p-Toluenesulfonic acid → HCID 71209216, compound

HRID 1912595Notes

Reaction equation

HRID 1912595 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.CO[CH:13](OC)[CH2:14][NH2:15].[BH4-].[Na+].[C:20](#[N:24])[CH2:21][C:22]#[N:23].CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1C=CC=CC=1>[NH2:23][C:22]1[N:15]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=2)[CH:14]=[CH:13][C:21]=1[C:20]#[N:24]

Participants

8

Reactant 6

HCID 6101p-Toluenesulfonic acidHCID 8010MalononitrileHCID 8471TriethylamineHCID 89728Aminoacetaldehyde dimethyl acetalHCID 5880883,4-DifluorobenzaldehydeHCID 4311764Sodium borohydride

Product 1

HCID 71209216HCID 71209216, compoundYield 78%

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Conditions

Temperature
130 °C

Procedure

A solution of 3,4-difluorobenzaldehyde (38.8 mL, 352 mmol) and 2,2-dimethoxyethanamine (38.3 mL, 352 mmol) in benzene (450 mL) was heated to reflux (130° C.) for 3 h using a Dean Stark trap to separate water. The mixture was concentrated and the residue was dissolved EtOH (450 mL), cooled to 0° C. and sodium borohydride (26.6 g, 704 mmol) was added in portions. Stirring at RT continued for 18 h. The mixture was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with water, brine, dried (Na2SO4) and concentrated. The residue was dissolved in DCM (1000 mL) and malononitrile (46.5 g, 704 mmol) and 4-methylbenzenesulfonic acid (242 g, 1407 mmol) were added and the mixture was stirred at RT for 18 h. Triethylamine (146 mL, 1056 mmol) was slowly added and the mixture was stirred at 70° C. for 2 h then concentrated. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3/water, brine, dried (Na2SO4), and concentrated. Purification with column chromatography provided 2-amino-1-(3,4-difluorobenzyl)-1H-pyrrole-3-carbonitrile (70 g, 273 mmol, 78% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 3.66-3.83 (br s, 2 H), 4.87-4.95 (s, 2 H), 6.11-6.28 (m, 2 H), 6.75-7.00 (m, 2 H), 7.00-7.35 (m, 1 H); LCMS (m/z) ES+=234 (M+1).

Workup

  1. customto separate water
  2. concentrationThe mixture was concentrated
  3. dissolutionthe residue was dissolved EtOH (450 mL)
  4. temperaturecooled to 0° C.
  5. concentrationThe mixture was concentrated
  6. customthe residue partitioned between EtOAc and water
  7. washThe organic phase was washed with water, brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated
  10. dissolutionThe residue was dissolved in DCM (1000 mL)
  11. stirringthe mixture was stirred at RT for 18 h
  12. stirringthe mixture was stirred at 70° C. for 2 h
  13. concentrationthen concentrated
  14. additionWater was added
  15. extractionthe mixture was extracted with EtOAc
  16. washThe organic layer was washed with water, saturated NaHCO3/water, brine
  17. dry with materialdried (Na2SO4)
  18. concentrationconcentrated
  19. customPurification with column chromatography

Sources & evidence

ORD record
ord-ae411838a6984dde9fa25758690073fc
Source dataset
uspto-grants-2013_12
Patent number
US08609653B2

Reaction notes

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