5-(Chloromethyl)-3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazole → 3-(4-Fluorophenyl)-1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-2-one

HRID 1667229Notes

Reaction equation

[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:23]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:21][C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=4)[N:23]=3)[C:9]2=[O:13])=[CH:4][CH:3]=1

Participants

Conditions

Temperature: 50 °C

Procedure

To 3-(4-fluorophenyl)pyrrolidin-2-one (0.106 g, 0.592 mmol; Example 189B) as suspension in tetrahydrofuran (0.5 mL) was added potassium t-butoxide (1.0 Min tetrahydrofuran) (0.651 mL, 0.651 mmol) dropwise at room temperature. After stirring for 15 minutes, 5-(chloromethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (0.171 g, 0.651 mmol) was added dropwise as a solution in tetrahydrofuran (0.5 mL). The reaction was heated to 50° C. for 1 hour. The reaction was concentrated, loaded onto silica gel SF15-12 g (Analogix®) and the product eluted using a gradient of 5% to 50% ethyl acetate/hexanes over 30 minutes (Flow rate=30 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J=8.1, 2H), 7.76 (d, J=8.2, 2H), 7.39-7.23 (m, 2H), 7.17-6.97 (m, 2H), 4.96 (d, J=17.0, 1H), 4.84 (d, J=16.5, 1H), 3.78 (t, J=8.9, 1H), 3.74-3.59 (m, 2H), 2.77-2.57 (m, 1H), 2.25 (ddt, J=8.0, 12.9, 20.7, 1H); MS (ESI+) m/z 406.1 (M+H)+.

Workup

concentrationThe reaction was concentrated
washthe product eluted
customover 30 minutes

Sources & evidence

ORD record: ord-ca4c4ee02cd14dde9fd984acb91b3d36
Source dataset: uspto-grants-2011_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08044069B2

Reaction notes

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