Formaldehyde → 4-(5-{[cis-2,6-Dimethyl-4-morpholinyl]methyl}-1H-tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile

Participants

Reaction Steps

To a solution of formaldehyde (37% in water) (0.114 ml, 1.53 mmol) in methanol (4 ml) was added cis-2,6-dimethylmorpholine (0.188 ml, 1.53 mmol, Alfa Aesar, Ward Hill, USA). The reaction mixture was stirred at room temperature for 2 hours before the addition of trimethylsilylazide (0.203 ml, 1.53 mmol) and 4-isocyano-2-(trifluoromethyl)benzonitrile (300 mg, 1.53 mmol, commercially available from Priaxon, Munich, Germany). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (50 ml) and water (20 ml). The aqueous layer was extracted with DCM (50 ml). The organic layers were combined, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (Biotage SP4) using Hexane:EtOAc as an eluant. Relevant fractions were combined and concentrated. This residue was dissolved in MeOH and loaded onto a 5 g SCX cartridge. The cartridge was washed with MeOH and eluted with methanolic ammonia. Relevant fractions were combined and concentrated and the product was left to dry in a vacuum oven overnight. The product was dissolved in 3 ml of DCM and 0.819 ml of 1M HCl in ether was added. The solvent was removed to afford the title compound as a pale yellow solid (340 mg).

Provenance & Evidence