1-(2-bromo-5-fluorophenyl)-5-methyl-1H-1,2,4-triazole → 4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile

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Reaction Conditions

Reaction Steps

To a solution of 1-(2-bromo-5-fluorophenyl)-5-methyl-1H-1,2,4-triazole (4.1 g, 16 mmol) in N-methylpyrrolidone (NMP, 30 mL) was added copper (I) cyanide, CuCN (1.72 g, 19.2 mmol; Aldrich) and the mixture was stirred in an oil bath heated at 140-150° C. under a nitrogen atmosphere for 3 h. After cooling, the solvent was removed in vacuo and the residue mixed with CH2Cl2 (50 mL), water (50 mL), and conc-NH4OH (50 mL). The mixture was stirred for 30 min, and the insoluble material was filtered through Celite®. The aqueous filtrate was extracted again with CH2Cl2. The combined CH2Cl2 filtrate and extracts were washed again with dilute NH4OH, dried (MgSO4), filtered and concentrated to a dark solid which was triturated with diethyl ether to give 1.6 g of the title compound as an off-white solid. An additional amount (750 mg) of the title compound was obtained from the mother liquor by column chromatography (SiO2, 5% Et2O—CH2Cl2) followed by trituration with Et2O. Total yield, 2.35 g (11.6 mmol, 73% yield); HPLC: 1.29 min (AP 99% at 254 nm); LC/MS m/z 203 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 2.50 (3H, s, 10-Me), 7.25 (1H, dd, J=8, 2.5 Hz, 3-CH), 7.30-7.36 (1H, m, 5-CH), 7.85 (1H, dd, J=8.8, 5.5 Hz, 6-CH), 8.00 (1H, s, 9-CH); 13C NMR (CDCl3, 125.8 Hz) δ ppm 12.7 (10-Me), 107.2 (d, J=Hz, 1-C), 114.6 (7-CN), 116.2, (d, J=25 Hz, 3-CH), 117.9 (d, J=23 Hz, 5-CH), 136.1 (d, J=10 Hz, 6-CH), 141.5 (d, J=l 1 Hz, 2-C), 152.3 (9-CH), 153.9 (8-C), 164.9 (d, J=261 Hz, 4-CF).

Provenance & Evidence