Ethyl 3-(trimethylsilyl)propynoate → 3-[1-[6-(2,4-Difluorophenyl)pyridin-2-yl]-2-oxo-4-(trimethylsilyl)but-3-yn-1-yl]-4-fluorobenzonitrile

HRID 1360681Notes

Reaction equation

HRID 1360681 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH2:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])[CH:12]=[CH:11][CH:10]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:35][Si:36]([CH3:45])([CH3:44])[C:37]#[C:38][C:39](OCC)=[O:40]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH:15]([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])[C:39](=[O:40])[C:38]#[C:37][Si:36]([CH3:45])([CH3:44])[CH3:35])[CH:12]=[CH:11][CH:10]=1

Participants

5

Reactant 3

HCID 568601Ethyl 3-(trimethylsilyl)propynoateHCID 2733832Lithium HexamethyldisilazideHCID 577003683-{[6-(2,4-Difluorophenyl)pyridin-2-yl]methyl}-4-fluorobenzonitrile

Product 1

HCID 577003693-[1-[6-(2,4-Difluorophenyl)pyridin-2-yl]-2-oxo-4-(trimethylsilyl)but-3-yn-1-yl]-4-fluorobenzonitrileYield 417.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 3-{[6-(2,4-difluorophenyl)pyridin-2-yl]methyl}-4-fluorobenzonitrile (from Step C above, 30.0 g, 92.3 mmol) in THF (700 mL) was added LiHMDS (276 mL, 276 mmol, 1M solution in THF) via cannula at −78° C. After stirring for 1 hr and 15 min at −78° C., ethyl 3-(trimethylsilyl)prop-2-ynoate (4.01 mL, 21.37 mmol) was added. The reaction was allowed to stir at −78° C. for 1 hr and was allowed to warm to 0° C. over 3 hours. The reaction was quenched with aqueous NH4Cl, extracted with ethyl acetate (2×). The organic layers were combined, washed with 0.5 N HCl, water, brine (2×), dried over MgSO4, and condensed in vacuo to yield a black oil. The crude material was purified via silica gel chromatography (100% CH2Cl2) to give the title compound (40.0 g).

Workup

  1. stirringto stir at −78° C. for 1 hr
  2. temperatureto warm to 0° C. over 3 hours
  3. customThe reaction was quenched with aqueous NH4Cl
  4. extractionextracted with ethyl acetate (2×)
  5. washwashed with 0.5 N HCl, water, brine (2×)
  6. dry with materialdried over MgSO4, and condensed in vacuo
  7. customto yield a black oil
  8. customThe crude material was purified via silica gel chromatography (100% CH2Cl2)

Sources & evidence

ORD record
ord-a2ce57f3f8474a7ca244b8a150f7932a
Source dataset
uspto-grants-2011_02
Patent number
US07879875B2

Reaction notes

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