Mechanistic and Synthetic Implications of the Diol-Ritter Reaction: Unexpected Yet Reversible Pathways in the Regioselective Synthesis of Vicinal-Aminoalcohols

The Ritter reaction of 1,2-diolmonoesters with nitriles to 1-vic-amido-2-esters proceeds through dioxonium and nitrilium cation intermediates. To provide the basis for the reaction mechanism, novel forms of these cations were isolated, characterized, and studied by spectroscopic methods and single crystal X-ray analysis. Ground and transition state energies were determined both experimentally and theoretically. Taken together, these data suggest that the reaction proceeds via rapid formation of the dioxonium cation 9, followed by rate determining yet reversible ring opening by acetonitrile to the corresponding nitrilium cation 10 (computed ΔG⧧ = 24.7 kcal at 50 °C). Rapid, irreversible hydration of the latter affords the corresponding vic-acetamido ester. Controlled addition of H2O to the dioxonium cation 9 in acetonitrile-d3 results in near-quantitative production of deuterated acetamido ester 13a. Kinetics of this conversion (9 to 13a) are biphasic, and the slow phase is ascribed to either direct cation...