Trifluoroacetic acid → Benzyl 1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate

HRID 390381Notes

Reaction equation

HRID 390381 reaction equation
[C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]=O)[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO.C(#N)C>[N:26]1([C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:25])[CH2:27][CH2:28][C:29]2([C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[NH:7][CH2:32]2)[CH2:30][CH2:31]1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 7516PhenylhydrazineHCID 2776272Benzyl 4-formylpiperidine-1-carboxylateHCID 4311764Sodium borohydride

Product 1

HCID 10914256Benzyl 1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylateYield 34.1%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 1140TolueneSolvent2×HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
35 °C

Procedure

A solution of phenyl hydrazine (1.29 g, 12.0 mmol) and trifluoroacetic acid (3.0 mL) in a 49:1 solution of toluene:acetonitrile (50 mL) is heated at 35° C. 4-Formyl-piperidine-1-carboxylic acid benzyl ester (2.7 g, 10.91 mmol) is dissolved in a 49:1 solution of toluene:acetonitrile (10 mL) and added dropwise to the mixture (WO2005046682). The mixture is stirred at 35° C. overnight. The resulting solution is cooled to 0° C., and methanol (5 mL) is added. NaBH4 (0.619 g, 16.38 mmol) is added portion wise to the solution and the mixture is stirred for 45 min. The reaction mixture is washed with aqueous NH4OH (6%, 25 mL) and brine (30 mL), dried over sodium sulfate, and evaporated to dryness to give a yellow solid. The crude solid is recrystallised from EtOAc to give a yellow solid (1.25 g, 1st crop). The mother liquor is evaporated and purified by silica gel chromatography, eluting with hexane:ethyl acetate (8:2) to give the title compound as a pale yellow solid (1.2 g, 2nd crop) with a total yield of (2.4 g, 76%). ESI/MS m/z 323 (M+H)+.

Workup

  1. temperatureThe resulting solution is cooled to 0° C.
  2. stirringthe mixture is stirred for 45 min
  3. washThe reaction mixture is washed with aqueous NH4OH (6%, 25 mL) and brine (30 mL)
  4. dry with materialdried over sodium sulfate
  5. customevaporated to dryness
  6. customto give a yellow solid
  7. customThe crude solid is recrystallised from EtOAc
  8. customto give a yellow solid (1.25 g, 1st crop)
  9. customThe mother liquor is evaporated
  10. custompurified by silica gel chromatography
  11. washeluting with hexane:ethyl acetate (8:2)

Sources & evidence

ORD record
ord-bd64ee2cb8404202a379e3efdf6c42ba
Source dataset
uspto-grants-2013_02
Patent number
US08383642B2

Reaction notes

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