Trifluoroacetic anhydride → (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-2,3-dihydro-1H-pyrrole-1-carboxylate

A three-necked flask equipped with a thermometer and a nitrogen inlet was charged with (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate (10.05 g, 22.16 mmol) and toluene (36 mL) and lowered into −55° C. cooling bath. When the internal temperature of the mixture reached −50° C., lithium triethylborohydride (23 mL of 1.0 M/THF, 23 mmol) was added dropwise over 30 min and the mixture stirred for 35 min while maintaining the internal temperature between −50° C. and −45° C. Hunig's base (16.5 mL, 94 mmol) was added dropwise over 10 min. Then, DMAP (34 mg, 0.278 mmol) was added in one batch, followed by the addition of trifluoroacetic anhydride (3.6 mL, 25.5 mmol) over 15 min, while maintaining the internal temperature between −50° C. and −45° C. The bath was removed 10 min later and the reaction mixture was stirred for 14 h while allowing it to rise to ambient temperature. The reaction mixture was diluted with toluene (15 mL), cooled with an ice-water bath and treated slowly with water (55 mL) over 5 min. The phases were separated and the organic layer washed with water (50 mL, 2×) and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; 5% EtOAc/hexanes) to afford (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (7.947 g, 82% yield) as a colorless viscous oil. LC-MS: [M+Na]+=460.19. Rt=2.41 min under the following HPLC conditions: Solvent gradient from 100% A: 0% B to 0% A: 100% B (A=0.1% TFA in 1:9 MeOH/water; B=0.1% TFA in 9:1 MeOH/water) over 2 min and hold for 1 min; detection at 220 nm; PHENOMENEX® Luna 3.0×50 mm S10 column. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.58 (m, 4H), 7.49-7.40 (m, 6H), 6.47 (br s, 1H), 5.07/5.01 (overlapping br d, 1H), 4.18 (br s, 1H), 3.89 (br s, 0.5H), 3.69 (br s, 1.5H), 2.90-2.58 (br m, 2H), 1.40/1.26 (overlapping br s, 9H), 0.98 (s, 9H).

1. customA three-necked flask equipped with a thermometer and a nitrogen inlet
2. customlowered into −55° C.
3. temperaturecooling bath
4. customreached −50° C.
5. temperaturewhile maintaining the internal temperature between −50° C. and −45° C
6. temperaturewhile maintaining the internal temperature between −50° C. and −45° C
7. customThe bath was removed 10 min later
8. stirringthe reaction mixture was stirred for 14 h
9. customto rise to ambient temperature
10. additionThe reaction mixture was diluted with toluene (15 mL)
11. temperaturecooled with an ice-water bath
12. additiontreated slowly with water (55 mL) over 5 min
13. customThe phases were separated
14. washthe organic layer washed with water (50 mL, 2×)
15. concentrationconcentrated in vacuo
16. customThe crude material was purified by flash chromatography (silica gel; 5% EtOAc/hexanes)

ORD record

ord-0484ba22b110412698f5d76e7572446e

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09303007B2