Diethyl (cyanomethyl)phosphonate → 3-(3,5-Dimethoxy-phenyl)-3-(3-fluoro-4-methoxy-phenyl)-acrylonitrile

HRID 2378273Notes

Reaction equation

HRID 2378273 reaction equation
C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([F:42])[CH:35]=2)=O)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>C1COCC1>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([F:42])[CH:35]=2)=[CH:9][C:10]#[N:11])[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1

Participants

5

Reactant 3

HCID 75676Diethyl (cyanomethyl)phosphonateHCID 2733832Lithium HexamethyldisilazideHCID 43474091(3,5-Dimethoxy-phenyl)-(3-fluoro-4-methoxy-phenyl)-methanone

Product 1

HCID 692036003-(3,5-Dimethoxy-phenyl)-3-(3-fluoro-4-methoxy-phenyl)-acrylonitrileYield 86%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of cyanomethylphosphonic acid diethyl ester (3.4 mL, 22 mmol) in THF (30 mL) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 21 mL, 21 mmol) dropwise. The mixture was stirred at room temperature for 40 min. (3,5-Dimethoxy-phenyl)-(3-fluoro-4-methoxy-phenyl)-methanone (3.1 g, 11 mmol) was added to the mixture. The mixture was refluxed for 4 h. The solution was poured into ice water (30 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-(3,5-dimethoxy-phenyl)-3-(3-fluoro-4-methoxy-phenyl)-acrylonitrile as an off-white solid (2.9 g, 86% yield) (isomer ratio is 1:0.7 by HNMR): mp: 91-93° C.; 1H NMR (DMSO-d6) δ 3.73 (s, 6H, 2CH3), [3.76 and 3.87 (2s)], 3.92 (s, 3H, CH3), 6.29 (s, 1H, CH), [6.33 (s)], 6.45-6.47 (m, 2H, Ar), 6.62-6.66 (m, 1H, Ar), 7.08-7.41 (m, 3H, Ar); 13C NMR (DMSO-d6) δ 55.42, 56.11, 56.19, 95.17, 96.31, 101.12, 102.04, 106.69, 107.12, 113.64, 113.72, 113.74, 114.85, 115.16, 116.59, 116.89, 117.98, 118.08, 125.53, 125.58, 126.23, 126.28, 129.18; 129.29, 129.95, 130.05, 138.71, 139.90, 148.26, 148.87, 149.15, 152.77, 153.13, 159.85, 159.99, 160.44; Anal. Calcd for C18H16NO3F: C, 69.00; H, 5.15; N, 4.47. Found: C, 68.92; H, 4.95; N, 4.42.

Workup

  1. additionwas added to the mixture
  2. temperatureThe mixture was refluxed for 4 h
  3. extractionThe aqueous layer was extracted with ethyl acetate (2×50 mL)
  4. washThe combined organic layers was washed with water (50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL)
  5. dry with materialdried over magnesium sulfate
  6. customRemoval of solvent and chromatography (Silica Gel)
  7. customgave

Sources & evidence

ORD record
ord-9d2d633cdb444469b76a039cc5810bd2
Source dataset
uspto-grants-2008_12
Patent number
US07470723B2

Reaction notes

Loading…