tert-Butyl acetate → (3-Chloro-isoquinolin-1-yl)-acetic acid tert.-butyl ester

Participants

Reaction Conditions

Reaction Steps

1,1,1,3,3,3-Hexamethyl-disilazane (27.4 ml, 20.37 g, 126.2 mmol) are dissolved in dry toluene (150 ml). After cooling to −78° C., n-BuLi (79 ml of a 1.6 M solution in hexanes, 126.2 mmol) is slowly added during 20 minutes. The white suspension is stirred at −78° C. for 15 minutes and at RT for 15 minutes, after which time a clear bright yellow solution is obtained. This solution is canulated into a second two-necked flask, containing Pd2(dba)3 (1.39 g, 1.51 mmol) and (2′-Dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (1.25 9, 3.18 mmol). After stirring at RT for 10 minutes, the clear dark red solution is cooled to −10° C. Acetic acid tert-butyl ester (15.7 ml, 13.5 g, 116.1 mmol) is added during 5 min. After 10 minutes at −10° C., 1,3-Dichloro-isoquinoline (10.0 g, 50.49 mmol) is added in one portion. The dark red solution is allowed to warm to RT. After 30 minutes at RT, TLC analysis indicates complete conversion of the starting material. The reaction mixture is filtered through a 2-cm pad of silica, which is rinsed with EtOAc/MeOH 98:2. After concentration, the residue is purified by FCC (toluene/CH2Cl2 2:1 to toluene/EtOAc 100:0 to 99:1 to 98:2 to 97:3 to 96:4 to 94:6 to 90:10) to afford (3-Chloro-isoquinolin-1-yl)-acetic acid tert.-butyl ester. This compound is dissolved in a saturated ethanolic solution of HCl (200 ml) and refluxed for 15 minutes. Concentration affords the title compound in quantitative yield. 1H NMR (DMSO, 400 MHz) δ 1.17 (t, J=8.8, 3H), 4.11 (q, J=8.8, 2H), 4.28 (s, 2H), 7.51 -7.57 (m, 1H), 7.61 (s, 1H), 7.61-7.66 (m,1H), 7.72 (d, J=8.8, 1H), 7.98 (d, J=8.8, 1H); ES-MS: 250 [M+H]+.

Provenance & Evidence