Acetic Acid → 3-((3-(1H-pyrazol-5-yl)piperidin-1-yl)methyl)-9H-carbazole

HRID 659616Notes

Reaction equation

HRID 659616 reaction equation
[NH:1]1[C:5]([CH:6]2[CH2:11]CN[CH2:8][CH2:7]2)=[CH:4][CH:3]=[N:2]1.[CH2:12]([N:14](C(C)C)C(C)C)C.[CH:21]1[C:33]2[NH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[C:23]([CH:34]=O)[CH:22]=1.C(O)(=O)C.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CCO.O.CO.C(Cl)Cl>[NH:1]1[C:5]([CH:6]2[CH2:7][CH2:8][CH2:12][N:14]([CH2:34][C:23]3[CH:22]=[CH:21][C:33]4[NH:32][C:31]5[C:26]([C:25]=4[CH:24]=3)=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:11]2)=[CH:4][CH:3]=[N:2]1

Participants

11

Reactant 6

HCID 176Acetic AcidHCID 81531DiisopropylethylamineHCID 504067Carbazole-3-carboxaldehydeHCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 211931144-(1H-Pyrazol-5-yl)piperidine

Product 1

HCID 679962863-((3-(1H-pyrazol-5-yl)piperidin-1-yl)methyl)-9H-carbazoleYield 9.4%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A 50-mL 3-necked round-bottomed flask was charged with a solution of 4-(1H-pyrazol-5-yl)piperidine (412 mg, 1.83 mmol, 1.50 equiv, 99%) in EtOH (10 mL). To this was added N-ethyl-N-isopropylpropan-2-amine (639 mg, 4.90 mmol, 4.00 equiv, 99%). After stirring for 30 minutes, 9H-carbazole-3-carbaldehyde (240 mg, 1.22 mmol, 1.00 equiv, 99%) was added followed by acetic acid (221 mg, 3.65 mmol, 3.00 equiv, 99%). The mixture was allowed to stir for 30 minutes at room temperature. To the mixture was then added NaBH3CN (156 mg, 2.45 mmol, 2.00 equiv, 99%). The resulting mixture was stirred for 16 hours at 40° C. in an oil bath. The reaction progress was monitored by TLC (DCM:MeOH=5:1). Upon completion, the mixture was diluted with H2O (20 mL) and, pH was adjusted to 8 with NaHCO3 (1 M). Then, the resulting solution was extracted with ethyl acetate (5×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a residue that was purified with silica gel column chromatography eluted with dichloromethane/methanol (20:1) affording 3-((3-(1H-pyrazol-5-yl)piperidin-1-yl)methyl)-9H-carbazole as white solid (38 mg, 9%). LCMS: [M+H]+: 331. 1H NMR (DMSO-d6, 300 MHz) δ 12.42 (s, 1H), 11.20 (s, 1H), 8.11-8.09 (d, 1H), 8.00 (s, 1H), 7.48-7.33 (m, 4H), 7.11-7.16 (m, 1H), 6.03 (s, 1H), 3.64 (s, 2H), 3.01-2.98 (d, 1H), 2.86-2.82 (s, 2H), 2.09-1.90 (m, 3H), 1.67-1.57 (m, 2H), 1.41-1.37 (m, 1H).

Workup

  1. stirringto stir for 30 minutes at room temperature
  2. stirringThe resulting mixture was stirred for 16 hours at 40° C. in an oil bath
  3. extractionThen, the resulting solution was extracted with ethyl acetate (5×20 mL)
  4. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  5. concentrationconcentrated
  6. customto give a residue that
  7. customwas purified with silica gel column chromatography
  8. washeluted with dichloromethane/methanol (20:1)

Sources & evidence

ORD record
ord-bf1a92f7037d43b39a79db4de9d903f1
Source dataset
uspto-grants-2011_12
Patent number
US08080566B1

Reaction notes

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