Ammonium Chloride → 1-(4-Fluorophenyl)-2-(3-fluoropyridin-4-yl)ethanone

HRID 41878Notes

Reaction equation

C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[CH3:18].[F:19][C:20]1[CH:30]=[CH:29][C:23]([C:24](OCC)=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[F:19][C:20]1[CH:30]=[CH:29][C:23]([C:24](=[O:25])[CH2:18][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[F:11])=[CH:22][CH:21]=1

Participants

Conditions

Temperature: 0 °C

Procedure

Lithium hexamethyldisilazide (1.0M in THF, 17.9 mL, 17.9 mmol) was cooled to 0° C. and 3-fluoro-4-methylpyridine (1.00 g, 0.926 mmol) in THF (50 mL) was added dropwise, keeping the solution temperature below 5° C. The mixture was then stirred for 1 hour at 0° C. and ethyl 4-fluorobenzoate in THF (50 mL) was added dropwise. The reaction was allowed to warm slowly to rt with stirring overnight. Aqueous ammonium chloride was added and the mixture was poured into EtOAc. The organic phase was separated dried (Na2SO4) and concentrated. Silica gel chromatography using a 10-50% EtOAc/heptanes gradient yielded 1.83 g (89%) of Ex 1-Step 6 product as a white solid: LCMS m/z 234.4 (M+1); 1H NMR (400 MHz, MeOH-d4) δ 8.41 (d, J=1.7 1H), 8.32 (d, J=4.8, 1H), 8.14 (dd, J=8.9, 5.4, 2H), 7.38 (dd, J=5.9, 5.1, 1H), 7.25 (dd, J=9.0, 9.0, 2H), 4.52 (s, 2H).

Workup

customthe solution temperature below 5° C
temperatureto warm slowly to rt
stirringwith stirring overnight
customThe organic phase was separated
dry with materialdried (Na2SO4)
concentrationconcentrated
customyielded 1.83 g (89%) of Ex 1-Step 6 product as a white solid

Sources & evidence

ORD record: ord-267317d5bfc544599631afa0bdf183b5
Source dataset: uspto-grants-2013_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08536164B2

Reaction notes

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