Phosgene-Free Synthesis of Verdazyl Radicals and Enantioselective 1,3-Dipolar Cycloaddition Reactions of Azomethine Imines Generated in situ from Verdazyl Radicals by Beom Youn A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Chemistry University of Toronto © Copyright by Beom Youn (2012) Phosgene-free synthesis of verdazyl radicals and enantioselective 1,3-dipolar cycloaddition reactions of azomethine imines generated in situ from verdazyl radicals Beom Youn Master of Science Graduate Department of Chemistry University of Toronto 2012 Abstract Verdazyl radicals started receiving attention as substrates for organic synthesis only a few years ago. Since then, the chemistry of verdazyl radicals has advanced at a very fast rate. There are now a number of generations of novel molecular scaffolds derived from verdazyl radicals. Traditionally, verdazyl radicals have been synthesized from mono-substituted alkyl hydrazine and phosgene, which are extremely dangerous to handle. Alkyl hydrazines are restricted from being imported into certain countries, including Canada. A completely new alkyl hydrazine- and phosgene-free synthesis is reported in this thesis. The new synthesis, relative to previously reported syntheses of verdazyl radicals, is safer, more economical and provides the ability to derivatize verdazyl radicals to a larger extent. In addition, enantioselective 1,3-dipolar cycloaddition reactions with various metal- or organo-catalysts are reported. The project is still in progress with the highest e.e. of > 90%. ii Table of Contents Abstract ……………………………………………………………………………………………i Table of Contents …………………………………………………………………………………ii List of Schemes…………………………………………………………………………………....v List of Figures…………………………………………………………………………………….vi List of Tables……………………………………………………………………………………viii List of Abbreviations……………………………………………………………………………..ix Chapter 1 Verdazyl Radicals…………………………………………………………………...1 Chapter 1.1 The First Discovery of Persistent Radical Radicals ……………….…...….1 Chapter 1.2 The Discovery and First Synthesis of Verdazyl Radicals…………..……….2 Chapter 1.3 Neugebauer’s Synthesis of 6-Oxo and Thioverdazyl Radicals…….………..3 Chapter 1.4 Milcent’s Variation on Neugebauer’s Synthesis………………….…...…….6 Chapter 1.5 Brook’s Verdazyl Radical Synthesis…….……………………….…………7 Chapter 1.6 Inorganic Verdazyl Radicals…………………………….……….………….9 References………………………………………………………………………………..10 Chapter 2 1,3-Dipolar Cycloadditions…………………………………………….…………..12 Chapter 2.1 Introduction to Cycloadditions………………………………….………….12 Chapter 2.2 1,3-Dipolar Cycloaddition……….…………………………………………13 Chapter 2.3 Stereoselective 1,3-Dipolar Cycloaddition Reactions………….…………..23 Chapter 2.4 Concluding Remarks………………………….…………………………....34 References…………………………………………………………………………….....35 Chapter 3 Evolution of Verdazyl Radicals as Substrates for 1,3-Dipolar Cycloaddition Reactions ………………………………………………………………………………………..38 Chapter 3.1 Discovery of the First 1,3-Dipolar Cycloaddition Reaction Initiated by an Azomethine Imine Generated In Situ from a Verdazyl Radical…..………………….….38 Chapter 3.2 Second Generation of Unique Scaffolds Derived from Verdazyl Radicals………………………………………………………………………………….40 iii Chapter 3.3 Heteraphanes from Verdazyl Radicals……………………………………...41 Chapter 3.4 Summary……….………….………………………….…………………….43 References……………………………….………………………………………………44 Chapter 4 Phosgene Free Synthesis of Verdazyl Radicals…….……………………………..48 Chapter 4.1. Introduction……...…………...……………………………………………48 Chapter 4.2. Experimental Section…………..………………………………………….49 Chapter 4.3. Results and Discussion………..…………………………………………...68 References……..………………….……………………………………………………..71 Chapter 5 Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Imines Generated in situ from Verdazyl Radicals…………...………..……………………………………………...72 Chapter 5.1. Introduction….………………………………….………………………….72 Chapter 5.2. Experimental Section …….…………………….………………………….75 Chapter 5.3. Results and Discussion………..………………………………………...…77 Chapter 5.4. Concluding Remark/Future Work ……………….………………………..85 References……………………………………………………………………………….88 iv List of Schemes Chapter 1 Scheme 1-1. First discovery and synthesis of verdazyl radicals ………………………...2 Scheme 1-2. Neugebauer’s synthesis of tetrazinanones………………………...………..4 Scheme 1-3. Decomposition reactions of hydrazine………..………………….………...4 Scheme 1-4. Reversed regiochemical selectivity of a t-butyl substituted hydrazine….....6 Scheme1-5. Milcent’s variation of Neugebauer’s synthesis………………………..........7 Scheme 1-6. Brook’s synthesis of 1,5-diisopropyl substituted 6-oxoverdazyl radicals…8 Scheme 1-7. Modification of Brook’s synthesis for unsymmetrical verdazyl radicals .....8 Scheme 1-8. Synthesis of phosphaverdazyl radicals …………………………………....9 Scheme 1-9. Synthesis of borataverdazyl radicals …………………………………........9 Chapter 4 Scheme 4-1. Retrosynthsis of a phosgene-free verdazyl radical synthesis……………..46 Scheme 4-2. Phosgene-free synthesis of verdazyl radicals………………………..........46 Scheme 4-3. Our modification of Milcent variation on Neugebauer’s synthesis………69 Chapter 5 Scheme 5-1. Asymmetric 1,3-DC reactions with azomethine imines and β-unsaturated aldehydes by Maruoka and et al………….…………………………………………......73 Scheme 5-2. Asymmetric 1,3-DC reaction with azomethine imines and homoallylic alcohols by Inomata and et al………………………………..………………………….73 Scheme 5-3. Asymmetric 1,3-DC of nitrones to olefins by Furukawa et al………........75 v List of Figures Chapter 2 Figure 2-1. Diels-Alder reaction between a butadiene and ethene……………………...12 Figure 2-1. 1,3-Dipoles of (a) propargyl-allenyl type, (b) allyl type with nitrogen as a central atom, and (c) allyl type with an oxygen as a central atom……………………….13 Figure 2-2. An examples of a 1,3-DCcompound with a heteroatom containing dipolarophile……………………………………………………………………………..14 Figure 2-3. Diradical mechanism of 1,3-DC……………………………………………15 Figure 2-4. Isoelectronic nature of allyl anion and 1,3-dipole…………………………..16 Figure 2-5. Directionless (or bidirectional) cyclic mechanism of 1,3-dipolar cycloadditions……………………………………………………………………………17 Figure 2-6. (a) FMO phase matching and (b) coefficient matching in a cycloaddition reaction…………………………………………………………………………………...18 Figure 2-7. HOMO/LUMO interaction between a 1,3-dipole and a dipolarophile……..18 Figure 2-8. Interaction of a filled orbital with (a) an empty orbital, and (b) with another filled orbital………………………………………………………………………………19 Figure 2-9. Sustmann Type I, II, and III for cycloaddition reactions………………...…20 Figure 2-10. Effect of Lewis acid on HOMO and LUMO energy levels….……………21 Figure 2-11. Resonance structures of an azomethine imine….………………………....21 Figure 2-12. 1,3-Dipolar cycloaddition of an azomethine imine with an alkene………..22 Figure 2-13. Examples of azomethine imines…………………………………………...22 Figure 2-14. Uskokovic’s enantioselective intramolecular 1,3-DC reaction….….……..23 Figure 2-15. The first asymmetric 1,3-DC reaction using a chiral dipolarophile…….…24 Figure 2-16. The first catalytic enantioselective 1,3-DC reaction….…………………...25 Figure 2-17. Gothelf and Jorgenson’s catalysts for asymmetric 1,3-DC….………….....26 Figure 2-18. Gothelf and Jorgenson’s asymmetric 1,3-DC….………………...………..27 Figure 2-19. The first organocatalytic Diels-Alder reaction by MacMillan…………….29 Figure 2-20. Asymmetric 1,3-DC reaction of nitrones and α,β-unsaturated aldehydes by MacMillan………………………………………………………………………………..30 vi Figure 2-21. Activation and deactivation of the 1,3-DC reaction by coordination of a Lewis acid…………………………………………………………………………….…31 Figure 2-22. Chiral tertiary amine thiourea catalysts for asymmetric 1,3-DC reactions by Wang et al……………………………………………………………………………….32 Figure 2-23. Asymmetric 1,3-DC of azomethine ylides and N-arylmaleimides via a postulated transition state by Wang et al……………………………………………..…32 Chapter 3 Figure 3-1. Attempted synthesis of 1-benzoyloxy-2-phenyl-2-(6-oxoverdazyl)ethane unimer…………………………………………………………………………………....38 Figure 3-2. Reaction mechanism of the 1,3-dipolar cycloaddition reaction of an azomethine imine generated in situ from a verdazyl radical…………………………….39 Figure 3-3. Trapping leucoverdazyl 3.3 by an alkylation reaction….…………………..39 Figure 3-4. NaH induced rearrangement of a cycloadduct derived from a verdazyl radical….………………………………………………………………………………...40 Figure 3-5. Proposed mechanism for the rearrangement of 3.7 to 3.8………………….41 Figure 3-6. Synthesis of paraheteraphanes from verdazyl radicals…………………..…42 Figure 3-7. Versatility of verdazyl radicals: structural motifs derived from verdazyl radicals….……………………………………………………………………………….43 Chapter 5 Figure 5-1. The second generation MacMillan catalyst…………………….…………..75 Figure 5-3. Working model of the transition state in the asymmetric 1,3-DC reaction of azomethine imines and homoallylic alcohols by Maruoka…..………………………….80 Figure 5-4. De-alkylation of verdazyl by proline or proline-derived catalysts………....81 Figure 5-5. Equilibrium between a nitrone-metal complex and an olefin-metal complex….………………………………………………………………………………82 Figure 5-6. Cyclophane coordination structure proposed by Anthony de Crsci……...…83 Figure 5-7. Coordination of verdazyl radicals to various metal centres by Robin Hicks…………………………………………………………………………………….84 Figure 5-8. N-[3,5-Bis(trifluoromethyl)phenyl]-N′-[(8a,9S)-6′-methoxy-9- cinchonanyl]thiourea….…………………………………………………………………86 vii List of Tables Table 4-1. Intermediates, products, and their yields for the phosgene-free verdazyl radical synthesis….…………………………………………………………………….60 Table 5-1. Asymmetric