General Pyrrolidine Synthesis via Iridium-Catalyzed Reductive Azomethine Ylide Generation from Tertiary Amides and Lactams

An iridium-catalyzed reductive generation of both stabilized and unstabilized azomethine ylides and their application to functionalized pyrrolidine synthesis via [3 + 2] dipolar cycloaddition reactions is described. Proceeding under mild reaction conditions from both amide and lactam precursors possessing a suitably positioned electron-withdrawing or a trimethylsilyl group, using 1 mol% Vaska's complex [IrCl(CO)(PPh3)(2)] and tetramethyldisiloxane (TMDS) as a terminal reductant, a broad range of (un)stabilized azomethine ylides were accessible. Subsequent regio- and diastereoselective, inter- and intramolecular dipolar cycloaddition reactions with variously substituted electron-deficient alkenes enabled ready and efficient access to structurally complex pyrrolidine architectures. Density functional theory (DFT) calculations of the dipolar cycloaddition reactions uncovered an intimate balance between asynchronicity and interaction energies of transition structures, which ultimately control the unusual selectivities observed in certain cases.

Automated summary

This study discusses an iridium-catalyzed method for the reductive generation of azomethine ylides and their use in pyrrolidine synthesis. The method allows for the efficient access to structurally complex pyrrolidine architectures through subsequent dipolar cycloaddition reactions with variously substituted electron-deficient alkenes. Density functional theory calculations reveal the control of unusual selectivities observed in certain cases by an intimate balance between asynchronicity and interaction energies of transition structures in the cycloaddition reactions.