Chloroacetaldehyde → 8-Fluoro-7-(trifluoromethyl)imidazo[1,2-a]pyridine

Participants

Reaction Conditions

Reaction Steps

A mixture of 2-chloro-3-fluoro-4-trifluoromethylpyridine (3.50 g, 17.5 mmol), benzophenone imine (3.50 g, 19.3 mmol), palladium(II) acetate (0.158 g, 0.70 mmol), caesium carbonate (8.00 g, 24.6 mmol) and BINAP (0.66 g, 1.05 mmol) was suspended in toluene (35 ml) and degassed with nitrogen for 1 h. The mixture was then heated at 115° C. for 18 h. The mixture was allowed to cool to ambient temperature, diluted with toluene (100 ml) and the organic phase was washed with water (100 ml) and brine (100 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give an orange oil. The oil was dissolved in propan-2-ol (60 ml), 5N hydrochloric acid (10 ml) added and the mixture heated at 50° C. for 30 min. The mixture was cooled to ambient temperature and solid sodium hydrogencarbonate (7.14 g, 85 mmol) added portionwise over 10 min, followed by addition of chloroacetaldehyde (2.75 g, 35.08 mmol). On complete addition the mixture was heated at 95° C. for 24 h. The mixture was allowed to cool to ambient temperature, filtered through a glass microfibre filter paper, the solid washed with ethanol (30 ml) and the filtrate evaporated. The residue was diluted with ethyl acetate (200 ml) and extracted with 5N hydrochloric acid (2×75 ml). The organics were filtered and then washed with ethyl acetate (2×100 ml). The aqueous phase was then made basic by the addition of solid sodium hydrogen-carbonate and extracted with ethyl acetate (2×150 ml). The organics were washed with brine (100 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give a brown oil. The oil was purified by flash column chromatography on silica eluting with dichloromethane on a gradient of methanol (0-2%). Collecting appropriate fractions gave 8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (1.5 g, 42%) as a pale yellow solid: δH (360 MHz, CDCl3) 6.92 (1H, dd, J 7 and 7), 7.75 (1H, d, J 3), 7.80 (1H, d, J 3), 8.04 (1H, d, J 7).

Provenance & Evidence