Redox Titanocene Catalysis in C–C Bond Formations and New Discoveries in Phosphorus-Mediated Bond-Forming Reactions

Organic methodology allows us to target important bond disconnects and design reactions to improve overall synthetic efficiency. Reaction design may stem from a need to access fragments not easily obtained through current methods or overcome limitations present in existing methodology. This dissertation describes the development of new bond-forming reactions utilizing the redox properties of titanium and phosphorus. Commercially available titanocene dichloride was employed to facilitate catalytic C–X activation of alkyl halides for the stoichiometric generation of reactive organometallics. This method allows for the in situ generation of organometallics with the versatile reactivity reticent of Grignard and Barbier processes, without the need for pre-generation of the reactive species. We initially evaluated our method through the addition of allylzinc reagents to carbonyl derivatives. Catalyst loadings as low as 1 mol% were achieved while the scope of the addition reaction includes aldehydes, ketones and esters. Exclusive 1,2-addition to α,β–unsaturated carbonyls and S_E2’ additions of γ-substituted allyl bromides were observed. An interesting phosphine additive effect was also developed that has proven especially influential in subsequent work by Wilson, Campos, and Gianino. The study of the calyxin family of natural products led to the design of a selective ortho-deprotection of phenolic protecting groups through the use of a mild Lewis acid. This method proved suitable for the removal of silyl, benzyl, acyl and ethereal protecting groups.

In conjunction with these efforts, investigations of new phosphorus-mediated redox reactions were explored. This dissertation highlights efforts toward new C–N and C–C bond forming strategies. Synthesis of amidines through a novel phosphorus protocol involving a proposed Beckmann-type rearrangement are described, as are initial results for C–N bond formation through phosphorus assisted 1,3 migrations of enol phosphites.

The synthetic strategies presented exploit the redox potential of both titanium and phosphorus for C–C and C–N bond-forming reactions. They compliment existing methods for the generation of synthetically useful intermediates via catalytic activation of alkyl halides and phosphorus-mediated migrations. These new approaches will enable unconventional bond disconnects for further application in organic synthesis.