Rerouting the Organocatalytic Benzoin Reaction toward Aldehyde Deuteration

Reactive
intermediates are key to halting and promoting chemical
transformations; however, due to their elusive nature, they are not
straightforwardly harnessed for reaction design. Herein, we describe
studies aimed at stabilizing reactive intermediates in the N-heterocyclic carbene (NHC) catalytic cycle, which enabled
the full shutdown of the known benzoin coupling pathway, while rerouting
its intermediates toward deuteration. The reversible nature of NHC
catalysis and the selective stabilization of reaction intermediates
facilitated clean hydrogen–deuterium exchange reactions of
aromatic aldehydes by D2O, even for challenging electron-withdrawing
substrates. In several cases, the addition of catalytic amounts of
phenyl boronic acid was used to further stabilize highly reactive
intermediates and mitigate the formation of benzoin coupling byproducts.
The mechanistic understanding at the foundation of this work resulted
in unprecedented mild conditions with base and catalyst loadings as
low as 0.1 mol %, and a scalable deuteration reaction applicable to
a broad substrate scope with outstanding functional group tolerance.
More importantly, adopting this approach enabled the construction
of a guideline for identifying the appropriate catalyst and conditions
for different substrates. Experimental studies combined with machine
learning and computational methods shed light on the nontrivial mechanistic
underpinnings of this reaction.