Nitrogen → HCID 53309345, compound

HRID 913502Notes

Reaction equation

HRID 913502 reaction equation
[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:8]([C:18]([F:21])([F:20])[F:19])[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=2.O.N#N.[CH3:33][N:34]1C(=O)CCC1>CC(OC)(C)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[C:33]([C:7]1[C:8]([C:18]([F:21])([F:20])[F:19])=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])#[N:34]

Participants

8

Reactant 4

HCID 947NitrogenHCID 962WaterHCID 13387N-methyl-2-pyrrolidoneHCID 53308825HCID 53308825, compound

Product 1

HCID 53309345HCID 53309345, compoundYield 85%

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 15413tert-Butyl methyl etherSolvent

Procedure

To a stirred solution of 1,1-dimethylethyl 2-methyl-4-(trifluoromethyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-indole-3-carboxylate (20.2 g, 45.2 mmol) in NMP (150 mL) was added deionized water (8 mL) and N2 was passed through the solution for 10 min with the aid of a glass pipette. 1,1′-Bis(diphenylphosphino)ferrocene (2.49 g, 4.49 mmol) and tris(dibenzylidineacetone)dipalladium(0) (2 g, 2.18 mmol) were added and the solution was stirred under N2 atmosphere at rt for 15 min. Zinc cyanide (3.95 g, 33.6 mmol) was added and the mixture was stirred an additional 10 min at rt. The reaction mixture was gradually heated to 80° C. (internal temperature) and maintained at this temperature for 3 h. After cooling to 35° C., the mixture was diluted with MTBE (100 mL) and washed with water (100 mL). The aqueous layer was back extracted with MTBE (2×100 mL) and the combined MTBE layers were washed with water (4×125 mL) and dried over MgSO4. The organic phase was filtered through a glass fritted funnel and the MTBE filtrate was stirred over decolorizing charcoal for 15 min. The charcoal mixture was filtered through a plug of silica gel (75 g) and the filtrate was concentrated at reduced pressure. Remaining material was triturated with hot MTBE, then diluted with i-octane, cooled to −15° C. and filtered to afford 1,1-dimethylethyl 5-cyano-2-methyl-4-(trifluoromethyl)-1H-indole-3-carboxylate as a beige solid (12.5 g, 85% yield): 1H NMR (DMSO-d6) δ 12.54 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 2.50 (s, 3H), 1.49 (s, 9H); MS (ES): m/z 323 (M−1).

Workup

  1. stirringthe mixture was stirred an additional 10 min at rt
  2. temperatureThe reaction mixture was gradually heated to 80° C. (internal temperature)
  3. temperaturemaintained at this temperature for 3 h
  4. temperatureAfter cooling to 35° C.
  5. washwashed with water (100 mL)
  6. extractionThe aqueous layer was back extracted with MTBE (2×100 mL)
  7. washthe combined MTBE layers were washed with water (4×125 mL)
  8. dry with materialdried over MgSO4
  9. filtrationThe organic phase was filtered through a glass fritted funnel
  10. stirringthe MTBE filtrate was stirred
  11. customfor 15 min
  12. filtrationThe charcoal mixture was filtered through a plug of silica gel (75 g)
  13. concentrationthe filtrate was concentrated at reduced pressure
  14. customRemaining material was triturated with hot MTBE
  15. additiondiluted with i-octane
  16. temperaturecooled to −15° C.
  17. filtrationfiltered

Sources & evidence

ORD record
ord-6f37d6d55dc749419fb3ec9e69825c8e
Source dataset
uspto-grants-2011_09
Patent number
US08026262B2

Reaction notes

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