Hydrogen Peroxide → 1-(tert-Butyl) 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate

Temperature

0 °C

4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (4.48 g, 19.71 mmol) was dissolved in THF (100 mL) and the stirred solution was cooled to 0° C. Borane-dimethylsulfide complex (1.9 mL, 19.7 mmol) was added and the reaction mixture was allowed to warm to RT o/n. After 16 h, water was added dropwise until no bubbling was observed. The stirred mixture was then cooled to 0° C. Aqueous NaOH (5M in H2O, 5.3 mL, 26.6 mmol), then H2O2 (30 wt % in H2O, 6.0 mL, 58.5 mmol) were added dropwise. The reaction was then warmed to 50° C. After 30 min, the mixture was diluted with ethyl ether and washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (25% to 75% EtOAc/Hex) to afford the title compound (2.08 g, 41%). 4-Methoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: 4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (861 mg, 3.32 mmol) was dissolved in DCM (6.6 mL) then 2,6-di-tert-butyl-4-methylpyridine (1.023 g, 4.98 mmol) and AgOTf (938 mg, 3.65 mmol) were added. The reaction mixture was cooled to 0° C. and iodomethane (0.25 mL, 3.98 mmol) was added. After 4 min, the reaction mixture was diluted with DCM and it was filtered over elite. The filtrate was concentrated to a residue which was dissolved in diethyl ether. The organic solution was washed with 10% HCl and brine, then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (20% to 80% EtOAc/Hex) to afford the title compound (479 mg, 53%).

1. additionBorane-dimethylsulfide complex (1.9 mL, 19.7 mmol) was added
2. temperatureto warm to RT o/n
3. temperatureThe stirred mixture was then cooled to 0° C
4. temperatureThe reaction was then warmed to 50° C
5. waitAfter 30 min
6. washwashed with water and brine
7. dry with materialThe organic phase was dried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated
10. customThe crude residue was purified by silica column chromatography (25% to 75% EtOAc/Hex)

ORD record

ord-37af670fc2c6490cb42704bbc43b9228

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08273341B2