N-methyl-2-pyrrolidone → 4-(1-Hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridine-2-carbonitrile

HRID 1426326Notes

Reaction equation

HRID 1426326 reaction equation
Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH3:16][N:17]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:11][C:8]([C:6]1[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=[C:2]([C:16]#[N:17])[CH:7]=1)([CH3:10])[CH3:9]

Participants

5

Reactant 2

HCID 13387N-methyl-2-pyrrolidoneHCID 86666501HCID 86666501, compound

Product 1

HCID 696731904-(1-Hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridine-2-carbonitrile

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
140 °C

Procedure

A solution of 2-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]propan-2-ol (0.230 g, 0.960 mmol, from Step B) and zinc cyanide (0.676 g, 5.76 mmol) in N-methylpyrrolidinone (4 mL) was degassed by bubbling a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.19 mmol) was added and degassed similarly for 5 additional minutes. The vial was sealed and heated in the microwave to 140° C. for 10 minutes. The reaction mixture was worked up by partitioning between water and ethyl acetate, extracting (3×), and drying the combined extracts over sodium sulfate. The dried extract was then filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-25% EtOAc/Hexanes afforded product (110 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J=1.5 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 1.62 (s, 6H); 19F NMR (282 MHz, CDCl3) δ−68.39 (s); LCMS (M+H)+: 231.1.

Workup

  1. customby bubbling a stream of nitrogen through the solution for 10 minutes
  2. customdegassed similarly for 5 additional minutes
  3. customThe vial was sealed
  4. customby partitioning between water and ethyl acetate
  5. extractionextracting (3×)
  6. dry with materialdrying the combined extracts over sodium sulfate
  7. extractionThe dried extract
  8. filtrationwas then filtered
  9. concentrationconcentrated
  10. washFlash chromatography on silica gel, eluting with a gradient from 0-25% EtOAc/Hexanes afforded product (110 mg, 50%)

Sources & evidence

ORD record
ord-c76a26d83598443bb39590ecb22cf153
Source dataset
uspto-grants-2015_01
Patent number
US08933085B2

Reaction notes

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