Tosylmethyl isocyanide → 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)acetonitrile

HRID 511929Notes

Reaction equation

HRID 511929 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC1C=CC(S([CH2:31][N+:32]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.COCCOC.C(Cl)Cl.CCOC(C)=O.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[C:31]#[N:32])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1

Participants

9

Reactant 3

HCID 161915Tosylmethyl isocyanideHCID 23665647Potassium tert-butoxideHCID 59192773(3-Fluoro-5-(trifluoromethyl)phenyl)(5-fluoropyridin-2-yl)methanone

Product 1

HCID 591929322-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)acetonitrileYield 72%

Reagents, catalysts & solvents 5

HCID 6344DichloromethaneSolventHCID 8058HexaneSolventHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolventHCID 86596206tert butanol DMESolvent

Procedure

To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(5-fluoropyridin-2-yl)methanone (2.43 g, 8.5 mmol), prepared as described in Procedure 2, in DME (60 mL), was added TosMIC (2.23 g, 11.4 mmol). The reaction mixture was cooled in an ice bath. A solution of potassium tert butoxide (1.0 M potassium ten butoxide in tert butanol, 22.8 mmol) in tert butanol/DME (22 mL t-BuOH, 20 mL DME) was added via a funnel at a slow stream. Upon completion of addition, the ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water (approx 50 mL). The aqueous phase was extracted with CH2Cl2 (3×50 mL) and the combined organic portions were washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The yellow oil was dissolved in CH2Cl2 and loaded directly onto a silica gel ISCO cartridge (120 g) with elution at 40 mL/min gradient 0 to 15% EtOAc in hexane over 30 min (RT=23-29 min) 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)acetonitrile (1.8 g, 72% yield) was isolated as a yellow oil. LCMS: RT=1.73 min [M+H] 298.99 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.98 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H(CDCl3) ppm 5.35 (s, 1 H), 7.31 (d, J=7.91 Hz, 1 H), 7.38 (d, J=8.79 Hz, 1 H), 7.46-7.47 (m, 2H), 7.50 (s, 1 H), 8.46 (s, 1 H).

Workup

  1. temperatureThe reaction mixture was cooled in an ice bath
  2. additionUpon completion of addition
  3. customthe ice bath was removed
  4. customThe reaction mixture was quenched with water (approx 50 mL)
  5. extractionThe aqueous phase was extracted with CH2Cl2 (3×50 mL)
  6. washthe combined organic portions were washed with sat. NaCl
  7. dry with materialdried over anhydrous Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customto yield a yellow oil

Sources & evidence

ORD record
ord-8cfd586cf16b42c8a3f34c4f603e2a6a
Source dataset
uspto-grants-2015_08
Patent number
US09102599B2

Reaction notes

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