous phase was acidified with a 10% HCl(aq) until the pH ≤ 2, then extracted with diethyl ether(3x10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, andfiltered. The solvent removed via rotary evaporation to yield 2,2-dimethyl-4-phenylbutanoic acid (164)(14 mg, 0.07 mmol) as a white solid in 61% yield. melting point (m. p.): 93-95 ◦C. 1H NMR (300MHz; CDCl3): δ 7.33-7.18 (m, 5H), 2.64 (dt, J = 8.2, 4.3 Hz, 2H), 1.90 (dt, J = 8.2, 4.3 Hz, 2H), 1.32(s, 6H). 13C NMR (75 MHz; CDCl3): δ 170.1, 142.2, 128.5, 128.5, 126.0, 42.6, 42.4, 31.6, 25.2. IR(neat): 3063, 3022, 2970, 2933, 2872, 1690, 1496, 1473, 1451, 1324, 1270, 1205 cm−1. HRMS-ESI(m/z) [M+Na]+ calcd for C12H16O2Na: 215.1048. Found: 215.1046.2.8.5 Synthesis of t-butylperesters2.8.5.1 General t-butyl perester synthesis procedure.174CH2Cl2, 0 °CROHOOHO+DCC, DMAPnROOnOTo a 0.1M solution of the corresponding carboxylic acid (1.0 equiv.) in dichloromethane, was added acatalytic amount (0.05 to 0.1 equiv.) of DMAP, followed by a 70% w/w solution of t-butylhydroperoxidein H2O (1.05 equiv.). The reaction mixture was cooled to 0◦C and stirred for 5 min. To the reactionmixture was added a 0.2 M solution of dicyclohexylcarbodiimide (DCC, 1.1 equiv), and the resultingmixture was stirred at 0 ◦C for 30 min, then at room temperature for 18 h. The reaction mixture wasfiltered through a small plug of silica to remove solids and polar impurities.OOO139t-Butyl 4-phenylbutaneperoxoate (139). 4-Phenylbutyric acid (137, 2.01 g, 12.2 mmol) was sub-jected to the general t-butyl per ester synthesis procedure. After filtration through the silica plug, thesolvent was removed by rotary evaporation. Flash column chromatography purification (10:1 petroleumether/diethyl ether) afforded perester 139 as a clear colorless oil in 96% yield. 1H NMR (300 MHz;CDCl3): δ 7.34-7.20 (m, 5H), 2.71 (t, J = 7.6 Hz, 2H), 2.36 (t, J = 7.4 Hz, 2H), 2.03 (quintet, J = 7.5Hz, 2H), 1.35 (s, 9H). 13C NMR (75 MHz; CDCl3): δ 170.9, 141.0, 128.5, 126.2, 83.4, 35.1, 30.6, 26.6,69Chapter 2. Fluorine transfer to alkyl radicals26.2. IR (neat): 3027, 2982, 2984, 1774, 1797, 1454, 1389, 1366, 1188, 1102.81 cm−1. HRMS-ESI(m/z) [M+Na]+ calcd forC14H20O3Na: 259.1310. Found: 259.1305.OOOCH3151t-Butyl 2-methyl-4-phenylbutaneperoxoate (151). 2-Methyl-4-phenylbutanoic acid (150, 1.29 g,7.25mmol) was subjected to the general t-butyl per ester synthesis procedure. After filtration through thesilica plug, the solvent was removed by rotary evaporation. Flash column chromatography purification(9:1 petroleum ether/diethyl ether) afforded perester 151 as a pale yellow oil in 84% yield. 1H NMR (300MHz; CDCl3): δ 7.31 (t, J = 7.4 Hz, 2H), 7.24-7.19 (m, 3H), 2.74-2.61 (m, 2H), 2.59-2.51 (m, 1H), 1.78(ddt, J = 13.3, 9.5, 6.5 Hz, 2H), 1.37 (s, 9H), 1.27 (d, J = 7.0 Hz, 3H). 13C NMR (75 MHz; CDCl3): δ173.9, 141.5, 128.6, 128.6, 126.2, 83.5, 37.1, 35.7, 33.6, 26.4, 17.7. IR (neat): 3027, 2981, 2933, 1773,1497, 1754, 1366, 1191, 1077 cm−1. HRMS-ESI (m/z) [M+Na]+ calcd for C15H22O3Na: 273.1467.Found: 273.1471.2.8.6 General fluorination procedureTo a Biotage microwave vial charged with commercially available N-fluorobenzenesulfonimide (NFSI, 5equiv.) under N2 was added a 0.21 m stock solution of the radical precursor (lauroyl peroxide or perester,1 equiv.) and internal standard (tetradecane, 5 equiv. for GC or ethyl trifluoroacetate 1 equiv. for NMR)in benzene−d6 or acetonitrile−d3. For each reaction, 0.3 mL of the initial stock solution was kept todetermine initial concentrations of substrate and internal standard (t0). The vial was sealed and thereaction was heated to reflux (or placed in a sealed NMR tube, inside a photoreactor and irradiated with300 nm UV light).OOOO9 9NFSIC14H30C6H6, 110 °CF9120 121Thermal radical fluorination of lauroyl peroxide to afford 1-fluoroundecane (121): Lauroyl per-oxide (120) (25 mg, 0.06 mmol) was subjected to the general radical fluorination procedure in C6D6.The reaction vial was placed in an oil bath, heated to 110 ◦C and the reaction was stirred for 4 h. 1HNMR spectroscopic analysis of the crude reaction mixture indicated the presence of 1-fluoroundecane70Chapter 2. Fluorine transfer to alkyl radicals(121). The reaction was repeated 3 times, with GC yields of 24%, 17%, and 18%, or 20% average overthe three trials.OOOO9 9NFSIC14H30C6H6hν = 300 nmF9120 121Photochemical radical fluorination of lauroyl peroxide to afford 1-fluoroundecane (121): Lau-royl peroxide (120) (25 mg, 0.06 mmol) was subjected to the general photochemical radical fluorinationprocedure. The reaction vial was placed in an NMR tube inside the photoreactor and irradiated with300 nm UV light for 4 h. 1H NMR spectroscopic analysis of the crude reaction mixture indicated thepresence of 1-fluoroundecane (121). The reaction was repeated 3 times, with GC yields of 37%, 33%,32%, or an 34% average over the three trials.C6D6, 110 °COOOFNFSIC14H30139 140Thermal radical fluorination to afford (3-fluoropropyl)benzene (140): Perester 139 (15 mg, 0.06mmol) was subjected to the general radical fluorination procedure in C6D6. The reaction vial was placedin an oil bath, heated to 110 ◦C and the reaction was stirred for 13 h. 1H NMR spectroscopic analysisof the crude reaction mixture indicated the presence of 3-fluoropropyl)benzene (140). The reaction wasrepeated 3 times, with GC yields of 26%, 19%, and 27%, or 24% average over the three trials.C6D6, 110 °COOONFSIC14H30F151 146Thermal radical fluorination to afford (3-fluorobutyl)benzene (146): Perester 151 (16 mg, 0.06mmol) was subjected to the general radical fluorination procedure in C6D6. The reaction vial was placedin an oil bath, heated to 110 ◦C and the reaction was stirred for 20 min. 1H NMR spectroscopic analysisof the crude reaction mixture indicated the presence of (3-fluorobutyl)benzene (146). The reaction wasrepeated 3 times, with GC yields of 99%, 99%, and 96%, or 98% average over the three trials.71Chapter 2. Fluorine transfer to alkyl radicalsC6D6, 110 °COOONFSIC14H30F153 154Thermal radical fluorination to afford (3-fluoro-3-methylbutyl)benzene (154): Perester 153 (6mg, 0.02 mmol) was subjected to the general radical fluorination procedure in C6D6. The reaction vialwas placed in an oil bath, heated to 110 ◦C and the reaction was stirred for 15 min. 1H NMR spectro-scopic analysis of the crude reaction mixture indicated the presence of (3-fluoro-3-methylbutyl)benzene(154). The reaction was repeated 3 times, with GC yields of 99%, 97%, and 99%, or 98% average overthe three trials.2.8.7 Synthesis of fluoride 159NaH, CH3ITHF, 0 °CHOHOHOHOOHHHHcholic acidOHOOOOHHHH157 165Synthesis of (R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trimethoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) pentanoic acid (165): To a suspension of NaH(2.523 gof a 60% suspension in mineral oil, 63.09 mmol) in 100 mL of dry tetrahydrofuran at 0 ◦C, wasadded via cannula a solution of commercially available cholic acid (5.035 g, 12.30 mmol) in 50 mL ofdry tetrahydrofuran. The resulting solution was stirred at 0 ◦C for 10 min and then was added methyliodide (1.8 mL, 4.104 g, 28.91 mmol). The reaction mixture was stirred for 18 h at ambient temperatureand then was added a second portion of NaH (2.054 g, 51.36mmol), followed by more methyl iodide (1.5mL, 3.42 g, 24.10 mmol). The reaction was stirred for an additional 18 h at ambient temperature. Thereaction mixture was quenched by slow addition of methanol then concentrated using rotary evaporation.The resulting mixture was diluted with ethyl acetate (50 mL) and poured on water (40 mL). The aqueouslayer was then extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were washedwith brine (25 mL), dried over Na2SO4 and filtered. The solvent was then removed by rotary evaporation72Chapter 2. Fluorine transfer to alkyl radicalsand the product was suspended over silica gel. Flash column chromatography purification (3:1 to 1:2hexanes/AcOEt gradient) yielded permethylated cholic acid (165) as a white solid (3.423 g) in 62% yield.m.p. 65− 70 ◦C. 1H NMR (400 MHz; CDCl3): δ 3.35 (s, 1H), 3.33 (s, 3H), 3.25 (s, 3H), 3.20 (s, 3H),3.13 (s, 1H), 3.00 (t, J = 11.0 Hz, 1H), 2.40 (td, J = 12.7, 4.1 Hz, 1H), 2.26-2.02 (m, 4H), 1.90-1.75(m, 8H), 1.57-1.30 (m, 9H), 1.06-0.92 (m, 5H), 0.90 (d, J = 6.1 Hz, 7H), 0.65 (s, 3H). 13C NMR (101MHz; CDCl3): δ 180.1, 82.1, 80.9, 77.1, 56.0, 55.9, 55.5, 46.4, 46.3, 42.8, 42.1, 39.8, 35.4, 35.2, 35.1,34.5, 31.1, 30.9, 28.1, 27.9, 27.5, 26.8, 23.3, 23.0, 22.1, 17.5, 12.6. IR (CDCl3): 3500-2480, 2930,2870, 2820, 1708, 1454, 1371, 1102, 756 cm−1. HRMS-ESI (m/z) [M+Na]+ calcd for C27H46O5Na:473.3243. Found: 473.3236.SOCl2CH3OH, 0 °COHOOOOHHHHOHOOOOHHH165 166Synthesis of (R)-methyl 4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-tri-methoxy-10,13-di-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (166): To a solution of acid165 (1.501 g, 3.33 mmol) in 40 mL of wet methanol at 0 ◦C, was added thionyl chloride (1.5 mL, 2.46g, 20.68 mmol). The reaction mixture was stirred at 0 ◦C for 2 h, then at ambient temperature for 18h. The solvent was removed by rotary evaporation and the reaction mixture was suspended in silica gel.Flash column chromatography purification (9:1 to 4:1 hexanes/AcOEt gradient) yielded ester 166 as athick transparent oil (1.308 g) in 71% yield. 1H NMR (300 MHz; CDCl3): δ 3.66 (s, 3H), 3.33 (d, J= 6.7 Hz, 4H), 3.25 (s, 3H), 3.21 (s, 3H), 3.14 (d, J = 2.7 Hz, 1H), 3.03-2.95 (m, 1H), 2.36-1.60 (m,15H), 1.50-1.18 (m, 9H), 0.90 (d, J = 6.6 Hz, 7H), 0.65 (s, 3H). 13C NMR (101 MHz; CDCl3): δ 174.6,81.9, 80.6, 76.9, 55.7, 55.6, 55.3, 51.3, 46.1, 46.0, 42.6, 41.9, 39.6, 35.2, 35.0, 34.8, 34.4, 30.9, 30.8,27.9, 27.7, 27.3, 26.7, 23.1, 22.8, 21.9, 17.3, 12.4. IR (CDCl3): 2934, 2870, 2819, 1740, 1454, 1371,1252, 1178, 1102, 756 cm−1. HRMS-ESI (m/z) [M+Na]+ calcd for C28H48O5Na: 487.3399. Found:487.3409.73Chapter 2. Fluorine transfer to alkyl radicalsLDA, CH3ITHF, -78 °COHOOOOHHHOHOOOOHHH166 167Synthesis of (4R)-methyl 2-methyl-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trime-thoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) pentanoate (167): To asolution of diisopropylamine (0.23 mL, 0.165 g, 1.63 mmol) in 5.0 mL of dry tetrahydrofuran at -78◦C, was added a 1.025 m solution of n-buthyllithium in hexanes (1.6 mL, 1.64 mmol). The resultingsolution was stirred at -78 ◦Cfor 30 min. Then was added via cannula a solution of ester 166 (0.605 g,1.30 mmol) in 7.0 mL of dry tetrahydrofuran. The resulting solution was stirred at -78 ◦C for 45 min.Finally was added methyl iodide (0.27 mL, 0.62 g, 4.3 mmol) in one portion. The resulting solution wasstirred at -78 ◦C for 1 h, then at ambient temperature for 18 h. The reaction mixture was quenched withsaturated NH4Cl(aq) (15mL), diluted and extracted with diethylether (3 x 20mL). The combined organicextracts were washed with brine (15mL), dried over Na2SO4 and filtered. Flash column chromatographypurification (19:1 to 9:1 hexanes/AcOEt gradient) yielded ester 167 as a white solid (0.323 g) in 52%yield. 1H NMR (400 MHz; CDCl3): δ 3.66 (s, 3H), 3.36 (t, J = 2.4 Hz, 4H), 3.25 (s, 3H), 3.21 (d, J= 8.5 Hz, 3H), 3.14 (d, J = 2.9 Hz, 1H), 2.99 (s, 1H), 2.62-2.56 (m, 1H), 2.21-2.05 (m, 3H), 1.89-1.61(m, 9H), 1.49-1.45 (m, 2H), 1.26-1.18 (m, 5H), 1.14 (d, J = 6.9 Hz, 3H), 1.03-0.96 (m, 2H), 0.93-0.89(m, 7H), 0.63 (s, 3H). 13C NMR (101 MHz; CDCl3): δ 157.5, 82.2, 80.9, 77.4, 56.0, 55.9, 55.5, 51.5,47.3, 46.3, 42.8, 42.1, 41.0, 39.8, 37.3, 35.4, 35.1, 34.6, 34.6, 28.1, 27.9, 27.6, 26.9, 23.3, 23.0, 22.1,19.1, 17.8, 12.6. IR (CDCl3): 2934, 2870, 2818, 1740, 1452, 1370, 1177, 1102 cm−1. HRMS-ESI (m/z)[M+Na]+ calcd for C29H50O5Na: 501.3556. Found: 501.3553.74Chapter 2. Fluorine transfer to alkyl radicalsNaOHCH3OH, r. t.OHOOOOHHHOHOOOOHHHH167 168Synthesis of (4R)-2-methyl-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-tri-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid (168): To a solu-tion of ester 167 (0.3231 g, 0.675 mmol) in 20 mL wet methanol at ambient temperature, was added a15% w/w solution on NaOH(aq) (5.0 mL, 0.75 g, 18.8 mmol). The resulting solution was heat to refluxfor 18 h. The reaction mixture was concentrated using rotary evaporation, then diluted with ethyl acetate(20mL) and acidified with a 10%HCl(aq) solution (15mL). The mixture was extracted with ethyl acetate(2 x 20 mL) and the combined organic extracts were washed with brine (15 mL), dried over Na2SO4,filtered. The solvent was removed by rotary evaporation to yield a yellow oil, which was suspended oversilica gel. Flash column chromatography purification (9:1 to 7:1 hexanes/AcOEt gradient) yielded acid16 as a white solid (0.152 g) in 48% yield. m.p. 86-89 ◦C. 1H NMR (400 MHz; CDCl3): δ 3.35 (s,1H), 3.32 (s, 3H), 3.24 (s, 3H), 3.19 (s, 3H), 3.12 (s, 1H), 2.99 (s, 1H), 2.58 (s, 1H), 2.22-1.99 (m, 3H),1.76 (ddd, J = 41.3, 28.4, 12.8 Hz, 9H), 1.49 (td, J = 29.9, 12.4 Hz, 4H), 1.32-1.16 (m, 10H), 1.02-0.88(m, 11H), 0.62 (s, 3H). 13C NMR (101 MHz; C6D6): δ 183.3, 82.1, 80.9, 77.1, 56.0, 55.8, 55.4, 47.3,46.3, 42.8, 42.1, 40.8, 39.8, 37.3, 35.4, 35.0, 34.6, 34.5, 28.1, 27.9, 27.6, 26.8, 23.3, 23.0, 22.1, 19.0,17.8, 12.6. IR (CDCl3): 3480-2350, 2935, 2871, 2821, 1706, 1465, 1372, 1184, 1102, 909, 757 cm−1.HRMS-ESI (m/z) [M+Na]+ calcd for C28H48O5Na: 487.3399. Found: 487.3402.75Chapter 2. Fluorine transfer to alkyl radicalsTBHP, DCC, DMAPCH2Cl2, 0 °COHOOOOHHHHOHOOOOHHHO168 158Synthesis of (4R)-tert-butyl 2-methyl-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trime-thoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) pentaneperoxoate (158):To a solution of acid 168 (0.199 g, 0.427 mmol) and 4-dimethylamino pyridine (12 mg, 0.10 mmol) in5.0 mL of dichloromethane at 0 ◦C, was added a 70% solution of TBHP in H2O (0.1 mmol, 0.063g, 0.70 mmol), followed by a solution of dicyclohexylcarbodiimide (0.104 g, 0.50 mmol) in 4.0 mLofdichloromethane. The resulting clear solution was stirred at 0 ◦C for 30 min. A white suspension wasformed, which was stirred for 3 h at ambient temperature. The solids were removed by gravity filtrationthrough filter paper and washed with dichloromethane (10mL). The solvent was removed by rotary evap-oration using a cold water bath. Flash column chromatography (4:1 to 1:1 petroleum ether/diethylether)yielded perester 158 as a white solid (0.184 g, 0.342 mmol) in 80% yield. m. p. 103-104 ◦C. 1HNMR (400 MHz; C6D6): δ 3.26 (s, 4H), 3.08 (s, 3H), 3.02-2.99 (m, 4H), 2.98-2.93 (m, 1H), 2.59-2.54(m, 1H), 2.51-2.41 (m, 2H), 2.34-2.28 (m, 1H), 2.13-2.00 (m, 2H), 1.82-1.37 (m, 12H), 1.22 (s, 10H),1.05 (d, J = 6.9 Hz, 4H), 1.01 (d, J = 6.5 Hz, 4H), 0.90 (td, J = 11.8, 5.0 Hz, 2H), 0.85-0.82 (m, 4H),0.63 (d, J = 7.0 Hz, 3H). 13C NMR (101 MHz; C6D6): δ 173.5, 82.4, 81.9, 80.9, 77.2, 55.6, 55.2, 47.4,46.5, 42.8, 42.3, 41.0, 40.0, 35.7, 35.1, 34.9, 34.6, 28.2, 28.0, 27.7, 27.5, 26.2, 23.5, 23.1, 22.18, 22.1,19.2, 18.9, 17.7, 16.5, 15.6, 12.6. IR (CDCl3): 2932, 2871, 2829, 1776, 1461, 1367, 1102, 753 cm−1.HRMS-ESI (m/z) [M+Na]+ calcd for C32H56O6Na: 559.3975. Found: 559.3958.76Chapter 2. Fluorine transfer to alkyl radicalsNFSICH3CN, 110 °COHOOOOHHHOHOOHHHFO158 159Synthesis of (3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-17-((2R)-4-fluoropentan-2-yl)-3,7,12-tri-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene (159): To a 500 µL mi-crowave vial was added commercially available N-fluorobenzensulfonimide (10.0 mg, 0.032 mmol, 3equiv.) and perester 158 (5.0 mg, 0.0093 mmol, 1 equiv.) then sealed, evacuated, and backfilled withN2. CD3CN (100 µL) was added and the reaction vessel was placed in an oil bath (maintained at 110±5◦C) such that the solvent line was slightly above the oil line. After 60 min, the reaction vessel wascooled immediately in an ice bath for 3 min. The seal was broken and the crude reaction mixture (100µL dichloromethane rinse) was injected onto an automated flash chromatography loading puck. Purifi-cation on a basified biotage SNAP 10 g column (pre-equilibration with 100 mL of a 75 : 25 : 10 solutionof hexanes : EtOAc : Et3N) by gradient flash chromatography (% EtOAc in hexanes for 1 column vol-ume then 1-12% EtOAc in hexanes over 10 column volumes, then 12% EtOAc in hexanes for 2 columnvolumes) yielded fluorinated compound 159 (2.2 mg, 54% yield) after rotary evaporation of fractions at20 ◦C. Fluorinde 159 was isolated as a 1:1 mixture of diastereomers. 1H NMR (400 MHz; CDCl3): δ4.87-4.64 (m, 1H), 3.38 (dt, J = 8.3, 2.7 Hz, 1H), 3.33 (s, 3H), 3.26 (s, 3H), 3.21 (s, 3H), 3.14 (s, 1H),3.02-2.97 (m, 1H), 2.24-2.02 (m, 3H), 1.97-1.66 (m, 9H), 1.43 (s, 3H), 1.34-1.16 (m, 10H), 1.03 (dq,J = 9.2, 3.2 Hz, 2H), 0.96 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 3.2 Hz, 1H), 0.90 (d, J = 17.2 Hz, 3H),0.67 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz; CDCl3): δ 91.9, 90.3, 89.6, 87.9, 82.2, 82.1, 80.9, 56.0,55.9, 55.6, 47.3, 47.1, 46.4, 46.3, 43.8, 43.6, 43.4, 43.2, 42.9, 42.8, 42.1, 39.8, 35.4, 35.1, 34.6, 34.1,34.0, 32.2, 30.5, 29.9, 28.1, 27.9, 27.7, 26.9, 23.3, 23.0, 22.2, 22.1, 22.0, 21.6, 21.3, 18.6, 17.8, 12.6,12.5. 19F {1H} NMR (282 MHz; CDCl3): δ -168.8, -174.8. IR (CDCl3): 2933, 2871, 2819, 1454, 1372,1184, 1125, 1102, 733 cm−1. HRMS-ESI (m/z) [M+Na]+ calcd for C27H47O3FNa: 461.3407. Found:461.3402.77Chapter 2. Fluorine transfer to alkyl radicals2.8.7.1 1H NMR yield determination of fluoroalkane 159Perester 158 (4mg, 0.0075mmol) was subjected to the general radical fluorination procedure in CD3CN.The reaction vial was placed in an oil bath, heated to 110 ◦C and the reaction was stirred for 60 min.1H NMR analysis of the crude reaction mixture, and comparison with a pure sample of fluoride 159,confirmed the presence of the desired product and allowed the calculation of the yield. The reaction wasrepeated 3 times, to give 75%, 65% and 66% yield, or average 68% NMR yield.Figure 2.10) depicts the first run to determine the 1H NMR yield of fluoroalkane 159. 2.10a corre-sponds to the t0 with the quartet of CF3CO2Et at 4.41 ppm and the methylene multiplet of perester 158 at2.63 ppm. The next spectrum (2.10b) is the crude reaction mixture with the doublet of the fluoroalkane159 at 4.75 ppm. Only half of the doublet is integrated as there is a slight impurity under the rightmostsignal.0.3722.53.03.54.04.55.05.56.0(a) 1H NMR quantification trial 1, t0.20.142.53.03.54.04.55.05.56.0(b) 1H NMR quantification trial 1.Figure 2.10. Quantification of fluoroalkane 159 utilizing 1H NMR analysis, trial 1.Figure 2.10 depicts runs two and three to determine the 1H NMR yield of fluoroalkane 159. 2.11acorresponds to the t0 with the quartet of CF3CO2Et at 4.41 ppm and the methylene multiplet of perester158 at 2.63 ppm. The next two spectrums (2.11b and 2.11c) are the crude reaction mixtures with thedoublet of the fluoroalkane 159 at 4.75 ppm. Only half of the doublet is integrated as there is a slightimpurity under the rightmost signal.78Chapter 2. Fluorine transfer to alkyl radicals0.45422.53.03.54.04.55.05.56.0(a) 1H NMR quantification trial 2 and 3, t0.20.1472.53.03.54.04.55.05.56.0(b) 1H NMR quantification trial 2.20.1492.53.03.54.04.55.05.56.0(c) 1H NMR quantification trial 3.Figure 2.11. Quantification of fluoroalkane 159 utilizing 1H NMR analysis, trials 2 and 3.79Chapter 3Direct C-F bond formation usingphotoredox catalysisMay it be a light to you in dark places, when all other lights go out.— J. R. R. Tolkien (1954)One of the factors that limited a more extensive exploration of the substrate scope in our fluorineatom transfer methodology, described in Chapter 2, was the thermal instability of the radical precursors(diacylperesters and t-butyl peresters). Since an alternative way to generate alkyl radicals from stableprecursors would greatly improve the practicality of our fluorination methodology, we decided to inves-tigate the use of light-mediated processes to generate alkyl radicals.In this chapter, the use of visible-light photoredox catalysis to generate C−F bonds through alkyl rad-ical intermediates will be described. Ruthenium trisbipyridyl was selected as our photocatalyst. Spec-troscopic and electrochemical studies to support an oxidative quenching reaction mechanism will alsobe presented.3.1 Visible-light photoredox catalysis3.1.1 Tris(bipyridine)ruthenium(II) ([Ru(bpy)3]2+) photoredox propertiesRuthenium trisbipyridyl, [Ru(bpy)3]2+(bpy = 2,2′-bypyridine, 169 in Figure 3.1), a d6 ruthenium com-plex, was first synthesized by Burstall in 1936 as the chloride salt ([Ru(bpy)3]Cl2).175 The combinationof robustness, chemical stability, luminescence emission, redox properties, excited-state lifetime and re-activity have made this particular complex one of the most widely studied and characterized chemicallyand photochemically.176–17880Chapter 3. Direct C-F bond formation using photoredox catalysisRuIINNNN NNTris(bipyridine)ruthenium(II)2+169Figure 3.1. Tris(bipyridine)ruthenium(II) ([Ru(bpy)3]2+) photocatalyst.[Ru(bpy)3]2+ absorbs light in the visible light region of the electromagnetic spectrum (λmax = 452nm).179 In Figure 3.2 the molecular orbital (MO) representations of the ground state, the excited stateand the reduced and oxidized forms of [Ru(bpy)3]2+ are depicted. Upon the absorption of a photon, oneelectron is promoted from the ground state t2gMOs of the ruthenium to the anti-bonding pi* orbital of oneof the ligands (2,2′-bypyridine) in what is called a metal-to-ligand charge transfer (MLCT) process. TheMLCT generates the singlet excited state *1[Ru(bpy)3]2+, which upon a fast intersystem crossing (ISC)gives rise to the catalyst triplet excited state *3[Ru(bpy)3]2+.t2gπ *eg *MLCT+ISCt2gπ *eg *t2gπ *eg *t2gπ *eg *Ru(bpy)32+Ground State*Ru(bpy)32+Excited State[Ru(bpy)3]+Reductant[Ru(bpy)3]3+OxidantActing asa reductantActing asan oxidantRuIINNNN NNRuIIINNNN NNFigure 3.2. Simplified molecular orbital representation of [Ru(bpy)3]2+ photochemistry.18081Chapter 3. Direct C-F bond formation using photoredox catalysisThe triplet excited state of [Ru(bpy)3]2+ has a lifetime of τ = 1100 ns,181 an unusually long timefor an excited state that allows it to react with other species in solution. *3[Ru(bpy)3]2+ can return tothe ground state through three different pathways: energy emission or transfer, oxidative quenching, orreductive quenching. In an energy transfer mechanism, *[Ru(bpy)3]2+ behaves as a photosensitizer bytransferring energy from the excited state to an adjacent photo-inert molecule. In a reductive quenchingpathway, *[Ru(bpy)3]2+ gains one electron to form [Ru(bpy)3]+ in situ, a strong reductant that can inturn reduce other species in solution. Alternatively, if the excited state *[Ru(bpy)3]2+ loses one electronthrough an oxidative quenching pathway, [Ru(bpy)3]3+ is generated in situ, which can oxidize othermolecules in solution.The photochemical versatility of ruthenium trisbipyridyl arises from the fact that its excited statecan either be oxidized or reduced, depending on which other species are present in solution. The abilityto donate and accept electrons is defined by redox potentials (Figure 3.3), which describe the potentialassociated with an electrochemical half reaction in the direction from the oxidized to the reduced species.Photoexcitation of the ground state leaves *[Ru(bpy)3]2+ with 2.12 eV of energy available for energytransfer processes. The reduction and oxidation potentials of the excited state are +0.77 V and −0.81V (aqueous solution, vs SCE)182 respectively, which renders *[Ru(bpy)3]2+ a readily reducible (to form[Ru(bpy)3]+) or oxidizable (to form [Ru(bpy)3]3+) species.Ru2+*3Ru2+*1Ru2+Ru+Ru3+strongoxidantstrongreductanthνMLCTISC+0.77 V-0.81 Vhν2.12 eV-1.33 V+1.29 VOxidativequenchingReductivequenchingFigure 3.3. Photoexcitation, oxidative and reductive quenching cycles for [Ru(bpy)3]2+.1793.1.2 Application of ruthenium (II) photoredox catalysis to organic synthesisPhotoredox catalysis has found applications in processes such as water splitting into hydrogen and oxy-gen,183,184 and carbon dioxide reduction to methane.185 In addition, [Ru(bpy)3]2+ and its analogues havebeen used in dye-sensitized solar cells,186 organic light-emitting diodes,187,188 polymerization initia-82Chapter 3. Direct C-F bond formation using photoredox catalysistors,189–191 and in photodynamic therapy.192 Several reviews that highlight the achievements of the useof photoredox catalysis in organic synthesis have been published.179,180,193–197Selected examples of theformation of C−H as well as C−C bonds will be described in the following section to illustrate theapplication of [Ru(bpy)3]2+ photocatalysis to organic synthesis.3.1.2.1 Photoredox C−H bond formationIn 1978, Kellog reported the reduction of phenacylsulphonium salts (i.e. 170) in the presence of differentdyes and visible light (Scheme 3.1).198 [Ru(bpy)3]Cl2 was one of several dyes evaluated, and it wasobserved that the presence of this coordination complex significantly reduced the reaction times requiredto achieve the transformation. Studies on the mechanism of this reaction suggested that it proceededthrough a single electron transfer pathway.199[Ru(bpy)3]Cl2 1 mol%acetone-d6 or CDCN325 °C, room lightOSPhBF4+NCO2EtEtO2C OSPh NCO2EtEtO2CBF4+ +100% 100% 100%170 171 172 173 174Scheme 3.1. Reduction of phenacylsulphonium salts through visible-light photocatalysis. 198The same group later reported the reduction of phenacylbromide and bromomalonates (Scheme 3.2)with 2,3-dihydrobenzothioazole (176) in the presence of photocatalysts, such as [Ru(bpy)3]Cl2, and vis-ible light.200 The reduced products were obtained in good to excellent yields. Increasing the number ofelectron withdrawing groups attached to the alkyl bromide resulted in higher yields and shorter reactiontimes.[Ru(bpy)3]Cl2, 5 mol%CDCN325 °C, 1.3 hfluorescent lampsO+O+BrSN HSNBr>95%Other substratesBr CNBr CNCNBr CO2EtBr CO2EtCO2Et40 h, >95% 0.7 h, >95% 70 h, 75-85% 1 h, >95%175 176 172 177178 179 180 181Scheme 3.2. Reduction of electron poor alkyl bromides.20083Chapter 3. Direct C-F bond formation using photoredox catalysisOther reductions that utilized [Ru(bpy)3]Cl2 as photocatalyst were independently discovered by thePac group in 1981 (Scheme 3.3).201,202 The use of 1-benzyl-1,4-dihydronicotinamide (BNAH, 183,Ered1/2 = +0.57 V vs SCE)203 as a reductive quencher allowed the reduction of a variety of electronpoor olefins, such as 182. The authors propose a mechanism where an initial reductive quenching ofthe excited state *[Ru(bpy)3]2+ by BNAH generates [Ru(bpy)3]+. This highly reductive species thenundergoes an SET to 182 to generate radical anion 186 that upon protonation generates radical 187. Re-duction of radical 187 and subsequent protonation would then generate diethylsuccinate 184. Studies onthe reduction of carbonyl groups have also been reported by Pac.204,205[Ru(bpy)3]Cl2, 2 mol%10:1 pyridine-CH3OHhν, 2 h+ +EtO2C CO2Et NPhCO2NH2EtO2CCO2EtNNCO2NH2H2NO2CPhPhBNAH[Ru(bpy)3]2+*[Ru(bpy)3]2+ [Ru(bpy)3]+BNAH BNAH-H+BNAReductivequenchinghνEtO2C CO2EtH+CO2EtEtO2CBNABNA++H+182182 183184184185185186187Scheme 3.3. Reduction of electron poor alkenes through photoredox catalysis.201,202In 1990, Fukuzumi and co-workers reported the reduction of phenacyl halides, such as 175 (Ered1/2 =−0.78 V vs SCE),206 in the presence of [Ru(bpy)3]Cl2, 9,10-dihydro-10-methylacridine (188, Ered1/2 =+0.8 V vs SCE)203 and visible light (Scheme 3.4).207 While phenacyl chloride did not react under thereaction conditions, both phenyl methyl acetone (172) and N-methylacridine (189) were obtained withor without the addition of HClO4, but the proposed mechanism of the reaction is different in the pres-ence or absence of the acid. When no HClO4 is added, a reductive quenching pathway mechanism isproposed where the excited state *[Ru(bpy)3]2+ gains one electron from 188 to generate [Ru(bpy)3]+ andthe oxidized AcrH2•+. [Ru(bpy)3]+ then reduces phenacylbromide (175) to regenerate [Ru(bpy)3]2+ andsimultaneously generate radical 190. Reduction of radical 190 by AcrH•, formed upon deprotonation84Chapter 3. Direct C-F bond formation using photoredox catalysisof AcrH2•+, generates phenyl methyl acetone and 189. In the presence of perchloric acid, an oxidativequenching mechanism is suggested, where the excited state *[Ru(bpy)3]2+ is first oxidized by proto-nated phenacyl bromide to generate [Ru(bpy)3]3+ and radical 190. Next, [Ru(bpy)3]3+ oxidizes 188 toAcrH2•+ and regenerates [Ru(bpy)3]2+. The loss of a proton by AcrH2•+ forms AcrH•, which reducesradical 190 to yield 189 and phenyl methyl acetone 172.[Ru(bpy)3]Cl2, 5 mol%hν λ = 452 nm CH3CN8 h, 25 °C+ +[Ru(bpy)3]2+*[Ru(bpy)3]2+[Ru(bpy)3]+hνOBrN NOHNo HClO4HClO4, 2 equiv.74%98%75%98%AcrH2 AcrH+No HClO4reductivequenchingAcrH2PhOHBrH+AcrH-H+[Ru(bpy)3]2+*[Ru(bpy)3]2+[Ru(bpy)3]3+hνWith HClO4oxidativequenching-H+PhOBrHPhOHBrAcrH2 AcrHHHOH175175188188188172172172189189189190190Scheme 3.4. Fukuzimi’s photocatalytic reduction of phenacyl halides.207Reduction of ketones using ruthenium (II) catalysts and visible light was first reported byWillner andco-workers in 1990.208 The photoreduction of activated ketones through the use of [Ru(bpy)3]Cl2, alongwith triethylamine as an electron donor and proton source, effectively produced alphahydroxy ketonesand esters.In 2006, Garcia and coworkers reported a photocatalytic Meerwein-Ponndorf-Verley-type reductionof ketones to alcohols using a [Ru(bpy)3]2+/viologen couple, along with triethanolamine (TEOA) andisopropanol (Scheme 3.5).209 In the proposed mechanism, the catalyst’s excited state *[Ru(bpy)3]2+ is85Chapter 3. Direct C-F bond formation using photoredox catalysisoxidatively quenched by a viologen (MV2+, Ered1/2 = −0.4 V vs SCE)210 to form [Ru(bpy)3]3+ andradical cation MV•+. TEOA is used as a sacrificial electron donor to regenerate [Ru(bpy)3]2+, whileradical cation MV•+ oxidizes isopropanol to acetone and generates MVH+. This species then reducesthe ketone substrates, such as oxo-phenyl-2-oxoethanoic acid methyl ester 191, to the correspondingalcohol product (192) and regenerate the viologen MV2+.[Ru(bpy)3](PF6)2 cat.viologen MV(PF6)2 cat.hνTEOA, iPrOHCH3CN[Ru(bpy)3]2+*[Ru(bpy)3]2+[Ru(bpy)3]3+hνOTEOAOOOHOOTEOAoxMV2+MVMVH+OOHR R'OHR R'OMV2+  = N NMVH+  = N NH191 192Scheme 3.5. Photocatalytic Meerwein-Pondorf-Verley.209A general photocatalytic protocol for the dehalogenation of α-haloketones has been developed byStephenson, Narayanam and Tucker (Scheme 3.6).211 In his system, Stephenson utilizes [Ru(bpy)3]Cl2,Hu¨nig’s base (iPr2NEt) and either formic acid or Hantzsch ester (171) to perform the reduction of thehalogen. The suggested mechanism, supported by radical clock experiments, involves the reductivequenching of the excited state *[Ru(bpy)3]2+ by Hu¨nig’s base to generate an aminium radical cation (195)and [Ru(bpy)3]+. A one-electron transfer from [Ru(bpy)3]+ to the halogenated substrate with concomitantlose of halide would then generate alkyl radical 196. The oxidation of the tertiary amino group, greatlydecreases the BDE of the protons α to this group. The bond dissociation energy of the N-methyl C−Hbond in Ar2NCH3 has been estimated to be 47 kcal/mol−1.212 The alkyl radical 196 then abstracts aproton at one of the alpha positions of 195 to generate the desired dehalogenated product and iminium ion197. The reduced products are obtained in excellent yields, and the reaction is chemoselective to aliphaticbromides and chlorides α to electron withdrawing groups over aromatic bromides (198) and vinylic86Chapter 3. Direct C-F bond formation using photoredox catalysisiodides (201). Protected (199) and unprotected (200) alcohols were compatible with the photocatalyticreduction conditions.[Ru(bpy)3]Cl2 2.5 mol%iPr2NEt, HCO2HDMF, hν[Ru(bpy)3]2+*[Ru(bpy)3]2+[Ru(bpy)3]+hνNNBrH BocBocNNHH BocBoc-X-iPr2NEtNCH3H3CHRXR'R R'X = Br, ClNCH3H3CRHR'Other substratesNNHH BocBocNO ORBrOOBnR = TBS       HOPhIOClBr193 194195196197198199200201Scheme 3.6. Stephenson’s tin-free reductive dehalogenation.2113.1.2.2 Photoredox C−C bond formationThe formation of C−C bonds though photoredox catalysis has also been thoroughly investigated. In1984, Tanaka and co-workers reported the dimerization of benzyl bromide (202) upon treatment with[Ru(bpy)3]Cl2 and BNAH (183) in pyridine/acetonitrile (Scheme 3.7).213 The reduction of benzyl bro-mide with 183 and UV-light irradiation had been previously reported by the same group.214 When theyinvestigated the use of [Ru(bpy)3]Cl2 and visible-light to promote the reduction of benzyl bromide totoluene, the authors observed a change in the mechanism and 203 was obtained preferentially.[Ru(bpy)3]Cl2, 0.5 mol%pyridine-CH3OHhν+ NPhCO2NH2Br93%202 183 203Scheme 3.7. Reductive dimerization of benzyl bromide.21387Chapter 3. Direct C-F bond formation using photoredox catalysisIn the same year, Cano-Yelo and Deronzier described the [Ru(bpy)3]2+ photocatalytized Pschorr re-action that converts aryldiazonium salts (204) into phenanthrene derivatives 205 (Scheme 3.8).215 Theproposed mechanism involves the quenching of the catalyst’s excited state *[Ru(bpy)3]2+ by 204 withconcomitant release of N2 to generate radical 206. Radical addition onto the adjacent aryl ring wouldthen form 207, which gets oxidized by [Ru(bpy)3]3+, and upon proton loss forms 205. The same oxida-tive [Ru(bpy)3]2+ pathway was later utilized to form aldehydes from alcohols at the benzylic position,with aryldiazonium salts as oxidants.216[Ru(bpy)3](BF4)2, 5 mol%CH3CN, hνR = H, Br, OMe+N2CO2H CO2HR RCO2HR*[Ru(bpy)3]2+ hν [Ru(bpy)3]2+[Ru(bpy)3]3+CO2HRHH+N2204 205206 207Scheme 3.8. Photoredox-catalyzed Pschorr reaction.215Photoredox catalysis has also been utilized to form carbon-carbon double bonds. Between 1983-84, Willner and co-workers reported the debromination of of 1,2-dibromides (such as 208) in bipha-sic systems to generate trans alkenes (Scheme 3.9).217,218 The viologen they used (C8V2+) has dif-ferent solubility properties depending on its oxidation state; C8V2+ is highly soluble in aqueous me-dia, while C8V•+ and C8V are soluble in organic solvents. In the aqueous layer, [Ru(bpy)3]2+ is ex-cited to *[Ru(bpy)3]2+ through visible-light irradiation, followed by quenching of the catalyst’s excitedstate by C8V2+ to generate C8V•+ and [Ru(bpy)3]3+. [Ru(bpy)3]2+ is regenerated by the reduction of[Ru(bpy)3]3+ by the electron donor (NH4)3EDTA. The radical cation, C8V•+, moves to the organiclayer where two of them exchange an electron to simultaneously generate C8V and C8V2+. C8V is strongenough to perform the reduction of dibromide 208 to radical 210. A second reduction of this radicalwould ultimately produce 210. Later studies lead the Willner group to report the reduction of vicinaldibromides through a reductive pathway utilizing triethylamine as the sacrificial electron donor.20888Chapter 3. Direct C-F bond formation using photoredox catalysisC8V2+⋅2Br-[Ru(bpy)3]Cl2, 0.7 mol%(NH4)3EDTAEtOAc/H2O, visible lightPhPhPhPhBrBrN NC8H17 C8H17NNC8H17 C8H17NNC8H17 C8H17NNC8H17 C8H17PhPhBr*[Ru(bpy)3]2+ [Ru(bpy)3]3+[Ru(bpy)3]2+C8V2+C8V2+C8VC8VC8Voxidationproducts(NH4)3EDTAEtOAcH2Ohν2x208208 209210Scheme 3.9. Photocatalytic debromination of 1,2-dibromides.218In 2008, Macmillan and Nicewicz reported the synergic use of photoredox catalysis and organocatal-ysis to perform enantioselective α-alkylation of aldehydes, mediated by the use of [Ru(bpy)3]2+ catalystand an asymmetric imidazolidinone 213 (Scheme 3.10).219 The substituted aldehydes were obtained ingood yields and enantioselectivities. The brominated substrates were limited to α-bomocarbonylic com-pounds. The proposed mechanism for this transformation, shown in Scheme 3.10, starts with the pho-toexcitation of [Ru(bpy)3]2+ to *[Ru(bpy)3]2+. A subsequent SET from a sacrificial enamine molecule,formed in situ from reaction of aldehyde 211 and organocatalyst 213, to the excited state generates thestrong reductant [Ru(bpy)3]+. The ruthenium (I) species then reduces the α-bromocarbonyl substrate(212), which expels bromide and the electron-deficient radical 215. A second molecule of enamine 216reacts with radical 215 to enantioselectively form a new C−C bond and carbon radical intermediate 217,which intersects the photocatalytic cycle at the reductive quenching of *[Ru(bpy)3]2+ to form iminium89Chapter 3. Direct C-F bond formation using photoredox catalysisintermediate 218. Hydrolysis of this iminium ion regenerates organocatalyst 213 and delivers the enan-tioenriched α-alkyl aldehyde product 214. A visible-light mediated α-benzylation of aldehydes was laterreported by the same group, but this transformation required the use of an iridium (III) catalyst, whichpresents a higher oxidation potential compared to the ruthenium catalyst.220             , 20 mol%[Ru(bpy)3]Cl2, 0.5 mol%2,6-lutidine, 2.0 equiv.DMF, visible lightHO[Ru(bpy)3]+ *[Ru(bpy)3]2+[Ru(bpy)3]2+hνEWGBr+RHOREWGNHNO MeMe t-BuNHNO MeMe t-Bu NNO MeMe t-BuRNNO MeMe t-BuEWGRNNO MeMe t-BuEWGRSETSETEWG+BrEWGOrganocatalyticcyclePhotocatalyticcycle211211212212213213214214215216216217218Scheme 3.10. Organo-/photocatalytic enantioselective α-alkylation of aldehydes.21990Chapter 3. Direct C-F bond formation using photoredox catalysisVisible-light photocatalyzed ring forming reactions have also been investigated. One class that hasbeen extensively studied by Yoon and co-workers is the [2 + 2] cycloaddition of enones.221 In 2008,Yoon demonstrated that [Ru(bpy)3]Cl2 catalyzes the transformation of bis(enone) 219 to cyclobutane-containing bicyclic dione 220 via a [2 + 2] cycloaddition in high yields and good diastereoselecivities(Scheme 3.11).222 Control experiments corroborated the necessity of each one of the reaction compo-nents. The proposed mechanism suggests that the excited state *[Ru(bpy)3]2+, formed upon visible-lightphotoexcitation of [Ru(bpy)3]2+, is reductively quenched by Hu¨nig’s base. The [Ru(bpy)3]+ thus formedtransfers one electron to the lithium activated enone to form the lithium-bound radical anion 221 andregenerate [Ru(bpy)3]2+. Radical 221 undergoes the [2 + 2] cycloaddition to generate ketyl radical 222,which is ultimately oxidized to form the cyclobutane containing product, 220.[Ru(bpy)3]Cl2, 5 mol%iPr2NEt, 2.0 equiv.LiBF4, 2.0 equiv.CH3CNvisible light[Ru(bpy)3]+*[Ru(bpy)3]2+[Ru(bpy)3]2+hνOPhOPhH HPhOPhOiPr2NEtiPr2NEtPhORLiPhORLiPhOR[2+2]H HPhOPhOLi-e-89% yield, >10:1 d.r.219220220221 222Scheme 3.11. Visible-light photocatalytic [2 + 2] enone cycloadditions.22291Chapter 3. Direct C-F bond formation using photoredox catalysisUnder the reaction conditions shown in Scheme 3.11, Yoon and co-workers observed that symmet-ric aryl bis(enones) containing electron-withdrawing and electron-donating groups effectively under-went [2 + 2] cycloadditions, while aliphatic enones and enoates fail to perform the desired cyclization(Figure 3.4). When unsymmetrical bis(enones) are utilized, the cyclization proceeds only if one of themis an aryl enone. The presence of an oxygen in the alkyl chain connecting both enones provided thecorresponding 3,4-substituted furan in high yield and a decrease in diastereoselectivity compared to itsall-carbon analogues.H HROROH HMeOPhOH HOEtOPhOOH HPhOPhOPhOPhOR = 4-MeOPhR = 4-ClPhR = 2-furylR = Me, OEt98%, 10:1 d.r.96%, >10:1 d.r.89%, >10:1 d.r.no reaction85%, >10:1 d.r.90%, 5:1 d.r.88%, >10:1 d.r.82%, >10:1 d.r.MeMeFigure 3.4. Photocatalytic [2 + 2] enone cycloadditions scope.22292Chapter 3. Direct C-F bond formation using photoredox catalysisThismethodology was latter used to enable cross intermolecular [2+2] cycloadditions (Scheme 3.12).223Enones 223 and 224 were selected to avoid homodimerization, since the former enone readily acceptsone electron from [Ru(bpy)3]+ to generate the radical anion intermediate, while the latter does not. Thereaction tolerates electron-donating as well as electron-withdrawing groups on the enone that acts as theelectron acceptor. It was also observed that the presence of an aryl substituent is required for the reac-tion to proceed. Substitution at the β-position of the electron accepting enone showed that the reactionwas sensitive to steric bulk (Scheme 3.12). Functionalized alkyl enones, with alkyl, esters and thioesterssubstituents, were also successfully used as cyclization partners.[Ru(bpy)3]Cl2, 5 mol%iPr2NEt, 2.0 equiv.LiBF4, 4.0 equiv.CH3CN, visible lightMeOMeOPh MeOPhO84% yield, >10:1 d.r.+MeMeOR'OMeMeOPhOR''84%,  >10:182%,  >10:153%,  >10:174%,  >10:10%,      ---R' = PhR' = 4-ClPhR' = 4-MeOPhR' = 2-furylR' = Etyield     d.r.70%,      6:164%,  >10:1  8%,  >10:161%,  >10:1R'' = EtR'' = i-PrR'' = i-BuR'' = CH2OBnyield     d.r.R'''OPhOMe84%,  >10:176%,  >10:165%,      5:188%,  >10:1R''' = MeR''' = EtR''' = OMeR''' = SEtyield     d.r.223 224 225Scheme 3.12. Crossed intermolecular photocatalytic [2 + 2] enone cycloadditions.223A disadvantage of the photocatalytic [2 + 2] cycloaddition reaction developed by Yoon (shown inScheme 3.11) is the requirement of at least one aryl enone for the cyclization reaction to proceed. Rec-ognizing this problem, Yoon, Tyson and Farey later reported the use of “cleavable redox auxiliaries”(Scheme 3.13).224 Carboxylate ester surrogates, such as saturated acyl phosphates, N-acyl pyrroles, pyra-zoles and 2-acylimidazole, were probed towards intramolecular [2 + 2] cycloaddition of aryl enones;the only functional group that gave good results was 2-acylimidazole. The reaction can be performedinter- and intramolecularly (i.e. 226, Scheme 3.13) with yields of 52 − 79% for the intermolecular ver-sion and of 65 − 90% of the intramolecular products (such as 227). The 2-acylimidazole group canbe cleaved in each case by treatment with methyl triflate, followed by the desired nucleophile and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) to obtain substituted cyclopropanes of the type 228.93Chapter 3. Direct C-F bond formation using photoredox catalysis[Ru(bpy)3]Cl2, 2.5 mol%iPr2NEt, 2.0 equiv.LiBF4, 0.5 equiv.CH3CN, visible lightOOBnOH HOBnOO87% yield, >10:1 d.r.NNMe NNMe1. MeOTf (76%)2. NucH, DBU H HOBnONucONuc = H2O, MeOH,           t-BuSH, BnNH2,            pyrrolidineH HOBnOONNMe226227227228Scheme 3.13. Photocatalytic [2 + 2] enone cycloadditions with cleavable redox auxiliaries. 224Other ruthenium-catalyzed photoredox systems explored by the Yoon group include the use of Brøns-ted acids to access 1,2-disubstituted cyclopentane rings,225 [2 + 2] cycloadditions of bis(styrenes) intra-226,227 and intermolecularly,228 [2 + 2] cycloadditions of 1,3-dienes,229 [3 + 2] cycloadditions of arylcyclopropyl ketones,230 radical cation Diels-Alder cycloadditions,231,232 as well as radical anion hetero-Diels-Alder cycloadditions.233Another example of C−C bond formation photocatalyized by [Ru(bpy)3]2+ comes from an extensionof the work reported by Stephenson and depicted in Scheme 3.6. The group’s approach consisted in inter-cepting alkyl radical 196, generated upon SET from [Ru(bpy)3]+ to the alkyl bromide (229), with a doublebond suitable for 5-exo or 6-exo cyclization to form carbocycles such as 230 (Scheme 3.14).234 Substi-tuted cyclopentane and cyclohexane products were obtained in good to excellent yields. The tricycliccarbocycle 232 was also synthesized in 69% yield through the tandem cyclization of 231, in a similardisconnection strategy to that used by Curran in 1985 in his total synthesis of (±)-∆9(12)-capnellene.235An iridium catalyst was used to perform the same transformation in less activated bromides, as the irid-ium catalyst has a higher oxidation potential (+1.51 V vs SCE for Ir(II)→Ir(III)).23494Chapter 3. Direct C-F bond formation using photoredox catalysis[Ru(bpy)3]Cl2 1.0 mol%NEt3,  2.0 equiv.DMF, blue LEDs85%NOOOMeO2C CO2Me MeO2C CO2Me MeO2C CO2MeTMSMeO2C CO2Me77% 69% 100% 92%[Ru(bpy)3]Cl2 1.0 mol%NEt3,  2.0 equiv.DMF, blue LEDs69%BrMeO2CCO2MeMeO2C CO2MeNOOOBr229 230231 232Scheme 3.14. Visible light photoredox catalytic radical cyclizations. 234Stephenson and co-workers also explored the intramolecular radical cyclization onto indoles andpyrroles through tandem radical cyclizations, where the radical is again generated as a result of a SETprocess from the highly reductive [Ru(bpy)3]+ to an alkyl bromide (Scheme 3.15).236 The cyclizationof structurally diverse substrate was achieved in good yields after the optimization of the reaction. Itwas observed that Hu¨nig’s base was not the optimal electron donor as it promoted the formation of thereductively dehalogenated product. After screening for amine bases, triethyl amine was determine to bethe optimal as it provided a more favourable ratio of reduced vs cyclized products. An intermolecularversion of this reaction where electron rich heterocycles are functionalized with malonates has also beenreported by the same research group.237The iminium ions generated upon the reductive quenching of the photogenerated excited state *[Ru(bpy)3]2+have been exploited to perform transformation such as Mannich reactions utilizing dual photoredox andLewis base catalysis,238 azomethine elide [3 + 2] cycloadditions,239 aza-Henry,240 Friedel-Crafts α-amidoalkylation,240 and asymmetric α-acylation of tertiary amines.24195Chapter 3. Direct C-F bond formation using photoredox catalysis[Ru(bpy)3]Cl2 1.0 mol%NEt3,  2.0 equiv.DMF, visible light60%N CO2MeCO2MeBrNCO2MeCO2MeNCO2MeCO2Me NCO2MeCO2MeNCO2MeCO2MeOBrNCO2MeCO2MeCNN NNCO2MeCO2MeMeO2C NCO2MeCO2MeCO2MeCO2MeCO2MeCO2Me73% 60% 55% 60%55% 62% 79% 95%[Ru(bpy)3]Cl2 1.0 mol%NEt3,  2.0 equiv.DMF, visible light79%TMP3 TMP4N NBrCO2MeCO2MeHHCO2MeCO2Me233 234Scheme 3.15. Intramolecular radical addition to indoles and pyrroles.236The work of DiRocco and Rovis is presented in Scheme 3.16.241 to illustrate the use of these iminiumintermediates. The authors combined the use of photocatalysis withN-heterocyclic carbene (NHC) catal-ysis to asymmetrically acylate tertiary amines, such as 235, with good yields and high enantioselectiv-ities. The reaction conditions require the use of meta-dinitrobenzene (mDNB, 239, Ered1/2 = −0.90V vs SCE)182 and [Ru(bpy)3]Cl2, along with NHC catalyst 237 for the transformation to occur. Inthe NHC catalytic cycle (see Scheme 3.16), the chiral N-heterocyclic carbene 237 reacts with alde-hyde 236 to generate the nucleophilic Breslow intemediate 242. Simultaneously, photoexcitation of[Ru(bpy)3]2+followed by oxidative quenching by mDNB forms [Ru(bpy)3]3+, which oxidizes tertiaryamine 235 and regenerates the ruthenium (II) catalyst. The new amino radical cation loses one protonand one electron to form iminium ion 241. The two catalytic cycles intersect when the Breslow inter-mediate 242 reacts with the iminium ion 241 to create a new enantioselectively controlled C−C bond(243). The final α-acylated product 238 is eliminated from adduct 243 and simultaneously regeneratesthe NHC catalyst 237.96Chapter 3. Direct C-F bond formation using photoredox catalysis             , 5.0 mol%[Ru(bpy)3]Cl2, 1.0 mol%m-DNB, 1.2 equiv.DCM, blue LEDs[Ru(bpy)3]3+ [Ru(bpy)3]2+*[Ru(bpy)3]2+hν+NPhOHEtNPhOEt81%, 92% eeNPhSETNPh-H+, -e-NONN BrBrBrNOR1R2NNHOEtNOR1R2NNHOEtNPhNO2NO2NO2NO2235235236236237237238238239240241242243Scheme 3.16. Photoredox and NHC dual catalysis for the asymmetric α-acylation of tertiary amines.24197Chapter 3. Direct C-F bond formation using photoredox catalysisRuthenium (II) visible-light photoredox catalysis has been successfully used in total synthesis byStephenson and co-workers to access (+)−gliocladin C.242 Additionally, iridium (III) catalysis has re-cently enabled the synthesis of (−)−pseudotabersonine, (−)−pseudovincadiffor-mine, and (+)−corona-ridine by the same research group,243 as well as (±)−pregabalin by the MacMillan group.244The investigation of fluorine incorporation to molecules through ruthenium (II) photoredox catalysishas been limited to C−CF3 bond formation.245–249 Since the interest of our group is the formation ofC−F bonds utilizing carbon radicals, and as many of the visible-light photocatalytic reactions have beendemonstrated to proceed through radicals mechanisms, we envisioned that photoredox catalysis had greatpotential in the direct formation of C−F bonds using electrophilic N−F reagents as sources of fluorinethrough the generation of alkyl radicals.3.2 Initial studies: photocatalytic halogen exchangeFrom Stephenson’s tin-free reduction work, we knew that the bromine in the α position of a carbonylgroup could be reduced via the formation of an alkyl radical.211 We envisioned that this radical couldbe trapped by a fluorine atom instead, if a suitable N−F reagent was present (Figure 3.5). With thisidea in mind, we started our investigation on the use of visible-light mediated single electron transferprocesses to generate alkyl radicals with substrates such as ethyl 2-bromo-propionate (244, R = CH3) andbromodiethylmalonate (244, R = CO2Et). The reductive quencher selected to generate [Ru(bpy)3]+ insitu was diisopropylethylamine (245).R1 R2XRu(I)Ru(II)Ru(II)* R1 R2"H  "R1 R2HX = Cl, Bre-N-FreagentR1 R2FProposedfluorinationTin-freereductionFigure 3.5. Proposed halogen exchange utilizing a visible-light mediated photoredox process.First, a 0.2 m solution of 2-bromopropionate, NFSI, DIPEA and [Ru(bpy)3](PF6)2 (246) in acetoni-trile was irradiated with visible light for 2.0 h (entry 1, Table 3.1); no product was observed. Changing98Chapter 3. Direct C-F bond formation using photoredox catalysisthe solvent for deuterated acetone and irradiating the sample for 2.25 h (entry 2), and extending theirradiation time for a period of 18 h (entry 3) also did not yield the desired product.Table 3.1. Halide exchange using visible-light promoted photoredox catalysis.ROOBr+ NFSI + [Ru(bpy)3](PF6)2Conditions+ iPr2NEt R OOF244 57 245 246 247Entry R Solvent Concentration (m) Time (h) 247, % yield1 CH3 CH3CN 0.2 2.0 02 CH3 Acetone−d6 0.2 2.25 03 CH3 Acetone−d6 0.2 18.0 04 CO2Et Acetone−d6 0.2 4.9 05 CO2Et Acetone−d6 0.5 5.0 06 CO2Et Acetone−d6 0.1 5.0 07 CO2Et Acetone−d6 0.02 5.0 08 CO2Et Acetone−d6 0.05 5.0 09 CO2Et CD3CN 0.03 5.6 010 CH3 Acetone−d6 0.025 18.6 011 CO2Et Acetone−d6 0.025 18.6 012 CO2Et Acetone−d6a 0.033 6.3 013 CO2Et Acetone−d6b 0.033 3.0 014 CO2Et Acetone−d6 0.033 2.5 0c15 CO2Et Acetone−d6 0.033 3.9 0d16 CO2Et Acetone−d6 0.02 5.3 0e17 CO2Et Acetone−d6 0.033 5.2 0f18 CO2Et Acetone−d6 0.033 4.0 0ga Freshly distilled from CaSO4;b Degassed using freeze-pump-thaw sequence;c Slow addition of DIPEA; d Slow addition of DIPEA, freshly distilled from CaH; e Fast addition of DIPEA;f DIPEA added in a 0.25 m solution; g Slow addition of 0.25 m NFSI solution at 1.0 mL/h.We switched to bromodiethylmalonate to see if the presence of another electron withdrawing groupwould favour the formation of the desired alkyl radical and subsequently the fluoroalkane. The irradiationof this reagent in a 0.2 m acetone solution with NFSI, DIPEA and catalyst [Ru(bpy)3](PF6)2 for 4.9h (entry 4) to generate fluoroalkane 247 was unsuccessful; only starting material was observed in the1H NMR spectra. Increasing the concentration to 0.5 m (entry 5), did not show any improvement. Itwas observed that this reaction was exothermic upon the final addition of DIPEA. To control the releaseof heat I tried lower reaction concentrations: 0.1, 0.02 and 0.05 m (entries 6 − 8). While a controlledheat dissipation was achieved at concentrations of 0.02 and 0.05 m, there was still no evidence of the99Chapter 3. Direct C-F bond formation using photoredox catalysisformation of the corresponding fluoroalkane 247. The use of acetonitrile at a lower concentration (0.03m, entry 9) was proved, but the product was not observed.Neither ethyl 2-bromo-propionate nor bromodiethylmalonate yielded the desired fluoroalkanes usingacetone as the solvent and prolonging the irradiation of the solution for 18.6 h (entries 10−11, Table 3.1).The use of freshly distilled acetone (entry 12) or a thoroughly degassed solution (entry 13) had no positiveeffect in the reaction. The variation of the rate of addition of neat DIPEA (entries 14− 16) or a solutionof it (entry 17) did not improve the results. I decided to switching then the order of addition and have theDIPEA in solution first to then add a solution of NFSI. This change did not yield the desired fluoralkaneeither (entry 18).As it had been observed that the reaction between DIPEA and NFSI was exothermic, we consid-ered the possibility that a reaction prior to the visible-light irradiation was taking place, and could beprecluding the photoredox cycle. The side reaction depicted in Scheme 3.17 was proposed, where diiso-propylethylamine defluorinates NFSI to form a stabilized negative charge on nitrogen (248) along withthe quaternary ammonium species 249. The reaction of NFSI and DIPEAwould leave the catalytic cyclewithout a reductive quencher to generate [Ru(bpy)3]+ from *[Ru(bpy)3]2+, impending thus the formationof the desired alkyl radical. The use of amines as reductive quenchers had to be avoided in the presenceof N−F sources of fluorine if the catalytic photoredox cycle was to be used. Instead of trying to pursuethe reductive pathway of the catalyst, we turned our attention to the use of substrates that would generatean alkyl radical upon oxidation, such as carboxylic acids.+NSSFOO O ON +NSSOO O ONF57 245 248 249Scheme 3.17. Possible side reaction between NFSI and DIPEA.3.3 Decarboxylative fluorination precedents and proposed visible-lightphotoredox approachShortly after our discovery of the ability of N−F reagents to transfer a fluorine atom to an alkyl radi-cal, other studies were reported by different groups on the use of Selectfluor R© to selectively fluorinatealkyl radicals.163,250,251 Concurrent to our own group’s investigation of decarboxylative methods to gen-erate alkyl radicals, Li and coworkers reported that the treatment of various aliphatic carboxylic acidswith AgNO3 and SelectfluorR© in an aqueous solution, generated fluoroalkanes in good yields through a100Chapter 3. Direct C-F bond formation using photoredox catalysisdecarboxylative pathway (Scheme 3.18).163 An initial oxidation of Ag(I) to Ag(II) through the transferof fluoride from Selectfluor R© was proposed. Ensuing decarboxylation of the corresponding aliphaticacid to generate an alkyl radical and Ag(II),252–254 followed by the transfer of fluorine atom to thealkyl radical would then generate the fluoroalkanes reported. The Li group later reported on the useof Selectfluor R© to perform aminofluorination,164 phosphonofluorination,165 and azidofluorination255 ofof unactivated alkenes, all proposed to occur through fluorine atom transfer to an alkyl radical.AgNO3(cat.)SelectfluoracidAcetone/H2O45°COHOFRRRR-CO2HAg(III)CO2Ag(II)Ag(I)FFR-FSelectfluorScheme 3.18. Silver-catalyzed decarboxylative fluorination of aliphatic carboxylic acids.163Investigations performed by my colleagues J. C. T. Leung and J. West, simultaneous to the re-port by Li in 2012,163 showed that the exposure of phenoxyacetic acids to UV light in the presenceof Selectfluor R© effectively promoted fluorination α to the phenolic oxygen, with loss of carbon dioxideto generate fluoromethyl ethers.256 In close collaboration with my colleague C. Chatalova, we expandedthe methodology to also allow access to difluoromethyl ethers (Scheme 3.19).256SelectfluorNaOHhν = 300 nmH2OOOHORO FRXXX=H, F252 253Scheme 3.19. Photo-fluorodecarboxylation of 2-aryloxy and 2-aryl carboxylic acids.256The mechanism that was proposed to explain the generation of the monofluoro and difluoro ethers,shown in Scheme 3.20, involves the initial formation of an excited state 254 upon UV-light irradiation.The excited state is then oxidized by one molecule of Selectfluor R© through an SET process to generate theradical cation 255. This species would then rapidly decarboxylate, similar to a Strecker degradation,257101Chapter 3. Direct C-F bond formation using photoredox catalysisto generate radical 256. Final fluorine atom transfer from another molecule of Selectfluor R© to this radicalgenerates the corresponding fluoromethyl ether.OOOO Fhν O OOSelectfluor O OOO-CO2OOSelectfluor254 255256Scheme 3.20. Photo-fluorodecarboxylationmechanism.256The use of phenoxyacetic acids as radical precursors is an improvement over t-butlylperesters or di-acylperoxides in terms of stability and ease of synthesis. However, even though the UV-light mediateddecarboxylative-flurination effectively provides access to mono- and diffluoromethylethers, its applica-bility is limited by the shift in absorption resulting from changes in the substitution patter at the aryl ring.We envisioned that transitioning to a photocatalyzed fluorination would overcome this problem as theabsorption of the catalyst is not substrate dependant.3.4 Catalytic photoredox decarboxylative fluorinationPhenoxyacetic acids have the additional advantage of no overlap in their light absorption region with thatof the photoredox catalyst [Ru(bpy)3]2+. As Figure 3.6 shows, the absorptions spectra of phenoxyaceticacid (257), Selectfluor R© (59) and [Ru(bpy)3]Cl2 in H2O overlap at lower wavelengths, but not in thevisible light region.102Chapter 3. Direct C-F bond formation using photoredox catalysisWavelength (nm) 200 300 400 500 6003210absorbance (a.u.) Phenoxyacetic acidSelectfluor[Ru(bpy)3]Cl2Figure 3.6. Absorption spectra of phenoxyacetic acid (257), Selectfluor R© (59) and [Ru(bpy)3]Cl2 in H2O.258We envisioned that upon visible light irradiation of [Ru(bpy)3]Cl2, the excited state formed could bereductively quenched by our substrate (phenoxiacetic acid) to generate the radical reactive intermediate.A rapid decarboxylation reaction could then afford an alkyl radical able to trap a fluorine atom from theN−F reagent present in the reaction (Figure 3.7).Ru(II)* Ru(I)Ru(II)N-FreagentProposedreductive quenchingROOOROOORORO F-CO2Figure 3.7. Proposed oxidation of phenoxyacetic acids via visible-light photoredox catalysis.To test this hypothesis, we initially utilized solutions of four different substrates in the presence ofphotocatalyst [Ru(bpy)3](PF6)2 and SelectfluorR©(Scheme 3.21). The substrates chosen were: phenoxy-103Chapter 3. Direct C-F bond formation using photoredox catalysisacetic acid (257), 4-fluorophenoxyacetic acid (259), 4-bromophenoxy-acetic acid (261) and 4-chloro-2-methoxyphenoxyacetic acid (263). Each substrate was examined in three different solvents: acetone,acetonitrile and water. Sodium hydroxide was used to improve the solubility of the substrates in water.The solutions were irradiated with visible light and analyzed using 1H NMR spectroscopy. The reactionproved to be uneffective when either acetone or acetonitrile were used as solvents. However, when thephotocatalytic reaction was performed in H2O, the corresponding fluoromethyl ethers (258, 260, 262and 264) were observed by 1H NMR.+ NFSI + [Ru(bpy)3](PF6)2SolventTime+ NaOHOOHOR1 R2O FR1 R2R1 = H,  R2 = HR1 = F,   R2 = HR1 = Br, R2 = HR1 = Cl, R2 = OCH3R1 = H,  R2 = HR1 = F,   R2 = HR1 = Br, R2 = HR1 = Cl, R2 = OCH3257 258259 260261 262263 264Scheme 3.21. Initial studies on the photoredox decarboxylative fluorination of phenoxyacetic acids.My next objective was to isolate the fluoromethyl ethers formed in each one of these reactions. Dis-appointingly, the purification of fluoroalkanes 258, 260, 262, utilizing flash column chromatography wasunsuccessful, and only traces of the products were obtained. The change from silica gel to alumina andfluorisil as stationary phases, did not improve the isolated yields in any of the cases. The solvent sys-tem was changed from hexanes and ethyl acetate, to petroleum ether and diethyl ether to facilitate theremoval of solvent through rotary evaporation without a hot water bath, as the products were volatile.This strategy did not have a significant impact on the isolated yields.Control experiments were performed to ensure all the components of the reaction were required inthis transformation. The results, summarized in Table 3.2, show that both catalyst and light are essentialto make this reaction proceed. Also, it was observed that the decarboxylative fluorination could alsooccur without the presence of sodium hydroxide (straight from the carboxylic acid), but the presence ofthe base increased the yield, likely due to the increased solubility of the substrate in the reaction media.As the high volatility of the products was having a large impact in the isolated yield, we decidedto prepare phenoxyacetic acids with higher molecular weights to minimize the lose of product in thepurification step. Simultaneously, we started a collaboration with the research group of Prof. J.-F. Paquinin Laval University to explore a wider variety of substrates suitable for our photocatalytic decarboxylativefluorination reaction.104Chapter 3. Direct C-F bond formation using photoredox catalysisTable 3.2. Photoredox decarboxylative fluorination control experiments.SelectfluorNaOH[Ru(bpy)3]Cl2light sourceH2O, 1 hO FOOHO257 258Entry a NaOH (equiv.) Light Sourceb Catalyst (mol %) 1H NMR yield (%)c1 1.5 500 W lamp 0 02 1.5 Noned 1 03 0 500 W lamp 1 644 1.5 500 W lamp 1 84a Conditions: 0.1 mmol phenoxyacetic acid, 3.5 equiv. of Selectfluor R©, 0.1 m solution in H2O;b The lamp was placed 30 cm away from the reaction flask; c 1H NMR yield determined using1,3,5-trimethoxybenzene as internal standard; d The reaction flask was covered with aluminumfoil, while all other reaction conditions were maintained the same.3.4.1 Synthesis of phenoxyacetic acidsSome phenoxyacetic acids, such as 257, 270, 259 and 261, are commercially available and were usedas received. Phenoxyacetic acid 263 had been previously synthesized in the laboratory by my colleagueClaire Chatalova Sazepin for other studies. The rest of the phenoxyacetic acids were prepared throughthe two step procedure shown in Scheme 3.22.K2CO3DMFOHROROEtOBrOEtONaOHMeOHOROHOOOHOt-Bu t-BuOOHOOOHOPhPhOONaOO81% 74% 78%44%NHOHOO55%OOHOClOOMeOHONaOO265 266 267 268269 270 263Scheme 3.22. Synthesis of phenoxyacetic acid substrates. Yields are reported over two steps..105Chapter 3. Direct C-F bond formation using photoredox catalysisThe synthesis of substrates 265−269 started from the corresponding phenol, which was treated withpotassium carbonate in N,N-dimethylformamide followed by bromoethyl acetate, to perform the alky-lation of the phenoxide via an SN2 reaction. The resulting ethyl ester was then hydrolized to yield thesubstituted phenoxyacetic acid, typically as white solids in moderate to good yields. The substrates wereselected based on the increasing steric bulk of the aromatic ring, as well as their different electroniccharacteristics, to analyze the effect these factors would have on the photocatalytic decorboxylative fluo-rination reaction.3.4.2 Catalytic photoredox decarboxylative fluorination scopeWith the different phenoxyacetic acids in hand, I proceeded to investigate each one of them in our pho-toredox decarboxylative fluorination conditions. Of all the substrates, the one that was synthesized firstwas 4-phenylphenoxyacetic acid (267). Optimization studies were performed with this substrate, and theresults are summarized in Table 3.3.Table 3.3. Optimization photoredox decarboxylative fluorination reaction conditions for substrate 267.SelectfluorNaOHCatalystLight sourceH2O:CH3CNO FOOHOPhPh267 271Entry Light Time Solvent Catalyst Selectfluor R© NaOH 1H NMRsource (h:min) ratio (equiv.) (equiv.) yield (%)a1 Sun lamp 5.0 1:0 [Ru(bpy)3](PF6)2 1.5 0.5 72 Sun lamp 1.5 3:1 [Ru(bpy)3](PF6)2 1.5 0.5 273 Sun lamp 8.0 1:3 [Ru(bpy)3](PF6)2 1.5 0.5 274 Sun lamp 6.0 3:1 [Ru(bpy)3](PF6)2 4.0 0.5 555 23 W 5.3 3:1 [Ru(bpy)3](PF6)2 4.0 0.5 706 500 W 5.3 3:1 [Ru(bpy)3](PF6)2 4.0 0.5 407 500 W 5.5 3:1 [Ru(bpy)3](PF6)2 1.5 0.5 25b8 500 W 5.5 2:1 [Ru(bpy)3](PF6)2 1.5 0.5 55b9 500 W 5.5 1:1 [Ru(bpy)3](PF6)2 1.5 0.5 67b10 500 W 5.5 1:2 [Ru(bpy)3](PF6)2 1.5 0.5 54b11 500 W 6.0 1:1 [Ru(bpy)3]Cl2 1.5 0.5 56b12 500 W 22.5 1:1 [Ru(bpy)3](PF6)2 1.5 0.5 6013 500 W 22.5 1:1 [Ru(bpy)3]Cl2 1.5 0.5 4814 500 W 2.5 1:1 [Ru(bpy)3]Cl2 3.5 1.5 9315 500 W 2.6 1:1 [Ru(bpy)3]Cl2 3.5 1.5 92ca 1H NMR yiled determined using 1,3,5-trimethoxybenzene as internal standard; b reaction did not go to completion;c isolated yield.106Chapter 3. Direct C-F bond formation using photoredox catalysisThe first problem that substrate 267 presented was poor solubility inwater, both as the protonated acidand the carboxylate species. This was inevitably reflected in the poor yield of fluoromethyl ether 271 ob-served in entry 1 of Table 3.3 (7%), even after 5 h of irradiation. Utilizing a 3:1 ratio of water/acetonitrileshowed a slight improvement in the yield (27%, entry 2) after only 1.5 h of irradiation. The same yieldwas obtained when the ratio was reversed to 1:3 water/acetonitrile, although it was necessary to irradiatethe sample for 8.0 h (entry 3). Increasing the number of equivalents of Selectfluor R© from 1.5 to 4, andswitching back to a 3:1 ratio of water/acetonitrile afforded 271 in 55% yield after 6.0 hours of irradiation(entry 4). Switching the light source from a sun lamp (GE 275W) to a low intensity 23W lamp improvedthe yield of fluoromethyl ether 271 to 70% after 5.3 h of irradiation (entry 5), while using a higher inten-sity 500 W lamp yielded only 40% of the same product (entry 6). The experiments described in entries7− 10 explored the use of 1.5 equiv. of Selectfluor R© and the 500 W lamp while systematically varyingthe ratio of water to acetonitrile used. From these series of experiments, the 1:1 water/acetonitrile ratioseemed to work best for this particular substrate. In the experiments of entries 7 − 10, remnants of thestarting material were detected, likely due to the poor solubility of the substrate in the different solventsystems. We also explored the use of the [Ru(bpy)3]Cl2 catalyst instead of [Ru(bpy)3](PF6)2, which hadbeen used in the experiments thus far. We expected that the greater solubility of the catalyst’s chloridesalt would improve the yield of the reaction, but little difference was observed when the counter ion waschanged (compare entry 9 vs entry 11). Increasing the irradiation time to 22.5 h did not improve the yieldof 271, regardless of the catalyst used (entries 12 − 13). Finally, increasing the number of equivalentsof Selectfluor R© to 3.5, while maintaining the solvent ratio 1:1 and the chloride version of the catalystgratifyingly provided the desired fluoromethylether in 93% yield after 2.5 h of irradiation with a 500W lamp (entry 14). Scaling up of the reaction under the optimized conditions provided 271 in 92%isolated yield.The optimized conditions for substrate 267 were used in the successful photocatalytic decarboxyla-tive fluorination of the rest of the phenoxyacetic acid substrates in good to excellent yields (Scheme 3.23).Phenoxyacetic acid 257 generated fluoromethylether 258 in 84% yield, determined by using 1,3,5-trime-thoxybenzene as the internal standard. The use of electron-withdrawing groups, such as fluorine (260)and bromine (262) showed a slight decrease in yield compared to phenoxyacetic acid with 67% and73% yields respectively. Increasing the alkyl substitution on the aromatic ring at the ortho, meta andpara positions did not have a significant impact on the yield of the fluorinated products (272, 273, 274).The fluorination of 269 was successfully performed to yield difluoromethylether 275 in 81% yield. Flu-oromethyl ethers 264, 276 and 277 were obtained in poor yields under our reaction conditions and the107Chapter 3. Direct C-F bond formation using photoredox catalysisanalysis of the crude 1H NMR specta revealed the presence of more than one fluorinated product. Fluori-nation of the aromatic ring in these substrates accounted for several of the multiple by-products observed.OROHO 3.5 equiv. Selectfluor,1.5 equiv. NaOH(aq),1 mol % [Ru(bpy)3]Cl2Visible light, 1:1 H2O/CH3CNORFO Ft-Bu t-BuO F O FPhPhO FO74% (95%) 65% (92%) 92% (93%)81%cNHOO FFO F O FFO FBr17% (84%) 21% (67%) 56% (73%)a 79% (85%)aO Ft-Bu(30%)b (0%)O FCl(25%)bOMeF258 260 262 272273 274 271 264275 276 277Scheme 3.23. Catalytic photoredox decarboxylative fluorination scope. NMR yields are presented in paren-thesis. aExperiments performed by O. Mahe´ in the Paquin Laboratory at the University of Laval;bCatalyst[Ru(bpy)3](PF6)2 was used;c2.2 equiv. of Selectfluor R© were used..It is important to note that while the use of our new visible-light mediated decarboxylative fluorina-tion conditions provides comparable yields with the UV-light mediated methodology previously reportedby our group,256 methylfluoroethers such as 271 and 274, which performed poorly under the previousUV-light mediated decarboxylative fluorination, can now be easily accessed under our new visible-lightconditions in excellent yields.Thus far in the investigation, only phenoxyacetic acid derivatives had been explored. In an ef-fort to expand the scope of our reaction further, alkoxyacetic acid 279 was synthesized. Alcohol 3-phenylpropan-1-ol (278) was alkylated with ethyl bromoacetate and immediately saponified (Scheme 3.24)to yield alkoxyacetic acid 279.108Chapter 3. Direct C-F bond formation using photoredox catalysis1)      NaOH, THF2) NaOH, MeOHBrOEtOOH OOHO278 279Scheme 3.24. Synthesis of alkoxyacetic acid 279.Alkoxyacetic acid 279 was then subjected to the optimized visible-light mediated photocatalytic de-carboxylative fluorination conditions (Scheme 3.25). 1H NMR analysis of the crude reaction revealedthe presence of starting material, but unfortunately no trace of the desired fluoromethyl ether 280. Thisresults suggests that the presence of aromatic ring α to the oxygen plays a determining role in the fluo-rination reaction.Selectfluor, NaOH[Ru(bpy)3]Cl2H2O/CH3Visible lightOOHOO F279 280Scheme 3.25. Visible-light photocatalytic mediated decarboxylative decarboxylation of alkoxyacetic acid280.Other fluoroalkanes we were interested in investigating were difluoromethyl ethers. As a proof ofconcept, phenoxyacetic acid 281, which I had previously synthesized for other studies, was subjectedto our visible-light mediated photocatalytic decarboxylative fluorination conditions (Scheme 3.26). The1H NMR analysis of the reaction mixture revealed that no difluormethyl ether 282 was generated underthis conditions, and only starting material was observed.Selectfluor, NaOH[Ru(bpy)3]Cl2H2O/CH3Visible lightClClOOHOClClO FF F281 282Scheme 3.26. Visible-light photocatalytic mediated decarboxylative decarboxylation of α-fluoroacetic acid281.109Chapter 3. Direct C-F bond formation using photoredox catalysisThe next substrate that was used to probe our visible-light photoredox catalysis methodology in thesynthesis of difluoromethylethers was 285. This substrate was synthesized through the initial alkylationof 4-phenylphenol (Scheme 3.27, 283) with ethyl bromofluoroacetate to yield α-fluoro ester 284 in 62%yield. Subsequent saponification provided 285 in 97% yield.K2CO3DMFOHOOEtOBrOEtONaOHMeOHOOHOFPhPh PhF F62% 97%283 284 285Scheme 3.27. Synthesis of α-fluoroacetic acid 285.When α-fluoroacetic acid 285 was subjected to our optimized photocatalytic fluorination conditions(Scheme 3.28), only traces of the desired difluoromethyl ether 286 were observed. Increasing the irra-diation time to 3.2 h did not have any effect in the amount of product generated. The failure to form thedifluoromethyl ethers may be a direct consequence of the presence of a fluoride atom next to the phenolicoxygen, as it would be more difficult to oxidize this position (see Figure 3.7). The species involved in theoxidation of the ring is definitely strong enough for simple aryloxyacetic acid, but it seems to be belowits scope to oxidize α-fluoroacetic acids.Selectfluor, NaOH[Ru(bpy)3]Cl21:1 H2O/CH3Visible lightPhOOHOPhO FFF285 286Scheme 3.28. Visible-light photocatalytic mediated decarboxylative decarboxylation of α-fluoroacetic acid281.3.4.3 Photoredox fluorination of estrone derivativeThe hormone estrone was selected to illustrate the use of our visible-light photocatalytic methodologyin the context of natural product synthesis. To install the phenoxyacetic acid functional group, estrone(287) was alkylated with ethyl bromoacetate to yield 288 in 72% yield (Scheme 3.29). Saponificationwith LiOH in methanol yielded the desired estrone derivative 289 in 74% yield.110Chapter 3. Direct C-F bond formation using photoredox catalysisK2CO3DMFBrOEtOLiOHMeOH72% 74%HOOHHHEstroneOOHHHOEtOOOHHHOHO287 288 289Scheme 3.29. Synthesis of estrone derivative 289.When the phenoxyacetic acid derivative of estrone, 289, was subjected to our visible-light mediatedphotocatalytic decarboxylative fluorination, multiple fluorinated products were observed in the 19FNMR.When the base was not added to the reaction (entry 1, Table 3.4), one product was observed in the1H NMR spectra. Scale up of the reaction using the base-free conditions, followed by flash columnchromatography purification of the reaction mixture revealed the presence of multiple products. Theexpected fluoroalkane 290 was the minor component of the mixture, isolated in 25% yield.Table 3.4. Optimization of photoredox decarboxylative fluorination reaction conditions for substrate 290.Selectfluor, NaOH[Ru(bpy)3]Cl2H2O:CH3Visible light500 WOOHHHHOOOOHHHF289 290Entry Time Solvent Selectfluor R© NaOH 1H NMR Isolated(min) ratio (equiv.) (equiv.) yield (%)a yield (%)1 55 1:1 3.5 0 - - - 252 40 1:0 1.5 1.0 26 - - -3 85 1:3 1.5 0 7 - - -4 75 1:1 1.5 0 60 - - -5 103 1:1 1.1 0 57 - - -6 72 1:1 1.5 0 - - - 51a 1H NMR yiled determined using 1,3,5-trimethoxybenzene as internal standardTo avoid polyfluorination of 289, the number of equivalents of Selectfluor R© was reduced from 3.5 to1.5. The use of equimolar quantities of the acid and NaOH to prevent deprotonation at other sites (entry2, Table 3.4) yielded only 26% of fluoromethyl ether 290. Increasing the amount of acetonitrile in thesolvent mixture under base-free conditions (entry 3) provided an even lower yield (7%). We returnedto the 1:1 solvent ratio while keeping Selectfluor R© at 1.5 equivalents (entry 4) to afford the desired111Chapter 3. Direct C-F bond formation using photoredox catalysisfluoroalkane in 60% by 1H NMR. A decrease in the amount of Selectfluor R© to 1.1 equivalents (entry5) did not further improve the yield. The conditions of entry 4 were used to scale up the reaction andprovided fluoromethyl ether 290 in an isolated yield of 51%.The successful fluorination of estrone derivative 289 illustrates the potential of our new visible-lightmediated methodology in the context of total or late stage synthesis. Remarkably, when this substratewas subjected to our previously reported UV-light mediated conditions, multiple fluorine signals wereobserved in the 19F NMR spectra, none of which corresponded to the desired fluoromethyl ether 290.3.5 Mechanistic studiesWhile our decarboxylative fluorination of phenoxyacetic acids provided satisfactory results, we had littleevidence of the mechanism that was taking place in this transformation. Several possibilities existed toexplain the observed results, specially in the catalytic cycle of [Ru(bpy)3]2+. Spectroscopic and electro-chemical studies were performed to collect evidence to elucidate the reaction mechanism.As it was shown in Figure 3.7, we initially proposed that the interaction of the excited state of[Ru(bpy)3]2+ with phenoxyacetic acid would result in the oxidation of the phenolic oxygen of the sub-strate with concomitant generation of [Ru(bpy)3]+ in solution through an SET process. Ensuing decar-boxylation of the resulting oxidized species would generate an alkyl radical capable of undergoing afluorine atom transfer from an N−F reagent to afford fluoromethyl ethers. Our proposed mechanism waslogical, but there were other possibilities that explained just as reasonably the reactivity that we were ob-serving. The catalyst could be reacting through an oxidative pathway (Figure 3.8), whereby the excitedtriplet state *3[Ru(bpy)3]2+ gets oxidized by Selectfluor R© to generate [Ru(bpy)3]3+. This ruthenium (III)species would, in turn, oxidize the phenoxyacetic acid substrates to generate the oxidized intermediate291. Another possibility was an energy transfer from the triplet excited state *3[Ru(bpy)3]2+ to the sub-strate. This pathway would then intercept the mechanism proposed for the photofluorodecarboxylationfluorination reaction.256Some key questions have to be answered to better understand what mechanism is operating, for in-stance what species is the excited state *3[Ru(bpy)3]2+ interacting with upon its formation? Selectfluor R© orphenoxyacetic acid? If the answer is Selectfluor R©, then what is oxidizing the phenoxyacetic acids, an-other Selectfluor R© molecule or [Ru(bpy)3]3+? To address these concerns, we started collaborations withthe research groups of Prof. Wolf and Prof. Bizzotto at UBC to study the reaction mechanism throughlaser spectroscopy and electrochemical techniques.112Chapter 3. Direct C-F bond formation using photoredox catalysis[Ru(bpy)3]2+*3[Ru(bpy)3]2+[Ru(bpy)3]+[Ru(bpy)3]3+MLCT+ISCOxidativequenchingReductivequenchingOOOOOONNFCl 2+NNFClNNFCl 2+NNFClOOOOOOEnergytransferEnergy transferOOOOOOSelectfluor OOOhν291291291Figure 3.8. Photoexcitation, oxidative and reductive quenching cycles for [Ru(bpy)3]2+.3.5.1 Transient absorption spectroscopy studiesTo determine what is quenching the *3[Ru(bpy)3]2+ excited state, we performed ultrafast transient ab-sorption spectroscopy studies. Transient absorption spectroscopy (TAS) is a technique that permits theanalysis of short lived excited states. This spectroscopic technique relies in the use of ultrafast lasers toinvestigate events taking places on a timescale as short as 50 fs.259 In TAS, first a laser pulse is usedto promote a fraction of the molecules in the sample to an electronically excited state (pump pulse) andan absorption spectrum is recorded. A second low intensity pulse (probe pulse) is passed through thesample with a delay time and a second absorption spectrum is recorded. A difference absorption spec-trum is then calculated by subtracting the absorption spectrum of the ground state from the spectrum ofthe excited state. In addition, a profile of difference absorption as a function of time and wavelength,113Chapter 3. Direct C-F bond formation using photoredox catalysiscontaining information of the dynamic processes occurring in the photoactive system, can be acquiredby varying the delay time between the two pulses and recording the difference at every point.The Wolf research group, in collaboration with LASIR at UBC, specializes in the use of transient ab-sorption spectroscopy to characterize the excited state properties of new ruthenium (II) complexes.260–262Since the study of the behaviour of the excited in our system was crucial to understudying the overallmechanism, we started a collaboration with Prof. Wolf to use transient absorption spectroscopy to aid inthe elucidation of a portion of the reaction mechanism. Dr. M. Majewski performed TAS experimentsto help us determine which catalytic pathway — reductive, oxidative or energy transfer — occurs duringour photoredox decarboxylative fluorination reaction. My contribution to this part of the study consistedin the preparation of the required substrate, Selectfluor R© and [Ru(bpy)3]2+ solutions.The strategy consisted in testing individually the two possible excited state quenchers, Selectfluor R© andphenoxyacetic acid, to assess which one interacted with *3[Ru(bpy)3]2+ and rule out one or two of thepossible catalytic pathways. First, the transient absorption spectra of [Ru(bpy)3](PF6)2 in H2O/CH3CNwas collected (Figure 3.9 a) as a reference. The spectra shows the characteristic band at ∼ 370 nm cor-responding to the presence of a reduced bipyridyl radical anion along with the bleaching at 450 nm,corresponding to the generation of ruthenium (III) (Figure 3.9 a, black). As time elapses, these two sig-nals become smaller (Figure 3.9 a, red) and eventually disappear after 2008 ns (Figure 3.9 a, purple) asall the ruthenium molecules decay back to their ground-state. The collected spectrum is consistent withprevious reports.263,264Subsequently, a solution of [Ru(bpy)3](PF6)2 in the presence of phenoxyacetic acid (257) was ana-lyzed using TAS. In the spectrum shown in Figure 3.9 b, the behaviour of the excited state *3[Ru(bpy)3]2+ isthe same as the one observed in the transient absorption spectrum of the [Ru(bpy)3]2+ alone. The lack ofchange in the spectrum b compared to a, suggests that the excited state does not interact with phenoxy-acetic acid, which rules out the energy transfer and reductive pathways of the catalytic cycle.Finally, a solution of [Ru(bpy)3](PF6)2 in the presence of SelectfluorR© was analyzed using transientabsorption spectroscopy. The resulting spectrum, Figure 3.9 c, shows a decrease in intensity of the bandat ∼ 370 nm after 278 ns (c black), compared to the same data point obtained when Selectfluor R© isabsent. The disappearance of the∼ 370 nm and 450 nm bands occurs more rapidly, which suggests thatthe excited state is not returning to the ground state through a normal decay, but rather is being “con-sumed” by another species present. Moreover, a positive band appears centred at 450 nm (c purple).This band was not found to decay in the time regimes studied (t ≤ 10 µs). These findings are more con-sistent with an oxidative pathway (Figure 3.8) whereby the excited state *3[Ru(bpy)3]2+ is first oxidizedby Selectfluor R© to [Ru(bpy)3]3+.114Chapter 3. Direct C-F bond formation using photoredox catalysisFigure 3.9. Excited state difference spectra of (a) [Ru(bpy)3](PF6)2, (b) [Ru(bpy)3](PF6)2 (0.11m) in thepresence of 2-phenoxyacetic acid (257, 2.5 mm) and (c) [Ru(bpy)3](PF6)2 (0.11 m) in the presence ofSelectfluor R© (2.6 mm) in 1:1 H2O/CH3CN (λmax = 450 nm).3.5.2 Cyclic voltammetry studiesTo generate the α-oxo methyl radical, an initial oxidation of phenoxyacetic acid was proposed. Sincewe have demonstrated that the triplet excited state *3[Ru(bpy)3]2+ does not directly oxidize our sub-strate, the other two possible oxidizing species present are [Ru(bpy)3]3+ and Selectfluor R©. As depictedin Figure 3.10, either *3[Ru(bpy)3]2+, [Ru(bpy)3]3+ or Selectfluor R© can potentially act as the oxidant ofphenoxyacetic acid. According to the TAS results, *3[Ru(bpy)3]2+ is not strong enough to oxidize phe-noxyacetic acid. It could be assumed that the oxidation potential of 257 is higher than +0.84 V, whichwould automatically rule out Selectfluor R© as the oxidant.115Chapter 3. Direct C-F bond formation using photoredox catalysis[Ru(bpy)3]3+*3[Ru(bpy)3]2+[Ru(bpy)3]+[Ru(bpy)3]3+NNFCl 2+NNFClE (V vs SCE)Ox.Red.-2.0 -1.0 0 1.0 2.0*3[Ru(bpy)3]2+-0.83 +0.33 +0.84 +1.29[Ru(bpy)3]2+[Ru(bpy)3]2+[Ru(bpy)3]+-1.33Figure 3.10. Redox pairs in the photocatalytic decarboxylative fluorination reaction.To unambiguously determine if [Ru(bpy)3]3+ oxidizes phenoxyacetic acid, we conducted cyclic voltame-try (CV) studies in collaboration with the Bizzotto group at UBC. Dr. Jannu´ R. Casanova-Moreno helpedme measure the oxidation potentials of two different species: Selectfluor R© and phenoxyacetic acid.The experiments were performed utilizing a saturated calomel electrode (SCE) as reference, alongwith a platinum coil counter electrode and a graphite working electrode. The use of a graphite workelectrode in an aqueous solution limits the upper oxidation potential that can be measured to that ofwater oxidation (+1.23 V).Cyclic voltammetry of phenoxyacetic acid (257) is shown in Figure 3.11. In the absence of a clearpeak, a half wave potential (E1/2), defined as the inflection point in the i-E (i = Current, E = Potential)curve was used as an indication of the electrochemical characteristics of the analytes. The half wavepotential was calculated to be E1/2 = +1.01 V vs SCE.The cyclic voltammetry of phenoxyacetic acid shows the peak corresponding to the oxidation of theanalyte, but lacks the peak corresponding to the reverse (reduction) reaction. The decomposition of theoxidized species, or the low reaction rate of the reverse reaction are some of the factors that could bepreventing the reduction peak from appearing in the CV.116Chapter 3. Direct C-F bond formation using photoredox catalysis0 0.2 0.4 0.6 0.8 1 1.2 1.4Potential (V)01x10-52x10-53x10-54x10-55x10-5Current (A)BlankPhenoxyacetic acid (1a)Figure 3.11. Cyclic voltammetry of phenoxyacetic acid (257).To appropriately compare the measured oxidation potential E1/2 of 257, the electrochemical proper-ties of Selectfluor R© were also studied under the same conditions. Cyclic voltammetry of Selectfluor R© isshown in Figure 3.12. The half wave potential was calculated to be E1/2 = +0.27 V vs SCE.0 0.2 0.4 0.6 0.8 1Potential (V)-8x10-6-6x10-6-4x10-6-2x10-602x10-6Current (A)BlankSelectfluorFigure 3.12. Cyclic voltammetry of Selectfluor R©.117Chapter 3. Direct C-F bond formation using photoredox catalysisFrom the E1/2 oxidation potentials measured, we can now unambiguously say that SelectfluorR© isnot strong enough to oxidize phenoxyacetic acid. Thus, we can confidently say that [Ru(bpy)3]3+ is thespecies that performs the oxidation of phenoxyacetic acid in this reaction, which is consistent with theoxidative pathway mechanism suggested by the results obtained from transient absorption spectroscopy.3.6 ConclusionThe use of photoredox catalysis has enabled us to the successfully synthesize aryl fluoromethyl ethersfrom phenoxyacetic acids through a decarboxylave fluorination reaction in good to excellent yields. Thisconstitutes the first example of a visible-light mediated photocatalytic C−F bond formation.The successful photocatalytic decarboxylative fluorination of an estrone derivative illustrates thepotential of this methodology as a tool for late stage total synthesis. Nevertheless, the generation of alkylradicals from alkoxyacetic acids remains a challenge to our current reaction conditions.Spectroscopic and electrochemical data support the oxidative quenching of the ruthenium catalystexcited state, *[Ru(bpy)3]2+, as the mechanism involved. It was also determined that Selectfluor R© wasnot a strong enough oxidant to accept one electron from the phenoxyacetic acid substrates.3.7 Experimentals3.7.1 General experimentalAll reactions were performed under nitrogen atmosphere in flame-dried glassware unless otherwisenoted. Distilled water sparged with argon was used to perform the photoredox reactions. All othersolvents, including those for NMR analysis, were used without further purification. All chemicals werepurchased from commercial sources and used as received. Thin layer chromatography (TLC) was per-formed on Whatman Partisil K6F UV254 pre-coated TLC plates or on Silicyle silica gel 60 A˚ F254 TLCplates. Chromatographic separations were effected over Silicycle Siliflash F60 silica gel. 3.0 m aqueoussodium hydroxide solution was prepared using distilled water.Infrared (IR) spectra were obtained using a PerkinElmer Frontier FT-IR/FIR Spectrometer with at-tenuated total reflectance (ATR) or a Thermo Scientific Nicolet 380 FTIR spectrometer. Wavenumbersare reported in inverse centimeters (cm−1). UV/Vis absorption spectra were obtained with a Varian Cary5000. Proton nuclear magnetic resonance (1H NMR) spectra were recorded using a Bruker AV-300 orAV-400 spectrometer. Fluorine nuclear magnetic resonance (19F NMR) spectra were recorded using aBruker AV-300. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded using a BrukerAV-300 or AV-400 spectrometer. Chemical shifts are reported in parts per million (ppm) and are ref-118Chapter 3. Direct C-F bond formation using photoredox catalysiserenced to the centerline of deuterochloroform (7.27 ppm 1H NMR; 77.0 ppm 13C NMR), DMSO−d6(2.50 ppm 1H NMR; 39.5 ppm 13C NMR), or acetonitrile−d3 (1.94 ppm1H NMR; 1.3 ppm 13C NMR).For 19F NMR, CFCl3 (0.0 ppm) is used as the external standard. High resolution mass spectra (HRMS)were recorded on either a Waters, a Micromass LCT spectrometer (HR-ESI), a Kratos MS-50 (HR-EI)or a LC/MS-TOF Agilent 6210 (HR-ESI).Photochemical reactions were performed using either a GE 275W GS Sunlamp or a 500 W halogenportable work light. Most photochemical reactions were performed in Biotage R©microwave vials placed30 cm from the light source. Transient absorbance spectra were collected using a Princeton InstrumentsSpectra Pro 2300i Imaging Triple Grating Monochromator/Spectrograph with a Hamamatsu DynamicRange Streak Camera (excitation source: EKSPLAPL2241Nd:YAG laser, fwhm= 35 ps). To produce anexcitation wavelength of 450 nm, an EKSPLA Model PG401 Picosecond Optical Parametric Generatorwas pumped at 355 nm by the PL2241 mode-locked laser. Monoexponential fits were calculated usingOrigin 7.5.3.7.2 General synthesis aryloxy acids1)      K2CO3, DMF2) NaOH, MeOHOHROROHOBrOEtOTo a 0.3 m solution of phenol (1 equiv.) in N,N-dimethylformamide (DMF), was added K2CO3 (1.2equiv.), and the resulting solution was stirred at ambient temperature for 30 min. Then was added ethylbromoacetate (1.2 equiv.) in one portion and the resulting solution was stirred at ambient temperaturefor 18 h. The solvent was removed using a high vacuum rotary evaporator until the volume was reducedto at least one third. To the resulting suspension was added H2O (a volume equivalent to the amountof DMF initially used), and dichloromethane was used to extract (3 x half the volume of DMF initiallyused). The combined organic extracts werewashed with brine, dried over Na2SO4, filtered and the solventremoved under reduced pressure via rotary evaporation. Flash column chromatography (hexanes/AcOEt)was performed to remove polar impurities. The corresponding ester was dissolved in methanol. To theresulting 0.5 m solution was added a 15% m/v NaOH(aq) solution (5.0 equiv.). The reaction mixturewas stirred for 18 h at ambient temperature. The solvent was removed via rotary evaporation and theresidue redissolved in the minimal amount of H2O possible. Concentrated hydrochloric acid was added119Chapter 3. Direct C-F bond formation using photoredox catalysisdrop wise until the pH was acidic. The white solid formed was filtered off and washed with cold H2O (5mL). The solid was dried under high vacuum for 24 h and pure aryloxyacetic acid was obtained.Phenoxyacetic acid (257), 4-fluorophenoxyacetic acid (259), and 4-bromophenoxy acetic acid (261),were acquired from commercial sources and were used as received.OOHO2652,4-Di-tert-butylphenoxyacetic acid (265). 2,4-Di-t-butylphenol (2.10 g, 10.2 mmol) was sub-jected to the general aryloxyacetic acid synthesis procedure to yield 0.81 g of acid 265 as a white solidin 81% yield over two steps. 1H NMR (300 MHz; CDCl3): δ 7.37 (d, J = 2.4 Hz, 1H), 7.18 (dd, J =8.5, 2.4 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 4.70 (s, 2H), 1.43 (s, 9H), 1.31 (s, 9H). 13C NMR (101 MHz;CDCl3): δ 171.0, 154.4, 143.1, 137.4, 123.9, 123.2, 111.4, 65.2, 34.9, 34.1, 31.4, 29.8. IR (neat): 2960,1739, 1712, 1362, 1233, 1105, 926, 825, 804 cm−1. HRMS-ESI (m/z) [M+Na]+ calcd for C16H24O3Na:287.1623; found: 287.1631.OOHO2662,4,6-Trimethylphenoxyacetic acid (266). 2,4,6-Trimethylphenol (0.83 g, 6.1 mmol) was subjectedto the general aryloxyacetic acid synthesis procedure to yield 0.98 g of acid 266 as needle shaped whitecrystals in 74% yield over two steps. 1H NMR (400 MHz; CDCl3): δ 6.84 (s, 2H), 4.45 (s, 2H), 2.25(d, J = 5.0 Hz, 9H). 13C NMR(101 MHz; CDCl3): δ 173.1, 152.5, 134.4, 130.2, 129.8, 68.6, 20.8, 16.3.IR (neat): 2908, 1708, 1733, 1483, 1435, 1255, 1201, 1146, 852, 794, 668 cm−1. HRMS-ESI (m/z)[M+Na]+ calcd for C11H14O3Na: 217.0841; found: 217.0840.120Chapter 3. Direct C-F bond formation using photoredox catalysisOOHOPh2674-Phenylphenoxyacetic acid (267). 4-Phenylphenol (3.41 g, 20.0 mmol) was subjected to the gen-eral aryloxyacetic acid synthesis procedure to yield 3.52 g of acid 267 as a white solid in 78% yield overtwo steps. 1H NMR (400 MHz; DMSO−d6): δ 7.60 (t, J = 7.3 Hz, 4H), 7.43 (t, J = 7.7 Hz, 2H), 7.31(t, J = 7.3 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 4.70 (s, 2H). 13C NMR(101 MHz; DMSO−d6): δ 170.2,157.4, 139.8, 133.0, 128.8, 127.7, 126.8, 126.2, 114.9, 64.7. IR (neat): 2584, 1734, 1709, 1484, 1237,1182, 914, 838, 763, 702 cm−1.OONaOONaOO269Sodium 2,2′-(((1-phenylethane-1,1-diyl)bis(4,1-phenylene))bis(oxy))diacetate (269). 4,4′-(1-Phenylethylidene)bisphenol (5.83 g, 20.1 mmol) was subjected to the general aryloxyacetic acid syn-thesis procedure, but the ester was not fully hydrolyzed. A second saponification step was, therefore,necessary. To a 0.5 m solution of the diester in MeOH, was added LiOH ·H2O (5.33 g, 127 mmol) andthe resulting solution was heated to reflux over night. The solvent was removed using rotary evaporationunder reduced pressure. The resulting white solid was not soluble in either neutral or acidic (pH < 2)aqueous conditions. NaOH was added until basic pH (pH > 12) was reached. The solution was heateduntil one third of the water was removed. The resulting solution was cooled to 0 ◦C and the solids wereisolated by vacuum filtration. The resulting solids were washed with 5 mL of cold water (0 ◦C) anddried in vacuo overnight. 3.93 g of dicarboxylate 269 were obtained as a white powder in 44% yield overtwo-steps. 1H NMR (400 MHz; DMSO−d6): δ 7.23 (t, J = 7.5 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 7.00(d, J = 7.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 4H), 6.72 (d, J = 8.9 Hz, 4H), 4.14 (s, 4H), 2.00 (s, 3H). 13CNMR (101 MHz; DMSO−d6): δ 172.0, 156.8, 149.7, 140.6, 129.1, 128.4, 128.0, 125.9, 113.9, 67.7,50.9, 30.5. IR (neat): 3376, 1598, 1508, 1429, 1416, 1336, 1232, 1189, 1062, 808 cm−1. HRMS-ESI(m/z) [M+Na]+ calcd for C24H22O6Na: 429.1314; found: 429.1319.121Chapter 3. Direct C-F bond formation using photoredox catalysisOOHHHHOO2892-(((8R,9S,13S,14S)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)acetic acid (289). Estrone (1.55 g, 2.03 mmol) was subjected to the generalaryloxyacetic acid synthesis procedure. The solid obtained after acidification with concentrated HClwas recrystallized from the minimal amount of hot EtOH to yield 0.34 g of acid 289 as flake-like whitecrystals in 53% yield over two steps. 1H NMR (400 MHz; CDCl3): δ 7.22 (d, J = 8.6 Hz, 1H), 6.73(dd, J = 8.6, 2.7 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 4.66 (s, 2H), 2.89 (t, J = 4.4 Hz, 2H), 2.52 (dd,J = 19.0, 8.5 Hz, 1H), 2.39 (dd, J = 10.1, 5.8 Hz, 1H), 2.27-1.94 (m, 5H), 1.66-1.38 (m, 6H), 0.91 (s,3H). 13C NMR (101 MHz; CDCl3): δ 221.5, 173.9, 155.5, 138.3, 133.7, 126.7, 114.9, 112.2, 65.0, 50.5,48.2, 44.1, 38.4, 36.0, 31.7, 29.7, 26.6, 26.0, 21.7, 14.0. IR (neat): 2929, 1760, 1709, 1611, 1572, 1493,1440, 1258, 1199, 1118, 1076, 895, 871, 809, 782, 746, 674 cm−1. HRMS-ESI (m/z) [M+Na]+ calcdfor C20H24O4Na: 351.1572; found: 351.1571.3.7.3 NMR-scale catalytic photoredox decarboxylative fluorination studiesTo a 0.5-2.0mLmicrowave vial containing the corresponding phenoxyacetic acid (0.1mmol, 1.0 equiv.),Selectfluor R© (0.35 mmol, 3.5 equiv.) and tris(2,2′-bipyridyl)dichlororuthenium(II) hexahydrate (0.001mmol, 0.01 equiv) under N2, was added either 1.0 mL of Ar sparged H2O or 1.0 mL a 1:1 mixture ofH2O/CH3CN degassed with Ar, followed by a 3.0 m NaOH(aq) solution (0.15 mmol, 1.5 equiv.). Thereaction mixture was irradiated using a 500 W visible light lamp, placed at 30 cm from the reaction, for1 h. At the end of the reaction, was added 1,3,5-trimethoxybenzene (0.03 mmol, 0.3 equiv.) as internalstandard, followed by 0.5 mL of CDCl3. The organic layer was removed using a pipette and filteredthrough Na2SO4 previous to NMR analysis.122Chapter 3. Direct C-F bond formation using photoredox catalysis3.7.4 General photoredox decarboxylative fluorination procedureSelectfluor, NaOH[Ru(bpy)3]Cl2.H2OH2O/CH3Visible lightORFOROHOTo a 2.0-5.0 mL microwave vial containing the corresponding phenoxyacetic acid (0.5 mmol, 1.0equiv.), Selectfluor R© (1.75 mmol, 3.5 equiv.) and tris(2,2′-bipyridyl)dichlororuthenium(II) hexahydrate(0.005 mmol, 0.01 equiv) under N2, was added a 1:1 mixture of H2O/CH3CN degassed with Ar, followedby a 3.0 m NaOH(aq) solution (0.75 mmol, 1.5 equiv.). The reaction mixture was irradiated using a 500W visible light lamp, placed at 30 cm from the reaction, for 1 h. The CH3CN was removed by rotaryevaporation, while the remaining aqueous layer was extracted with dichlormethane (3 x 10 mL). Thecombined organic extracts were washed with brine, dried over Na2SO4, filtered and the solvent removedvia rotary evaporation. Flash column chromatography yielded the corresponding fluoromethyl ethers.O F258(Fluoromethoxy)benzene (258). Phenoxyacetic acid (257, 72 mg, 0.48 mmol) was subjected tothe general catalytic photoredox decarboxylative fluorination procedure. The reaction was run in argon-sparged water (no co-solvent was required). All rotary evaporations were carried out using a cold waterbath. Purification via bulb-to-bulb Kugelrohr distillation afforded 10 mgof fluoroether 258 as a clearcolorless oil in 17% yield (84% NMR yield). Spectral data for 257 were identical to those previouslyreported.265O FF2601-Fluoro-4-(fluoromethoxy)benzene (260). 4-Fluorophenoxyacetic acid (88 mg, 0.52 mmol) wassubjected to the general catalytic photoredox decarboxylative fluorination procedure. The reaction wasrun in Ar sparged water H2O exclusively, no co-solvent was required. All rotary evaporations werecarried out using a cold water bath. Purifcation via bulb-to-bulb Kugelrohr distillation afforded 22 mg of123Chapter 3. Direct C-F bond formation using photoredox catalysisfluoroether 260 as a clear colorless oil in 21% yield (67% NMR yield). Spectral data for 260 wereidentical to those previously reported.265O FPh2714-(Fluoromethoxy)-1,1′-biphenyl (271). 4-Phenylphenoxyacetic acid (267, 115 mg, 0.514 mmol)was subjected to the general catalytic photoredox decarboxylative fluorination procedure. Purificationby flash column chromatography (hexanes/AcOEt, 95:5 to 9:1) afforded 93 mg of fluoroether 271 as awhite solid in 92% yield (93% NMR yield). 1H NMR (400 MHz; CDCl3): δ 7.57-7.55 (m, 4H), 7.44(t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H), 5.76 (d, JH−F = 54.6 Hz, 2H).13C NMR(101 MHz; CDCl3): δ 140.6, 136.8, 128.9, 128.6, 127.3, 127.1, 117.1, 100.9 (d, JC−F = 219.3Hz). 19F NMR(282 MHz; CDCl3): δ -148.8 (t, JF−H = 54.80 Hz). IR (neat): 3034, 1608, 1481, 1292,1234, 1092, 947, 836, 757, 688 cm−1. HRMS-EI (m/z) [M*]+ calcd for C13H11OF: 202.0794; found:202.0793.O F2732,4-Di-tert-butyl-1-(fluoromethoxy)benzene (273). 2,4-Di-tert-butylphenoxyacetic acid (265, 136mg, 0.516 mmol) was subjected to the general catalytic photoredox decarboxylative fluorination proce-dure. Purification by flash column chromatography (hexanes/AceOEt, 99:1 to 49:1) afforded 91 mg offluoroether 273 as a white solid in 74% yield (95% NMR yield). 1H NMR (400 MHz; CDCl3): δ 7.41 (d,J = 2.4 Hz, 1H), 7.26 (dd, J = 8.8, 1.9 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 5.80 (d, JH−F = 55.0 Hz, 2H),1.45 (s, 9H), 1.36 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 153.9, 145.7, 138.2, 124.2, 124.1, 115.1,101.2 (d, JC−F = 217.5 Hz), 35.2, 34.6, 31.7, 30.2. 19F NMR (282 MHz; CDCl3): δ -146.7 (t, JF−H =55.0 Hz). IR (neat): 2960, 1500, 1362, 1223, 1110, 973, 818, 796 cm−1. HRMS-EI (m/z) [M*]+ calcdfor C15H23OF: 238.1733; found: 238.1732.124Chapter 3. Direct C-F bond formation using photoredox catalysisO F2742-(Fluoromethoxy)-1,3,5-trimethylbenzene (274). 2,4,6-Trimethylphenoxyacetic acid (266, 105mg, 0.541 mmol) was subjected to the general catalytic photoredox decarboxylative fluorination pro-cedure. Purification by flash column chromatography (95:5 petroleum ether/Et2O) afforded 59 mg offluoroether 274 as a clear colourless oil in 65% yield (92% NMR yield). 1H NMR (400 MHz; CDCl3):δ 6.87 (s, 2H), 5.61 (s, 1H), 5.47 (s, 1H), 2.27 (s, 3H), 2.26 (s, 6H). 13C NMR (101 MHz; CDCl3): δ152.0, 134.6, 130.6, 129.6, 104.5 (d, JC−F = 220.6 Hz), 20.8, 16.7. 19F NMR (282 MHz; CDCl3): δ-146.7 (t, JF−H = 55.1 Hz). IR (neat): 2924, 2853, 2156, 2034, 1491, 1475, 1207, 1166, 1139, 1082,965, 854, 756 cm−1. HRMS-EI (m/z) [M*]+ calcd for C10H13OF: 168.0950; found: 168.0952.O FOF2754,4′-(1-Phenylethane-1,1-diyl)bis((fluoromethoxy)benzene) (275). Dicarboxylate (275, 221 mg,0.490 mmol) was subjected to the general catalytic photoredox decarboxylative fluorination procedure.Purification by flash column chromatography (95:5 hexanes/AcOEt) afforded 140 mg of bis-fluoroether275 as a clear colorless oil in 80% yield. 1H NMR (400 MHz; CDCl3): δ 7.30-7.22 (m, 3H), 7.10-7.04 (m, 6H), 6.99 (d, J = 8.8 Hz, 4H), 5.71 (d, JH−F = 54.7 Hz, 4H), 2.16 (s, 3H). 13C NMR (101MHz; CDCl3): δ 155.0, 155.0, 149.1, 144.3, 130.1, 128.7, 128.1, 126.2, 116.0, 101.0 (d, JC−F = 219.2Hz), 51.7, 30.8. 19F NMR (282 MHz; CDCl3): δ -148.8 (t, JF−H = 54.8 Hz). IR (neat): 2938, 1508,1296, 1225, 1184, 1095, 968, 907, 819, 729, 701 cm−1. HRMS-EI (m/z) [M*]+ calcd for C22H20O2F2:354.1431; found: 354.1434.125Chapter 3. Direct C-F bond formation using photoredox catalysisOOHHHF290(8R,9S,13S,14S)-3-(Fluoromethoxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one (290). Phenoxyacetic acid 289 (170 mg, 0.510 mmol) was subjected toa slightly modified the general catalytic photoredox decarboxylative fluorinaton procedure. The use ofNaOH(aq) solution was omitted and only 1.5 equiv. of Selectfluor R© were used. Purification by flashcolumn chromatography (hexanes/AcOEt, 95:5 to 9:1) afforded 78 mg of fluoroether 290 as a whitesolid in 50% yield (60% NMR yield). 1H NMR (400 MHz; CDCl3): δ 7.24 (d, J = 8.6 Hz, 1H), 6.88(dd, J = 8.5, 2.3 Hz, 1H), 6.83 (s, 1H), 5.68 (d, JH−F = 54.9 Hz, 2H), 2.91 (dd, J = 8.3, 3.5 Hz, 2H),2.51 (dd, J = 18.7, 8.6 Hz, 1H), 2.39 (dd, J = 9.4, 4.1 Hz, 1H), 2.27 (d, J = 10.0 Hz, 1H), 2.19-1.95 (m,4H), 1.63-1.44 (m, 6H), 0.91 (s, 3H). 13C NMR (101 MHz; CDCl3): δ 220.8, 154.9, 138.3, 135.1, 126.7,116.9, 114.2, 100.9 (d, JC−F = 217.8 Hz), 50.5, 48.0, 44.1, 38.3, 35.9, 31.6, 29.6, 26.5, 25.9, 21.7, 13.9.19F NMR (282 MHz; CDCl3): δ -148.2 (t, JF−H = 54.9 Hz). IR (neat): 2938, 2868, 1737, 1492, 1285,1238, 1118, 972, 816, 778 cm−1. HRMS-ESI (m/z) [M+H]+ calcd for C19H24O2F: 303.1760; found:303.1756.3.7.5 Comparative photofluorodecarboxylation experimentsSubstrates 267, 266 and 289 were subjected to our previously reported photofluorodecarboxylation flu-orination conditions.256 The general photofluorodecarboxylation fluorination procedural specificationsare described below.3.5 equiv. Selectfluor1.5 equiv. NaOH7:3 H2O/CH3300 nm lightORFOROHOTo an Ar filled Falcon tube charged with the corresponding phenoxyacetic acid (0.1 mmol, 1.0equiv.), was added an Ar sparged 7:1 H2O/CH3CN mixture (1.0 mL) followed by a 3.0 m NaOH(aq)solution (0.05 mL, 0.15 mmol, 1.5 equiv.). The resulting mixture was stirred for 5 min then addedSelectfluor R© (0.35 mmol, 3.5 equiv.), and left to stir for an additions 7 min. The resulting solutionswere irradiated inside a Rayonet RPR-100 immersion photoreactor with 300 nm light (15 RPR-3000126Chapter 3. Direct C-F bond formation using photoredox catalysisA˚ lamps used) for 1 h. To the resulting crude mixture was added trimethoxybenzene (0.033 mmol,0.033 equiv.) as internal standard. The reaction was extracted with chloroform−d3, the organic layerwas filtered through Na2SO4 and then analyzed by1H NMR and 19F NMR spectroscopy.O FPh2714-(Fluoromethoxy)-1,1′-biphenyl (271). 4-Phenylphenoxyacetic acid (267) was subjected to gen-eral photofluorodecarboxylation fluorination conditions. The substrate is not completely soluble underthe reaction conditions even after the use of base to for the carboxylate. 1H NMR analysis showed fluo-romethyl ether 271 was obtained in 43% yield.O F2742-(Fluoromethoxy)-1,3,5-trimethylbenzene (274). 2,4,6-Trimethylphenoxyacetic acid (266) wassubjected to general photofluorodecarboxylation fluorination conditions. NMR analysis shows that allthe starting material was consumed, however multiple fluorination products were obtained and little ofthe desired fluoromethyl ether 274 was detected.OOHHHF290(8R,9S,13S,14S)-3-(Fluoromethoxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one (290). Phenoxyacetic acid 289 was subjected to general photofluorode-carboxylation fluorination conditions. NMR analysis shows that while 75% of the starting material wasconsumed, only traces of the desired fluoromethyl ether 290 were observed. Multiple fluorination prod-ucts were detected as well in the 19F NMR spectrum.127Chapter 3. Direct C-F bond formation using photoredox catalysis3.7.6 Cyclic voltametry studiesElectrochemical properties of Selectfluor R© and phenoxyacetic acid (257) were investigated using cyclicvoltametry (CV). A three electrode cell was employed consisting of a saturated calomel reference elec-trode (SCE), a Pt coil counter electrode and a graphite rod working electrode (Goodfellow). Solutions ofthe electroactive molecules (∼ 1 mm) were prepared in a 10 mm phosphate buffer (pH = 6.9) containing10 mm KNO3 supporting electrolyte.Cyclic voltammetry of phenoxyacetic acid (257) is shown in Figure 3.12. Potential was cycled at100 mV/s between 0 and 1.4 V vs SCE. In the absence of a clear peak for phenoxyacetic acid (257), ahalf wave potential (E1/2), defined as the inflection point in the i-E (i = Current, E = Potential) curvewas used as an indication of the electrochemical characteristics of the analytes. The half wave potentialwas calculated to be E1/2 = +1.01 V.Cyclic voltammetry of Selectfluor R© is shown in Figure 3.12. Potential was cycled at 100 mV/sbetween 0 and 1.0 V vs SCE. The half wave potential was calculated to be E1/2 = +0.27 V.3.7.7 Lamp emission measurementsThe emission spectrum of this 500 W halogen portable work lamp was measured using an Ocean Op-tics HR4000CG Composite-grating (CG) Spectrometer, by the Paquin group at Universite´ Laval. Theresults are shown in Figure 3.13. It is corroborated that no UV component is present in radiation emit-ted by this lamp. Also important of note is the emission at 450 nm, which is the wavelength at which[Ru(bpy)3]2+ absorbs.200 400 600 800 1000Wavelength (nm)02000400060008000Absolute IntensityFigure 3.13. Measured emission of 500 W lamp.128Chapter 4Chemoselectivity of alkoxy radicalcyclization onto silyl enol ethers vscyclization onto substituted alkenes,1,5-HAT and β-fragmentationAll we have to decide is what to do with the time that is given to us.— J. R. R. Tolkien (1954)Alkoxy radicals (RO•, 16 in Figure 1.5) are reactive intermediates that posses an unpaired electronat an oxygen atom. Analogous to carbon radicals, their reactivity is complementary to oxygen ionicreactions and it provides versatile options for the construction of molecular complexity. Despite theirsynthetic potential, alkoxy radicals have been largely under-utilized compared to their carbon counter-parts, mainly due to the difficulty to suppress undesired competing reactions.Previous studies in the Sammis group had shown that the use of silyl enol ethers as radical acceptorsstrongly favoured 5-exo cyclizations over other reaction pathways.266 This chapter presents a more de-tailed investigation on the selectivity of alkoxy radical cyclizations onto silyl enol ethers when alternativereaction pathways, such as 1,5-HAT and β-fragmentation, are possible. The selectivity assessment wasachieved through the use of intramolecularly competing substrates.129Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.1 Generation of alkoxy radicalsIn the 1950s, the methods for alkoxy radical generation involved either pyrolysis or photolysis of unstable,and often explosive, oxygenated species such as organic peroxides, nitrates, nitrites (Figure 4.1, a), andhypochlorites (Figure 4.1, d).267 The common feature in all these functional groups is the presence ofhomolytically weak oxygen-heteroatom bonds.While oxygen forms strong bonds to hydrogen (i.e. BDEHO−H = 119 kcal mol−1), oxygen bondsto other heteroatoms, such as nitrogen (BDERO−NO = 41 kcal mol−1), sulfur (BDERO−SR = 53kcal mol−1), chlorine (BDEHO−Cl = 56 kcal mol−1), and another oxygen atom (BDEHO−OH = 50kcal mol−1)5 are weak and can be homolytically cleaved under photolytic or thermal conditions (seeTable 1.1 for other relevant O−X BDEs).R OR OR O R OR OR OClNOO R'ONSArSSArR O R ONOONSR OI(a)(b)(c)(f)(g)(h)(d) (e)Figure 4.1. Selected alkoxy radical precursors.Efforts to generate alkoxy radicals under safer and milder conditions lead Beckwith and coworkersin the late 1980’s to successfully use N-alkoxypyridinethiones (Figure 4.1, f),268 and O-alkyl benzene-sulphenates (Figure 4.1, e)269 to generate alkoxy radicals. More recently, alkoxy radical precursors havebeen prepared using the N-(alkoxy)-4-(p-chlorophenyl)thiazole-2(3H)-thione group (Figure 4.1, c),270as well as the photostable N-alkoxyphthalimide (Figure 4.1, h) moiety.The radical precursor selected for the studies described in this chapter was the N-alkoxy-phthalimidegroup (Figure 4.1, h).271 Under thermal condition, organo-tin compounds are used to induce the homol-ysis of the oxygen-heteroatom bond of N-alkoxyphthalimides. Typically, the reaction conditions requirethe use of AIBN (Scheme 4.1), which upon thermal decomposition promotes the formation of tributyltin130Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationradicals that react with the phthalimide’s sp2 hybridized oxygen to form alkoxy radical 293 along withthe tin adduct 294. In the illustrative example presented in Scheme 4.1, the alkoxy radical 293 formedrapidly performs a 1,5-hydrogen atom transfer to generate a secondary carbon radical, which ultimatelytraps a deuterium atom from Bu3SnD. Additionally, N-alkoxyphthalimides form adduct 294 under tin-mediated conditions, which does not react any further under the reaction conditions.Bu3SnD, AIBNC6H6ON99% (95% D)OOPhOO NOOPhOBu3SnHOHPhOD292 293 294 295Scheme 4.1. Tributyltinhydride mediated generation of alkoxy radicals from N-alkoxphthalimide 292. 271N-Alkoxyphthalimide are bench stable, readily installed, can be carried through several syntheticsteps, and contrary to N-alkoxypyridinethiones, its O−N bond is not as easily photolyzed. These char-acteristics made them ideal alkoxy radical precursors for our investigation, as they are easy to manage inambient light conditions4.2 Reactivity of alkoxy radicalsAnalogous to their carbon counterparts, alkoxy radicals can undergo a variety of intra- and intermolecularreactions,11 such as cylizations, 1,5-hydrogen atom transfer (1,5-HAT), and β-fragmentation(Figure 4.2).Any of the reaction pathways of alkoxy radicals leads to the formation of a thermodynamically more sta-ble carbon radical. The position where the carbon radical will be formed can be predicted and controlledthrough the strategic designing of the substrates and appropriate selection of the radical precursor.131Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationORHOHROOR ROH RO+RR'' R'R''R'1,5-Hydrogen Atom TransferCyclizationβ − fragmentationn n = 1,2 nFigure 4.2. Alkoxy radical modes of reactivity.A cyclization occurs through the intramolecular addition of the alkoxy radical to a double bond toform oxygen-containing heterocycles. For instance, 4-penten-1-oxyl radical (296) can cyclize in twodifferent modes, 5-exo-trig or 6-endo-trig, to form THF and tetrahydropyran (THP) rings respectively(Scheme 4.2). As radical processes are kinetically controlled, tetrahydrofuran radical 298 is formedpreferentially over tetrahedronpyran radical 300 (98:2 ratio).272 Utilizing competition kinetics, the rateof 5-exo cyclization of 296 was determined to be 5.2× 108 s−1 at 80 ◦C.269OOOOO5-exo6-endo296 297 298299 300Scheme 4.2. 5-exo and 6-endo cyclizations of alkoxy radical 296.Alkoxy radical cyclizations have rarely been used in total synthesis. In 2003, Hartung et al. reportedthe stereoselective synthesis of (+)-allo-muscarine, along with other muscarine derived products, via a5-exo cyclization of alkoxy radicals (Scheme 4.3).273 The alkoxy radical precursor 302 was accessed inseven steps frommethyl-(S)-lactate (301). The key 5-exo cyclization stepwas performed under photolyticconditions (350 nm) in the presence of BrCCl3. The carbon radical generated after the cyclization was132Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationtrapped as a bromide, which provided a synthetic handle for further functionalization. Deprotection andsubstitution of the bromine for an ammonium group yielded (+)-allo-muscarine.BrCCl3 (8 equiv.)hν (350 nm)C6H6, 20 °COHCO2CH3 7 stepsOOBzNS SOBrBzO79%, 1:2 cis/trans2 stepsONMe3HOBr(+)-allo-muscarine301 302 303 304Scheme 4.3. Total synthesis of (+)-allo-muscarine.273In a 1,5-HATthe alkoxy radical abstracts a proton situated in the five position with respect to theoxygen. 1,5-Hydrogen atom transfer reactions are exothermic processes, since the BDE of a O−H bondis higher than the BDE of a C−H bond on an sp3 hybridized carbon (Table 1.1). 1,5-HATto alkoxyradicals occur preferentially through chair-like transition states (Scheme 4.4).274,275 This is the reasonwhy 1,5-hydrogen atom transfers are favoured over 1,2-, 1,3-, 1,4- and 1,6-hydrogen atom transfers.276O O HRHOH305 306 307Scheme 4.4. 1,5-Hydrogen atom transfer performed by an alkoxy radical.The first example of a 1,5-HAT was reported by Barton and co-workers in 1960 (Scheme 4.5).277The authors reported the isolation of oxime 309 in 34.2 % upon photolysis of nitrite 308. The initialgeneration of an alkoxy radical from the nitrite group is followed by the 1,5-hydrogen abstraction fromthe methyl at position 18 of the pregnan steroid derivative. The new carbon radical then recombines withthe nitroso radical to form aldoxyme 309.OAcOHHHHHUV-light, 10 °CC6H6, 2-5 hOHAcOHHHHHN ONOH308 309Scheme 4.5. Barton’s alkoxy radical 1,5-HAT.277133Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationThe different reaction pathways of alkoxy radicals are always competing with each other. Whenalkoxy radical cyclizations were first reported by Surzur, Bertrand and Nouguier in 1969,278 they ob-served that the photolysis of alkyl nitrites 310 (Scheme 4.6) yielded different mixtures of THF rings,311, 312 and 313, along with the linear compounds 314 and 315, depending on the substitution patternof the nitrite radical precursor. If the alkoxy radicals generated through the photolysis of the N−O bondundergo a 5-exo cyclization, THF rings are generated. Ketone 315 is formed upon β-elimination of R5through the homolytic scission of the C−R5 bond. Alcohol 314 forms when the alkoxy radical simplytraps a hydrogen atom. This early discovery clearly illustrates the challenge multiple reaction pathwayspose for the use of alkoxy radicals in organic synthesis.hν, 35 °CC6H6ONOR2R3 R4 R5OR4R5 NR2OHOR4R5R2R3 OR4R5 R2+ +R1OHR2R3 R4 R5R1R4R2R3R1O+R1 R1310311 312 313314 315Scheme 4.6. First reported alkoxy radical intramolecular 5-exo cyclization.2784.3 Electrophilicity and nucleophilicity of radicalsThere are several factors controlling the reactivity and regioselectivity of free radical substitution andaddition reactions,279 such as the strength of the broken bond, steric effects, electron delocalization(resonance), strength of the formed bond and polarity effects. Specifically, polarity effects have a strongimpact in the transition state of substitution radical transformations.The methyl and trifluoromethyl radicals behaviour illustrates the effect polarity can have in radicalreactions (Figure 4.3). The presence of three highly electronegative atoms directly attached to the carbonwhere the radical resides leads to a dipole moment pointing away from the radical and towards the fluorineatoms. On the other hand, the dipole moment of the methyl radical would be pointing in the directionof the radical as the methyl group is slightly electron donating. The direct consequence of this dipoledifference can be observed in the transition state of the hydrogen atom abstraction from HCl. When thetrifluoromethyl radical reacts with HCl, the dipoles of the radical and the acid are opposite to each other(eq. 4.1, Figure 4.3) destabilizing the transition state, which in consequence increases the activation134Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationenergy for this reaction. Alternatively, in the transition state of the abstraction of hydrogen from HCl bya methyl radical (eq. 4.2, Figure 4.3), the slightly electron donating nature of the methyl radical directsits dipole in the same direction as the polarized hydrogen chloride molecule, which confers a higherstability to the transition state and consequently facilitates the hydrogen atom transfer reaction.F3C + H Cl F3C H Cl F3CH + Clδ+ δ- δ+ δ-(4.1)H3C + H Cl H3C H Cl H3CH + Clδ+ δ- δ+ δ-(4.2)Figure 4.3. Polar effects in radical substitution.279Polar effects also affect the addition of radicals to olefins. Alkyl radicals (methyl,279 hexyl, cyclo-hexyl, t-butyl,280–282 phenyl283,284), display higher rates of addition when the alkene has electron with-drawing groups attached to it. In contrast, the trifluoromethyl radical addition reaction rate decreaseswhen reacting with electron deficient olefins.279 Based on this results, alkyl radicals are said to be “nu-cleophilic”, while trifluoromethyl radicals are “electrophilic”. Other radicals that have been observedto display electrophilic behaviour are the hydroxyl,285 benzoyloxy284 and t-butoxy radicals;286 theseradicals were found to react faster with electron-rich double bonds than electron-deficient ones.The term polar effects has been more recently substituted by the description of the nucleophilicityor electrophilicity of radicals in terms of frontier molecular orbitals. Radicals have a singly occupiedmolecular orbital (SOMO), which can interact with both the highest occupied molecular orbital (HOMO)and the lowest occupied molecular orbital (LUMO) of other reacting molecules to lower the energy ofthe transition state (Figure 4.4).287SOMOHOMOSOMOLUMOSOMOHOMOLUMOa) SOMO-HOMO interaction b) SOMO-LUMOinteraction c) SOMO-HOMO/LUMO interactionFigure 4.4. SOMO interactions with HOMO and LUMO.The philicity of the radical will be dictated by the energy of the SOMO of the radical relative tothe HOMO and the LUMO of the reacting partner.288 Which of the two MOs the SOMO will interact135Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationwith is strictly dependant on which molecular orbital is energetically closer to it. Nucleophilic radicalstypically have a high-energy SOMO (Figure 4.5, a) that will preferentially interact with the low lyingLUMO (characteristic of an electrophilic species) of the other reacting molecule. On the other hand,an electrophilic radical (Figure 4.5, b) will more easily interact with the high lying HOMO (intrinsic ofnucleophilic type molecules) of the reacting parter.SOMOHOMOLUMOa) High-energy SOMO     − a nucleophilic radicalSOMOHOMOLUMOb) Low-energy SOMO      − an electrophilic radicalFigure 4.5. Electrophilic vs nucleophilic radicals. 279An important implication of MOs interactions governing the reactivity of radicals is that despite rad-icals being highly reactive species, high chemo and regioselectivity can be achieved in radical mediatedprocesses by simply varying the philicity of the radicals generated in the propagation steps.4.4 Reaction rates of oxygen-centered radicalsThe successful use of alkoxy radicals as reactive intermediates in organic synthesis requires careful plan-ning to avoid undesired side reactions. Like any kinetically controlled reaction, when two or more differ-ent radical reaction pathways are in competition, the major product will be that resulting from the fastestreaction. Consequently, the knowledge and understanding of radical reaction rates is of paramount impor-tance as it permits the prediction of what radical processes will occur preferentially. Reaction substratescan then be designed accordingly.Radical reaction rate coefficients or rate constants (k) have been determined through both direct andindirect methods. An absolute rate constant is typically determined through the use of spectroscopictechniques like time resolved laser flash photolysis.289 Alternatively, relative rate constants can be de-termined through competition experiments where the product distribution of two simultaneous radicalreactions reflects how fast is one compared to the other. If the absolute value of one of the reaction ratesis known, the rate of the other can be calculated from the product distribution. Some relevant carbon andoxygen radical reaction rate constants are presented in Table 4.1.136Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationTable 4.1. Selected absolute carbon and alkoxy radical rate constants.Entry Reaction Absolute Rate Constant Reference1 CH3 + Bu3Sn H CH4 + Bu3Sn k(25) = 1.0 × 107 m−1s−1 2902 (CH3)3C + Bu3Sn H (CH3)3CH + Bu3Sn k(25) = 1.8× 106 m−1 s−1 2903 Ph + Bu3Sn H PhH + Bu3Sn k(25) = 7.8× 108 m−1 s−1 2914RHH3CRH H k(25) = 1.0× 102 s−1 2925 k(25) = 9.4× 107 s−1 293,2946 k(25) = 2.4× 105 s−1 2957PhPhPhPh k(25) = 4.5× 107 s−1 296,2978 k(25) = 2.8× 104 s−1 2989 k(25) = 4.1× 103 s−1 29810 k(25) = 5.2× 103 s−1 29811 ROHOHRH Hk(20) = 2.7× 107 s−1 29912OOk(30) = 5 ± 2× 108 s−1 27213 OPhPhOPhPh+k(20) = 2.2× 107 s−1 299Alkoxy radicals react significantly faster than its carbon-centered counterparts. For instance, a 1,5-HAT performed by a carbon radical occurs with a rate constant k = 1.0 × 102 s−1(entry 4, Table 4.1)while the same reaction performed by an alkoxy radical proceeds five orders of magnitude faster (k =2.7×107 s−1, entry 11, Table 4.1). If we compare the 5-exo cyclization rate constants, entry 6 (Table 4.1)shows that a primary carbon radical cyclizes to form a cyclopentane with a rate of k = 2.4 × 105s−1, while the alkoxy radical equivalent (entry 12, Table 4.1) does so three orders of magnitude faster(k = 5× 108 s−1).The reason why alkoxy radicals have not been extensively used in synthesis has not been their highreaction rate constants, but rather the potential competition between the possible reaction pathways astheir reaction rate constants are all in close proximity to each other (see entries 11 − 13, Table 4.1).137Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationA conceivable solution to this problem would be to design substrates that would strongly favour onereaction pathway over the others. In the Sammis group, we turned to the electron rich silyl enol ethergroup to aid in the formation of five and six membered oxygen-containing saturated heterocycles throughthe cyclization of alkoxy radicals.4.5 Silyl enol ethers as radical reactive partnersOne of the direct consequence of competing pathways in alkoxy radical chemistry is the challenging syn-thesis of THP rings through a cyclization reaction. For instance, 5-hexane-1-yl radical 316 can certainlyundergo a 6-exo cyclization to generate THP ring 317 (Scheme 4.7), but it can also perform a 1,5-HAT atthe allylic position to form radical 318. The competition between these two reaction pathways preventsthe formation of the THP ring in high yields.OHHOOHH1,5-HAT6-exocyclization316317318Scheme 4.7. Competing 6-exo cyclization and 1,5-HAT reaction pathways of 5-hexen-1-yl radical.Three examples that illustrate this chemoselectivity problem are presented in Scheme 4.8. The firstexample (eq. 4.3, Scheme 4.8)300 shows that the use of electron-poor olefin 319, which is typicallyregarded as a good radical acceptor, yields tetrahydropyran 320 in less than 5% yield. When an unsub-stituted terminal alkene, such as 321, acts as the radical acceptor instead (eq. 4.4),301 the yield of thecorresponding THP 322 increases to 27%. The lack of electron-withdrawing groups directly attached tothe olefin favours the 6-exo cyclization pathway by raising the energy of the HOMO of the alkene. In-creasing the alkyl substitution of the double bond further increases the electron density and consequentlythe HOMO energy of the alkene, which favours the cyclization pathway (323, eq. 4.5),302 to afford thecorresponding THP ring 324 in 39% yield.These examples demonstrate that highly reactive species, such as alkoxy radicals, can be controlledthrough the bias of the reactive partner or the system in general. Since alkoxy radicals are electrophilicspecies,284–286 the use of highly electron-rich or high-energy HOMO reactive partners will favour thereactivity of the alkoxy radical towards one pathway by increasing its reaction rate.138Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationOPhSOOCH3Bu3SnHEt2B, THF23 °CO OOCH3(4.3)Bu3SnHAIBNO(4.4)OBrCO2EtEtO2CEtO2C CO2Et< 5% conv.BrCCl3, AIBNC6H6, 80 °CO(4.5)39% yieldONS SH3CO Br27% yield319 320321 322323 324Scheme 4.8. Alkoxy radical cyclizations to form tetrahydropyrans.This key concept was demonstrated earlier in our group by Dr. Zlotorzynska and Dr. Zhai, in thesuccessful synthesis of tetrahydropyran (THP) 326 through the use of highly electron-rich silyl enolethers SEE (Scheme 4.9).266 Under the same reaction conditions, the use of a terminal alkene afforded2-methyltetrahydropyran in less than 5% conversion. It was shown then that the use of electron-richspecies as radical acceptors significantly favoured the 6-exo cyclization over a 1,5-HAT pathway, despitethe fact that the latter has a rate of 2.7 × 107 s−1 (Table 4.1, entry 11).Bu3SnH, AIBNC6H6, 80 °CO74% yieldOTBSON OTBSOO325 326Scheme 4.9. Alkoxy radical cyclizations onto silyl enol ethers. 266Silyl enol ethers, as radical cyclization acceptors, not only favoured radical cyclization to form THFand THP rings but also provided oxacycles with a synthetic handle to perform further transformations inthe form of a silyl protected oxygen. In order to make silyl enol ethers practical as radical acceptors for139Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationorganic synthesis, it was necessary to investigate how the rate of cyclization of alkoxy radicals onto silylenol ethers compared to competing pathways different to a 1,5-HAT at an allylic position.4.6 Competition studies using silyl enol ethers as radical acceptorsOur approach to assess the selectivity of alkoxy radicals consisted in the use of competition substratesspecifically designed to provide more than one possible reaction pathway for the generated alkoxy radi-cal. The five different types of competition substrates designed for this study are intended to probe thechemoselectivity of competing cyclizations onto silyl enol ethers vs other alkyl substituted olefins (sub-strate A, Figure 4.6), 1,5-HAT(substrates B and C), β-fragmentation(substrate D) and multiple pathways(substrate E), both in 5-exo and 6-exo cyclization modes. Competition substrates of the types D and Ewere investigated by Dr. Zlotorzynska and C. Dunbar. The results of the β-fragmentation investiga-tion will be included in the summary Table 4.2 to provide a complete overview of the alkoxy radicalschemoselectivity.R2R1 OOTBSOOTBSCompeting cyclizationsCyclization vs 1,5-HATROOTBSHHR1, R2 = H, alkylR1, R2 = alkyl, arylR2R1R = alkyl, arylO OTBSCyclization vs β-fragmentation vs 1,5-HATHR = alkyl, arylCyclization vs β-fragmentationROOTBSHArAB CEDFigure 4.6. Designed competition substrates.140Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.6.1 Synthesis of competition substrates4.6.1.1 Synthesis of competition substrate 332The synthesis of 332 started with addition of the in situ generated but-3-en-1-ylmagnesium bromide toaldehyde 327 to afford alcohol 328 (Scheme 4.10). An ensuing Mitsunobu reaction effectively installedthe N-alkoxyphthalimide group to yield 329. The TBS group was then removed using (1S)-(+)-10-camphorsulfonic acid in methanol to provide alcohol 330 in 34% yield over three steps.HMg0THF34% over 3 stepsPhthNOHPh3P, DIADTHF0 °C to r.t.OHPhthNOOBrOTBSOHOTBSPhthNOCSAMeOHOTBS327 328329330Scheme 4.10. Synthesis of alcohol 330.Alcohol 330 was transformed into aldehyde 331 utilizing a Ley oxidation (Scheme 4.11). This alde-hyde was immediately converted to silyl enol ether 332 through a soft enolization procedure with a yieldof 31% over two steps with a diastereomeric E/Z ratio of 12:88.OHPhthNOTBSOTf, DIPEACH2Cl2, 0 °CNMO, TPAPCH2Cl2, 0 °C HPhthNOPhthNO OTBSO31% over 2 steps(E/Z) = 12:88330 331332Scheme 4.11. Synthesis of competition substrate 332.141Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.6.1.2 Synthesis of competition substrate 340The synthesis of competition substrate 340 started with the triethylsilyl (TES) protection of 5-hexene-1-ol (333, Scheme 4.12) with triethylsilyl chloride and imidazole (imid.) in DMF at 0 ◦C. Subsequenttreatment of the resulting alkene (334) withmeta-chloroperbenzoic acid (mCPBA) generated epoxide 335in 81% yield over two steps. Epoxide opening using (E)-but-2-en-1-ylmagnesium chloride, followed bya Mitsunobu reaction on the resulting alcohol (336) afforded the key N-alkoxyphthalimide 337 in 60%yield over two steps.OH OTESOTESOTESCl, imid.DMF, 0 °CmCPBACH2Cl2, 0 °C81% over 2 stepsMgClCuITHF, 0 °C to r.t.OTESOH60% over 2 stepsPhthNOHPh3P, DIADTHF0 °C to r.t.OTESPhthNO333 334 335336337Scheme 4.12. Synthesis of N-alkoxyphthalimide 337.With theN-alkoxyphthalimide installed, the TESgroupwas removed using (1S)-(+)-10-camphorsulfonicacid (CSA) in methanol (Scheme 4.13), which yielded primary alcohol 338 in 56% yield. Ley oxidation,followed by soft enolization of the resulting aldehyde (339) with diisopropylethylamine (DIPEA) and t-butyldimethylsilyltriflate provided competition substrate 340 in 23% yield over two steps in an E/Z ratioof 16:84.142Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation56% yield23% over 2 steps(E/Z) = 16:84OTESPhthNO CSAMeOHTBSOTf,DIPEACH2Cl20 °CNMO, TPAPCH2Cl2, 0 °COHPhthNOHPhthNO OPhthNO OTBS337 338339340Scheme 4.13. Synthesis of competition substrate 340.4.6.1.3 Synthesis of competition substrates 348 and 349The synthesis of competition substrates 348 and 349 started with the reduction of ethyl 5-methylhex-4-enoate (341, Scheme 4.14) with diisobutylaluminum hydride (DIBAL) in dichloro-methane at -78 ◦C,to afford aldehyde 342 in 84% yield. Nucleophilic addition of the in situ generated Grignard reagentderived from bromide 343, provided access to secondary alcohol 344 in 86% isolated yield. Installationof the N-alkoxyphthalimide through a Mitsunobu reaction, followed by CSA deprotection of the TBSgroup yielded primary alcohol 346 in 80% yield over two steps.OEtDIBALCH2Cl2-78 °C84%Mg0THF80% over 2 stepsPhthNOHPh3P, DIADTHF0 °C to r.t.OHPhthNOOHOBrOTBSOTBSOHOTBSPhthNOCSAMeOH86%341 342343343344345346Scheme 4.14. Synthesis of N-alkoxyphthalimide 346.143Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationPrimary alcohol 346 was transformed into the aldehyde 347 through a Swern oxidation reaction(Scheme 4.15). Two different soft enolization conditions were utilized to generate the desired cis andtrans enriched silyl enol ethers. The treatment of aldehyde 347withDIPEAand t-butyldimethylsilyltriflateyielded cis-enriched competition substrate 348 in 66% yield over two steps with a 20:80 E/Z ratio. Theuse of DBU and t-butyldimethylsilylchloride in dichloromethane at 0 ◦C instead, afforded trans-enrichedcompetition substrate 349 in 57% yield with 67:33 E/Z ratio.57%(E/Z) = 67:33OHPhthNOTBSOTf, DIPEA     CH2Cl2, 0 °CDMSO, (COCl)2Et3NCH2Cl2, -78 °C HPhthNOPhthNO OTBSPhthNOOOTBS66% over 2 steps(E/Z) = 20:80   TBSCl, DBUCH2Cl2, 0 °C346 347348349Scheme 4.15. Synthesis of competition substrates 348 and 349.4.6.1.4 Synthesis of competition substrate 325The synthesis of competition substrate 325 started with the monoprotection of 1,6-hexyldiol (350) witht-butyldimethylsilyl chloride to provide mono silyl alcohol 351 in 65% yield (Scheme 4.16). A sub-sequent Mitsunobu reaction afforded N-alkoxyphthalimide 352 in 72% yield. Deprotection of the t-butyldimethylsilyl (TBS) group utilizing CSA in methanol provided alcohol 353 in 58% yield.144Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationOH58%PhthNOHPh3P, DIADTHF0 °C to r.t.NaH, TBSClTHF, 0 °COHOTBSOHOTBSPhthNOOHPhthNO72%CSAMeOH65%350 351353353Scheme 4.16. Synthesis of alcohol 353.Alcohol 353 was oxidized under Ley oxidation conditions to yield aldehyde 354 (Scheme 4.17).Immediate soft enolization of the newly formed aldehyde afforded competition substrate 325 in 58%yield with a 10:90 E/Z ratio.58% over 2 steps(E/Z) = 12:88PhthNOTBSOTf, DIPEACH2Cl2, 0 °CNMO, TPAPCH2Cl2, 0 °COHPhthNOOPhthNOOTBSH353 354325Scheme 4.17. Synthesis of N-alkoxyphthalimide 325.4.6.1.5 Synthesis of competition substrate 360The preparation of competition substrate 360 started with the Swern oxidation of monoprotected diol351 (Scheme 4.18), followed by the addition of methyl lithium to the resulting aldehyde 355, to affordsecondary alcohol 356. The installation of theN-alkoxyphthalimide was performed through aMitsunobureaction, which yielded 357 in 51% yield over three steps.145Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationOTBS51% over 3 stepsPhthNOHPh3P, DIADTHF0 °C to r.t.DMSO, (COCl)2Et3NCH2Cl2, -78 °CMeLi, CuITHFOHHOOTBSOHOTBSPhthNOOTBS351 355 356357Scheme 4.18. Synthesis of N-alkoxyphthalimide 357.The TBS group in 357 was removed using (1S)-(+)-10-camphorsulfonic acid in methanol to yieldalcohol 358 in 68% yield (Scheme 4.19). Subsequent Ley oxidation of 358, followed by soft enolizationof the resulting aldehyde 359 successfully generated competition substrate 360 in 67% yield over 2 stepsin a 10:90 E/Z ratio.68% yield67% over 2 steps(E/Z) = 10:90PhthNO CSAMeOHTBSOTf,DIPEACH2Cl20 °CNMO, TPAPCH2Cl2, 0 °COTBSPhthNOOHPhthNOOHPhthNOOTBS357 358359360Scheme 4.19. Synthesis of competition substrates 360.4.6.1.6 Synthesis of competition substrate 367Competition substrate 367 was prepared starting with the Swern oxidation of monoprotected alcohol361 to provide aldehyde 362 in 45% yield (Scheme 4.20). Addition of n-butyl lithium to the aldehydegenerated secondary alcohol 363 in 86% yield. The N-alkoxyphthalimide group was installed through a146Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationMitsunobu reaction to afford phthalimide 364, which was then treated with (1S)-(+)-10-camphorsulfonicacid in methanol to remove the TBS protecting group and form 365 in 84% over two steps.OTBSBuLiTHF,-78 °C86% yield84% over 2 stepsCSAMeOHHOOTBSHODMSO, (COCl)2,Et3NCH2Cl2,-78 °COTBSOHOTBSPhthNOOHPhthNO45% yieldPhthNOHPh3P, DIADTHF0 °C to r.t.361 362 363364365Scheme 4.20. Synthesis of alcohol 365.A Ley oxidation of alcohol 365 (Scheme 4.21), followed by soft enolization of the resulting aldehyde366 successfully generated competition substrate 367 in 44% yield over two steps, in a 11:89 E/Z ratio.OHPhthNOTBSOTf, DIPEACH2Cl2, 0 °CNMO, TPAPCH2Cl2, 0 °C HPhthNOPhthNO OTBSO44% over 2 steps(E/Z) = 11:89365 366367Scheme 4.21. Synthesis of competition substrates 360.4.6.1.7 Synthesis of competition substrate 372The synthesis of competition substrate 372 is very similar to that of competition substrate 367. Aldehyde362 was treated with the in situ generated Grignard of 4-phenyl-1-butylbromide to form alcohol 368 in82% yield (Scheme 4.22). An ensuing Mitsunobu reaction afforded N-alkoxyphthalimide 369, followedby CSA deprotection in methanol yielded alcohol 370 in 70% yield over two steps.147Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationOTBSMg0, I2THF,-78 °C82% yield70% over 2 stepsCSAMeOHH OTBSOHPhOTBSPhthNOPhOHPhthNOPhPhthNOHPh3P, DIADTHF0 °C to r.t.OBr362 368369370Scheme 4.22. Synthesis of alcohol 370.Transformation of alcohol 370 into aldehyde 371 was achieved through a Ley oxidation. Soft eno-lization of aldehyde 371 afforded competition substrate 372 in 32% yield over two steps, in a ratio of10:90 E/Z silyl enol ethers.PhOHPhthNOTBSOTf, DIPEACH2Cl2, 0 °CNMO, TPAPCH2Cl2, 0 °CPhHPhthNOPhPhthNO OTBSO32% over 2 steps(E/Z) = 10:90370 371372Scheme 4.23. Synthesis of competition substrates 360.4.6.2 Competing 5-exo alkoxy radical cyclization onto silyl enol ether and ontosubstituted alkenesWith all the competition substrates in hand, we proceeded to perform the competition experiments. Inorder for this competition experiments to be generalizable and self-consistent, the electronics of theradical acceptor have to be the overriding factor that determines the ratio of the products. J. C. T. Leung,in the Sammis research group, collected evidence to suggest that this assumption was valid through the148Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationuse of competition substrate 373 (Scheme 4.24, eq. 4.6), which explores the cyclization selectivity of aterminal alkene and a trans dialkyl-substituted alkene. The treatment of N-alkoxyphthalimide 373 withtributyltin hydride in refluxing benzene yielded cyclization products 374 and 375 in an 83:17 ratio. Thisratio matches well with the one expected from the individual relatives rate constants of cyclization ofan alkoxy radical onto a terminal alkene and a trans-substituted alkene reported by Hartung and Gallow(Scheme 4.24, eq. 4.7 and 4.8).272 We assumed then, based on these observations, that steric factors donot greatly affect the cyclization product distribution and that this ratio is primarily determined by theelectronics of the double bond.PhthNO Bu3SnH, AIBNC6H6, 80 °CO+O(4.6)O Bu3SnH, AIBNC6H6, 80 °CO(4.7)O Bu3SnH, AIBNC6H6, 80 °CO(4.8)k = [5 ± 2 x 108] x 1.2 ± 0.1 s-1 trans                            x 0.78 ± 0.07 s-1 cisk = [5 ± 2 x 108] x 7.1 ± 0.6 s-1 trans                            x 2.9 ± 0.3 s-1 cis373 374 375376 377378 379Scheme 4.24. Comparison of literature cyclization rates with competing cyclization substrate. 303Utilizing competition substrates type A (Scheme 4.25), we started the investigation on the chemose-lectivity of alkoxy radical 5-exo cyclization onto silyl enol ethers compared to an alkyl-substituted alkene.The competition substrates were subjected to our general radical cyclization conditions, where they weretreated with tributyltin hydride in a solution of refluxing deuterated benzene. The use of benzene−d6(C6D6) as the solvent is intended to minimize the error that can arise from the removal of non-deuteratedsolvent, especially for substrates where the products are volatile. The reaction mixtures where thenanalyzed using 1H NMR spectroscopy to determine the ratio of the two cyclization products. It is im-portant to note that in each of these reactions, no starting material was detected in the corresponding 1HNMR spectra.Substrates of type A can cyclize either onto the alkene radical acceptor to form the carbon radical380, or onto the silyl enol ether to form radical 381. The product distribution of the THF rings 382 and383 will be directly dependant on their rates of cyclization.149Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationR2OOR2+OR1TBSOOTBSOTBSR1R1R2OR2+OR1OTBSOTBSR1R2A380381382383Scheme 4.25. Substrates type A: alkoxy radicals competing 5-exo cyclizations.We performed the cyclization of competition substrate 332, which features a terminal alkene and asilyl enol ether as the two possible cyclization sites for the generated alkoxy radical (Scheme 4.26). The1H NMR analysis of the reaction mixture showed that the product 384, resulting from the cyclizationonto the terminal alkene, was formed in a 11:89 ratio compared to THF ring 385, which is formed uponcyclization onto the silyl enol ether. Knowing that the 5-exo cyclization rate constant of an alkoxy radicalonto a terminal alkene is k(30) = 5 ± 2 × 108 s−1,272 one can estimate the reaction rate constant of 5-exo cyclization of an alkoxy radical to be in the order of 109 s−1.PhthNO Bu3SnH, AIBNC6D6, 80 °CO+OTBSOOTBSOTBS11:89332 384 385Scheme 4.26. Competing 5-exo cyclization of alkoxy radicals onto a silyl enol ether and a terminal alkene.We next examined the selectivity of cyclization substrate 340 (Scheme 4.27), which simultaneouslyoffers the possibility of radical cyclization onto an dialkyl-substituted alkene as well as a silyl enol ether.1H NMR analysis of the crude reaction mixture showed that the product of alkoxy radical cyclizationonto the dialkyl-substituted alkene, THF 386, was present in 33% while the alkoxy radical cyclizationonto the silyl enol ether was formed in 67%. The increase in olefin substitution results in the subsequentincrease of cyclization product 386 observed compared to the cyclization product 384. This is attributedto the increased electron density of the double bond with increasing alkyl substitution, which favours thereaction with the electrophilic alkoxy radical.150Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationPhthNO Bu3SnH, AIBNC6D6, 80 °CO+OTBSOOTBSOTBS33:67340 386 387Scheme 4.27. Competing 5-exo cyclization of alkoxy radicals onto a silyl enol ether and a trans dialkyl-substituted alkene.The predictability and self consistency of these competition experiments is further confirmed throughthe comparison of the product distribution of substrates 332 and 340. Since the competition of alkoxy rad-ical cyclization onto a terminal olefin and a dialkyl-substituted olefin (Scheme 4.24) provided a productration of 17:89 of cyclization onto the terminal olefin to cyclization onto the dialkyl-substituted alkene,and knowing that the competing cyclization of an alkoxy radical onto a dialkyl-substituted alkene and asilyl enol ether generates a 386/387 product ratio of 33:67, we could predict that if a terminal olefin wasin competition with a silyl enol ether, the product distribution would be 91:9 of cyclization onto the silylenol ether vs cyclization onto the terminal olefin. Indeed, this prediction is close to what was observedfor the cyclization of 332 (89:11 product ratio).The next competition substrate explored was 348 (Scheme 4.28), which was designed to comparethe performance of silyl enol ethers as alkoxy radical cyclization acceptors in the presence of a trialkyl-substituted alkene. We wanted to probe this particular substrate to investigate the performance of thetrialkyl-substituted alkene that had previously allowed Hartung and Gottwald to the synthesis of THP324 in 39% yield (see Scheme 4.8)302 in the presence of a silyl enol ether, which had dramatically im-proved the isolated yield of the cyclization product 326 to 74% (Scheme 4.9).266 The 1H NMR analysisof the crude reaction mixture of the cyclization of 348 revealed that the products resulting from thealkoxy radical cyclizing onto the silyl enol ether 388 and onto the trialkyl-substituted alkene 389 was47:53. There is no significant selectivity of the secondary alkoxy radical towards either of the two rad-ical acceptors to perform a 5-exo cyclization. Utilizing an E-enriched silyl enol ether as alkoxy radicalacceptor instead (competition substrate 349), has no effect on the product distribution.151Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationPhthNO Bu3SnH, AIBNC6D6, 80 °CO+OTBSOOTBSOTBSPhthNO Bu3SnH, AIBNC6D6, 80 °CO+OOTBSOTBS47:5348:52OTBS348388388389389349Scheme 4.28. Competing 5-exo cyclization of alkoxy radicals onto a silyl enol ether (cis and trans enriched)and a trialkyl-substituted alkene.Despite the lack of selectivity observed in the last two competition substrates (348 and 349), it is clearfrom the superior 6-exo over 1,5-HAT selectivity displayed by silyl enol ether in the synthesis of THPrings (Scheme 4.9) compared to that of a trialkyl-substituted alkene (Scheme 4.8), that these two radicalacceptors behave differently and a significant change in the product distribution should be observed. Itis possible that our designed competition substrates are effective to differentiate the selectivity of alkoxyradicals as long as the two radical acceptors available to interact with the alkoxy radical in a 5-exo cy-clization mode have a large difference in their corresponding reaction rates. As oxygen-centered radicalreactions are so fast, small differences in reaction rate constants might not be appreciable using thesecompetition substrates. Another factor that might explain the greater selectivity observed in 6-exo cy-clizations is rate of this reaction compared to the 5-exo cyclization. As 6-exo cyclizations are slower, theelectronic difference of the radical acceptors will have a greater impact on the product distribution.4.6.3 Competing 1,5-HAT and alkoxy radical cyclization onto silyl enol ethersThe two different types of substrates that were designed to investigate the chemoselectivity of alkoxyradicals towards cyclization and 1,5-HAT reactions are the substrates B and C shown in Figure 4.6.Competition substrates of type B were designed to asses the selectivity of alkoxy radicals between a 6-exo cyclization mode vs 1,5-HAT, while competition substrates of type C target the selectivity of alkoxyradicals towards a 5-exo cyclization mode vs 1,5-HAT.Competition substrates of type B (Scheme 4.29) were designed to compare an alkoxy radical 6-exo cyclization onto a silyl enol ether vs a 1,5-HAT from a stabilized allylic position (BDEC−H allylic =88 kcal mol−1).5 The cyclization onto the silyl enol ether would generate carbon radical 390, while the1,5-HATwould generate carbon radical 391. The synthesis of primary and secondary N-alkoxyphthalimi-des, aimed to assess the effect steric hinderance on the alkoxy radical would have on the product distri-bution of the reaction.152Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationR +OTBS+BOOTBSOHHOROTBSOTBSOHOROTBS390391392393Scheme 4.29. Substrates type B: alkoxy radicals 6-exo cyclization competing with 1,5-HAT.The first competition substrate investigated was 325, which upon homolysis generates a primaryalkoxy radical that can undergo either a 1,5-HAT at an allylic position or a 6-exo cyclization onto a silylenol ether. Competition substrate 325 had been previously studied by Dr. Zlotorzynska and Dr. Zhai(Scheme 4.9), who obtained 326 in 89% conversion and 74% isolated yield.266 In their initial study, Dr.Zlotorzynska and Dr. Zhai removed the benzene from the reaction mixture through rotary evaporationbefore proceeding with the determination of the product ratio by 1H NMR. We wanted to discard thepossibility of any product loss in the rotary evaporation process, so 325was again prepared and subjectedit to our cyclization conditions utilizing benzene−d6 (Scheme 4.30). Gratifyingly, the product ratioobtained was 90:10 of THP 326 resulting from the 6-exo cyclization pathway against the alcohol 394formed upon the 1,5-HAT reaction. The results are consistent with what was previously observed in ourgroup.Bu3SnH, AIBNC6D6, 80 °C+OTBS90:10OOTBSPhthNOOTBSOH325 326 394Scheme 4.30. Competing 6-exo cyclization of alkoxy radicals onto a silyl enol ether and 1,5-HAT.We next examined competition substrate 360 (Scheme 4.31) to assess if a more hindered alkoxyradical would modify the product distribution when a 1,5-HAT at an allylic position competed witha 6-exo cyclization onto a silyl enol ether. After subjecting N-alkoxyphthalimide 360 to our radicalcyclization conditions, the THP product (395), resulting from the 6-exo cyclization onto a silyl enolether, and alcohol 396, generated from a 1,5-HAT, were observed to be present in the crude reactionmixture in an 86:14 ratio. This results suggests that the increase in steric bulk (from H in 325 to CH3 in360) of the alkoxy radical side has a small impact on the selectivity of 6-exo cyclization onto a silyl enolether vs 1,5-HAT.153Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationBu3SnH, AIBNC6D6, 80 °C+OTBS86:14OOTBSPhthNOOTBSOH360 395 396Scheme 4.31. Competing 6-exo cyclization of alkoxy radicals onto a silyl enol ether and 1,5-HAT.Radical 5-exo cyclizations are known to be faster than 6-exo cyclizations (see Table 4.1, entries 6 and10). To probe whether or not 5-exo cyclization of alkoxy radicals onto silyl enol ethers were faster thanalkoxy radical 1,5-HAT, competition substrates of typeC (Scheme 4.32) were prepared. These substratescan undergo either a 5-exo cyclization onto a silyl enol ether to give 398 or a 1,5-HAT to form 397.RO+OROTBSOTBS +OROTBSCHROH TBSOROH TBSO397398399400Scheme 4.32. Substrates type C: alkoxy radicals 5-exo cyclization competing with 1,5-HAT.We first investigated competition substrate 367 (Scheme 4.33), which offers the alkoxy radical thepossibility to undergo a 5-exo cyclization reaction onto a silyl enol ether or a 1,5-HAT from a secondaryalkyl carbon (BDEC−H sec = 98 kcal mol−1).5 After 367 reacted under our radical cyclization condi-tions, THF ring 401 resulting from a 5-exo cyclization was the only product detected by 1HNMRanalysis.The results show that the rate of 5-exo radical cyclization onto a silyl enol ether is faster than the rate of1,5-HAT to an alkoxy radical from an alkylic position, so much that full chemoselectivity towards the5-exo cyclization reaction over the hydrogen translocation is observed.PhthNO Bu3SnH, AIBNC6D6, 80 °C+OTBSOOTBS>95:5OH OTBS367 401 402Scheme 4.33. Competing 5-exo cyclization of alkoxy radicals onto a silyl enol ether and 1,5-HAT.We next decided to test the limits of our system and probe whether the generation of a more sta-ble radical through 1,5-HAT would affect the chemoselectivity towards 5-exo cyclization onto silyl enolethers. Competition substrate 403 (Scheme 4.34) offers the possibility of abstracting a hydrogen from154Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationa benzylic position (BDEC−H benzylic = 90 kcal mol−1)5 through a 1,5-HAT, or perform a 5-exo cy-clization onto a silyl enol ether. After 403 was subjected to our standard cyclization conditions and uponanalysis of the crude reaction mixture, the only product observed was THF 404. No alcohol 405 wasdetected, which indicates that 5-exo cyclization onto a silyl enol ether will occur exclusively even whenthere is the possibility of generating a stabilized benzylic radical.PhPhthNO Bu3SnH, AIBNC6D6, 80 °C+OPhTBSOOTBS>95:5PhOH OTBS403 404 405Scheme 4.34. Competing 5-exo cyclization of alkoxy radicals onto a silyl enol ether and 1,5-HAT from abenzylic position.4.6.4 Alkoxy radical chemoselectivity study summaryStudies on the chemoselectivity of alkoxy radicals with respect to β-fragmentation were also performedin the group by Dr. Zlotorzynska and C. Dunbar. The results from my investigations on the chemoselec-tivity of alkoxy radicals towards 5-exo and 6-exo cyclization, 1,5-HAT, as well as the β-fragmentation stud-ies performed by other members of the Sammis group are summarized in Table 4.2.The competition experiments performed show a clear tendency of alkoxy radicals to react prefer-entially with highly electron rich species. The use of silyl enol ethers as radical acceptors permits agreater control over the chemoselectivity of the highly reactive alkoxy radical species, by exploiting theelectrophilicity of the latter.Alkoxy radicals 5-exo cyclization onto silyl enol ethers (SEEs) is preferred over cyclization onto aterminal alkene with good selectivity (competition substrates type A). An alkoxy radical 5-exo cycliza-tion selectivity onto a silyl enol ether is only moderate when competing with a dialkyl-substituted alkene,and is not selective at all when competing with a trialkyl-substituted alkene.The studies on the selectivity of alkoxy radical cyclization over 1,5-HAT revealed that the cyclizationpathway is greatly preferred both in the 5-exo and the 6-exo cyclization modes when silyl enol ethers areused as radical acceptors. For the 6-exo cyclization, the selectivity is good for primary alkoxy radicals,secondary alkoxy radicals and phenyl substituted silyl enol ethers.In the case of 5-exo cyclizations onto silyl enol ethers competing with 1,5-HAT, the selectivity wasexcellent towards the cyclization pathway. No product resulting from the 1,5-HATwas observed in eitherof the cyclization experiments. As observed with competing 5-exo cyclizations, the use of electron richolefins as SEEs suppresses the competing 1,5-HAT pathway in substrates of types B and C.155Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationTable 4.2. Alkoxy radical selectivity twards cyclization onto silyl enol ether summary.Type of Competition Substitution Selectivity towardsSubstrate SEE cyclizationCompeting 5-exo cyclizationsR2O TBSOR1AR1, R2 = H 89 : 11R1 = H, R2 = CH3 67 : 33R1, R2 = CH3 48 : 52Cyclization versus 1,5-HATR1OTBSBOHR2R1, R2 = H 90 : 10R1 = CH3, R2 = H 86 : 14R1 = H, R2 = Ph 83 : 17266RO OTBSCHR = CH3 > 95 : 5R = Ph > 95 : 5Cyclization versus β-fragmentationO OTBSHR DR = CH2CH3 > 95 : 5266R = Ph 84 : 16266Cyclization versusβ-fragmentation and 1,5-HATOOTBSHArE R = Ph 41% cyclization303With respect to β-fragmentation, the studies performed by my colleague Dr. Zlotorsynzka (com-petition substrates D) showed that a primary alkoxy radical favours 5-exo cyclization onto silyl enolethers over fragmentation almost exclusively. Even when the alkoxy radical β-fragmentation pathwaygenerates a phenyl-stabilized carbon radical, the 5-exo cyclization onto a silyl enol ether showed good se-lectivity. Additionally, when all three alkoxy radical reaction pathways, cyclization (6-exo), 1,5-HAT andβ-fragmentation to form a stabilized radical, are in competition, the 6-exo cyclization product was ob-served in 41%, while the sum of the other two reaction pathway products were observed in 59%.156Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.7 ConclusionsStudies were performed to probe the selectivity of 5-exo and 6-exo alkoxy radical cyclization onto silylenol ethers compared to cyclization onto substituted alkenes, 1,5-HAT, and β-fragmentation reactions.The investigation was completed utilizing eleven different intramolecular competition substrates, sevenof which I synthesized. The results indicate that the use of the electron-rich silyl enol ether group ef-fectively directs the reactivity of alkoxy radicals towards the cyclization reactions and minimizes thegeneration of products derived from other reaction pathways. Rising the HOMO of the radical acceptorreduces the energy gap between this molecular orbital and the SOMO of the alkoxy radical, which resultsin the good selectivity observed towards cyclization onto silyl enol ethers.Alkoxy radicals underwent preferential 5-exo cyclization onto silyl enol ethers compared to 5-exo cy-clization onto either terminal or dialkyl-substituted olefins, yet no selectivity was observed when thecompeting alkoxy radical acceptor was a tryalkyl-substituted olefin. Both 5-exo and 6-exo alkoxy radicalcyclizations onto silyl enol ethers were strongly preferred over 1,5-HAT and β-fragmentation reactions,even when the 5-position was allylic or benzylic.The high chemoselectivity observed in the 5-exo and 6-exo cyclization of alkoxy radicals onto silylenol ethers should enable a broader application of alkoxy radical chemistry in the context of the synthesisof structurally complex molecules.4.8 Experimentals4.8.1 General methodsAll reactions were performed under a nitrogen atmosphere in flame-dried glassware. Tetrahydrofuran(THF), diethyl ether, and dichloromethane were purified by solvent purification system. All other solventswere used without further purification. Thin layer chromatography (TLC) was performed on UV254 pre-coated TLC plates. Chromatographic separations were effected over 230-400 mesh silica gel. Silica gelwas stirred with triethylamine prior to packing. 50% saturated aqueous ammonium chloride solution(50% NH4Cl(aq)) was made using a 1:1 v/v of saturated aqueous ammonium chloride solution and dis-tilled water. 50% saturated aqueous sodium bicarbonate solution (50% NaHCO3(aq)) was made using a1:1 v/v of saturated aqueous sodium bicarbonate solution and distilled water. All chemicals were pur-chased from commercial sources and used as received.A syringe pumpwas used for all slow additions. Melting points are uncorrected. Infrared (IR) spectrawere obtained using an FT-IR spectrometer. Proton nuclear magnetic resonance (1H NMR) spectra wererecorded using a 300 MHz or 400 MHz spectrometer. Carbon nuclear magnetic resonance (13C NMR)157Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationspectra were recorded using a 300 MHz or 400 MHz spectrometer. Chemical shifts are reported in partsper million (ppm) and are referenced to the centerline of deuterochloroform (7.27 ppm 1H NMR; 77.0ppm 13C NMR) or benzene−d6 (7.16 ppm1H NMR; 128.1 ppm 13C NMR).4.8.2 Detailed synthesis of cyclizations precursors4.8.2.1 Synthesis of competition substrate 332 procedureBrMg0THFHOOTBSOHTBSOPhthNOHPh3P, DIADTHF0 °C to r.t.OTBSPhthNOOTBSPhthNOOHPhthNOCSAMeOHOTBSOH327328328329329 330Synthesis of 2-((90hydroxynon-1-en-5-yl)oxy)isoindoline-1,3-dione (330). To flame-dried roundbottom flask containing Mg0 turnings (0.39 g, 16.1 mmol) and two I2 crystals, a solution of 4-bromobut-1-ene (1.0 mL, 1.34 g, 9.93 mmol) in 10 mL of THF was slowly added. The initiation of the Grignardreagent formation was indicated by the colour disappearance from the solution. After two hours ofcontinuos sitrring at ambient temperature the solution was cooled to 0 ◦C and a solution of aldehyde327 (5.0 mmol) in 10 mL of dry THF was added via cannula. The solution turned pale yellow and wasfurther sitrred for one hour. The reaction was then quenched with a saturated solution of NH4Cl(aq) andextracted with Et2O (3 x 15mL). The combined organic extracts were washed with brine, then dried overNa2SO4 and filtered. The solvent was removed by rotary evaporation.1H NMR confirmed the obtentionof alcohol 328, which was used without further purification.To a 0.1 m solution of secondary alcohol 328 in THF at 0 ◦C was added triphenyl phosphine (1.98g, 7.55 mmol) and N-hydroxyphthalimide (1.83 g, 11.22 mmol), followed DIAD (1.8 mL, 1.85 g, 9.14mmol), which was slowly added over 15 min. The reaction was stirred for 18 h before quenching withsaturated solution of NaHCO3(aq) until the aqueous layer was not bright red in colour. The combinedorganic extracts were washed with brine, dried over Na2SO4 and filtered. The solvent was removed158Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationthrough rotary evaporation and the resulting oil semi purified by FCC (95:5 hexanes/AcOEt). A colouredimpurity could not be removed and the pthalimide was used without further purification.To a solution of phthalimide 329 in 50 mL of methanol was added (1S)-(+)-10-camphorsulfonic acid(0.11 g, 0.47 mmol) in one portion. The solution was stirred at ambient temperature for 1:30 h. Thesolvent was removed via rotary evaporation and the resulting oil purified by FCC (4:1 hexanes/AcOEt).Alcohol 330 (0.52 g, 1.71 mmol) was isolated as a pale white oil in 34% yield over three steps. Charac-terization of ?? matched previously reported data.266OHPhthNOTBSOTf, DIPEACH2Cl2, 0 °CNMO, TPAPCH2Cl2, 0 °C HPhthNOPhthNO OTBSOHPhthNO O330331331332Synthesis of 2-((1-((t-butyldimethylsilyl)oxy)nona)1,80diene050yl)oxy)isoindo-line-1,3-dione (332).To a solution of alcohol 330 in 20 mL of dry dichloromethane and 4 A˚ molecular sieves, was added N-methylmorpholin-N-oxide (0.41 g, 3.46 mmol). The resulting suspension was cooled to 0 ◦C beforeaddition of tetrabutylammonium perruthenate (0.03 g, 0.09 mmol). The resulting solution was stirredfor an additional 50 min and then allowed to warm to ambient temperature. The reaction was then fil-tered through a layers of celite over silica gel, and the filtrates were washed with Et2O. The filtrate wascollected and the solvent removed by rotary evaporation. TLC analysis showed no starting material waspresent, so aldehyde 331 was used without further purification.To a 0.1m solution of aldehyde 331 in dry dichloromethane at 0 ◦C, was added diisopropylethylamine(0.6 mL, 0.45 g, 3.44 mmol) followed by t-butyldimethylsilyl trifluoromethylsulfonate (0.59 mL, 0.68g, 2.57 mmol). The resulting solution was stirred for 30 min at 0 ◦C, then an additional 1:30 h atambient temperature. The reaction was quenched with a saturated solution of NaHCO3(aq) and extractedwith dichloromethane (3 x 15 mL). The combined organic extracts were washed with brine, dried overNa2SO4 and filtered. The solvent was removed through rotary evaporation. FCC purification (98:2 to95:5 hexanes/AcOEt) yielded silyl enol ether 332 in 31% yield over two steps in a 12:88 E/Z ratio. Theproduct characterization matched literature data.266159Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.8.2.2 Synthesis of competition substrate 340 procedureOH OTESOTESOTESCl, imid.DMF, 0 °CmCPBACH2Cl2, 0 °C333 334 335Synthesis of triethyl(4-(oxiran-2-yl)butoxy)silane (335).304 To a 2.4 m solution of imidazole (5.78g, 84.91 mmol) and 5-hexen-1-ol (5.0 mL, 4.25 g, 42.43 mmol) in DMF at 0 ◦C was slowly addedtriethylsilyl chloride (7.4 mmol, 6.65 g, 44.09 mmol). After 5 min the ice bath was removed and theresulting solution was stirred at ambient temperature for 1 h. The mixture was then diluted with H2O(30 mmol) and extracted with Et2O (3 x 20 mL). The combined organic extracts were washed withH2O (2 x 10 mmol), brine (10 mmol), dried over Na2SO4, and filtered. Removal of solvent using rotaryevaporation yielded 9.47 g of alkene 334, which was used without further purification.To a 0.25 m solution of mCPBA (19.00 g 77% purity, 14.63 g, 84.78 mmol) in dichloromethane at0 ◦C was added 334 via cannula. The reaction mixture was stirred at 0 ◦Cfor 15 min. The ice bathwas removed and the resulting solution was stirred for 18 h at ambient temperature The reaction mixturewas concentrated to half its volume, quenched with 1.0 m NaOH solution until no solids were observed,extracted with dichloromethane (3 x 40 mmol), washed with brine (30 mL). The combined organicextracts were dried over Na2SO4 and filtered. Removal of the solvent by rotary evaporation followed byflash column chromatography purification (4:1 hexanes/AcOEt elution system) yielded 7.91 g of 335 asa yellow oil in a 81% yield over two steps. 1H NMR(300 MHz; CDCl3): δ 3.61 (t, J = 6.1 Hz, 2H), 2.90(dd, J = 3.5, 2.9 Hz, 1H), 2.74 (t, J = 4.5 Hz, 1H), 2.46 (dd, J = 5.0, 2.7 Hz, 1H), 1.60-1.50 (m, 6H),0.95 (t, J = 7.9 Hz, 9H), 0.59 (q, J = 7.9 Hz, 6H). 13C NMR(75 MHz; CDCl3): δ 62.7, 52.4, 47.2, 32.7,32.4, 22.5, 6.9, 4.5. HRMS-ESI (m/z) [M+Na]+ calcd for C12H26O2NaSi: 253.1600. Found: 253.1605.160Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationOTESOMgClCuITHF, 0 °C to r.t.OTESPhthNOPhthNOHPh3P, DIADTHF0 °C to r.t.OTESOHOTESOH335336336337Synthesis of (E)-2-((1-((triethylsilyl)oxy)dec-8-en-5-yl)oxy)isoindoline-1,3-dione (337). A two-neck flask equipped with reflux condenser and septum addition port containing magnesium churnings(0.74 g, 28.8 mmol, 2.5 equiv.) was added a small iodine crystal. Crotyl chloride (1.7 mL, 17.3 mmol,1.5 equiv.) in THF (20 mL + 15 mL rinse) was added dropwise maintaining a gentle reflux. The result-ing suspension was refluxed for 1 h then cooled to ambient temperature. To a separate flask containingcopper (I) iodide (243 mg, 1.12 mmol, 0.1 equiv.) and 335 (2.69 g, 11.5 mmol, 1.0 equiv.) was addedTHF (11.5 mmol) and cooled to 0 ◦C in an ice/water bath. To the cloudy grey suspension was added theGrignard solution over 15 min. The color in the reaction mixture changed from cloudy grey to brightyellow to orange-red to red-black. The reaction was stirred for 18 h and allowed to warm to ambient tem-perature. The blue-black solution was quenched with 50% saturated NH4Cl(aq) (100 mL) and extractedwith Et2O (3 x 50 mL). The organics were washed with brine (25 mL), dried over Na2SO4, filtrated, andconcentrated by rotary evaporation to provide a yellow oil. Purification by flash chromatography (3:1Hexanes/Et2O) provided 2.25 g of a clear colorless oil. The oil was use without further purification.To alcohol 336 (2.25 g, 7.8 mmol, 1.0 equiv.) was added N-hydroxypthalimide (1.91 g, 11.7 mmol,1.5 equiv.), triphenylphosphine (2.83 g, 10.9 mmol, 1.4 equiv.), and THF (80 mL). The solution wascooled to 0 ◦C in an ice/water bath and diisopropyl azodicarboxylate (2.2 mL, 10.9 mmol, 1.4 equiv.)was added in two portions over 20 min. The colorless solution turned to an orange-red solution duringaddition. The reaction was stirred for 18 h and allowed to warm to ambient temperature. The light-yellowsolution was poured into AcOEt (250 mmol), washed with 50% saturated NaHCO3(aq) (3 x 70 mL), andbrine (50 mL). The yellow organic extract was dried over Na2SO4, filtrated and concentrated by rotaryevaporation to provide a yellow semi-solid. Triphenylphosphineoxide solid was triturated with hexanesuntil no color remained. The organics were collected and the solvent was removed by rotary evaporation.Purification by flash chromatography (7:2 Hexanes/Et2O) yielded 2.0 g of N-alkoxypthalimide 337 as aclear colorless oil in 60% yield. 1H NMR (400 MHz; CDCl3): δ 7.82 (dd, J = 5.3, 3.1 Hz, 2H), 7.73 (dd,J = 5.3, 3.2 Hz, 2H), 5.50-5.38 (m, 2H), 4.23 (q, J = 6.0 Hz, 1H), 3.61 (d, J = 5.7 Hz, 2H), 2.20 (ddt, J161Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation= 37.6, 14.8, 7.6 Hz, 2H), 1.75-1.67 (m, 4H), 1.62 (d, J = 5.6 Hz, 3H), 1.55 (t, J = 6.3 Hz, 4H), 0.94 (t,J = 7.9 Hz, 9H), 0.58 (q, J = 7.9 Hz, 6H). 13C NMR (101 MHz; CDCl3): δ 164.5, 134.5, 130.6, 125.7,123.5, 87.9, 62.8, 33.0, 32.5, 32.4, 28.2, 22.6, 21.4, 18.1, 6.9, 4.6. IR (CDCl3): 2952, 2875, 180, 1737,1732, 1700, 976, 701 cm−1. HRMS-ESI (m/z) [M+Na]+ calcd for C24H37NO4NaSi: 454.2390. Found454.2397.OTESPhthNO CSAMeOHTBSOTf,DIPEACH2Cl20 °CNMO, TPAPCH2Cl2, 0 °COHPhthNOHPhthNO OPhthNO OTBS337 338339340Synthesis of 2-(((8E)-1-((t-butyldimethylsilyl)oxy)deca-1,8-dien-5-yl)oxy)iso-indoline-1,3-dione (340). To a solution of silyl ether 337 (906 mg, 2.1 mmol, 1.0 equiv.) in methanol (10.5 mL)was added (1S)-(+)-10-camphorsulfonic acid (46 mg, 0.2 mmol, 0.1 equiv.). The reaction was stirredfor 1 h at ambient temperature, then poured into 50% saturated NaHCO3(aq) (50 mL) and extracted withEt2O (3 x 20 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4,and filtrated. The solvent was then removed by rotary evaporation. Purification by flash chromatography(1:4 Hexanes/Et2O) yielded 374 mg (56%) N-alkoxypthalimide 338 as a clear colorless oil.To a 0.1m solution of 338 (0.2 g, 0.62mmol) in dichloromethane, 4 A˚ powdered molecular sieves (0.2g) and N-methylmorpholin-N-oxide (NMO) (0.15 g, 1.32 mmol) were added. The resulting suspensionwas cooled to 0 ◦C and stirred for 30 min. tetrabutylammonium perruthenate (0.01 g, 0.03 mmol) wasadded and the reaction was stirred for another 1 h at 0 ◦C. The reaction mixture was diluted with hexanes(10 mL) and filtered over layers of celite and silica. The solids were washed with hexanes (25 mL), thenwith Et2O (25 mL). The organics were combined and the solvent was removed by rotary evaporation toyield aldehyde 339 as a clear colorless oil. The crude material was used without further purification.To a solution of 339 in dichloromethane (6 mL) was added diisopropylethylamine (0.25 mL, 0.29g, 1.44 mmol) in one portion. The resulting solution was cooled to 0 ◦C and stirred for 5 min. t-Butyldimethylsilyl trifluoromethanesulfonate (0.21 mL, 0.24 g, 0.91 mmol) was then added and thereaction was stirred 30 min at 0 ◦C, then stirred at ambient temperature for 18 h. The reaction wasquenched with saturated solution of NaHCO3 (1 x 10 mL), extracted with dichloromethane (3 x 10 mL).162Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationThe combined organic extracts were washed with brine, dried over Na2SO4, and filtered. The solvent wasthen removed by rotary evaporation. Purification by flash column chromatography (95:5 hexanes/AcOEt)yielded competition substrate 340 (0.06 g) as a clear colorless oil in 23% yield over 2 steps, 16:84 E/Zratio. 1H NMR (400 MHz; CDCl3): δ 7.88-7.79 (m, 2H), 7.79-7.70 (m, 2H), 6.33 (d, J = 11.9 Hz, 1H(0.16 trans)), 6.18 (d, J = 5.8 Hz, 1H (0.84 cis)), 5.57-5.35 (m, 2H), 4.51-4.46 (m, 1H), 4.31-4.23 (m,1H), 2.38-2.13 (m, 4H), 1.86-1.70 (m, 5H), 1.64 (d, J = 5.1 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 6H). 13CNMR (101 MHz; CDCl3): δ 18.07, 19.5, 21.5, 25.8, 28.1, 32.4, 32.5, 48.5, 87.8, 123.5, 125.6, 129.3,130.7, 134.5, 139.2, 164.5, -5.2. IR (CDCl3): 2928, 2856, 1737, 1256, 1120, 976, 838, 702 cm−1.HRMS-ESI (m/z) [M+Na]+ calcd for C24H35NO4NaSi: 452.2233. Found 452.2225.4.8.2.3 Synthesis of competition substrates 348 and 349 procedureOEtDIBALCH2Cl2, -78 °COHOBrOTBSMg0THFHOOTBSOH341342342344Synthesis of 1-((t-butyldimethylsilyl)oxy)-9-methyldec-8-en-5-ol (344). To a 0.25 m solution ofethyl 5-methylhex-4-enoate (1.02 g, 6.56 mmol) in anhydrous dichloromethane at -78 ◦C was added a1.0 m solution of DIBAL-H in hexanes (9.5 mL, 9.5 mmol) over 5 min. The reaction was stirred for 22min, then quenched with a 1:1 mixture H2O/MeOH (40 mL). The mixture was stirred for 2 hat ambienttemperature. The resulting gel was filtered over Na2SO4/Celite and washed with dichloromethane (3x 10 mL). Removal of solvent by rotary evaporation yielded 5-methylhex-4-enal 342 (0.60 g) in 84%yield. The product was confirmed by 1H NMR spectroscopy and utilized without further purification.1H NMR (CDCl3, 400 MHz) 9.77 (s, 1 H), 5.10 (t, 1 H, J = 7.2 Hz), 2.47 (t, 2 H, J = 7.2 Hz), 2.33 (q, 2H, J = 7.4 Hz), 1.70 (s, 3 H), 1.64 (s, 3 H). Full characterization of this compound has been reported.305To flame dried Mg0 (0.39 g, 1596 mmol) and two crystals of iodine was added a 1.0 m solutionof (4-bromobutoxy)(t-butyl)dimethylsilane306 (2.81 g, 10.52 mmol) in 10.5 mLTHF over 10 min. Thereaction mixture was stirred at reflux for 30min. The resulting solution was transferred by cannula (whilewarm) into another flask containing a 0.5m solution of aldehyde 342 (0.59 g, 5.25mmol) in THF at 0 ◦C.The resulting yellow solution was stirred for 18 h. The reaction was quenched with saturated NH4Cl(aq)(15 mL) then extracted with Et2O (3 x 10 mL). The combined organic extracts were washed with brine163Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation(15 mL), dried over Na2SO4, and filtered. Removal of solvent by rotary evaporation and purification byflash column chromatography (9:1 hexanes/AcOEt) yielded 1.36 g of alcohol 344 as a clear colorless oilin 86%. 1H NMR (400 MHz; CDCl3) d 5.14 (t, 1 H, J = 8 Hz), 3.52-3.69 (m, 3 H), 2.05-2.15 (m, 2 H)1.69 (s, 3 H), 1.63 (s, 3 H), 1.41-1.58 (m, 8 H), 0.90 (s, 9 H), 0.05 (s, 6 H). 13C NMR(101 MHz; CDCl3)d 132.0, 124.2, 71.7, 63.1, 37.3, 37.2, 32.8, 26.0, 24.4, 21.9, 18.3, 17.7, -5.3. IR (CDCl3): 3353, 2930,2858, 1472, 1262, 1387, 1255, 1102, 836, 775 cm−1. HRMS-ESI (m/z) [M+H]+ calcd for C17H37O2Si:301.2563. Found 301.2569.PhthNOHPh3P, DIADTHF0 °C to r.t.OTBSPhthNOOTBSPhthNOOHPhthNOCSAMeOHOTBSOH344 345345 346Synthesis of 2-((1-hydroxy-9-methyldec-8-en-5-yl)oxy)isoindoline-1,3-dione (346). To a 0.1m so-lution of alcohol 344 (0.74 g, 2.46mmol) and triphenylphosphine (0.97 g, 3.70mmol) in anhydrous THFat 0 ◦C was added N-hydroxyphthalimide (0.60 g, 3.70 mmol) in one portion. To the resulting yellowsolution was added diisopropylazodicarboxylate (0.88 mL, 0.90 g, 4.47 mmol) dropwise over 40 min.The reaction was stirred at ambient temperature for 2:45 h, diluted with Et2O, and washed with saturatedNaHCO3(aq) until the aqueous phase was colorless. The combined organic extracts were washed with10% HCl(aq) (10 mL), brine (10 mL), dried over Na2SO4, and filtered. Removal of the solvent usingrotary evaporation and purification using flash column chromatography (95:5 hexanes/AcOEt) yielded0.93 g of N-alkoxyphthalimide 346 and a silyl-containing impurity. The crude material was used withoutfurther purification.To a 0.1 m solution of N-alkoxyphthalimide 346 (0.53 g, 1.18 mmol) in MeOH, CSA (0.04 g, 1.79mmol) was added in one portion. The resulting solution was stirred for 2.5 h at ambient temperature.Removal of solvent by rotary evaporation and purification by flash column chromatography (gradienthexanes/AcOEt) yielded 0.61 g of alcohol 346 as a clear colorless oil in 80% yield with 9.2% solventimpurity. 1H NMR (400 MHz; CDCl3): δ 7.82 (dt, J = 5.9, 3.1 Hz, 2H), 7.75 (dt, J = 5.9, 3.1 Hz, 2H),5.11 (ddd, J = 7.1, 5.8, 1.3 Hz, 1H), 4.25 (dd, J = 7.1, 4.1 Hz, 1H), 3.68 (t, J = 6.0 Hz, 2H), 2.18 (t, J = 7.6Hz, 2H), 1.72-1.62 (m, 16H). 13C NMR (101 MHz; CDCl3): δ 164.6, 134.5, 132.3, 129.2, 123.8, 123.6,88.0, 77.5, 77.1, 76.8, 62.7, 32.8, 32.2, 25.8, 23.9, 20.9, 17.9. IR (CDCl3): 2937, 1789, 1783, 1375,164Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation1188, 1123, 1082, 1015, 977, 878, 702 cm−1. HRMS-ESI (m/z) [M+Na]+ calcd for C19H25NO4Na:354.1681. Found 354.1674.OHPhthNOTBSOTf, DIPEACH2Cl2, 0 °CDMSO, (COCl)2Et3NCH2Cl2, -78 °C HPhthNOPhthNO OTBSOHPhthNO O346 347347 348Synthesis of 2-((1-((t-butyldimethylsilyl)oxy)-9-methyldeca-1,8-dien-5-yl)oxy) isoindoline-1, 3-dione (348). To a 1.5m solution of oxalyl chloride (0.43 mL, 0.64 g, 5.01mmol) in dry dichloromethaneat -78 ◦C (acetone/dry ice) was added a 5.0 m solution of dimethylsulfoxide (0.71 mL, 0.78 g, 9.99mmol) in dichloromethane and stirred for 1 h. A 0.5 m solution of alcohol 346 (0.33g, 1.01 mmol) indichloromethane was then added dropwise and stirred for an additional 2 h at -78 ◦C. The acetone/dry-ice bath was removed and triethyl amine (2.8mL, 2.03 g, 20.09mmol) was added, forming a white solid.The solution was stirred 4 h at ambient temperature, quenched with saturated NaHCO3(aq) (10 mL) andextracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with brine(10 mL), dried over Na2SO4, and filtered. Removal of solvent by rotary evaporation and purification byflash column chromatography (9:1, hexanes/AcOEt) yielded aldehyde 347 as a yellow oil. The crudematerial was used without further purification.To a 0.1 m solution of aldehyde 347 (0.09 g, 0.28 mmol) in dichloromethane at 0 ◦C was addeddiisopropylethyl amine (0.11 mL, 0.08 g, 0.6 mmol). The resulting yellow solution was stirred for 30min at ambient temperature, then cooled to 0 ◦C, and t-butyldimethylsilyl trifluoromethanesulfonate(0.11 mL, 0.12 g, 0.45 mmol) was added dropwise over 5 min. The reaction mixture was stirred for 2h at ambient temperature. The reaction was quenched with saturated NaHCO3(aq) (10 mL) and extractedwith dichloromethane (3 x 10 mL). The combined organic extracts were washed with brine (10 mL),dried over Na2SO4, and filtered. Removal of solvent by rotary evaporation and purification by flashcolumn chromatography (9:1 hexanes/AcOEt) yielded 0.12 g of competition substrate 348 as a clearcolorless oil in 66% yield over 2 steps, 20:80 E/Z ratio. 1H NMR (400 MHz; CDCl3) δ 7.80-7.88 (m,2 H), 7.68-7.79 (m, 2 H), 6.33 (d 0.2 H, J = 11.8 Hz, trans), 6.18 (d, 0.8 H, J = 5.7 Hz, cis), 5.13 (t,1 H, J = 7.0), 4.49 (q, 1 H, J = 7.0 Hz), 4.19-4.34 (m, 1 H), 2.14-2.37 (m, 4 H), 1.70-1.84 (m, 4 H),1.68 (s, 3 H), 0.91 (s, 9 H), 0.11 (s, 5 H). 13C NMR (101 MHz; CDCl3): δ 164.5, 139.2, 134.4, 129.3,123.5, 109.9, 109.5, 88.0, 35.2, 32.7, 32.5, 25.9, 25.8, 23.8, 19.6, -5.2. IR (neat): 2929, 2857, 1791,165Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation1735, 1655, 1467, 1363, 1256, 1188, 1121, 977, 838, 702 cm−1. HRMS-ESI (m/z) [M+Na]+ calcd forC25H37NO4NaSi: 466.2390. Found 466.2393.TBSOCl, DBUCH2Cl2, 0 °CPhthNOHPhthNO OOTBS347 349Synthesis of 2-((1-((t-butyldimethylsilyl)oxy)-9-methyldeca-1,8-dien-5-yl)oxy) isoindoline-1, 3-dione (349). To a solution of crude aldehyde 347 (0.121 g, 0.367mmol) in 4.2mLof dry dichloromethanewas added 1,8-diazabicyclo(5.4.0)undec-7-ene (0.13 mL, 0.132 g, 0.869 mmol) in one portion, fol-lowed by t-butyldimethylsilyl chloride (0.0992 g, 0.658 mmol). The resulting solution was stirred atambient temperature for 4 h. The reaction was quenched with saturated NaHCO3 and extracted withdichloromethane (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), driedover Na2SO4, and filtered. Removal of solvent by rotary evaporation and purification by flash columnchromatography (95:5 hexanes/AcOEt) yielded 0.093 g of N-alkoxyphthalimide 349 as a clear colorlessoil in 57% yield as a 67:33 mixture of E/Z isomers. 1H NMR (400 MHz; CDCl3): δ 7.83 (dd, J = 5.4,3.1 Hz, 2H), 7.74 (dd, J = 5.6, 2.9 Hz, 2H), 6.32 (d, J = 11.8 Hz, 0.67 H, trans), 6.17 (d, J = 5.8 Hz, 0.33H, cis), 5.12-5.10 (m, 1H), 4.99 (dt, J = 11.9, 7.5 Hz, 1H), 4.48 (dd, J = 13.2, 7.0 Hz, 1H), 4.27-4.20 (m,1H), 2.23-2.14 (m, 4H), 1.75-1.62 (m, 9H), 0.90 (d, J = 3.8 Hz, 9H), 0.11 (s, 6H). 13C NMR (101 MHz;CDCl3): δ 164.5, 139.2, 134.4, 129.3, 123.5, 109.9, 109.5, 88.0, 35.2, 32.7, 32.5, 25.9, 25.8, 23.8, 19.6,-5.2. IR (neat): 2929, 2857, 1791, 1735, 1655, 1467, 1363, 1256, 1188, 1121, 977, 838, 702 cm−1.HRMS-ESI (m/z) [M+Na]+ calcd for C25H37NO4NaSi: 466.2390. Found 466.2393.166Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.8.2.4 Synthesis of competition substrates 325 procedureOHCSAMeOHNaH, TBSClTHF, 0 °COHOTBSPhthNOOHPhthNOOTBSOHOTBSOHOTBSPhthNOPhthNOHPh3P, DIADTHF0 °C to r.t.350351351352352 353Synthesis of 2-((6-hydroxyhexyl)oxy)isoindoline-1,3-dione (353). A flame-dried round bottomflask was charged with a 60% suspention of sodium hydride (1.02 g, 25.5 mmol of NaH), which waswashed with dry hexanes (3 x 10 mL) and then dried under high vacuum. 60 mL of dry THF were addedto form a suspension, then was added a solution of 1,6-hexyldiol (350, 3.13 g, 26.5 mmol) in 60 mL ofTHF. The resulting solution was stirred at ambient temperature for one hour. The solution was cooledto 0 ◦C, then was added t-butyldimethylsilyl chloride (3.05 g, 20.2 mmol) in one portion, allowed towarm to ambient temperature and stirred for 18 h. The reaction was quenched with a saturated solutionof Na2CO3(aq) and extracted with Et2O (3 x 15 mL). The combined organic extracts were washed withbrine, dried over Na2SO4 and filtered. FCC purification yielded 3.07 g of monoprotected alcohol 351 asa clear colourless oil in 65% yield. The product was confirmed by 1H NMR.To a solution of 351 (1.07 g, 4.60 mmol) and triphenylphosphine (1.85 g, 7.05 mmol) in 50 mL ofdry THF at 0 ◦C, was added N-hydroxyphthalimide (1.13 g, 6.93 mmol), followed by drop wise additionof diisopropylazodicarboxylate (1.6 mL, 1.64 g, 8.13 mmol) over 10 min. The resulting solution wasstirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O, then quenched witha saturated solution of NaHCO3(aq). The combined organic extracts were washed with a 10% HCl(aq)solution, then washed with brine, dried over Na2SO4, filtered and the solvent removed via rotary evapo-ration. FCC purification (9:1 then 4:1 hexanes/AcOEt) provided 1.26 g of N-alkoxyphthalimide 352 asa clear colourless oil in 72% yield. The product was confirmed by 1H NMR.To a solution of phthalimide 352 in 40 mL of methanol was added (1S)-(+)-10-camphorsulfonic acid(1.26 g, 3.33 mmol) in one portion. The solution was stirred at ambient temperature for 2 h. The solventwas removed via rotary evaporation. Purification via FCC (gradient hexanes/AcOEt) yielded 0.51 g ofalcohol 353 as a white solid in 58%. m. p. 89 − 90 ◦C. Characterization of 353 matched previously167Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationreported data.266 1H NMR (300 MHz; CDCl3): δ 7.83 (dt, J = 5.9, 3.2 Hz, 2H), 7.75 (dt, J = 5.9, 3.2Hz, 2H), 4.21 (t, J = 6.5 Hz, 2H), 3.67 (q, J = 5.8 Hz, 2H), 1.81 (quintet, J = 7.0 Hz, 2H), 1.64-1.38(m, 7H). 13C NMR (75 MHz; CDCl3): δ 163.8, 134.6, 129.1, 123.6, 78.5, 62.9, 32.7, 28.2, 25.4, 25.4.IR (neat): 3335, 2918, 2894, 2866, 1788, 1735, 1466, 1398, 1373, 1187, 1131, 1084. 1016, 879, 701cm−1. HRMS-EI (m/z) [M]+ calcd for C14H17NO4: 263.11576. Found 263.11561.OHPhthNOOPhthNOHOPhthNO PhthNOOTBSHNMO, TPAPCH2Cl2, 0 °CTBSOTf,DIPEACH2Cl20 °C353 354325325Synthesis of 2-((6-t-butyldimethylsilyl)oxy)hex-5-en-1-yl)isoindoline-1,3-dione (325). To a solu-tion of alcohol 353 (0.26 g, 0.99 mmol) in 10 mL of dry dichloromethane and 4 A˚ molecular sieves,was added N-methylmorpholin-N-oxide (0.23 g, 2.0 mmol). The resulting suspension was cooled to 0◦C before addition of tetrabutylammonium perruthenate (15 mg, 0.043 mmol). The resulting solutionwas stirred for an additional hour and then allowed to warm to ambient temperature. The reaction wasthen filtered through a layers of celite over silica gel, and the filtrates were washed with dichloromethane.The filtrate was collected and the solvent removed by rotary evaporation. TLC analysis showed no start-ing material was present, so aldehyde 354 was used without further purification.To a 0.1m solution of aldehyde 354 in dry dichloromethane at 0 ◦C, was added diisopropylethylamine(0.4 mL, 0.30 g, 2.30 mmol) followed by t-butyldimethylsilyl trifluoromethylsulfonate (0.35 mL, 0.40g, 1.52 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction wasquenched with a saturated solution of NaHCO3(aq) and extracted with dichloromethane (3 x 15 mL).The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. The solvent wasremoved through rotary evaporation. FCC purification (9:1 hexanes/AcOEt) yielded silyl enol ether 325as a clear colourless oil in 58% yield over two steps in a 10:90 E/Z ratio. The product characterizationmatched literature reported data.266 1H NMR (300 MHz; CDCl3): δ 7.83 (dd, J = 5.4, 3.2 Hz, 2H), 7.74(dd, J = 5.5, 3.1 Hz, 2H), 6.22 (dd, J = 16.2, 8.9 Hz, 1H), 4.98 (dt, J = 11.9, 7.5 Hz, ), 4.44 (q, J = 6.6Hz, 1H), 4.23-4.18 (m, 2H), 2.15 (qd, J = 7.3, 1.2 Hz, 2H), 1.86-1.76 (m, 2H), 1.59-1.49 (m, 2H), 0.91(s, 9H), 0.11 (s, 6H). 13C NMR (75 MHz; CDCl3): δ 163.8, 139.1, 134.5, 123.6, 109.9, 78.7, 27.8, 25.8,25.7, 23.3, 18.4, -5.2. IR (neat): 2954, 2930, 2857, 1735, 1468, 1256, 1187, 1127, 1082, 878, 838, 701cm−1. HRMS-ESI (m/z) [M+Na]+ calcd for C20H29NO4NaSi: 398.1764. Found 398.1768.168Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.8.2.5 Synthesis of competition substrates 360 procedureOTBSPhthNOHPh3P, DIADTHF0 °C to r.t.DMSO, (COCl)2Et3NCH2Cl2, -78 °CMeLi, CuITHFOHOTBSOHOTBSOHOTBSOHOTBSOHOTBSPhthNO351355355356356357Synthesis of 2-((7-((t-butyldimethylsilyl)oxy)heptan-2-yl)oxy)isoindoline-1,3-dione (357). To a1.5 m solution of oxalyl chloride (1.2 mL, 1.77 g, 13.97 mmol) in dichloromethane at -78 ◦C, was addeda 5.0 m solution of dimethylsulfoxide (2.0 mL, 5.81 g, 57.39 mmol) over 10 min and stirred 30 min.6-((t-butyldimethylsilyl)oxy)hexan-1-ol307 (1.02 g, 4.40 mmol, 1.5 m in dichloromethane) was addedover 10 min and the resulting solution was stirred for 1 h. Finally, triethylamine (8.0 mL, 5.81 g, 57.39mmol) was added over 1 min and stirred for 1 h. The resulting solution was allowed to warm to ambienttemperature and stirred for 2 h. The suspension was quenched with saturated NaHCO3(aq) (15 mL), andextracted with dichloromethane (3 x 20 mL). The combined organic extracts were washed with brine (10mL), dried over Na2SO4, and filtered. The organics were removed by rotary evaporation and the resultingoil was purified by flash column chromatography (9:1 hexanes/AcOEt) to yield 1.0 g of aldehyde 355.To aldehyde 355 (0.23 g, 0.66 mmol) in 5.0 mLof THF, was added copper (I) iodide (0.0116 g, 0.06mmol) and the resulting suspension was placed in a cold water bath. Methyl lithium (1.6 m in Et2O, 1.0mL, 1.6mmol) was added slowly over 10min. The resulting solution was stirred at ambient temperaturefor 18 h. The reaction was quenched with saturated NH4Cl(aq) solution (10mL), and extracted with Et2O(3 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4 andfiltered. The solvent was removed via rotary evaporation and purified by flash column chromatography(9:1 then 8:2 hexanes/AcOEt) to yield alcohol 356 as a light yellow oil.To a solution of alcohol 356 (0.1832 g, 0.74 mmol) and triphenylphosphine (0.1889 g, 0.72 mmol)in 5.0 mLof THF at 0 ◦C, was added N-hydroxyphthalimide (0.1177 g, 0.72 mmol) in one portion.Diisopropyl azodicarboxylate (0.17 mL, 0.1746 g, 0.86 mmol) was slowly added over 15 min. The169Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationreaction was stirred at ambient temperature for 18 h. The reaction was then diluted with Et2O andwashed with saturated NaHCO3(aq) until the aqueous phase was colorless, then washed with 10% HCl(aq)(10 mL), brine (5 mL) and dried over Na2SO4. The solids were filtered and the solvent was removedusing rotary evaporation. Purification by flash column chromatography (95:5 hexanes/AcOEt) yielded0.185 g of N-alkoxyphthalimide 357 as a clear colorless oil (51% yield over 3 steps). 1H NMR (300MHz; CDCl3): δ 7.82 (dd, J = 5.5, 3.1 Hz, 2H), 7.73 (dd, J = 5.5, 3.1 Hz, 2H), 4.36 (d, J = 6.2 Hz,1H), 3.60 (t, J = 6.4 Hz, 2H), 1.86-1.36 (m, 8H), 1.32 (d, J = 6.2 Hz, 3H), 0.87 (s, 9H), 0.03 (s, 6H).13C NMR (75 MHz; CDCl3): δ 164.5, 134.5, 129.1, 123.5, 84.6, 63.3, 35.0, 32.9, 26.10, 25.96, 25.2,18.9, 18.5, -5.1. IR (CDCl3): 2931, 2857, 1791, 1737, 1468, 1375, 1255, 1098, 976, 836, 702 cm−1.HRMS-EI (m/z) [M]+ calcd for C21H33NO4NaSi: 414.2077. Found: 414.2087.CSAMeOHOTBSPhthNOOHPhthNO357 358Synthesis of 2-((7-hydroxyheptan-2-yl)oxy)isoindoline-1,3-dione (358). To a solution of phthal-imide 357 (0.1847 g, 0.4728 mmol) in 10 mL of wet MeOH, was added (1S)-(+)-10-camphorsulfonicacid (0.0158 g, 0.068 mmol) in one portion. The reaction mixture was stirred for 2 h at ambient temper-ature. Removal of solvent by rotary evaporation and purification by flash column chromatography (4:1 to3:2 hexanes/AcOEt) yielded 0.0894 g of alcohol 358 as a clear colorless oil (68% yield). 1H NMR (300MHz; CDCl3): δ 7.83 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 4.38 (sextet, J = 6.0 Hz,1H), 3.67 (d, J = 3.7 Hz, 2H), 1.87-1.40 (m, 9H), 1.33 (d, J = 6.3 Hz, 3H). 13C NMR (75 MHz; CDCl3):δ 164.5, 134.6, 129.1, 123.6, 84.4, 62.9, 35.0, 32.7, 25.7, 25.0, 19.1. IR (CDCl3): 3391, 2936, 2862,1789, 1732, 1467, 1377, 1188, 1124, 1082, 1016, 976, 879, 702 cm−1. HRMS-EI (m/z) [M]+ calcd forC15H19NO4: 277.13141. Found: 277.13115.170Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationOHPhthNOOPhthNOHOPhthNO PhthNOOTBSHNMO, TPAPCH2Cl2, 0 °CTBSOTf,DIPEACH2Cl20 °C358 359360360Synthesis of (Z)-2-((7-((t-butyldimethylsilyl)oxy)hept-6-en-2-yl)oxy)isoindo-line-1,3-dione(360). To a 0.1 m solution of alcohol 358 (0.0736 g, 0.2663 mmol) in dry dichloromethane was added 4A˚molecular sieves (0.06 g) and the mixture was cooled to 0 ◦C using an ice bath. N-methylmorpholin-N-oxide (0.0638 g, 0.5446 mmol) and tetrabutylammonium perruthenate (0.0159 mmol) were then added.The resulting black suspension was stirred for 1h at 0 ◦C, allowed to warm to ambient temperature andstirred for 1 h. The reaction was filtered through a celite/silica, washed with hexanes (10 mL) and thenwith dichloromethane (10 mL). Removal of solvent by rotary evaporation yielded aldehyde 359, whichwas used without further purification.To crude aldehyde 359 in 3.0 mL of dry dichloromethane at 0 ◦C was added diisopropylethyl amine(0.1 mL, 0.074 g, 0.57 mmol) in one portion followed by t-butyldimethylsilyl trifluoromethanesulfonate(0.1 mL, 0.12 g, 0.44 mmol). The resulting solution was stirred at ambient temperature for 18 h. Thereaction was quenched with saturated NaHCO3 solution (5 mL) and extracted with dichloromethane(3 x 5 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4, andfiltered. Removal of the solvent by rotary evaporation and purification by flash column chromatography(9:1 hexanes/AcOEt) provided silyl enol ether 360 (0.21 g, 0.57 mmol) as a clear colorless oil in 67%yield (2 steps) as a 10:90 E/Z ratio of isomers. 1H NMR (400 MHz; C6D6): δ 7.31 (dd, J = 5.4, 3.1Hz, 2H), 6.80 (dd, J = 5.4, 3.1 Hz, 2H), 6.34 (d, J = 11.9 Hz, ), 6.19 (d, J = 5.8 Hz, 1H), 5.16 (dt, J =11.9, 7.5 Hz, ), 4.53 (q, J = 6.6 Hz, 1H), 4.36 (q, J = 6.0 Hz, 1H), 2.30 (t, J = 7.1 Hz, 2H), 1.90-1.59(m, 5H), 1.23 (d, J = 6.2 Hz, 3H), 0.94 (s, 9H), 0.05 (d, J = 1.8 Hz, 6H). 13C NMR (101 MHz; C6D6):δ 164.1, 139.1, 133.7, 129.6, 123.0, 110.5, 84.6, 35.1, 25.9, 25.7, 24.1, 19.2, -5.3. IR (CDCl3): 2929,2856, 1790, 1733, 1653, 1466, 1374, 1255, 1187, 1080, 975, 878, 836, 701 cm−1. HRMS-TOF ES+(m/z) [M]+ calcd for C21H32NO4Si: 390.2101. Found: 390.2091.171Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.8.2.6 Synthesis of competition substrates 367 procedureOTBSHOOTBSHODMSO, (COCl)2,Et3NCH2Cl2,-78 °C361 362Synthesis of 5-((t-butyldimethylsilyl)oxy)pentanal (362). To a solution of oxalylchloride (0.55mL, 0.81 g, 10.32 mmol) in 20 mL of dry dichloromethane at -78 ◦C was added dimethylsulfoxide(2.40 mL, 2.64 g, 20.80 mmol) (gas release observed). The resulting solution was stirred at -78 ◦C for5 min before adding 5-((t-butyldimethylsilyl)oxy)pentan-1-ol (2.50 mL, 2.25 g, 10.35 mmol). The re-action was stirred for an additional 20 min at -78 ◦C. Triethylamine (7.50 mL, 5.45 g, 69.69 mmol)was added in one portion and the reaction was stirred at -78 ◦C for 10 min and then let warm to ambienttemperature for 45min. The reaction was diluted with 25.0mL of H2O, stirred 15min, and washed with10% HCl(aq) (10 mL), saturated NaHCO3(aq) (10 mL), brine (10 mL), dried over Na2SO4, and filtered.The solvent was removed by rotary evaporation and purification by flash column chromatography (95:5hexanes/AcOEt) yielded 1.01 g of aldehyde 362 as a clear colorless oil in 45% yield. Characterizationmatched the previously reported data.308BuLiTHF,-78 °COTBSHOOTBSOH362 363Synthesis of 1-((t-butyldimethylsilyl)oxy)nonan-5-ol (363). To a solution of aldehyde 362 (0.503g, 2.32 mmol) in 8.0 mL of dry THF at -78 ◦C was added a 1.6 m solution of butyllithium in hexanes(2.20 mL, 3.52 mmol). The resulting bright yellow solution was stirred at -78 ◦C for 1 h, then let warmto ambient temperature. The reaction was quenched with saturated NH4Cl(aq) (10 mL) and extractedwith Et2O (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried overNa2SO4, and filtered. Removal of solvent by rotary evaporation followed by flash column chromatog-raphy purification (95:5 hexanes/AcOEt) yielded 0.55 g of alcohol 363 as a clear colorless oil in 86%yield. 1H NMR (400 MHz; CDCl3): δ 3.62 (t, J = 6.3 Hz, 3H), 1.59-1.31 (m, 16H), 0.89 (s, 9H), 0.05(s, 6H). 13C NMR (101 MHz; CDCl3): δ 72.1, 63.3, 37.3, 33.6, 32.9, 28.0, 26.1, 22.9, 22.1, 22.0, 14.2,-5.1. IR (neat): 3339, 2956, 2930, 2859, 1463, 1388, 1362, 1254, 1098, 1006, 940, 833, 810, 774 cm−1.HRMS-ESI (m/z) [M+H]+ calcd for C15H35O2Si: 275.2406. Found 275.2410.172Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationCSAMeOHOTBSOHOTBSPhthNOOHPhthNOPhthNOHPh3P, DIADTHF0 °C to r.t.OTBSPhthNO363364364365Synthesis of 2-((1-hydroxynonan-5-yl)oxy)isoindoline-1,3-dione (365). To a solution of alcohol363 (0.55 g, 2.01 mmol), triphenylphosphine (0.79 g, 3.02 mmol) and N-hydroxyphthalimide (0.496 g,3.04mmol) in 20mL of dry THF at 0 ◦Cwas added diisopropyl azodicarboxylate (0.75mL, 0.77 g, 3.81mmol) dropwise over 15 min. The icebath was the removed and the reaction was stirred for 18 h. Thereaction mixture was diluted with Et2O and washed with saturated NaHCO3(aq) until the aqueous phasewas colorless, then the combined organic extracts were washed brine (15 mL), dried over Na2SO4, andfiltered. Removal of solvent by rotary evaporation and flash column chromatography purification (96:4hexanes/AcOEt) yielded 0.925 g of N-alkoxyphthalimide 364 as a yellow oil. The product was usedwithout further purification. 1H NMR (400 MHz; CDCl3): δ 7.82 (dd, J = 5.5, 3.1 Hz, 2H), 7.73 (dd, J= 5.4, 3.1 Hz, 2H), 4.23 (t, J = 5.9 Hz, 1H), 3.62 (t, J = 5.0 Hz, 2H), 1.71-1.61 (m, 5H), 1.57-1.31 (m,10H), 0.91 (t, J = 7.3 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H). 13C NMR (101 MHz; CDCl3): δ 164.5, 134.5,129.2, 123.5, 88.4, 63.1, 33.0, 32.3, 32.23, 27.2, 26.1, 22.9, 21.4, 18.5, 14.1, -5.1.To a solution of N-alkoxyphthalimide 364 in 20 mL MeOH was added CSA (0.05 g, 0.22 mmol).The resulting solution was stirred for 18 h. Removal of solvent by rotary evaporation and flash columnchromatography purification (4:1 hexanes/AcOEt) yielded 0.52 g of alcohol 365 as a white solid in 84%yield over 2 steps. m. p.: 56-56 ◦C. 1H NMR (400 MHz; CDCl3): δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H),7.74 (dd, J = 5.4, 3.1 Hz, 2H), 4.23 (t, J = 5.5 Hz, 1H), 3.68 (s, 2H), 1.70-1.35 (m, 14H), 0.91 (t, J = 7.2Hz, 3H). 13C NMR (101 MHz; CDCl3): δ 164.6, 134.6, 129.2, 123.6, 88.3, 62.7, 32.8, 32.3, 32.2, 27.3,22.9, 20.9, 14.2. IR (neat): 3409, 2938, 2869, 1790, 1728, 1468, 1375, 1188, 1123, 1082, 1016, 977,879, 702 cm−1. HRMS-ESI (m/z) [M+Na]+ calcd for C17H23NO4Na: 328.1525. Found 328.1532.173Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationOHPhthNOTBSOTf, DIPEACH2Cl2, 0 °CNMO, TPAPCH2Cl2, 0 °C HPhthNOPhthNO OTBSOHPhthNO O365366366367Synthesis of 2-((1-((t-butyldimethylsilyl)oxy)non-1-en-5-yl)oxy)isoindoline-1,3-dione (367). Toalcohol 365 (0.516 g, 1.69 mmol) and 4 A˚ molecular sieves (0.51 g) in 17 mL of dry dichloromethaneat 0 ◦C was added N-methylmorpholin-N-oxide (0.396 g, 3.38 mmol) and the reaction was stirred for10 min. Tetrapropylammonium perruthenate (0.030 g, 0.084 mmol) was then added in one portion.The resulting black suspension was stirred 1 h at 0 ◦C, then allowed to warm to ambient temperatureand stirred for an additional hour. The reaction was filtered through celite and silica gel, washed withhexanes (30 mL), then washed with Et2O (15 mL). The organics were combined and the solvent wasremoved by rotary evaporation to yield 0.35 g of crude aldehyde 366 as a clear colorless oil. The materialwas used without further purificationTo a solution of crude aldehyde 366 in 17.0 mL of dry dichloromethane at 0 ◦C as added diiso-propylethyl amine (0.59 mL, 0.438 g, 3.39 mmol) in one portion and the reaction was stirred for 10 min.t-Butyldimethylsilyl trifluoromethanesulfonate (0.60mL, 0.69 g, 2.8mmol) was then added and the reac-tion was stirred at ambient temperature for 18 h. The reaction was quenched with saturated NaHCO3(aq)(10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washedwith brine (10 mL), dried over Na2SO4, and filtered. Removal of solvent by rotary evaporation and flashcolumn chromatography purification (98:2 hexanes/AcOEt) yielded 0.31 g of N-alkoxyphthalimide 367as a clear colorless oil in 44% yield (2 steps) as an 11:89 mixture of E/Z isomers. 1H NMR (400 MHz;CDCl3): δ 7.82 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dt, J = 5.8, 3.1 Hz, 2H), 6.32 (d, J = 11.9 Hz, 0.11),6.16 (d, J = 5.8 Hz, 0.89 H), 4.98 (dt, J = 11.9, 7.5 Hz, ), 4.48 (q, J = 6.6 Hz, 1H), 4.25 (quintet, J =6.0 Hz, 1H), 2.29-2.18 (m, 2H), 1.78-1.68 (m, 4H), 1.57-1.32 (m, 5H), 0.89 (s, 9H), 0.10 (d, J = 1.5 Hz,6H). 13C NMR (101 MHz; CDCl3): δ 164.5, 139.2, 134.4, 129.3, 123.5, 109.5, 88.2, 32.5, 32.1, 27.1,25.8, 22.9, 19.6, 18.4, 14.2, -5.2. IR (neat): 3033, 2956, 2931, 2859, 1791, 1731, 1656, 1468, 1363,1255, 1188, 1122, 1102, 1083, 976, 878, 835, 779, 699 cm−1. HRMS-ESI (m/z) [M+Na]+ calcd forC23H35NO4NaSi: 440.2233. Found 440.2240.174Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationOTBSMg0, I2THF,-78 °CH OTBSOHPhOBr362 3684.8.2.7 Synthesis of competition substrates 372 procedureSythesis of 8-((t-butyldimethylsilyl)oxy)-1-phenyloctan-4-ol (368). To flame dried Mg0 (0.172 g, 7.07mmol) and 2 crystals of iodine was added a solution of 1-bromo-3-phenylpropane (0.75mL, 0.98 g, 4.94mmol) in 5.0 mL of dry THF dropwise, maintaining a gentle reflux. The resulting solution was stirredat ambient temperature for 1 h. This solution was then added via cannula into a solution of aldehyde 362(0.501 g, 2.313 mmol) in 5.0 mL of dry THF at 0 ◦C. The resulting solution was stirred at 0 ◦C for 1 h,then at ambient temperature for 18 h. The reaction mixture was quenched with saturated NH4Cl(aq) (15mL) and extracted with Et2O (3 x 10mL). The combined organic were washed with brine (10mL), driedover Na2SO4, and filtered. Removal of solvent by rotary evaporation and flash column chromatographypurification (95:5 hexanes/AcOEt) provided 0.64 g of alcohol 368 as a clear colorless oil in 82% yield.1H NMR (400 MHz; CDCl3): δ 7.32 (t, J = 7.1 Hz, 3H), 7.22 (t, J = 6.5 Hz, 3H), 3.65 (t, J = 6.2 Hz,3H), 2.67 (t, J = 6.9 Hz, 2H), 1.85-1.68 (m, 2H), 1.60-1.42 (m, 9H), 0.93 (s, 9H), 0.09 (s, 6H). 13CNMR (101 MHz; CDCl3): δ 142.5, 128.5, 128.4, 125.9, 71.9, 63.3, 37.4, 37.2, 36.1, 32.9, 27.6, 26.1,26.1, 22.1, -5.1. IR (neat): 3387, 2930, 2858, 1605, 1497, 1462, 1389, 1362, 1255, 1099, 836, 776, 699cm−1. HRMS-ESI (m/z) [M+Na]+ calcd for C20H36O2NaSi: 359.2382. Found 359.2389.CSAMeOHOTBSOHPhOTBSPhthNOPhOHPhthNOPhPhthNOHPh3P, DIADTHF0 °C to r.t.OTBSPhthNOPh368369369370Synthesis of 2-((8-hydroxy-1-phenyloctan-4-yl)oxy)isoindoline-1,3-dione (370). To a solution ofalcohol 368 (0.64g, 1.89 mmol), triphenylphosphine (0.75 g, 2.85 mmol) and N-hydroxyphthalimide(0.390 g, 2.39 mmol) in 20.0 mL of dry THF at 0 ◦C was added diisopropyl azodicarboxylate (0.70 mL,0.72 g, 3.56 mmol) dropwise over 15 min. The icebath was then removed and the reaction mixture wasstirred for 18 h. The reaction was diluted with Et2O and washed with saturated NaHCO3(aq) until the175Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationaqueous phase was colorless. The combined organic extracts were washed brine (15 mL), dried overNa2SO4, and filtered. Removal of solvent using rotary evaporation and flash column chromatographypurification (96:4 hexanes/AcOEt) yielded 0.755 g of N-alkoxyphthalimide369 as a yellow oil. Theproduct was used without further purification.To a solution of N-alkoxyphthalimide369 in 20 mLwet MeOHwas added CSA (0.04 g, 0.19 mmol).The resulting solution was stirred for 18 h at ambient temperature. Removal of solvent by rotary evapo-ration and flash column chromatography purification (4:1 hexanes/AcOEt) yielded 0.49 g of alcohol 370as a clear colorless oil in 70% yield over 2 steps. 1H NMR (400 MHz; CDCl3): δ 7.89 (dd, J = 5.4, 3.1Hz, 2H), 7.80 (dd, J = 5.5, 3.1 Hz, 2H), 7.33-7.21 (m, 5H), 4.32 (t, J = 5.6 Hz, 1H), 3.71 (t, J = 5.9Hz, 2H), 2.79-2.66 (m, 2H), 1.97-1.59 (m, 11H). 13C NMR (101 MHz; CDCl3): δ 164.6, 142.3, 134.6,129.1, 128.6, 128.4, 125.9, 123.6, 88.0, 62.7, 35.9, 32.7, 32.16, 32.05, 26.9, 20.9. IR (neat): 3416,2940, 2863, 1789, 1726, 1467, 1455, 1374, 1188, 1124, 1082, 976, 878, 699 cm−1. HRMS-ESI (m/z)[M+Na]+ calcd for C22H25NO4Na: 390.1681. Found 390.1685.PhOHPhthNOTBSOTf, DIPEACH2Cl2, 0 °CNMO, TPAPCH2Cl2, 0 °CPhHPhthNOPhPhthNO OTBSOPhHPhthNO O370371371372Synthesis of 2-((8-((t-butyldimethylsilyl)oxy)-1-phenyloct-7-en-4-yl)oxy)iso-indoline-1,3-dione(372). To a suspension of alcohol 370 (0.487 g, 1.33 mmol) and 4 A˚ molecular sieves (0.50 g) in14 mL dichloromethane at 0 ◦C, was added N-methylmorpholin-N-oxide (0.322 g, 2.74 mmol) in oneportion. After stirring for 10 min, tetrapropylammonium perruthenate (0.026 g, 0.074 mmol) was addedin one portion. The black suspension was stirred for 1 h at 0 ◦C, allowed to warm to ambient temper-ature, and stirred for 1 additional hour. The suspension was filtered through a bed of celite over silicagel, washed with hexanes (30 mL), then washed with Et2O (15 mL). The combined organic extractswere removed by rotary evaporation to yield 0.22 g of crude aldehyde 371 as a clear colourless oil. Theproduct was used without further purification.To a solution of crude aldehyde 371 in 14 mL of dichloromethane at 0 ◦C, was added diisopropy-lethyl amine (0.46 mL, 0.341 g, 2.64 mmol) in one portion and stirred for 10 min t-Butyldimethylsilyltrifluoromethanesulfonate (0.47 mL, 0.54 g, 2.05 mmol) was added dropwise over 2 min and the re-sulting solution was allowed to warm to ambient temperature while stirring for 18 h. The reaction was176Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationquenched with saturated NaHCO3(aq) (5mL), extracted with dichloromethane (3 x 10 mL)The combinedorganic extracts were washed with brine (10 mL), dried over Na2SO4, and filtered. The solvent wasremoved by rotary evaporation and purified by flash column chromatography (98:2 hexanes/AcOEt) toafford 0.20 g of N-alkoxyphthalimide 372 as a clear colorless oil (32% yield over 2 steps) as a 10:90mixture of E/Z isomers. 1H NMR (400 MHz; CDCl3): δ 7.30 (dd, J = 5.4, 3.1 Hz, 2H), 7.19-7.05 (m,21H), 6.79 (dd, J = 5.4, 3.1 Hz, 2H), 6.51 (d, J = 11.9 Hz, 0.1 H), 6.16 (d, J = 5.8 Hz, 0.9 H), 5.19 (dt, J= 11.9, 7.5 Hz, ), 4.60 (q, J = 6.6 Hz, 1H), 4.40 (quintet, J = 5.8 Hz, 1H), 2.70-2.45 (m, 4H), 2.09-1.72(m, 6H), 0.92 (s, 9H), 0.03 (s, 5H). 13C NMR (101 MHz; CDCl3): δ 164.1, 142.6, 139.2, 133.6, 129.5,128.8, 128.5, 122.9, 109.9, 100.1, 87.8, 36.1, 32.9, 32.3, 26.9, 25.7, 20.0, 18.4, -5.4. IR (neat): 3029,2951, 2930, 2858, 1791, 1730, 1655, 1468, 1363, 1255, 1188, 1120, 1082, 976, 878, 835, 779, 748, 697cm−1. HRMS-ESI (m/z) [M+Na]+ calcd for C28H37NO4NaSi: 502.2390. Found 502.2379.4.8.3 General radical cyclization procedureA solution of tributyltin hydride (40 µL, 0.15 mmol, 1.5 equiv.) and azobisisobutyronitrile (3.3 mg,0.02 mmol, 0.2 equiv.) in 2 mL benzene−d6 was added at a rate of 1.0 mL/hto a refluxing solution ofN-alkoxypthalimide (0.1 mmol, 1.0 equiv.) in benzene−d6 (5 mL, 0.02 m). The reaction mixture wasrefluxed at 80 ◦C for 4 h before cooling to ambient temperature. An aliquot was taken directly from thereaction vessel for 1H NMR analysis with a Bruker AV400 inverse spectrometer (20 scans, 4 sec overallpulse sequence).This procedure was used for all cyclization precursors, except 348 and 349, where the reaction wasperformed in regular degassed benzene and the final reaction mixture was subjected to work up, consist-ing of removal of solvent by rotary evaporation, and 1H NMR spectroscopy analysis was performed inCDCl3.4.8.4 Cyclization productsCyclization of competition substrates 332, 340, 348 and 349, yielded an diastereomeric mixture oftetrahydrofurans 384 and 385, 386 and 387, 388 and 389, which could not be separated by flash columnchromatography due to their similar polarity. Isolation of tetrahydrofurans 401 and 406 was achievedusing flash column chromatography.177Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationOOTBS401t-Butyl((5-butyltetrahydrofuran-2-yl)methoxy)dimethylsilane (401). Flash chromatography ofthe crude cyclization of 367 (98:2 hexanes/AcOEt) yielded tetrahydropyran 401. 1H NMR (400 MHz;CDCl3): δ 4.06-3.82 (m, 2H), 3.65-3.49 (m, 2H), 2.02-1.89 (m, 2H), 1.76-1.69 (m, 1H), 1.47-1.25 (m,9H), 0.89 (s, 13H), 0.06 (s, 6H). 13C NMR (101 MHz; CDCl3): δ 79.7, 79.1, 66.2, 35.7, 32.0, 31.1,28.6, 28.4, 26.1, 23.0, 14.2, -5.1. HRMS-ESI (m/z): [M+Na]+ calculated for C15H32O2SiNa, 295.2069;found, 295.2073.OPh OTBS406t-Butyldimethyl((5-(3-phenylpropyl)tetrahydrofuran-2-yl)methoxy)silane (406). Flash chromatog-raphy of the crude cyclization of 372 (98:2 hexanes/AcOEt) yielded tetrahydropyran 406. 1H NMR (400MHz; CDCl3): δ 7.29-7.26 (m, 3H), 7.19 (d, J = 7.2 Hz, 3H), 4.06-3.86 (m, 2H), 3.65-3.50 (m, 2H),2.64 (t, J = 7.2 Hz, 2H), 2.03-1.88 (m, 2H), 1.77-1.61 (m, 4H), 1.50-1.44 (m, 2H), 0.90 (s, 9H), 0.06(s, 6H). 13C NMR (101 MHz; CDCl3): δ 142.7, 128.58, 128.38, 125.8, 106.3, 79.6, 79.1, 66.2, 36.1,32.0, 28.32, 28.23, 28.17, 28.02, 23.2, -5.1. HRMS-ESI (m/z): [M+Na]+ calculated for C20H34O2SiNa,357.2226; found, 357.2219.178Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.8.5 NMR analysis of the reaction mixtures4.8.5.1 Analysis of competition substrate 332PhthNO Bu3SnH, AIBNC6D6, 80 °CO+OTBSOOTBSOTBS11:89332 384 385Cyclization of substrate 332 was repeated twice (Figure 4.7). The spectra shown in 4.7a correspondto the first cyclization and the spectra shown in 4.7b correspond to the second cyclization. Analysisindicates that cyclization reaction yields a ratio of cyclization products 384:385 of 11 : 89.1.730.091623.54.04.55.05.56.06.57.07.5ppm(a) 1H NMR quantification trial 1.1.570.079123.54.04.55.05.56.06.57.07.5ppm(b) 1H NMR quantification trial 2.Figure 4.7. 1H NMR analysis of the crude reaction mixture of the cyclization of competition substrate 332.179Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.8.5.2 Analysis of competition substrate 340PhthNO Bu3SnH, AIBNC6D6, 80 °CO+OTBSOOTBSOTBS33:67340 386 387Cyclization of substrate 340 was repeated twice (Figure 4.8). The spectra shown in 4.8a correspondto the first cyclization and the spectra shown in 4.8b correspond to the second cyclization. Analysisindicates that cyclization reaction yields a ratio of cyclization products 386:387 of 33 : 67.1.280.29323.03.54.04.55.05.56.06.57.07.5ppm(a) 1H NMR quantification trial 1.1.290.29323.03.54.04.55.05.56.06.57.07.5ppm(b) 1H NMR quantification trial 2.Figure 4.8. 1H NMR analysis of the crude reaction mixture of the cyclization of competition substrate 340.180Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.8.5.3 Analysis of competition substrates 348 and 349PhthNO Bu3SnH, AIBNC6D6, 80 °CO+OTBSOOTBSOTBSPhthNO Bu3SnH, AIBNC6D6, 80 °CO+OOTBSOTBS47:5348:52OTBS348388388389389349Cyclization of substrate 348 was repeated twice (Figure 4.9). The spectra shown in 4.9a correspondto the first cyclization and the spectra shown in 4.9b correspond to the second cyclization. Analysisindicates that cyclization reaction yields a ratio of cyclization products 388:389 of 47 : 53.10.87423.54.04.55.05.56.06.57.07.58.0ppm(a) 1H NMR quantification trial 1.0.9260.91423.03.54.04.55.05.56.06.57.07.58.0(b) 1H NMR quantification trial 2.Figure 4.9. 1H NMR analysis of the crude reaction mixture of the cyclization of competition substrate 348.181Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentationCyclization of substrate 349 was repeated twice (Figure 4.10). The spectra shown in 4.10a cor-respond to the first cyclization and the spectra shown in 4.10b correspond to the second cyclization.Analysis indicates that cyclization reaction yields a ratio of cyclization products 388:389 of 48 : 52.0.540.55823.03.54.04.55.05.56.06.57.07.5ppm(a) 1H NMR quantification trial 1.0.5120.4823.03.54.04.55.05.56.06.57.07.5ppm(b) 1H NMR quantification trial 2.Figure 4.10. 1H NMR analysis of the crude reaction mixture of the cyclization of competition substrate 349.4.8.5.4 Analysis of competition substrate 325Bu3SnH, AIBNC6D6, 80 °C+OTBS90:10OOTBSPhthNOOTBSOH325 326 394Cyclization of substrate 325, was repeated in benzene−d6 (Figure 4.11). Analysis of the crude reac-tion mixture showed that cyclization reaction yields a ratio of cyclization products 326:394 of 90 : 10.182Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation60.213.03.54.04.55.05.56.06.57.07.58.0Figure 4.11. 1H NMR analysis of the crude reaction mixture of the cyclization of competition substrate 325.4.8.5.5 Analysis of competition substrate 360Bu3SnH, AIBNC6D6, 80 °C+OTBS86:14OOTBSPhthNOOTBSOH360 395 396Substrate 360 was cyclized and the analysis of the crude reaction mixture indicates that reactionprovides an 84 : 16 ratio of 395 to 396 (Figure 4.12).26.113.03.54.04.55.05.56.06.57.07.5ppmFigure 4.12. 1H NMR analysis of the crude reaction mixture of the cyclization of competition substrate 360.183Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.8.5.6 Analysis of competition substrate 367PhthNO Bu3SnH, AIBNC6D6, 80 °C+OTBSOOTBS>95:5OH OTBS367 401 402Substrate 367 was cyclized and the analysis of the crude reaction mixture indicates that reactionprovides a > 95 : 5 ratio of 401 to 402 (Figure 4.13).4.112.223.54.04.55.05.56.06.57.07.5ppmFigure 4.13. 1H NMR analysis of the crude reaction mixture of the cyclization of competition substrate 367.184Chapter 4. Chemoselectivity of alkoxy radical cyclization onto silyl enol ethers vs cyclization ontosubstituted alkenes, 1,5-HAT and β-fragmentation4.8.5.7 Analysis of competition substrate 372PhPhthNO Bu3SnH, AIBNC6D6, 80 °C+OPhTBSOOTBS>95:5PhOH OTBS372 406 407Substrate 372 was cyclized and the analysis of the crude reaction mixture indicates that reactionprovides a > 95 : 5 ratio of 406 to 407 (Figure 4.14).4.432.3223.54.04.55.05.56.06.57.07.5ppmFigure 4.14. 1H NMR analysis of the crude reaction mixture of the cyclization of competition substrate 372.185Chapter 5Conclusions and future workNothing in life is to be feared, it is only to be understood. Now is thetime to understand more, so that we may fear less.— Marie Curie (1867− 1934)Fluorine atom transfer to alkyl radicals  (Chapter 2)Catalytic photoredox decarboxylative fluorination  (Chapter 3)Alkoxy radical chemoselectivity  (Chapter 4)OC6D6, 120 °CNFSIOOOF3.5 equiv. SelectfluorRu(bpy)3Cl2, 1 mol %1.5 equiv. NaOH1:1 H2O/CH3CNVisible lightORFOROHORRR2 OTBSHnBu3SnH, AIBNC6D6, 80 °CHOR2 OTBSnOOTBSR1R1R2 nO R2 OTBSHnR1R1n = 0, 1++Cyclization 1,5-HATβ-fragmentationFigure 5.1. Studies performed in thesis work.186Chapter 5. Conclusions and future workThree different research projects have been presented in this thesis (Figure 5.1). Two of them cor-respond to new radical methodologies to selectively install fluorine in molecules utilizing N−F fluorinereagents (Chapter 2 and Chapter 3), and the third is a study on the chemoselectivity of alkoxy radicalcyclization onto silyl enol ethers (Chapter 4).It is particularly important to highlight the relevance of the fluorination studies that have been pre-sented as part of this thesis work. Our first report on the use of electrophilic N−F reagents to transferfluorine atoms to alkyl radicals in 2012, has enabled the development of a remarkable number of newmethodologies and studies that exploit this newly discovered type of reactivity.162–165Merging the high synthetic versatility of radical chemistry with safe fluorine atom transfer reagentshas and invaluable potential in the future synthesis of fluorine containing molecular targets, in bothindustry and academic settings.Chapter 1 of this written work described concepts from the two major topics of this thesis: radicalchemistry and fluorine chemistry. The first part summarized key concepts of radical chemistry, suchas the general properties of carbon radicals, their reactivity and generation methods. Oxygen-centeredradicals, with emphasis on acyloxy radicals, were also briefly discussed in this chapter. The secondpart was an account on fluorine chemistry history, its natural occurrence in organic compounds and theeffect of the presence of this atom on the bioactivity of some molecules. Additionally, a description oftraditional nucleophilic and electrophilic sources of fluorine was also included.5.1 Chapter 2: conclusions and future workIn Chapter 2, it was demonstrated that common N−F electrophilic sources of fluorine, such as NFSI andSelectfluor R©, are able to transfer a fluorine atom to alkyl radicals generated either thermo- or photolyti-cally. Initial DFT calculation studies performed by Prof. Kennepohl and co-workers determined that theN−F bond dissociation energy of NFSI and Selectfluor R© were 63.4 kcal/mol and 61.0 kcal/mol respec-tively. The photolysis and thermolysis of lauroyl peroxide was effective to prove the concept of fluorineatom transfer from NFSI to alkyl radicals (Table 5.2, entry 1). Other radical precursors, such as trialkylboranes, were also investigated. Ultimately, the use of t-butylperesters allowed the effective synthesis ofprimary, secondary and tertiary fluoroalkanes in good to excellent yields (Table 5.2, entries 2− 4). Thepotential utility of this newly developed radical fluorination methodology in the context of total synthesiswas illustrated in the fluorination of a cholic acid derivative (Table 5.2, entry 5).187Chapter 5. Conclusions and future workTable 5.1. Fluorine atom transfer to alkyl radicals, results summary.Entry Substrate % yield Product % yield a1 Lauroyl peroxide, 120 N/AF121 242OOO139 96F140 243OOOCH3151 84F146 984OOOCH3H3C153 19 bF154 985OHOOHHHOO O158 80OHOFOHHH159 68 ca Quantified via GC. b Synthesized by C. Chatalova Sazepin. c Quantified via 1H NMR.We are confident that the first step in the fluorine atom transfer reaction is the initial generation of analkyl radical. However, it is unclear wether the following step is a direct fluorine atom transfer througha homolytic bimolecular substitution (SH2) mechanism, or a single electron transfer (SET) (Figure 5.2),followed by fluoride transfer.188Chapter 5. Conclusions and future work+R FR+SETSH2NSSFPhPhO O O ONSSPhPhO O O ONSSPhPhO O O OF+ R R F+408408Figure 5.2. Possible fluorine atom transfer mechanisms.As both mechanisms generate the same final products, identifying which of them is occurring in thereaction would necessarily have to focus on what makes them different: the presence or absence of acarbocation. One characteristic that differentiates a carbocation from a carbon radical is the ability ofthe former to perform 1,2-hydrogen and 1,2-alkyl shifts. Radicals do not regularly undergo 1,2-alkylshifts due to the presence of an extra electron in the system compared to carbocations. As the transitionstate of the migration involves a three-center, two-electron bond, one of the electrons of the radical wouldneed to populate an anti-bonding orbital. The transition state for radical migration is less favoured thanthe one for the corresponding carbocation.309My colleague Wei Zhang in the Sammis group is already exploring the possibility in the elucidationof the mechanistic details of the reaction, through the use of a classic carbocation 1,2-alkyl shift reaction:the pinacol rearrangement (Scheme 5.1). In this reaction a 1,2-diol (409) reacts via an unimolecularnucleophilic substitution (SN1) reaction under acidic conditions to form an α-hydroxy carbocation (410).The carbocation rapidly undergoes a 1,2-alkyl shift to form either an aldehyde or a ketone (411). Asubstrate designed similar to 412 would directly test the fluorine atom transfer mechanism. If an SH2reaction occurs, then an α-hydroxy fluoride (413) should be observed as a product of this transformation.However, if the reaction proceeds through an SET process, with concomitant formation of a carbocation,we would expect to observe the product resulting from the 1,2-alkyl shift (414).189Chapter 5. Conclusions and future workPinacol rearrangementR1OHOHR2 H2SO4 R1HOHR2 R1R2OHProposed carbocation-trapping experimentR2OHR3 R2HOHR3R2R3OHO O R1= tBuO,C6H6, 110 °C, orR1= H, Ru(bpy)3Cl21:1 H2O/CH3CNvisible lightSH2SETR2FOHR3R1409 410 411412413414Scheme 5.1. Pinacol rearrangement mechanistic study.190Chapter 5. Conclusions and future work5.2 Chapter 3: conclusions and future workThe use of trisbipyridyl ruthenium (II) catalyst in a photoredox decarboxylative fluorination reaction togenerate C−F bonds was described in Chapter 3. This represents the first example on the applicationof visible light photoredox catalysis to the direct formation of carbon−fluorine bonds. Fluorination ofphenoxyacetic acid derivatives under our photocatalytic fluorination conditions afforded different mono-,di- and trisubstituted aryl fluoromethylethers (Table 5.2). Phenoxyacetic acids substituted with electronwithdrawing groups were satisfactorily fluorinated under the photocatalytic reaction conditions, whileelectron donating groups provided mostly products with fluorination in the aryl ring. Some substratesthat had been previously investigated under a UV-light mediated methodology with poor results, werefluorinated in good yields with our visible-light photocatalytic method, such as 271 and 274. Addition-ally, the applicability of this new methodology in late stage or natural product synthesis was exemplifiedby fluorinating a phenoxyacetic acid derived from estrone (Table 5.2, entry 8).Based on the experimental evidence obtained from TAS and CV studies, we propose the mecha-nism shown in Figure 5.3. An initial oxidation of the catalysts excited state by Selectfluor R© generates[Ru(bpy)3]3+, which oxidizes the substrate (phenoxyacetic acid). The resulting radical cation rapidlydecarboxylates to form an alkyl radical that forms the desired fluoromethyl ether upon fluorine atomtransfer from Selectfluor R©.Ru(bpy)33+ *Ru(bpy)32+Ru(bpy)32+hνSETOxidativephotocatalyticcycleNNFCl 2+NNFClPhOOOPhOOOPhOPhO SelectfluorPhO FFigure 5.3. Proposed photoredox decarboxylative fluorination mechanism.191Chapter 5. Conclusions and future workTable 5.2. Catalytic photoredox decarboxylative fluorination, results summary.OROHO 3.5 equiv. Selectfluor,1.5 equiv. NaOH(aq),1 mol % Ru(bpy)3Cl2Visible light, 1:1 H2O/CH3CNORFEntry Substrate % yield Product 1H NMR Isolated% yield % yield1O CO2H257 N/AO F258 84 172O CO2HF259 N/AO FF260 67 213O CO2HBr261 N/AO FBr262 73 a 56 a4O CO2HtBu tBu265 81O FtBu tBu273 95 745O CO2H266 75O F274 92 656O CO2HPh267 78O FPh271 92 657O CO2NaPhCH3 2269 44O FPhCH3 2275 - - 818OOHHHHOO289 74OOHHHF290 - - 51a Experiments performed by Dr. O. Mahe´.192Chapter 5. Conclusions and future workThe photoredox methodology presented in Chapter 3, while effective for the preparation of monoflu-oromethyl aryl ethers, was unsuccessful in the synthesis of difluoromethyl aryl ethers. We believe this is aconsequence of the presence of a florine atom in the alkyl radical precursor (416 and 417 in Scheme 5.2).A fluorine adjacent to the phenolic oxygen atom likely increases the oxidation potential of the molecule,which might fall out of the range of species oxidizable by [Ru(bpy)3]3+.SelectfluorCatalystVisible lightOR1FOR1OHOF FF FOR1FOR1OHOFFor or416 417418 419Scheme 5.2. Proposed synthesis of di- and trifluoromethyl ethers through catalytic photoredox decarboxyla-tive fluorination.In Chapter 3, the oxidation potential of phenoxyacetic acids was determined to beE1/2 = +1.01 V vsSCE. According to our mechanistic studies, [Ru(bpy)3]3+(E1/2 = +0.77 V vs SCE)182 is responsible forthe oxidation of the substrate. If the oxidation potential of the substrate increases, [Ru(bpy)3]3+ mightnot be a strong enough oxidant to promote the decarboxylation reaction.The oxidation potential of ruthenium and iridium photoredox catalysts can be tuned by modifying thestructure of the ligands.180 Several catalysts reported in the literature, such as tris(bipyrazyl)ruthenium(II)(Ru(bpz)2+3 , 420, E1/2 = 1.86(1.95) V vs SCE)310–312 and tris(bipyrimidine)ruthenium(II) (Ru(bpm)2+3 ,421, E1/2 = 1.98 V vs SCE),313 have higher oxidation potentials than [Ru(bpy)3]2+ does (Figure 5.4).These catalysts could be utilized in our photoredox decarboxylative fluorination to target substrates withhigher oxidation potentials, such as 416 and 417 to enable the synthesis of difluoro- (418) and trifluo-romethyl ethers (419).Alternatively, the measurement of the oxidation potentials of the fuorophenoxyacetic acids could beperformed to determine whether or not the proposed photocatalysts would be suitable for the synthesisof difluoro- and trifluoromethyl ethers.193Chapter 5. Conclusions and future workRuIINNNNNNNNNNNNTris(bipyrazyl)ruthenium(II)2+RuIINNNNN NN NNNNNTris(bipyrimidine)ruthenium(II)2+420 421Figure 5.4. Alternative photo catalysts with stronger oxidation potentials for the transition Ru(III)→Ru(II).5.3 Chapter 4: conclusions and future workFinally, Chapter 4 described the design, synthesis and application of competing cyclization substrates toprobe the chemoselectivity of 5-exo cyclization of alkoxy radicals onto silyl enol ethers compared to 5-exo cyclization onto alkyl substituted alkenes, 15HAT! and β-fragmentation (see summary in Table 4.2).It was observed that alkoxy radicals favour 5-exo cyclization onto a silyl enol ether over 5-exo cyclizationonto terminal and disubstituted alkenes, while the 5-exo cyclization onto trisubstituted alkenes gave in-conclusive results. Furthermore, 5-exo cyclization onto silyl enol ethers also outcompeted 1,5-HAT andβ-fragmentation reaction pathways.A reaction sequence that I unfortunately did not have time to explore was the combination of ourfluorine atom transfer reaction with alkoxy radical mediated processes. The idea is to combine the rapidconstruction of molecular complexity through radical tandem reactions and simultaneously install a flu-orine atom selectively at the final stage. For instance, a substrate such as 422 would enable an alkoxyradical 1,5-HAT to be followed by a 5-exo cyclization to form 424. The final fluorine atom transfer wouldgenerate products of type 425.O OHOH OHF1,5-HAT5-exocyclizationFluorineatomtransfer422 423 424 425Scheme 5.3. Tandem radical 1,5-HAT, 5-exo cyclization and fluorine atom transfer reaction.194Bibliography1. Nicolaou, K. C.; Sorensen, E. Classics in Organic Synthesis, 1st ed.; WILEY-VCH: Weinhem,Federal Republic of Germany, 1996.2. Gomberg, M. J. Am. Chem. 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Chem. 1983, 22, 1617–1622.207Appendix ASelected spectra for Chapter 2208Selected spectra for Chapter 2Methyl 2-methyl-4-phenylbutanoate (149):2.871.151.061.0622.844.9801234567891011121.7191.7231.7431.7681.7902.0192.0452.0642.0902.4892.5122.5352.6262.6522.6793.7127.1997.2237.2377.2917.3137.340OCH3OCH3-20-100102030405060708090100110120130140150160170180190200210220ppm17.25033.59135.51839.05451.651126.017128.471128.515141.741177.096OCH3OCH3209Selected spectra for Chapter 2t-Butyl 4-phenylbutaneperoxoate (139):9.022.051.9724.9801234567891011121.3531.9802.0042.0292.0542.0792.3332.3582.3822.6832.7092.7347.1957.2197.2497.2527.2977.3227.345OOO-20-100102030405060708090100110120130140150160170180190200210220ppm26.22326.58830.59535.06583.379126.188128.533141.016170.889OOO210Selected spectra for Chapter 2t-Butyl 2-methyl-4-phenylbutaneperoxoate (151):3.48.971.91.0522.932.3501234567891011121.2601.2831.3701.7191.7401.7511.7621.7711.7841.7931.8061.8171.8382.5072.5302.5512.5542.5782.5862.6102.6172.6332.6422.6582.6802.6872.7112.7367.1917.2147.2187.2417.2447.2887.3137.338OOOCH3-20-100102030405060708090100110120130140150160170180190200210220ppm17.72526.39633.63035.67137.10083.536126.240128.586128.644141.470173.895OOOCH3211Selected spectra for Chapter 2(R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-Trimethoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) pentanoic acid (165):3.226.665.098.898.124.371.051.091.173.0632.871.2201234567891011120.6490.8910.9070.9211.0171.0311.0461.0611.1811.2131.2501.2971.3911.4221.4531.4821.5031.5281.5601.5671.6051.7481.7931.8331.8871.8971.9201.9432.0182.0482.0662.0782.1442.1752.2062.2392.2472.2642.3652.3752.3912.4012.4282.4392.9712.9983.0263.1333.2043.2503.3283.3527.260OHOOOOHHHH-20-10010203040506070809010011012013014015016017018019020021022012.62417.50522.11023.00723.28426.83927.47227.90528.12230.88531.08134.53035.05035.20135.41239.78842.11342.79946.26846.40555.48155.81655.98377.08380.92982.100180.142OHOOOOHHHH212Selected spectra for Chapter 2(R)-Methyl 4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-tri-methoxy-10,13-dimethylhexa-decahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (166):3.087.479.1415.11.141.133.113.124.16301234567891011120.6480.8940.9150.9760.9790.9971.0201.0391.0781.1801.2221.2321.2441.2581.3001.3051.3351.3511.3651.3911.4511.4621.5001.6001.7031.7161.7251.7451.7801.7921.8101.8391.8482.0022.0272.0422.0542.0662.0812.0932.1052.1292.1682.1712.2122.2152.2372.2472.2542.3152.3312.3492.3652.9542.9772.9913.0053.0133.0283.1313.1403.2063.2493.3273.3503.6597.260OHOOOOHHH-20-10010203040506070809010011012013014015016017018019020021022012.37317.30421.89722.78223.05626.65527.29127.70427.88730.82730.88834.35334.80535.00335.18839.55841.87542.57646.02146.14351.29555.28755.56155.74276.86780.62881.861174.646OHOOOOHHH213Selected spectra for Chapter 2(4R)-Methyl 2-methyl-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trimethoxy-10,13-dime-thylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) pentanoate (167):3.047.022.22.735.282.258.962.960.7031.131.123.1433.942.79012345678910111213ppm0.6280.8920.9010.9180.9310.9320.9600.9690.9860.9951.0021.0201.0291.0831.1001.1301.1471.1771.1811.2141.2581.4471.4551.4751.4841.4931.6081.6121.6981.7331.7381.7491.7811.7891.7981.8041.8121.8131.8151.8261.8321.8511.8551.8611.8711.8791.8952.0532.0642.0832.1782.2072.5642.5732.5812.5852.5912.6002.6092.6182.9913.1323.1393.2503.3503.3563.362OHOOOOHHH-20-10010203040506070809010011012013014015016017018019020021022012.58417.82619.14822.11023.02323.31126.89027.62927.91428.12434.57234.63335.07335.42037.33039.76441.01842.11542.83246.27447.25851.50155.54555.84556.00177.36280.89682.166157.468OHOOOOHHH214Selected spectra for Chapter 2(4R)-2-Methyl-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-tri-methoxy-10,13-dimethylhexa-decahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid (168):3.0510.69.543.638.593.180.9861.041.143.1133.021.12012345678910110.6240.8760.9130.9280.9570.9951.0221.1621.1781.2161.2451.2881.3221.4091.4361.4671.4971.5531.5901.6511.6841.7361.7771.8001.8271.8581.9952.0282.0422.0692.0942.1302.1612.1922.2242.5792.9893.1193.1923.2383.3153.3537.260OHOOOOHHHH-20-10010203040506070809010011012013014015016017018019020021022012.61217.78019.02722.09522.98023.29726.82227.56927.88528.10634.50334.54835.02935.38037.29139.76240.77842.08742.78446.29047.30055.43755.80455.95677.08080.89082.145183.286OHOOOOHHHH215Selected spectra for Chapter 2(4R)-t-Butyl 2-methyl-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trimethoxy-10,13-di-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) pentaneperoxoate (158):3.043.72.334.014.0810.312.41.90.9832.110.9571.044.2934.1201234567891011120.2960.3820.3850.6190.6360.8210.8360.8510.8720.8810.8890.9060.9310.9401.0051.0211.0421.0601.2201.3691.3761.3841.3971.4051.4221.4301.4341.4431.4601.4911.4931.4941.5231.5241.5291.5301.5361.5521.6091.6411.6461.7101.7471.7711.7771.7841.8041.8051.8111.8192.0032.0082.0332.0362.0662.0702.0852.1102.1342.2792.2882.2892.3102.3182.3202.3412.4152.4282.4472.4532.4582.4762.4872.5082.5402.5502.5572.5582.5632.5682.5772.5862.9342.9452.9502.9612.9712.9762.9792.9903.0013.0163.0223.0803.261OHOOOOHHHO-20-10010203040506070809010011012013014015016017018019020021022012.58015.58216.46517.67018.90519.19422.09022.17823.08023.53726.17327.45627.65228.00128.21334.58534.91935.08635.65339.99541.03142.26642.79846.54947.43155.22655.58377.19180.86081.86282.428173.512OHOOOOHHHO216Selected spectra for Chapter 2(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-17-((2R)-4-Fluoropentan-2-yl)-3,7,12-trimethoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene (159):2.973.470.8233.391.529.53.429.183.060.9891.042.913.0331.141.0401234567891011120.6620.6790.9280.9360.9530.9691.0021.0101.0191.0261.0341.0411.0501.1591.2521.2571.2671.2731.2831.3181.3271.3331.3421.4301.5841.6601.6661.6941.6991.7511.7901.7991.8091.8361.8451.8531.8701.8941.9181.9231.9481.9722.0202.0282.0392.0552.0662.0802.0872.0972.1062.1172.1272.1452.1772.2062.2392.9652.9822.9933.0043.0213.1383.2083.2593.3293.3653.3723.3793.3863.3933.3994.6434.6594.6754.6794.6904.6964.7004.7054.7114.7164.7214.7264.7364.7414.7494.7514.7644.7804.7964.8114.8214.8264.8364.8414.8464.8514.8624.8667.260OHOFOHHH-20-10010203040506070809010011012013014015016017018019020021022012.53512.62817.82318.58621.32821.55722.00022.11822.22723.02023.30026.88527.68727.91928.12529.85730.47232.17334.03334.09834.58335.07335.41339.76642.11442.83042.87543.21843.40843.56643.77446.27846.35047.12647.34055.55355.85756.00580.89082.11482.19187.94889.56690.26691.882OHOFOHHH217Selected spectra for Chapter 2-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-100102030405060-174.800-168.784OHOFOHHH218Appendix BSelected spectra for Chapter 3219Selected spectra for Chapter 32,4-Di-t-butylphenoxyacetic acid (265):8.538.7420.9732.470.9370.96201234567891011121.3121.4324.6996.6726.7007.1607.1687.1897.1977.2607.3647.372OOHO-20-10010203040506070809010011012013014015016017018019020021022029.76931.44434.11234.88765.15776.83877.16077.480111.355123.164123.871137.448143.097154.357170.997OOHO220Selected spectra for Chapter 32,4,6-Trimethylphenoxyacetic acid (266):8.8622.08012345678910111213ppm2.2462.2594.4456.8367.260OOHO-20-10010203040506070809010011012013014015016017018019020021022016.28220.79268.64076.84277.16077.479129.823130.204134.437152.503173.098OOHO221Selected spectra for Chapter 34-Phenylphenoxyacetic acid (267):22.021.012.074.07012345678910111213ppm2.5004.6986.9807.0027.2897.3077.3257.4087.4277.4467.5777.5987.613OOHOPh-20-10010203040506070809010011012013014015016017018019020021022038.89439.10239.30939.51939.72839.93540.14564.660114.874126.211126.760127.706128.848132.976139.757157.450170.206OOHOPh222Selected spectra for Chapter 3Sodium 2,2′-(((1-phenylethane-1,1-diyl)bis(4,1-phenylene))bis(oxy))diacetate (269):2.9943.943.911.981.11.9701234567891011122.0302.5004.0676.6826.7116.8406.8707.0177.0417.1697.1927.2327.2587.281OONaOONaOO-20-10010203040506070809010011012013014015016017018019020021022030.48438.89339.10339.31339.52039.73039.94040.14750.91567.706113.895125.919127.961128.364129.117140.626149.748156.792171.969OONaOONaOO223Selected spectra for Chapter 34-(Fluoromethoxy)-1,1′ -biphenyl (271):21.880.9671.93.79012345678910111213ppm5.6895.8267.1507.1727.3187.3377.3557.4167.4357.4547.5517.5687.573O FPh-20-10010203040506070809010011012013014015016017018019020021022076.84677.16077.47699.844102.023117.087127.064127.258128.553128.935136.829140.576O FPh224Selected spectra for Chapter 3-240-220-200-180-160-140-120-100-80-60-40-20020406080100-148.976-148.782-148.587O FPh2,4-di-t-Butyl-1-(fluoromethoxy)benzene (273):8.868.8411.020.9721.080.988012345678910111213ppm1.3631.4475.7275.8647.1037.1247.2437.2497.2667.2707.4057.411O F225Selected spectra for Chapter 3-20-10010203040506070809010011012013014015016017018019020021022030.19831.68134.58735.15076.84177.16077.47599.978102.139115.056124.051124.189138.204145.700153.948O F-240-220-200-180-160-140-120-100-80-60-40-20020406080100-146.921-146.726-146.532O F226Selected spectra for Chapter 32-(Fluoromethoxy)-1,3,5-trimethylbenzene (274):5.732.9710.9831.95012345678910111213ppm2.2582.2705.4755.6126.868O F1-20-10010203040506070809010011012013014015016017018019020021022016.69620.79476.84177.16077.479103.463105.655129.641130.567134.624152.030O F227Selected spectra for Chapter 3-240-220-200-180-160-140-120-100-80-60-40-20020406080100-146.885-146.689-146.495O F4,4′-(1-Phenylethane-1,1-diyl)bis((fluoromethoxy)benzene) (275):2.9722.013.865.873.17012345678910111213ppm2.1615.6435.7796.9766.9987.0417.0487.0537.0657.0707.0827.0957.1007.1047.2187.2337.2367.2607.2767.2807.297O FOF228Selected spectra for Chapter 3-20-10010203040506070809010011012013014015016017018019020021022030.81051.66876.84177.16077.47899.776101.954116.044126.234128.089128.683130.054144.305149.072154.999155.030O FOF-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-100102030405060-149.040-148.847-148.652O FOF229Selected spectra for Chapter 32-(((8R,9S,13S,14S)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)acetic acid (289):3.096.235.190.9841.011.9620.9950.9961.02012345678910111213ppm0.9081.3821.4021.4101.4371.4571.4661.4771.4871.5021.5141.5261.5331.5451.5741.5971.6021.6261.6481.6561.9401.9461.9681.9781.9861.9921.9982.0052.0092.0222.0362.0442.0572.0742.0872.1102.1322.1582.1802.2022.2192.2302.2462.2712.3722.3852.3962.4122.4812.5022.5282.5502.8772.8872.8994.6566.6666.6726.7136.7196.7346.7417.2067.227OOHHHHOO-20-10010203040506070809010011012013014015016017018019020021022013.97821.72125.98726.58129.74831.65536.01438.36044.08448.18950.51964.96776.84677.16077.478112.154114.901126.705133.677138.277155.542173.862221.523OOHHHHOO230Selected spectra for Chapter 3(8R,9S,13S,14S)-3-(Fluoromethoxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one (290):2.96.054.111.010.9640.9851.890.99310.9160.9480.958012345678910111213ppm0.9111.4421.4641.4761.4871.4921.5061.5111.5311.5371.5451.5781.6011.6071.6291.9471.9531.9701.9771.9902.0042.0092.0282.0332.0392.0482.0612.0772.0902.0992.1202.1452.1682.1902.2572.2822.3782.3872.4002.4122.4722.4932.5182.5402.8932.9022.9142.9225.6125.7496.8296.8636.8686.8846.8907.2297.250OOHHHF-20-10010203040506070809010011012013014015016017018019020021022013.92221.66325.94626.49529.64831.64535.92738.27344.09548.03950.47976.84177.16077.47899.898102.062114.216116.854126.672135.068138.268154.902220.813OOHHHF231Selected spectra for Chapter 3-240-220-200-180-160-140-120-100-80-60-40-20020406080100-148.363-148.170-147.974OOHHHF232Appendix CSelected spectra for Chapter 4233Selected spectra for Chapter 4(E)-2-((1-((Triethylsilyl)oxy)dec-8-en-5-yl)oxy)isoindoline-1,3-dione (337):5.818.766.020.9270.9260.918201234567891011120.5550.5830.5950.6100.6350.9320.9470.9580.9730.9850.9991.5361.5451.5531.5611.5702.1702.4562.4652.4722.4822.7342.7472.7642.9022.9112.9152.9243.5973.6183.6387.260OTESO2-(((8E)-1-((t-Butyldimethylsilyl)oxy)deca-1,8-dien-5-yl)oxy)iso-indoline-1,3-dione (340):6.079.872.368.211.050.8442.040.8642.82.062012345678910111213ppm0.1030.1210.8810.8961.5311.5451.6261.6391.7271.7441.7451.7592.2012.2032.2202.2282.2382.2492.2532.2684.2384.2394.2544.2684.4544.4704.4865.4535.4656.1616.1757.2447.2607.7267.7347.7397.7477.8167.8247.8297.837PhthNO OTBS234Selected spectra for Chapter 41-((t-Butyldimethylsilyl)oxy)-9-methyldec-8-en-5-ol (344):6.249.589.513.133.22.173.181012345678910111213ppm0.0400.8871.4271.4331.4351.4471.4541.4641.4761.4841.4871.4911.4971.5091.5141.5221.5321.5441.6181.6842.0412.0592.0792.0862.1062.1243.5933.6093.6255.1095.1125.1245.1275.1305.1425.1457.260OTBSOH-20-100102030405060708090100110120130140150160170180190200210220-5.13817.80818.49422.07524.52825.84126.11332.92537.34437.49663.29471.81276.84177.16077.478124.324132.126OTBSOH235Selected spectra for Chapter 42-((1-Hydroxy-9-methyldec-8-en-5-yl)oxy)isoindoline-1,3-dione (346):15.92.052.051.0212.031.98012345678910111213ppm1.6171.6321.6481.6691.6811.6971.7041.7111.7202.1642.1832.2013.6643.6793.6944.2304.2444.2524.2585.0895.0925.1035.1065.1095.1215.1247.2607.7317.7397.7457.7537.7627.8177.8257.8317.838OHPhthNO-20-10010203040506070809010011012013014015016017018019020021022017.85320.92723.90225.83532.22032.76362.71476.83477.14977.46788.010123.574123.745129.200132.339134.549164.572OHPhthNO236Selected spectra for Chapter 42-((1-((t-Butyldimethylsilyl)oxy)-9-methyldeca-1,8-dien-5-yl)oxy) isoindoline-1,3-dione (348):69.756.623.8841.030.8641.040.8490.1062.0420123456789101112ppm0.1020.1050.8950.9020.9051.6231.6721.7021.7201.7361.7401.7471.7551.7641.7692.1842.1852.2022.2132.2142.2322.2512.2722.2924.2304.2454.2604.2754.2904.4594.4784.4934.5105.1035.1215.1355.1396.1636.1776.2546.2696.2706.3046.3347.2607.7147.7247.7317.7387.7457.7557.8057.8157.8237.8287.8367.8457.849PhthNO OTBS-20-100102030405060708090100110120130140150160170180190200210220-5.22017.89919.61325.79625.88132.55332.67787.969109.527109.923123.544129.290134.476139.233164.532PhthNO OTBS237Selected spectra for Chapter 42-((1-((t-Butyldimethylsilyl)oxy)-9-methyldeca-1,8-dien-5-yl)oxy) isoindoline-1,3-dione (349):4.377.628.213.711.120.4980.77210.3980.7231.721.74012345678910111213ppm0.0880.8711.5811.6341.6721.6871.7132.1102.1272.1462.1652.1802.1942.1972.1984.1704.1754.1764.1794.1854.1914.2054.2204.2344.2404.4254.4434.4594.4764.9184.9374.9484.9564.9664.9865.0675.0695.0775.0876.1286.1436.2696.2997.2267.6957.7027.7097.7167.7827.7907.7957.803PhthNOOTBS238Selected spectra for Chapter 42-((6-Hydroxyhexyl)oxy)isoindoline-1,3-dione (353):7.222.061.9521.961.901234567891011121.3781.3961.4141.4221.4311.4371.4531.4751.4871.4981.5061.5301.5371.5451.5541.5581.5731.5911.6041.6161.6391.6621.7631.7851.8101.8331.8553.6433.6643.6823.7034.1904.2124.2347.2607.7307.7407.7487.7587.7727.8087.8227.8327.8407.850OHPhthNO-20-100102030405060708090100110120130140150160170180190200210220ppm25.38325.40328.20932.65762.85676.74077.16077.58478.499123.637129.090134.590163.826OHPhthNO239Selected spectra for Chapter 42-((6-t-Butyldimethylsilyl)oxy)hex-5-en-1-yl)isoindoline-1,3-dione (325):5.529.382.212.111.7620.8260.08930.8781.951.8601234567891011120.1140.9091.4291.4891.5131.5231.5381.5471.5641.5891.7631.7861.8131.8261.8361.8592.1152.1192.1392.1432.1632.1672.1882.1924.1854.1954.2304.4104.4344.4534.4774.9334.9584.9734.9834.9985.0236.1796.1996.2236.2637.2607.7247.7357.7437.7537.8207.8307.8387.848PhthNOOTBS-20-100102030405060708090100110120130140150160170180190200210220ppm-5.22618.40523.31125.65725.79327.85078.717109.923123.600134.522139.087163.805PhthNOOTBS240Selected spectra for Chapter 42-((7-((t-Butyldimethylsilyl)oxy)heptan-2-yl)oxy)isoindoline-1,3-dione (357):5.679.333.258.1620.9131.921.8401234567891011120.0290.8721.2411.2491.3081.3291.3641.3721.3821.3891.3951.4151.4671.4891.5091.5311.5571.7471.7671.7901.8121.8161.8381.8613.5773.5983.6194.3074.3284.3484.3694.3904.4107.2607.7147.7257.7337.7437.8037.8137.8227.832OTBSPhthNO-20-100102030405060708090100110120130140150160170180190200210220ppm-4.98518.63419.09525.38026.11626.25233.01035.17563.42376.88977.31377.73884.714123.683129.289134.634164.605OTBSPhthNO241Selected spectra for Chapter 42-((7-Hydroxyheptan-2-yl)oxy)isoindoline-1,3-dione (358):3.249.972.0812.041.9301234567891011121.3201.3411.3961.4051.4251.4511.4731.4771.4951.5051.5211.5371.5501.5631.5751.5851.6091.6191.6311.6521.7641.7671.7851.7921.8081.8301.8401.8531.8611.8691.8713.6593.6714.3274.3484.3684.3884.4084.4297.2607.7267.7367.7447.7547.8157.8257.8337.844OHPhthNO-20-100102030405060708090100110120130140150160170180190200210220ppm19.06824.97025.65632.71834.97762.85876.73677.16077.58584.409123.595129.136134.560164.547OHPhthNO242Selected spectra for Chapter 4(Z)-2-((7-((t-Butyldimethylsilyl)oxy)hept-6-en-2-yl)oxy)isoindo-line-1,3-dione (360):6.139.122.984.781.8210.8770.1030.8660.1022.021.9901234567891011120.0470.9401.2181.2391.6141.6201.6301.6411.6531.6601.6691.8421.8451.8491.8631.8711.8801.8851.8942.2782.3022.3222.3262.3494.3114.3164.3384.3584.3774.3984.5014.5214.5254.5454.5695.1185.1435.1575.1685.1825.2086.1876.2076.3286.3686.7786.7886.7966.8067.1607.2897.2997.3077.317PhthNOOTBS-20-100102030405060708090100110120130140150160170180190200210220-5.229-2.80718.25418.98423.61025.45925.78234.62076.84477.16077.47484.628110.080123.536129.173134.463138.973164.466PhthNOOTBS243Selected spectra for Chapter 41-((t-Butyldimethylsilyl)oxy)nonan-5-ol (363):6.3612.513.8301234567891011120.0470.8921.3141.3301.3771.3921.4121.4201.4291.4431.4511.4611.4681.4741.4941.5021.5201.5301.5361.5421.5511.5943.6013.6173.6327.260OTBSOH-20-100102030405060708090100110120130140150160170180190200210220-5.12214.21921.95722.05922.91226.13427.97632.91633.63337.31063.29072.06276.84477.16077.477OTBSOH244Selected spectra for Chapter 42-((1-Hydroxynonan-5-yl)oxy)isoindoline-1,3-dione (365):3.0914.22.0111.951.96012345678910111213ppm0.8960.9140.9321.3491.6001.6131.6281.6361.6441.6501.6601.6651.6751.6881.6973.6784.2204.2344.2477.2607.7317.7397.7457.7537.8157.8237.8297.837OHPhthNO-20-10010203040506070809010011012013014015016017018019020021022014.15320.89822.92527.34532.16632.26732.78362.71488.344123.575129.167134.562164.612OHPhthNO245Selected spectra for Chapter 42-((1-((t-Butyldimethylsilyl)oxy)non-1-en-5-yl)oxy)isoindoline-1,3-dione (367):5.918.954.54.011.9910.880.1060.8510.0971.951.94012345678910111213ppm0.1000.1030.8941.3211.3251.3411.3591.3761.3941.4091.4281.4551.4721.4761.4941.5141.5311.5531.5751.6751.6911.6941.7091.7191.7291.7361.7421.7471.7611.7651.7822.1812.1842.2022.2172.2362.2542.2722.2904.2204.2354.2504.2654.2804.4534.4714.4864.5044.9474.9664.9774.9854.9965.0146.1586.1726.3016.3317.2607.7217.7297.7347.7427.7527.8107.8187.8247.832PhthNO OTBS-20-100102030405060708090100110120130140150160170180190200210220-5.23214.15218.38819.57022.94425.76327.13632.14932.47888.220109.515123.501129.261134.432139.182164.508PhthNO OTBS246Selected spectra for Chapter 48-((t-Butyldimethylsilyl)oxy)-1-phenyloctan-4-ol (368):5.88.969.12.082.0833.072.5501234567891011120.0480.8951.3831.3921.4121.4321.4431.4581.4711.4861.5001.5111.5231.5311.5431.5571.6401.6591.6731.6791.6841.6931.7001.7531.7681.7721.7791.7881.7921.8061.8112.6172.6342.6523.5953.6113.6267.1617.1767.1937.2607.2767.296OTBSOHPh-20-100102030405060708090100110120130140150160170180190200210220-5.11622.05226.08726.12627.61532.87536.05337.16337.34563.26571.88876.84177.16077.479125.855128.425128.545142.547OTBSOHPh247Selected spectra for Chapter 42-((8-Hydroxy-1-phenyloctan-4-yl)oxy)isoindoline-1,3-dione (370):11.82.021.9815.281.911.88012345678910111213ppm1.5821.6001.6031.6111.6441.6601.6751.6841.6991.7121.7291.7391.7551.7751.7881.8001.8121.8261.8361.8471.8611.8681.8851.8941.8971.9051.9211.9421.9501.9581.9662.6932.7152.7332.7553.7003.7153.7304.3084.3224.3367.2077.2257.2427.2607.2917.3107.3197.3287.7947.8027.8087.8167.8267.8767.8847.8897.897OHPhthNOPh-20-10010203040506070809010011012013014015016017018019020021022020.89426.90432.05532.17432.72335.92462.65587.978123.596125.892128.438128.590129.154134.581134.916142.287164.571OHPhthNOPh248Selected spectra for Chapter 42-((8-((t-Butyldimethylsilyl)oxy)-1-phenyloct-7-en-4-yl)oxy)iso-indoline-1,3-dione (372):5.718.666.091.862.0210.8720.1070.850.09915.321.981.96012345678910111213ppm0.1030.1070.8981.7001.7041.7171.7231.7331.7411.7491.7571.7661.7811.8021.8601.8641.8811.9031.9101.9191.9261.9422.1892.2032.2062.2222.2402.2582.6092.6252.6312.6432.6592.6662.6852.7022.7082.7242.7362.7422.7584.2814.2974.3114.4424.4614.4754.4934.9354.9544.9654.9724.9845.0026.1606.1746.2896.3187.1387.1567.1747.1777.2027.2187.2427.2607.2687.2797.7367.7437.7497.7577.7637.7677.8137.8237.8317.8377.845PhPhthNO OTBS-20-100102030405060708090100110120130140150160170180190200210220-5.24919.60425.77626.79632.04232.52935.98587.872109.404123.516125.817128.393128.602129.244134.457139.242142.427164.477PhPhthNO OTBS249Selected spectra for Chapter 4t-Butyl((5-butyltetrahydrofuran-2-yl)methoxy)dimethylsilane (401):612.78.50.9361.890.980.9510.3360.9530.607012345678910111213ppm0.0560.8931.2081.2181.2261.2301.2531.2871.2891.3021.3061.3151.3321.3471.3601.3651.3721.3821.3951.3971.4141.4311.4451.4521.4601.4681.4801.4891.5511.5871.5921.6021.6111.6921.7101.7151.7221.7251.7331.7401.7431.7481.7541.7561.8891.9011.9111.9171.9261.9431.9651.9711.9741.9801.9892.0032.0123.4933.5073.5193.5243.5333.5373.5503.5633.6103.6133.6223.6243.6363.6393.6483.8063.8113.8213.8273.8363.8423.8713.8863.8913.9063.9213.9363.9504.0094.0234.0264.0394.0524.0554.0697.260OOTBS-20-100102030405060708090100110120130140150160170180190200210220-5.13814.21222.97126.11228.36728.60931.06432.02435.71266.19579.06779.722OOTBS250Selected spectra for Chapter 4t-Butyldimethyl((5-(3-phenylpropyl)tetrahydrofuran-2-yl)methoxy)silane (406):69.032.183.952.011.920.9510.9430.3650.9370.6272.752.86012345678910111213ppm0.0630.8991.4421.4481.4531.4581.4611.4671.4751.4801.4851.4871.4961.6141.6201.6251.6311.6351.6401.6471.6561.6661.6721.6791.6981.7051.7091.7181.7221.7291.7321.7441.7471.7511.7551.7711.8761.8901.8931.9041.9121.9151.9211.9301.9361.9401.9511.9611.9701.9761.9841.9921.9972.0012.0062.0212.0262.6202.6402.6563.4983.5123.5243.5353.5383.5483.5613.5743.6103.6223.6363.6483.8553.8613.8763.9263.9413.9453.9603.9754.0124.0244.0294.0414.0544.0587.1767.1947.2577.2687.2747.294OPh OTBS-20-100102030405060708090100110120130140150160170180190200210220-5.11823.24628.01828.16828.23128.32332.02936.12766.17779.14479.570106.314125.786128.378128.576142.670OPh OTBS251

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