Dimethylformamide → 4-{[6-(2,4-Difluorophenyl)pyridin-2-yl]methyl}-3,5-difluorobenzonitrile

HRID 1360693Notes

Reaction equation

Br[C:2]1[CH:22]=[C:21]([F:23])[C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:8]=2)=[C:4]([F:24])[CH:3]=1.[CH3:25][N:26](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:9]1[N:8]=[C:7]([CH2:6][C:5]2[C:21]([F:23])=[CH:22][C:2]([C:25]#[N:26])=[CH:3][C:4]=2[F:24])[CH:12]=[CH:11][CH:10]=1

Participants

Conditions

Temperature: 120 °C

Procedure

To a solution of 2-(4-bromo-2,6-difluorobenzyl)-6-(2,4-difluorophenyl)pyridine (from Step D above, 7.32 g, 18.5 mmol) in wet DMF (200 mL of DMF and 2 mL water) was added Zn(CN)2 (1.74 g, 14.8 mmol), tris(dibenzylideneacetone)dipalladium (842 mg, 0.92 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (1.23 g, 2.22 mmol) and heated to 120° C. for 1 hr (monitored via LCMS). After the reaction cooled to ambient temperature, the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with water (4×), brine (3×), dried over MgSO4, and condensed in vacuo. The crude material was purified via silica gel chromatography (hexanes/ethyl acetate) to give the title compound (6.1 g).

Workup

temperatureAfter the reaction cooled to ambient temperature
extractionextracted with EtOAc (3×)
washThe combined organic layers were washed with water (4×), brine (3×)
dry with materialdried over MgSO4, and condensed in vacuo
customThe crude material was purified via silica gel chromatography (hexanes/ethyl acetate)

Sources & evidence

ORD record: ord-08ab5dbea82348979b5018c825331daf
Source dataset: uspto-grants-2011_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07879875B2

Reaction notes

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