2-Chloromethyl 2-(trimethylsilyl)ethyl ether → (S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one

Participants

Reaction Conditions

Reaction Steps

804 mg (3.2 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) is dissolved in 16 ml dry THF and cooled to −78° C. After the addition of 2.21 ml butyl lithium in hexane (1.59 M), the yellow solution is stirred at −78° C. for 30 min. Subsequently, 680 □l (640 mg=3.84 mmol) (2-chloromethoxyethyl)-trimethylsilane (SEM-Cl) is added and stirring is continued at −20° C. for 5 h. The mixture is then allowed to warm up to room temperature overnight. The reaction is then quenched by addition of 10 ml saturated NH4Cl solution followed by 10 ml water and extracted with 2×40 ml isopropyl acetate. The layers are separated and the organic layer dried over MgSO4, filtered and evaporated. The resulting residue (1.33 g) is purified using column chromatography (dichloromethane:triethylamine=99.5:0.5→dichloromethane:methanol:triethylamine=98.5:1:0.5) to give (S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one (1-a, R1=SEM) as a yellow oil. NMR (400 MHz, CDCl3, □/ppm): 7.58 (m, 4H); 7.47 (m, 2 H); 7.37 (m, 1 H); 7.30 (m, 2 H); 5.04 (d, J=10.6, 1 H); 4.70 (d, J=10.6, 1 H); 4.03 (m, 1 H); 3.59 (m, 2 H); 3.24 (dd, J=4.2, 13.4, 1 H); 2.67 (dd, J=9.1, 13.4, 1 H); 2.33 (t, J=8.2, 2 H); 2.10 (m, 1 H); 1.81 (m, 1 H); 1.00 (m, 2 H); 0.06 (s, 9 H). MS (ESI, m/e) 382 [M+H]+; 763 [2M+H]+. IR (solution in CH2Cl2, □/cm−1): 3057; 2951; 1702; 1487; 1414; 1249; 1073; 859; 836; 759; 697.

Provenance & Evidence