Nitrogen → 6-((6-((2-(2,4-Difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)oxy)nicotinonitrile

HRID 63258Notes

Reaction equation

[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:21])([F:20])[C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:11][O:10]1.F[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].N#N>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:20])([F:21])[C:13]2[N:18]=[CH:17][C:16]([O:19][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=3)=[CH:15][CH:14]=2)[CH2:11][O:10]1

Participants

Conditions

Temperature: 25 °C

Procedure

To a magnetically stirred mixture of 6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-ol (500 mg, 1.671 mmol) and 6-fluoronicotinonitrile (224 mg, 1.838 mmol) in dry DMSO (5.570 mL) was added Cs2CO3 (653 mg, 2.005 mmol) in a 20 mL vial under N2 atmosphere. The reaction mixture was stirred at 25° C. for 16 h. The reaction was quenched with water and extracted with Et2O (3×). The combined organic layers were dried by passing through a phase separator and volatiles were removed under a gentle stream of N2. The resulting residue was loaded onto a pad of Celite® and purified by flash chromatography (SiO2, 5-30% EtOAc/Hexanes over 8 min, 30% for 4 min) to yield the title compound as a colorless oil (667 mg, 99%): 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=2.2 Hz, 1H), 8.44 (dd, J=2.3, 0.7 Hz, 1H), 8.00 (dd, J=8.6, 2.3 Hz, 1H), 7.61 (dd, J=8.6, 2.5 Hz, 1H), 7.57 (dd, J=8.6, 0.7 Hz, 1H), 7.41 (dd, J=14.7, 8.2 Hz, 1H), 7.15 (dd, J=8.6, 0.7 Hz, 1H), 6.89-6.82 (m, 1H), 6.76 (ddd, J=9.8, 8.9, 2.5 Hz, 1H), 3.47 (d, J=4.9 Hz, 1H), 3.02-2.98 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −106.85 (dd, J=258.0, 8.5 Hz, 1F), −107.45-−108.24 (m, 2F), −109.31 (q, J=8.5 Hz, 1F); ESIMS m/z 402 ([M+H]+).

Workup

customThe reaction was quenched with water
extractionextracted with Et2O (3×)
customThe combined organic layers were dried
customwere removed under a gentle stream of N2
custompurified by flash chromatography (SiO2, 5-30% EtOAc/Hexanes over 8 min, 30% for 4 min)

Sources & evidence

ORD record: ord-ddae4c0e405745f4b0dd8e08bc6fc595
Source dataset: uspto-grants-2016_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09447073B2

Reaction notes

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