Background and overview[1-2]
(S)-(-)-2-Bromo-1-α-methylbenzyl alcohol is a chiral secondary alcohol and an important intermediate for the synthesis of optically active drugs. It is generally selectively prepared from o-bromoacetophenone. Prepared by reduction.
Preparation[1-2]
Report 1,
Asymmetric synthesis of (S)-(-)-2-bromo-1-α-methylbenzyl alcohol:
Add 0.5 mmol of 1-(2-bromophenyl)ethanol into the test tube, add 1.5 mmol of dipropylene glycol dimethyl ether, fill it with an oxygen balloon, and react at 120°C for 12 hours until the reaction is complete. Add sodium formate to the reaction system. 2.5 mmol, then add 0.0025 mmol catalyst B, add 4 mL of methanol: water (3:1), replace with nitrogen 3 times, react at 50°C for 12 hours, wash with water after the reaction, extract the aqueous phase with ethyl acetate 3 times, and combine the organic phases Concentrated to dryness, separated by column chromatography (petroleum ether: ethyl acetate = 10:1), Rohm and Haas obtained (S)-(-)-2-bromo-1-α-methylbenzyl alcohol (67.3 mg) , the yield is 91%, and the ee value is 88%. HPLC separation conditions: Chiral column Daicel OD-H column, mobile phase: n-hexane/isopropyl alcohol = 97:3 (volume ratio), flow rate: 1.0ml/min, wavelength: 215nm, temperature, 25°C, t1= 20.63min, t2=23.05min; 1H NMR (MHz, CDCl3): δ=7.61-7.52 (m, 2H), 7.38-7.34 (m, 1H ),7.17-7.12(m,1H),5.24(q,J＝6.4Hz,1H),2.85(s,1H), 1.48(d,J＝6.4Hz,3H);13 C NMR (100MHz, CDCl3): δ=144.7,132.6,128.8,127.9, 126.7,121.7,69.1,23.6.
Report 2,
Add phenylruthenium dichloride (〔RuCl2beneze〕2) (0.05mmol, 25 mg) into a 100mL Schlenk bottle, and bridge the chiral bisphosphine ligand (Rax)-BuP ( 0.105mmol, 64.3mg), N,N-dimethylformamide 6 mL, stir the reaction at 100°C under nitrogen protection. After cooling the solution to room temperature, add chiral diamine (R, R)-DPEN (0.105 mmol, 23 mg), continue to stir the reaction at this temperature, distill the solvent under reduced pressure, add dichloromethane to dissolve the solid, and concentrate the solution , add hexane to the concentrated solution to produce a brown precipitate, filter, and distill the filtrate solvent under reduced pressure to obtain an earthy yellow solid as a ruthenium catalyst precursor. 31p NMR (CDCl3, 202MHz) δ=47.5ppm(s) of the ruthenium catalyst precursor.
Add ruthenium catalytic precursor (0.0025mmol, 2.5mg), potassium tert-butoxide 0.114mmol, and n-butanol 1mL into a 100mL Schlenk bottle. Stir and dissolve at room temperature. Add o-bromoacetophenone (2.5mmol, 2.5mmol, 0.34mL), transferred to a 30mL autoclave with stirring, hydrogen atmosphere, 5MPa, stirring and reaction at 20°C for 48 hours. The hydrogen gas in the kettle was evacuated, followed by flash column chromatography and concentration under reduced pressure. The reaction conversion rate measured by gas chromatography was 99wt%, and the product was 89%ee(S)-(-)-2-bromo-1-α-methylbenzyl alcohol.
References
[1] [Chinese invention] CN201910258055.5 A method for deracemization to synthesize chiral alcohols
