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

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Reaction Steps

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).

Provenance & Evidence