Methanol → Benzimidazole

Participants

Reaction Conditions

Reaction Steps

To a stirring suspension of 5′,6′-Diamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol (8.90 g, 39.7 mmol) and p-toluenesulfonic acid (1.63 g, 8.55 mmol, 0.2 eq) in toluene was added triethyl orthoformate (21.5 mL, 129 mmol, 3.0 eq) in two portions. The first (11 mL) was added in a fast dropwise addition manner the mixture stirred to 16 hr at 100° C. Methanol (10 mL) was added followed by the final portion of triethyl orthoformate (10.5 mL) and the reaction stirred an additional 1 hr at 110° C. The solution was cooled and concentrated to a dark solid. The resulting solid was triturated from Acetonitrile/Water (20:1) giving 6.0 g of benzimidazole as a brown powder. Benzimidazole (5.72 g, 26.2 mmol) was dissolved in DMF (100 mL) and imidazole (3.75 g, 55.1 mmol, 2.1 eq) followed by tert-butyl-diphenylsilylchloride (15.0 mL, 58.4 mmol, 2.2 eq) were added and the reaction stirred for 16 hr at 23° C. The reaction was quenched with sat'd NaHCO3 (20 mL) and then diluted (100 mL) with water. EtOAc (500 mL) was added and the layers partitioned. The organic was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by chromatography eluting with EtOAc/Heptane giving desired product as an oil, which was precipitated in Acetone to afford 5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-3H-imidazo[4,5-b]pyridine as an orange solid (4.75 g, 10.4 mmol, 40%). MS ESI m/z 457.3 (M+H)+.

Provenance & Evidence