Transition Metal-Free Regioselective Phosphonation of Pyridines: Scope and Mechanism

Abstract

Regioselective phosphonation of pyridines is an interesting transformation in synthesis and medicinal chemistry. We report herein a metal-free approach enabling access to various 4-phosphonated pyridines. The method consists of simply activating the pyridine ring with a Lewis acid (BF3·OEt2) to facilitate the nucleophilic addition of a phosphine oxide anion. The formed sigma complex is subsequently oxidized with an organic oxidant (chloranil) to yield the desired adducts in good to excellent yields. We furthermore showed that access to C2-phosphoinated pyridines can be achieved in certain cases with strong Lewis basic phosphorus nucleophiles or with strong Lewis acidic pyridines. Both experimental and computational mechanistic investigations were undertaken and allowed us to understand the factors controlling the reactivity and selectivity of this reaction.