Acetic Acid → 1-Oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxamidine

HRID 77358Notes

Reaction equation

HRID 77358 reaction equation
O[NH:2][C:3]([C:5]1[N:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[NH:12][C:13](=[O:14])[C:8]2=[CH:7][CH:6]=1)=[NH:4].C(O)(=O)C.C([O-])=O.[NH4+]>CO.[Pd].[Ni].O>[O:14]=[C:13]1[NH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:10][N:9]2[C:5]([C:3]([NH2:4])=[NH:2])=[CH:6][CH:7]=[C:8]12

Participants

8

Reactant 3

HCID 176Acetic AcidHCID 2723923Ammonium formateHCID 178513229HCID 178513229, compound

Product 1

HCID 727149451-Oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxamidineYield 45.5%

Reagents, catalysts & solvents 4

HCID 935NickelCatalystHCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of N-hydroxy-1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxamidine (Example 3) (0.03 g, 89.2 μmol) suspended in methanol (1.5 mL) and glacial acetic acid (0.15 mL) was treated with 10% palladium on carbon (5 mg). The reaction was stirred at room temperature under hydrogen (1 atm) at 50° C. for 2 h. The reaction was treated with ammonium formate (16.9 mg, 0.27 mmol) and then heated at reflux for 5 h. The reaction mixture was treated with slurry of Raney nickel in water (˜0.2 mL). The resulting mixture was stirred under hydrogen (1 atm) at room temperature overnight. At this time the reaction was filtered through Celite®. The filtrate was concentrated in vacuo to afford a light yellow semi-solid. The solid was triturated with diethyl ether, collected by filtration and then dried in vacuo to afford a light green solid. This solid was further triturated with a saturated aqueous sodium bicarbonate solution, collected by filtration and dried in vacuo to afford 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxamidine (13 mg, 44%) as light brown solid. 1H NMR (methanol-d4) δ ppm 8.11 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.78-7.84 (m, 3H), 7.50-7.56 (m, 1H). LC-MS calcd. for C15H11F3N4O [(M+H)+] 321, obsd. 321.0.

Workup

  1. temperatureheated
  2. temperatureat reflux for 5 h
  3. stirringThe resulting mixture was stirred under hydrogen (1 atm) at room temperature overnight
  4. filtrationAt this time the reaction was filtered through Celite®
  5. concentrationThe filtrate was concentrated in vacuo
  6. customto afford a light yellow semi-solid
  7. customThe solid was triturated with diethyl ether
  8. filtrationcollected by filtration
  9. customdried in vacuo
  10. customto afford a light green solid
  11. customThis solid was further triturated with a saturated aqueous sodium bicarbonate solution
  12. filtrationcollected by filtration
  13. customdried in vacuo

Sources & evidence

ORD record
ord-7b60579cdd0f41ec9107963bd21ac131
Source dataset
uspto-grants-2014_09
Patent number
US08841299B2

Reaction notes

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