2-Chloro-5-fluoro-4-nitro-1-oxo-1lambda~5~-pyridine → 2-Chloro-5-fluoropyridin-4-amine

Participants

Reaction Steps

2-Chloro-5-fluoropyridine (9), a highly volatile substance, was synthesized from thermolysis of 2-chloro-5-pyridinediazonium tetrafluoroborate (8). Hand, E. S.; Baker, D. C. Synthesis 1989, 905-908. The isolation of 9 by the literature procedure was very complicated, in that it included repeated extractions, repeated distillations, treatment with sulfuric acid and sodium hydroxide, and steam distillation. In our hands, the reported yield of 70% was difficult to obtain after these operations. To improve upon these complicated procedures, following the thermolysis of compound 8, the reaction mixture was directly treated with 50% hydrogen peroxide and trifluoroacetic acid to give 2-chloro-5-fluoropyridine-N-oxide (10), which was easily isolated, with a total yield of 73%. Nitration of 10, followed by catalytic hydrogenation of the resulting 2-chloro-5-fluoro-4-nitropyridine-1-oxide (11) removed the N-oxide function, as well as reduced the nitro group to give the desired 4-amino-2-chloro-5-fluoropyridine (12). N-Oxidation of commercially available 2,5-dichloropyridine (13), followed by nitration and reduction yielded 4-amino-2,5-dichloropyridine (16).

Provenance & Evidence