Investigations toward a unified reaction pathway of thermal and TBSOTf-mediated oxidopyrylium-alkene (5 + 2) cycloadditions

Abstract

Oxidopyrylium-based (5 + 2) cycloadditions are crucial reactions to construct seven-membered carbocycles containing an ether bridge (i.e. oxabicyclo[3.2.1]octanes). Intramolecular silyloxypyrone-based (5 + 2) cycloadditions were investigated and revealed several features: (1) the TBDPS thermal process proceeds via a zwitterionic oxidopyrylium intermediate similar to previously reported TBS variants; (2) the TBSOTf-mediated reaction proceeds through a cationic oxidopyrylium intermediate; (3) quantum chemical calculations predict a stepwise process for an electron-rich dipolarophile for each set of conditions. The thermal silyloxypyrone-based (5 + 2) cycloadditions were extremely dependent on the nature of the dipolarophile and the silyl transfer group. The TBDPS enhances the rate compared to the TBS variant but only for less polarized alkenes. Relatively neutral alkenes were the least reactive for both, whereas electron-deficient and electron-rich dipolarophiles were more reactive providing evidence for ambident oxidopyrylium intermediates. TBSOTf-mediated cycloadditions, however, revealed evidence for a cationic intermediate that follows a more consistent mechanistic trend. Qualitative rate studies, Hammett linear free energy relationships, and theoretical calculations combine to provide evidence for both mechanistic scenarios.