Lithium borohydride → HCID 24985460, compound

HRID 913390Notes

Reaction equation

HRID 913390 reaction equation
[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18](OCC)=[O:19])[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15].[Li+].[BH4-].CO.C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:18][OH:19])[N:6]2[CH2:13][C:14]([F:16])([F:17])[F:15].[OH:19][CH2:18][C:5]1[N:6]([CH2:13][C:14]([F:17])([F:15])[F:16])[C:7]2[C:3]([CH:4]=1)=[CH:2][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2

Participants

6

Reactant 3

HCID 4148881Lithium borohydride2×HCID 21226129Dichloromethane methanolHCID 24985292HCID 24985292, compound

Product 2

HCID 24985460HCID 24985460, compoundYield 63%HCID 24985461HCID 24985461, compoundYield 6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To an ice-cold solution of ethyl 4-chloro-5-cyano-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate (0.45 g, 1.36 mmol) in THF (12 mL), under N2, was added LiBH4 (2 M THF solution, 2.04 mL, 4.08 mmol). The mixture was stirred at rt for 8 h. Additional LiBH4 (2M THF solution, 3 mL, 6 mmol) was added and stirred at rt for 60 h. The mixture was cooled in an ice bath and quenched by sequential dropwise addition of water and 1N HCl (exothermic). The mixture was partitioned between EtOAc and water. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (10-80% EtOAc-hexanes gradient) to afford a mixture of the title compounds. A second flash chromatography (0-2% MeOH—CH2Cl2 gradient) afforded 4-chloro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H-indole-5-carbonitrile (Example 10) as a white solid (0.25 g, 63% yield) (MS (ES) m/z 289 (M+1)) and 2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H-indole-5-carbonitrile (Example 11) (0.021 g, 6% yield) (MS (ES) m/z 255 (M+1)).

Workup

  1. stirringstirred at rt for 60 h
  2. temperatureThe mixture was cooled in an ice bath
  3. customquenched by sequential dropwise addition of water and 1N HCl (exothermic)
  4. customThe mixture was partitioned between EtOAc and water
  5. washThe organic phase was washed with sat'd brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by flash chromatography (10-80% EtOAc-hexanes gradient)
  9. customto afford

Sources & evidence

ORD record
ord-9ad6eef3c76b4d808d800128df93e8bb
Source dataset
uspto-grants-2011_09
Patent number
US08026262B2

Reaction notes

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