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Synlett 2005(1): 42-48  
DOI: 10.1055/s-2004-835667
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Efficient and General Synthesis of Indolo[2,3-a]carbazoles Using the Fischer Indole Synthesis

Yong-Zhou Hu*, You-Qin Chen
Zhejiang University, Department of Medicinal Chemistry, School of Pharmaceutical Science, Hangzhou 310031, P. R. China
Fax: +86(571)87217412; e-Mail: huyz@zjuem.zju.edu.cn;
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Publication History

Received 11 September 2004
Publication Date:
29 November 2004 (online)

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Abstract

Synthetically important indolo[2,3-a]carbazoles were obtained in a one-pot reaction via Fischer indole synthesis starting from 2-amino-cyclohexanone hydrochloride and substituted arylhydrazines hydrochloride in the presence of acidic media.

Key words

Fischer indole synthesis - indolo[2,3-a]carbazole alkaloids - 2-amino-cyclohexanone - arylhydrazine - heterocycle

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General Procedure for Indolo[2,3- a ]carbazoles (1a-i, 1m-p): The 2-amino-cyclohexanone hydrochloride 2 (0.334 mmol) and substituted arylhydrazine hydrochloride 3 (4 equiv) were dissolved in 1.5 mL 95% HOAc and 0.5 mL TFA. The mixture was heated to 100 °C until TLC analysis showed complete consumption of the intermediate 1-oxo-1,2,3,4-tetrahydrocarbazoles 4. The mixture was cooled to r.t., H2O was added and the solid was collected by filtration. The crude products were purified by chromatography on silica gel using petroleum ether-EtOAc (5:1) as eluant. The yields in Table [2] represent the average of two or more runs.

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All new compounds gave satisfactory analytical and spectral data. Data for selected compounds are as follows:
Compound 1o (Table [2] , entry 15): mp >300 °C. IR (KBr): 3357.15, 3300.33, 3054.31, 1695.67, 1599.14, 1488.63, 740.66 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 11.24 (s, 1 H, NH), 11.04 (s, 1 H, NH), 8.14 (d, J = 7.6 Hz, 1 H, Ar-H), 7.73 (s, 1 H, Ar-H), 7.66 (t, J = 7.6 Hz, 2 H, Ar-H), 7.62 (d, J = 7.6 Hz, 2 H, Ar-H), 7.54 (t, J = 7.6 Hz, 2 H, Ar-H), 7.47 (t, J = 7.2 Hz, 1 H, Ar-H), 7.37 (t, J = 7.6 Hz, 1 H, Ar-H), 7.28-7.32 (m, 2 H, Ar-H), 7.16 (t, J = 7.6 Hz, 1 H, Ar-H), 6.90 (t, J = 7.6 Hz, 1 H, Ar-H). MS (EI): m/z = 332 [M+]. Anal. Calcd for C24H16N2: C, 86.72; H, 4.85; N, 8.43. Found: C, 86.61; H, 4.78; N, 8.35.
Compound 1p (Table [2] , entry 16): mp >300 °C. IR (KBr): 3419.72, 3355.40, 1703.65, 1567.85, 1455.51, 806.60, 704.63 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 11.53 (s, 1 H, NH), 11.32 (s, 1 H, NH), 8.31 (s, 1 H, Ar-H), 7.85 (s, 1 H, Ar-H), 7.74-7.78 (m, 2 H, Ar-H), 7.60-7.66 (m, 4 H, Ar-H), 7.54 (t, J = 6.4 Hz, 7.2 Hz, 1 H, Ar-H), 7.42 (d, J = 8.4 Hz, 1 H, Ar-H), 7.35 (d, J = 8.4 Hz, 1 H, Ar-H), 7.23 (s, 1 H, Ar-H). MS (EI): m/z = 403 [M + 2], 401 [M+]. Anal. Calcd for C24H14Cl2N2: C, 71.83; H, 3.52; N, 6.98. Found: C, 71.69; H, 3.45; N, 6.83.

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General Procedure for the Synthesis of Compounds (1j-l): The 2-amino-cyclohexanone hydrochloride 2a (50 mg, 0.334 mmol) was added to a solution of ortho-halophenyl-hydrazines hydrochloride 3j-l (4 equiv) in n-propyl alcohol (2 mL) at r.t., then the reaction mixture was refluxed for 3 h. The solvent was removed in vacuo, glacial HOAc (3 mL) was added to the residue, and the mixture was refluxed for 12 h. The mixture was cooled to r.t., H2O was added and the solid was collected by filtration. The crude products were purified by chromatography on silica gel using petroleum ether-EtOAc (15:1) as eluant. The results are depicted in Table [2] (entries 10-12).