p-Xylyl bromide → (S)-3-((tert-Butyldimethylsilyl)oxy)-1-(4-methylbenzyl)pyrrolidin-2-one

HRID 1507262Notes

Reaction equation

[Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:10]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]

Participants

Conditions

Temperature: 0 °C

Procedure

(S)-3-((tert-Butyldimethylsilyl)oxy)pyrrolidin-2-one (5 g, 23.22 mmol) was dissolved in anhydrous THF (46.4 ml) and the reaction mixture was cooled to 0° C. under a nitrogen atmosphere. Sodium hydride (1.393 g, 34.8 mmol) was then added in one portion and the reaction mixture was allowed to stir for 5 min before the dropwise addition of 1-(bromomethyl)-4-methylbenzene (5.37 g, 29 mmol) in anhydrous THF (46 ml). The reaction was allowed to stir at 0° C. for 5 min, then the cooling bath was removed and mixture was allowed to warm to rt overnight. The reaction was cautiously quenched with water (100 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layers were then washed with brine (200 mL) and dried (MgSO4). Evaporation of the solvent in vacuo gave the crude product (9.6 g, oil) which was then purified by silica gel chromatography (330 g of silica) eluting with a gradient of 0% to 20% ethyl acetate in hexanes to provide 6.53 g (88%) of the desired product. LC/MS (Conditions B) RT=4.320 min, (M+H)+=320.3; 1H NMR (400 MHz, chloroform-d) δ 7.15 (s, 4H), 4.42 (s, 2H), 4.37 (t, J=7.6 Hz, 1H), 3.32-3.18 (m, 1H), 3.10 (dt, J=9.7, 7.5 Hz, 1H), 2.36 (s, 3H), 2.29 (dtd, J=12.6, 7.6, 3.1 Hz, 1H), 1.97-1.84 (m, 1H), 0.95 (s, 9H), 0.20 (d, J=10.3 Hz, 6H).

Workup

customthe cooling bath was removed
temperatureto warm to rt overnight
customThe reaction was cautiously quenched with water (100 mL)
extractionextracted with ethyl acetate (3×100 mL)
washThe combined organic layers were then washed with brine (200 mL)
dry with materialdried (MgSO4)
customEvaporation of the solvent in vacuo
customgave the crude product (9.6 g, oil) which
customwas then purified by silica gel chromatography (330 g of silica)
washeluting with a gradient of 0% to 20% ethyl acetate in hexanes

Sources & evidence

ORD record: ord-6d874cdf5c7e48c9bedc16a92d6913e6
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09221796B2

Reaction notes

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