N-methyl-2-pyrrolidone → 4-(Methoxymethyl)-6-(trifluoromethyl)pyridine-2-carbonitrile

HRID 1426329Notes

Reaction equation

HRID 1426329 reaction equation
Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=1.[CH3:15][N:16]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>[CH3:10][O:9][CH2:8][C:6]1[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([C:15]#[N:16])[CH:7]=1

Participants

5

Reactant 2

HCID 13387N-methyl-2-pyrrolidoneHCID 866665022-Chloro-4-(methoxymethyl)-6-(trifluoromethyl)pyridine

Product 1

HCID 696735024-(Methoxymethyl)-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-chloro-4-(methoxymethyl)-6-(trifluoromethyl)pyridine (0.5 g, 2 mmol, from Step B) and zinc cyanide (1.56 g, 13.3 mmol) in N-methylpyrrolidinone (8 mL) was degassed by bubbling a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.51 g, 0.44 mmol) was added and the mixture was degassed similarly for 5 minutes. The reaction vial was sealed and heated in the microwave to 140° C. for 10 minutes. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous portion was extracted with two further portions of ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-30% EtOAc/Hexanes afforded purified product (0.36 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.87-7.83 (m, 2H), 4.60 (dd, J=0.9 Hz, 2H), 3.51 (s, 3H); 19F NMR (376 MHz, CDCl3) 5-68.55 (s); LCMS (M+H)+: 217.1.

Workup

  1. customby bubbling a stream of nitrogen through the solution for 10 minutes
  2. customthe mixture was degassed similarly for 5 minutes
  3. customThe reaction
  4. customvial was sealed
  5. customThe reaction mixture was partitioned between water and ethyl acetate
  6. extractionthe aqueous portion was extracted with two further portions of ethyl acetate
  7. washThe combined organic extracts were washed with water
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. washFlash chromatography on silica gel, eluting with a gradient from 0-30% EtOAc/Hexanes
  12. customafforded
  13. custompurified product (0.36 g, 80%)

Sources & evidence

ORD record
ord-0112f9b9e7764b05a9ebf466293568f9
Source dataset
uspto-grants-2015_01
Patent number
US08933085B2

Reaction notes

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