Design and Structure of New Classes of Phosphorus-Based 1,3-Dipolar Cycloaddition Reagents

This thesis describes the design of unique classes of 1,3-dipolar cycloaddition reagents. The purpose of this study was to develop general and practical methods for the modular syntheses of heterocycles via 1,3-dipolar cycloaddition. It was found that several 1,3-dipolar reagents can be generated from imines, acid chlorides, and isocyanides or trivalent phosphorus derivatives, and can be exploited in cycloadditions for pyrrole synthesis.;Chapter 3 demonstrates that, in addition to isocyanides, phosphites and phosphonites may also mediate the one-pot reaction of imines, acid chlorides, and alkynes to synthesize pyrroles. The most rapid cycloadditions and optimal pyrrole yields are obtained with PPh(catechyl) (catechyl = o-O 2C6H4). This third generation protocol is proposed to involve amido-substituted Wittig-type intermediates. Upon cycloaddition with alkynes, these intermediates abstract oxygen from the former acid chloride unit generating phosphonate as the reaction byproduct. This oxidation of the phosphorus(III) mediator during pyrrole synthesis is analogous to the oxidation of carbon monoxide to carbon dioxide during the palladium-catalyzed pyrrole synthesis.;In Chapter 4, a closer inspection of the cycloaddition intermediate reported in Chapter 3 reveals these are a new class of phosphorus-based 1,3-dipolar cycloaddition reagent. These substrates undergo cycloaddition with alkynes to form pyrroles in a fashion directly analogous to Münchnones. Their ability to participate in cycloaddition is dependent upon the PR3 employed, and 1H, 13C and 31P NMR analysis suggest this PR3-dependence arises from a varying structure of the phosphorus-containing intermediate, with electron poor phosphonites and phosphites favoring the cyclic 1,3-dipolar structure, while more electron rich phosphines adopt a classic acyclic Wittig-type valence tautomer. This has been confirmed by X-ray crystallographic studies. In addition to representing a new class of dipole, the presence of the phosphorus unit creates a large steric and electronic bias across the 1,3-dipole, allowing for the regiospecific cycloaddition of unsymmetrical alkynes to form pyrroles.;Chapter 5 discloses an alternative route for the generation of phosphorus-based 1,3-dipoles, via Wadsworth-Emmons reagents rather than Wittig-type reagents. These substrates also participate in (3+2) cycloaddition with alkynes to afford pyrroles with elimination of phosphate. The amido-substituted phosphonate precursors of the Wadsworth-Emmons reagents may be generated in situ via a TMSOTf-catalyzed Arbuzov reaction of imines, acid chlorides, and phosphites of the form (RO)2POTMS. This was exploited in an overall three-component synthesis of pyrroles with complete and independent control of all five pyrrole substituents.;In Chapter 2, a direct synthesis of pyrroles from imines, acid chlorides, and alkynes mediated by isocyanides is reported. This reaction proceeds with a range of each of these substrates, providing a method to generate families of pyrroles in high yield. This discovery evolved out of the palladium-catalyzed synthesis of Münchnones, a reaction reported by our research group. Münchnones are a known class of 1,3-dipole with practical applications in the synthesis of pyrroles. Mechanistic studies suggest that the isocyanide-mediated reaction involves the generation of imino analogues of Münchnones, which liberate isocyanate rather than carbon dioxide upon pyrrole formation.