Cyclobutanone → 4-[(1-Cyanocyclobutyl)amino]-2-fluoro-N-methylbenzamide

Participants

Reaction Conditions

Reaction Steps

TMS-CN (29.7 g, 300 mmol) was added to a mixture of N-methyl-2-fluoro-4-aminobenzamide 4a (16.8 g, 100 mmol) and cyclobutanone (14 g, 200 mmol) in 90% acetic acid (200 mL). The reaction mixture was stirred at 80° C. for 24 h. The mixture was cooled and diluted with water (200 mL). The suspension was extracted with ethyl acetate (3×200 mL). Combined organic layers were washed with brine (4×100 mL), dried (MgSO4) and concentrated in vacuo to dryness. The residue was triturated with a mixed solvent of hexanes and ethylether (20 mL-20 mL) to remove cyclobutanone cyanohydrin. The solid was collected by filtration, affording the title compound 6a (20 g, 84% yield). MS (ES-API Negative): 246 (M−H)−. 1H NMR (CDCl3, 500 MHz): δ 7.92 (1H, dd, J=8.4, 8.4 Hz), 6.76 (1H, q, J=4.3 Hz), 6.48 (1H, dd, J=8.3, 1.9 Hz), 6.29 (1H, dd, J=14.3, 1.9 Hz), 4.72 (1H, br s), 2.97 (3H, d, J=4.4 Hz), 2.85-2.75 (2H, m), 2.4-2.35 (2H, m), 2.3-2.15 (1H, m), 1.95-1.85 (1H, m).

Provenance & Evidence