Enantioselective functionalization at the C4 position of pyridinium salts through NHC catalysis

Abstract

A catalytic method for the enantioselective and C4-selective functionalization of pyridine derivatives is yet to be developed. Herein, we report an efficient method for the asymmetric β-pyridylations of enals that involve N-heterocyclic carbene (NHC) catalysis with excellent control over enantioselectivity and pyridyl C4-selectivity. The key strategy for precise stereocontrol involves enhancing interactions between the chiral NHC-bound homoenolate and pyridinium salt in the presence of hexafluorobenzene, which effectively differentiates the two faces of the homoenolate radical. Room temperature is sufficient for this transformation, and reaction efficiency is further accelerated by photo-mediation. This methodology exhibits broad functional group tolerance and enables facile access to a diverse range of enantioenriched β-pyridyl carbonyl compounds under mild and metal-free conditions.

N-Functionalized Pyridinium Salts: A New Chapter for Site-Selective Pyridine C–H Functionalization via Radical-Based Processes under Visible Light Irradiation

“…In 2022, we reported the enantioselective functionalization of enals via C4-addition to pyridinium salts through single-electron NHC catalysis (Figure ). This methodology exhibited excellent site- and enantioselectivity under mild, metal-free conditions. A direct SET process between chiral enolate form 108 and pyridinium salt 52a produces amidyl radical 55 along with homoenolate radical 109 .…”

Radical NHC Catalysis

“…37 As suggested, the reaction proceeds through In 2022, Hong and co-workers reported an NHC-catalyzed stereoselective β-pyridylation of enal derivatives (Scheme 21). 94 The authors proposed that the cascade proceeds through SET between a chiral NHC-bound homoenolate and a pyridinium salt, affording the corresponding homoenolate radical which in turn reacts at the C4-position of the pyridine moiety. Subsequent homolytic N−N bond cleavage and nucleophilic attack an alcohol release the NHC catalyst to afford the targeted β-pyridylated ester.…”

N-Amino pyridinium salts in organic synthesis

“…The same group have further achieved visible light mediated enantioselective hydropyridylation of enones utilizing pivalate based N -aminopyridinium EDA complex (Scheme 32c). 73 NHC bound homoenolate radical 121 directs the C4 addition of N -aminopyridinium salts from a particular direction yielding enantio-enriched C4-alkylated pyridines 119 .…”