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 9 attack by acetamide
to form cation 16 via O-alkylation or
by reversible ether formation. Deuterium labeling studies suggest O-alkylated cation 16 does not directly isomerize
to N-alkylated cation 18; instead, it
reverts to vic-amidoester 13a via the
nitrilium pathway. Preliminary results indicate high regioselectivity
for primary amide formation in the diol-Ritter sequence.