N-Boc-pyrrolidine → Tert-butyl 2-(6-(benzylthio)isoquinolin-1-yl)pyrrolidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

A 100-mL round-bottom flask was charged with tert-butyl 1-pyrrolidinecarboxylate (1.625 ml, 9.27 mmol) and THF (23.33 ml) to give a clear solution. The flask was flushed with Ar (g), then cooled in a −30° C. dry ice-acetone bath for 10 min. Sec-butyllithium (1.4 M in cyclohexane) (8.75 ml, 12.25 mmol) was added drop wise over 5 min. The resulting mixture was stirred for 10 minutes at −30° C., then zinc chloride (1.0 M in diethyl ether) (7.00 ml, 7.00 mmol) was added drop wise. The reaction was stirred for 5 minutes, then the cooling bath was removed. After 25 min, a solid mixture of 6-(benzylthio)-1-chloroisoquinoline (from Intermediate LLL, step 1; 1.0 g, 3.50 mmol), Pd(Ph3P)4 (0.809 g, 0.700 mmol), and copper(i) iodide (0.333 g, 1.750 mmol) was added in one portion. The reaction was capped and stirred at 60° C. for one hour. The reaction was filtered through a pad of diatomaceous earth, washing thoroughly with ethyl acetate. The filtrate was concentrated and purified via column chromatography (80 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane followed by a 20% MeOH/EtOAc flush) to afford tert-butyl 2-(6-(benzylthio)isoquinolin-1-yl)pyrrolidine-1-carboxylate as a yellow solid. (ESI) 421.3 (M+H)+.

Provenance & Evidence