Dimethylformamide → 5-((4-Methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile

HRID 515779Notes

Reaction equation

HRID 515779 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[CH:4]=[C:3]([C:18]([F:21])([F:20])[F:19])[C:2]([C:22]#[N:23])=[N:7][CH:6]=2)=[CH:11][CH:12]=1

Participants

6

Reactant 2

HCID 6228DimethylformamideHCID 250200336-Chloro-N-((4-methoxyphenyl)methyl)-5-(trifluoromethyl)-3-pyridinamine

Product 1

HCID 250200345-((4-Methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Procedure

An oil bath was preheated to 180° C. A mixture of 6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine (19.45 g, 61.55 mmol), Zn(CN)2 (8.7 g, 73.86 mmol), and dppf (6.8 g, 12.31 mmol) in DMF (250 mL) was stirred at room temperature while bubbling nitrogen for 5 min. Pd2(dba)3 (2.8 g, 3.07 mmol, 0.05 eq.) was then added and the reaction mixture was placed inside the pre-heated bath. The bath temperature dropped to 160° C. The mixture started refluxing when the bath temperature reached 170° C. (takes 20 min). Refluxed for 10 min. The reaction mixture was cooled to room temperature and it was filtered through a pad of celite. The pad of celite was washed with EtOAc. The solvent was removed using a rotovap hooked up to a high vac. pump. The black residue was partitioned between EtOAc and water. An orange solid (some dppf by-product) precipitated and was filtered and washed with EtOAc. The organic layer was washed with brine (2×), dried over sodium sulfate, and concentrated to dryness. The black residue was dissolved in DCM and loaded onto a silica gel plug. The plug was washed with DCM (to get rid of some of the fast eluting impurities) followed by 1:1 EtOAc/hexanes (to move the desired). The fractions containing the desired were combined, evaporated to dryness and the residue obtained was purified by column chromatography on silica gel eluting with 0 to 50% EtOAc/hexanes to afford 15 g of 5((4-methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile as reddish thick oily residue. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.01 (t, 1H), 7.31 (m, 3H), 6.92 (d, 2H), 4.41 (d, 2H), 3.73 (s, 3H).

Workup

  1. customAn oil bath was preheated to 180° C
  2. customwhile bubbling nitrogen for 5 min
  3. additionThe bath temperature dropped to 160° C
  4. temperatureThe mixture started refluxing when the bath temperature
  5. customreached 170° C.
  6. custom(takes 20 min)
  7. temperatureRefluxed for 10 min
  8. temperatureThe reaction mixture was cooled to room temperature
  9. filtrationit was filtered through a pad of celite
  10. washThe pad of celite was washed with EtOAc
  11. customThe solvent was removed
  12. customThe black residue was partitioned between EtOAc and water
  13. customAn orange solid (some dppf by-product) precipitated
  14. filtrationwas filtered
  15. washwashed with EtOAc
  16. washThe organic layer was washed with brine (2×)
  17. dry with materialdried over sodium sulfate
  18. concentrationconcentrated to dryness
  19. dissolutionThe black residue was dissolved in DCM
  20. washThe plug was washed with DCM (
  21. customto get rid of some of the
  22. washfast eluting impurities)
  23. additionThe fractions containing the
  24. customevaporated to dryness
  25. customthe residue obtained
  26. customwas purified by column chromatography on silica gel eluting with 0 to 50% EtOAc/hexanes

Sources & evidence

ORD record
ord-89a6a82f17b6456990889a09d4975560
Source dataset
uspto-grants-2015_08
Patent number
US09108944B2

Reaction notes

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