Methylation of primary amines using NaBH3CN/Paraformaldehyde
To a solution of primary amine 21 (219 mg, 0.5 mmol) in acetic acid (5 mL) were added paraformaldehyde (45 mg, 1.5 mmol) and sodium cyanoborohydride (314 mg, 1.5 mmol). The mixture was vigorously stirred at 40°C. At 8-h intervals (four times), paraformaldehyde (45 mg, 1.5 mmol), and sodium cyanoborohydride (314 mg, 1.5 mmol) were stepwise added to the mixture. The product was then worked up in the usual manner and purified by flash chromatography to give the dimethylated product 23 (208 mg, 95%).
The addition of 10 eqv. paraformaldehyde and 5 eqv. NaBH3CN at once and stirring the mixture at room temp for 48h gave 100% yield of di- and monomethylated products, in a 1:1 ratio.
Reference: J. Org. Chem. 61, 4412-4422 (1996)