Potassium hydride → N-(6-Cyano-9-thiazol-5-ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide

HRID 545540Notes

Reaction equation

HRID 545540 reaction equation
[H-].[K+].[Cl-].C(C[P+](C)(C)C)#[N:5].[S:11]1[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[CH:12]1.[C:18]([C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]1[CH2:27][CH2:26][CH:25]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH2:24][C:23]2=1)#[N:19]>C1COCC1.O>[NH3:5].[CH3:16][OH:17].[C:18]([C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:16][C:15]1[S:11][CH:12]=[N:13][CH:14]=1)[C:28]1[CH2:27][CH2:26][CH:25]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH2:24][C:23]2=1)#[N:19]

Participants

8

Reactant 4

HCID 82127Potassium hydrideHCID 27632165-ThiazolylmethanolHCID 57431662N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramideHCID 57431663(Cyanomethyl)trimethylphosphonium chloride

Product 2

HCID 21705897Ammonia methanolHCID 59161201N-(6-Cyano-9-thiazol-5-ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramideYield 42%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Add potassium hydride (30% w/w in mineral oil, 129 mg, 0.97 mmol) to a slurry of cyanomethyl-trimethyl-phosphonium chloride (prepare according to the procedure essentially as described in Tsunoda, T.; et al., Tetrahedron Lett. (1996) 37, 2459-2462) (166 mg, 1.10 mmol) at 0° C. under nitrogen. Allow the reaction mixture to warm to room temperature and stir for 3 h. Add a solution of thiazol-5-ylmethanol (100 mg, 0.87 mmol) in THF (2 mL), then add N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 5) (122 mg, 0.44 mmol) and heat at 70° C. for 18 h. Cool to room temperature and dilute with water (40 mL). Extract into EtOAc (3×50 mL) and dry the organic portion (MgSO4). Filter and concentrate to afford the crude product, (340 mg) as a yellow oil. Purify on silica gel (24 g) using 5% (2M NH3/MeOH)/CH2Cl2, and then re-purify on silica gel (40 g) using 80:18:2 EtOAc:hexanes:(2M NH3/MeOH) to afford 70 mg (42%) of the title compound as an orange solid. MS (ES): m/z 379 (M+1), 377 (M−1); 1H-NMR (CDCl3): δ 8.78 (s, 1H), 7.83 (d, 1H, J=1.3 Hz), 7.74 (s, 1H), 7.47 (dd, 1H, J=8.6, 1.5 Hz), 7.38 (d, 1H, J=8.4 Hz), 5.53 (d, 1H, J=7.9 Hz), 5.50 (s, 2H), 4.42 (m, 1H), 3.16 (dd, 1H, J=15.4, 5.3 Hz), 2.97-2.80 (m, 2H), 2.62 (dd, 1H, J=15.4, 7.5 Hz), 2.37 (m, 1H), 2.21 (m, 1H), 2.05 (m, 1H), 1.20 (dd, 6H, J=7.0, 1.8 Hz).

Workup

  1. customprepare
  2. customat 0° C.
  3. temperatureCool to room temperature
  4. extractionExtract into EtOAc (3×50 mL)
  5. dry with materialdry the organic portion (MgSO4)
  6. filtrationFilter
  7. concentrationconcentrate
  8. customto afford the crude product, (340 mg) as a yellow oil
  9. customPurify on silica gel (24 g)
  10. customre-purify on silica gel (40 g)

Sources & evidence

ORD record
ord-2c489fb7eb764e01a54af43a691b6a57
Source dataset
uspto-grants-2011_05
Patent number
US07935722B2

Reaction notes

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