p-Toluenesulfonic acid → HCID 71209216, compound

Participants

Reaction Conditions

Reaction Steps

A solution of 3,4-difluorobenzaldehyde (38.8 mL, 352 mmol) and 2,2-dimethoxyethanamine (38.3 mL, 352 mmol) in benzene (450 mL) was heated to reflux (130° C.) for 3 h using a Dean Stark trap to separate water. The mixture was concentrated and the residue was dissolved EtOH (450 mL), cooled to 0° C. and sodium borohydride (26.6 g, 704 mmol) was added in portions. Stirring at RT continued for 18 h. The mixture was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with water, brine, dried (Na2SO4) and concentrated. The residue was dissolved in DCM (1000 mL) and malononitrile (46.5 g, 704 mmol) and 4-methylbenzenesulfonic acid (242 g, 1407 mmol) were added and the mixture was stirred at RT for 18 h. Triethylamine (146 mL, 1056 mmol) was slowly added and the mixture was stirred at 70° C. for 2 h then concentrated. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3/water, brine, dried (Na2SO4), and concentrated. Purification with column chromatography provided 2-amino-1-(3,4-difluorobenzyl)-1H-pyrrole-3-carbonitrile (70 g, 273 mmol, 78% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 3.66-3.83 (br s, 2 H), 4.87-4.95 (s, 2 H), 6.11-6.28 (m, 2 H), 6.75-7.00 (m, 2 H), 7.00-7.35 (m, 1 H); LCMS (m/z) ES+=234 (M+1).

Provenance & Evidence