Dimethylamine → (6-Dimethylaminomethyl-2-methyl-indolizin-3-yl)-acetic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

(6-Cyano-2-methyl-indolizin-3-yl)-acetic acid tert-butyl ester (500 mg, 1.76 mmol) is dissolved in a mixture of water (5.0 ml), pyridine (10 ml) and glacial acetic acid (5.0 ml). Sodium hypophosphite monohydrate (1.51 g, 14.1 mmol, 8 equiv) and Raney nickel (approx. 210 mg) are added at room temperature. The reaction mixture is heated to 75° C. for 1 h, cooled to room temperature, filtered through Celite and concentrated in vacuo. The residue is taken up in THF (5.0 ml) and treated with dimethylamine (5.3 M solution in EtOH, 1.66 ml, 8.8 mmol, 5.0 equiv). The mixture is stirred at room temperature for 18 hours. A solution of sodium cyanoborohydride (128 mg, 1.94 mmol, 1.1 equiv) in MeOH (0.5 ml) and glacial acetic acid (5.0 ml) are added, and the solution is stirred at room temperature for 2 hours. The reaction mixture is diluted with water and adjusted to pH 8-9 by the addition of concentrated aqueous NaHCO3 solution. Extraction with EtOAc, washing with brine, drying over Na2SO4 and removal of solvent affords the crude reaction product. Purification via flash chromatography (EtOAc/hexane 4:1, +0.2% NEt3) yields the title compound (122 mg, 23%). 1H NMR (400 MHz, CDCl3): δ=7.62 (s, 1H), 7.20 (d, J=9.0 Hz, 1H), 7.00 (s, 1H), 6.56 (dd, J=9.3/1.5 Hz. 1H), 3.52 (s, 2H), 3.22 (s, 2H), 2.19 (s, 6H), 1.35 (s, 9H). MS (ES+): 303 (M+H)+.

Provenance & Evidence