Regioselective Amidomethylation of 4-Chloro-3-fluoropyridine by Metalation and Minisci-Type Reactions.

The synthesis of a series of 2-amidomethylated pyridines (-) was investigated, starting from 4-chloro-3-fluoropyridine. Kinetic deprotonation at -75 °C followed by reaction with DMF gave 2-formyl-4-chloro-3-fluoropyridine regioselectively, which was converted to 2-aminomethyl analogue via sulfinamide . Alternatively, Minisci-type amidomethylation under Ag/persulfate or photoredox-mediated conditions using a series of amino acid derivatives gave (-, , and ) in 30-74% yield and isomer ratios in the range 6.7:1 to >50:1. The latter methods gave overall yields similar to that of the deprotonation approach, but were shorter and more amenable to scale-up. In particular, N-Boc analogue was obtained in a single step. The amidomethylations of another six 3-fluoropyridines under the photoredox conditions were briefly examined.