P(NMe₂)₃-Mediated Regioselective N-Alkylation of 2-Pyridones via Direct Deoxygenation of α-Keto Esters

Abstract

A practical and regioselective direct N-alkylation of 2-pyridones is enabled by use of α-keto esters in the P(NMe2)3-mediated deoxygenation process. The reaction proceeds under mild conditions to produce N-alkylated 2-pyridones with high selectivity and generality, and the protocol is shown to be applicable for the scale-up synthesis, which makes it promising for practical applications.

Palladium-Catalyzed anti-Michael-Type Hydroamination of N-(Quinolin-8-yl)acrylamide with 2-Pyridones

“…N -Alkylated 2-pyridones are a prevalent structural motif in a wide array of naturally occurring and biologically active compounds (Scheme A). − Consequently, numerous synthetic methods have been devised to construct these structures, aiming to address potential issues regarding selective synthesis. A traditional approach involves the nucleophilic addition of 2-pyridones to alkyl electrophiles, a well-established and promising reaction in organic synthesis. − Furthermore, aza-Wacker-type reactions, involving the addition of 2-pyridones to alkenes, have recently been established as an optimal method for synthesizing N -alkylated 2-pyridones in an atom-economical manner. − However, the tautomeric equilibrium between 2-pyridone and 2-hydroxypyridine causes an ambident nucleophilic nature, , sometimes leading to the formation of an isomeric mixture of N - and O -alkylated products (Scheme B). ,,, Moreover, the use of a base, often a strong Brønsted base, for activating 2-pyridone substrates diminishes the utility of the reaction in terms of atom economy and substrate generality. An alternative synthesis of N -alkylated 2-pyridones involves constructing the 2-pyridone ring through cyclization or annulation reactions. − While this method can yield the desired product without forming the O -alkylated product, the lengthy reaction sequence for preparing the functionalized starting materials limits its broad applicability.…”