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New synthetic methods using single-electron processes Zlotorzynska, Maria 2012

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   NEW SYNTHETIC METHODS USING SINGLE-ELECTRON PROCESSES  by  MARIA ZLOTORZYNSKA B.Sc., University of Ottawa, 2006    A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF  THE REQUIREMENTS FOR THE DEGREE OF    DOCTOR OF PHILOSOPHY  in  THE FACULTY OF GRADUATE STUDIES (Chemistry)   THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)     JULY 2012 © Maria Zlotorzynska, 2012ii  Abstract This thesis presents investigations of alkoxy and aminyl radical cyclizations onto silyl enol ethers, as well as the development of a new photoinduced electron transfer-promoted redox fragmentation of N-alkoxyphthalimides.  Chapter 1 describes our studies of alkoxy radical cyclizations using silyl enol ethers as acceptors.  Cyclizations to form tetrahydrofurans displayed a high degree of chemoselectivity relative to competing 1,5-hydrogen atom transfer, fragmentation and cyclization pathways.  The rate acceleration imparted by the silyl enol ether allowed for a highly chemoselective 6-exo cyclization, a difficult mode of alkoxy radical reactivity to access due to competing 1,5- hydrogen atom transfers.  Chapter 2 describes applications of silyl enol ether acceptors to aminyl radical cyclizations and the factors that lead to high diastereoselectivity in these cyclizations.  This methodology allows for the synthesis of the 2-hydroxymethylpyrrolidine core found in many polyhydroxylated alkaloid natural products.  In the course of our synthesis of the alkaloid CYB- 3, we found that the cyclization diastereoselectivity was dependent on a complex combination of sterics and olefin geometry.  Alkyl- and aryl-substituted substrates cyclized with high selectivity regardless of olefin geometry or substitution pattern.  When electronegative substituents were introduced alpha to the silyl enol ether, only Z-silyl enol ethers provided high cyclization diastereoselectivities. iii  Chapter 3 describes a new fragmentation reaction of N-alkoxyphthalimides mediated by visible light and a Ru(bpy)3 2+ photocatalyst.  Our mechanistic data support a unique concerted intramolecular fragmentation process, initiated by a single electron transfer to the phthalimide from either the metal catalyst or directly from a tertiary amine additive.  The redox fragmentation reaction was applied to aryl, allylic and lactol derivatives.  We found that the reaction could be carried out under catalyst-free conditions, but the yields of many substrates were improved in the presence of Ru(bpy)3 2+.  The redox fragmentation of N-alkoxyphthalimides was applied to the mild and selective redox fragmentation of sensitive nitrogen-containing heterocycles.   iv  Preface Chapter 1 is based on research conducted with Dr. Huimin Zhai and was published in 2008: Zlotorzynska, M.; Zhai, H.; Sammis, G. M. Org. Lett. 2008, 10, 5083.  I wrote this manuscript in collaboration with my supervisor, Prof. Glenn Sammis.  Dr. Huimin Zhai synthesized and characterized the silyl enol ethers and corresponding tetrahydrofurans in Table 1.2, entries 3, 4, 7 and 8, as well all compounds in Scheme 1.29 and Scheme 1.32. The experiments depicted in Scheme 1.27, Scheme 1.30 and Scheme 1.31 were carried out by other members of the Sammis lab and this work was published in 2010: Rueda-Becerril, M.; Leung, J. C. T.; Dunbar, C. R.; Sammis, G. M. J. Org. Chem., 2011, 76, 7720.  All other synthesis, characterization and experimental work in this chapter was performed by me.  Chapter 2 is based on research conducted with Dr. Huimin Zhai and was published in two manuscripts in 2009 and 2010: (a) Zhai, H; Zlotorzynska, M.; Sammis, G. Chem. Commun., 2009, 5716. (b) Zlotorzynska, M.; Zhai, H.; Sammis, G. M. J. Org. Chem. 2010, 75, 864.  Dr. Huimin Zhai synthesized and characterized the compounds depicted in Scheme 2.31, Table 2.1, Scheme 2.45 Scheme 2.45 and Table 2.2, entries 1 and 3.  All other synthesis, characterization and experimental work in this chapter was performed by me.  Chapter 3 is based on research published in 2011: Zlotorzynska, M.; Sammis, G. M. Org. Lett. 2011, 13, 6264.  I wrote this manuscript in collaboration with my supervisor, Prof. Glenn Sammis. I carried out all experimental work in this chapter, as well as the synthesis and characterization of all compounds.  v  Table of Contents Abstract ....................................................................................................................................... ii Preface ........................................................................................................................................ iv Table of Contents ........................................................................................................................ v List of Tables ............................................................................................................................ viii List of Figures ............................................................................................................................ ix List of Schemes ............................................................................................................................ x List of Abbreviations and Symbols ...................................................................................... xviii Acknowledgements .................................................................................................................. xxi Chapter 1. Chemoselective Alkoxy Radical Cyclizations onto Silyl Enol Ethers ................. 2 1.1 Introduction............................................................................................................... 2 1.2 Generation of Alkoxy Radicals ................................................................................ 3 1.3 Alkoxy Radical Reactivity ...................................................................................... 10 1.3.1 Alkoxy Radical Cyclizations .............................................................................. 11 1.3.2 Intramolecular Hydrogen Atom Transfer to Alkoxy Radicals ............................ 15 1.3.3 Fragmentation Reactions of Alkoxy Radicals .................................................... 16 1.3.4 Tetrahydropyran Synthesis Using Alkoxy Radical Cyclizations ........................ 18 1.4 Proposed Alkoxy Radical Cyclization onto Oxygenated Alkenes ......................... 21 1.5 Preparation of Substrates ........................................................................................ 22 1.6 Results and Discussion ........................................................................................... 26 1.7 Future Work ............................................................................................................ 35 1.8 Conclusion .............................................................................................................. 37 1.9 Experimental ........................................................................................................... 39 1.9.1 General Experimental ......................................................................................... 39 1.9.2 Syntheses of Silyl Enol Ethers 1.105, 1.106a,b,e and f ...................................... 40 1.9.3 Cyclizations of Silyl Enol Ethers 1.105, 1.106a,b,e and f .................................. 50 1.9.4 Intermolecular Alkoxy Radical Additions .......................................................... 54 vi  Chapter 2. Construction of Protected Hydroxylated Pyrrolidines Using Aminyl Radical Cyclizations ............................................................................................................................... 56 2.1 Introduction............................................................................................................. 56 2.2 Carbon-Centred Radical Strategies for Pyrrolidine Synthesis................................ 57 2.3 Nitrogen-Centred Radical Strategies for Pyrrolidine Synthesis ............................. 69 2.3.1 Indirect Methods for Generation of Aminyl Radicals ........................................ 69 2.3.2 Direct Methods for Generation of Aminyl Radicals ........................................... 72 2.3.3 Kinetics of Neutral Aminyl Radical Cyclizations ............................................... 74 2.4 Proposed Aminyl Radical Cyclizations onto Silyl Enol Ethers.............................. 75 2.5 Results and Discussion ........................................................................................... 76 2.5.1 Polyhydroxylated Alkaloids ................................................................................ 78 2.5.2 Diastereoselectivity Studies ................................................................................ 79 2.5.3 Synthesis of CYB-3 ............................................................................................ 81 2.5.4 Beckwith-Houk Transition State Analysis of Aminyl Radical Cyclizations ...... 87 2.6 Future Work ............................................................................................................ 96 2.7 Conclusion .............................................................................................................. 98 2.8 Experimental ........................................................................................................... 99 2.8.1 General Experimental ......................................................................................... 99 2.8.2 Synthesis of Azides 2.126, 2.131, 2.134 and Z-2.131 ......................................... 99 2.8.3 Cyclizations of Azides 2.126, 2.131, 2.134 and Z-2.131 .................................. 106 2.8.4 Syntheses of Azides 2.108g,h ........................................................................... 109 2.8.5 Synthesis of Azide 2.152 .................................................................................. 113 2.8.6 Cyclizations of Azides E-2.108g,h and 2.152 .................................................. 116 Chapter 3. Photoinduced Electron Transfer-Promoted Redox Fragmentation of N- Alkoxyphthalimides ................................................................................................................ 119 3.1 Introduction........................................................................................................... 119 3.2 Photochemistry and Radical Reactivity of Alkylphthalimide Derivatives ........... 120 3.3 Single Electron Transfer Reactions Mediated by Visible Light ........................... 125 3.4 Photoredox Properties of Ruthenium Bipyridyl Complexes ................................ 126 3.5 Photoinduced Electron Transfer (PET) Reactions ................................................ 128 3.5.1 Reductive PET Reactions.................................................................................. 128 3.5.2 Oxidative PET Reactions .................................................................................. 138 3.5.3 Redox Neutral PET Reactions .......................................................................... 146 3.6 Photoredox Chemistry of Oxygenated Phthalimide Derivatives .......................... 151 vii  3.7 Results and Discussion ......................................................................................... 156 3.8 Conclusion ............................................................................................................ 172 3.9 Experimental ......................................................................................................... 173 3.9.1 General Experimental ....................................................................................... 173 3.9.2 Synthesis of Substrates...................................................................................... 174 3.9.3 Optimization and Control Experiments ............................................................ 189 3.9.4 Photoredox Fragmentation Reactions ............................................................... 190 3.9.5 Mechanistic Experiments .................................................................................. 199 Bibliography ............................................................................................................................ 201 Appendix A: Selected Spectra for Chapter 1 ....................................................................... 215 Appendix B: Selected Spectra for Chapter 2 ....................................................................... 232 Appendix C: Selected Spectra for Chapter 3 ....................................................................... 251      viii  List of Tables Table 1.1. Homolytic bond strengths for selected single bonds to oxygen. ................................... 4 Table 1.2. Alkoxy radical cyclization to form substituted tetrahydrofurans. ............................... 28 Table 2.1. Cyclization of alkyl and phenyl substituted substrates. ............................................... 80 Table 2.2. Cyclization of 3-methyl and phenyl substituted substrates. ........................................ 94 Table 3.1. Optimization of solvent and concentration. ............................................................... 158 Table 3.2. Optimization of amine additive. ................................................................................ 159 Table 3.3. Control experiments. ................................................................................................. 160 Table 3.4. Redox fragmentation of para-substituted N-benzyloxyphthalimides. ...................... 164 Table 3.5. Aryl substrate scope................................................................................................... 167 Table 3.6. Extended substrate scope. .......................................................................................... 169 Table 3.7. List of Diagnostic NMR Peaks in (CD3)2CO ............................................................ 191   ix  List of Figures Figure 1.1. Selected examples of alkoxy radical precursors that undergo homolysis under photochemical conditions. .............................................................................................................. 5 Figure 1.2.  Relative rate constants for 5-exo-trig cyclizations of 1.41, 1.42 and 1.43. ............... 11 Figure 1.3. Beckwith-Houk transition states for the 5-exo cyclization of alkoxy radicals. .......... 12 Figure 1.4. Silyl enol ether substrates used in alkoxy radical cyclization studies. ....................... 22 Figure 1.5. Beckwith-Houk transition states for the cyclizations of Z- and E-silyl enol ethers. .. 29 Figure 2.1. Selected polyhydroxylated alkaloids. ......................................................................... 79 Figure 3.1. Ruthenium bipyridyl complex 3.27. ......................................................................... 126 Figure 3.2. Photoredox reactivity of Ru(bpy)3 2+ and representative quenchers. ........................ 127 Figure 3.3. Proposed alkoxy radical formation via photoinduced SET to an N-alkoxyphthalimide.  .................................................................................................................................................... 155 Figure 3.4 Two possible photochemical redox mechanisms. ..................................................... 159    x  List of Schemes Scheme 1.1. Generation of an alkoxy radical by photolysis of N-alkoxypyridinethione 1.7. ........ 6 Scheme 1.2. Generation of an alkoxy radical by reaction N-alkoxypyridinethione 1.11 with tributyltin radical. ........................................................................................................................... 6 Scheme 1.3. Generation of an alkoxy radical by reaction of N-alkoxyphthalimide 1.15 with tributyltin radical. ........................................................................................................................... 7 Scheme 1.4. In situ generation of hypoiodite 1.20 followed by cyclization to afford tetrahydropyran 1.21. ...................................................................................................................... 7 Scheme 1.5. Generation of alkoxy radical 1.24 via homolytic epoxide ring opening. ................... 9 Scheme 1.6. Generation of alkoxy radical 1.27 via homolytic epoxide ring opening, followed by 5-exo cyclization. ............................................................................................................................ 9 Scheme 1.7. Alkoxy radical reactivity. ......................................................................................... 10 Scheme 1.8. Possible cyclization pathways for alkoxy radical 39. .............................................. 11 Scheme 1.9. Selected examples of diastereoselective alkoxy radical cyclizations. ..................... 13 Scheme 1.10. Synthesis of allo-(+)-muscarine. ............................................................................ 14 Scheme 1.11. Cyclization and fragmentation products resulting from photolysis of 1.61. .......... 15 Scheme 1.12. Intramolecular hydrogen atom transfer. ................................................................. 15 Scheme 1.13. Radical relay cyclization to form cyclopentane 1.71. ............................................ 16 Scheme 1.14.  Synthesis of tetrahydrofuran subunit of (–)-amphidinolide K. ............................. 16 Scheme 1.15. Fragmentation of a strained, tertiary oxygen-centred radical. ............................... 17 Scheme 1.16. -fragmentation to form aldehyde 1.82. ................................................................ 18 Scheme 1.17. Possible 1,5-hydrogen atom transfer and 6-exo cyclization pathways of alkoxy radical 1.86. .................................................................................................................................. 18 xi  Scheme 1.18. Synthesis of tetrahydropyran 1.94 via 6-exo-trig radical cyclization. ................... 20 Scheme 1.19. 6-Exo alkoxy radical cyclization to form tetrahydropyran 1.99. ........................... 20 Scheme 1.20. 6-Exo alkoxy radical cyclization to form tetrahydropyran 1.101. ......................... 21 Scheme 1.21. Proposed alkoxy radical cyclization onto a silyl enol ether. .................................. 21 Scheme 1.22. Synthesis of silyl enol ethers 1.105 and 1.106a. .................................................... 22 Scheme 1.23. Synthesis of silyl enol ether 1.106b. ...................................................................... 23 Scheme 1.24. Synthesis of silyl enol ether 1.106e. ...................................................................... 24 Scheme 1.25. Synthesis of silyl enol ether 1.106f. ....................................................................... 25 Scheme 1.26. Alkoxy radical cyclizations to form tetrahydrofurans 1.120 and 1.121a. ............. 26 Scheme 1.27. Competition experiment to examine relative rates of cyclization vs. 1,5-hydrogen atom transfer to form a secondary carbon radical. ....................................................................... 30 Scheme 1.28. Competition experiment to examine relative rates of cyclization vs. 1,5-hydrogen atom transfer to form a secondary benzylic radical. ..................................................................... 31 Scheme 1.29. Competition experiment to examine the relative rate of cyclization onto a silyl enol ether vs. a terminal olefin. ............................................................................................................ 32 Scheme 1.30. Competition experiment to examine the relative rate of cyclization onto a silyl enol ether vs. an alkyl-substituted olefin. ............................................................................................. 32 Scheme 1.31. Competition experiment to examine the relative rate of cyclization onto a silyl enol ether vs. a gem-dialkyl substituted olefin. .................................................................................... 33 Scheme 1.32. 6-Exo cyclization of silyl enol ether 1.108 to form tetrahydropyran 1.149 and alcohol 1.150................................................................................................................................. 34 Scheme 1.33. Proposed alkoxy radical cyclization onto a silyl ketene acetal. ............................. 35 Scheme 1.34. Attempted synthesis of cyclization precursor 1.151. ............................................. 36 xii  Scheme 1.35. Intermolecular alkoxy radical addition to silyl ketene acetal 1.156. ..................... 36 Scheme 2.1. Attempts at pyrrolidine formation by carbon radical cyclization. ........................... 57 Scheme 2.2. Pyrrolidine formation by radical cyclization. .......................................................... 58 Scheme 2.3. Mechanism of sulfenyl radical-mediated cyclization. ............................................. 59 Scheme 2.4. Sulfenyl radical-mediated cyclization to form pyrrolidine 2.12. ............................. 59 Scheme 2.5. Retrosynthetic analysis of kainic acid (2.13). .......................................................... 60 Scheme 2.6. Sulfenyl radical-mediated cyclization to form pyrrolidines 2.17 and 2.18, followed by oxidative elimination of 2.17 to form pyrrolidines 2.19 and 2.20. .......................................... 60 Scheme 2.7. Tandem addition-cyclization-elimination reaction to form pyrrolidine 2.23. ......... 60 Scheme 2.8. Cyclization of amine 2.24 to form pyrrolidine 2.29, en route to kainic acid (2.13). 61 Scheme 2.9. Pyrrolidine formation by ketyl radical cyclization onto an oxime ether.................. 62 Scheme 2.10. Radical cyclization of imine 2.32. ......................................................................... 62 Scheme 2.11. Exclusive 5-exo cyclization of imine 2.35 to form pyrrolidine 2.36. .................... 63 Scheme 2.12. Dependence of the ratio of 2.39 and 2.40 on Bu3SnH concentration. ................... 63 Scheme 2.13. Proposed alternate mechanism for the formation of pyrrolidine 2.40. .................. 64 Scheme 2.14. Carbon radical cyclization onto an azide. .............................................................. 65 Scheme 2.15. Reduction of iodide 2.49. ....................................................................................... 66 Scheme 2.16. Radical cyclization followed by tosylation to form pyrrolidine 2.56. ................... 66 Scheme 2.17. Reduction of bromide 2.57. ................................................................................... 67 Scheme 2.18. Radical cyclization of bromide 2.59 to form pyrrolidine 2.60............................... 67 Scheme 2.19. Radical cyclization to form the tetracyclic core of (±)-aspidospermidine (2.64). . 68 Scheme 2.20. Carbon radical cyclization onto an azide for the synthesis of (±)-horsfiline (2.68).  ...................................................................................................................................................... 68 xiii  Scheme 2.21. Tandem radical cyclization of imines 2.69a and 2.69b. ........................................ 70 Scheme 2.22. Synthesis of spirocyclic pyrrolidines by tandem radical cyclization. .................... 70 Scheme 2.23. Tandem radical cyclization to form indolizidine 2.81. .......................................... 71 Scheme 2.24. Attempted 5-endo radical cyclization of imine 2.83. ............................................. 72 Scheme 2.25. Radical decomposition of tetrazene 2.87. .............................................................. 72 Scheme 2.26. Electrochemical oxidation of lithium amide 2.90. ................................................. 73 Scheme 2.27. Precursors for direct generation of aminyl radicals. .............................................. 74 Scheme 2.28. Kinetics of neutral aminyl radical cyclizations. ..................................................... 74 Scheme 2.29. Tandem cyclization of phenylsulfenimide 2.103. .................................................. 75 Scheme 2.30. Proposed aminyl radical cyclization onto a silyl enol ether................................... 76 Scheme 2.31. Radical cyclization of azide 2.108a to form pyrrolidine 2.111a. .......................... 77 Scheme 2.32. Radical cyclization of azide 2.112 to form acyclic amine 2.113 and pyrrolidine 2.114. ............................................................................................................................................ 78 Scheme 2.33. Synthesis of cyclization precursor 2.126. .............................................................. 82 Scheme 2.34. Radical cyclization of azide 2.126 using standard stannyl radical conditions to afford pyrrolidine 2.127 and acyclic amine 2.128. ....................................................................... 82 Scheme 2.35. Radical cyclization of 3-methyl substituted substrates 1.106g and 2.108g. .......... 83 Scheme 2.36. Radical cyclization of azide 2.126 using Et3B/O2 as a radical initiator to afford pyrrolidine 2.127 and acyclic amine 2.128. .................................................................................. 83 Scheme 2.37. Radical cyclization of azide 2.126 using Ph3SnH afford pyrrolidine 2.127 and acyclic amine 2.128. ..................................................................................................................... 84 Scheme 2.38. Synthesis of silyl enol ether 2.131 ......................................................................... 84 Scheme 2.39. Cyclization of azide 2.131 to afford pyrrolidine 2.132 and acyclic amine 2.133. . 85 xiv  Scheme 2.40. Synthesis of silyl enol ethers 2.134 and Z-2.131. .................................................. 86 Scheme 2.41. Cyclization of azides 2.134 and Z-2.131 to afford pyrrolidines 2.135 and 2.132.. 86 Scheme 2.42. Beckwith-Houk transition states for the cyclization of Z-silyl enol ether Z-2.131. 88 Scheme 2.43. Beckwith-Houk transition states for the cyclization of E-silyl enol ethers 2.134.. 89 Scheme 2.44. Stereoelectronic interaction in Beckwith-Houk transition states for the cyclization of E-silyl enol ether 2.134. ........................................................................................................... 91 Scheme 2.45. Synthesis of cyclization precursors Z-2.108g and Z-2.108h. ................................. 92 Scheme 2.46. Synthesis of cyclization precursors E-2.108g and E-2.108h. ................................ 92 Scheme 2.47. Synthesis and radical cyclization of azide 2.152 to form pyrrolidine 2.153. ......... 95 Scheme 2.48. Attempted cyclization of azide 2.153 to form piperidine 2.154. ........................... 96 Scheme 2.49. 6-Exo amidyl radical cyclizations. ......................................................................... 96 Scheme 2.50. Proposed 6-exo cycilzation of an amidyl radical onto a silyl enol ether to form a protected piperidine. ..................................................................................................................... 97 Scheme 2.51. Proposed aminium cation radical cyclization to form piperidine 2.164. ............... 97 Scheme 3.1. Photoinduced radical abstraction and recombination of N-methylphthalimide (3.1) and tetrahydrofuran (3.3). ........................................................................................................... 121 Scheme 3.2. Photoinduced Norrish type II reaction of N-propylphthalimide (3.9). .................. 122 Scheme 3.3 Photoinduced intramolecular SET reaction. ........................................................... 123 Scheme 3.4. Deuterium-labelling study to distinguish between an SET or a hydrogen abstraction mechanism. ................................................................................................................................. 123 Scheme 3.5. Photoinduced intermolecular SET. ........................................................................ 124 Scheme 3.6. Samarium-mediated SET and photoinduced cyclization of bis-phthalimide 3.25. 125 Scheme 3.7. Photoreduction of phenacyl sulfonium salt 3.28 and related substrates. ............... 128 xv  Scheme 3.8. Photoreduction of benzyl bromide (3.36), both with and without Ru(bpy)3 2+ catalyst. ....................................................................................................................................... 129 Scheme 3.9. Mechanism of photoreduction of benzyl bromide in the presence of Ru(bpy)3 2+ (A) and in the absence of photocatalyst (B). ..................................................................................... 131 Scheme 3.10. Ru(bpy)3 2+-promoted photoreduction of activated bromides in the presence of dihydrobenzothiazole 3.41. ......................................................................................................... 132 Scheme 3.11. Radical cyclization initiated by visible-light photocatalysis................................ 133 Scheme 3.12. Mechanism of radical cyclization initiated by photoredox catalysis. .................. 134 Scheme 3.13. Photocatalyzed reduction of glycosyl bromide 3.62 to initiate an intermolecular radical addition. .......................................................................................................................... 135 Scheme 3.14. Photocatalyzed reduction of activated ketones using reductive quenching of Ru(bpy)3 2+  by Et3N. .................................................................................................................... 136 Scheme 3.15. Photocatalyzed reduction of activated ketones using oxidative quenching of Ru(bpy)3 2+  by MV 2+. ................................................................................................................... 136 Scheme 3.16. Mechanism of ketone photoreduction using oxidative quenching of Ru(bpy)3 2+  by MV2+. .......................................................................................................................................... 138 Scheme 3.17. Photooxidation of aryl alcohols to aldehydes via visible-light photocatalysis. ... 139 Scheme 3.18. Mechanism of photocatalytic aryl alcohol oxidation. .......................................... 140 Scheme 3.19. Aerobic oxidation of an activated bromide through a combination of organocatalysis and visible-light photocatalysis. ....................................................................... 141 Scheme 3.20. Mechanism of aerobic photooxidation. ................................................................ 141 Scheme 3.21. Isotopic labelling experiment to determine origin of oxygen atom. .................... 142 xvi  Scheme 3.22. Photooxidation of tetrahydroisoquinolone 3.90 to iminium 3.91, followed by nucleophilic addition. ................................................................................................................. 143 Scheme 3.23. Mechanism of amine photooxidation. .................................................................. 144 Scheme 3.24. Photooxidative aza-Henry reaction of pyrrolidine 3.95. ...................................... 144 Scheme 3.25. Photoredox- and organocatalytic Mannich reaction. ........................................... 144 Scheme 3.26. Visible-light photocatalytic deprotection of PMB ether 3.98. ............................. 145 Scheme 3.27. Mechanism of photocatalytic PMB deprotection................................................. 146 Scheme 3.28. Enantioselective α-alkylation of aldehydes by a combination of photoredox catalysis and amine organocatalysis. .......................................................................................... 147 Scheme 3.29. Mechanism of enantioselective photocatalytic α-alkylation. ............................... 148 Scheme 3.30. Extension of enantioselective photocatalytic α-alkylation. ................................. 149 Scheme 3.31. Mechanism of [2+2] enone cycloaddition mediated by Ru(bpy)3 2+ visible light photocatalysis. ............................................................................................................................ 150 Scheme 3.32. Radical decarboxylation initiated by photoinduced SET to N-acyloxyphthalimide 3.129. .......................................................................................................................................... 152 Scheme 3.33. Photosensitized decarboxylative Michael addition. ............................................. 153 Scheme 3.34. Photoinduced SET mechanism of radical decarboxylative Michael addition. .... 154 Scheme 3.35. Attempted alkoxy radical generation using visible light photocatalysis.............. 156 Scheme 3.36. Photoinduced redox fragmentation of N-benzyloxyphthalimide (1.155). ........... 157 Scheme 3.37. Attempted photoinduced redox fragmentation of N-benzyloxysuccinimide (3.141).  .................................................................................................................................................... 161 Scheme 3.38. Stepwise or concerted redox fragmentation mechanisms. ................................... 162 Scheme 3.39. Redox fragmentation of N-alkoxyphthalimide 3.144. ......................................... 163 xvii  Scheme 3.40. Redox fragmentiation of N-alkoxyphthalimide 3.147. ........................................ 163 Scheme 3.41. Proposed redox fragmentation mechanism. ......................................................... 165 Scheme 3.42. Photoinduced fragmentation of N-alkoxyphthalimide 3.152. .............................. 166 Scheme 3.43. Two-step oxidation of isochroman (3.161). ......................................................... 171    xviii  List of Abbreviations and Symbols  chemical shift Ac acetyl acac acetylacetone AIBN azoisobutyronitrile Ar aryl BDMAP 1,6-bis(dimethylamino)pyrene Bn benzyl BNAH 1-benzyl-1,4-dihydronicotinamide bpy bipyridine Bu butyl Bz benzoyl °C degrees Celsius cm-1 reciprocal centimeters d doublet DBU 1,8-diazabicycloundec-7-ene dd doublet of doublets DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DIAD diisopropyl azodicarboxylate DIBAL-H diisobutylaluminium hydride DMA dimethylacetimide DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide dr diastereomeric ratio dtbbpy 4,4'-di-t-butyl-2,2'-bipyridine E entgegen ee enantiomeric excess ESI electrospray ionization Et ethyl GE General Electric h hour H enthalpy change 1,5-HAT 1,5-hydrogen atom transfer HPLC-MS high-performance liquid chromatography-mass spectrometry HRMS high resolution mass spectrum hν light i iso IR infrared xix  J coupling constant k rate constant kcal kilocalories LDA lithium diisopropylamide LRMS low resolution mass spectrum LUMO lowest unoccupied molecular orbital m multiplet M molarity or parent mass Me methyl MHz megahertz min minute mmol millimole mol mole MV methyl viologen NOE nuclear Overhauser effect nm nanometer NMR nuclear magnetic resonance OTf trifluoromethanesulfonate p para PCC pyridinium chlorochromate PET photoinduced electron transfer Ph phenyl Phth phthalimide PMB 4-methoxybenzyl PMP para-methoxyphenyl ppm parts per million ppy 2,2’-phenylpyridyl Pr propyl PTOC N-hydroxypyridine-2-thione q quartet qt quintet R undefined portion of a molecule R rectus s second or singlet S sinister SCE Saturated Calomel Electrode SET single electron transfer SN2 bimolecular nucleophilic substitution SOMO singly occupied molecular orbital t triplet xx  t tert TBS tert-butyldimethylsilyl TEOA triethanolamine TES triethylsilyl THF tetrahydrofuran TMS trimethylsilyl Trt trityl Ts para-toluenesulfonyl UV ultraviolet UV-Vis ultraviolet-visible  V volt W watt X undefined halogen Z zusammen    xxi  Acknowledgements First and foremost, I would like to thank my supervisor, Prof. Glenn Sammis, for his guidance and encouragement over the years. His commitment to my education and seemingly endless enthusiasm to help me with all my endeavours will forever be appreciated.  I also wish to thank my thesis committee members: Prof. Raymond Anderson, Prof. Mark MacLachlan and especially Prof. Marco Ciufolini for his assistance in editing my thesis. Additionally, I am continually thankful for the excellent training I received from my undergraduate supervisor, Prof. André Beauchemin. I will always be grateful for the support I have received from my group members, Jay Wickenden, Hai Zhu, Joe Leung, Natalie Campbell, Montserrat Rueda-Becerril and Claire Chatalova Sazepin.  I especially want to thank Jay for his friendship, entertaining rants and sense of humor.  Jay has been one of my closest friends since our very first days at UBC and I truly   appreciated being able to vent and laugh about our graduate experiences together.  I would also like to acknowledge Dr. Huimin Zhai, my coauthor on three publications, for his invaluable research contributions. My graduate work would not have been possible without the dedicated support staff in the Chemistry Department at UBC. I wish to thank the staff of the NMR lab, the Mass Spectrometry lab, Chem stores and the main office for all their work over the years.  In particular, I wish to thank Ken Love for his assistance in setting up our laboratories.  I would also like to thank the Natural Sciences and Engineering Research Council (NSERC) for funding throughout my graduate degree. Finally, I wish to thank my parents for their enduring love and support throughout my education. 1    CHAPTER ONE: Chemoselective Alkoxy Radical Cyclizations Onto Silyl Enol Ethers2 Chapter 1. Chemoselective Alkoxy Radical Cyclizations onto Silyl Enol Ethers 1.1 Introduction Moses Gomberg’s discovery of the triphenylmethyl radical in 1900 marked the birth of the field of free radical organic chemistry and set the foundation for the study of the kinetic and mechanistic behaviour of this highly reactive intermediate.1  However, it was not until the 1970s that applications of radical methods to organic synthesis began to be investigated.  Intramolecular carbon-centred radical reactions are particularly attractive to synthetic chemists as the reaction conditions for radical generation are generally mild, and they exhibit highly predictable behaviour and functional group tolerance.  While these radical reactions have been applied extensively to carbon-carbon bond formation in the context of natural product synthesis, carbon-oxygen bond forming reactions using alkoxy radicals are not as highly utilized.  Despite progress in the field, methods based on alkoxy radicals are not sufficiently developed for the synthesis of complex substrates.  The few examples of alkoxy radical cyclizations used in the context of natural product synthesis are limited to simple tetrahydrofuran-containing structures.  Furthermore, the application of alkoxy radical cyclizations to tetrahydropyran synthesis has been hampered by low chemoselectivity relative to competing hydrogen atom transfer pathways.   In this chapter, I will present an overview of common alkoxy radical generation methods and describe the cyclization, hydrogen atom transfer and fragmentation behaviour of this highly reactive species.  I will also discuss efforts to improve the selectivity for cyclization reactions.  Increasing the electron density of the alkene acceptor through alkyl or aryl substitution has been shown to accelerate the rate of alkoxy radical cyclization.  However, low chemoselectivity 3 relative to competing radical processes has impeded the development of alkoxy radical-based approaches as a general methodology for oxacycle synthesis.  Prior to our work, heteroatom- substituted alkenes had not been investigated as acceptors for alkoxy radicals.  Thus, we sought to investigate the kinetic effects of further increasing the electron density of the alkoxy radical acceptor.   Silyl enol ethers were chosen as acceptors, as they can be readily synthesized from their parent aldehydes and provide access to α-oxygenated oxacyclic products with a versatile synthetic handle for further functionalization.  We examined the diastereo- and chemoselectivity of 5-exo and 6-exo alkoxy radical cyclizations onto silyl enol ethers.  The results of these studies, as well as preliminary applications to intermolecular alkoxy radical additions, will be discussed. 1.2 Generation of Alkoxy Radicals The generation of alkoxy radicals has been extensively studied.2  Applications to synthetic organic chemistry have largely focused on generation of alkoxy radicals from alcohol derivatives as alkoxy radicals cannot be formed from direct oxygen-hydrogen bond homolysis of an alcohol due to the strength of the this bond.  While oxygen forms relatively strong bonds with hydrogen and carbon, bonds with other heteroatoms, such as nitrogen,3 sulfur4 or chlorine,5 are significantly weaker (Table 1.1).  These alkoxy radical precursors readily undergo homolysis under either photochemical or thermal conditions.   4 Table 1.1. Homolytic bond strengths for selected single bonds to oxygen.6 Entry Bond Homolytic Bond Strength (kcal/mol) 1 (H3C)3CO–OC(CH3)3 38 2 (H3C)3CO–NO 41 3 HO–Cl 60 4 H3CO–SCH3 63 5 H3CO–CH3 83 6 H3CO–H 104  The oxygen-heteroatom bond can be introduced into a molecule in one of two ways, both of which rely on a nucleophilic displacement reaction.  Alkoxy radical precursors can be synthesized by reacting the parent alcohol with an appropriate electrophile.  Alternatively, the oxygen atom destined to become a radical is incorporated into the molecule by an SN2 reaction using a nucleophile containing an oxygen-heteroatom bond. 5  Figure 1.1. Selected examples of alkoxy radical precursors that undergo homolysis under photochemical conditions. Homolysis of the oxygen-heteroatom bond to generate an alkoxy radical can be induced under photochemical conditions.  Selected examples of these alkoxy radical precursors are depicted in Figure 1.1.  Other precursors in this class are N-alkoxypyridinethione derivatives, which undergo homolysis by irradiation with visible light (Scheme 1.1).  Photolysis of N- alkoxypyridinethione 1.7 leads to cleavage of the oxygen-nitrogen bond, followed by a 5-exo cyclization to generate a carbon radical intermediate (1.9).7  Because there is no external radical source, the carbon radical 1.9 is trapped by the rearomatized pyridinethiol group (1.8). Thus, in addition to generating the alkoxy radical, this functional group allows for remote functionalization of the products.  The use of ambient light is attractive because of the extremely mild reaction conditions needed to induce homolysis, without need for any external reagents.  However, the photosensitivity of this functional group limits the stability of the alkoxy radical precursors and necessitates installation of the N-alkoxypyridinethione group immediately prior to the homolysis reaction.  Furthermore, synthesis of these alkoxy radical precursors generally proceeds in low yield due to the ambident nature of the N-hydroxypyridinethione nucleophile. 6  Scheme 1.1. Generation of an alkoxy radical by photolysis of N-alkoxypyridinethione 1.7.     Scheme 1.2. Generation of an alkoxy radical by reaction N-alkoxypyridinethione 1.11 with tributyltin radical. In addition to photolysis, homolysis of an oxygen-heteroatom bond can also be induced by treatment with a stannyl radical.  In an early example, Beckwith showed that treatment of an N- alkoxypyridinethione 1.1 (Scheme 1.2) with tributyltin hydride and AIBN in refluxing benzene results in homolytic cleavage of the O-N bond.8  Hydrogen atom transfer to the resultant alkoxy radical provides alcohol 1.14.  N-Alkoxyphthalimides (1.15) are another functional group that react with stannyl radicals to generate alkoxy radicals (Scheme 1.3).9  In contrast to other oxygen-nitrogen bond containing alkoxy radical precursors, N-alkoxyphthalimides are readily installed, are bench-stable, and can be carried through a number of synthetic steps.  The N- alkoxyphthalimide moiety is not sensitive to visible light and does not undergo oxygen-nitrogen bond homolysis upon UV irradiation.10  Addition of a stannyl or silyl radical to the carbonyl of the N-alkoxyphthalimide leads to homolysis of the oxygen-nitrogen bond.  Hydrogen atom transfer from the metal hydride terminates the reaction.  Because reductive radical conditions are 7 employed, functionalization by trapping with heteroatom-centred radicals is not possible using this method of alkoxy radical generation.   Scheme 1.3. Generation of an alkoxy radical by reaction of N-alkoxyphthalimide 1.15 with tributyltin radical. Generation of an alkoxy radical directly from the free alcohol can be accomplished by treatment with a strong oxidant, such as PhI(OAc)2/ I2  11 or Pb(OAc)2. 12  In an example by Togo, reaction of 1.19 under oxidative conditions leads to in situ formation of hypoiodite 1.20 (Scheme 1.4).  Homolysis of the oxygen-iodine bond generates an alkoxy radical, which adds to the aromatic ring.  Further oxidation affords bicyclic product 1.21 in good yield.    Scheme 1.4. In situ generation of hypoiodite 1.20 followed by cyclization to afford tetrahydropyran 1.21. All alkoxy radical precursors described thus far rely on homolysis of weak oxygen- heteroatom bonds.  While homolysis of carbon-oxygen bonds is generally difficult, fragmentation can occur in strained systems such as epoxides.  The most commonly used example of this strategy is formation of a carbonyl radical alpha to an epoxide, which induces carbon-oxygen bond homolysis.  This fragmentation occurs at a rate of approximately 1010 s-1,13 which is even higher than that of cyclopropylcarbinyl radical opening (9.4 x 107 s–1).14  The first 8 example of this fragmentation was reported by Barton (Scheme 1.5)15 and utilized a Barton- McCombie deoxygenation16 to generate the cyclopropylcarbinyl radical (1.23).  Fragmentation of this radical led to formation of alkoxy radical 1.24.  Finally, trapping of the alkoxy radical by hydrogen atom transfer from Bu3SnH followed by esterification afforded the 3,5-dinitrobenzyl ester of (+)-trans-carveol (1.25) in 65% yield.  The formation of an alkoxy radical intermediate is supported by the reaction of the cis-diastereomer under the same reaction conditions (1.26, Scheme 1.6).  In addition to alcohol 1.28, Barton also observed formation of pinol (1.30), presumably from 5-exo cyclization of alkoxy radical intermediate 1.27.  The geometry of the trans-diastereomer 1.21 (Scheme 1.5) prohibits an analogous cyclization. 9  Scheme 1.5. Generation of alkoxy radical 1.24 via homolytic epoxide ring opening.   Scheme 1.6. Generation of alkoxy radical 1.27 via homolytic epoxide ring opening, followed by 5-exo cyclization.  10 1.3 Alkoxy Radical Reactivity  Scheme 1.7. Alkoxy radical reactivity. Despite progress in the field, alkoxy-radical cyclizations are still not widely utilized in natural product synthesis, compared to carbon-centred cyclization analogs, as alkoxy radicals can readily undergo a number of competing intra- and intermolecular processes.  In addition to cyclization, alkoxy radicals are prone to 1,5-hydrogen atom transfer and -fragmentation reactions (Scheme 1.7).  Thus, a detailed understanding of potential competing pathways is necessary to developing a new alkoxy radical cyclization methodology.   11 1.3.1 Alkoxy Radical Cyclizations  Scheme 1.8. Possible cyclization pathways for alkoxy radical 39. Alkoxy radical cyclizations have been applied to the synthesis of a variety of oxacycles.17  By far, the most thoroughly studied of these is the formation of tetrahydrofurans via 5-exo-trig cyclization onto alkenes.  This is a kinetically controlled process and therefore the 5-exo mode of cyclization is generally favoured over the 6-endo mode (Scheme 1.8).  4-Penten-1-oxyl radical 1.39 cyclizes to give tetrahydrofuran 1.38 with virtually complete selectivity over the competing 6-endo pathway.  The rate constant of this 5-exo cyclization has been derived from competition kinetics to be 5.2 x 108 s-1 at 80 °C.18  While solvent effects were found to have minimal influence on the rate, substitution at the terminal position of the alkene acceptor can greatly accelerate the cyclization.  For example, gem-dialkyl substitution increases the rate of cyclization 16 times for the trans diastereomer over the analogous unsubstituted substrate (Figure 1.2).19   Figure 1.2.  Relative rate constants for 5-exo-trig cyclizations of 1.41, 1.42 and 1.43.    12  Figure 1.3. Beckwith-Houk transition states for the 5-exo cyclization of alkoxy radicals. The diastereoselectivity of 5-exo alkoxy radical cyclizations can be rationalized by a model analogous to that developed by Beckwith20 and Houk21 for carbon radical ring closure reactions.  This model considers the cyclization as proceeding through either a boat-like or chair-like transition state (Figure 1.3).  The lowest energy, and thus most populated, transition state is one in which the steric interactions are minimized.  Of the two chair-like transition states (1.44 and 1.45), 1.44 has substituents oriented in the pseudo-equatorial position and is therefore favoured.  While boat-like transition state 1.49, leading to the opposite diastereomer (1.47), has fewer steric interactions than boat-like transition state 1.48, it is still higher in energy compared to chair-like transition state 1.44 due to A1,3-strain.  This model has been validated experimentally and correctly predicts the preference for tetrahydrofuran products with 2,3-trans, 2-4-cis or 2,5-trans stereochemistry (Scheme 1.9).18,22    13  Scheme 1.9. Selected examples of diastereoselective alkoxy radical cyclizations. There are few examples of alkoxy radical cyclizations used in the context of natural product synthesis and they are limited to simple structures with low functionalization.  Hartung reported the synthesis of (+)-allo-muscarine (1.60, Scheme 1.10),23 one of the biologically active components of the mushroom Amanita muscaria.  Starting from methyl-(S)-lactate (1.56), cyclization precursor 1.57 was synthesized in 5 steps.  Photolysis of 1.57 in the presence of BrCCl3 allowed for functionalization of the tetrahydrofuran product by trapping of the resulting carbon radical with bromine.  A mixture of diastereomers 1.58 and 1.59 was obtained after cyclization. In accordance with the Beckwith-Houk model, the (2R,3S,5S)-diastereomer 1.58 was the major product.  This product was further functionalized in two steps to provide the target product, allo-(+)-muscarine (1.60).  14  Scheme 1.10. Synthesis of allo-(+)-muscarine. In an attempt to improve the diastereoselectivity of the alkoxy radical cyclization, Hartung increased the steric bulk of the alcohol protecting group at C-3 (Scheme 1.11).24  The selectivity for desired diastereomer did indeed improve and tetrahydrofuran 1. 62 was isolated as the sole cyclic product.  However, the yield was dramatically lower in comparison to the cyclization of 1.57 (Scheme 1.10) and four acyclic other products (1.63, 1.64, 1.65 and 1.66) were also observed in addition to tetrahydrofuran 1.62.  These side-products are likely a result of - fragmentation, which is known to readily occur in -siloxy substituted alkoxy radicals.25,26  This example illustrates the chemoselectivity challenges that can arise in the application of alkoxy radical cyclization to natural product synthesis.  15  Scheme 1.11. Cyclization and fragmentation products resulting from photolysis of 1.61.  1.3.2 Intramolecular Hydrogen Atom Transfer to Alkoxy Radicals  Scheme 1.12. Intramolecular hydrogen atom transfer. Intramolecular 1,5-hydrogen atom transfer reactions (1,5-HAT) are another alkoxy radical mode of reactivity (Scheme 1.12).27  Because the homolytic bond strength of an oxygen- hydrogen bond is higher than that of a carbon-hydrogen bond, these reactions are generally exothermic.  For example, a 1,5-HAT in pentoxy radical 1.33 affords the carbon radical 1.34 with a H of –5 kcal/mol.28  1,5-HATs occur preferentially via a cyclic chair-like transition state 1.67,29 and, therefore, 1,5-hydrogen atom transfer generally dominates over competing 1,2-, 1,3-, 1,4- or 1,6-hydrogen atom transfers.30  An exception to this behaviour is the selectivity of a 1,6- hydrogen atom transfer when the resulting carbon radical is stabilized datively by an adjacent heteroatom.31  While HAT reactions can compete with cyclization processes, the selectivity of 1,5-HATs can be exploited for the synthesis of remotely functionalized products.  Other 16 members of our group have investigated 1,5-HAT to an alkoxy radical as a means of generating carbon radicals for subsequent cyclization (Scheme 1.13).32  This methodology has been applied to the synthesis of a variety of carbocycles and heterocycles, including the tetrahydrofuran subunit of (–)-amphidinolide K (1.74, Scheme 1.14).  Scheme 1.13. Radical relay cyclization to form cyclopentane 1.71.   Scheme 1.14.  Synthesis of tetrahydrofuran subunit of (–)-amphidinolide K.  1.3.3 Fragmentation Reactions of Alkoxy Radicals Alkoxy radicals can readily undergo -fragmentation to form a carbon-oxygen double bond and an alkyl radical.26  This process is of special interest to physical organic chemists and fragmentations of alkoxy radicals are often used as free radical clocks for competition kinetic 17 experiments.33  -Fragmentation is especially favoured in strained cyclic systems, such as cyclobutanes (Scheme 1.15).  For example, treatment of bromide 1.75 with a stannyl radical generates carbon radical 1.76, which adds into the carbonyl to form alkoxy radical 1.77.34  This radical then fragments to give the ring-expansion product 1.78.  The fragmentation is favoured by both the relief of ring strain and the formation of a more stable carbon radical and a strong carbon-oxygen double bond.  Scheme 1.15. Fragmentation of a strained, tertiary oxygen-centred radical. Because fragmentations of alkoxy radicals proceed under thermodynamic control, the regioselectivity can be predicted based on carbon radical stability after C-C bond cleavage.  An example by Hartung is depicted in Scheme 1.16.35  Either bond A or bond B in alkoxy radical 1.80 could fragment to give carbon radical 1.81 or 1.83.  Stabilization by the phenyl group favours cleavage of bond A and aldehyde 1.82 is sole product of this reaction.  Therefore, alkoxy radicals with radical stabilizing groups in the beta position are especially prone to fragmentation. 18  Scheme 1.16. -fragmentation to form aldehyde 1.82. 1.3.4 Tetrahydropyran Synthesis Using Alkoxy Radical Cyclizations   Scheme 1.17. Possible 1,5-hydrogen atom transfer and 6-exo cyclization pathways of alkoxy radical 1.86. 19 Prior to our work, a traditional limitation of alkoxy radical methodologies had been difficulty in forming six-membered ring systems via cyclization onto alkenes due to competing 1,5-HAT reactions (Scheme 1.17).  Stabilization of the carbon radical (1.88) by the adjacent alkene favours this transfer and in most cases, products from 1,5-HAT are predominant in the reaction mixture.36  Thus, there are very limited examples of tetrahydropyran syntheses using 6- exo alkoxy radical cyclizations, and the few that do exist involve activated substrates.  For example, Murphy demonstrated that Thorpe-Ingold activation promotes cyclization to some extent (Scheme 1.18).37  However cyclopentane 1.97, resulting from 1,5-hydrogen atom transfer followed by cyclization, is the major product.  The 6-exo cyclization pathway can also be accelerated somewhat by increasing the alkyl substitution of the alkene acceptor (Scheme 1.19).36  The yield of the tetrahydropyran product remains low, with the majority of the mass balance being 1,5-hydrogen atom transfer products.  Efficient cyclization of alkoxy radicals onto alkyl-substituted alkenes can be achieved if the 1,5-hydrogens are absent (Scheme 1.20),38 but this strategy limits the scope and utility of this method of tetrahydropyran formation as it requires substitution at the 5-position.  Thus, the low chemoselectivity for 6-exo cyclization has impeded the development of alkoxy radical methodologies for tetrahydropyran synthesis. 20  Scheme 1.18. Synthesis of tetrahydropyran 1.94 via 6-exo-trig radical cyclization.    Scheme 1.19. 6-Exo alkoxy radical cyclization to form tetrahydropyran 1.99.  21  Scheme 1.20. 6-Exo alkoxy radical cyclization to form tetrahydropyran 1.101.  1.4 Proposed Alkoxy Radical Cyclization onto Oxygenated Alkenes Despite the limitations, alkoxy radical cyclization is a rapid method of synthesizing oxacycles from simple linear precursors.  This methodology would be more amenable to synthetic applications if the chemoselectivity were improved.  Alkoxy radicals are highly electrophilic,39 and therefore increasing the electron density of the alkene acceptor should accelerate the cyclization reaction over competing pathways.  While alkyl substitution has been shown to increase the rate of cyclization, the effect of heteroatom substitution has not been studied.  We were particularly interested in cyclizations involving silyl enol ethers, as the cyclization precursors can be easily synthesized from their parent aldehydes (Scheme 1.21).  Furthermore, the oxygen-radical cyclization would provide oxacycles with a modular protected primary alcohol substituent.  Scheme 1.21. Proposed alkoxy radical cyclization onto a silyl enol ether. Our planned studies required synthesis of the compounds depicted in Figure 1.4.  A discussion of the preparation of these substrates is presented in the following section. 22  Figure 1.4. Silyl enol ether substrates used in alkoxy radical cyclization studies. 1.5 Preparation of Substrates  Scheme 1.22. Synthesis of silyl enol ethers 1.105 and 1.106a. 23 Silyl enol ether 1.110 served as a common precursor for both N-alkoxypyridinethione 1.105 and N-alkoxyphthalimide 1.106a (Scheme 1.22).  Soft enolization of known 5-tosyloxypentenal (1.109)40 afforded Z-silyl enol ether 1.110 in quantitative yield.  The geometry of the silyl enol ether was determined by the magnitude of the J-coupling constant of the vinylic proton geminal to the siloxy group (J = 5.9 Hz).  Subsequent SN2 displacement installed the photolabile alkoxy radical precursor.  The S-adduct was also formed during this reaction, thus accounting for the poor yield of N-alkoxypyridinethione 1.105.  Using the same tosylate precursor (1.110), nucleophilic substitution by N-hydroxyphthalimide afforded the cyclization precursor 1.106a.  The N-alkoxyphthalimide product (1.106a) was obtained in much higher yield than the analogous N-alkoxypyridinethione (1.105) and was much more stable.     Scheme 1.23. Synthesis of silyl enol ether 1.106b. Synthesis of silyl enol ether 1.106b (Scheme 1.23) was accomplished in two steps from known phenyl ketone 1.11241 by SN2 displacement of the bromide by N-hydroxyphthalimide, followed treatment with TBSOTf and Hünig’s base.  Silyl enol ether 1.106b was isolated as exclusively the Z-diastereomer and the geometry was confirmed by NOE difference spectroscopy. 24  Scheme 1.24. Synthesis of silyl enol ether 1.106e. The synthesis of silyl enol ether 1.106e began with known ester 1.114 (Scheme 1.24).42  Following hydroboration of the alkene and protection of the resultant primary alcohol as a TBS ether, the ester was reduced with LiAlH4 and the N-alkoxyphthalimide was installed by a Mitsunobu reaction.  N-Alkoxyphthalimide 1.115 was obtained in 15% yield over these 4 steps.  Deprotection of the TBS ether provided alcohol 1.116 in 84% yield.  Finally, oxidation with PCC and silylation under soft enolization conditions afforded the target silyl enol ether 1.106e in 44% yield over two steps, as a 84:16 mixture of Z and E diastereomers. 25  Scheme 1.25. Synthesis of silyl enol ether 1.106f. Silyl enol ether 1.106f was synthesized from known ester 1.11743 in a similar manner as silyl enol ether 1.106e, with the exception of the primary alcohol protecting group (Scheme 1.25).  A TES group was used in place of a TBS group to allow for direct oxidation to aldehyde 1.119 without prior deprotection.  The target silyl enol ether 1.106f was obtained in 58% yield as a 72:28 mixture of Z and E diastereomers after silylation of aldehyde 1.119 under soft enolization conditions. Compounds 1.106c, 1.106d, 1.106g, 1.106g, 1.106h, 1.107 and 1.108 were prepared by Dr. Huimin Zhai using methods similar to those described above.  26 1.6 Results and Discussion   Scheme 1.26. Alkoxy radical cyclizations to form tetrahydrofurans 1.120 and 1.121a. We began by investigating silyl enol ethers as acceptors for 5-exo alkoxy radical cyclizations, using an N-alkoxypyridinethione as the alkoxy radical precursor.44  Gratifyingly, irradiation of 1.105 with visible light afforded tetrahydrofuran 1.120 in excellent yield.  This reaction represents the first example of an alkoxy radical cyclization onto a heteroatom- substituted alkene acceptor. We next explored this reaction under reductive radical conditions, using an N- alkoxyphthalimide to generate the alkoxy radical.  Treatment of N-alkoxyphthalimide 1.106a with either Bu3SnH or (TMS)3SiH and AIBN in refluxing benzene resulted in the desired 5-exo cyclization in quantitative conversion by 1H NMR spectroscopy (Scheme 1.26).  While photolysis of N-alkoxypyridinethione 1.105 provided tetrahydrofuran 1.120 with a protected aldehyde in the alpha position, cyclization under reductive metal hydride conditions afforded a tetrahydrofuran product with a protected α-alcohol (1.121a).  Thus, tetrahydrofuran products 27 with different oxidation states at the alpha position can be readily accessed by modifying the method of alkoxy radical generation. After establishing the fundamental reactivity, we next investigated the chemo- and diastereoselectivities of alkoxy radical cyclizations onto silyl enol ethers (Table 1.2).  We chose to use N-alkoxyphthalimides as alkoxy radical precursors due their stability and ease of synthesis.  The isolated yield of tetrahydrofuran 1.121a (entry 1) was lower than what would be expected based on the quantitative conversion observed by 1H NMR spectroscopy (Scheme 1.26).  However, no other by-products were observed in the 1H NMR spectrum of the crude mixture and therefore the low yield is likely a result of the volatility of the product.  All other cyclizations proceeded in good to excellent yields.  The relative configuration of the cyclized products was determined by deprotecting the silyl ethers and comparing the spectroscopic properties of the products to that of literature compounds.  The major stereoisomers observed were consistent with those predicted by the Beckwith-Houk model and in comparable diastereoselectivity to what has been previously reported for alkoxy radical cyclization onto terminal alkenes.18,45  Silyl enol ether 1.106f (entry 7) in particular provided high diastereoselectivty of the corresponding tetrahydrofuran 1.121f.  Increasing the steric bulk from a methyl to a phenyl group (entry 8) provided tetrahydrofuran 1.121g in comparable yield as a single diastereomer.     28 Table 1.2. Alkoxy radical cyclization to form substituted tetrahydrofurans.  Entry Substrate (a) Product(b) Yield (%)(c) d.r.(d) 1   1.106a   1.121a 51(e) – 2   1.106b   1.121b 69 67:33 3 1.106c 1.121c 81 67:33 4    1.106d 1.121d 73 66:43 5 1.106e 1.121e 86 58:42 6 1.106f 1.121f 82 72:28 7 1.106g 1.121g 71 92:8 8 1.106h 1.121h 68 >95:5(f) (a) Reactions were carried out on >0.25 mmol scale.  (b) The relative configuration was determined by derivatization of the product and comparison to known compounds.  (c) Isolated yields of the mixture of diastereomers after flash chromatography.  (d) The diastereomeric ratio was determined by 1H NMR spectroscopy of crude reaction mixtures. (e) The product was obtained in >95% converstion by 1H NMR spectroscopy with no other side products.  (f) No other isomers could be detected by 1H NMR spectroscopy. 29  Figure 1.5. Beckwith-Houk transition states for the cyclizations of Z- and E-silyl enol ethers. The geometry of the silyl enol ether had an influence on the cyclization diastereoselectivity.  The diastereoselectivity for the trans tetrahydrofuran 1.121g dropped to 88:12 when the E- isomer of silyl enol ether 1.106g was used.  This difference in diastereoselectivity can be rationalized using the Beckwith-Houk transition state model.  The cyclization proceeds through one of four possible transition states (Figure 1.5), two of which are chair-like (1.122 and 1.124 for Z-silyl enol ether; 1.127 and 1.129 for E-silyl enol ether) and two of which are boat-like (1.123 and 1.125 for Z-silyl enol ether; 1.128 and 1.130 for E-silyl enol ether). Both chair-like transition states 1.122 and 1.127, which provide the trans-substituted tetrahydrofuran, have few 30 major steric interactions, as compared to all alternative transition states.  The slightly higher diastereoselectivity observed in the cyclization of the Z-silyl enol ether can be rationalized by comparing chair-like transition states 1.124 and 1.129, leading to cis-substituted tetrahydrofuran 1.126.  While both transition states have a syn-pentane-like interaction between the methyl substituent and a hydrogen, transition state 1.124 also contains a significant A1,3 interaction between the methyl and siloxy substituents.  Similarly, the steric interactions in boat-like transition state 1.125, leading to the cis-tetrahydrofuran, are more pronounced than in the analogous boat-like transition state 1.130 for the E-silyl enol ether.  Thus, the magnitude of the energy difference between the transition state leading to the trans-tetrahydrofuran and those leading to the cis-tetrahydrofuran is greater in the cyclization of the Z-enol ether and therefore this cyclization is more diastereoselective than the cyclization of the E-enol ether.   Scheme 1.27. Competition experiment to examine relative rates of cyclization vs. 1,5-hydrogen atom transfer to form a secondary carbon radical.  31  Scheme 1.28. Competition experiment to examine relative rates of cyclization vs. 1,5-hydrogen atom transfer to form a secondary benzylic radical. The utility of silyl enol ethers as alkoxy radical acceptors was demonstrated by the high chemoselectivity of these cyclizations.  No fragmentation was observed in substrates that could undergo -scission to secondary carbon radicals (Table 1.2, entries 4 and 5).  While some fragmentation was observed in substrate 1.106e (entry 6), which can fragment to a highly stabilized benzyl radial, tetrahydrofuran 1.121g was the major product (84:16 cyclization/fragmentation) and was isolated in excellent yield.  Cyclizations were completely chemoselective relative to 1,5-hydrogen abstraction; silyl enol ethers 1.106d (entry 5) and 1.106f (entry 7) cyclized to give the expected tetrahydrofuran products exclusively.  The chemoselectivity of secondary alkoxy radical cyclizations remained high even when the C-H bond available for 1,5-hydrogen abstraction was weakened (Scheme 1.27 and Scheme 1.28) .46  Silyl enol ethers 1.131 and 1.136 cyclized to provide the corresponding tetrahydrofurans exclusively.  32  Scheme 1.29. Competition experiment to examine the relative rate of cyclization onto a silyl enol ether vs. a terminal olefin. We next investigated the chemoselectivity of alkoxy radical cyclization onto a silyl enol ether relative to other cyclization pathways, using a competition experiment in which the alkoxy radical could undergo a 5-exo cyclization onto either a silyl enol ether or a terminal olefin (Scheme 1.29).  The alkoxy radical generated from N-alkoxyphthalimide 1.107 displayed high chemoselectivity for addition to the silyl enol ether, providing tetrahydrofuran 1.141 in 81% isolated yield.  A related study by other members of our laboratory further probed the chemoselectivity of alkoxy radical cyclization onto silyl enol ethers relative to alkyl-substituted alkenes (Scheme 1.30, Scheme 1.31).Error! Bookmark not defined.  The chemoselectivity for cyclization onto the silyl enol ether decreased with increasing alkyl-substituion on the competing alkene.  A competition experiment involving a gem-dimethyl substituted alkene provided an almost equimolar mixture of the two possible cyclization products.    Scheme 1.30. Competition experiment to examine the relative rate of cyclization onto a silyl enol ether vs. an alkyl-substituted olefin.   33  Scheme 1.31. Competition experiment to examine the relative rate of cyclization onto a silyl enol ether vs. a gem-dialkyl substituted olefin. Based on the results of the competition experiment depicted in Scheme 1.29, we had hypothesized that silyl enol ethers may increase the rate of 6-exo cyclizations such that they outcompete 1,5-hydrogen atom transfer.  However,  further competition experiments (Scheme 1.30 and Scheme 1.31) suggested that siloxy substitution of the alkene acceptor accelerates the rate of alkoxy radical cyclization to the same extent as gem-dialkyl substitution.  Given the low chemoselectivity for 6-exo cyclization onto gem-dialkyl substituted alkenes, we anticipated that 6-exo cyclization onto a silyl enol ether would not prove to be a viable strategy for tetrahydropyran synthesis.  To our delight, the alkoxy radical generated from N- alkoxyphthalimide 1.108 cyclized onto the silyl enol ether with excellent chemoselectivity relative to the competing 1,5-hydrogen atom transfer pathway (Scheme 1.32).  The yield of tetrahydropyran 1.149 was significantly higher than what had been observed in analogous cyclizations onto gem-dialkyl substituted alkenes.36  A possible explanation for this discrepancy is that the competition substrates can measure rate differences up to a certain threshold.  The cyclization rates of both processes are extremely fast, and thus subtle differences may be impossible to observe this method.  6-Exo cyclizations, however, are slower processes and, therefore, differences in electron density are expressed to a greater degree.  The cyclization of silyl enol ether 1.108 represents the first example of a high-yielding 6-exo alkoxy radical cyclization in the presence of abstractable hydrogen atoms. This advance has the potential to 34 provide a reliable and predictable new reaction for use in the total synthesis of tetrahydropyran- containing natural products.  Scheme 1.32. 6-Exo cyclization of silyl enol ether 1.108 to form tetrahydropyran 1.149 and alcohol 1.150. In addition to the significant rate acceleration, utilizing silyl enol ethers as acceptors for alkoxy radical cyclizations provides access to synthetically valuable products.  In earlier examples of alkoxy radical cyclizations onto simple alkenes, the synthetic utility of the cyclization products could be increased by trapping the carbon radicals with functional groups such as a halogen or sulfur.  However, these methods do not provide easy access to α- hydroxylated oxacycles, a motif common in bioactive tetrahydrofuran- and tetrahydropyran- containing natural products.47  In contrast, cyclizations onto silyl enol ethers provide oxacyclic products functionalized with a modular protected aldehyde or alcohol substituent, which can act as a handle for further transformations.   One drawback of this methodology, as well as most other alkoxy radical methods, is the paucity of stable alkoxy radical precursors that react under organotin-free conditions.  The ideal alkoxy radical precursor is one that is bench-stable, can be carried through a number of synthetic transformations and reacts to generate the alkoxy radical under mild, non-toxic conditions.  N- Alkoxyphthalimides satisfy the former requirements, but alkoxy radical generation from these precursors requires stoichiometric amounts of tributyltin hydride, a highly neurotoxic reagent.  Tris(trimethylsilyl)silane may be used in place of the tributyltin hydride,48 however it is an expensive reagent and reacts to generate the alkoxy radical at a much slower rate than under 35 stannyl radical conditions.  Many other alkoxy radical precursors exhibit low levels of chemical stability or necessitate the use of high-intensity UV irradiation.  Thus the utility of our methodology, as well as alkoxy radical methodologies in general, would be greatly improved if a better alkoxy radical generation method were developed.  Our efforts towards this goal will be elaborated upon in Chapter 3. 1.7 Future Work  Scheme 1.33. Proposed alkoxy radical cyclization onto a silyl ketene acetal. We have demonstrated that a significant increase in rate of alkoxy radical cyclizations can be achieved by siloxy substitution of the alkene acceptor.  We hypothesized that utilizing an acceptor with even higher electron density, such as a silyl ketene acetal, could further increase the rate and chemoselectivity of these cyclizations.  Futhermore, cyclization onto a silyl ketene acetal would provide oxacyclic products in the aldehyde oxidation state at the α-position (Scheme 1.33).  Unfortunately, the synthesis of these substrates was significantly more challenging.  Unlike silyl enol ethers, which can be generated by soft enolization conditions, synthesis of silyl ketene acetals necessitates the use a strong base such as LDA.  Synthesis of silyl ketene acetal 1.151 (Scheme 1.34) was unsuccessful as the strongly basic conditions needed for the enolization resulted in decomposition of the starting material.  36  Scheme 1.34. Attempted synthesis of cyclization precursor 1.151. While these synthetic challenges may impede the development of silyl ketene acetals as acceptors for alkoxy radical cyclizations, they may be more suitable as acceptors for intermolecular alkoxy radical additions.  To date, there are no synthetically useful examples of this reaction.  Intermolecular alkoxy radical additions to π-systems are significantly slower than their intramolecular counterparts and therefore suffer from low chemoselectivity relative to other intra- and intermolecular processes.  For example, the tert-butoxy radical adds to the π-system of norbornene with a rate constant of 1.2x106 M-1s-1 at 28 °C,49 two orders of magnitude slower than cyclization of the 4-penten-1-oxyl radical.  Increasing the electron density of the acceptor may increase the rate of addition of intermolecular alkoxy radical addition.   Scheme 1.35. Intermolecular alkoxy radical addition to silyl ketene acetal 1.156.  Treatment of N-alkoxyphthalimide 1.155 with stannyl radical conditions in the presence of silyl ketene acetal 1.156 resulted in a mixture of products (Scheme 1.35).  In addition to benzyl alcohol (1.159), resulting from hydrogen atom transfer from tributyltin hydride to the alkoxy radical, we observed the addition product 1.157 and aldehyde 1.158 resulting from in situ 37 hydrolysis of addition product 1.157.  These products were observed in a 1:0.69:1 ratio by 1H NMR spectroscopy.  Considering the fact that the rate of hydrogen atom transfer to the alkoxy radical from tributyltin hydride is 6.6 x 108 M-1s-1 at 80 °C,4a this preliminary experiment suggests that the rate of addition of the benzyloxy radical to the alkene acceptor is accelerated by the oxygen substituents.  Quenching of the alkoxy radical by hydrogen atom transfer from tributyltin hydride is a competing pathway.  Thus, the yield of the addition product may be increased if the alkoxy radical is generated under hydride-free conditions.   1.8 Conclusion We have demonstrated the first example of an alkoxy radical cyclization onto a heteroatom- substituted acceptor.  The diastereoselectivity of 5-exo cyclizations was comparable to analogous cyclizations onto alkenes, with Z-silyl enol ethers exhibiting higher stereoselectivity than E-silyl enol ethers.  The utility of silyl enol ethers as alkoxy radical acceptors was demonstrated by the high chemoselectivity of these cyclizations.  Only products resulting from 5-exo cyclization were observed in substrates that could undergo a competing 1,5-hydrogen atom transfer reaction.  Cyclization also predominated over -fragmentation, even when the alkoxy radical could fragment to a highly stabilized benzyl radical.  We also utilized silyl enol ethers as the acceptor for a 6-exo cyclization to provide the corresponding tetrahydropyran product in high yield.  Prior to our work, formation of six-membered ring systems via alkoxy radical cyclization onto alkenes had been limited due to competing 1,5-hydrogen atom transfers.  The work presented in this chapter supports our hypothesis that increasing the electron density of the acceptor leads to an acceleration of the rate of addition of the alkoxy radical to an alkene relative to competing pathways. 38 In summary, we have found that oxygen-centred radicals chemoselectively cyclize onto silyl enol ethers with fewer side reactions than with alkenes to provide a synthetically general method for the formation of both 5- and 6-membered α-siloxy substituted oxacycles.  This high selectivity for heteroatom-centred radicals has the potential to provide a reliable and predictable new reaction for use in total synthesis. 39 1.9 Experimental 1.9.1 General Experimental All reactions were performed under a nitrogen atmosphere in flame-dried glassware. Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl.  Dichloromethane was distilled from calcium hydride. Thin layer chromatography (TLC) was performed on Whatman Partisil K6F UV254 pre-coated TLC plates. Chromatographic separations were effected over Fluka 60 silica gel. Triethylamine washed silica gel was stirred with triethylamine prior to packing. All chemicals were purchased from commercial sources and used as received. A KD-Scientific KDS100 syringe pump was used for all slow additions. Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected. Infrared (IR) spectra were obtained using a Thermo Nicolet 4700 FT-IR spectrometer. Proton nuclear magnetic resonance (1H NMR) spectra were recorded in deuterochloroform using a Bruker AV- 300 or AV-400 spectrometer. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded in deuterochloroform using a Bruker AV-300 or AV-400 spectrometer.  Chemical shifts are reported in parts per million (ppm) and are referenced to the centreline of deuterochloroform (7.27 ppm 1H NMR; 77.0 ppm 13C NMR). Low resolution mass spectra (LRMS) and high resolution mass spectra (HRMS) were recorded on either a Bruker Esquire-LC spectrometer (for LRMS) or a Waters/Micromass LCT spectrometer (for HRMS). 40 1.9.2 Syntheses of Silyl Enol Ethers 1.105, 1.106a,b,e and f  (Z)-5-(tert-Butyldimethylsilyloxy)pent-4-enyl 4-methylbenzenesulfonate (1.110): To a solution of 5-tosyloxypentanal40 (4.44 g, 17.3  mmol) and diisopropylethylamine (4.50 g, 34.6 mmol) in CH2Cl2 (90 mL) at 0 °C was added tert-butyldimethylsilyl trifluoromethanesulfonate (6.90 g, 26.0 mmol) dropwise over 5 min. The resulting solution was stirred for 1 h, then quenched with saturated NaHCO3 (20 mL) and extracted with CH2Cl2 (2x30 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a yellow oil. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded 6.4 g (100%) of silyl enol ether 1.110 (Z/E = >95:5) as a yellow oil. IR (neat) 2955, 1655, 1599, 1471 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.17 (d, J = 5.9 Hz, 1H), 4.34 (q, J = 7.4 Hz, 1H), 4.04 (t, J = 7.0 Hz, 2H), 2.45 (s, 3H), 2.10 (q, J = 7.3 Hz, 2H), 1.71 (qd, J = 7.1, 6.9 Hz, 2H), 0.90 (s, 9H), 0.11 (s, 6H); 13C NMR (100 MHz, CDCl3)  144.5, 139.7, 133.4, 129.7, 127.9, 108.0, 70.4, 28.8, 25.6, 21.6, 19.5, 18.2, -5.4; HRMS-ESI (m/z): [M+Na]+ calcd for C18H30O4SSiNa, 393.1532; found, 393.1525.   (Z)-1-(5-(tert-Butyldimethylsilyloxy)pent-4-enyloxy)pyridine-2(1H)-thione (1.105): A solution of 1.110 (5.80 g, 15.3 mmol), 1-hydroxypyridine-2(1H)-thione (2.80 g, 22.1 mmol), K2CO3 (8.93 g, 64.6 mmol) and NBu4HSO4 (750 mg, 2.2 mmol) in MeCN (43 mL) was stirred at 41 ambient temperature for 48 h in the dark. The slurry was then taken up in Et2O (30 mL) and washed with water (20 mL), 1 M NaOH (20 mL) and brine (20 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a brown oil. Purification by flash chromatography (3:1 hexanes/EtOAc) afforded 1.07 g (22%) of pyridinethione 1.105 as a bright yellow oil.  IR (neat) 2955, 2930, 2217, 1655, 1607, 1526, 1447, 1259 cm-1; 1H NMR (400 MHz, CDCl3)  7.78 (d, J = 7.0 Hz, 1H), 7.66 (dd, J = 8.6, 1.6 Hz, 1H), 7.14 (ddd, J = 8.7, 6.9, 1.6 Hz, 1H), 6.58 (td, J = 6.8, 2.0 Hz, 1H), 6.25 (d, J = 5.9 Hz, 1H), 4.49 (q, J = 7.0 Hz, 1H), 4.44 (t, J = 6.7 Hz, 2H), 2.30 (q, J = 7.4 Hz, 2H), 1.88 (qt, J = 6.9 Hz, 2H), 0.93 (s, 9H), 0.14 (s, 6H); 13C NMR (400 MHz, CDCl3)  175.7, 139.7, 138.1, 137.9, 132.7, 113.0, 108.7, 76.1, 30.9, 27.3, 25.6, 19.7, -5.4; HRMS-ESI (m/z): [M+H]+ calcd for C16H28NO2SiS, 326.1610. Found: 326.1607.   (Z)-2-(5-(tert-Butyldimethylsilyloxy)pent-4-enyloxy)isoindoline-1,3-dione (1.106a): To a solution of 1.110 (1.50 g, 4.0 mmol) and N-hydroxyphthalimide (1.00 g, 6.0 mmol) in DMF (8 mL) was added diisopropylethylamine (1.00 g, 8.0 mmol). The resulting red solution was heated to 90 °C for 5 h and then allowed to cool to ambient temperature.  The reaction was diluted with Et2O (10 mL) and washed with saturated NaHCO3 (3x10 mL) and brine (10 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a red oil. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded 916 mg (63%) of phthalimide 1.106a as a colourcolourless oil.  IR (neat) 2955, 1791, 1732, 1657, 1468 cm-1; 1H NMR (400 MHz, CDCl3)  7.82-7.92 (m, 2H), 7.75 (dd, J = 5.5, 3.1 Hz, 2H), 6.21 (d, J 42 = 5.9 Hz, 1H), 4.51 (q, J = 7.4 Hz, 1H), 4.22 (t, J = 7.2 Hz, 2H), 2.26 (q, J = 7.0 Hz, 2H), 1.87 (qt, J = 7.2 Hz, 2H), 0.92 (s, 9H), 0.13 (s, 6H); 13C NMR (100 MHz, CDCl3) 163.7, 139.4, 134.4, 129.0, 123.4, 108.7, 78.4, 28.1, 25.6, 19.7, 18.3, -5.4; HRMS-ESI (m/z): [M+Na]+ calcd for C19H27NO4SiNa, 384.1607. Found: 384.1603.   2-(5-Oxo-5-phenylpentyloxy)isoindoline-1,3-dione (1.113): To a solution of 5-bromo-1- phenylpentan-1-one41 (3.62 g, 15.0 mmol) and N-hydroxyphthalimide (3.67 g, 22.5 mmol) in DMF (30 mL) was added diisopropylethylamine (3.90 g, 30.0 mmol). The resulting red solution was heated to 90 °C for 5 h and then allowed to cool to ambient temperature.  The reaction was diluted with Et2O (30 mL) and washed with saturated NaHCO3 (3x20 mL) and brine (20 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a red oil. Purification by recrystallization (hexanes/EtOAc) afforded 2.19 g (44%) of phthalimide 1.113 as a white solid.  mp 118-120 °C; IR (neat) 2941, 1789, 1731, 1685, 1374 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.3 Hz, 2H), 7.78-7.92 (m, 2H), 7.74 (dd, J = 5.5, 3.3 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 4.26 (t, J = 6.2 Hz, 2H), 3.12 (t, J = 7.0 Hz, 2H), 1.82-2.08 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 199.8, 163.6, 136.9, 134.4, 132.9, 128.9, 128.5, 128.0, 123.4, 78.1, 37.8, 27.6, 20.4; HRMS-ESI (m/z): [M+H]+ calcd for C19H16NO4: 322.1079. Found: 322.1071.  43  (Z)-2-(5-(tert-Butyldimethylsilyloxy)-5-phenylpent-4-enyloxy)isoindoline-1,3-dione (1.106b): To a solution of 1.113 (1.00 g, 3.1 mmol) and diisopropylethylamine (0.80 g, 4.6 mmol) in CH2Cl2 (15 mL) at 0 °C was added tert-butyldimethylsilyl trifluoromethanesulfonate (1.20 g, 6.2 mmol) dropwise over 5 min. The resulting solution was stirred for 1 h, then quenched with saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (2x10 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a yellow oil. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded 1.12 g (87%) of silyl enol ether 1.106b (Z/E = >95:5) as a colourcolourless oil.  IR (neat) 2955, 2930, 1790, 1732, 1468 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.79-7.93 (m, 2H), 7.74 (dd, J = 5.5, 2.9 Hz, 2H), 7.44 (d, J = 6.6 Hz, 2H), 7.18-7.34 (m, 3H), 5.15 (t, J = 7.1 Hz, 1H), 4.26 (t, J = 6.8 Hz, 2H), 2.42 (q, J = 7.3 Hz, 2H), 1.94 (qd, J = 7.2, 7.0 Hz, 2H), 0.98 (s, 9H), -0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 163.5, 150.2, 139.5, 134.3, 128.9, 127.8, 127.4, 125.9, 123.4, 110.0, 78.2, 28.1, 25.8, 22.2, 18.2, -4.1; HRMS-ESI (m/z): [M+Na]+ calcd for C25H31NO4SiNa: 460.1920. Found: 460.1914.   2-(5-(tert-Butyldimethylsilyloxy)-2-ethylpentyloxy)isoindoline-1,3-dione (1.115): To a solution of ethyl 2-ethylpent-4-enoate42 (3.47 g, 22.2 mmol) in THF (80 mL) at 0 °C was added a borane solution in THF (35 mL, 1 M) dropwise over 1 h. After the mixture was stirred at 0 °C for 3 h, H2O (5 mL) was cautiously added. The stirring was continued for an additional 15 min, 44 and then an aqueous NaOH solution (15 mL, 20%) was added along with an aqueous solution of H2O2 (5 mL, 30%). The reaction was stirred at 0 °C for 30 min and then saturated with solid K2CO3, and the layers were separated. The aqueous layer was extracted with CH2C12 (3x30 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a colourcolourless oil. Purification by flash chromatography (1:1 hexanes/EtOAc) provided 1.44 g of the alcohol as a colourcolourless oil. The crude alcohol was dissolved in CH2Cl2 (24 mL).  tert-Butyldimethylchlorosilane (2.0 g, 13.5 mmol) and triethylamine (1.82 g, 18.0 mmol) were added, and the solution was stirred at ambient temperature for 3 h. The mixture was then washed with brine (20 mL) and extracted with CH2Cl2 (20 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a colourcolourless oil. Purification by flash chromatography (9% EtOAc in hexanes) provided 1.89 g of the silyl ether as a colourcolourless oil. The silyl ether was dissolved in Et2O (32 mL) and added dropwise over 10 min to a suspension of LiAlH4 (220 mg, 5.8 mmol) in Et2O (16 mL) at 0 °C. After stirring for 10 min, water (10 mL) was cautiously added to the solution and the mixture was stirred for an additional 10 min. The layers were separated and the aqueous layer was extracted with Et2O (20 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide 1.50 g of the crude alcohol a colourless oil, which was used without further purification. The crude alcohol was dissolved in a solution of THF (20 mL), PPh3 (2.08 g, 7.9 mmol), and N- hydroxyphthalimide (1.30 g, 7.9 mmol). Diisopropyl azodicarboxylate (1.60 g, 7.9 mmol) was added dropwise over 2 h. The resulting mixture was stirred for 20 h, then extracted with Et2O (20 mL) and washed with saturated NaHCO3 (3x20 mL). Purification by flash chromatography (50% EtOAc in hexanes) afforded 1.30 g (15% over 4 steps) of phthalimide 1.115 as a colourless 45 oil.  IR (neat) 2956, 2858, 1790, 1736, 1468, 1371 cm-1; 1H NMR (400 MHz, CDCl3)  7.77- 7.87 (m, 2H), 7.73 (dd, J = 5.2, 3.4Hz, 2H), 4.09 (d, J = 6.1 Hz, 2H), 3.63 (t, J = 6.2 Hz, 2H), 1.75-1.89 (m, 1H), 1.39-1.69 (m, 6H), 0.96 (t, J = 7.5 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) 163.4, 134.3, 128.9, 123.3, 81.0, 63.3, 38.4, 29.8, 26.5, 25.9, 23.4, 18.3, 10.7, -5.3; HRMS-ESI (m/z) [M+Na]+ calcd for C21H33NO4NaSi: 414.2077. Found: 414.2070.   2-(2-Ethyl-5-hydroxypentyloxy)isoindoline-1,3-dione (1.116): A solution of 1.115 (1.30 g, 3.3 mmol) and p-toluenesulfonic acid monohydrate (632 mg, 3.3 mmol) in methanol (15 mL) was stirred at ambient temperature for 2 h. The mixture was then diluted with Et2O (20 mL) and washed with brine (15 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a colourless oil. Purification by flash chromatography (1:1 hexanes/EtOAc) afforded 855 mg (94%) of alcohol 1.116 as a colourless oil.  IR (neat) 3398, 2938, 2876, 1788, 1732, 1466 cm-1; 1H NMR (400 MHz, CDCl3) 7.81- 7.88 (m, 2H), 7.72-7.79 (m, 2H), 4.17 (dd, J = 8.53, 5.18 Hz, 1H), 4.10 (dd, J = 8.53, 6.40 Hz, 1H), 3.71 (q, J = 5.69 Hz, 2H), 1.74-1.85 (m, 1H), 1.67-1.73 (m, 2H), 1.46-1.60 (m, 4H), 0.98 (t, J = 7.46 Hz, 3H); 13C NMR (100 MHz, CDCl3)  163.2, 134.2, 128.5, 123.1, 80.4, 62.4, 38.2, 29.4, 26.2, 23.2, 10.6 ; HRMS-ESI (m/z) [M+Na]+ calcd for C15H19NO4Na: 300.1212. Found: 300.1211.  46  (Z)-2-(5-(tert-Butyldimethylsilyloxy)-2-ethylpent-4-enyloxy)isoindoline-1,3-dione (1.106e): Pyridinium chlorochromate (869 mg, 4.0 mmol) was added in one portion to a solution of 1.116 (855 mg, 3.1 mmol) in CH2Cl2 (16 mL). The solution was stirred at ambient temperature for 5 h, then filtered through a three-layered pad of alumina, Celite and silica. The solvent was removed by rotary evaporation to give 580 mg of the crude aldehyde as a colourless oil, which was used without further purification. To a solution of the crude aldehyde (580 mg, 2.1 mmol) and diisopropylethylamine (850 mg, 3.2 mmol) in CH2Cl2 (10 mL) at 0 °C was added tert- butyldimethylsilyl trifluoromethanesulfonate (542 mg, 4.2 mmol) dropwise over 5 min. The resulting solution was stirred for 1 h, then quenched with saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (2x10 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a yellow oil. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded 530 mg (44% over two steps) of silyl enol ether 1.106e (Z/E = 84:16) as a colourless oil.  IR (neat) 2957, 1790, 1732, 1655, 1467, 1362 cm-1; 1H NMR (400 MHz, CDCl3) 7.77-7.86 (m, 2H), 7.70-7.77 (m, 2H), 6.33 (d, J = 11.9 Hz, trans 0.1H), 6.25 (d, J = 5.8 Hz, cis 0.8H), 4.98 (ddd, J = 11.8, 8.1, 7.8 Hz, 0.1H), 4.47-4.56 (q, J = 7.3 Hz, 0.8H), 4.01-4.16 (m, 2H), 2.05-2.35 (m, 2H), 1.72-1.91 (m, 1H), 1.54-1.67 (m, 1H), 1.34-1.53 (m, 1H), 0.98 (t, J = 7.5 Hz, 3H), 0.90 (s, 9H), 0.11 (s, 6H); 13C NMR (100 MHz, CDCl3)  163.4, 139.8, 134.3, 128.9, 123.3, 107.0, 81.3, 39.2, 25.5, 24.1, 23.3, 18.1, 10.9, -5.5 ; HRMS-ESI (m/z) [M+Na]+ calcd for C12H31NO4NaSi: 412.1920. Found: 412.1917. 47  2-(2-Phenyl-5-(triethylsilyloxy)pentyloxy)isoindoline-1,3-dione (1.118): To a solution of methyl 2-phenylpent-4-enoate43 (4.36 g, 25 mmol) in THF (80 mL) at 0 °C was added a borane solution in THF (35 mL, 1 M) dropwise over 1 h. After the mixture was stirred at 0 °C for 3 h, H2O (5 mL) was cautiously added. The stirring was continued for an additional 15 min, and then an aqueous NaOH solution (15 mL, 20%) was added along with an aqueous solution of H2O2 (5 mL, 30%). The reaction was stirred at 0 °C for 30 min and then saturated with solid K2CO3, and the layers were separated. The aqueous layer was extracted with CH2C12 (3x30 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a colourless oil. Purification by flash chromatography (1:1 hexanes/EtOAc) to provide 1.50 g of the alcohol. The alcohol was dissolved in CH2Cl2 (24 mL).  Chlorotriethylsilane (1.63 g, 10.8 mmol) and triethylamine (1.45 g, 14.4 mmol) were added, and the solution was stirred at ambient temperature for 3 h. The mixture was then washed with brine (20 mL) and extracted with CH2Cl2 (20 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a colourless oil. Purification by flash chromatography (9% EtOAc in hexanes) provided 1.80 g of the silyl ether as a colourless oil. The crude silyl ether was dissolved in Et2O (32 mL) and added dropwise over 10 min to a suspension of LiAlH4 (220 mg, 5.8 mmol) in Et2O (16 mL) at 0 °C. After stirring for 10 min, water (10 mL) was cautiously added to the solution and the mixture was stirred for an additional 10 min. The layers were separated and the aqueous layer was extracted with Et2O (20 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide 1.71 g of the crude alcohol as a colourless oil. The crude alcohol 48 was dissolved in a solution of THF (20 mL), PPh3 (1.23 g, 5.8 mmol), and N- hydroxyphthalimide (1.98 g, 7.5 mmol). Diisopropyl azodicarboxylate (1.52 g, 7.5 mmol) was added dropwise over 2 h. The resulting mixture was stirred for 20 h, then extracted with Et2O (20 mL) and washed with saturated NaHCO3 (3x20 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a yellow oil. Purification by flash chromatography (1:1 CH2Cl2/hexanes) afforded 1.21 g (11% over 4 steps) of phthalimide 1.118 as a colourless oil.  IR (neat) 3029, 2952, 2875, 1790, 1732, 1605, 1373 cm-1; 1H NMR (400 MHz, CDCl3)  7.62-7.88 (m, 4H), 7.11-7.38 (m, 5H), 4.43 (dd, J = 9.0, 6.7 Hz, 1H), 4.30 (dd, J = 9.0, 7.4 Hz, 1H), 3.48-3.65 (m, 2H), 3.03-3.25 (m, 1H), 1.99-2.19 (m, 1H), 1.62-1.77 (m, 1H), 1.38-1.58 (m, 2H), 0.94 (t, J = 7.8 Hz, 9H), 0.57 (q, J = 7.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 163.3, 141.0, 134.3, 128.9, 128.5, 127.8, 126.7, 123.3, 82.0, 62.7, 44.7, 30.3, 29.0, 6.7, 4.4; HRMS-ESI (m/z) [M+Na]+ calcd for C25H33NO4NaSi: 462.2077. Found: 462.2072.   5-(1,3-Dioxoisoindolin-2-yloxy)-4-phenylpentanal (1.119): Dimethylsulfoxide (481 mg, 6.2 mmol) was added dropwise over 2 min to a solution of oxalyl chloride (391 mg, 3.1 mmol) in CH2Cl2 (10 mL) at –78 °C. After stirring for 20 min, a solution of 1.118 (1.21 g, 2.8 mmol) in CH2Cl2 (5.6 mL) was added over 30 min. After stirring for 1 h at –78 °C, triethylamine (1.40 g, 14 mmol) was added and the reaction mixture was stirred for 30 min.  The solution was then warmed to ambient temperature and stirred for 16 h. The mixture was then washed with brine (10 mL) and extracted with CH2Cl2 (15 mL). The organic extracts were dried over Na2SO4, 49 filtered, and the solvent was removed by rotary evaporation to provide a yellow oil. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded 263 mg of aldehyde 1.119 (29%) as a colourless oil, as well as 617 mg (51%) of 1.118 as recovered starting material.  IR (neat) 3023, 1790, 1732, 1373 cm-1; 1H NMR (400 MHz, CDCl3)  9.68 (s, 1H), 7.62-7.82 (m, 4H), 7.23- 7.35 (m, 2H), 7.13-7.23 (m, 3H), 4.37 (dd, J = 9.0, 5.9 Hz, 1H), 4.28 (t, J = 8.7 Hz, 1H), 3.01- 3.18 (m, 1H), 2.30-2.52 (m, 3H), 1.76-2.04 (m, 1H); 13C NMR (100 MHz, CDCl3)  201.7, 163.2, 139.7, 134.3, 128.6, 127.7, 127.0, 123.3, 81.4, 43.9, 41.3, 25.0. MS-ESI (m/z): [M+Na]+ 346.2.   (Z)-2-(5-(tert-Butyldimethylsilyloxy)-2-phenylpent-4-enyloxy)isoindoline-1,3-dione (1.106f): To a solution of 1.119 (263 mg, 0.8 mmol) and diisopropylethylamine (207 mg, 1.2 mmol) in CH2Cl2 (4 mL) at 0 °C was added tert-butyldimethylsilyl trifluoromethanesulfonate (317 mg, 1.6 mmol) dropwise over 5 min. The resulting solution was stirred for 1 h, then quenched with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2x5 mL). The combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a yellow oil. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded 200 mg (58%) of silyl enol ether 1.106f (Z/E = 72:28) as a yellow oil.  IR (neat) 2929, 2856, 1791, 1735, 1659, 1468 cm-1; 1H NMR (400 MHz, CDCl3)  7.67-7.86 (m, 4H), 7.11-7.32 (m, 5H), 6.23 (d, J = 11.9 Hz, 0.4H), 6.19 (d, J = 5.8 Hz, 0.6H), 4.88 (dt, J = 11.9, 7.8 Hz, 0.4H), 4.46-4.53 (m, 0.7H), 4.39-4.46 (m, 1H), 4.27-4.39 (m, 1H), 3.17-3.28 (m, 0.7H), 3.09-3.17 (m, 0.5H), 2.57- 2.71 (m, 1H), 2.45-2.52 (m, 0.8H), 2.30-2.37 (m, 0.7H), 0.91 (s, 6H), 0.86 (s, 4H), 0.10 (s, 1H), 50 0.09 (s, 2H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3) 163.2, 142.0, 141.3, 140.6, 139.8, 134.3, 134.2, 128.8, 128.3, 128.2, 127.8, 127.7, 126.6, 126.4, 123.3, 123.2, 107.6, 106.7, 81.3, 80.9, 77.2, 60.3, 45.4, 44.7, 30.8, 27.3, 25.6, 25.5, 20.9, 18.2, 18.1, 17.9, 14.1, -3.7, -5.4, -5.5 ; HRMS- ESI (m/z) [M+Na]+ calcd for C25H31NO4NaSi: 460.1920. Found: 460.1907.  1.9.3 Cyclizations of Silyl Enol Ethers 1.105, 1.106a,b,e and f  2-((tert-Butyldimethylsilyloxy)(tetrahydrofuran-2-yl)methylthio) pyridine (1.120): A solution of silyl enol ether 1.104 (1.07 g, 3.3 mmol) in degassed benzene (11 mL) was irradiated with a 100W incandescent lightbulb for one hour. The solvent was then removed by rotary evaporation to provide a yellow oil. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded 1.00 g (93%) of tetrahydrofuran 1.120 (1:1 mixture of diastereomers) as a yellow oil. IR (neat) 2929, 2857, 1578, 1454, 1415, 1252 cm-1; 1H NMR (400 MHz, CDCl3)   8.26-8.39 (m, 1H), 7.34-7.44 (m, 1H), 7.05-7.21 (m, 1H), 6.82-6.96 (m, 1H), 6.08 (dd, J = 8.0, 4.1 Hz, 1H), 4.10-4.20 (m, 1H), 3.80-3.89 (m, 1H), 3.74 (dddd, J = 14.8, 7.6, 7.5, 5.3 Hz, 1H), 1.69-1.99 (m, 4H), 0.77 (s, 9H), 0.01 (s, 4H), -0.10 (s, 1.5H), -0.14 (s, 1.5H); 13C NMR (400 MHz, CDCl3) 158.1, 149.4, 149.2, 136.0, 136.0, 128.3, 123.7, 123.4, 119.8, 119.7, 82.4, 82.3, 82.0, 81.2, 69.2, 69.0, 28.3, 26.5, 26.3, 25.7, 18.0, -4.6, -4.7, -5.1, -5.2; HRMS-ESI (m/z): [M+Na]+ calcd for C16H27NO2SiS, 348.1429; found, 348.1427.    51 Cyclizations to form tetrahydrofurans 2.121a, b, e, f NMR-scale Cyclization Procedure To a solution of 1.106a (3.6 mg, 0.01 mmol), AIBN (0.16 mg, 0.01 mmol) and trimethoxybenzene (0.55 mg, 0.0033 mmol, 0.33 equiv.) in d6-benzene (0.5 mL) was added either Bu3SnH (3.8 mg, 0.013 mmol) or (TMS)3SiH (3.2 mg, 0.013 mmol). The solutions were heated to 90 °C in NMR tubes fitted with J. Young valves. After 18 h, the resulting solutions were analyzed by 1H NMR spectroscopy. The yield of tetrahydrofuran 2.121a was determined to be >95% for each reaction, based using 1,3,5-trimethoxybenzene as an internal standard.  General Cyclization Procedure A solution of Bu3SnH (1.3 equiv.) and AIBN (0.1 equiv.) in degassed benzene (2 mL) was added by syringe pump to a refluxing solution of silyl enol ether in degassed refluxing benzene (0.02 M) at a rate of 1.0 mL/h. After refluxing for an additional 2 h, the solution was allowed to cool to room temperature and the solvent was removed by rotary evaporation. Purification by flash chromatography afforded the cyclized products.  General Deprotection Procedure for Sterechemistry Determination An NMR sample of the tetrahydrofuran (5 mg) was dissolved in MeOH (1 mL) and p- toluenesulfonic acid monohydrate (10 mg, 0.053 mmol) was added. After stirring for 4-16 h, the solution was diluted with Et2O (2 mL) and washed with water (2 mL). The solvent was removed by rotary evaporation a crude oil. The NMR spectra of the crude alcohols were compared with literature compounds.  52 tert-Butyldimethyl((tetrahydrofuran-2-yl)methoxy)silane (1.121a): Silyl enol ether 1.106a (296 mg, 0.8 mmol) was subjected to the general cyclization procedure. Purification by flash chromatography (98:2 hexanes/EtOAc) afforded 90 mg (52%) of tetrahydrofuran 1.121a as a colourless oil.  IR (neat) 2928, 2857, 1472, 1462 cm-1; 1H NMR (400 MHz, CDCl3)  3.90-4.02 (m, 1H), 3.79-3.87 (m, 1H), 3.70-3.79 (m, 1H), 3.53-3.65 (m, 2H), 1.78-1.96 (m, 3H), 1.60-1.75 (m, 1H), 0.89 (s, 9H), 0.05 ppm (s, 6H); 13C NMR (100 MHz, CDCl3)  79.4, 68.4, 65.8, 27.8, 25.9, 25.7, 18.4, -5.4; HRMS-ESI (m/z): [M+Na]+ calcd for C11H24O2SiNa, 239.1443; found, 239.1448.  tert-Butyldimethyl(phenyl(tetrahydrofuran-2-yl)methoxy)silane (1.121b): Silyl enol ether 1.106b (550 mg, 1.3 mmol) was subjected to the general cyclization procedure. Purification by flash chromatography (98:2 hexanes/EtOAc) afforded 262 mg (69%) of tetrahydrofuran 1.121b (cis:trans = 67:33) as a colourless oil.  The tetrahydrofuran was subjected to the general deprotection procedure and the relative configuration was confirmed by comparison to the desilylated alcohol.a IR (neat) 2955, 2927, 2857, 1472, 1462 cm-1; 1H NMR (400 MHz, CDCl3) 7.19-7.44 (m, 5H), 4.79 (d, J = 4.3 Hz, 0.7 H, cis), 4.69 (d, J = 5.5 Hz, 0.3 H, trans), 4.02-4.12 (m, 0.3H), 3.94-4.02 (m, 0.7H), 3.89 (q, J = 6.9 Hz, 0.7H), 3.65-3.82 (m, 1.3H), 1.87-2.05 (m, 1.5H), 1.75-1.85 (m, 0.8H), 1.60-1.75 (m, 1.8H), 0.84-0.96 (m, 9H), 0.04-0.09 (m, 3H), -0.05 (s, 1H), -0.09 (s, 2H)  δ 13C NMR (100 MHz, CDCl3) δ 142.6, 141.8, 127.9, 127.7, 127.0, 126.3, 84.1, 83.2, 77.2, 76.5, 68.8, 68.4, 27.0, 26.1, 25.8, 25.8, 25.6, 18.2, -4.8, -4.9; HRMS-ESI (m/z) [M+Na]+ calcd for C17H28O2NaSi: 315.1756. Found: 315.1752.                                                  a Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Org. Chem. 2005, 70, 2342. b Miura, K.; Okajima, S.; Hondo, T.; Nakagawa, T.; Takahashi, T. Hosomi, A. J. Am. Chem. Soc. 53  tert-Butyl((4-ethyltetrahydrofuran-2-yl)methoxy)dimethylsilane (1.121e): Silyl enol ether 1.106e (325 mg, 0.8 mmol) was subjected to the general cyclization procedure. Purification by flash chromatography (98:2 hexanes/EtOAc) afforded 168 mg (86%) of tetrahydrofuran 1.121e (cis:trans = 58:42). The relative configuration was determined by analogy to tetrahydrofuran 1.121f. IR (neat) 2958, 2928, 2858, 1463, 1361, 1254 cm-1; 1H NMR (400 MHz, CDCl3) 3.85-4.09 (m, 2H), 3.45-3.70 (m, 2H), 3.38 (dt, J = 13.8, 8.0 Hz, 1H), 2.01-2.22 (m, 1.6H), 1.89 (ddd, J = 12.6, 7.7, 5.3 Hz, 0.4H), 1.51-1.69 (m, 1.3H), 1.34-1.48 (m, 2H), 1.20-1.33 (m, 0.7H), 0.81-0.98 (m, 13H), 0.07 (s, 6H); 13C NMR (100 MHz, CDCl3)  80.1, 79.1, 73.6, 73.3, 66.0, 41.7, 40.6, 34.6, 34.0, 25.9, 18.3, 12.9, 12.8, -5.4; HRMS-ESI (m/z) [M+Na]+ calcd for C13H28O2NaSi: 267.1756. Found: 267.1762.  tert-Butyldimethyl((4-phenyltetrahydrofuran-2-yl)methoxy)silane (1.121f): Silyl enol ether 1.106f (200 mg, 0.46 mmol) was subjected to the general cyclization procedure. Purification by flash chromatography (98:2 hexanes/EtOAc) afforded 111 mg (82%) of tetrahydrofuran 1.121f as a colourless oil (cis:trans = 72:28). The tetrahydrofuran was subjected to the general deprotection procedure and the relative configuration was confirmed by comparison to the desilyled alcohol.b  IR (neat) 2929, 2857, 1604, 1472 cm-1;  1H NMR (400 MHz, CDCl3)  7.19-7.39 (m, 5H), 4.09- 4.34 (m, 2H), 3.73-3.85 (m, 2H), 3.65-3.73 (m, 1H), 3.34-3.52 (m, 1H), 2.36-2.46 (m, 0.6H), 2.28 (ddd, J = 12.8, 8.1, 5.0 Hz, 0.4H), 2.06-2.13 (m, 0.4H), 1.90-1.98 (m, 0.6H), 0.94 (s, 9H),                                                  b Miura, K.; Okajima, S.; Hondo, T.; Nakagawa, T.; Takahashi, T. Hosomi, A. J. Am. Chem. Soc. 2000, 122, 11348. 54 0.12 (s, 6H); 13C NMR (100 MHz, CDCl3) 142.3, 141.7, 128.5, 127.3, 126.5, 126.4, 80.5, 79.7, 74.8, 74.6, 65.9, 65.7, 45.5, 44.5, 36.6, 36.1, 25.9, 25.8, 18.4, -5.3; HRMS-ESI (m/z) [M+Na]+ calcd for C17H28O2NaSi: 315.1756. Found: 315.1762.  1.9.4 Intermolecular Alkoxy Radical Additions  A solution of Bu3SnH (36 mg, 0.22 mmol) and AIBN (36 mg, 0.22 mmol) in d6-benzene (2 mL) was added by syringe pump to a refluxing solution of N-alkoxyphthalimide 1.155 (402 mg, 1.08 mmol) and silyl ketene acetal 1.156 (402 mg, 1.08 mmol) in d-benzene (x mL) at a rate of 1.0 mL/h. After refluxing for an additional 2 h, the solution was allowed to cool to room temperature and an aliquot was taken directly for 1H NMR analysis. Analysis of the 1H NMR spectrum showed no remaining N-alkoxyphthalimide 1.155, and products 1.157, 1.158 and 1.159 in a 1:0.69:1 ratio, respectively.        55    CHAPTER TWO: Construction of Protected Hydroxylated Pyrrolidines Using Aminyl Radical Cyclizations  56 Chapter 2. Construction of Protected Hydroxylated Pyrrolidines Using Aminyl Radical Cyclizations 2.1 Introduction Pyrrolidines are a component of many biologically active natural products and pharmaceuticals.  This structural motif can be rapidly constructed from linear precursors by radical cyclization.  The majority of radical-based approaches to pyrrolidine synthesis utilize carbon radicals.  Despite their potential for rapid heterocycle synthesis, aminyl radical cyclizations to form carbon-nitrogen bonds have not received the same level of attention due to both kinetic and thermodynamic considerations.  This chapter will provide an overview of the applications of carbon and aminyl radical cyclizations to pyrrolidine synthesis and the challenges inherent in these methodologies. Aminyl radical cyclizations are notably slower than their alkoxy and carbon radical analogs.  Reaction yields suffer as a result of reversibility, leading to mixtures of cyclic and acyclic products.50  Given our previous work on chemoselective alkoxy radical cyclizations onto silyl enol ethers (Chapter 1), we hypothesized that this radical acceptor could also improve the efficiency of aminyl radical cyclizations by dative stabilization of the carbon radical intermediate formed upon cyclization.  The results of studies on the substrate scope and diastereoselectivity of aminyl radical cyclizations onto silyl enol ethers will be discussed. This new aminyl radical cyclization was subsequently applied to the synthesis of a silyl- protected analog of CYB-3, a polyhydroxylated alkaloid.  In the course of optimizing the key cyclization step, we found that the diastereoselectivity was dependent on a complex combination of sterics and olefin geometry.  Prior to our work, little was known about how much the significant increase in electron density of the alkene acceptor affects the diastereoselectivity of 57 5-exo radical cyclizations.  An analysis of the influences of stereoelectronic effects in the Beckwith-Houk transition states will be presented. 2.2 Carbon-Centred Radical Strategies for Pyrrolidine Synthesis An early report by Padwa explored the application of carbon-radical cyclizations to the synthesis of pyrrolidines (Scheme 2.1).51  Initial attempts to cyclize thiobutenyl amine 2.1a were unsuccessful, yielding only acyclic amine 2.4a resulting from quenching of the carbon radical by tributyltin hydride.  Dative stabilization of the carbon radical by the adjacent nitrogen presumably slows the rate of cyclization such that hydrogen transfer is predominant.52  Substituting the nitrogen with an electron-withdrawing sulfonimide resulted into some pyrrolidine (2.3b) formation, albeit in low yield.  Scheme 2.1. Attempts at pyrrolidine formation by carbon radical cyclization. High-yielding carbon radical cyclizations to form pyrrolidines were possible if the initial carbon radical is beta to the nitrogen.  Treatment of bromide 2.5a with tributyltin hydride and catalytic AIBN afforded 87% yield of pyrrolidine 2.6a (Scheme 2.2).  Geminally substituted olefin 2.5b cyclized to give exclusively the 5-exo product 2.6b in 92% yield.  This regioselectivity is in contrast to cyclizations of related substrates containing only carbon atoms, which afford mixtures of 5-exo and 6-endo products (exo:endo = 40:60).53  Padwa postulated that 58 the high regioselectivity encountered in the nitrogen-containing substrates is a result of the shorter C-N bond, which promotes the 5-exo trig cyclization mode.  Scheme 2.2. Pyrrolidine formation by radical cyclization. Bertrand also investigated carbon radical strategies for pyrrolidine synthesis.54  Like Padwa, he focused on the formation of the 3,4 carbon-carbon bond of the pyrrolidine ring from an acyclic precursor.  Bertrand’s strategy, however, relied on sulfenyl-radical mediated generation of the carbon radical instead of the more traditional stannyl-radical approach (Scheme 2.3).  Sulfinyl radicals are easily generated from photolysis of sulfonyl halides or phenylselenosulfonates and add readily to unsaturated systems.55  After cyclization of carbon radical intermediate 2.8, the resultant carbon radical (2.9) is trapped by either a halogen or selenium radical, depending on which sulfenyl radical source is employed.  In this way, pyrrolidines with two new functionalities can be constructed from synthetically simple linear precursors.  These cyclizations are selective for the cis isomer; for example, tosyl-amine 2.11 cyclizes to give pyrrolidine 2.12 in a diastereomeric ratio of 77:23 (Scheme 2.3).  Similar approaches to pyrrolidine synthesis by addition of carbon radicals to diallyl amine derivatives have been reported by Ciufolini,56 Studer57 and Zard.58 59  Scheme 2.3. Mechanism of sulfenyl radical-mediated cyclization.   Scheme 2.4. Sulfenyl radical-mediated cyclization to form pyrrolidine 2.12. The sulfinyl-radical mediated strategy employed in Scheme 2.3 was investigated as a potential route toward kainic acid (2.13), a marine natural product with potent neurotransmitting activity (Scheme 2.5).59  Bertrand envisioned that a sulfenyl-radical mediated cyclization could yield intermediate 2.14.60  The sulfonyl group could be used to install a carboxylic acid and oxidative elimation of the selenide could furnish the isopropenyl chain.  While amine 2.16 cyclized to provide only the desired 2,3-trans diastereomers, selectivity was poor with respect to the 3,4 configuration (Scheme 2.6).  Furthermore, treatment of the 3,4-cis diastereomer with hydrogen peroxide provided a mixture of oxidative elimination products.  Oxidative elimination of the trans diastereomer provided higher regioselectivity (92:8) of the desired isopropenyl chain. However, the configuration of the product was not suitable for kainic acid.  Thus, this methodology had to be modified for the synthesis of kainic acid. 60  Scheme 2.5. Retrosynthetic analysis of kainic acid (2.13).   Scheme 2.6. Sulfenyl radical-mediated cyclization to form pyrrolidines 2.17 and 2.18, followed by oxidative elimination of 2.17 to form pyrrolidines 2.19 and 2.20.   Scheme 2.7. Tandem addition-cyclization-elimination reaction to form pyrrolidine 2.23. Exploiting the reversibility of sulfinyl radical additions to alkenes, Bertrand devised a tandem addition-cyclization-elimination reaction that sets the pyrrolidine core and introduces the isoprenyl chain in one step (Scheme 2.7).  Cyclization of tosyl-substituted substrate 2.21 61 generates carbon radical 2.22, which undergoes -fragmentation, setting the requisite double bond.  The final fragmentation step eliminates a sulfinyl radical, which can further react with the starting material.  Treatment with a catalytic amount of p-tolueneselenosulphonate and heat provided diastereomeric pyrrolidines 2.19 and 2.25 in 76% yield (Scheme 2.8).  The diastereomeric ratio was improved when the reaction was performed at a lower temperature with photochemical initiation, albeit with some decrease of yield.  Elaboration of the cis-pyrrolidine (2.19) to kainic acid was later performed by Naito and coworkers in six steps.61    Scheme 2.8. Cyclization of amine 2.24 to form pyrrolidine 2.29, en route to kainic acid (2.13).  Naito’s contributions to radical strategies for pyrrolidine synthesis also include formation of the 3,4 carbon-carbon bond by ketyl radical addition to an oxime ether.62,63  Treatment of aldehyde 2.26 with tributyltin hydride and AIBN provided pyrrolidine 2.28 as a 30:70 mixture of cis and trans isomers in 54% isolated yield (Scheme 2.9).63a  Both the yield and diastereoselectivity were improved using samarium iodide as a single electron donor at low temperature.63b  This strategy was also successfully applied to the synthesis of six and seven membered nitrogen heterocycles, including the azacycloheptanol core of (–)-balanol.64 62  Scheme 2.9. Pyrrolidine formation by ketyl radical cyclization onto an oxime ether. In addition to the aforementioned radical carbon-carbon bond forming reactions, pyrrolidines can also be synthesized from acyclic precursors by direct C-N bond formation via carbon radical cyclization using imines as radical acceptors.  However, these reactions generally suffer from poor regioselectivity, giving mixtures of 6-endo and 5-exo products.  An early example of this mode of reactivity was reported by Takano during his synthesis of the Cryptostyline alkaloids (Scheme 2.10).65  Cyclization of aryl bromide 2.32 afforded tetrahydroisoquinoline 2.34 resulting from a 6-endo cyclization as the major product, along with 10% yield of pyrrolidine 2.33.  The 5-exo pathway can be promoted by increasing the sterics of the imine.  For example, Takano found that imines derived from acetophenone and benzophenone cyclized to give exclusively the pyrrolidine product (Scheme 2.11).65b    Scheme 2.10. Radical cyclization of imine 2.32.  63  Scheme 2.11. Exclusive 5-exo cyclization of imine 2.35 to form pyrrolidine 2.36.  The regioselectivity of aryl radical cyclization onto imines is significantly different than that of aryl radical cyclizations onto alkenes, which generally provide the 6-endo product in less than 1% yield.53  Warkentin proposed that this intriguing reversal of regioselectivity is a product of both kinetic and thermodynamic factors.  The formation of a C-C single bond is favoured over the C-N bond by approximately 10 kcal/mol.66  Furthermore, the geometry of the imine group favours the endo mode of cyclization; the C-C=N bond angle is 119°, whereas the C-C=C bond angle is 125°.  The tightening of this angle improves the alignment between the SOMO of the radical and *-obital of the imine in the transition state.  Scheme 2.12. Dependence of the ratio of 2.39 and 2.40 on Bu3SnH concentration. In the course of his studies on the regioselectivity of aryl radical cyclizations onto imines, Warkentin found that the regioselectivity of carbon radical additions to imines was highly influenced by the concentration and rate of addition of tributyltin hydride (Scheme 2.12).66a  Slow addition of 1.4 equivalents of tributyltin hydride and 0.35 equivalents of AIBN over 18 hours to a solution of bromide 2.38 in refluxing benzene afforded tetrahydroquinoline 2.39 and pyrrolidine 2.40 in a 16:1.  However, this ratio decreased to 4.2:1 when a single addition of 9.8 64 equivalents of Bu3SnH and 0.06 equivalents of AIBN was used.  This was unexpected, as the initial 6-endo or 5-exo cyclization rates should be independent of tin hydride concentration.  Warkentin postulated that other processes dependent on tin hydride concentration govern the product distribution.  For example, hydrogen transfer to the carbon radical formed after 5-exo cyclization could be slow due to stabilization of the radical by the adjacent nitrogen.  Although reversibility is not a factor in these reactions, Warkentin postulates that the 5-exo product could be lost to radical-radical couplings before hydrogen transfer could occur. Higher concentrations of tributyltin hydride would favour the hydrogen transfer, thus increasing the amount of 5-exo product formed. It is also possible that pyrrolidine 2.40 is formed through an alternate mechanism involving tin radical addition to the imine and hydrogen transfer to the resultant carbon radical, followed by abstraction of the bromide and homolytic substitution at nitrogen with loss of tributyl tin radical (Scheme 2.13).67  This process would be favoured at higher concentrations of tributyltin hydride.  Scheme 2.13. Proposed alternate mechanism for the formation of pyrrolidine 2.40. Azides have been shown to act as acceptors for carbon radicals, without the regioselectivity issues that have plagued analogous imine cyclizations.68  Spagnolo published the first example of a carbon radical addition to an azide (Scheme 2.14) utilizing diazonium salt 2.44 as the precursor 65 for aryl radical 2.45.69  The aryl radical radical, generated by reduction with an iodide ion, underwent cyclization onto an azide to generate carbazolyl radical 2.46.  This radical can either undergo hydrogen atom transfer to afford carbazole 2.47, or dimerize to afford 2.48.    Scheme 2.14. Carbon radical cyclization onto an azide. Kim later demonstrated the applicability of this methodology to the synthesis of pyrrolidines.70  Since azides are known to be susceptible to attack by a stannyl radical,71 selective generation of the carbon radical was essential for the success of this methodology.  Iodides preferentially react under standard stannyl radical conditions to generate carbon radical; azide-containing iodide 2.49 reacts cleanly to provide the reduced product 2.51 in 91% yield (Scheme 2.15).  Thus, treatment of iodide 2.52 with tributyltin hydride and AIBN, followed by cyclization of carbon radical 2.46 onto the azide provided nitrogen radical intermediate 2.54 (Scheme 2.16).  Extrusion of dinitrogen and hydrogen-atom transfer afforded pyrrolidine 2.55; tosylation upon workup provided pyrrolidine 2.56 in 88% yield.  66  Scheme 2.15. Reduction of iodide 2.49.     Scheme 2.16. Radical cyclization followed by tosylation to form pyrrolidine 2.56. Stannyl radical conditions cannot be used to cleanly effect the cyclization of carbon radicals generated from less reactive radical precursors, such as bromides and thiocarbonates, because of a competing reaction of the stannyl radical with the azide.  For example, treatment of bromide 2.57 affords 54% of carbon reduction product 2.51 and 25% of azide reduction product 2.58 after tosylation (Scheme 2.17).  However, azides are relatively inert to silyl radicals and, therefore, if tris(trimethylsilyl)silane is used in place of tributyltin hydride, the carbon radical is formed selectively.  Treatment of bromide 2.59 with tris(trimethylsilyl)silane and AIBN in refluxing benzene, followed by tosylation, affords pyrrolidine 2.60 in 76% yield (Scheme 2.18).  67  Scheme 2.17. Reduction of bromide 2.57.   Scheme 2.18. Radical cyclization of bromide 2.59 to form pyrrolidine 2.60. Murphy has demonstrated the synthetic utility of radical cyclizations onto azides in the synthesis of a number of alkaloid natural products.72  A tandem cyclization was used to set the tetracyclic core of (±)-aspidospermidine (2.64, Scheme 2.19).72a,b  The carbon radical generated by treatment of iodide 2.61 with tris(trimethylsilane) and AIBN cyclized onto the alkene, and a subsequent cyclization of radical intermediate 2.62 onto the pendant azide afforded tetracycle 2.63 in 95% yield as a single diastereomer.  A similar approach was applied to the synthesis of (±)-horsfiline (2.68, Scheme 2.20).72c 68  Scheme 2.19. Radical cyclization to form the tetracyclic core of (±)-aspidospermidine (2.64).   Scheme 2.20. Carbon radical cyclization onto an azide for the synthesis of (±)-horsfiline (2.68).  69 2.3 Nitrogen-Centred Radical Strategies for Pyrrolidine Synthesis  Aminyl radical cyclization has emerged as a powerful method to the direct formation of the C-N bond in pyrrolidines and other nitrogen-containing heterocycles.73  The nitrogen radical can be generated either directly from a radical precursor, or by a tandem reaction in which a carbon radical first adds to an unsaturated nitrogen derivative to form the aminyl radical.  Nitrogen-centred radical cyclizations to form pyrrolidines can proceed either through a neutral aminyl radical or an aminium cation radical.  For the purposes of this overview, only neutral aminyl radicals will be presented.  2.3.1 Indirect Methods for Generation of Aminyl Radicals  As previously described, imines can serve as acceptors for carbon radical cyclizations.  However, direct pyrrolidine formation using this method is difficult due to regioselectivity issues.  The inherent selectivity towards carbon-carbon bond formation can nevertheless be exploited for pyrrolidine synthesis by tethering an alkene acceptor to the imine.  Thus, the nitrogen radical formed after the initial carbon radical addition can then cyclize to form a bicyclic species.   Bowman and coworkers investigated the application of this tandem approach to a variety of bicyclic nitrogen heterocycles.74  After formation imine 2.69a in situ, treatment with tributyltin hydride and AIBN afforded 32% yield of 2.72a (Scheme 2.21).  Substituting the alkene acceptor with a phenyl group increased the yield of the bicyclic product to 62%, presumably because stabilization of the carbon radical by the phenyl group suppresses the reverse ring-opening reaction.  70  Scheme 2.21. Tandem radical cyclization of imines 2.69a and 2.69b.   Scheme 2.22. Synthesis of spirocyclic pyrrolidines by tandem radical cyclization. Synthesis of spirocyclic pyrrolidines using this approach initially failed; only monocyclic products (2.73a or 2.73b) were observed (Scheme 2.22).74  The yields of 2.75a and 2.75b could be increased through the addition of a Lewis acid.  Bowman proposed that the complexation by MgBr2.OEt2 with the nitrogen increases the electrophilicity of the aminyl radical and thus enhances the rate of the second cyclization.  The yields could also be increased without use of a Lewis acid by phenyl substitution of the alkene acceptor (2.76).  However, the yields remained modest for this motif despite these attempts at activation. A similar tandem approach was applied to the synthesis of indolizidines.74  Treatment of phenylselenide 2.78 with standard Bu3SnH conditions afforded indolizidine 2.81 in 26% yield, as an equimolar mixture of two diastereomers (Scheme 2.23).  As was previously observed in the 71 work of Takano65 and Warkentin,66 the 6-endo cyclization of the initial carbon radical onto the imine was preferred.  No products resulting from a 5-exo cyclization onto the imine were isolated.  However the presence of a large amount of polymeric material in the reaction mixture suggests that the intermediate carbon radical 2.82 could undergo polymerization before the second cyclization event can occur.  Unsurprisingly, attempts at pyrrolizidine synthesis using an analogous approach were not successful, due to the unfavourability of the inital 5-endo cyclization (Scheme 2.24).  Only the acyclic amine, after NaBH4 reduction, was isolated and no cyclized products were observed.  Scheme 2.23. Tandem radical cyclization to form indolizidine 2.81.  72  Scheme 2.24. Attempted 5-endo radical cyclization of imine 2.83.  2.3.2 Direct Methods for Generation of Aminyl Radicals  Scheme 2.25. Radical decomposition of tetrazene 2.87. Early investigations on aminyl radical generation focused on thermal or photolytic decomposition of tetrazene derivatives (Scheme 2.25).75  Heating tetrazene 2.87 resulted in a radical extrusion of molecular nitrogen, and the resulting aminyl radical cyclized onto the pendant alkene to give pyrrolidine 2.88 as the major product, as well as a minor amount of the piperidine 2.89 from 6-endo cyclization.  A number of non-cyclic products resulting from radical-radical couplings and disproportionation reactions were observed as well.  While these studies generated valuable mechanistic data, the high initial concentration of radicals and lack of good chain propagation steps limit the synthetic utility of this aminyl radical generation method. 73  Scheme 2.26. Electrochemical oxidation of lithium amide 2.90. Another early report on aminyl radical generation utilized electrochemical oxidation of lithium amides.76  Suginome studied the application of this methodology to the synthesis of 1- methyl-2,5-disubstituted pyrrolidines (Scheme 2.26).  Electrolysis of lithium alkenylamide 2.90, generated from the parent amine and butyllithium at low temperature, provided pyrrolidine 2.92.  In general, reaction yields were higher for 2-aryl than for 2-alkyl alkenylamines.  Furthermore, all cyclizations proceeded in high regio- and diastereoselectivity; only cis-pyrrolidines resulting from 5-exo cyclizations were observed.  The exclusive formation of the cis diastereomer was attributed to steric constraints imposed on the reaction by the platinum electrode surface.77  Intriguingly, the electrochemical oxidation produces neutral aminyl radicals, which generally display low reactivity especially at low temperature.  The reaction may be accelerated by the presence of the lithium cation, which has been shown to act as a Lewis acid in promoting aminyl radical reactions.  The most common and versatile precursors for aminyl radical cyclizations (Scheme 2.27) involve a homolysis of a weak nitrogen-heteroatom bond, such as those found in N-chloroamines (2.93),78 arylsulfenamides (2.94)79 and N-hydroxypyridine-2-thione (PTOC) carbamates (2.95).80  This homolysis maybe induced either by thermal or photochemical conditions or by reductive stannyl radical mediated conditions.  The fate of the carbon radical formed after cyclization depends on the conditions of the nitrogen radical initiation.  If reductive conditions are employed, the carbon radical is trapped by hydrogen atom transfer.  In the absence of an external 74 radical trapping agent, the carbon radical undergoes “self-trapping” by a chlorine radical, in the case of N-chloramines, or a pyridylthiylradical, in the case of PTOC carbamates.  Scheme 2.27. Precursors for direct generation of aminyl radicals.  2.3.3 Kinetics of Neutral Aminyl Radical Cyclizations  Scheme 2.28. Kinetics of neutral aminyl radical cyclizations. Aminyl radical additions to π-systems are a rapid method for the synthesis of pyrrolidines from simple linear precursors.  However, 5-exo aminyl radical cyclizations are notably slower than their alkoxy or carbon radical analogs.  Through competition kinetics Newcomb derived the 75 rate constants for both the cyclization of 2.98 and the ring-opening of carbon radical 2.99 (Scheme 2.28).50  When carbon radical 2.99 is generated from phenylselenide 2.100, both cyclic and acyclic products are observed, supporting the proposed equilibrium between the cyclic radical 2.99 and acyclic radical 2.98.  Furthermore, the cyclization of aminyl radical 2.98 is not favoured thermodynamically as the equilibrium constant between 2.98 and 2.99 is 0.35.81  Regardless of whether the aminyl radical is generated indirectly or directly, the synthetic utility of these reactions generally suffer from these kinetic and thermodynamic factors.   Yields can be improved by changing the substitution on the alkene acceptor.  For example, aryl substitution increases the rate of cyclization by a factor of 10, presumably by stabilizing the carbon radical formed upon cyclization (Scheme 2.28).  Coupling the aminyl radical cyclization with an irreversible process, such as a subsequent carbon radical cyclization, can also be used as a strategy to shift the equilibrium to favour the cyclized product (Scheme 2.29).79  While these structural changes do increase reaction yields, the constraints placed on the radical acceptor narrow the scope of pyrrolidine products that can be synthesized using aminyl radical cyclization.  Scheme 2.29. Tandem cyclization of phenylsulfenimide 2.103. 2.4 Proposed Aminyl Radical Cyclizations onto Silyl Enol Ethers Given our previous work on chemoselective alkoxy radical cyclizations onto silyl enol ethers,44 we hypothesized that this radical acceptor could also improve the efficiency of nitrogen- centred radical cyclizations (Scheme 2.30).  Aminyl radicals are less electrophilic and therefore the rate may not be accelerated by the increased electron density to the same extent as in alkoxy 76 radical cyclizations.  However, dative stabilization of the carbon radical by the siloxy group may shift the equilibrium between 2.106 and 2.107 to favour the cyclized product.  Furthermore, the siloxy-substituted pyrrolidine would have a synthetically versatile handle that allows for a wider range of further functionalization than in the case of aryl-substituted alkene acceptors.  Scheme 2.30. Proposed aminyl radical cyclization onto a silyl enol ether. 2.5 Results and Discussion Early investigations by Huimin Zhai focused on cyclization precursor 2.108a (Scheme 2.31).82  Azides were chosen as the aminyl radical source as they can be easily installed and carried through a multiple step synthesis.  By contrast, PTOC carbamates require the use of phosgene for their synthesis and are light-sensitive.83  Furthermore, unlike most other aminyl radical precursors, azides provide access to secondary, unprotected amines.  Gratifyingly, treatment of azide 2.108a with standard tributyltin hydride conditions afforded 75% isolated yield of desired pyrrolidine 2.111a.  Although the reaction proceeds through a tin-bound aminyl radical, the labile tin-nitrogen bond is hydrolyzed upon workup and only the free secondary amine is isolated.  As a control experiment, azide 2.108a was heated to reflux in benzene in the absence of tributyltin hydride.  No change in starting material was observed, excluding a possible cycloaddition pathway. 77  Scheme 2.31. Radical cyclization of azide 2.108a to form pyrrolidine 2.111a.   In addition to providing ready access to the 2-hydroxymethylpyrrolidine core of many polyhydroxylated alkaloids, the aminyl radical cyclization depicted in Scheme 2.31 is noteworthy as it represents the first example of a tin-bound aminyl radical cyclization onto an alkene.  Tin-bound aminyl radicals are more nucleophilic than free aminyl radicals,84 and prior to our work, the only reported radical acceptors for this species were carbonyls.85  Because of the absence of data on the intramolecular additions of tin-bound aminyl radicals to simple alkenes, we synthesized azide-containing alkene 2.112 and subjected it to standard stannyl radical conditions (Scheme 2.32).  1H NMR analysis of the crude reaction mixture showed pyrrolidine 2.114 as a minor product, with the majority of the mass balance was acyclic amine 2.113.  This stands in contrast to the excellent yield of pyrrolidine 2.111a obtained employing a silyl enol ether as the radical acceptor (Scheme 2.31).  This is intriguing, as increased electron density imparted by the siloxy substituent should make attack by a nucleophilic radical species unfavourable.  However, these results support our hypothesis that dative stabilization of the carbon radical formed after cyclization shifts the equilibrium between acyclic and cyclic intermediates such that pyrrolidine formation is favoured.  Thus, the cyclization depicted in Scheme 2.31  represents a new mode of reactivity for tin-bound aminyl radicals. 78  Scheme 2.32. Radical cyclization of azide 2.112 to form acyclic amine 2.113 and pyrrolidine 2.114.    2.5.1 Polyhydroxylated Alkaloids Polyhydroxylated alkaloids are a diverse class of pyrrolidine, piperidine, pyrrolizidine, indolizidine, and nortropane natural products isolated from both plants and microorganisms.86  These compounds can be potent competitive and reversible inhibitors of glycosidases by serving as furanose and pyranose mimics.87  The few polyhydroxylated alkaloids that are commercially available have promising therapeutic potential, including efficacy as anticancer, antiviral, and antidiabetic agents.86c  However, the full medicinal potential of the polyhydroxylated alkaloids is limited by compound availability and toxicity.  Since many compounds in this class contain a pyrrolidine nucleus, we were surprised to find there were no existing radical methodologies for synthesizing this key motif in highly oxygenated systems.  Many alkaloids in this class possess a 2-hydroxymethylpyrrolidine core (Figure 2.1), and thus we envisaged that a nitrogen-centred radical cyclization onto a silyl enol ether would be a powerful method for the synthesis of these natural products.  We hypothesized that this nitrogen-radical centred approach would allow for the rapid synthesis of polyhydroxylated alkaloids from simple linear substrates.  Furthermore, unlike existing non-radical methods starting from proline and other amino acid derivatives, such an approach could access pyrrolidines with substitution at the 3- and 5-positions. 79  Figure 2.1. Selected polyhydroxylated alkaloids. 2.5.2 Diastereoselectivity Studies Further investigations by Huimin Zhai focused on the scope of this new radical cyclization.88  As in previous examples of alkoxy radical additions, aminyl radical additions to silyl enol ethers demonstrated a high degree of chemoselectivity (Table 2.1).  Azides 2.108e and 2.108f, which could undergo -fragmentation to secondary carbon radicals, cyclized to the corresponding pyrrolidines with no fragmentation by-products observed.  Products resulting from 1,5-hydrogen abstraction were also not observed (entries 4 and 5).  However, in contrast to previous work on alkoxy radical cyclizations, silyl enol ethers cannot be used to effect 6-exo cyclizations,89 presumably due to the lower electrophilicity of radicals relative to alkoxy radicals.84   80 Table 2.1. Cyclization of alkyl and phenyl substituted substrates.  Entry Substrate (a) Product(b) Yield (%)(c) d.r. 1   2.108a   2.111a 75 – 2   2.108b   2.111b 62 90:10 3 2.108c 2.111c 78 65:35 4    2.108d 2.111d 66(e) 84:16 5 2.108e 2.111e 79 72:28 6 2.108f 2.111f 77 89:11 7 2.108g 2.111g 71 93:7 8 2.108h 2.111h 68 >95:5  (a) Reactions were carried out on >0.25 mmol scale.  (b) The relative configuration was determined by derivatization of the product and comparison to known compounds.  (c) Isolated yields of the mixture of diastereomers after flash chromatography.  (d) The diastereomeric ratio was determined by 1H NMR spectroscopy of crude reaction mixtures. (e) Isolated yield of the trans-stereoisomer. The cis-isomer was also isolated in 12% yield. 81 The diastereoselectivity of these cyclizations was higher than what was previously observed in alkoxy radical cyclizations onto silyl enol ethers.  Substrates with substitution at C3 cyclized to provide pyrrolidines in especially high diastereoselectivity (Table 2.1, entries 7 and 8).  Since many polyhydroxylated alkaloids possess substitution at C3 in a trans relationship to the hydroxymethyl substituent at C2, we envisaged that this motif could be readily synthesized via our new aminyl radical cyclization.  Thus, we sought to demonstrate the synthetic utility of our methodology in the stereoselective synthesis of a silyl-protected analog of CYB-3 (2.115, Figure 2.1), an alkaloid isolated from the seeds and leaves of Castanospermum australe.90,91  While its structure appears to be simple, the oxygenation and stereochemistry make it a challenging synthetic target.92,93 2.5.3 Synthesis of CYB-3 Our investigations began with the synthesis of cyclization precursor 2.126 in five steps from the known (S)-methyl-3,5-dihydroxypentanoate (2.121, Scheme 2.33).94  Converstion of the primary alcohol to an iodide and protection of the secondary alcohol with a TBS group provided ester 2.123 in excellent yield.  Reduction of the ester by DIBAL-H, followed by silyl enol ether formation provided silyl enol ether 2.125 as a 40:60 mixture of E- to Z-isomers.  Finally, displacement of the iodide with azide afforded the key cyclization precursor 2.126. 82  Scheme 2.33. Synthesis of cyclization precursor 2.126. Azide 2.126 was subjected to standard aminyl radical generation conditions (Scheme 2.34).  Surprisingly, cyclization of silyl enol 2.126 proceeded with relatively low diastereoselectivity, providing pyrrolidine 2.127 as a 60:40 mixture of trans to cis isomers.  Furthermore, a majority of the mass balance corresponded to amine 2.128, presumably from intermolecular hydrogen atom transfer to the nitrogen radical from tributyltin hydride.  This was inconsistent with previous cyclizations of analogous substrates; both aminyl and alkoxy radicals with C3 substitution cyclized in high diastereoselectivity and yield (Scheme 2.35).  Scheme 2.34. Radical cyclization of azide 2.126 using standard stannyl radical conditions to afford pyrrolidine 2.127 and acyclic amine 2.128.   83  Scheme 2.35. Radical cyclization of 3-methyl substituted substrates 1.106g and 2.108g.  In an effort to increase the diastereoselectivity of the cyclization, we effected the cyclization at a lower temperature.  We utilized a different initiation method (Scheme 2.36) as AIBN requires elevated temperatures for radical formation.  Treatment of azide 2.126 with triethylborane and oxygen at ambient temperature95 in the presence of tributyltin hydride formed pyrrolidine 2.127 with increased diastereoselectivity than under refluxing conditions.  However, there was also a significant increase in the amount of acyclic amine 2.128.     Scheme 2.36. Radical cyclization of azide 2.126 using Et3B/O2 as a radical initiator to afford pyrrolidine 2.127 and acyclic amine 2.128. We hypothesized that we may be able to increase the ratio of pyrrolidine 2.127 to amine 2.128 by decreasing the electron density of the tin-bound nitrogen-centred radical, as a more electrophilic nitrogen-centred radical should cyclize onto the electron-rich enol ether at a faster rate.  Utilizing triphenyltin hydride in place of tributyltin hydride, cyclization of azide 2.126 led 84 to a slight increase in the ratio of cyclized pyrrolidine 2.127 and amine 2.128 (Scheme 2.37).  It also provided pyrrolidine 2.127 in higher yield, presumably due to the increased steric bulk around the nitrogen-centred radical.     Scheme 2.37. Radical cyclization of azide 2.126 using Ph3SnH afford pyrrolidine 2.127 and acyclic amine 2.128.  Scheme 2.38. Synthesis of silyl enol ether 2.131 Steric congestion in the transition state of the cyclization may lower the rate of cyclization, leading to poor ratios of cyclic pyrrolidine 2.127 and acyclic amine 2.128.  To test this, we synthesized the TES-protected silyl enol ether 2.131 (Scheme 2.38), using an analogous synthetic route to that of silyl enol ether 2.126.  Silyl enol ether 2.131 was then subjected to standard stannyl radical conditions (Scheme 2.39).  Indeed, decreasing the steric size of the silyl protecting group, from TBS to TES, provided an increase in both the ratio of pyrrolidine 2.131 to 85 primary amine 2.132 and the diastereoselectivity of the cyclized product.  Despite the improved yield of pyrrolidine 2.132, the diastereoselectivity was still significantly lower than cyclizations of both alkoxy and aminyl radicals with similar substitution patterns.   Scheme 2.39. Cyclization of azide 2.131 to afford pyrrolidine 2.132 and acyclic amine 2.133. Thus far, all attempts to form the silyl-protected CYB-3 analog via aminyl-radical cyclization utilized silyl enol ethers that were mixtures of E and Z isomers.  To test whether the decreased diastereoselectivies in these cyclizations is a result of differences in selectivities for the E- and Z-silyl enol ethers, silyl enol ethers 2.130 and Z-2.127 were synthesized from aldehyde 2.130 (Scheme 2.40).  The synthesis of these substrates was analogous to that of 2.126 (Scheme 2.33), with the exception of the silyl enol ether formation step.  The E-Silyl enol ether (2.134) was synthesized using TBSCl and DBU in dichloromethane at 35 °C to form the thermodynamic product.  The Z-silyl enol ether was prepared using TESCl and DBU at 0 °C purification by flash chromatography provided Z-2.131 as a single diastereomer.  86  Scheme 2.40. Synthesis of silyl enol ethers 2.134 and Z-2.131.   Scheme 2.41. Cyclization of azides 2.134 and Z-2.131 to afford pyrrolidines 2.135 and 2.132. With both cyclization precursors 2.134 and Z-2.131 in hand, we subjected each to the stannyl radical conditions (Scheme 2.41).  While E-silyl enol ether 2.134 cyclized with no diastereoselectivity, Z-silyl enol ether Z-2.131 cyclized to give trans-pyrrolidine 2.132 as a single diastereomer, providing the target silyl-protected CYB-3 in 77% isolated yield.  There is a slight contribution to diastereoselectivity from the difference in steric size between the silyl enol ether substituents.  However the dramatic discrepancy in the cyclizations of silyl enol ethers 87 2.134 and Z-2.131 suggests that the geometry of the oxygenated alkene is the dominant factor in the diastereoselectivity of this reaction.  2.5.4 Beckwith-Houk Transition State Analysis of Aminyl Radical Cyclizations The diastereoselectivity of 5-exo radical cyclizations can be predicted using the transition state models developed by Beckwith20 and Houk.21  Using this analysis, we can rationalize the high diastereoselectivity observed in the cyclization of Z-silyl enol ether Z-2.131 (Scheme 2.42).  The cyclization proceeds through one of four transition states, two of which are chair-like (2.137 and 2.139) and two of which are boat-like (2.138 and 2.140). Chair transition state 2.137, which provides the observed trans-substituted pyrrolidine, has few major steric interactions.  The siloxy substituent at C3 is in the equatorial position and the silyl enol ether is oriented to minimize A 1,3- strain.  The alternative chair-like transition state should be significantly higher in energy due to A1,3-strain between the siloxy substituents. Both boat transition states 2.138 and 2.140 also contain significant steric interactions, which should make them higher in energy than the preferred chair-like transition state 2.137.  Thus, the trans diastereomer predicted using this steric minimization argument is in accordance with what was observed in the cyclization of Z- silyl enol ether Z-2.131. 88  Scheme 2.42. Beckwith-Houk transition states for the cyclization of Z-silyl enol ether Z-2.131. It is much more difficult to rationalize the poor diastereoselectivity of the cyclization of E- silyl enol ether 2.134 using a similar Beckwith-Houk transition state analysis (Scheme 2.43).  As in the cyclization of Z-silyl enol ether Z-2.131, the chair transition state (2.141) leading to the trans-substituted pyrrolidine (trans-2.135) has few steric interactions.  The alternative chair transition state (2.143) leading to the cis-substituted pyrrolidine (cis-2.135) should be slightly higher in energy due to the steric interaction between the siloxy group at C3 and the hydrogen at C1.  The steric interactions present in boat transition state 2.144, which also provides cis- substituted pyrrolidine 2.135, should raise the energy of this pathway as well.  Though transition 89 states 2.143 and 2.144 are closer in energy to 2.141 than for Z-silyl enol ether Z-2.131, the cyclization of E-silyl enol ether 2.134 should still favour the trans-pyrrolidine.  Analogous cyclizations of alkoxy radicals onto E-silyl enol ethers with aryl or alkyl substitution at C3 provided excellent selectivity.  Thus, the lack of selectivity in the cyclization of azide 2.134 suggests that steric minimization is not the only factor in reaction diastereoselectivity.  Scheme 2.43. Beckwith-Houk transition states for the cyclization of E-silyl enol ethers 2.134. A possible explanation for the low diastereoselectivity of the cyclization of azide 2.134 is the presence of a stereoelectronic interaction in one of the transition states (Scheme 2.44).  In chair transition state 2.141, the *C-O of the siloxy group is aligned with the - system of the silyl enol ether, which should lead to decreased electron density of the olefin.  90 This interaction is not present in chair transition state 2.143 and boat transition state 2.144 as the *C-O of the siloxy group and the -system of the silyl enol ether are orthogonal.  Since the nitrogen-centred radical is slightly electrophilic, the decreased electron density in the olefin should slow the cyclization rate of transition state 2.141 in comparison with transition states 2.143 and 2.144.  Presumably, the stereoelectronic interactions are comparable to the higher steric demand in transtion states 2.143 and 2.144 leading to similar rates of cyclization.  This interaction is also present in transition state for the cyclization of Z-2.131 (2.137), but the steric interactions are apparently sufficiently significant to outweigh the stereoelectronic effects.  91  Scheme 2.44. Stereoelectronic interaction in Beckwith-Houk transition states for the cyclization of E-silyl enol ether 2.134.  92  Scheme 2.45. Synthesis of cyclization precursors Z-2.108g and Z-2.108h.   Scheme 2.46. Synthesis of cyclization precursors E-2.108g and E-2.108h. The presence of a stereoelectronic interaction in substrates with siloxy substitution at C3 is supported by the results of cyclizations of analogous substrates with alkyl and aryl substitution. The σ* of these substituents is less accessible for interaction with the π-system as they are higher in energy.  The synthesis of these substrates from readily available diols is illustrated in Scheme 2.45 and Scheme 2.46.  The syntheses and cyclizations of Z-enriched silyl enol ethers Z-2.108g  and Z-2.108h was carried out by Huimin Zhai, while I performed the syntheses and cyclizations of E-enriched silyl enol ethers E-2.108g  and E-2.108h.  Aldehydes 2.146a and 2.146b, which served as the common intermediates for both E and Z silyl enol ether substrates, were synthesized independently by both Huimin Zhai and me.  Synthesis of Z-enriched silyl enol ethers Z-2.108g and Z-2.108h was accomplished by treatment of the aldehyde precursors with TBSOTf and Hünig’s base at 0 °C followed by displacement of the tosylate with sodium azide 93 (Scheme 2.45).  The order of the enolization and displacement steps had to be reversed for the synthesis of E-enriched silyl enol ethers E-2.108g and E-2.108h, as the enolization conditions necessary for E-selectivity led to elimination of the tosylate.  Displacement of tosylate 2.146, followed by treatment with TBSCl and DBU at 35 °C afforded the E-enriched silyl enol ethers E-2.108g and E-2.108h in good yields (Scheme 2.46). The results of the cyclizations of silyl enol ethers Z-2.108g-h and E-2.108g-h are summarized in Table 2.2.  Methyl-substituted Z-silyl enol ether Z-2.108g cyclized in high yield and with excellent diastereoselectivity.  As was observed in substrates with siloxy substitution, cyclization of the corresponding E-silyl enol ether (E-2.108g) provided trans-pyrrolidine 2.111g with lower diastereoselectivity.  However, this difference in selectivity between E and Z silyl enol ethers was not as pronounced as what was observed for the siloxy substituted substrates.  The A-value for a methyl substituent (1.74 kcal/mol)96 is only moderately higher than for a siloxy substituent (1.06 kcal/mol)97 and thus an argument based on steric minimization alone is insufficient to explain the increase in selectivity between the cyclizations of E-silyl enol ethers 2.130 and E-2.108g.  However, it is consistent with the stereoelectronic interaction shown in transition state 2.141 (Scheme 2.44) as the siloxy substituent has a significantly lower energy * orbital.  Furthermore, this drop in diastereoselectivity was not observed in the cyclization of phenyl substituted substrates; both silyl enol ethers Z-2.108h and E-2.108h cyclized to give the trans isomer exclusively.  The A-value of a phenyl group (3.0 kcal/mol)98 is significantly higher than that of either a methyl or siloxy group and therefore the steric influence apparently outweighs any stereoelectronic effects in the transition state for the cyclization of E-2.108h.99   94 Table 2.2. Cyclization of 3-methyl and phenyl substituted substrates.  Entry Substrate (a) Product(b) Yield (%)(c) d.r. 1 Z-2.108g 2.111g 71 93:7 2 E-2.108g 2.111g 72 79:21 3  Z-2.108h 2.111h 68 >95:5 4 E-2.108h 2.111h 70 >95:5 (a) Reactions were carried out on >0.25 mmol scale.  (b) The relative configuration was determined by derivitization of the product and comparison to known compounds.  (c) Isolated yields of the mixture of diastereomers after flash chromatography.  (d) The diastereomeric ratio was determined by 1H NMR spectroscopy of purified products.  Further evidence of this stereoelectronic interaction is provided by the diastereoselectivity observed in the cyclization of E-silyl enol ether 2.152, readily synthesized in 5 steps from known epoxide 2.149 (Scheme 2.47).  There should be no stereoelectronic interaction between the - system and the *C-O of the silyl ether as the siloxy substituent is homoallylic to the silyl enol ether.  The cyclization diastereoselectivity should, therefore, be governed exclusively by steric factors.  Indeed, cyclization of E-silyl enol ether 2.152 provided pyrrolidine 2.153 in 75:25 ratio of cis to trans diastereomers.  Since substrates with substitution at C3 are known to cyclize with higher diastereoselectivity than those with substitution at C4 (Table 2.1), a simple steric 95 minimization argument cannot account for the equimolar ratio obtained for the cyclization of E- silyl enol ether 2.134.  Scheme 2.47. Synthesis and radical cyclization of azide 2.152 to form pyrrolidine 2.153. We have demonstrated the utility of aminyl radical cyclizations as a method for the synthesis of polyhydroxylated alkaloids from simple linear precursors.  Our synthesis of silyl- protected CYB-3 provides valuable insight into the effects on selectivity of silyl enol ether geometry and substitution alpha to the aminyl radical acceptor.  As many polyhydroxylated alkaloids possess oxygen substituents at the 3-position of the 2-hydroxymethylpyrrolidine core (Figure 2.1), an understanding of the factors governing selectivity should aid in future applications of aminyl radical cyclizations to the synthesis of more complex alkaloids.  96 2.6 Future Work  Scheme 2.48. Attempted cyclization of azide 2.153 to form piperidine 2.154. We envisage an extension of our methodology to the synthesis of piperidine derivatives via 6-exo cyclization onto oxygenated alkenes.  An attempt by Dr. Huimin Zhai to form piperidine 2.154 by cyclization of azide 2.153 was unsuccessful (Scheme 2.480).  Only amine 2.155, resulting from either an inter- or intramolecular hydrogen atom transfer, was observed.  The discrepancy between this result and the successful 6-exo cyclization of an alkoxy radical (Chapter 1) is likely due to the low electrophilicity of the tin-bound aminyl radical.  Thus, decreasing the electron density of nitrogen-centred radical may improve the efficiency of the 6- exo cyclization.  Scheme 2.49. 6-Exo amidyl radical cyclizations.   Amidyl radicals are known to cyclize at a much faster rate than aminyl radicals.100  While 6-exo cyclizations of amidyl radicals to form lactams are precedented,101 cyclizations in which the carbonyl is external to the ring are not known (Scheme 2.49).  The cyclization of amidyl radical 2.158 is estimated to be 100 times slower than that of amidyl 2.156 and, thus, 97 competition with both intra- and intermolecular hydrogen atom transfers becomes difficult.102  Utilizing electron-rich silyl enol ethers as acceptors for these radicals may accelerate the rate of 6-exo cyclization such that it outcompetes these undesired pathways (Scheme 2.50).  The electron density of the amidyl radical could be further decreased using electron-deficient amides, such as trifluoroacetamide derivative 2.160b.  Cyclizations of sulfonamidyl radicals will also be explored as a method for the synthesis of protected piperidine derivatives.  Scheme 2.50. Proposed 6-exo cycilzation of an amidyl radical onto a silyl enol ether to form a protected piperidine.   Scheme 2.51. Proposed aminium cation radical cyclization to form piperidine 2.164. Another strategy to increase the electrophilicity of aminyl radicals is protonation to form aminium radical cations.  The rate of 5-exo cyclization of an aminium radical cation is four orders of magnitude faster than the analogous aminyl radical cyclization.103  6-Exo cyclizations of aminium radical cations onto terminal alkenes have been attempted, but generally provided the corresponding acyclic amines as the predominant products.104  These cyclizations may be more successful if the electron density of the acceptor was increased.  However, the conditions necessary to generate these radical cations would not be compatible with acid-sensitive silyl enol ethers and, thus, a more robust oxygenated acceptor would be needed for this cyclization.  Alkyl enol ethers should be more stable to the acidic medium.  Utilizing a benzyl enol ether as a radical 98 acceptor (2.162), for example, would provide a piperidine product with a protected alcohol in the alpha position (2.164).  2.7 Conclusion In summary, we have developed a new aminyl radical cyclization methodology utilizing silyl enol ethers as acceptors.  This method provides ready access to 2- hydroxymethylpyrrolidine, a structural motif found in many biologically active polyhydroxylated alkaloids.  Furthermore, our work represents the first example of a tin-bound aminyl radical cyclization onto an alkene.  Prior to our work, the only reported radical acceptors for this species were carbonyls.  Thus, our work represents a new mode of reactivity for tin- bound aminyl radicals. We applied our new aminyl radical cyclization methodology to the synthesis of the silyl- protected analog of polyhydroxylated alkaloid CYB-3.  In the course of optimizing the key cyclization step, we found that the diastereoselectivity was inconsistent with previous cyclizations of analogous alkoxyl and aminyl radicals.  While temperature, tin hydride source, and sterics of the substituent all influenced the cyclization selectivity, the geometry of the silyl enol ether had the most dramatic effect on selectivity.  Cyclizations of Z-silyl enol ethers provide high diastereoselectivities for all substrates examined.  However, the diastereoselectivity using E-silyl enol ethers was significantly lower when an electronegative substituent was adjacent to the silyl enol ether.  The low diastereoselectivities in cyclizations of E-silyl enol ethers with electron-withdrawing substituents are likely due to a combination of small steric differentiation between the transition states and a stereoelectronic interaction that decreases the electron density from the olefin.   Cyclization diastereoselectivities of substrates with alkyl or aryl substitution were excellent regardless of olefin geometry or substitution pattern.  Our work on the elucidation 99 of the factors that lead to high aminyl radical cyclization diastereoselectivites should greatly expand the utility of this methodology in complex natural product synthesis.  2.8 Experimental 2.8.1 General Experimental Please refer to the general experimental section in Chapter 1 for details. Optical rotations were recorded using a Perkin-Elmer 241 ML Polarimeter. 2.8.2 Synthesis of Azides 2.126, 2.131, 2.134 and Z-2.131  (3R)-Methyl-3-hydroxy-5-iodopentanoate (2.122): A solution of (3S)-3,5-dihydroxy-pentanoic acid methyl ester (2.121) (6.31 g, 42.6 mmol), triphenylphosphine (17.37 g, 64.5 mmol), pyridine (10.20 g, 129.0 mmol), and iodine (10.91 g, 43.0 mmol) in benzene (500 mL) was stirred for 18 h at room temperature.  The reaction mixture was then filtered through a pad of Celite. The filtrate was concentrated by rotary evaporation to provide a light yellow oil. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded 8.42 g (76%) of the iodide. 2.122 as a colourless oil. []D24 = –14.9° (c = 0.7, CH2Cl2); IR (neat) 3434, 2950, 1730, 1436 cm - 1; 1H NMR (400 MHz, CDCl3) δ 4.01-4.11 (m, 1H), 3.65 (s, 3H), 3.32 (d, J = 4.4 Hz, 1H), 3.24 (t, J = 6.4 Hz, 2H), 2.38-2.50 (m, 2H), 1.82-1.98 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 172.5, 67.5, 51.7, 40.6, 39.7, 2.0; HRMS-ESI (m/z): [M+Na]+ calcd for C6H11O3INa: 280.9651. Found: 280.9657.  100  (3R)-Methyl-(tert-Butyl-dimethyl-silanyloxy)-5-iodo-pentanoate (2.123): A solution of alcohol 2.122 (1.49 g, 5.8 mmol) and triethylamine (1.17 g, 11.6 mmol) in CH2Cl2 (50 mL) was cooled to 0 °C and tert-butyldimethylsilyl trifluoromethanesulfonate (2.30 g, 8.7 mmol) was added dropwise over 3 min. The resulting solution was stirred for 45 min and then washed with saturated NaHCO3 solution (40 mL). The layers were separated the aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to provide a yellow oil. Purification by flash chromatography (9:1 hexanes/EtOAc) afforded 2.04 g (94%) of silyl ether 2.123 as a colourless oil. []D24 = –18.9° (c = 2.6, CH2Cl2); (neat) 2952, 2929, 2856, 1738, 1436 cm -1; 1H NMR (400 MHz, CDCl3) δ 4.18 (qt, J = 5.8 Hz, 1H), 3.69 (s, 3H), 3.28-3.11 (m, 2H), 2. 31-2.58 (m, 2H), 1.90-2.13 (m, 2H), 0.88 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3, 69.3, 51.6, 42.0, 41.3, 25.7, 17.9, 1.4, -4.5, -4.7; MS-CI (m/z): [M+H]+ calcd for C12H26IO3Si: 373.3. Found: 373.2.   (3R)-(tert-Butyl-dimethyl-silanyloxy)-5-iodo-pentanal (2.124): Ester 2.123 (1.98 g, 5.3 mmol) was dissolved in CH2Cl2 (27 mL), cooled to –78 °C, and DIBAL-H (1.0 M in hexanes, 10.7 mL) was added in one portion. The solution was stirred for 30 min, then quenched with 20 mL 1:1 MeOH:H2O. The resulting solution was warmed to ambient temperature and stirred for 15 min. The mixture was then filtered through anhydrous MgSO4 and the solids were rinsed with EtOAc (70 mL). The filtrate was concentrated by rotary evaporation to provide the crude aldehyde as a 101 colourless oil. Purification by flash chromatography (5:1 hexanes/EtOAc) afforded 1.55 g (86%) of aldehyde 2.124 as a colourless oil. []D24 = –20.6° (c = 10.8, CH2Cl2); IR (neat) 2953, 2928, 2887, 2856, 1724, 1471 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.80 (t, J = 2.4 Hz, 1H), 4.28 (qt, J = 5.5 Hz, 1H), 3.18 (t, J = 7.1 Hz, 2H), 2.49-2.64 (m, 2H), 1.92-2.16 (m, 2H), 0.88 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.0, 68.0, 50.4, 41.3, 25.7, 17.9, 1.4, 1.3, -4.4, -4.6, -4.6; MS-CI (m/z): [M+H]+ calcd for C11H24IO2Si: 343.1. Found: 343.2.   (3R)-Bis-(tert-butyldimethylsilanyloxy)-5-iodo-pent-1-ene (2.125): A solution of alcohol 2.124 (500 mg, 1.56 mmol) and diisopropylethylamine (377 mg, 2.92 mmol) in CH2Cl2 (8.0 mL) was cooled to 0 °C and tert-butyldimethylsilyl trifluoromethanesulfonate (579 mg, 2.19 mmol) was added dropwise over 2 min. The resulting solution was stirred for 2 h and then washed with saturated NaHCO3 solution (15 mL). The layers were separated the aqueous layer was extracted with CH2Cl2 (15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to provide a yellow oil. Purification by flash chromatography (hexanes) afforded 610 mg (91%) of silyl enol ether 2.125 (E/Z  40:60) as a colourless oil. IR (neat) 2929, 2857, 1471, 1252, 1048 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.45 (d, J = 12.0 Hz, 1H, E), 6.19 (d, J = 5.6 Hz, 1H, Z), 4.99 (dd, J = 12.0, 8.8 Hz, 1H, E), 4.77-4.84 (m, 1H, Z), 4.52 (dd, J = 8.8, 5.6 Hz, 1H, E), 4.12- 4.20 (m, 1H, E), 3.19-3.28 (m, 2H), 1.91-2.10 (m, 2H), 0.98 (s, 9H), 0.96 (s, 9H), 0.92 (s, 9H), 0.91 (s, 9H), 0.18 (s, 3H), 0.14 (s, 3H), 0.10 (s, 102 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.5, 138.7, 113.6, 113.4, 70.8, 66.1, 42.5, 42.3, 25.916, 25.877, 25.63, 25.61, 18.1, 3.4, 3.2, -4.0, -4.3, -4.6, -4.9, -5.2, -5.4.c   (3R)-Bis-(tert-butyldimethylsilanyloxy)-5-azido-pent-1-ene (2.126): A solution of iodide 2.125 (457 mg, 1.0 mmol) and NaN3 (130 mg, 2.0 mmol) in DMF (8 mL) was heated to 50 °C for 1 h. The resulting yellow mixture was taken up in Et2O (10 mL) and washed with brine (5x10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to provide crude azide as a yellow oil. Purification by flash chromatography (19:1 hexanes/EtOAc) afforded 237 mg (64%) of azide 2.126 (E/Z  40:60) as a yellow oil. IR (neat) 2954, 2928, 2857, 2095, 1655, 1472, 1463 cm-1;1H NMR (400 MHz, CDCl3) δ 6.40 (d, J = 12.3 Hz, 1H, E), 6.15 (d, J = 6.2 Hz, 1H, Z), 4.81 (dd, J = 12.0, 8.1 Hz, 1H, E), 4.49 (dd, J = 8.5, 6.2 Hz, 1H, Z), 3.21-3.41 (m, 2H), 1.71-1.88 (m, 2H), 0.94 (s, 9H), 0.93 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.14 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.3, 138.4, 114.0, 113.6, 68.0, 63.5, 48.0, 38.1, 37.3, 25.9, 25.7, 25.7, 25.6, 25.5, -2.9, -4.4, - 4.8, -5.1, -5.3, -5.5; MS-ESI (m/z): [M+H]+ calcd for C17H37N3NaO2Si2: 394.2. Found: 394.3.                                                   c Mass spectroscopy was attempted, but was not successful.  The material was further derivatized for structural proof.  103  (3R)-5-Iodo-3-(triethylsilanyloxy)pentanal (2.129): To a solution of alcohol 2.121 (2.51 g, 9.7 mmol) and imidazole (990 mg, 14.6 mmol) in CH2Cl2 (35 mL) at 0 °C was added chlorotriethylsilane (1.77 g, 11.6 mmol) dropwise over 3 min. The solution was stirred for 40 min and a white precipitate appeared during this time. The reaction was quenched with saturated NaHCO3 solution (30 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation to provide 4.14 g of silyl ether as a yellow oil. The crude product was dissolved in CH2Cl2 (27 mL), cooled to –78 °C, and DIBAL-H (1.0 M in hexanes, 29 mL) was added in one portion. The solution was stirred for 2 h, then quenched with 20 mL 1:1 MeOH:H2O. The resulting solution was warmed to ambient temperature and stirred for 15 min. The mixture was then filtered through anhydrous MgSO4 and the solids were rinsed with EtOAc (100 mL). The filtrate was concentrated by rotary evaporation to provide the crude aldehyde (2.129) as a colourless oil. Purification by flash chromatography (9:1 hexanes/EtOAc) afforded 2.01 g (61%) of aldehyde S3 as a colourless oil. IR (neat) 2954, 2909, 2875, 1723, 1457 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.81 (t, J = 2.4 Hz, 1H), 4.30 (dt, J = 6.2, 5.5 Hz, 1H), 3.21 (t, J = 7.3 Hz, 2H), 2.57-2.60 (m, 2H), 2.00-2.12 (m, 2H), 0.97 (t, J = 7.9 Hz, 9H), 0.65 (q, J = 7.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 201.0, 68.0, 50.6, 41.4, 6.8, 5.0, 1.3.      (3S)-5-Azido-3-(triethylsilanyloxy)pentanal (2.130): A solution of iodide 2.129 (1.87g, 5.5 mmol) and NaN3 (710 mg, 10.9 mmol) in DMF (20 mL) was heated to 50 °C for 18 h. The 104 resulting yellow mixture was taken up in Et2O (30 mL) and washed with brine (5x20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to provide the crude azide as a yellow oil. Purification by flash chromatography (19:1 hexanes/EtOAc) afforded 447 mg (31%) of azide 2.130 as a yellow oil. []D24 = –34.0° (c = 0.2, CH2Cl2); IR (neat) 2955, 2912, 2877, 1064, 1724, 1458 cm -1; 1H NMR (400 MHz, CDCl3) δ 9.82 (t, J = 2.4 Hz, 1H), 4.35 (qt, J = 5.8 Hz, 1H), 3.39-3.43 (m, 2H), 2.61 (dd, J = 5.8, 2.1 Hz, 2H), 1.78-1.83 (m, 2H), 0.97 (t, J = 7.9 Hz, 9H), 0.63 (q, J = 7.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 201.0, 65.0, 51.0, 47.5, 36.4, 6.7, 4.8.   (3R)-Bis-(triethylsilanyloxy)-5-azido-pent-1-ene (2.131): To a solution of 2.130 (45 mg, 0.17 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (52 mg, 0.34 mmol) in CH2Cl2 (0.9 mL) was added chlorotriethylsilane (38 mg, 0.26 mmol). The solution was stirred for 20 h. The resulting yellow solution was then concentrated by rotary evaporation. Purification by flash chromatography (hexanes) afforded 21 mg (33%) of the silyl enol ether 2.131 (Z/E = 40:60), along with 82 mg of triethylsilanol as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 6.41 (d, J = 11.9 Hz, 1H, E), 6.19 (dd, J = 5.9, 1.1 Hz, 1H, Z) 4.98 (dd, J = 12.1, 8.5 Hz, 1H, E), 4.79-4.87 (m, 1H, Z), 4.48 (dd, J = 8.7, 5.9 Hz, 1H, Z), 4.00-4.23(m, 1H, E), 3.45-3.17 (m, 2H), 1.62-1.94 (m, 2H), 0.93 (t, J = 9 Hz, 9H, triethylsilanol), 0.53 (q, J = 9 Hz, 6H, triethylsilanol).  105  (E)-(3R)-5-Azido-3-triethylsilanyloxy-1-(tert-butyl-dimethyl-silanyloxy)-pent-1-ene (2.134): To a solution of 2.130 (50 mg, 0.19 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (86 mg, 0.57 mmol) in CH2Cl2 (2 mL) was added tert-butyldimethylsilyl chloride (57 mg, 0.38 mmol). The solution was heated to 35 °C in a sealed tube for 14 h. The solution was stirred for 20 h. The resulting yellow solution was then concentrated by rotary evaporation. Purification by flash chromatography (99:1 hexanes/EtOAc) afforded 54 mg (76%) of silyl enol ether 2.134 (Z/E < 5:95). 1H NMR (400 MHz, CDCl3) δ 6.40 (d, J = 12.0 Hz, 1H), 4.98 (dd, J = 8.5, 12.0 Hz, 1H), 3.95-4.25 (m, 1H), 3.17-3.44 (m, 2H), 1.74-1.90 (m, 1H), 1.63-1.75 (m, 1H), 0.95 (t, J = 8.0 Hz, 9H), 0.93 (s, 9H), 0.60 (q, J = 8.0 Hz, 6H), 0.16 (s, 6H).   (Z)-(3R)-Bis-(triethylsilanyloxy)-5-azido-pent-1-ene (Z-2.131): To a solution of aldehyde 2.130 (80 mg, 0.31 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (142 mg, 0.93 mmol) in CH2Cl2 (2 mL) at 0 °C was added chlorotriethylsilane (93 mg, 0.62 mmol) in one portion. The solution was stirred for 15 min, then the solution was allowed to warm to room temperature and stirred for 18 h. The resulting yellow solution was then concentrated by rotary evaporation. Purification by flash chromatography (hexanes) afforded 17 mg of the silyl enol ether Z-2.131 (Z/E > 95:5), along with 74 mg of triethylsilanol as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 6.19 (dd, J = 5.9, 1.1 Hz, 1H), 4.79-4.87 (m, 1H), 4.48 (dd, J = 8.7, 5.7 Hz, 1H), 3.33 (t, J = 7.4 Hz, 2H), 1.69-1.76 (m, 2H), 0.93 (t, J = 9 Hz, 9H, triethylsilanol), 0.53 (q, J = 9 Hz, 6H, triethylsilanol). 106 2.8.3 Cyclizations of Azides 2.126, 2.131, 2.134 and Z-2.131  A solution of azide 2.126 (402 mg, 1.08 mmol) Bu3SnH (409 mg, 1.4 mmol), AIBN (36 mg, 0.22 mmol) in degassed benzene (22 mL) was heated to 80 °C and stirred for 18 h. The solution was allowed to cool to room temperature and the solvent was removed by rotary evaporation. Analysis of the 1H NMR spectrum showed no remaining starting material, and products 2.127d and 2.128 in a 46:54 ratio. Pyrrolidine 16 was present in a 60:40 ratio of trans and cis isomers.   To a solution of azide 2.128 (186 mg, 0.5 mmol) and tributyltin hydride (218 mg, 0.75 mmol) in non-degassed benzene (10 mL) at ambient temperature was added triethylborane (0.5 mL, 1.0 M solution in hexane). The solution was stirred for 30 min in a round bottom flask open to the atomosphere. The solvent was removed by rotary evaporation. Analysis of the 1H NMR spectrum showed no remaining starting material, and products 2.127 and 2.128 in a 37:63 ratio. Pyrrolidine 2.128 was present in a 82:18 ratio of trans and cis isomers.                                                    d Häberli, A.; Leumann, C. J. Org. Lett., 2001, 3, 489. 107  A solution of azide 2.126 (186 mg, 0.5 mmol), Ph3SnH (228 mg, 0.65 mmol), AIBN (16.4 mg, 0.2 mmol) in degassed benzene (10 mL) was heated to 80 °C and stirred for 18 h. The solution was allowed to cool to room temperature and the solvent was removed by rotary evaporation. Analysis of the 1H NMR spectrum showed no remaining starting material, and products 2.127 and 2.128  in a 52:48 ratio. Pyrrolidine 2.127 was present in a 80:20 ratio of trans and cis isomers.   A solution of azide 2.131 (21 mg, 0.06 mmol) Bu3SnH (106 mg, 0.36 mmol), AIBN (9.2 mg, 0.08 mmol) in degassed benzene (6 mL) was heated to 80 °C and stirred for 18 h. The solution was allowed to cool to room temperature and the solvent was removed by rotary evaporation. Analysis of the 1H NMR spectrum showed no remaining starting material, and products 2.132 and 2.133 in a 54:46 ratio. Amine 14 was present in a 80:20 ratio of trans and cis isomers.   A solution of azide 2.134 (54 mg, 0.14 mmol) Bu3SnH (55 mg, 0.19 mmol), AIBN (6.1 mg, 0.16 mmol) in degassed benzene (20 mL) was heated to 80 °C and stirred for 4 h, and the solution was allowed to cool to room temperature and the solvent was removed by rotary evaporation. 108 Analysis of the 1H NMR spectrum showed no remaining starting material, and products 2.135 and 2.136 in a 79:21 ratio. Amine 2.135 was present in a 50:50 ratio of trans and cis isomers. Purification by flash chromatography (49:1 CH2Cl2/MeOH) afforded 28 mg of pyrrolidine 25 (57%) as a 1:1 mixture of cis and trans diastereomers. 1H NMR (400 MHz, CDCl3) δ 4.30-4.32 (m, 1H, cis), 4.11-4.16 (m, 1H, trans), 3.58-3.79 (m, 1H), 3.08-3.18 (m, 1H), 2.89-3.00 (m, 2H), 2.74-2.89 (m, 1H), 2.06 (broad s, 1H), 1.83-2.01 (m, 2H), 0.96 (t, J = 7.9 Hz, 9H), 0.90 (s, 9H), 0.59 (q, J = 7.9 Hz, 6H), 0.06 (s, 6H).   Azide Z-2.131 was taken up in benzene (10 mL) and the solution was degassed by bubbling with N2 for 30 min. The solution was then brought to reflux and a solution of tributyltin hydride (73 mg, 0.25 mmol) and AIBN (9 mg, 0.05 mmol) in benzene (2 mL) was added dropwise over 2 hours. After refluxing for an additional 11 h, the solution was allowed to cool to room temperature and the solvent was removed by rotary evaporation. Analysis of the 1H NMR spectrum showed no remaining starting material, and products 2.132 and 2.133 in a 80:20 ratio. Purification by flash chromatography (49:1 CH2Cl2/MeOH) afforded 12 mg of pyrrolidine 2.132 (77% from silyl enol ether 20) as the trans diastereomer. []D24 = –17.2° (c = 0.8, CH2Cl2); IR (neat) 2955, 2876, 1652, 1458 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.05-4.18 (m, 1H), 3.45-3.65 (m, 2H), 3.01-3.14 (m, 1H), 2.98-3.01 (m, 2H), 1.77-1.99 (m, 3H), 0.96 (t, J = 7.9 Hz, 18H), 0.60 (q, J = 7.9 Hz, 12H); 13C NMR (100 MHz, CDCl3) δ 73.9, 68.5, 63.4, 45.1, 35.6, 6.9, 5.0, 4.5; HRMS-ESI (m/z): [M+H]+ calcd for C17H40NO2Si2: 346.2598. Found: 346.2605.  109 2.8.4 Syntheses of Azides 2.108g,h  5-Hydroxy-3-methylpentyl 4-methylbenzenesulfonate (2.146a): To a solution of 3-methyl 1,5-petanediol (11.82 g, 100.0 mmol) and p-toluenesulfonyl chloride (3.81 g, 20.0 mmol) in CH2Cl2 (100 mL) at 0 °C was added triethylamine (3.04 g, 30.0 mmol) dropwise over 10 min. The resulting solution was stirred for 3 h, then quenched with water (50 mL) and extracted with CH2Cl2 (2x30 mL). The combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a pale yellow oil. Purification by flash chromatography (2:1 hexanes/EtOAc) afforded 4.55 g of the tosylate as a colourless oil.  Dimethylsulfoxide (2.61 g, 33.4 mmol) was added dropwise over 5 min to a solution of oxalyl chloride (2.54 g, 20 mmol) in CH2Cl2 (90 mL) at –78 °C. After stirring for 20 min, a solution of the tosylate (4.55 g, 16.7 mmol) in CH2Cl2 (42 mL) was added over 10 min. After stirring for 1 h at –78 °C, triethylamine (8.45 g, 84 mmol) was added and the reaction mixture was stirred for 40 min.  The solution was then warmed to ambient temperature and stirred for 2 h. The mixture was then washed with brine (50 mL) and extracted with CH2Cl2 (30 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a yellow oil. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded 3.05 g (68%) of aldehyde 2.146a as a clear, colourless oil. The spectroscopic properties matched those obtained by Dr. Huimin Zhai, who fully characterized this compound.  1H NMR (400 MHz, CDCl3) δ 9.63 (t, J = 1.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 3.97-4.09 (m, 2H), 2.40 (s, 3H), 2.32 (ddd, J = 16.4, 5.2, 1.6 Hz, 1H), 2.08-2.24 (m, 2H), 1.61-1.72 (m, 1H), 1.46- 1.57 (m, 1H), 0.86 (d, J = 6.4 Hz, 3H). 110   5-Azido-3-methylpentanal (2.138a): To a solution of tosylate 2.146a (2.25 g, 8.3 mmol) in DMF (30 mL) was added sodium azide (1.08 g, 16.6 mmol). The mixture was heated to 50 °C for 30 min, then allowed to cool to ambient temperature and diluted with Et2O (30 mL). The mixture was washed with water (2x15 mL), brine (15 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation to provide a yellow oil. Purification by flash chromatography (3:2 petroleum ether/Et2O) afforded 814 mg (69%) of azide 2.148a as a clear, colourless oil. IR (neat) 2961, 2977, 2089, 1721, 1462 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 3.20-3.37 (m, 2H), 2.31-2.45 (m, 1H), 2.18-2.31 (m, 1H), 2.03-2.18 (m, 1H),  1.50-1.67 (m, 1H), 1.28-1.50 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.6, 50.3, 48.4, 35.1, 25.2, 19.3; HRMS-ESI (m/z) [M+Na]+ calcd for C6H11N3ONa: 164.0800. Found: 164.0796.   (E)-(5-Azido-3-methylpent-1-enyloxy)(tert-butyl)dimethylsilane (E-2.108g): To a solution of aldehyde 2.148a (141 mg, 1.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (457 mg, 3.0 mmol) in CH2Cl2 (6 mL) was added tert-butyldimethylsilyl chloride (301 mg, 2.0 mmol). The solution was heated to 35 °C in a sealed tube for 18 h. The resulting yellow solution was then concentrated by rotary evaporation. Purification by flash chromatography (19:1 hexanes/EtOAc) afforded 243 mg (95%) of silyl enol ether E-2.108g (Z/E = 17:83) as a clear, colourless oil. IR 2955, 2930, 2858, 2092, 1660, 1472 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.26 (d, J = 11.9 Hz, 1H, E), 6.18 (d, J = 5.8 Hz, 1H, Z), 4.78 (dd, J = 11.9, 9.2 Hz, 1H, E), 4.21 (dd, J = 9.2, 5.8 Hz, 111 1H, Z), 3.19-3.30 (m, 2H), 2.71-2.84 (m, 1H), 1.58-1.69 (m, 1H), 1.43-1.54 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H), 0.93 (s, 9H), 0.14 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 140.3, 138.4, 115.9, 114.8, 49.9, 49.6, 36.4, 36.3, 30.0, 26.2, 25.7, 25.6, 22.0, 21.2, 18.3, –5.3, –5.5; HRMS-ESI (m/z) [M+Na]+ calcd for C12H25N3ONaSi: 278.1665. Found: 278.1668.   5-Hydroxy-3-phenylpentyl 4-methylbenzenesulfonate (2.145b): To a solution of 3- phenylpentane-1,5-diole (4.13 g, 23 mmol) and p-toluenesulfonyl chloride (3.28 g, 17.2 mmol) in CH2Cl2 (100 mL) at 0 °C was added triethylamine (2.33 g, 23 mmol) dropwise over 10 min. The resulting solution was stirred for 3 h, then quenched with water (50 mL) and extracted with CH2Cl2 (2x30 mL). The combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a pale yellow oil. Purification by flash chromatography (2:1 hexanes/EtOAc) afforded 3.01 g the tosylate as a colourless oil. Dimethylsulfoxide (1.41 g, 18 mmol) was added dropwise over 5 min to a solution of oxalyl chloride (1.37 g, 11 mmol) in CH2Cl2 (45 mL) at –78 °C. After stirring for 20 min, a solution of the tosylate (3.01 g, 9 mmol) in CH2Cl2 (23 mL) was added over 10 min. After stirring for 1 h at –78 °C, triethylamine (4.55 g, 45 mmol) was added and the reaction mixture was stirred for 40 min.  The solution was then warmed to ambient temperature and stirred for 2 h. The mixture was then washed with brine (50 mL) and extracted with CH2Cl2 (30 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a                                                  e Bryan, J. and Lok, K. P. Can. J. Chem. 1979, 57, 1025–1032. 112 yellow oil. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded 2.05 g (68%) of aldehyde 2.146b as a clear, colourless oil.  The spectroscopic properties matched those obtained by Dr. Huimin Zhai, who fully characterized this compound.  1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.17-7.30 (m, 3H), 7.06 (d, J = 6.8 Hz, 2H), 3.89-4.00 (m, 1H), 3.73-3.83 (m, 1H), 3.26-3.37 (m, 1H), 2.74 (dd, J = 16.8, 8.0 Hz, 1H), 2.66 (dd, J = 16.8, 6.8 Hz, 1H), 2.45 (s, 3H), 2.01-2.12 (m, 1H), 1.82-1.98 (m, 1H).   5-Azido-3-phenylpentanal (2.148b): To a solution of tosylate 2.146b (2.05 g, 6.2 mmol) in DMF (25 mL) was added sodium azide (800 mg, 12.3 mmol). The mixture was heated to 50 °C for 30 min, then allowed to cool to ambient temperature and diluted with Et2O (20 mL). The mixture was washed with water (2x15 mL), brine (15 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation to provide a yellow oil. Purification by flash chromatography (3:1 hexanes/EtOAc) afforded 942 mg (75%) of azide 2.148b as a clear, colourless oil. IR (neat) 3039, 2935, 2725, 2092, 1720, 1494 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H), 7.29-7.41 (m, 2H), 7.12-7.28 (m, 3H), 3.27-3.43 (m, 1H), 3.15-3.26 (m, 1H), 2.97-3.14 (m, 1H), 2.60-2.88 (m, 2H), 1.92-2.05 (m, 1H), 1.75-1.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 200.8, 142.0, 128.9, 127.4, 127.1, 50.2, 49.0, 37.0, 35.2; HRMS-ESI (m/z) [M+Na]+ calcd for C11H13N3ONa: 226.0956. Found: 226.0961.  113  (E)-(5-Azido-3-phenylpent-1-enyloxy)(tert-butyl)dimethylsilane (E-2.108h): To a solution of azide 2.148b (203 mg, 1.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (457 mg, 3.0 mmol) in CH2Cl2 (6 mL) was added tert-butyldimethylsilyl chloride (301 mg, 2.0 mmol). The solution was heated to 35 °C in a sealed tube for 18 h. The resulting yellow solution was then concentrated by rotary evaporation. Purification by flash chromatography (19:1 hexanes/EtOAc) afforded 302 mg (95%) of silyl enol ether E-2.108h (Z/E = 25:75) as a clear yellow oil. IR 2954, 2929, 2858, 2094, 1657, 1463 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.28-7.37 (m, 2H), 7.13-7.26 (m, 3H), 6.35 (d, J = 12.0 Hz, 1H, E), 6.28 (d, J = 5.8 Hz, 1H, Z), 5.15 (dd, J = 11.6, 9.2 Hz, 1H, E), 4.61 (dd, J = 9.6, 5.8 Hz, 1H, Z), 3.97 (dd, J = 16.0, 8.2 Hz, 1H, Z), 3.24-3.34 (m, 2H), 1.81-2.08 (m, 2H), 0.93 (s, 9H), 0.14 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 144.4, 141.3, 139.0, 128.6, 127.1, 126.3, 126.1, 113.9, 112.6, 49.7, 49.5, 41.2, 37.4, 35.8, 35.6, 25.7, 25.6, 18.3, –5.3; HRMS-ESI (m/z) [M+Na]+ calcd for C17H27N3ONaSi: 340.1821. Found: 340.1826.  2.8.5 Synthesis of Azide 2.152   5-Azido-4-(tert-butyldimethylsiloxy)pentan-1-ol (2.150): To a solution of epoxide 2.149f (2.74 g, 19.0 mmol) in MeOH (75 mL) was added a slurry of sodium azide (6.18 g, 95 mmol) and ammonium chloride (2.14 g, 40 mmol) in H2O (10 mL). The mixture was heated at 80 °C for 1 h, then allowed to cool to ambient temperature. The mixture was then taken up in H2O (80 mL)                                                  f Yudin, A. K; Chiang, J. P.; Adolfsson, H.; Copéret, C. J. Org. Chem., 2001, 66, 4713. 114 and extracted with EtOAc (3x40 mL). The combined organic extracts were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation to provide 2.78 g of the azide as a clear oil, which was used without further purification. The crude azide was then taken up in CH2Cl2 (50 mL), and tert-butyldimethylsilyl chloride (2.69 g, 17.8 mmol) and imidazole (1.53 g, 23 mmol) were added in one portion. After stirring for 3 h, additional tert- butyldimethylsilyl chloride (1.80 g, 12.0 mmol) and imidazole (1.53 g, 23 mmol), as well as 4- dimethylaminopyridine (200 mg, 1.6 mmol) were added and the resulting mixture was stirred for another 1.5 h. The mixture was then washed with water (50 mL) and extracted with CH2Cl2 (40 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation to provide clear oil. Purification by flash chromatography (4:1 hexanes/EtOAc) gave 3.96 g of silyl ether as a clear oil. This oil was taken up in MeOH (60 mL) and potassium carbonate (5.44 g, 39 mmol) was added. The mixture was stirred for 1 h, then taken up in Et2O (100 mL) and washed with saturated NH4Cl solution (2x50 mL). The organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation to provide the crude alcohol as a clear oil. Purification by flash chromatography (1:1 hexanes/Et2O) afforded 3.16 g (64% over 3 steps) of alcohol 2.150 as a clear, colourless oil. IR (neat) 2929, 2857, 2098, 1472, 1361, 1254 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.83-3.88 (m, 1H), 3.62-3.69 (m, 2H), 3.29 (dd, J = 12.3, 4.4 Hz, 1H), 3.20 (dd, J = 12.3, 5.8 Hz, 1H), 1.60- 1.64 (m, 4H), 0.91 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 71.4, 62.8, 56.3, 31.4, 28.2, 25.7, 18.0, –4.67, –4.73; HRMS-ESI (m/z) [M+Na]+ calcd for C11H25N3O2NaSi: 282.1614. Found: 282.1619.  115  5-Azido-4-(tert-butyldimethylsilyloxy)pentanal (2.151): Dimethylsulfoxide (781 mg, 10.0 mmol) was added dropwise over 2 min to a solution of oxalyl chloride (762 mg, 6.0 mmol) in CH2Cl2 (25 mL) at –78 °C. After stirring for 20 min, a solution of alcohol 2.150 (1.30 g, 5.0 mmol) in CH2Cl2 (13 mL) was added over 10 min. After stirring for 1 h at –78 °C, triethylamine (2.53 g, 25.0 mmol) was added. The solution was then warmed to ambient temperature and stirred for 15 min. The mixture was then washed with brine (50 mL) and extracted with CH2Cl2 (30 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a yellow oil. Purification by flash chromatography (4:1 hexanes/Et2O) affprded 803 mg (62%) of aldehyde 2.151 as a clear, colourless oil. IR (neat) 2929, 2099, 1725, 1254 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.78 (t, J = 1.3 Hz, 1H), 3.83-3.88 (m, 1H), 3.27 (dd, J = 12.8, 4.8 Hz, 1H), 3.15 (dd, J = 12.7, 5.4 Hz, 1H), 2.52 (dt, J = 7.3, 1.5 Hz, 2H), 1.75-1.94 (m, 2H), 0.90 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.6, 70.3, 56.3, 39.3, 26.7, 25.7, 17.9, –4.7, –4.8; HRMS-ESI (m/z) [M+Na] + calcd for C11H23N3O2NaSi: 280.1457. Found: 280.1453.   (E)-5-Azido-2-tert-butyl-dimethylsiloxy-1-(tert-butyldimethylsiloxy)pent-1-ene (2.152): To a solution of aldehyde 2.151 (386 mg, 1.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (673 mg, 4.5 mmol) in CH2Cl2 (9 mL) was added tert-butyldimethylsilyl chloride (452 mg, 3.0 mmol). The solution was heated to 35 °C in a sealed tube for 18 h. The resulting yellow solution 116 was then concentrated by rotary evaporation. Purification by flash chromatography (19:1 hexanes/EtOAc) afforded 553 mg (99%) of silyl enol ether 2.152 (Z/E = 24:76) as a clear yellow oil. IR 2929, 2099, 1662, 1253 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.29 (d, J = 12.0 Hz, 1H, E), 4.94 (td, J = 12.0, 7.6 Hz, 1H, E), 4.45 (td, J = 7.6, 5.6 Hz, 1H, Z), 3.73-3.89 (m, 1H), 3.28 (dd, J = 12.4, 4.0 Hz, 1H), 3.16 (dd, J = 12.4, 6.4 Hz, 1H), 2.17-2.36 (m, 2H), 0.96 (s, 9H), 0.95 (s, 9H), 0.18 (s, 3H), 0.17 (s, 3H), 0.16 (s, 3H), 0.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.5, 140.6, 105.7, 104.3, 72.1, 72.0, 56.4, 55.9, 33.2, 29.7. 25.8, 25.7, 18.3, 18.0, -4.7, -4.8, -5.2; HRMS-ESI (m/z) [M+Na]+ calcd for C17H37N3O2NaSi: 394.2322. Found: 394.2317.  2.8.6 Cyclizations of Azides E-2.108g,h and 2.152 General Cyclization Procedure A solution of Bu3SnH (1.2 equiv), AIBN (0.1 equiv), and silyl enol ether in degassed benzene (0.05 M) was heated to 80 °C and stirred for the time specified, and the solution was allowed to cool to room temperature and the solvent was removed by rotary evaporation. Purification by flash chromatography afforded the cyclized products.  2-(tert-Butyldimethylsiloxymethyl)-3-methylpyrrolidine (2.111g): Silyl enol ether E-2.108g (90 mg, 0.35 mmol) was subjected to the general cyclization procedure for 4 h. Purification by flash chromatography (19:1 EtOAc/MeOH) afforded 58 mg (72%) of pyrrolidine 2.111g (trans:cis = 79:21) as a light yellow oil. IR (neat) 2928, 2856, 1472, 1463, 1361, 1252 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.68 (dd, J = 10.1, 4.3 Hz, 1H), 3.55 (dd, J = 10.1, 5.5 Hz, 1H), 2.86-3.00 (m, 2H), 2.59-2.65 (m, 1H), 1.91-2.02 (m, 1H), 1.76-1.86 (m, 1H), 1.03 (d, J = 6.6 Hz, 3H, trans), 117 0.96 (d, J = 6.9 Hz, 0.8H, cis),0.89 (s, 9H), 0.05 (s, 6H). Full characterization was performed by Dr. Huimin Zhai, who obtained pyrrolidine 2.111g from cyclization of Z-2.108g.  2-(tert-Butyldimethylsiloxymethyl)-3-methylpyrrolidine (2.111h): Silyl enol ether E-2.108h (317 mg, 1.0 mmol) was subjected to the general cyclization procedure for 2 h. Purification by flash chromatography (19:1 CH2Cl2/MeOH) afforded 204 mg (70%) of pyrrolidine 2.111h (trans:cis >95:5) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.19-7.33 (m, 5H), 3.73 (dd, J = 10.2, 3.4 Hz, 1H), 3.54 (dd, J = 10.2, 4.4 Hz, 1H), 3.14-3.21 (m, 3H), 3.00 (q, J = 8.5 Hz, 1H), 2.24- 2.33 (m, 1H), 1.95-2.05 (m, 1H), 0.90 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H). Full characterization was performed by Dr. Huimin Zhai, who obtained pyrrolidine 2.111h from cyclization of Z- 2.108h.  2-(tert-Butyldimethylsiloxymethyl)-3-methylpyrrolidine (2.153): Silyl enol ether 2.152 (372 mg, 1.0 mmol) was subjected to the general cyclization procedure for 18h. Purification by flash chromatography (19:1 CH2Cl2/MeOH) gave 300 mg (86%) of pyrrolidine 2.153 (cis:trans = 75:25) as a light yellow oil. IR (neat) 2928, 2856, 1472, 1463, 1361, 1252 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.31-4.36 (m, 1H), 3.64 (d, J = 5.4 Hz, 1.5H, cis), 3.35-3.57 (m, 0.25H, trans), 3.34-3.43 (m, 0.25H, trans), 3.04-3.17 (m, 1H), 2.83-2.90 (m, 1.5H, cis), 2.58-2.76 (m, 0.40H, trans), 1.99-2.06 (m, 1H), 1.86 (br, 1H), 1.46 (ddd, J = 10.5, 6.7, 3.8 Hz, 1H), 0.90 (s, 9H), 0.88 (s, 9H), 0.04-0.06 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 73.4, 65.6, 59.8, 55.8, 38.1, 25.9, 25.8, 25.2, 18.4, 18.1, –4.8, –5.4; HRMS-ESI (m/z) [M+H]+  calcd for C17H40NO2Si2: 346.2598. Found: 346.2590. 118     CHAPTER THREE: Photoinduced Electron Transfer-Promoted Redox Fragmentation of N-Alkoxyphthalimides   119 Chapter 3. Photoinduced Electron Transfer-Promoted Redox Fragmentation of N-Alkoxyphthalimides 3.1 Introduction As discussed in Chapter 1, N-alkoxyphthalimides provide ready access to alkoxy radicals.  This alkoxy radical precursor is attractive to synthetic chemists as it can be readily installed, is bench-stable and can be carried through a number of synthetic steps.  However, to date, the most commonly used method for alkoxy radical generation from N-alkoxyphthalimides is by reaction with a stoichiometric amount of tributyltin hydride and a radical initiator (such as AIBN).  While this is an efficient method of generating alkoxy radicals, organotin compounds exhibit high levels of toxicity and removal of the tin by-products from reaction mixtures is often difficult.105  Tris(trimethylsilyl)silane may be used in place of the tributyltin hydride, however it is an expensive reagent that must be used in stoichiometric amounts.  Furthermore, the Si-H bond is stronger than the Sn-H bond and the alkoxy radical is generated at a much slower rate.  Thus, the utility of N-alkoxyphthalimides as alkoxy radical precursors would be improved if a new mild and non-toxic method for their homolysis were developed. Phthalimide derivatives have a rich history of photochemical reactivity, highlighted in seminal reports by Kanaoka,106 Mazzocchi,107 and Mariano and Yoon.108  While alkylphthalimides are known to undergo a variety of radical reactions induced by photoinduced electron transfer (PET), there a few examples of similar processes involving oxygenated phthalimides.  Oda and Okada have demonstrated that single electron reduction of N- acyloxyphthalimides triggers N-O bond homolysis, mediated by visible light and a Ru(bpy)3 2+ catalyst.109  Visible light photocatalysis has been known to synthetic organic chemists since the 1970s; however, the first decade of this century marked a renaissance in the applications of 120 photoredox processes.  The recent rapid expansion in methods using Ru(bpy)3 2+ visible light photocatalysis highlights its utility as a mild method for generating free radicals and initiating SET reactions. We hypothesized that a PET reaction mediated by a Ru(bpy)3 2+ photocatalyst could trigger N-O bond homolysis in N-alkoxyphthalimides to provide access to alkoxy radicals.  Surprisingly, we observed that N-alkoxyphthalimides underwent a redox fragmentation reaction upon treatment with visible light photocatalytic conditions to give an aldehyde and phthalimide.  This chapter will discuss the photoreactivity of alkylphthalimides.  I will also provide an overview of the field of Ru(bpy)3 2+ visible light photocatalysis and its applications to oxygenated phthalimide derivatives.  Mechanistic investigations and synthetic applications of the PET- promoted redox fragmentation of N-alkoxyphthalimides will be presented.  3.2 Photochemistry and Radical Reactivity of Alkylphthalimide Derivatives Among the most active areas of study in the field of organic photochemistry has been the behaviour of carbonyl groups.110  While initial studies largely focused on the photoreactivity of aldehydes and ketones, starting in the 1970’s, cyclic imides, and in particular phthalimides, began to receive increased attention from the photochemical community.106  In addition to photochemical reactions characteristic of ketones, such as additions, reductions, cycloadditions and Norrish reactions, phthalimide derivatives undergo several unique transformations initiated by excited state SET.111 N-Alkylphthalimides absorb light at a wavelength of approximately 290 nm, corresponding to a π,π* transition.106  Thus, the reactivity of phthalimides under UV irradiation stems from the putative biradical intermediate 3.2 (Scheme 3.1).  In solvents bearing readily abstractable 121 hydrogen atoms, this intermediate is reduced by a hydrogen atom transfer.  For example, irradiation of N-methylphthalimide (3.1) in THF affords the photoadduct 3.8 as well as a small amount of reduced product 3.7 (Scheme 3.1).112  A similar product distribution is observed when dioxane or diethyl ether is used as the solvent.  In contrast to the well-known photoreduction of benzophenone,113 the pinacol-like product 3.6 was not observed under these conditions.  Scheme 3.1. Photoinduced radical abstraction and recombination of N-methylphthalimide (3.1) and tetrahydrofuran (3.3). Hydrogen atom transfer to the phthalimide biradical intermediate can occur intramolecularly in N-alkylphthalimides with longer alkyl chains.  This results in a Norrish type II reaction, similar to what has been previously observed in other carbonyl systems (Scheme 3.2).114  However, Norrish type II reactions of N-alkylphthalimides give unique products, as the azacyclobutanol intermediate (3.11) can undergo a ring expansion.  Thus, this reaction can be exploited for the synthesis of benzazepinediones (3.12).  122  Scheme 3.2. Photoinduced Norrish type II reaction of N-propylphthalimide (3.9).  Unlike their simple ketone counterparts, irradiation of N-alkylphthalimide substrates containing a good electron donor in the N-tether results in an SET to the phthalimide.  These photoinduced electron transfer (PET) reactions are fast processes and will outcompete 1,5- hydrogen atom transfers.  A representative example by Mariano illustrates the difference in reactivity between phthalimide 3.9 (Scheme 3.2) and silyl-containing phthalimide 3.13 (Scheme 3.3).115  While 3.13 possesses a hydrogen gamma to the carbonyl, and thus could undergo a 1,5- hydrogen atom transfer, an intramolecular electron transfer from the C-Si bond occurs exclusively to provide amidol 3.16 in near quantitative yield.  This mechanism is supported by the results of a deuterium labelling study (Scheme 3.4).  When the reaction is run in 30% D2O- CD3CN and monitored by 1H-NMR only the O-D analog of 3.16 is observed.  No C-D incorporation is observed, suggesting that the reaction does not occur via a 1,6-hydrogen atom transfer followed by protodesilylation.  This mode of reactivity is a consequence of the large excited-state reduction potentials of phthalimides.  If the oxidation potential of the electron donor is less than 2.1 V,116 the free energy of the SET to the photoexcited phthalimide will be negative and occur rapidly (k = 1 x 10 10 M-1s-1).117  The reactivity of phthalimides under photo- induced electron transfer (PET) conditions has been applied to the synthesis of a variety of heterocycles. 123   Scheme 3.3 Photoinduced intramolecular SET reaction.   Scheme 3.4. Deuterium-labelling study to distinguish between an SET or a hydrogen abstraction mechanism. In addition to intramolecular PET processes, phthalimides also undergo intermolecular PET in the presence of good electron donors (Scheme 3.5).118   In an example by Mariano, an alpha- silyl thioether (3.19) acts as the single electron donor.119  Photo-excitation of the phthalimide induces electron transfer from the sulfur. The sulfur radical cation resulting from this transfer is stabilized by hyperconjugation of the alpha σC-Si bond, and thus solvent-promoted desilylation 124 leads to formation of a carbon radical species (3.23).  Recombination of phthalimide radical 3.22 and carbon radical 3.23 provides the product (3.24) in good yield.  Scheme 3.5. Photoinduced intermolecular SET.  The phthalimide ground state is also capable of undergoing single electron reduction.  As in PET processes, a radical anion intermediate is formed.  An example by Chiara demonstrates the utility of samarium-mediated SET of phthalimides (Scheme 3.6).120  Treatment of bis- phthalimide 3.25 with SmI2 provides the intramolecular pinacol-like coupling product 3.26 in excellent yield.  Previous attempts to cyclize the same substrate under photochemical conditions provided the product in much lower yield.121  Therefore, SET processes can be complementary to photochemical activation of phthalimides and in some cases, enhance the reactivity of these substrates. 125  Scheme 3.6. Samarium-mediated SET and photoinduced cyclization of bis-phthalimide 3.25.  3.3 Single Electron Transfer Reactions Mediated by Visible Light As described in the previous section, phthalimides display unique reactivity initiated by photoinduced single electron transfer.  However, UV irradiation must be used to effect these reactions, because phthalimides, like most organic molecules, do not absorb wavelengths in the visible spectrum.  Visible light is an attractive mediator of chemical reactions as sunlight is a cheap and abundant energy source and obviates the need for high-intensity UV irradiation setups.122  Because ultraviolet wavelengths are not abundant in the solar spectrum, photoreactions initiated by sunlight require an external reagent that absorbs visible light and can act as a single electron shuttle. Both metal-based and organic dyes have been known as single electron transfer agents since the 1970s.  However, there were few examples of reactions using these visible light photocatalysts until very recently.  Following reports in 2008 by Yoon and MacMillan utilizing visible light photocatalysis to promote SET reactions under visible light irradiation, there has 126 been a rapid expansion in the applications of this methodology to a variety of organic transformations.  By far, the most widely used visible light photocatalysts are Ru(bpy)3 2+ salts.  The following section will detail their unique photoredox properties and applications to organic synthesis.  3.4 Photoredox Properties of Ruthenium Bipyridyl Complexes    Figure 3.1. Ruthenium bipyridyl complex 3.27. The synthesis of Ru(bpy)3 2+ salts was first reported by Burstall in 1936 (Figure 3.1, 3.27).123 However, it was not until over 30 years later that the unique photo- and electrochemical properties of this complex were investigated.124,125  In particular, research efforts have focused on the conversion of solar energy into electrical current or into fuel by photoreduction of water and CO2. 126  Applications of this catalyst, and to a lesser extent iridium-based catalysts,127 to synthetic organic chemistry began to be developed in the 1970s.  The Ru(bpy)3 2+ catalyst is attractive to synthetic chemists as, in addition to its exceptional chemical stability, the photoexcited state of this complex is able to serve as both a single electron donor or acceptor, depending on the conditions employed.   127  The absorption spectrum of Ru(bpy)3 2+ exhibits a strong band centred at 452 nm, well within the visible spectrum.  Irradiation with visible light produces a long-lived (600 s) photoexcited state, Ru(bpy)3 2+* with high quantum efficiency.128  Since the absorption band of Ru(bpy)3 2+ is broad, there is a wide range of wavelengths in the visible spectrum that can induce photoexcitation.  This excited state can then be readily oxidized or reduced by the appropriate quencher (Figure 3.2).  Oxidative quenching generates Ru(bpy)3 3+, a strong oxidant (1.29 V vs. SCE in CH3CN), while reductive quenching generates Ru(bpy)3 +, a strong reductant (-1.33 V vs. SCE in CH3CN). 129  A subsequent single electron transfer regenerates the Ru(bpy)3 2+ ground state.  The ability of the photocatalyst to shuttle between three oxidation states makes it a highly versatile mediator of single electron transfer (SET) between an electron-rich donor and an electron-poor acceptor.  Figure 3.2. Photoredox reactivity of Ru(bpy)3 2+ and representative quenchers.130  128 3.5 Photoinduced Electron Transfer (PET) Reactions  The versatility of photocatalysis has been exploited to effect a number of organic transformations.  These photo-induced electron transfer (PET) reactions can be broadly classified into three categories: oxidative, which involve a net loss of electrons from the substrate, reductive, which involve a net gain of electrons into the substrate and redox neutral, in which the substrate initially undergoes either an oxidative or reductive SET, followed by a subsequent transfer that restores the initial redox state of the substrate.  In all classes, a reductive or oxidative quencher is employed to serve as either the donor or acceptor of electrons.  3.5.1 Reductive PET Reactions  Scheme 3.7. Photoreduction of phenacyl sulfonium salt 3.28 and related substrates.  One of the earliest examples of Ru(bpy)3 2+ as a photoredox catalyst was demonstrated by Kellogg in 1978 (Scheme 3.7).131  This work involved the reduction of sulfonium salt 3.28 by the 129 Hantzsch ester (3.29), which acts as the reductive quencher and hydrogen source.  Ammonium salt 3.32 and phosphonium salt 3.33 also underwent reduction under these conditions, albeit in much lower yields.  In the absence of Ru(bpy)3Cl2, the reaction of 3.28 and 3.29 reaches complete conversion in 48 h upon exposure to ambient light.  The addition of 1 mol% of Ru(bpy)3Cl2 led to an acceleration of the reaction, such that full conversion was achieved in only 0.3 h.  The authors suggested that this acceleration is due to participation of Ru(bpy)3 2+ in SET reactions between the Hantzsch ester and 3.28, although no mechanism was proposed.  In a subsequent report, Kellogg disclosed the reduction of 4-nitrobenzyl bromide under the same conditions.132  Benzyl bromide did not undergo reduction, presumably because it is not sufficiently electron-deficient for SET under these conditions.  Scheme 3.8. Photoreduction of benzyl bromide (3.36), both with and without Ru(bpy)3 2+ catalyst. Tanaka later demonstrated the feasibility of reducing benzyl bromide using a photoredox process (Scheme 3.8), in which 1-benzyl-1,4-dihydronicotinamide (BNAH, 3.37), serves as the reductive quencher and hydrogen source.  Interestingly, the reaction goes to completion both with and without the Ru(bpy)3 2+ catalyst, but with divergent results.  In the absence of catalyst, toluene (3.38) is the major product, along with a small amount of dimer 3.39.  However, in the presence of catalyst, this product distribution is reversed.  Tanaka’s mechanistic rationale is 130 presented in Scheme 3.9.  Both mechanisms (A and B) proceed through a benzyl radical.  In mechanism A, this benzyl radical is subsequently reduced by another SET from Ru(bpy)3 +.  The anion formed then acts a nucleophile in a reaction benzyl bromide, forming dimer 3.39.  It can be inferred that reduction of the benzyl radical by Ru(bpy)3 + outcompetes hydride transfer from either BNAH or BNAH radical.  The authors noted some similarity to reductions using sodium naphthalenide, which also generates benzyl anions from benzyl halides via a two-electron transfer.  In the absence of Ru(bpy)3 2+ catalyst (mechanism B), this second reduction cannot occur.  Therefore, the benzyl radical generated from reduction of benzyl bromide accepts a hydrogen from BNAH to afford toluene as the major product.  A trace amount of dimer 3.39 is formed by radical recombination.  Omission of pyridine under both catalytic and catalyst-free conditions led to significantly reduced yields, although its role in the SET mechanism has not been elucidated. 131  Scheme 3.9. Mechanism of photoreduction of benzyl bromide in the presence of Ru(bpy)3 2+ (A) and in the absence of photocatalyst (B).  The scope of reductive debromination reactions by visible light photocatalysis was expanded upon by Kellogg in 1985 (Scheme 3.10).133  Complete reduction of bromoacetophenone (3.40) by dihydrobenzothiazole 3.41 was achieved in the absence of Ru(bpy)3 2+ catalyst by heating the reaction mixture to 55 °C for 20 h.  Addition of Ru(bpy)3Cl2  and irradiation of the reaction mixture with ambient light allowed for full conversion in only 1.3 h at ambient temperature.  A variety of activated bromides were explored and higher yields were achieved in the reduction of the most electron-deficient substrates. 132  Scheme 3.10. Ru(bpy)3 2+-promoted photoreduction of activated bromides in the presence of dihydrobenzothiazole 3.41.  133  Scheme 3.11. Radical cyclization initiated by visible-light photocatalysis. Visible light photocatalysis began to receive increased attention at the beginning of the 21st century as more chemists recognized the synthetic potential of this mode of reactivity.  Many utilized visible light photocatalysis as a mild and tin-free method for generating carbon radicals.  One example by Stephenson involves photocatalyzed debromination to effect a classical intramolecular radical cyclization (Scheme 3.11).134  A mechanism for this transformation was proposed (Scheme 3.12).  After reductive quenching of the photoexcited catalyst by Et3N, the C-Br bond is reduced to generate carbon radical 3.58.  This radical undergoes a 5-exo cyclization onto the pendant alkene.  The reaction is terminated by a hydride transfer from the triethylammonium radical cation to afford the cyclized product 3.50 and an iminium by-product (3.61).  Reduction of bromomalonate derivatives proceeded in high yields to give the corresponding cyclic products (3.51, 3.52 and 3.53) under Ru(bpy)3 2+ catalysis.  However treatment of less electron-deficient substrates, such as those bearing only one electron-134 withdrawing group alpha to the bromide, resulted in recovery of starting material.  Thus, an iridium-based photocatalyst (3.57) was utilized.  Ir(ppy)2(dtbbpy)PF6 (Figure 3.1, 3.57) undergoes the same SET mechanism as its Ru-based analog.  However, the reductive potential of Ir2+ (1.51 V vs. SCE) is higher than that of Ru+ (1.31 V vs. SCE).  Therefore, it is able to efficiently reduce less electron-deficient substrates to afford cyclic products 3.54, 3.55 and 3.56.    Scheme 3.12. Mechanism of radical cyclization initiated by photoredox catalysis. Gagné utilized a similar strategy, coupling photocatalytic debromination with a subsequent intermolecular radical reaction (Scheme 3.13).135  A nucleophilic carbon radical is generated by photocatalyzed reduction of a glycosyl bromide derivative (3.62).  Addition of this radical to an electron-poor acceptor affords α-C-glycoside 3.65 as a single anomer.  This work is reminiscent of older studies by Giese, which utilized the same substrates under standard stannyl radical conditions and produced similar results.136  In contrast to the work of Stephenson, the amine 135 used as the reductive quencher (iPr2NEt) was not an adequate hydride donor for the termination step.  Hantzsch ester (3.63) was added to suppress radical polymerization.  Scheme 3.13. Photocatalyzed reduction of glycosyl bromide 3.62 to initiate an intermolecular radical addition. Visible light photocatalysis has been applied to the reduction of carbonyls.  Studies by Willner137 and Garcia138 have demonstrated that both the reductive and oxidative quenching of Ru(bpy)3 2+* can be exploited.  Willner’s work preceded that of Garcia, and utilized Et3N as a reductive quencher (Scheme 3.14).  The reduced photocatalyst, Ru(bpy)3 +, then transfers a single electron to the ketone thus regenerating the ground state catalyst.  A hydrogen atom transfer from the radical cation of Et3N (3.60) to radical anion 3.61 completes the reduction of the substrate.  As in previous examples of reductive photocatalysis, the amine serves both a single electron donor and a hydrogen atom source. 136  Scheme 3.14. Photocatalyzed reduction of activated ketones using reductive quenching of Ru(bpy)3 2+  by Et3N.   Scheme 3.15. Photocatalyzed reduction of activated ketones using oxidative quenching of Ru(bpy)3 2+  by MV 2+. 137  While García’s work in 2006138 involved the same net reduction reaction, the mechanism proceeds through an oxidative quenching of Ru(bpy)2+* (Scheme 3.15).  This reduction utilizes a catalytic amount of methylviologen (MV2+, 3.70)139 to oxidize Ru(bpy)2+* (Scheme 3.16).  After this single electron transfer step, the resulting viologen radical intermediate (3.72) abstracts a hydrogen from the solvent, isopropanol.  The reduced viologen derivative (MVH+) subsequently transfers a hydride to the carbonyl of the substrate.  The ground state Ru(bpy)3 2+ catalyst is regenerated by a single electron transfer from TEOA.  When the reaction is carried out in the absence of ketone, MVH+ can be detected by HPLC-MS.  Furthermore, if a non-hydrogen donating solvent is used in place of isopropanol, no reduced product is formed and no MVH+ is observed.  UV-Vis spectroscopy of this reaction mixture exhibited a band (=600 nm) consistent with an accumulation of viologen radical 3.72. These data support the proposed single electron transfer from Ru(bpy)3 2+* to MV2+, followed by hydrogen transfer from isopropanol to the viologen radical 3.72.  Acetophenone and cyclohexanone were also reduced to their corresponding alcohols in 80% and 78% yields, respectively, demonstrating that activation of the carbonyl is not required for the reaction to occur.  Furthermore, there is potential for an enantioselective variant of this reaction if a chiral viologen catalyst is used. 138  Scheme 3.16. Mechanism of ketone photoreduction using oxidative quenching of Ru(bpy)3 2+  by MV2+. 3.5.2 Oxidative PET Reactions  Because visible light photocatalysts can shuttle between 3 different oxidation states, they can be used to effect oxidations in addition to reductions.  As in the aforementioned examples of reductive photocatalysis, either the reductive or oxidative quenching cycles can be exploited.  Regardless of the quenching mechanism, this subclass of reactions results in products with an overall higher oxidation state than the substrate. 139  Scheme 3.17. Photooxidation of aryl alcohols to aldehydes via visible-light photocatalysis.  An early example of oxidation by visible light photocatalysis was published by Deronzier and Cano-Yelo in 1984 (Scheme 3.17) and involved the oxidation of benzyl alcohols.140  Aryldiazonium salt (3.77) was employed as the electron acceptor and oxidative quencher for RuL3 2+* (Scheme 3.18).  Following SET to aryldiazonium 3.77 from RuL3 2+*, alcohol 3.76 transfers an electron to RuL3 3+, regenerating the ground state catalyst.  Hydrogen transfer from the radical cation 3.81 to aryl radical 3.82 followed by deprotonation by collidine affords the oxidized product, 3.78.  A side reaction of aryl radical 3.81 is a Pschorr cyclization to afford fluorenone 3.80.141  A number of primary benzylic alcohols were investigated as substrates.  In accordance with the oxidative mechanism, the best yield was achieved with an electron-rich system.  140  Scheme 3.18. Mechanism of photocatalytic aryl alcohol oxidation.  A more recent example by Jiao combined organocatalysis and photocatalysis to effect oxidations of activated alkyl halides (Scheme 3.19).142  A variety of bromides and chlorides were efficiently oxidized, but all substrates required double activation alpha to the oxidized carbon; all substrates contained either two aryl groups, or one aryl group and one electron-withdrawing group.  A catalytic amount of 4-methoxypyridine was crucial to the success of this reaction.  A nucleophilic displacement by the organocatalyst forms cationic intermediate 3.86 (Scheme 3.20).  Initially, a sacrificial amount of this intermediate is thought to react with air and base to produce a radical intermediate capable of reductively quenching Ru(bpy)3 2+*.  The Ru(bpy)3 + formed after this single electron transfer then transfers an electron to cationic intermediate 3.86, which 141 fragments to regenerate the organocatalyst and a benzyl radical (3.88).  Trapping of the benzyl radical and further oxidation by molecular oxygen leads to the carbonyl-containing product 3.66a.  The superoxide radical (O2 –) formed in the final oxidation step can then act as the reductive quencher in the catalytic cycle.  Although this reaction proceeds through an initial reduction of the substrate by Ru(bpy)3+, further steps lead to an overall oxidation.  Scheme 3.19. Aerobic oxidation of an activated bromide through a combination of organocatalysis and visible-light photocatalysis.   Scheme 3.20. Mechanism of aerobic photooxidation. The role of molecular oxygen in this mechanism was further probed by conducting labelling experiments (Scheme 3.21).  When the reaction is carried out in an atmosphere of 18O2, 18O was incorporated into carbonyl of the product (18O-3.66a).  Conversely, inclusion of labelled water 142 (H2 18O) in the reaction conditions did not lead to formation of a labelled product.  These experiments suggest that the oxygen in the product results from trapping of a benzyl radical by molecular oxygen.   Scheme 3.21. Isotopic labelling experiment to determine origin of oxygen atom.  Carbon-nitrogen bond oxidations by visible light photocatalysis have been studied by Stephenson.143  Oxidation of tertiary amines to iminium ions had previously been observed in reductive dehalogenation reactions (Scheme 3.12).  Stephenson hypothesized that visible light photocatalysis may be a synthetically viable method of generating an iminium ion, utilizing an alkyl halide as the oxidant.  Indeed, treatment of amine 3.90144 with Ru(bpy)3 2+ in the presence of bromomalonate derivative 3.46 led to full conversion to methoxyaminal 3.92, likely resulting from trapping of iminium 3.91 with methanol (Scheme 3.22).  Exclusion of the alkyl bromide (3.46) from the reaction conditions provided full conversion to 3.92, albeit at a much slower rate.  An aza-Henry reaction145 was also effected under the same conditions, utilizing nitromethane in place of methanol as the solvent.  While comparable yields of aza-Henry product 3.93 were obtained using either Ru(bpy)3Cl2 and Ir(ppy)2(dtbbpy)PF6, the iridium-based catalyst provided a significant rate acceleration. 143  Scheme 3.22. Photooxidation of tetrahydroisoquinolone 3.90 to iminium 3.91, followed by nucleophilic addition.  The proposed mechanism for this aza-Henzy reaction is depicted in Scheme 3.23.  The photoexcited catalyst (IrL3 3+*) undergoes reductive quenching by the substrate (3.90), generating radical cation 3.94.  The ground state catalyst is regenerated by a SET from an oxidant.  A hydrogen atom transfer from radical cation 3.94 to the reduced oxidant generates iminium 3.91, which is trapped by the solvent to afford the product (3.93).  While Stephenson speculates that the oxidant in this reaction could be either molecular oxygen or nitromethane, there is insufficient experimental evidence to definitively establish the identity of the oxidant.  Degassing the reaction mixture prior to irradiation slows the rate somewhat, which implies that oxygen does play a role in the mechanism but is not necessarily required.  Furthermore, products resulting from nitromethane reduction were not observed by 1H NMR spectroscopy.  Therefore, while it is plausible that both oxygen and nitromethane act as oxidants in this mechanism, further evidence is needed to support this hypothesis.  144  Scheme 3.23. Mechanism of amine photooxidation.  A variety of N-aryltetrahydroisoquinolines were synthesized in excellent yields under the optimized photocatalysis conditions.  However, the oxidation of pyrrolidine 3.95 provided a low yield of the aza-Henry product 3.96 (Scheme 3.24).  Therefore, the scope of this reaction is limited to substrates activated by an aryl ring.  Nucleophiles other than nitromethane were investigated by Rueping (Scheme 3.25).146  In this study, the iminium generated by the photocatalyzed oxidation underwent a Mannich reaction catalyzed by L-proline.  Scheme 3.24. Photooxidative aza-Henry reaction of pyrrolidine 3.95.   Scheme 3.25. Photoredox- and organocatalytic Mannich reaction.   145  Scheme 3.26. Visible-light photocatalytic deprotection of PMB ether 3.98.  Subsequent to the work on iminium generation, Stephenson employed a similar strategy for the photocatalytic deprotection of PMB ethers (Scheme 3.26).147  However, this reaction is mechanistically distinct in that it exploits the oxidative, rather than reductive, quenching of the excited photocatalyst by bromotrichloromethane (Scheme 3.27).  A single electron is subsequently transferred from the aryl ring of the substrate (3.98) to regenerate the ground state catalyst (IrL3 3+).  A hydrogen atom from radical cation 3.104 is transferred to the trichloromethyl radical generated from oxidative quenching.  This step forms oxycarbenium ion 3.105 and chloroform, which can be observed by 1H NMR and GC in the reaction mixture.  Finally, hydrolysis of oxycarbenium ion 3.105 affords the free alcohol product in good yield.  This reaction can be seen as complementary and mechanistically similar to the traditional deprotection by stoichiometric DDQ, as both reactions proceed through SET from the aryl ring.148  Photocatalysis, however, offers a distinct advantage in that the by-product of the oxidant is volatile and thus allows for simplified purification.  146  Scheme 3.27. Mechanism of photocatalytic PMB deprotection. 3.5.3 Redox Neutral PET Reactions   In the aforementioned examples, reactions utilizing visible light photocatalysis resulted in products that are either oxidized or reduced relative to their parent starting materials.  There is another subclass of reactions in which there is no net oxidation state change, as one SET is followed by another in the opposite direction.  The seminal works of Yoon and MacMillan, which sparked a renewed interest in this field, fall under this category. 147  Scheme 3.28. Enantioselective α-alkylation of aldehydes by a combination of photoredox catalysis and amine organocatalysis. In 2008, MacMillan reported a transformation that merged photoredox catalysis using Ru(bpy)3 2+ with asymmetric organocatalysis (Scheme 3.28).149  Using organocatalyst 3.108 and standard photoredox conditions, aldehyde 3.107 was asymmetrically alkylated with various activated alkyl halides.  This intermolecular alpha-alkylation of aldehydes utilizes SOMO activation of enamines, a mode of reactivity previously employed by MacMillan using stoichiometric oxidants.150  In the photoredox work, a sacrificial amount of enamine 3.113 (generated from aldehyde 3.107 and organocatalyst 3.108) acts as a reductive quencher for Ru(bpy)3 2+* (Scheme 3.29).  Ru(bpy)3+ then transfers a single electron to the alkyl bromide, generating carbon radical 3.116.  Addition of this carbon radical to enamine 3.113 is followed by oxidation of the resulting radical (3.114) by Ru(bpy)3 2+*.  Thus, carbon radical 3.114 acts as the reductive quencher of Ru(bpy)3 2+* for the remainder of the catalytic cycle.  Finally, hydrolysis of the iminium generated by reductive quenching affords the chiral alkylated product 3.109.  A range of electron-deficient alpha-bromo carbonyls were investigated as alkylating agents (Scheme 3.28), providing their corresponding products in excellent yields with high 148 enantiopurity (88-99% ee).  MacMillan has extended this work to utilize other alkylating sources (Scheme 3.30), specifically trifluoromethyliodide151 and aryl bromides.152   Scheme 3.29. Mechanism of enantioselective photocatalytic α-alkylation.  149  Scheme 3.30. Extension of enantioselective photocatalytic α-alkylation.  150  Scheme 3.31. Mechanism of [2+2] enone cycloaddition mediated by Ru(bpy)3 2+ visible light photocatalysis. Yoon has applied photoredox catalysis to effect formal [2+2] cycloadditions of aryl enones (Scheme 3.31).153  Whereas classical [2+2] cycloadditions necessitate the use of high-intensity UV radiation, this photocatalytic reaction can be conducted using incident sunlight.  This methodology utilizes Ru(bpy)3+, generated from the reductive quenching of Ru(bpy)3 2+* by iPr2NEt, as a single electron reductant.  Radical anion 3.125 undergoes a subsequent cycloaddition, followed by single electron oxidation by the radical cation of iPr2NEt or Ru(bpy)3 2+* to afford the cyclobutanone product (3.128).  Excellent yields and diastereoselectivity of the cyclobutanone products were reported.  The lithium salt additive (LiBF4) is thought to act as a Lewis acid, activating the enone for one-electron reduction.  Yoon’s investigations were inspired by the work of Krische and Bauld, who previously reported analogous [2+2] cycloadditions of radical anions generated from bis(enone) substrates either by 151 cathodic reduction or by reaction with a cobalt-based catalyst.154  Yoon subsequently reported the application of this methodology to crossed intermolecular [2+2] enone cycloadditions,155 as well as complementary strategy for [2+2] cycloadditions of electron-rich olefins.156  3.6 Photoredox Chemistry of Oxygenated Phthalimide Derivatives While the reactivity of N-alkylphthalimides under both photochemical and SET conditions has been extensively studied, little is known about the behaviour of other phthalimide derivatives under these conditions.  Before our investigations, there had only been two examples of PET involving an oxygenated phthalimides.109,157  The work by Okada and Oda is also the only study on the photochemical reactivity of phthalimides in visible light.  Early studies on visible light PET reactions of N-acyloxyphthalimides utilized 1,6-bis(dimethylamino)pyrene (BDMAP, 3.130) as a stoichiometric single electron reductant (Scheme 3.32).157  Similarly to ruthenium and iridium based photocatalysts, BDMAP absorbs light to produce an excited singlet state (BDMAP*).  The photoexcited state is capable of transferring a single electron to the carbonyl of the N-acyloxyphthalimide.158  As in other SET processes involving phthalimides, a radical anion is formed (3.131).  Homolytic cleavage of the N-O bond followed by radical decarboxylation generates carbon radical 3.132 and the reduced phthalimide (3.135).  Trapping of the radical by hydrogen transfer from either the solvent or tBuSH affords the reduction product 3.134.  Excellent yields were achieved using a number of primary, secondary and tertiary N- acyloxyphthalimide substrates.  While this reaction proceeds through a similar radical anion intermediate as seen previously in PET reactions of N-alkylphthalimides, the reactivity of N- acyloxyphthalimides is notably different due to the presence of the weak N-O bond.  152  Scheme 3.32. Radical decarboxylation initiated by photoinduced SET to N-acyloxyphthalimide 3.129. Okada and Oda later expanded on their original studies by applying the PET reactivity of acyloxyphthalimides to effect a radical addition reaction (Scheme 3.33).109  In this methodology, the Ru(bpy)3 2+ visible light photocatalyst was used to mediate the electron transfer.  Treatment of N-acyloxyphthalimide 3.136 with Ru(bpy)3Cl2 and BNAH (3.137) results in radical decarboxylation and addition of a carbon radical to an electron-deficient acceptor (3.137).  As the oxygenated phthalimide moiety is reduced, this reaction is an example of a reductive photoredox process (see section 3.5.3).  153  Scheme 3.33. Photosensitized decarboxylative Michael addition.  The mechanism for this transformation is depicted in Scheme 3.34.  As in similar ruthenium-mediated photoredox reactions, the photoexcited Ru(bpy)3 2+* complex undergoes reductive quenching by BNAH to generate Ru(bpy)3 +.  This reduced complex then transfers a single electron to the phthalimide.  As in the previous example (Scheme 3.32), this SET induces N-O cleavage and radical decarboxylation to produce a carbon radical.  Radical addition to the Michael acceptor and trapping of the subsequent radical with hydrogen transfer from BNAH affords the product.  The BNA radical formed as a result of this hydrogen transfer, as well as after reductive quenching of the photoexcited ruthenium complex, can also serve as the single electron reductant of the phthalimide.  The quantum yields for all substrates were greater than unity, indicating that this reaction proceeds through a radical chain reaction mechanism. 154  Scheme 3.34. Photoinduced SET mechanism of radical decarboxylative Michael addition.  Oda and Okada’s studies highlight the utility of PET reactions involving substrates with a weak heteroatom-heteroatom bond adjacent to the PET acceptor.  It is noteworthy, however, that despite the rapid expansion in the field of visible light photocatalysis in the past decade, this structural motif has been ignored.  This underrepresented substrate class has great synthetic potential under visible-light promoted SET conditions as the latent reactivity of the weak bond may be released under mild conditions to undergo numerous fragmentation possibilities or provide access to heteroatom-centred radicals. We were particularly intrigued by Oda and Okada’s work because of our previous studies utilizing N-alkoxyphthalimides as alkoxy radical precursors.  Despite the fact that the radical chemistry of this functional group was first investigated in the 1970s,159 prior to our investigations nothing was known about the reactivity of this species under either SET or PET conditions.  Based on the precedent set by Oda and Okada’s work, we hypothesized the N- alkoxyphthalimides may behave like N-acyloxyphthalimides and undergo N-O bond homolysis under PET conditions (Figure 3.3).  Whereas the radical anion of an N-acyloxyphthalimide 155 radically decarboxylates to generate a carbon radical, the radical anion of an N- alkoxyphthalimide could give access to an alkoxy radical.  Currently, reaction with a stoichiometric amount of tributyltin hydride and a radical initiator (such as AIBN) is the standard method for alkoxy radical generation from N-alkoxyphthalimides.159  While this is an efficient method of generating alkoxy radicals, organotin compounds exhibit high levels of toxicity.  Tris(trimethylsilyl)silane may be used in place of the tributyltin hydride; however, it is an expensive reagent and reacts to generate the alkoxy radical at a much slower rate than under stannyl radical conditions.  Both the tin-phthalimide and silane-phthalimide adducts that are a by-product of the alkoxy radical generation reaction can be difficult to remove from reaction mixtures.  Thus, we hypothesized that PET via visible light photocatalysis could fill the need for a mild, non-toxic and economical method of alkoxy radical generation from N- alkoxyphthalimides.  Figure 3.3. Proposed alkoxy radical formation via photoinduced SET to an N-alkoxyphthalimide.   156 3.7 Results and Discussion We began our investigations with N-alkoxyphthalimide 1.106a (Scheme 3.35).160  In our previous work on alkoxy radical cyclizations, this substrate readily cyclized upon homolytic cleavage of the N-O bond.44  Therefore, we hypothesized that if indeed an alkoxy radical is generated by the visible light photocatalytic conditions, we should observe the presence of tetrahydrofuran 1.121a.  As our proposed fragmentation mechanism (Figure 3.3) required a single electron reduction of the phthalimide, it was necessary to generate Ru(bpy)3 + in the course of the reaction.  Thus, a good electron donor, Hünig’s base (iPr2NEt) was chosen as the reductive quencher of the photoexcited Ru(bpy)3 2+* species.  Disappointingly, irradiation of N- alkoxyphthalimide 1.106a with a 275 W sunlamp in the presence of Ru(bpy)3(PF6)2 and iPr2NEt did not result in any change in the starting material.  As Yoon had previously demonstrated that a Lewis acid was necessary for a successful PET to enones, we speculated that Lewis activation of the phthalimide carbonyl may facilitate the electron transfer.153  However, inclusion of LiBF4 in the reaction conditions did not result in any conversion of N-alkoxyphthalimide 1.121a.  Scheme 3.35. Attempted alkoxy radical generation using visible light photocatalysis. A screen of N-alkoxyphthalimide substrates revealed that N-benzyloxyphthalimide (1.155) is reactive under the PET conditions.  Unexpectedly, however, benzaldehyde (3.78a) was observed as the major product by 1H NMR spectroscopy (Scheme 3.36).  Phthalimide (3.135) was also observed in the 1H NMR spectrum of the crude reaction mixture.  The benzylic carbon is oxidized, however there is no net change in the oxidation state of the N-alkoxyphthalimide.  157 This process is an example of a redox fragmentation,161 and the oxidized and reduced products formed are the aldehyde and phthalimide, resptively.  We surveyed the literature and found no examples of photocatalyst-mediated PET redox fragmentations.  Given the lack of precedent for this type of photochemical transformation, we speculated that the mechanism of the redox fragmentation may not be promoted by light.162  For example, a possible explanation for the formation of benzaldehyde in this reaction is a base-mediated elimination.163  However, no change in starting material was observed when light was excluded from the reaction conditions, indicating that this redox fragmentation is indeed photochemical.  Scheme 3.36. Photoinduced redox fragmentation of N-benzyloxyphthalimide (1.155). A screen of reaction conditions revealed that benzaldehyde is always the major product of this reaction.  Increasing the dilution of the reaction to 0.02 M (entry 2) accelerated the rate of the reaction; the reaction time needed for complete consumption of the starting material dropped from 240 minutes to 60 minutes.  A similar rate acceleration was observed at 0.1 M when the solvent was changed from acetonitrile to acetone (entry 3).  Despite the faster reaction rate observed for these conditions (entries 2 and 3), neither the change in dilution nor change in solvent resulted in a higher reaction yield.  Combining both the dilution and change in solvent to acetone (entry 4) resulted in a remarkable increase in the yield of benzaldehyde.  Diluting the reaction further to 0.005 M resulted in even faster conversion of starting material (entry 5).  However, as the reaction yield was not higher at this concentration, 0.02 M was chosen as the optimal concentration for reasons of practicality. 158 Table 3.1. Optimization of solvent and concentration.  Entry Solvent ([  ]) Yield (%) a Time (min) 1 CD3CN (0.1 M) 40 240 2 CD3CN (0.02 M) 40 60 3 (CD3)2CO (0.1 M) 23 60 4 (CD3)2CO (0.02 M) 79 60 5 (CD3)2CO (0.005 M) 79 10  a  Determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.   We next optimized the amount and identity of the amine additive (Table 3.2).  Both the yield and reaction rate were increased when increasing the amount of iPr2NEt to three equivalents (entry 2).  Intriguingly, the reaction went to completion in good yield when a substoichiometric amount of iPr2NEt was used (entry 3), albeit at a slower rate. This suggests that amine is regenerated in reaction mechanism.  Other tertiary amines were also tested (entries 4 and 5).  However, iPr2NEt remained the optimal amine additive for the redox fragmentation reaction.    159 Table 3.2. Optimization of amine additive.  Entry Amine (equivs) Yield (%) a Time (min) 1 iPr2NEt (2) 79 60 2 iPr2NEt (3) 86 30 3 iPr2NEt (0.5) 84 60 4 Et3N (3) 84 30 5 4-methyl-morpholine (3) 52 30  a  Determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.    Figure 3.4 Two possible photochemical redox mechanisms.   160 Table 3.3. Control experiments.  Entry Deviation from optimized conditions Yield(%) (a) 1 None 86 2 No light 0 3 No Ru(bpy)3(PF6)2, no amine additive, no LiBF4 0 4 No amine additive 0 5 Pyridine instead of iPr2NEt 0 6 No LiBF4 33 7 No Ru(bpy)3(PF6)2 78 8 No Ru(bpy)3(PF6)2, no light 0 9 No Ru(bpy)3(PF6)2, no amine additive Trace (<5) 10 No Ru(bpy)3(PF6)2, Et3N instead of iPr2NEt 72 11 No Ru(bpy)3(PF6)2, 0.1 M 35  (a)  Determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.   There are two general mechanistic classes of photoreactions that may be occurring in this new redox fragmentation.  Analogous to peroxy species, the reaction could proceed through direct homolysis of the oxygen-heteroatom bond followed by subsequent redox behaviour, (Figure 3.4, path A).164  Alternatively, a PET process could initiate the redox fragmentation (path B).  With optimized conditions for the redox fragmentation in hand, we performed a number of control experiments to further probe the mechanistic nature of this reaction (Table 3.3).  As previously mentioned, no benzaldehyde was observed when the reaction was carried out in the dark (entry 2) and thus the redox fragmentation is photomediated.    No change in starting material was observed when N-alkoxyphthalimide 1.155 was exposed to visible light without 161 any other reagents (Table 3.3, entry 3) or in the absence of the amine additive (entry 4).  Substitution of iPr2NEt with pyridine (entry 5), a poor electron donor, also resulted in no change in starting material.  These data suggest this reaction does not proceed through direct photolysis of the N-alkoxyphthalimide and that an electron transfer is necessary to initiate the reaction.  Exclusion of LiBF4 from the reaction conditions (entry 6) resulted in a significantly decreased yield of benzaldehyde, suggesting that Lewis acid activation of the phthalimide accelerates the PET reaction.  Further supporting a PET mechanism, the conjugation in the N-alkoxyphthalimide moiety is necessary as demonstrated by the lack of reactivity of N-benzyloxysuccinimide (3.141, Scheme 3.37).  Thus, the redox fragmentation of N-alkoxyphthalimide 1.155 likely proceeds through a radical anion intermediate, similar to that formed in Oda and Okada’s studies on the PET reactivity of N-acyloxyphthalimides.109  Scheme 3.37. Attempted photoinduced redox fragmentation of N-benzyloxysuccinimide (3.141). Surprisingly, a good yield of benzaldehyde was obtained in the absence of Ru(bpy)3 2+ photocatalyst (Table 3.3, entry 7).  As light is needed to effect the reaction (entry 8), the redox fragmentation is still a photo-mediated process under these conditions.  It is noteworthy, therefore, that the LUMO of the N-alkoxyphthalimide is sufficiently low in energy that visible light can promote the transfer on an electron directly from the tertiary base.165  A slightly less electron-rich donor, Et3N, can also be used to effect this photo-induced electron transfer, albeit in somewhat lower yield (entry 10).166 162 With evidence for a PET-initiated fragmentation, we sought to determine if the redox fragmentation is stepwise (Scheme 3.38, path A), or concerted (Scheme 3.38, path B).  Phthalimide substrate 3.142 (Scheme 3.39) was subjected to the optimized reaction conditions to differentiate between these two mechanistic possibilities.  If PET is followed exclusively by N-O homolysis to first provide an alkoxy radical (Scheme 3.38, path A), then we should observe tetrahydrofuran 3.144 as the major product.  Alkoxy radical cyclization onto a terminal olefin is fast (~6 x 108 s-1)167 and will outcompete any intermolecular redox reaction leading to ketone 3.143, especially under the dilute reaction conditions.  Treatment of 3.142, both with and without inclusion of the Ru(bpy)3 2+ catalyst, provided 3.143 as the major product, suggesting that path B (Scheme 3.38) is the dominant mechanism.  A trace amount of 3.144 was detected by GC indicating that N-O bond homolysis may be a minor pathway.  Scheme 3.38. Stepwise or concerted redox fragmentation mechanisms.  163  Scheme 3.39. Redox fragmentation of N-alkoxyphthalimide 3.144. Another possible stepwise fragmentation pathway involves the formation of a benzylic radical intermediate prior to fragmentation.  A radical clock experiment was used to test this mechanistic possibility (Scheme 3.40).  If a discrete carbon radical alpha to the phenyl group is indeed formed during the reaction, cyclopropyl-opened product 3.147 should be observed.14  Consistent with a concerted mechanism, we observed no evidence of this ring opening when cyclopropane 3.145 was subjected to the reaction conditions.  Furthermore, diluting the reaction improved its efficiency (Table 3.1), which supports an intramolecular, rather than intermolecular, elimination.  While this improved efficiency may be a result of less self- quenching of the Ru(bpy)3 2+* by Ru(bpy)3 2+ at higher dilution, comparable yields of benzaldehyde were obtained when the reaction of N-benzyloxyphthalimide (1.155) was run at higher concentration both with and without the addition of the photocatalyst (Table 3.1, entry 3, Table 3.3 entry 11).  Therefore, it is unlikely that self-quenching is a dominant factor in the difference in reaction efficiency at higher concentration.  Scheme 3.40. Redox fragmentiation of N-alkoxyphthalimide 3.147.  164 Table 3.4. Redox fragmentation of para-substituted N-benzyloxyphthalimides.(a)  Entry R Substrate Product Yield (%)b,c 1 F 3.148a 3.149a 82 (81) 2 Cl 3.148b 3.149b 62 (54) 3 Br 3.148c 1.149c 62 (64)  4 H 1.155 3.78a 86 (78) 5 OMe 3.148d 3.78c 55 (50) d 6 NO2 3.148e 3.149e <5 (<5) (a)Reactions were irradiated with a 275 W GE sunlamp for 30 min (see Experimental).  bDetermined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. Numbers in brackets indicate the reaction yield without Ru(bpy)3 2+ catalyst.  c In all of the reactions there is <5% benzyl alcohol formed.  dThe yield of these reaction can can be improved if the reaction time is increased to 40 min.  See Experimental for details.   We next tested aryl substrates with both electron-donating and electron-withdrawing substituents at the para position, both with and without the addition of the Ru(bpy)3 2+ catalyst (Table 3.4).  We did not observe a clear trend between the reaction rate and the electronics of the aryl ring.  Fluoro-substituted aryl derivative 3.148a provided high yields relative to the unsubstituted substrate (1.155), while both less electron-withdrawing substituents than fluorine, such as chlorine (3.148b) and bromine (3.148c), provided similar yields to the electron-rich methoxy-substituted aryl substrate (3.148d).  This general lack of dependence on the electronics of the aryl ring suggests that there is no significant anionic or radical character in the rate- determining step.  No product was observed for the para-nitro substituted substrate 3.148e, which may be due to the propensity of the nitro group to itself undergo SET.168 165  Scheme 3.41. Proposed redox fragmentation mechanism. Based on the aforementioned mechanistic experiments, we propose the redox fragmentation reaction proceeds via the mechanism depicted in Scheme 3.41.  Reductive quenching of the photoexcited Ru(bpy)3 2+* species generates Ru(bpy)3 +, which transfers a single electron to the carbonyl of the phthalimide to form radical anion 3.150.  In the absence of the photocatalyst, this single electron is transferred directly from the amine base.  The radical anion intermediate undergoes either a radical or anionic elimination to provide the formally oxidized aldehydic product 3.78a and formally reduced phthalimide (3.135).  Consistent with a redox process, there is no net electron change in this transformation.  An electron is donated to the phthalimide in the first PET step and following the fragmentation, an electron is transferred back from the phthalimide radical anion 3.151 to either the radical cation of iPr2NEt or the photoexcited  Ru(bpy)3 2+* catalyst.  The regeneration of the amine in this mechanism is supported by the fact 166 that the PET-promoted redox fragmentation of 1.155 can be carried out to completion using sub- stoichiometric amount of the amine (Table 3.2, entry 3).  Scheme 3.42. Photoinduced fragmentation of N-alkoxyphthalimide 3.152.  The behaviour of N-alkoxyphthalimides under visible light PET conditions is markedly different than that of similar substrates under UV irradiation alone.  A recent study by Lucarini examined the photoreactivity of N-benzyloxyphthalimide 3.152.10  Photoexcitation of the phthalimide carbonyl could lead to a biradical intermediate (Scheme 3.42, 3.155), analogous to that observed in UV photolysis of N-alkylphthalimides.  Since this substrate possesses an abstractable benzylic hydrogen, the biradical could then undergo a redox fragmentation (Scheme 3.42, Path B) to phthalimide (3.135) and benzophenone (3.79).  However, Lucarini found that UV irradiation of N-alkoxyphthalimide 3.152 results only in C-O homolytic cleavage products (Scheme 3.42, Path A).  Presumably, a single electron reduction of the phthalimide moiety is necessary to initiate the redox fragmentation reaction.  Although little is known about the 167 reactivity of N-alkoxyphthalimides under either UV irradiation or PET conditions, the contrast of our studies with Lucarini’s work demonstrates the unique behaviour of this oxygenated phthalimide derivative. Table 3.5. Aryl substrate scope.(a) Entry Substrate Product Yield (%)(b) Time (min) 1   3.157a   3.30 54 (52) 150 2 3.157b 3.158b 65 (52) 35 3    3.157c 3.1580c 61 (59) 40 4 3.157d 3.158d 11 (5) 120 5 3.157e 3.158e 51 (34) 20  (a)  Conditions: Ru(bpy)3(PF6)2 (5 mol %), iPr2NEt (3 equiv), LiBF4(2 equiv), (CD3)2CO, 23 °C. Reactions were irradiated with a 275 W GE floodlight.  (b) Determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. Numbers in brackets indicate the reaction yield without Ru(bpy)3 2+ catalyst.  To further probe the scope of this new reaction, we examined aryl substrates with a variety of substitution patterns (Table 3.5). Secondary N-alkoxyphthalimide 3.157a provided acetophenone (3.30) in lower yields, both with and without the inclusion of the photocatalyst 168 (entry 1), than did the analogous primary N-alkoxyphthalimide 1.155.  The reaction time for this substrate was also significantly longer.  Substrates with either electron-withdrawing (entry 2) or electron-donating (entry 3) groups in the ortho position provided products in comparable yields.  The highly electron-rich trimethoxybenzyl substrate 3.157d reacted very sluggishly and the starting material remained mostly unconsumed even after 2 hours (entry 4).  Conversely, perfluoro aryl substrate 3.157a was rapidly consumed, although the reaction yield was modest (entry 5).  Presumably, the electronics of the aryl ring affect the rate of the initial electron transfer.  In all substrates examined, higher yields were achieved with the inclusion of the Ru(bpy)3 2+ photocatalyst.   169 Table 3.6. Extended substrate scope.(a) Entry substrate product Yield (%)(b) Time (min) 1    3.159a    3.160a 76 (41) 60 2   3.159b   3.160b 81 (72) 90 3   3.159c   3.160c 71 (59) 40 4   3.159d   3.160d 72 (59) 150 5   3.159e   3.160e 20 (28) 150 6   3.159f   3.160f 63 (71) 60 7   3.159g   3.160g >95 (86) 15  (a)  Conditions: Ru(bpy)3(PF6)2 (5 mol %), iPr2NEt (3 equiv), LiBF4 (2 equiv), (CD3)2CO, 23 °C. Reactions were irradiated with a 275 W GE sunlamp.  (b) Determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. Numbers in brackets indicate the reaction yield without Ru(bpy)3 2+ catalyst.  This redox fragmentation reaction is not only mechanistically interesting but also has potential as a synthetically useful oxidation methodology.  The reaction conditions are extremely mild as all that is required is an amine base, a non-halogenated solvent, a commercially available lithium salt and a catalytic amount of Ru(bpy)3 2+.  A visible light source is used and thus no 170 specialized UV photolysis equipment is required.  We hypothesized our redox fragmentation methodology could be used as a mild oxidation method for challenging aromatic nitrogen- containing substrates (Table 3.6, entries 1-3).  Standard oxidation protocols for these aromatic heterocycles typically use manganese dioxide in super-stoichiometric amounts (over 5 equivalents).169,170  Furthermore, nitrogen-containing heterocycle oxidations using conventional methodologies can be problematic due to over-oxidation side reactions.171  PET-mediated redox fragmentation of N-alkoxyphthalimide derivatives could provide a mild and selective alternative. We were pleased to observe that, under our optimized Ru(bpy)3 2+  photocatalytic conditions, indole containing N-alkoxyphthalimide 3.159a provided the corresponding aldehyde 3.160a in high yield (Table 3.6, entry 1).  Notably, the mild, basic reaction conditions leave the acid- sensitive Boc group intact.  The reaction efficiency remained comparably high on larger scale, with the Ru(bpy)3 2+  conditions providing indole 3.160a in 83% isolated yield  The redox fragmentation of imidazole derivatives also proceeded smoothly (Table 3.6, entries 2-3).  Both methyl-substituted imidazole 3.159b and unprotected imidazole 3.159c underwent redox fragmentation to provide the corresponding aldehydes (3.160b and 3.160c) in high yields.  While metal-free conditions provided the corresponding aldehydes in modest to good yields, the reaction benefited from the addition of a photocatalyst. We also investigated the scope of the reaction beyond aryl alcohol derivatives.  N- Allyloxyphthalimide 3.159d was readily converted to the α,β-unsaturated aldehyde 3.160d (Table 3.6, entry 4).  The reaction of N-cinnamylphthalimide 3.159e, however, was sluggish and provided low yields, both with and without addition of the Ru(bpy)3 2+ catalyst.  We were also able to access higher oxidation states from N-alkoxyphthalimides (entries 6 and 7).  With benzylic activation (entry 7), the redox fragmentation proceeds in quantitative yield in the 171 presence of the Ru(bpy)3 catalyst.  Interestingly, the reaction of lactol derivative 3.159f was the only example in which exclusion of the catalyst provided a significantly higher yield of the fragmentation product than under Ru(bpy)3 2+ conditions.  The redox fragmentation of both lactol derivatives also proceeded comparably well on a larger scale, with the catalyst-free conditions providing lactone 3.160f in 61% isolated yield and the Ru(bpy)3 2+  conditions providing lactone 3.160g in 89% isolated yield.  Scheme 3.43. Two-step oxidation of isochroman (3.161). The N-alkoxyphthalimide required for the PET redox fragmentation can be readily installed through a simple SN2 reaction or by copper-mediated C-H functionalization.172  This effectively incorporates a protected carbonyl into the molecule.  Once installed, N-alkoxyphthalimides are stable to a wide range of reaction conditions and thus can be carried through a number of synthetic steps.173  These latent carbonyls can then be selectively unmasked under the very mild redox fragmentation conditions.  For example, this redox fragmentation process allows for the conversion of hydrocarbons to carbonyl derivatives in only two steps (Scheme 3.43).   172 3.8 Conclusion Phthalimide derivatives undergo a variety of radical reactions initiated by single electron reduction.  Based on Okada and Oda’s work on radical decarboxylations of N- acyloxyphthalimides mediated by Ru(bpy)3 2+ visible light photocatalysis, we hypothesized that we may be able to induce N-O bond homolysis of N-alkoxyphthalimides under PET conditions to provide an alternative to standard metal-hydride alkoxy radical formation methodologies.  While we did not observe alkoxy radical generation under these conditions, we elucidated a novel redox fragmentation mechanism initiated by PET. In summary, we have developed a mild method for the redox fragmentation of activated N- alkoxyphthalimides.  The reactions proceed through a PET to the N-alkoxyphthalimide followed by a concerted elimination to afford an oxidized carbon and a reduced phthalimide.  The electron transfer can occur direcly from iPr2NEt, but for most substrates the reaction yields were improved when a Ru(bpy)3 2+ photocatalyst was employed.  This process is mechanistically distinct from previous photoinduced redox fragmentations.   This reaction constitutes the first example of a visible light promoted-PET redox fragmentation.  The redox fragmentation of N- alkoxyphthalimides was applied to the mild and selective redox fragmentation of sensitive nitrogen-containing heterocycles. Furthermore, the N-hydroxyphthalimides can be readily installed using simple substitution or C-H activation reactions.  The resulting N- alkoxyphthalimides can then either serve as a protecting group or unmasked under mild reaction conditions.   173 3.9 Experimental 3.9.1 General Experimental A 275 W GE Sunlamp was used for all photochemical reactions.  Deuterated acetone used in these reactions was first distilled over Ca(SO4)2 then degassed with four freeze-pump-thaw cycles and stored under argon.  Acetone for scaled-up photochemical reactions was distilled over Ca(SO4)2.  Diisopropylethylamine and acetonitrile were purified by distillation from CaH2.  Ru(bpy)2(PF6)2 was prepared by literature methods. 156  All reactions were performed under a nitrogen atmosphere in flame-dried glassware.  Tetrahydrofuran and dichloromethane were purified by MBRAUN MB-SPS solvent purification system.  Thin layer chromatography (TLC) was performed on Whatman Partisil K6F UV254 pre- coated TLC plates.  Chromatographic separations were effected over Fluka 60 silica gel.  Triethylamine washed silica gel has been stirred with triethylamine prior to packing.  All chemicals were purchased from commercial sources and used as received, unless otherwise noted. Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected.  Infrared (IR) spectra were obtained using a Thermo Nicolet 6700 FT-IR spectrometer.  Proton nuclear magnetic resonance (1H NMR) spectra were recorded in deuterochloroform using a Bruker AV-400 spectrometer.  Carbon nuclear magnetic resonance (13C NMR) spectra were recorded in deuterochloroform using a Bruker AV-400 spectrometer.  Chemical shifts are reported in parts per million (ppm) and are referenced to the centreline of deuterochloroform (7.27 ppm 1H NMR; 77.0 ppm 13C NMR).  Low resolution mass spectra (LRMS) and high resolution mass spectra (HRMS) were recorded on either a Bruker Esquire-LC spectrometer (for LRMS) or a Waters/Micromass LCT spectrometer (for HRMS). 174 3.9.2 Synthesis of Substrates  N-Benzyloxyphthalimide (1.155): To a solution of N-hydroxyphthalimide (3.26 g, 40 mmol) and diisopropylethylamine (7.75 g, 60 mmol) in DMF (50 mL), was added benzyl bromide (3.42 g, 20 mmol). The mixture was heated at 70 °C for 1 h, then allowed to cool to room temperature and taken up in EtOAc (75 mL). The mixture was then washed with 10% HCl solution (3x50 mL), 1 M NaOH solution (3x50 mL) and brine (70 mL). It was then dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 4.05 g (80%) of N-alkoxyphthalimide 1.155 as a white powder, which was used without further purification. The spectroscopic properties were consistent with those previously published.172 1H NMR (400 MHz, CDCl3) 7.82 (dd, J = 5.5, 3.0 Hz, 2H), 7.74 (dd, J = 5.5, 3.0 Hz, 2H), 7.55 (dd, J = 6.5, 2.9 Hz, 2H), 7.39 (dd, J = 4.9, 1.8 Hz, 3H), 5.22 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 163.4, 134.4, 133.7, 129.9, 129.3, 128.9, 128.5, 123.5, 79.8.   N-(Benzyloxy)succinimide (3.141): To a solution of N-hydroxysuccinimide (1.73 g, 15 mmol) and diisopropylethylamine (2.58 g, 20 mmol) in DMF (20 mL), was added benzyl chloride (1.26 g, 10 mmol. The mixture was heated at 70 °C for 4 h, then allowed to cool to room temperature and taken up in EtOAc (50 mL). The mixture was then washed with 10% HCl solution (2x30 175 mL), sat. NaHCO3 solution (2x30 mL) and brine (50 mL). It was then dried over MgSO4, filtered through a pad of Celite and concentrated by rotary evaporation to afford 1.13 g (55%) of N- (benzyloxy)succinimide 3.141 as a white powder, which was used without further purification. m.p. 159-163 °C; IR (neat) 3480, 3036, 2973, 3944, 1780, 1703, 1471, 1422, 1393, 1296, 1254, 1201 cm-1; 1H NMR (400 MHz, CDCl3)  7.45-7.56 (m, 2H), 7.33-7.45 (m, 3H), 5.13 (s, 2H), 2.66 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 171.1, 133.2, 129.8, 129.4, 128.5, 78.6, 25.4; HRMS-ESI (m/z) [M+Na]+ calcd for C11H11NO3Na: 228.0637 Found: 228.0641.   N 2-((1-Phenylpent-4-en-1-yl)oxy)phthalimide (3.142): To a solution of 1-phenylpent-4-en-1- olg (1.25 g, 7.7 mmol) and Et3N (1.24 g, 12.3 mmol) in CH2Cl2 (25 mL) at 0 °C was added methanesulfonyl chloride (1.05 g, 9.2 mmol), dropwise over 5 min. The reaction mixture was then allowed to warm to ambient temperature and stirred for 1 h. It was then washed with brine (2x20 mL). The organic layer was dried over MgSO4, filtered and the solvent was removed by rotary evaporation to provide a yellow oil. The crude mesylate was taken up in DMF (15 mL). N-Hydroxyphthalimide (1.88 g, 12.0 mmol) and diisopropylethylamine (2.00 g, 15.5 mmol) were added and the resulting mixture at 70 °C for 1 h, then allowed to cool to room temperature and taken up in Et2O (50 mL). The mixture was then washed with sat. NaHCO3 solution (3x25                                                  g Janza, B.; Studer A. J. Org. Chem. 2005, 70, 6991.  176 mL) and brine (50 mL). It was then dried over Na2SO4, filtered and concentrated by rotary evaporation to give a yellow oil. Purification by column chromatography (95:5 to 75:5 hexanes/EtOAc) followed by recrystallization (EtOH) afforded 300 mg (17% over 2 steps) of N- alkoxyphthalimide 3.142 as a white powder. m.p. 106-108 °C; IR (neat) 3496, 3066, 3035, 2943, 2863, 1783, 1722, 1640, 1456, 1361, 1260, 1211 cm-1; 1H NMR (400 MHz, CDCl3) 7.61-7.89 (m, 4H), 7.41-7.57 (m, 2H), 7.29-7.40 (m, 3H), 5.81-5.92 (m, 1H), 5.35 (t, J = 6.9 Hz, 1H), 5.09 (d, J = 1.5 Hz, 1H), 5.00-5.06 (m, 2H), 2.25-2.47 (m, 1H), 2.13-2.25 (m, 2H), 1.84-2.13 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 163.7, 137.9, 137.4, 134.2, 129.0, 128.8, 128.3, 128.1, 123.3, 115.4, 88.6, 34.0, 29.8; HRMS-ESI (m/z) [M+Na]+ calcd for C19H17NO3Na: 330.1106. Found: 330.1107.   N-(1-Cyclopropyl-1-phenylmethoxy)phthalimide (3.145): To a solution of 4-fluorobenzyl alcohol (1.45 g, 10 mmol), PPh3 (3.93 g, 15 mmol), and N-hydroxyphthalimide (2.45 g, 15 mmol) in THF (30 mL), was added diisopropyl azodicarboxylate (3.03 g, 15 mmol) dropwise over 5 min. The resulting mixture was stirred for 18 h, then taken up in EtOAc (40 mL) and washed with saturated NaHCO3 (3x40 mL) and brine (2x30 mL). The organic extracts were dried over MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a thick yellow oil. Purification by recrystallization (EtOH) afforded 1.23 g (42%) of N- alkoxyphthalimide 3.145 as a white powder. The spectroscopic properties were consistent with those previously published.172 177 1H NMR (400 MHz, CDCl3) 7.76-7.84 (m, 2H), 7.66-7.76 (m, 2H), 7.58 (d, J = 6.7 Hz, 2H), 7.29-7.43 (m, 3H), 4.61 (d, J = 9.4 Hz, 1H), 1.45-1.58 (m, 1H), 0.67-0.82 (m, 1H), 0.52-0.67 (m, 2H), 0.22-0.32 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 163.9, 137.9, 134.3, 128.9, 128.3, 127.9, 123.3, 93.5, 14.8, 5.4, 1.8.    N-(4-Fluorobenzyloxy)phthalimide (3.148a): To a solution of 4-fluorobenzyl alcohol (518 mg, 4.1 mmol), PPh3 (1.63 g, 6.2 mmol), and N-hydroxyphthalimide (1.01 g, 6.2 mmol) in THF (15 mL), was added diisopropyl azodicarboxylate (1.25 g, 6.2 mmol) dropwise over 5 min. The resulting mixture was stirred for 20 h, then taken up in EtOAc (20 mL) and washed with saturated NaHCO3 (3x20 mL) and brine (2x30 mL). The organic extracts were dried over MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a thick yellow oil. Purification by recrystallization (EtOH) afforded 785 mg (71%) of N-alkoxyphthalimide 3.148a as a white powder. m.p. 155-156 °C; IR (neat) 3487, 2965, 1775, 1723, 1603, 1513, 1466, 1387, 1226 cm-1; 1H NMR (400 MHz, CDCl3)  7.83 (dd, J = 5.6, 2.9 Hz, 2H), 7.75 (dd, J = 5.3, 3.2 Hz, 2H), 7.47-7.60 (m, 2H), 6.97-7.14 (m, 2H), 5.19 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 163.4, 163.3 (d, JC-F = 248.4 Hz), 134.43, 131.8 (d, JC-F = 9.2 Hz), 129.6 (d, JC-F = 3.1 Hz), 128.8, 123.5, 115.5 (d, JC-F = 21.5 Hz), 79.0; HRMS-ESI (m/z) [M+Na] + calcd for C15H10NO3FNa: 294.0542. Found: 294.5044.  178  N-(4-Chlorobenzyloxy)phthalimide (3.148b): To a solution of 4-chlorobenzyl alcohol (713 mg, 5 mmol), PPh3 (1.96 g, 7.5 mmol), and N-hydroxyphthalimide (1.23 g, 7.5 mmol) in THF (15 mL), was added diisopropyl azodicarboxylate (1.52 g, 7.5 mmol) dropwise over 5 min. The resulting mixture was stirred for 36 h, then taken up in EtOAc (20 mL) and washed with saturated NaHCO3 (3x20 mL) and brine (2x30 mL). The organic extracts were dried over MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a thick yellow oil. Purification by recrystallization (EtOH) afforded 1.18 g (82%) of N-alkoxyphthalimide 3.148b as a white powder. m.p. 131-133 °C; IR (neat) 3501, 3097, 3067, 3042, 2951, 1788, 1717, 1597, 1491, 1465, 1356, 1212 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.79-7.88 (m, 2H), 7.66-7.79 (m, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 5.19 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 163.4, 135.3, 134.5, 132.2, 131.1, 128.8, 123.5, h 78.9; HRMS-ESI (m/z) [M+Na]+ calcd for C15H10NO3ClNa: 310.0247. Found: 310.0244.   N-(4-Bromobenzyloxy)phthalimide (3.148c): To a solution of 4-bromobenzyl alcohol (811 mg, 4.3 mmol), PPh3 (1.70 g, 6.5 mmol), and N-hydroxyphthalimide (1.05 g, 6.5 mmol) in THF (15 mL), was added diisopropyl azodicarboxylate (1.70 g, 6.5 mmol) dropwise over 5 min. The                                                  h This peak represents two overlapping signals. HMBC spectroscopy showed correlations between this peak and protons on both the phthalimide and aryl rings. 179 resulting mixture was stirred for 18 h, then taken up in EtOAc (20 mL) and washed with saturated NaHCO3 (3x20 mL) and brine (2x30 mL). The organic extracts were dried over MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a thick yellow oil. Purification by recrystallization (EtOH) afforded 959 mg (67%) of N-alkoxyphthalimide 3.148c as a white powder. m.p. 134-136 °C; IR (neat) 3490, 3054, 2959, 2895, 1778, 1716, 1593, 1487, 1463, 1389, 1183 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.79-7.86 (m, 2H), 7.72-7.79 (m, 2H), 7.52 (m, J = 8.2 Hz, 2H), 7.42 (m, J = 8.5 Hz, 2H), 5.17 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 163.4, 134.5, 132.7, 131.7, 131.4, 128.8, h 123.5, 78.9; HRMS-ESI (m/z) [M+H]+ calcd for C15H11NO3Br: 331.9929. Found: 331.9922.   N-(4-Methoxybenzyloxy)phthalimide (3.148d): To a solution of 4-methoxybenzyl alcohol (1.38 g, 10 mmol), PPh3 (3.93 g, 15 mmol), and N-hydroxyphthalimide (2.45 g, 15 mmol) in THF (30 mL), was added diisopropyl azodicarboxylate (3.03 g, 15 mmol) dropwise over 5 min. The resulting mixture was stirred for 20 h, then taken up in EtOAc (40 mL) and washed with saturated NaHCO3 (3x40 mL) and brine (2x40 mL). The organic extracts were dried over MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a thick yellow oil. Purification by recrystallization (EtOH) afforded 2.31 g (82%) of N-alkoxyphthalimide 3.148d as a white powder. m.p. 136-138 °C; IR (neat) 3032, 2945, 2880, 2841, 1784, 1723, 1608, 1514, 1382, 1302, 1254 cm-1; 1H NMR (400 MHz, CDCl3) δ ppm 7.77-7.88 (m, 2H), 7.68- 7.77 (m, 2H), 7.46 (m, J = 8.5 Hz, 2H), 6.90 (m, J = 8.5 Hz, 2H), 5.16 (s, 2H), 3.81 (s, 3H); 13C 180 NMR (100 MHz, CDCl3) δ 163.5, 160.4, 134.3, 131.6, 128.9, 125.8, 123.4, 113.9, 79.5, 55.2; HRMS-ESI (m/z) [M+Na]+ calcd for C16H13NO4Na: 306.0742. Found: 306.0747.   N-(4-Nitrobenzyloxy)phthalimide (3.148e): To a solution of N-hydroxyphthalimide (1.22 g, 7.5 mmol) and diisopropylethylamine (1.29 g, 10 mmol) in DMF (10 mL), was added 4- nitrobenzyl chloride (858 mg, 10 mmol). The mixture was heated at 70 °C for 2 h, then allowed to cool to room temperature and taken up in EtOAc (75 mL). The mixture was then washed with 10% HCl solution (3x50 mL), 1 M NaOH solution (3x50 mL) and brine (70 mL). It was then dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 4.05 g (80%) of N- alkoxyphthalimide 3.148e as a yellow powder, which was used without further purification. The spectroscopic properties were consistent with those previously published.i 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.5 Hz, 2H), 7.79-7.87 (m, 2H), 7.67-7.79 (m, 4H), 5.31 (s, 2H);  13C NMR (100 MHz, CDCl3) δ 163.3, 148.3, 140.8, 134.7, 130.0, 128.6, 123.7, 78.2.                                                   i Wang, S- X.; Li, X- W; Li, J- T. Ultrasonics Sonochemistry 2008, 15, 336-36 181  N-(1-Phenylethoxy)phthalimide (3.157a): To a solution of 1-phenylethanol (543 mg, 4.3 mmol), PPh3 (1.70 g, 6.5 mmol), and N-hydroxyphthalimide (1.05 g, 6.5 mmol) in THF (15 mL), was added diisopropyl azodicarboxylate (1.31 g, 6.5 mmol) dropwise over 5 min. The resulting mixture was stirred for 20 h, then taken up in EtOAc (20 mL) and washed with saturated NaHCO3 (3x20 mL) and brine (2x20 mL). The organic extracts were dried over MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a thick yellow oil. Purification by recrystallization (EtOH) afforded 750 mg (65%) of N-alkoxyphthalimide 3.157d as a white powder. The spectroscopic properties were consistent with those previously published.172 1H NMR (400 MHz, CDCl3) .72-7.80 (m, 2H), 7.64-7.72 (m, 2H), 7.52 (dd, J = 7.8, 1.7 Hz, 2H), 7.29-7.40 (m, 3H), 5.51 (q, J = 6.4 Hz, 1H), 1.73 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.8, 139.0, 134.3, 128.9, 128.8, 128.3, 127.6, 123.3, 85.1, 20.4.   N-(2-Fluorobenzyloxy)phthalimide (3.157b): To a solution of 2-fluorobenzyl alcohol (538 mg, 4.3 mmol), PPh3 (1.68 g, 6.4 mmol), and N-hydroxyphthalimide (1.04 g, 6.4 mmol) in THF (15 mL), was added diisopropyl azodicarboxylate (1.29 g, 6.4 mmol) dropwise over 5 min. The resulting mixture was stirred for 20 h, then taken up in EtOAc (20 mL) and washed with saturated NaHCO3 (3x20 mL) and brine (2x20 mL). The organic extracts were dried over 182 MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a thick yellow oil. Purification by recrystallization (EtOH) afforded 800 mg (69%) of N-alkoxyphthalimide 3.157b as a white powder. m.p. 151-154 °C; IR (neat) 3500, 3099, 3070, 3043, 2993, 2958, 1790, 1720, 1618, 1587, 1489, 1366, 1247 cm-1; 1H NMR (400 MHz,  CDCl3)  7.78-7.88 (m, 2H), 7.68-7.78 (m, 2H), 7.57 (td, J = 7.4, 1.5 Hz, 1H), 7.32-7.45 (m, 1H), 7.17 (td, J = 7.5, 1.0 Hz, 1H), 7.08 (t, J = 9.1 Hz, 1H), 5.31 (s, 2H); 13C NMR (100 MHz, CDCl3)  163.3, 161.6 (d, JC-F = 250.87 Hz), 134.4, 132.2 (d, JC-F = 3.06 Hz), 131.4 (d, JC-F = 7.65 Hz), 128.8, 124.2 (d, JC- F = 3.06 Hz), 123.5, 121.3, 115.5 (d, JC-F = 21.42 Hz), 73.0 (d, JC-F = 3.06 Hz); HRMS-ESI (m/z) [M+Na]+ calcd for C15H10NO3FNa: 294.0542. Found: 294.5036.   N-(2-Methoxybenzyloxy)phthalimide (3.157c): To a solution of 2-methoxybenzyl alcohol (691 mg, 5 mmol), PPh3 (1.96 g, 7.5 mmol), and N-hydroxyphthalimide (1.23 g, 7.5 mmol) in THF (15 mL), was added diisopropyl azodicarboxylate (1.52 g, 7.5 mmol) was added dropwise over 5 min. The resulting mixture was stirred for 36 h, then taken up in EtOAc (20 mL) and washed with saturated NaHCO3 (3x20 mL) and brine (2x20 mL). The organic extracts were dried over MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a thick yellow oil. Purification by recrystallization (EtOH) afforded 875 mg (62%) of N-alkoxyphthalimide 3.157c  as a white powder. m.p. 103-106 °C; IR (neat) 3500, 3099, 3021, 2979, 2943, 2837, 1790, 729, 1601, 1590, 1509, 1461, 1431, 1385, 1356, 1254 cm-1; 1H NMR (400 MHz,  CDCl3)  7.76-7.86 (m, 2H), 7.66-7.76 (m, 2H), 7.44 (dd, J = 7.5, 1.4 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 183 6.94 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 5.30 (s, 2H), 3.77 (s, 3H) ; 13C NMR (100 MHz, CDCl3) δ 163.4, 158.4, 134.2, 132.1, 131.0, 128.9, 123.3, 122.4, 120.5, 110.6, 74.5, 55.5; HRMS-ESI (m/z) [M+Na]+ calcd for C16H13NO4Na: 306.0742. Found: 306.0740.   N-(2,4,6-Trimethoxybenzyloxy)phthalimide (3.157d): To a solution of 2, 4, 6- trimethoxybenzyl alcohol (465 mg, 2.3 mmol), PPh3 (9.8 g, 3.5 mmol), and N- hydroxyphthalimide (571 mg, 3.5 mmol) in THF (8 mL), was added diisopropyl azodicarboxylate (918 mg, 3.5 mmol) dropwise over 5 min. The resulting mixture was stirred for 18 h, then taken up in EtOAc (20 mL) and washed with saturated NaHCO3 solution (3x20 mL) and brine (2x20 mL). The organic extracts were dried over MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a thick yellow oil. Purification by recrystallization (EtOH) afforded 346 mg (44%) of N-alkoxyphthalimide 3.157d as a white powder. m.p. 194-197 °C (decomp.); IR (neat) 2961, 2836, 1784, 1724, 1593, 1454, 1376, 1321, 1233 cm-1; 1H NMR (400 MHz, CDCl3)  7.77 (dd, J = 5.3, 3.2 Hz, 2H), 7.69 (dd, J = 5.5, 3.1 Hz, 2H), 6.02 (s, 2H), 5.33 (s, 2H), 3.79 (s, 3H), 3.66 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 163.5, 162.7, 160.9, 133.9, 129.1, 122.9, 103.8, 90.1, 67.8, 55.7, 55.2; HRMS-ESI (m/z) [M+Na]+ calcd for C18H17NO6Na: 366.0954. Found: 366.0954. 184  N-(2,3,4,5,6-Pentafluorobenzyloxy)phthalimide (3.157e): To a solution of 2,3,4,5,6- pentafluorobenzyl alcohol (759 mg, 3.8 mmol), PPh3 (1.50 g, 5.7 mmol), and N- hydroxyphthalimide (930 mg, 5.7 mmol) in THF (13 mL), was added diisopropyl azodicarboxylate (1.15 g, 5.7 mmol) dropwise over 5 min. The resulting mixture was stirred for 18 h, then taken up in EtOAc (20 mL) and washed with saturated NaHCO3 solution (3x20 mL) and brine (2x20 mL). The organic extracts were dried over MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a thick yellow oil. Purification by recrystallization (EtOH) afforded 600 mg (46%) of N-alkoxyphthalimide 3.157e as a white powder. m.p. 136-138 °C; IR (neat) 3503, 3097, 2981, 1784, 1724, 1656, 1524, 1507, 1467, 1391, 1222 cm-1; 1H NMR (400 MHz, CDCl3)  7.80-7.91 (m, 2H), 7.73-7.80 (m, 2H), 5.34 (t, J = 1.5 Hz, 2H);  13C NMR (100 MHz, CDCl3) δ 163.2, 146.2 (dm, JC-F = 253.8 Hz), 142.4 (dm, JC-F = 254.3 Hz), 137.4 (dm, JC-F = 252.4 Hz), 134.8, 128.6, 123.8, 108.3 (td, JC-F = 17.7, 4.4 Hz), 65.9; HRMS-ESI (m/z) [M+Na]+ calcd for C15H6NO3F5Na: 366.0166. Found: 366.0158. 185  tert-Butyl-2-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)-1H-indole-1-carboxylate (3.159a): To a solution of 1-(tert-butyloxycarbonyl)-3-(hydroxymethyl)indolej (1.70 g, 6.8 mmol), PPh3 (2.70 g, 10.3 mmol), and N-hydroxyphthalimide (1.67 g, 10.3 mmol) in THF (33 mL), was added diisopropyl azodicarboxylate (2.08 g, 10.3 mmol) dropwise over 5 min. The resulting mixture was stirred for 18 h, then taken up in EtOAc (30 mL) and washed with saturated NaHCO3 solution (3x30 mL) and brine (2x30 mL). The organic extracts were dried over MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a thick yellow oil. Purification by recrystallization (EtOH) afforded 1.51 g (56%) of N-alkoxyphthalimide 3.159a as a white powder. m.p. 173-176 °C (decomp.); IR (neat) 3124, 2989, 2936, 2890, 1785, 1437, 1725, 1594, 1455, 1371, 1359, 1274, 1260, 1236 cm-1; 1H NMR (400 MHz, CDCl3)  8.15 (d, J = 7.6 Hz, 1H), 7.94-8.10 (m, 1H), 7.81-7.94 (m, 2H), 7.65-7.80 (m, 3H), 7.35 (m, 2H), 5.39 (s, 2H), 1.68 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 163.6, 149.4, 135.6, 134.4, 129.5, 128.9, 127.2, 124.9, 123.5, 123.1, 119.8, 115.2, 113.7, 84.1, 71.4, 28.1; HRMS-ESI (m/z) [M+Na]+ calcd for C22H20N2O5Na: 415.1270. Found: 415.1277.                                                   j Kobayashi, S.; Miyamura, H.; Akiyama, R.; Ishida, T. J. Am. Chem. Soc. 2005, 127, 9251- 9254. 186  N-((1-Methyl-1H-imidazol-2-yl)methoxy)phthalimide (3.159b): To a solution of 2- chloromethyl-1-methylimidazole hydrochloride (1.25 g, 7.5 mmol) and triethylamine (3.04 g, 30.0 mmol) in DMF (20 mL) was added N-hydroxyphthalimide (2.45 g, 15 mmol). The solution was stirred for 18 h, then taken up in EtOAc (30 mL) and washed with saturated NaHCO3 solution (3x20 mL) and brine (2x20 mL). The organic extracts were dried over MgSO4, filtered, and the solvent was removed by rotary evaporation to provide a white powder. Purification by recrystallization (EtOH) provided 1.10 g (57%) of N-alkoxyphthalimide 3.159b as a white powder. m.p. 159-163 °C; IR (neat) 3202, 3130, 3113, 321, 2983, 2953, 1782, 1773, 1727, 1606, 1497, 1466, 1439, 1416, 1356, 1345, 1285, 1254 cm-1; 1H NMR (400 MHz, CDCl3) δ ppm 7.62- 7.79 (m, 4H), 6.97 (s, 1H), 6.90 (s, 1H), 5.24 (s, 2H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1, 141.1, 134.4, 128.7, 128.3, 123.4, 123.3, 70.1, 33.2; HRMS-ESI (m/z) [M+H]+ calcd for C13H12N3O3: 258.0879. Found: 258.0876.    N-((1H-Imidazol-5-yl)methoxy)phthalimide (3.159c): Prepared using literature methods.k 1H NMR (400 MHz, (CD3)2CO) 7.79-7.89 (m, 4H), 7.68 (broad s, 1H), 7.30 (broad s, 1H ), 5.18 (s, 2H).                                                  k Arimoto, M.; Yokohama, S.; Sudou, M.; Ichikawa, Y.; Hayano, T.; Tagawa, H.; Furukawa, M. J. Antibiot. 1988, 41, 1795. 187  N-(3-Methylbut-2-enyloxy)phthalimide (3.159d): To a solution of N-hydroxyphthalimide (1.22 g, 7.5 mmol) and diisopropylethylamine (1.29 g, 10 mmol) in DMF (10 mL), was added 1- bromo-3-methyl-2-butene (745 mg, 5 mmol). The mixture was heated at 70 °C for 1 h, then allowed to cool to room temperature and taken up in EtOAc (20 mL). The mixture was then washed with 10% HCl solution (3x20 mL), 1 M NaOH solution (3x20 mL) and brine (40 mL). It was then dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 1.139 g (98%) N-alkoxyphthalimide 3.159d as a white powder, which was used without further purification. The spectroscopic properties were consistent with those previously published.l 1H NMR (400 MHz, CDCl3) 7.84 (dd, J = 5.3, 3.2 Hz, 2H), 7.75 (dd, J = 5.5, 3.0 Hz, 2H), 5.54 (t, J = 7.8 Hz, 1H), 4.72 (d, J = 7.6 Hz, 2H), 1.77 (s, 3H), 1.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.8, 143.6, 134.3, 128.9, 123.4, 117.1, 74.0, 25.9, 18.1.   N-[(E)-3-Phenyl-2-propenyloxy)phthalimide (3.159e): To a solution of N-hydroxyphthalimide (1.22 g, 7.5 mmol) and diisopropylethylamine (1.29 g, 10 mmol) in DMF (10 mL), was added cinnamyl bromide (985 mg, 5 mmol). The mixture was heated at 70 °C for 1 h, then allowed to cool to room temperature and taken up in EtOAc (20 mL). The mixture was then washed with 10% HCl solution (3x20 mL), 1 M NaOH solution (3x20 mL) and brine (40 mL). It was then                                                  l Proctor, A. J.; Beautement, K.; Clough, J. M.; Knightand, D. W.; Li, Y. Tetrahedron Lett. 2006, 47, 5151. 188 dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 1.05 g (75%) N- alkoxyphthalimide 3.159e as a yellow powder, which was used without further purification. The spectroscopic properties were consistent with those previously published: Lee, J. M.; Park, E. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130, 7824. 1H NMR (400 MHz, CDCl3) 7.83 (dd, J = 5.3, 3.2 Hz, 2H), 7.73 (dd, J = 5.2, 3.1 Hz, 2H), 7.39 (d, J = 7.0 Hz, 2H), 7.28-7.36 (m, 3H), 6.68 (d, J = 15.8 Hz, 1H), 6.48 (dt, J = 15.8,7.0 Hz, 1H), 4.88 (d, J = 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 163.8, 137.5, 135.8, 134.4, 128.8, 128.6, 128.4, 126.9, 123.5, 122.0, 78.6.   N-(Tetrahydrofuran-2-yloxy)phthalimide (3.159f): Prepared by literature methods.172 1H NMR (400 MHz, CDCl3) 7.78-7.88 (m, 2H), 7.64-7.78 (m, 2H), 5.79 (d, J = 4.6 Hz, 1H), 4.28- 4.45 (m, 1H), 3.97-4.09 (m, 1H), 2.20-2.38 (m, 2H), 2.04-2.20 (m, 1H), 1.87-2.04 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 163.9, 134.3, 129.1, 123.4, 108.8, 69.1, 30.8, 22.5.   N-(1H-3,4-Dihydroxy-2-benzopyranyl-1-oxy)phthalimide (3.159g): Prepared by literature methods.172 1H NMR (400 MHz, CDCl3) 7.83-7.92 (m, 2H), 7.74-7.81 (m, 2H), 7.66-7.74 (m, 1H), 7.29-7.42 (m, 2H), 7.21 (d, J = 6.7 Hz, 1H), 6.21 (s, 1H), 4.71 (td, J = 12.3, 3.0 Hz, 1H), 4.04 (dd, J = 11.6, 5.2 Hz, 1H), 3.12 (ddd, J = 17.3, 12.4, 5.8 Hz, 1H), 2.73 (dd, J = 16.6, 2.9 Hz, 189 1H); 13C NMR (100 MHz, CDCl3) δ 163.8, 134.8, 134.3, 129.5, 129.3, 129.2, 128.7, 128.4, 126.6, 123.4, 102.1, 59.6, 27.4.  3.9.3 Optimization and Control Experiments Optimization Procedure and Control Experiments for the Redox Fragmentation of N- Benzyloxyphthalimide (1.155): To an oven-dried 0.5-2 mL Biotage microwave vial equipped with a stir bar was added N-alkoxyphthalimide 1.155 (10 mg, 0.04 mmol), LiBF4 (7.5 mg, 0.08 mmol, 2.0 equiv), Ru(bpy)3(PF6)2 (1.7 mg, 0.002 mmol, 5 mol%) and trimethoxybenzene (2 mg, 0.012 mmol, 0.3 equiv) as the internal standard. The vial was sealed, then thoroughly evacuated and filled with N2. Solvent was then added, followed by base. The reaction mixture was then sparged with bubbling N2 for 5 min in the dark. An aliquot was removed and kept in the dark until NMR analysis.  The ratio of the integrals of the diagnostic peak of the starting materal to the integral of the trimethoxybenzene peak ( = 6.08 ppm) was corrected as described below. The reaction was then illuminated with a 275 W GE sunlamp and stirred for the length of time indicated in Table 3.1 and Table 3.3. The light was turned off and another aliquot was taken for NMR analysis. Product yield was determined by determining the ratio of the diagnostic product peak integral to that of trimethoxybenzene, after correction as described below, and dividing it by the corrected ratio of the starting material and trimethoxybenzene peak integrals.    190 3.9.4 Photoredox Fragmentation Reactions Procedure for Construction of Calibration Curve and NMR Yield Determination: For each calibration curve, eight 500 L standard solutions in (CD3)2CO were prepared.  Each solution contained 0.003 mmol trimethoxybenzene, starting material (0.004–0.011 mmol) and product (0.003-0.010 mmol). 1H NMR spectra were taken for each standard solution and processed using ACD/SpecManager 11.0.  The diagnostic peaks of trimethoxybenzene ( = 6.08 ppm), the starting material and product (Table 3.7) were integrated.  The ratio of the starting material and trimethoxybenzene peak integrals was calculated for each sample, and plotted against the molar ratio of the starting material and trimethoxybenzene using Microsoft Excel 2010.  A similar plot was made for the product peak integrals.  Linear regression analysis of each curve provided an equation relating the ratio of integrals of the starting material or product and trimethoxybenzene to the molar ratio of the starting material or product and trimethoxybenzene.  These equations were used to correct the integral ratios obtained from 1H NMR spectra in all experiments used to determine NMR yields.   191 Table 3.7. List of Diagnostic NMR Peaks in (CD3)2CO Experiment Starting Material Peak () Product Peak () Table 3.4, entry 1 5.22 (s, 2H) 10.02 (s, 1H) Table 3.4, entry 2 5.23 (s, 2H) 10.05 (s, 1H) Table 3.4, entry 3 5.22 (s, 2H) 10.04 (s, 1H) Table 3.4, entry 4 5.23 (s, 2H) 10.06 (s, 1H) Table 3.4, entry 5 5.15 (s, 2H) 9.91 (s, 1H) Table 3.4, entry 6 NA NA Table 3.5, entry 1 5.49 (q, J = 6.62 Hz, 1H) 2.58 (s, 3H) Table 3.5, entry 2 5.31 (s, 2H) 10.34 (s, 1H) Table 3.5, entry 3 5.26 (s, 2H) 10.45 (s, 1H) Table 3.5, entry 4 5.22 (s, 2H) 10.30 (s, 1H) Table 3.5, entry 5 5.45 (s, 2H) 10.29 (s, 1H) Table 3.6, entry 1 5.42 (s, 2H) 10.13 (s, 1H) Table 3.6, entry 2 5.29 (s, 2H) 9.70 (s, 1H) Table 3.6, entry 3 5.19 (s, 2H) 9.84 (s, 1H) Table 3.6, entry 4 5.46-5.52 (m, 1H) 9.97 (d, J = 7.99 Hz, 1H) Table 3.6, entry 5 4.86 ppm (dd, J = 7.2, 1.0 Hz, 2H) 10.45 (s, 1H) Table 3.6, entry 6 3.92-3.97 (m, 1H) 4.30 (t, J = 6.83 Hz, 2H) Table 3.6, entry 7 6.16 (s, 1H) 4.52 (t, J = 6.14 Hz, 2H)  General Procedure 1 for Redox Fragmentation: To an oven-dried 0.5-2 mL Biotage microwave vial equipped with a stir bar was added the N-alkoxyphthalimide (0.04 mmol), LiBF4 (7.5 mg, 0.08 mmol, 2.0 equiv), Ru(bpy)3(PF6)2 (1.7 mg, 0.002 mmol, 5 mol%) and trimethoxybenzene (2 mg, 0.012 mmol, 0.3 equiv) as the internal standard. The vial was sealed, then thoroughly evacuated and filled with N2. Deuterated acetone (2 mL) was then added, followed by diisopropylethylamine (16 mg, 0.12 mmol, 3.0 equiv). The reaction mixture was then sparged with bubbling N2 for 5 min in the dark. An aliquot was removed and kept in the dark until NMR analysis. The reaction was then illuminated with a 275 W GE sunlamp and stirred until no starting material was observed by TLC. The light was turned off and another aliquot was taken for NMR analysis. Product yield was determined as described above. 192 General Procedure 2 for Redox Fragmentation: To an oven-dried 0.5-2 mL Biotage microwave vial equipped with a stir bar was added the N-alkoxyphthalimide (0.04 mmol), LiBF4 (7.5 mg, 0.08 mmol, 2.0 equiv) and trimethoxybenzene (2 mg, 0.012 mmol, 0.3 equiv) as the internal standard. The vial was sealed, then thoroughly evacuated and filled with N2. Deuterated acetone (2 mL) was then added, followed by diisopropylethylamine (16 mg, 0.12 mmol, 3.0 equiv). The reaction mixture was then sparged with bubbling N2 for 5 min in the dark. An aliquot was removed and kept in the dark until NMR analysis. The reaction was then illuminated with a 275 W GE sunlamp and stirred until no starting material was observed by TLC. The light was turned off and another aliquot was taken for NMR analysis. Product yield was determined as described above. Each substrate was subjected to both General Procedure 1 and General Procedure 2.  4-Fluorobenzaldehyde (3.149a): N-Alkoxyphthalimide 3.148a (10.8 mg) was subjected to General Procedure 1 for 30 min to give 82% yield by 1H NMR spectroscopy of aldehyde 3.149a. N-Alkoxyphthalimide 3.148a (10.8 mg) was subjected to General Procedure 2 for 30 min to give 81% yield by 1H NMR spectroscopy of aldehyde 3.149a.  4-Chlorobenzaldehyde (3.149b): N-Alkoxyphthalimide 3.148b (11.5 mg) was subjected to General Procedure 1 for 30 min to give 62% yield by 1H NMR spectroscopy of aldehyde 3.149b. N-Alkoxyphthalimide 3.148b (11.5 mg) was subjected to General Procedure 2 for 30 min to give 54% yield by 1H NMR spectroscopy of aldehyde 3.149b. 193  4-Bromobenzaldehyde (3.149c): N-Alkoxyphthalimide 3.148c (13.3 mg) was subjected to General Procedure 1 for 30 min to give 62% yield by 1H NMR spectroscopy of aldehyde 3.149c. N-Alkoxyphthalimide 3.148c (13.3 mg) was subjected to General Procedure 2 for 30 min to give 64% yield by 1H NMR spectroscopy of aldehyde 3.149c.  Benzaldehyde (3.78a): N-Alkoxyphthalimide 1.155 (10.1 mg) was subjected to General Procedure 1 for 30 min to give 86% yield by 1H NMR spectroscopy of aldehyde 3.78a. N-Alkoxyphthalimide 1 (10.1 mg) was subjected to General Procedure 2 for 30 min to give 78% yield by 1H NMR spectroscopy of aldehyde 3.78a. N-Alkoxysuccinimde 3.141 (8.2 mg) was subjected to General Procedure 1 for 40 min; aldehyde 2 was not detected by 1H NMR spectroscopy. N-Alkoxysuccinimide 3.141 (8.2 mg) was subjected to General Procedure 2 for 60 min; aldehyde 3.78a was not detected by 1H NMR spectroscopy.  4-Methoxybenzaldehyde (3.78c): N-Alkoxyphthalimide 3.148d (11.3 mg) was subjected to General Procedure 1. After 30 min, the yield of aldehyde 3.78c was 55% by 1H NMR spectroscopy. Increasing the reaction to 40 min gave 65% yield by 1H NMR spectroscopy of aldehyde 11d. N-Alkoxyphthalimide 3.148d (11.3 mg) was subjected to General Procedure 2. After 30 min, the yield of aldehyde 3.78c was 50% 194 by 1H NMR spectroscopy. Increasing the reaction time to 40 min gave 61% yield by 1H NMR spectroscopy of aldehyde 11d.  4-Nitrobenzaldehyde (3.149e): N-Alkoxyphthalimide 3.148e (12.0 mg) was subjected to General Procedure 1 for 30 min; aldehyde 3.149e was not detected by 1H NMR spectroscopy. N-Alkoxyphthalimide 3.148e (12.0 mg) was subjected to General Procedure 2 for 30 min; aldehyde 3.149e was not detected by 1H NMR spectroscopy.   Acetophenone (3.30): N-Alkoxyphthalimide 3.157a (10.6 mg) was subjected to General Procedure 1 for 150 min to give 54% yield by 1H NMR spectroscopy of acetophenone 3.30. N-Alkoxyphthalimide 3.157a (10.6 mg) was subjected to General Procedure 2 for 120 min to give 52% yield by 1H NMR spectroscopy of acetophenone 3.30.   2-Flurobenzaldehyde (3.158b): N-Alkoxyphthalimide 3.157b (10.8 mg) was subjected to General Procedure 1 for 35 min to give 65% yield by 1H NMR spectroscopy of aldehyde 3.158b. N-Alkoxyphthalimide 3.157b (10.8 mg) was subjected to General Procedure 2 for 35 min to give 52% yield by 1H NMR spectroscopy of aldehyde 3.158b.  2-Methoxybenzaldehyde (3.158c): N-Alkoxyphthalimide 3.157c (11.3 mg) was subjected to General Procedure 1 for 40 min to give 61% yield 195 by 1H NMR spectroscopy of aldehyde 3.158c. N-Alkoxyphthalimide 3.157c (11.3 mg) was subjected to General Procedure 2 for 40 min to give 59% yield by 1H NMR spectroscopy of aldehyde 3.158c.  2,4,5-Trimethoxybenzaldehyde (3.158d): N-Alkoxyphthalimide 3.157d (13.7 mg) was subjected to General Procedure 1 for 120 min to give 11% yield by 1H NMR spectroscopy of aldehyde 3.158d. N-Alkoxyphthalimide 3.157d (13.7 mg) was subjected to General Procedure 2 for 120 min to give 5% yield by 1H NMR spectroscopy of aldehyde 3.158d.  2,4,5-Trimethoxybenzaldehyde (3.158e): N-Alkoxyphthalimide 3.157e (13.7 mg) was subjected to General Procedure 1 for 20 min to give 51% yield by 1H NMR spectroscopy of aldehyde 3.158e. N-Alkoxyphthalimide 3.157e (13.7 mg) was subjected to General Procedure 2 for 20 min to give 34% yield by 1H NMR spectroscopy of aldehyde 3.158e.    tert-Butyl-2-formyl-1H-indole-1-carboxylate (3.160a): N- Alkoxyphthalimide 3.159a (15.7 mg) was subjected to General Procedure 1 for 60 min to give 71% yield by 1H NMR spectroscopy of aldehyde 3.160a. N-Alkoxyphthalimide 3.159a (15.7 mg) was subjected to General Procedure 2 for 60 min to give 59% yield by 1H NMR spectroscopy of aldehyde 3.160a. 196 Scale-up procedure: To an oven-dried 50 mL Schlenk flask equipped with a stir bar was added the N-alkoxyphthalimide 3.159a (200 mg, 0.5 mmol), LiBF4 (94 mg, 1.0 mmol, 2.0 equiv) and Ru(bpy)3(PF6)2 (21 mg, 0.025 mmol, 5 mol%). The flask was sealed, then thoroughly evacuated and filled with N2. Acetone (25 mL) was then added, followed by diisopropylethylamine (193 mg, 1.5 mmol, 3.0 equiv). The solution was subjected to 3 freeze-pump-thaw cycles, then sparged with bubbling N2 for 10 min in the dark. The reaction was then illuminated with visible light for 2h. The light was then turned off and the solvent was removed by rotary evaporation. The residue was taken up in EtOAc (10 mL) and washed with saturated NaHCO3 solution (4x5 mL) and brine (2x5 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation. The crude was purified by column chromatography (90:10 hexanes:EtOAc) to afford 104 mg (83%) of aldehyde 3.160a as a white powder. The spectroscopic properties were consistent with those previously published: Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693. 1H NMR (400 MHz, CDCl3) 10.11 (s, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.24 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.35-7.46  (m, 2H), 1.72 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 185.7, 148.8, 136.5, 136.0, 126.1, 124.6, 122.1, 121.6, 115.1, 85.6, 28.1.   1-Methyl-1H-imidazole-2-carbaldehyde (3.160b): N-Alkoxyphthalimide 3.159b (10.3 mg) was subjected to General Procedure 1 for 90 min to give 76% yield by 1H NMR spectroscopy of aldehyde 3.160b. N- Alkoxyphthalimide 3.159b (10.3 mg) was subjected to General Procedure 2 for 90 min to give 41% yield by 1H NMR spectroscopy of aldehyde 3.160b.  197 5-Imidazolecarboxaldehyde (3.160c): N-Alkoxyphthalimide 3.159c (10.0 mg) was subjected to General Procedure 1 for 40 min to give 81% yield by 1H NMR spectroscopy of aldehyde 3.160c. N-Alkoxyphthalimide 3.159c (10.0 mg) was subjected to General Procedure 2 for 40 min to give 72% yield by 1H NMR spectroscopy of aldehyde 3.160c.  3-Methylbut-2-enal (3.160d): N-Alkoxyphthalimide 3.159d (9.3 mg) was subjected to General Procedure 1 for 150 min to give 72% yield by 1H NMR spectroscopy of aldehyde 3.160d. N-Alkoxyphthalimide 3.159d (9.3 mg) was subjected to General Procedure 2 for 120 min to give 59% yield by 1H NMR spectroscopy of aldehyde 3.160d.  Cinnamaldehyde (3.160e): N-Alkoxyphthalimide 3.159e (11.2 mg) was subjected to General Procedure 1 for 150 min to give 20% yield by 1H NMR spectroscopy of aldehyde 3.160e. N-Alkoxyphthalimide 3.159e (11.2 mg) was subjected to General Procedure 2 for 120 min to give 28% yield by 1H NMR spectroscopy of aldehyde 3.160e. -Butryolactone (3.160f): N-Alkoxyphthalimide 3.159f (9.3 mg) was subjected to General Procedure 1 for 60 min to give 63% yield by 1H NMR spectroscopy of lactone 3.160f. N-Alkoxyphthalimide 3.159f (9.3 mg) was subjected to General Procedure 2 for 35 min to give 71% yield by 1H NMR spectroscopy of lactone 3.160f. Scale up procedure: To an oven-dried 50 mL Schlenk flask equipped with a stir bar was added the N-alkoxyphthalimide 3.159f (175 mg, 0.75 mmol) and LiBF4 (141 mg, 2.25 mmol, 2.0 198 equiv). The flask was sealed, then thoroughly evacuated and filled with N2. Acetone (35 mL) was then added, followed by diisopropylethylamine (291 mg, 2.3 mmol, 3.0 equiv). The solution was subjected to 3 freeze-pump-thaw cycles, then sparged with bubbling N2 for 15 min in the dark. The reaction was then illuminated with visible light and stirred for 2 h. The light was then turned off and the solvent was removed by rotary evaporation. The crude was purified by Kugelrohr distillation to afford 39 mg (60%) of lactone 3.160f as a clear oil. The spectroscopic properties were consistent with those of commercially available -butryolactone. 1H NMR (400 MHz, CDCl3) 4.19-4.39 (m, 2H), 2.31-2.52 (m, 2H), 2.11-2.31 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 177.6, 68.3, 27.5, 21.9.  Isochroman-1-one (3.160g): N-Alkoxyphthalimide 3.159g (11.8 mg) was subjected to General Procedure 1 for 15 min to give >95% yield by 1H NMR spectroscopy of lactone 3.160g. N-Alkoxyphthalimide 3.159g (11.8 mg) was subjected to General Procedure 2 for 15 min to give 86% yield by 1H NMR spectroscopy of lactone 3.160g. Scale up procedure: To an oven-dried 50 mL Schlenk flask equipped with a stir bar was added the N-alkoxyphthalimide 3.159g (207 mg, 0.7 mmol), LiBF4 (131 mg, 1.4 mmol, 2.0 equiv) and Ru(bpy)3(PF6)2 (30 mg, 0.035 mmol, 5 mol%). The flask was sealed, then thoroughly evacuated and filled with N2. Acetone (35 mL) was then added, followed by diisopropylethylamine (271 mg, 2.1 mmol, 3.0 equiv). The solution was subjected to 3 freeze-pump-thaw cycles, then sparged with bubbling N2 for 15 min in the dark. The reaction was then illuminated with visible light and stirred for 45 min. The light was then turned off and the solvent was removed by rotary evaporation. The residue was taken up in Et2O (20 mL) and washed with 1 M NaOH solution 199 (4x5 mL) and brine (2x10 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation. The crude was purified by column chromatography (75:25 hexanes:EtOAc) to afford 92 mg (89%) of lactone 3.160g as a clear yellow oil. The spectroscopic properties were consistent with those previously published.m 1H NMR (400 MHz, CDCl3) 8.07 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 4.52 (t, J = 5.6 Hz, 2H), 3.05 (t, J = 5.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 165.0, 139.5, 133.6, 130.2, 127.5, 127.2, 125.1, 67.2, 27.7.  3.9.5 Mechanistic Experiments  N-Alkoxyphthalimide 3.142 (12. 3 mg) was subjected to General Procedure 1 for 4 h. 1H NMR analysis of the reaction mixtures showed ketone 3.143 as the major product (31%), and a trace amount of tetrahydrofuran 6. The presence of tetrahydrofuran 3.144 was confirmed by GC analysis, with comparision to an authentic sample. N-Alkoxyphthalimide 3.142 (12. 3 mg) was subjected to General Procedure 2 for 4 h. 1H NMR analysis of the reaction mixtures showed ketone 3.143 as the major product (22%).                                                   m Dohi, T.; Takenaga, N.; Goto, A.; Fujioka, H.; Kita, Y. J. Org. 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The relative electron densities of Et3N and iPr2NEt can approximated by comparing the pKa’s of their conjugate acids (Et3N +H = 10.65, iPr2N +(Et)H = 11.26 in H2O). Hall, H.K., Jr. J. A.m. Chem. Soc. 1957, 79, 5441. 167. Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1988, 110, 4415.  168. Kornblum, N. Aldrichimica Acta 1990, 23, 71. 169. For representative examples of the oxidation of imidazole alcohols, see: (a) Basso, D.; Broggini, G.; Passarella, D.; Pilati, T.; Terraneo, A.; Zecchi, G. Tetrahedron 2002, 58, 4445. (b) Batten, M. P.; Canty, A. J.; Cavell, K. J.; Ruether, T.; Skelton, B. W.; White, A. H. Inorg. Chim.  Acta 2006, 359, 1710. (c) McNab, H. J. Chem. Soc. Perkin Trans. 1 1987, 653. 214  170. For representative examples of the oxidation of indole alcohols, see: (a) Zheng, C.; Lu, Y.; Zhang, J.; Chen, X.; Chai, Z.; Ma, W.; Zhao, G. Chem—Eur.  J. 2010, 16, 5853. (b) Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. 1994, 59, 7164. 171. For representative examples of the manganese dioxide over–oxidation, see: (a) Kumar, C. N. S. S. P.; Devi, C. L.; Rao, V. J.; Palaniappa, S. Synlet. 2008, 2023. (b) Mohanakrishnan, A. K.; Srinivasan, P. C. Synth. Commun. 1995, 25, 2407. 172. Lee, J. M.; Park, E. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130, 7824. 173. For a representative example of the use of N-alkoxyphthalimides in small molecule synthesis, see ref 32. 215    Appendix A: Selected Spectra for Chapter 1 216 mz03-104-a_001000fid.esp 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 6.369.752.151.983.122.110.940.982.032.00 7. 80 7. 78 7. 35 7. 33 6. 18 6. 16 4. 37 4. 35 4. 34 4. 05 4. 04 4. 02 2. 45 2. 11 2. 09 2. 07 1. 72 1. 71 1. 69 1. 59 0. 90 0. 11mz03-104-a_002000fid 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.1 0.2 0.3 4 .5 .6 .7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 14 4. 49 13 9. 67 13 3. 35 12 9. 74 12 7. 85 10 7. 96 70 .4 3 28 .8 2 25 .5 9 21 .5 9 19 .5 2 18 .2 0 -5 .4 2   217          mz04-026-a-1_002000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 17 5. 79 13 9. 71 13 8. 11 13 2. 74 11 3. 01 10 8. 77 76 .1 6 27 .3 5 25 .6 5 19 .7 5 18 .2 9 - 5. 33   mz04-026-a-1_001000fid 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 .1 2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 5.869.522.131.803.251.001.201.051.001.14 7. 79 7. 77 7. 67 7. 65 7. 65 7. 16 7. 15 7. 14 7. 11 6. 60 6. 60 6. 58 6. 58 6. 26 6. 24 4. 52 4. 50 4. 47 4 .4 5 4 .4 4 4. 42 2. 33 2. 31 2. 29 2. 27 1. 92 1 .9 0 1. 88 1. 87 1. 85 0. 93 0. 14 218         mz03-096-a_002000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 16 3. 68 13 9. 41 13 4. 37 12 9. 01 1 23 .4 4 10 8. 71 78 .4 0 28 .0 9 25 .6 3 19 .6 6 18 .2 6 -5 .3 8   mz03-096-a_001000fid.esp 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 7 0.8 0.9 N or m al iz ed  In te ns ity 5.829.092.131.981.940.950.942.001.87 7. 86 7. 85 7. 84 7. 84 7. 76 7. 75 7. 75 7. 74 6. 22 6. 21 4. 53 4. 51 4. 50 4. 24 4. 22 4. 21 2. 29 2 .2 7 2. 25 2. 24 1. 91 1 .8 9 1. 87 1. 85 1. 84 0. 92 0. 13 219            mz03-095-a_002000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 19 9. 79 16 3. 56 13 6. 85 13 4. 40 13 2. 91 12 8. 52 12 8. 02 12 3. 44 78 .0 9 37 .8 1 2 7. 58 20 .4 0   mz03-095-a_001000fid.esp 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 4.072.002.001.981.002.052.002.00 8. 00 7. 98 7. 82 7. 76 7. 75 7. 73 7. 55 7. 46 7. 44 4. 28 4. 26 4. 24 3. 13 3. 12 3. 10 2. 01 1. 99 1. 97 1. 92 1. 90 1. 89 220             mz03-098-a_002000fid 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 16 3. 55 15 0. 15 13 9. 45 13 4. 33 12 8. 92 12 7. 82 12 5. 86 12 3. 38 11 0. 00 78 .2 3 2 8. 12 25 .8 0 22 .1 7 18 .2 4 -4 .0 7  mz03-098-a_001000fid.esp 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 1 2 3 4 5 .6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 5.798.781.981.911.960.953.011.972.001.89 7. 84 7. 84 7. 83 7. 82 7. 75 7. 74 7. 74 7. 73 7. 43 7. 29 7. 27 5. 17 5 .1 5 5. 13 4. 28 4. 26 4. 25 2. 44 2 .4 2 2. 41 2. 39 1. 98 1. 96 1. 94 1. 92 1. 91 0. 98 -0 .0 4 221 Zhai-II-71_002000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 16 3. 44 13 4. 31 12 8. 95 12 3. 34 80 .9 7 63 .3 2 38 .4 5 29 .8 3 26 .4 5 25 .9 2 23 .4 0 18 .2 9 10 .7 5 -5 .3 2 Zhai-II-71_001000fid.esp 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 6.039.283.166.311.112.012.054.00 7. 83 7. 81 7. 81 7. 74 7. 73 7. 73 7. 72 4. 10 4. 09 3. 65 3. 63 3. 61 1. 78 1. 77 1. 61 1 .6 0 1. 58 1. 51 1. 49 1. 45 0. 98 0. 96 0. 88 0. 05 222 mz04-068-a_001000fid.esp 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 3.024.222.471.062.051.071.052.001.94 7. 85 7. 84 7. 83 7. 77 7. 76 7. 75 7. 74 4. 19 4. 17 4. 16 4. 15 4. 12 4. 10 4. 10 3 .7 2 3. 70 3. 69 1. 84 1. 82 1. 81 1. 72 1. 70 1. 69 1. 69 1. 55 1. 53 1. 52 1. 48 1. 00 0. 99 0. 97                    mz04-068-a_002000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 16 3. 24 13 4. 18 12 8. 49 12 3. 08 80 .4 4 62 .3 9 38 .1 7 29 .3 6 26 .2 4 23 .1 5 10 .6 0    223 MZ04-071-A_001000FID.esp 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 5.509.082.811.150.931.051.762.010.750.130.760.142.002.02 7. 83 7. 82 7. 82 7. 81 7. 74 7. 74 7. 73 7. 72 6. 35 6. 32 6 .2 5 6. 24 5. 00 4. 99 4. 97 4. 52 4. 51 4. 49 4. 15 4. 14 4. 13 4. 12 4. 07 4. 06 4. 04 2. 27 2. 25 2. 23 2. 22 2. 20 1. 84 1. 82 1. 48 1. 46 1. 45 1. 41 1. 00 0. 98 0. 90 0. 11          mz04-071-a_002000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 16 3. 41 13 9. 79 13 4. 25 12 8. 95 12 3. 28 10 6. 98 81 .2 6 39 .1 6 25 .6 5 25 .5 4 23 .3 4 18 .1 1 10 .9 2 -5 .3 1 -5 .4 6   224 mz04-051-a-2_001000fid.esp 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 6.018.922.141.461.030.982.020.991.005.363.87 7. 82 7. 81 7. 80 7. 79 7. 74 7. 72 7. 32 7. 30 7. 28 7 .2 8 7. 25 7. 21 7. 20 7. 18 4. 45 4. 43 4. 43 4. 41 4. 32 4. 31 4. 30 3. 61 3 .6 0 3. 59 3. 59 3. 58 3. 16 3. 15 3. 15 2. 08 2. 06 2. 05 1. 72 1. 70 1. 53 1. 51 1. 50 1. 49 0. 96 0. 94 0. 92 0. 60 0. 58 0. 56 0. 54          mz04-051-a-2_002000fid.esp 200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 8 .9 1.0 N or m al iz ed  In te ns ity 16 3. 32 14 0. 95 13 4. 33 12 8. 87 12 8. 46 12 7. 83 12 6. 72 12 3. 34 82 .0 1 62 .6 9 44 .6 9 30 .3 1 28 .9 7 6. 72 4. 36    225 mz04-052-b_001000fid.esp 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 1.112.910.991.001.005.094.000.91 9. 68 7. 77 7. 77 7. 76 7. 75 7. 71 7. 70 7. 70 7. 69 7. 30 7. 28 7. 21 7. 19 7. 17 4. 39 4. 38 4. 37 4. 28 4. 26 3. 13 3. 11 3. 08 2 .4 7 2. 45 2. 43 2. 41 2. 40 2. 37 1. 98 1. 96 1. 95 1. 94          mz04-052-b_002000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 20 1. 74 16 3. 18 13 9. 66 13 4. 33 12 8. 58 12 7. 65 12 3. 26 81 .4 2 43 .8 6 41 .2 7 24 .9 8   226 mz04-054-a_001000fid.esp 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 N or m al iz ed  In te ns ity 2.901.921.354.805.670.670.791.220.510.681.110.930.660.440.600.367.744.03 7. 83 7. 80 7. 80 7. 78 7. 73 7. 72 7. 72 7. 32 7. 31 7. 30 7. 27 7. 25 7. 23 7. 19 7. 17 7. 01 6 .2 4 6. 21 6. 20 6. 18 4. 91 4. 89 4. 52 4 .5 0 4. 48 4. 45 4 .4 3 4. 42 4. 37 4. 36 4. 35 3. 27 3. 25 3. 23 3. 21 3. 14 2. 67 2. 65 2. 64 2. 60 2. 50 2. 48 2. 47 2. 30 0. 91 0. 86 0. 10 0. 09 0. 06          mz04-054-a_002000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 .5 0.6 0.7 0.8 .9 1.0 N or m al iz ed  In te ns ity 16 3. 24 14 2. 01 13 9. 81 13 4. 21 12 8. 78 12 8. 20 12 7. 71 12 3. 21 10 7. 58 10 6. 66 81 .3 0 77 .4 3 77 .0 0 76 .5 7 60 .2 7 4 5. 38 44 .7 4 30 .7 8 2 7. 27 25 .5 8 25 .5 2 18 .1 7 1 8. 08 14 .1 0 -3 .6 5 -5 .4 8   227 mz04-065-a_001000fid.esp 9 8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 1.451.603.419.244.321.161.000.981.000.991.130.970.96 8. 34 8. 33 8. 33 7. 38 7. 37 7. 18 7. 15 7. 13 7. 10 7. 08 6. 90 6. 89 6. 89 6. 09 6. 08 6. 07 6. 06 4. 18 4. 17 4. 16 4. 15 4. 15 4. 14 3. 83 3. 82 3. 75 3. 73 1. 96 1. 94 1. 92 1. 91 1. 90 1. 87 1. 81 1. 79 0. 77 0. 01 -0 .1 0 -0 .1 4          mz04-065-a_002000fid.esp 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 15 8. 11 14 9. 37 14 9. 20 13 6. 02 12 8. 28 12 3. 71 11 9. 83 11 9. 77 82 .3 9 82 .3 2 81 .2 1 69 .2 4 68 .9 7 28 .2 5 25 .7 1 18 .0 0 -4 .5 6 -5 .1 2 - 5. 18    228 mz03-099-a-1_003000fid.esp 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 N or m al iz ed  In te ns ity 6.249.561.043.182.071.031.011.00 3. 96 3. 95 3. 85 3. 83 3. 77 3. 75 3. 61 3. 60 3. 58 3. 57 3. 55 3. 54 1. 92 1 .9 0 1. 89 1. 88 1. 86 1. 85 1. 83 1. 69 1. 67 0. 89 0. 05             mz03-099-a-1_002000fid.esp 96 88 80 72 64 56 48 40 32 24 16 8 0 -8 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 .8 0.9 1.0 N or m al iz ed  In te ns ity 79 .4 2 68 .3 6 65 .8 3 27 .7 8 25 .9 2 25 .7 2 18 .3 5 -5 .3 5   229 mz03-100-a-jul28_001000fid.esp 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 1.750.952.629.041.750.771.511.300.700.680.360.310.675.00 7. 39 7. 37 7. 34 7. 32 7. 31 7. 30 7. 27 7. 23 4 .7 9 4. 78 4. 70 4. 68 4. 00 3. 99 3. 98 3. 98 3. 90 3. 88 3. 78 3. 76 2. 01 1. 99 1. 96 1. 95 1. 82 1. 72 1. 71 1. 69 1. 68 1. 67 0. 92 0. 91 0. 09 -0 .0 9                   mz03-100-a_002000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 14 2. 62 14 1. 84 12 7. 93 12 6. 33 84 .1 2 77 .2 1 76 .4 7 68 .7 6 68 .4 2 26 .9 6 26 .0 6 25 .8 3 25 .6 3 18 .2 1 -4 .8 3 -4 .9 2 230 mz04-072-a_002000fid.esp 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 6.0312.480.712.021.660.431.561.012.011.96 4. 01 3. 99 3. 92 3. 65 3. 64 3. 63 3. 60 3. 56 3. 40 3. 38 3. 37 3. 35 2. 16 2. 13 2. 12 1. 61 1. 61 1. 60 1. 41 1. 41 1. 40 1. 39 1. 38 0. 94 0. 92 0. 91 0. 87 0. 07               mz04-072-a_003000fid.esp 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 80 .0 9 79 .1 1 7 3. 32 65 .9 6 41 .7 5 40 .6 4 34 .6 3 33 .9 8 25 .9 0 18 .3 3 12 .8 6 12 .7 7 -5 .3 7 231 mz04-057-b_001000fid.esp 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 N or m al iz ed  In te ns ity 5.819.000.610.410.390.570.930.752.061.885.10 7. 35 7. 33 7. 31 7. 29 7. 28 7. 27 7. 26 7. 24 4. 28 4. 27 4. 25 4. 21 4 .1 9 4. 17 3. 80 3 .7 9 3. 77 3. 70 3. 69 3. 69 3. 49 3. 47 2. 41 2. 40 2. 38 2. 36 2. 28 2. 11 2. 08 1. 98 1. 95 1. 92 0. 94 0. 12          mz04-057-b_002000fid.esp 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 .6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 14 2. 30 14 1. 70 12 8. 47 12 7. 26 12 6. 51 12 6. 43 80 .4 7 79 .6 8 74 .6 1 65 .8 6 65 .7 1 45 .5 3 44 .5 1 36 .5 6 36 .1 0 25 .9 4 25 .7 5 1 8. 38 -5 .3 0 232    Appendix B: Selected Spectra for Chapter 2 233 mz06-094-a_001000fid.esp 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008 0.0009 0.0010 N or m al iz ed  In te ns ity 3.199.132.042.032.022.961.00 4. 22 4. 20 4. 19 4. 19 4. 17 4. 16 3. 69 3. 22 3. 21 3. 20 3. 20 2. 51 2. 49 2. 48 2. 47 2. 09 2. 08 2. 08 2. 06 2. 06 2. 04 0. 88 0. 12 0. 08  mz06-094-a_002000fid.esp 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008 0.0009 0.0010 N or m al iz ed  In te ns ity 17 1. 34 69 .3 0 51 .5 7 42 .0 0 41 .3 3 25 .7 1 17 .9 2 1 .4 3 -4 .5 1 -4 .7 1   234 mz06-095-a_002000fid 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0.00005 0.00010 0.00015 0.00020 0.00025 0.00030 0.00035 0.00040 0.00045 N or m al iz ed  In te ns ity 2.838.972.071.842.000.880.84 9. 81 9. 80 9. 80 4. 31 4. 30 4. 28 4. 28 4. 27 4. 25 3. 22 3. 20 3. 18 2. 58 2 .5 7 2. 57 2. 56 2. 08 2. 07 2. 06 2. 05 0. 88 0. 13 0. 10  mz06-095-a_001000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008 0.0009 0.0010 N or m al iz ed  In te ns ity 20 0. 99 68 .0 2 50 .4 1 41 .2 5 25 .7 1 17 .9 1 1. 36 -4 .4 0 -4 .5 6   235     236 mz06-104-a_001000fid 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008 0.0009 0.0010 N or m al iz ed  In te ns ity 8.9813.122.082.000.320.600.590.61 6. 41 6. 38 6. 16 6. 14 6. 14 5. 00 4. 98 4. 97 4. 95 4. 82 4. 80 4. 51 4. 49 4. 49 4. 47 4. 16 3. 37 3. 36 3 .3 5 3. 33 3. 31 1. 82 1. 80 1. 78 1. 77 1. 73 1. 72 1. 71 1. 71 0. 94 0. 89 0. 88 0. 14 0. 06 0. 03  mz06-104-a_002000fid 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008 0.0009 0.0010 N or m al iz ed  In te ns ity 14 2. 32 13 8. 45 11 3. 99 11 3. 64 67 .9 5 63 .5 3 48 .0 2 38 .1 4 37 .2 6 25 .8 9 25 .5 2 18 .0 9 -2 .9 5 -4 .4 2 -5 .1 4 -5 .3 1   237 mz06-047-a_001000fid.esp 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008 0.0009 0.0010 N or m al iz ed  In te ns ity 6.582.172.181.060.99 9. 82 9. 81 4. 32 4. 31 4. 30 4. 29 3 .2 3 3. 21 3. 20 2. 60 2. 59 2. 59 2. 58 2. 57 1. 56 0. 99 0. 97 0. 95 0. 66 0. 64 0. 62 mz06-047-a_003000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.0001 0.0002 0.0 03 4 5 6 . 7 0.0008 0.0009 0.0010 N or m al iz ed  In te ns ity 20 0. 99 6 7. 97 50 .5 5 4 1. 37 6. 83 4. 99 1. 28    238 mz06-048-a_001000fid.esp 11 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008 0.0009 0.0010 N or m al iz ed  In te ns ity 6.922.001.951.940.950.86 9. 82 9. 82 9. 81 7. 27 4. 38 4 .3 6 4. 35 4. 33 4. 32 3. 43 3. 41 3. 39 2 .6 1 2. 60 2. 60 1. 83 1. 81 1. 79 1. 78 0. 99 0. 97 0. 95 0. 66 0. 64 0. 62 0. 60  mz06-060-a_002000fid 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 . 8 9 10 N or m al iz ed  In te ns ity 20 1. 02 77 .3 2 77 .0 0 76 .6 8 65 .0 4 50 .9 7 47 .4 8 36 .3 9 6. 71 4. 82   239 mz06-026-a_001000fid.esp 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 0 0.000005 0.000010 0.000015 0.000020 0.000025 0.000030 0.000035 0.000040 0.000045 0.000050 0.000055 0.000060 0.000065 N or m al iz ed  In te ns ity 50.5292.621.782.000.750.440.390.32  mz06-049-a_001000fid.esp 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 .0008 0.0009 0.0010 N or m al iz ed  In te ns ity 6.926.4924.282.502.221.030.981.00 6. 41 6. 38 5. 01 4. 99 4. 98 4. 96 4. 19 4. 18 4. 17 4. 16 4. 15 4. 15 3. 40 3. 39 3. 37 3. 36 3. 34 3. 32 3. 31 1. 84 1. 82 1. 80 1. 79 1. 72 1. 72 1. 70 1. 70 0. 98 0. 96 0. 93 0. 92 0. 63 0. 61 0. 59 0. 57 0. 16   240 mz06-056-a_001000fid 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0 0.00001 0.00002 0.00003 0.00004 0.00005 0.00006 0.00007 0.00008 0.00009 0.00010 0.00011 0.00012 0.00013 N or m al iz ed  In te ns ity 50.38114.332.801.731.030.980.81 6. 20 6. 20 6. 18 6. 18 4. 86 4. 84 4. 83 4. 81 4. 79 4 .5 0 4. 49 4. 48 4. 46 3. 36 3 .3 3 3. 31 1. 77 1. 75 1. 74 1. 74 1. 71 1. 69  mz06-050-a_001000fid.esp 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 7 0.0008 0.0009 0.0010 N or m al iz ed  In te ns ity 8.498.542.161.440.710.691.910.50 7. 27 4. 32 4. 32 4. 31 4. 31 3. 74 3. 73 3. 66 3. 61 3. 60 3. 58 3. 57 2. 95 2. 94 2. 94 2. 93 2. 06 2. 06 2. 05 1. 73 1. 55 1. 07 1. 05 0. 97 0. 96 0. 90 0. 87 0. 62 0. 60 0. 58 0. 57 0. 10 0. 09 0. 06   241 mz06-059-a_001000fid.esp 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008 0.0009 0.0010 N or m al iz ed  In te ns ity 14.263.671.762.000.88 4. 15 4. 13 3. 60 3. 58 3. 58 3. 56 3. 06 2. 97 2. 96 2. 95 1. 89 1. 88 1. 87 1. 86 0. 98 0. 96 0. 94 0. 63 0. 61 0. 59 0. 57  mz06-059-a_002000fid.esp 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.0001 0.0002 0.0003 . 4 . 5 0.0006 0.0007 0.0008 0.0009 0.0010 N or m al iz ed  In te ns ity 73 .8 8 68 .5 1 63 .3 9 45 .0 5 35 .5 5 6. 93 4. 95 4. 50   242 mz07-105-a_001000fid.esp 11 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 3.000.990.881.910.73 9. 67 7. 27 3. 31 3. 30 3. 28 3. 26 3. 25 3. 23 3. 22 2. 40 2. 36 2. 35 2. 34 2. 25 2. 24 2. 16 1. 60 1. 57 1. 44 1. 42 0. 93 0. 91  mz07-105-a_002000fid.esp 220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 20 1. 61 77 .3 2 77 .0 0 76 .6 8 50 .3 4 48 .8 3 35 .1 0 25 .2 4 19 .2 8   243 mz07-107-a_001000fid.esp 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 N or m al iz ed  In te ns ity 5.969.380.990.760.162.000.150.750.20 7. 27 6. 27 6. 24 6. 19 6. 17 4 .8 0 4. 78 4. 77 4. 75 4. 23 4. 21 4. 20 3. 31 3 .3 0 3. 28 3. 28 3. 26 3. 24 3. 23 3. 23 2. 17 2. 16 1. 63 1. 61 1. 60 1. 59 1. 47 1. 45 1. 45 1. 03 1. 01 0. 93 0. 14  mz07-107-a_002000fid.esp 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 8 0.0000009 0.0000010 N or m al iz ed  In te ns ity 14 0. 25 13 8. 44 11 5. 89 11 4. 84 77 .3 2 77 .0 0 76 .6 8 49 .9 1 49 .6 0 36 .4 1 36 .3 0 29 .9 9 26 .2 4 25 .6 8 25 .5 7 22 .0 2 21 .1 8 18 .3 3 -5 .2 9 -5 .5 0   244 mz07-108-a_001000fid.esp 10 9 8 7 6 5 4 3 2 1 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 1.172.181.043.361.00 9. 68 7. 36 7. 34 7 .2 2 7. 20 3. 37 3. 36 3. 35 3. 35 3. 20 3. 19 3. 08 3. 05 2. 80 2. 80 2. 78 2. 78 2. 77 2. 76 1. 99 1. 98 1. 97 1. 97 1. 86 1. 84 1. 59 mz07-108-a_002000fid.esp 200 180 160 140 120 100 80 60 40 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 20 0. 84 14 2. 02 12 8. 90 12 7. 40 12 7. 08 77 .3 0 7 7. 00 76 .6 8 50 .2 4 49 .0 3 37 .0 0 3 5. 22     245 mz07-109-a_001000fid.esp 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 5.739.001.962.640.230.230.680.232.79 7. 32 7. 30 7. 22 7. 21 7. 20 6. 36 6. 33 6. 29 6. 27 5. 17 5. 15 5. 14 5. 12 4. 63 4. 61 4. 61 4. 61 4. 59 3. 96 3. 32 3. 30 3. 30 3. 30 3. 28 3. 26 3. 24 1. 99 1. 98 1. 97 1. 96 1. 96 1. 92 1. 90 1. 89 1. 57 0. 93 0. 89 0. 88 0. 86 0. 77 0. 15 0. 14 0. 12 0. 10 0. 04 mz07-109-a_002000fid.esp 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.00 0003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 14 4. 41 14 1. 31 13 9. 03 12 8. 57 12 7. 13 12 6. 31 12 6. 08 11 3. 85 11 2. 64 77 .3 2 77 .0 0 76 .6 8 76 .5 3 49 .7 4 49 .4 6 41 .2 2 37 .4 4 35 .7 5 35 .5 5 25 .6 5 25 .5 6 18 .3 0 -5 .2 1 - 5. 26     246 mz07-125-a_001000fid.esp 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 6.219.504.261.002.20 7. 27 3. 88 3. 85 3. 68 3. 67 3. 66 3. 65 3. 65 3. 31 3. 28 3. 27 3. 22 3. 21 1. 65 1. 65 1. 64 1 .6 3 1. 62 1. 57 1. 55 0. 92 0. 13 0. 10 mz07-125-a_002000fid.esp 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 . 4 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 77 .3 2 77 .0 0 76 .6 8 76 .6 4 7 1. 38 62 .7 9 56 .3 4 31 .4 4 28 .1 5 25 .7 4 17 .9 8 -4 .6 7   247 mz07-126-a_001000fid.esp 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 N or m al iz ed  In te ns ity 2.5610.251.981.941.061.000.95 9. 78 9. 78 9. 77 3. 86 3. 85 3. 84 3. 28 3. 26 3. 25 3. 18 3. 16 2. 53 2 .5 2 2. 52 2. 50 1. 88 1. 87 1. 83 1. 82 1. 80 0. 90 0. 10 0. 07  mz07-126-a_002000fid.esp 200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 6 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 20 1. 57 77 .3 2 77 .0 0 76 .6 8 70 .2 7 56 .2 8 39 .3 0 26 .9 5 25 .6 9 17 .9 1 -4 .6 5 -4 .8 0     248 mz07-127-a_001000fid 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 13.0020.831.531.000.800.210.741.02 7. 27 6. 30 6 .2 7 6. 26 6. 26 6 .2 4 6. 24 4. 94 4. 92 4. 91 4. 90 4. 89 4. 87 4. 41 3. 75 3. 75 3. 74 3. 27 3. 26 3. 24 3. 23 3. 16 3. 14 3. 12 3. 11 2. 15 2. 14 2. 13 2. 12 2. 11 2. 11 2. 09 1. 60 1. 59 0. 95 0. 94 0. 93 0. 92 0. 91 0. 87 0. 87 0. 17 0. 15 0. 14 0. 11 0. 09 0. 04 0. 02 mz07-127-a_002000fid 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 . 8 . 9 10 N or m al iz ed  In te ns ity 14 2. 49 14 0. 56 10 5. 72 10 4. 32 77 .3 2 77 .0 0 76 .6 8 72 .0 9 71 .9 5 56 .4 3 55 .8 8 33 .1 6 29 .6 9 25 .7 7 25 .6 5 18 .2 7 18 .0 1 -4 .6 5 -4 .8 2 -5 .2 4     249 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 7. 27 3. 70 3. 68 3. 66 3. 65 3. 57 3. 55 3. 54 3. 52 2. 96 2. 94 2. 92 2. 92 2. 61 2. 13 1. 95 1. 93 1. 81 1. 04 0. 91 0. 89 0. 88 0. 05  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 .3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 6.3211.981.500.971.003.301.011.009.83 7. 33 7 .3 1 7. 29 7. 27 7. 25 7. 23 7. 21 7. 19 3. 72 3. 56 3. 55 3. 55 3. 21 3. 20 3 .1 9 3. 18 3. 17 3. 01 2. 99 2. 03 2. 00 2. 00 1. 55 0. 94 0. 93 0. 92 0. 90 0. 88 0 .1 2 0. 12 0. 11 0. 05   250 mz07-128-a_001000fid.esp 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 12.0018.690.700.991.450.250.80 7. 27 4. 35 4. 34 4. 34 4. 33 4. 33 4. 32 3. 65 3. 64 3. 14 3. 13 2 .8 7 2. 87 2. 86 2. 04 2. 04 2. 02 2. 02 1. 73 1. 49 1. 48 1. 47 1. 46 0. 92 0. 91 0. 90 0. 88 0. 14 0 .1 3 0. 06 0. 05 0. 04 mz07-128-a_002000fid 88 80 72 64 56 48 40 32 24 16 8 0 -8 -16 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 . 4 5 . 6 0.0000007 0.0000008 0.0000009 0.0000010 N or m al iz ed  In te ns ity 77 .3 2 77 .0 0 76 .6 8 76 .6 4 73 .4 1 65 .5 5 59 .8 4 55 .8 1 38 .0 8 25 .9 4 25 .8 4 25 .6 6 25 .1 6 18 .3 5 18 .0 6 -4 .7 6 -5 .3 5   251    Appendix C: Selected Spectra for Chapter 3 252 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 4.002.002.821.90 7. 51 7. 50 7. 49 7. 49 7. 40 7. 39 7. 27 5. 13 2. 66 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 17 1. 07 13 3. 24 12 9. 85 12 8. 49 78 .5 5 77 .3 2 77 .0 0 76 .6 8 25 .3 6    253 10 9 8 7 6 5 4 3 2 1 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 0.981.981.022.001.001.013.032.034.11 7. 74 7. 73 7. 72 7. 68 7. 48 7. 45 7. 33 7. 32 7. 27 5. 90 5. 87 5. 86 5. 83 5. 82 5. 37 5. 35 5. 09 5. 09 5. 05 5. 03 5. 01 2. 34 2 .3 2 2. 32 2. 30 2. 21 2. 20 2. 03 2. 01 2. 00 1. 99 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 .9 N or m al iz ed  In te ns ity 16 3. 67 13 7. 92 13 7. 38 13 4. 21 12 8. 81 12 8. 29 12 8. 06 12 3. 29 11 5. 37 88 .6 1 77 .3 2 77 .0 0 76 .6 8 34 .0 1 2 9. 75   254 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 2.001.941.921.931.88 7. 85 7. 83 7. 82 7. 82 7. 76 7. 75 7. 75 7. 73 7. 27 7. 07 7. 05 5. 19 1. 57   180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 8 0.9 N or m al iz ed  In te ns ity 16 4. 53 16 3. 40 16 2. 06 13 4. 43 13 1. 80 12 8. 76 12 3. 48 11 5. 61 11 5. 40 78 .9 5 77 .3 2 77 .0 0 76 .6 8   255 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 2.001.901.932.001.94 7. 84 7. 84 7. 83 7. 81 7. 76 7. 73 7. 50 7. 48 7 .3 7 7. 35 7. 27 5. 19 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 16 3. 39 13 5. 30 13 4. 48 13 1. 11 12 8. 76 12 3. 52 78 .8 9 77 .3 2 77 .0 0 76 .6 8   256 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 2.001.962.061.941.95 7. 83 7 .8 3 7. 82 7. 81 7 .7 6 7. 53 7. 51 7. 43 7. 41 5. 17 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 16 3. 40 13 4. 49 13 1. 72 13 1. 37 12 8. 76 12 3. 54 78 .9 4 77 .3 2 77 .0 0 76 .6 8   257 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 16 3. 52 16 0. 43 13 4. 34 13 1. 63 12 8. 90 12 5. 82 12 3. 43 11 3. 91 79 .4 7 77 .3 2 77 .0 0 76 .6 8 55 .2 4  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 3.002.021.961.931.951.94 7. 82 7. 81 7. 81 7. 80 7. 74 7. 73 7. 47 7. 45 7. 27 6. 91 6. 89 5. 16 3. 81 258 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 2.000.950.960.960.971.951.94 7. 84 7. 83 7 .8 2 7. 81 7. 75 7. 74 7. 73 7. 57 7. 56 7. 39 7. 17 7. 08 7. 06 5. 31 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 16 3. 30 16 2. 80 16 0. 31 13 4. 40 13 2. 17 13 1. 38 12 4. 23 12 3. 47 12 1. 27 11 5. 60 11 5. 39 72 .9 4   259 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 3.122.070.991.010.991.022.002.03 7. 81 7. 80 7. 79 7. 73 7. 72 7. 72 7. 71 7. 45 7. 43 6 .9 4 6. 88 6. 86 5. 30 3. 77 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 16 3. 42 15 8. 45 13 4. 22 13 2. 09 12 8. 95 12 3. 28 12 2. 43 12 0. 49 11 0. 63 74 .5 3 55 .4 8   260 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 N or m al iz ed  In te ns ity 5.993.052.001.922.001.95 7. 78 7. 77 7. 77 7 .7 6 7. 71 7. 70 7. 69 7. 68 6. 02 5. 33 3. 79 3. 66 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 16 3. 51 16 0. 93 13 3. 91 12 9. 11 12 2. 96 10 3. 91 90 .1 8 67 .8 7 55 .6 8 55 .2 1   261 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 2.001.951.93 7. 86 7. 85 7. 83 7. 79 7. 78 7. 77 7. 76 5. 34 5. 34 180 160 140 120 100 80 60 40 20 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 16 3. 20 14 7. 59 14 7. 51 14 5. 09 14 5. 02 14 3. 70 14 1. 15 13 8. 65 13 4. 75 12 8. 58 12 3. 77 10 8. 51 10 8. 47 10 8. 33 10 8. 29 10 8. 15 10 8. 12 65 .8 8   262 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N or m al iz ed  In te ns ity 9.552.001.982.881.950.910.89 8. 15 7 .8 6 7. 85 7. 84 7. 78 7. 77 7. 76 7. 76 7. 27 5. 39 1. 68 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 16 3. 55 14 9. 38 13 5. 56 13 4. 43 12 9. 53 12 8. 95 12 7. 21 12 3. 51 12 3. 14 11 9. 83 11 5. 16 11 3. 71 84 .0 7 77 .3 2 77 .0 0 76 .6 8 71 .3 8 28 .1 3   263 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 2.922.000.960.943.83 7. 76 7. 75 7. 74 7. 73 7. 70 7. 70 7. 69 7. 68 7. 27 6. 97 6. 90 5. 24 3. 93 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 N or m al iz ed  In te ns ity 16 3. 08 14 1. 08 13 4. 36 12 8. 69 12 8. 25 12 3. 42 12 3. 26 77 .3 2 77 .0 0 76 .6 8 70 .1 4 33 .1 9  

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