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

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.

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

References

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16a

Spectral Data for 1-Oxo-6-chloro-1,2,3,4-tetrahydrocarbazole ( 4e): mp 218 °C (lit. [22] mp 220 °C). IR (KBr): 3269.91, 3065.63, 2944.19, 2867.84, 1652.68, 1539.99, 1481.58, 810.98, 734.34 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.27-2.32 (m, 2 H, CH₂), 2.67 (t, J = 6.0 Hz, 2 H, CH₂), 2.98 (t, J = 5.6 Hz, 2 H, CH₂), 7.32-7.38 (m, 2 H, ArH), 7.65 (s, 1 H, ArH), 8.97 (s, 1 H, NH). MS (EI):
m/z = 221 [M + 2], 219 [M⁺]. Anal. Calcd for C₁₂H₁₀ClNO: C, 65.61; H, 4.59; N, 6.38. Found: C, 65.49; H, 4.51; N, 6.25.

16b

Spectral Data for 3,8-Dichloroindolo[2,3- a ]carbazole ( 1e): mp >300 °C (lit. [1] mp >300 °C). IR (KBr): 3404.88, 3078.94, 1570.63, 1492.32, 875.91, 811.22 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.25 (s, 2 H, NH), 8.24 (d, J = 1.6 Hz, 2 H, H-4, H-7), 7.95 (s, 2 H, H-5, H-6), 7.70 (d, J = 8.4 Hz, 2 H, H-1, H-10), 7.37 (dd, J = 8.4, 2.0 Hz, 2 H, H-2, H-9). MS (EI): m/z = 327 [M + 2], 325 [M⁺]. Anal. Calcd for C₁₈H₁₀Cl₂N₂: C, 66.48; H, 3.10; N, 8.61. Found: C, 66.35; H, 3.07; N, 8.42.

17 Hughes DL. Org. Prep. Proced. Int.  1993,  25:  607 

18

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.

19

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.

20 Murakami Y. Watanabe T. Yokoyama Y. Naomachi J. Iwase H. Watanabe N. Morihata M. Okuyama N. Kamakura H. Takahashi T. Atoda H. Tojo T. Morita K. Ishii H. Chem. Pharm. Bull.  1993,  41:  1910 

21

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).

22 Gazengel JM. Lancelot JC. Rault S. Robba M. J. Heterocycl. Chem.  1990,  27:  1947