3,5-Difluorobenzyl bromide → 3-(3,5-Difluorophenyl)-2-[2'-(3-methoxypropyl)-3-methylbiphenyl-4-yl]propanenitrile

HRID 2194925Notes

Reaction equation

[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[C:14]([CH3:21])[CH:13]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:36]Br>C1COCC1.[NH4+].[Cl-]>[F:32][C:33]1[CH:34]=[C:35]([CH2:36][CH:18]([C:15]2[CH:16]=[CH:17][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:13][C:14]=2[CH3:21])[C:19]#[N:20])[CH:38]=[C:39]([F:41])[CH:40]=1

Participants

Conditions

Temperature: -78 °C

Procedure

To a solution of [2′-(3-methoxypropyl)-3-methylbiphenyl-4-yl]acetonitrile (1.2 eq.) from step 1 in THF (0.02M) at −78° C. was added lithium hexamethyldisilazide (LiHMDS; 1.3 eq.). The reaction mixture was stirred 15 min at −78° C. To the resulting solution was cannulated a solution of 3,5-difluorobenzyl bromide (1 eq.) in THF (0.04M). The final mixture was allowed to warm slowly to room temperature and then stirred and extra 4 h. The resulting mixture was poured in saturated aqueous NH4Cl and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50% in 30 min) afforded the desired compound as a colorless oil.

Workup

temperatureto warm slowly to room temperature
stirringstirred and extra 4 h
extractionextracted with EtOAc
extractionThe organic extract
dry with materialwas dried over Na2SO4
filtrationfiltered
concentrationconcentrated
customPurification by column chromatography on silica gel (Combi-Flash by ISCO)
washeluting with Hex/EtOAc (0 to 50% in 30 min)

Sources & evidence

ORD record: ord-a7e6c0f2639848618e79ddba11ff9445
Source dataset: uspto-grants-2012_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08334308B2

Reaction notes

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