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.