Hydrogen Peroxide → 3-chloro-2-cyanopyridine-N-oxide

Participants

Reaction Conditions

Reaction Steps

To a solution of 3-chloro-2-cyanopyridine (40 g, 0.29 mol) in 500 mL acetic acid was added hydrogen peroxide (30%, 52 g, 0.45mol) dropwise. After stirring at 90° C. for 18 h, the reaction is cooled to 25° C. and a solution of sodium sulfite (57 g, 0.45 mol) in H2O was added dropwise. The reaction was concentrated to remove the bulk of the acetic acid and the residue is partitioned between 1M NaOH and CH2Cl2. The CH2Cl2 layer was dried (MgSO4), filtered, concentrated, and recrystallized from EtOAc to provide 23 g (51%) of 3-chloro-2-cyanopyridine-N-oxide. The resulting N-oxide (12.2 g, 79 mmol) was dissolved in DMF (160 mL) at 0° C. Methyl thioglycolate (7.1 mL, 79 mmol) was added followed by sodium methoxide (8.5 g, 160 mmol) in portions. The reaction was strred for 1 h. The reaction was poured onto ice and the resulting solid was collected by filtration, washed with water, dissolved in CH2Cl2, dried (MgSO4), filtered, concentrated, and recrystallized from EtOAc. 10.6 g (60%) of methyl 3-amino-thieno[3,2-b]pyridine-4-oxide carboxylate was obtained. The pyridine-N-oxide (10.6 g, 47 mmol) was mixed with phosphorous oxychloride (100 mL). The reaction was heated to 80° C. for 30 min. The reaction was concentrated and partitioned between CH2Cl2 and 5% aq.NaHCO3 solution. The CH2Cl2 layer was dried (MgSO4), filtered, concentrated, and chromatographed (5:1 hex:EtOAc) to yield methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate (8.3 g, 73%): 1H NMR (300 MHz, CDCl3) d 3.92 (s, 3H), 6.15 (bs, 2H), 7.37 (d, 1H), 7.99 (d, 1H); MS (DCI/NH3) m/e 243 (M+H)+ ; followed by methyl 3-amino-7-chloro-thieno[3,2-b]pyridine-2-carboxylate (2.0 g, 18%): 1H NMR (300 MHz, CDCl3) d 3.93 (s, 3H), 6.20 (bs, 2H), 7.41 (d, 1H), 8.54 (db, 1H); MS (DCINH3) mle 243 (M+H)+.

Provenance & Evidence