Download PDF
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;
Further Information

Publication History

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

    Permissions and Reprints All articles of this category

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

    References

  • 1 Bonjouklian R. Smitka TA. Doolin LE. Molloy RM. Debono M. Shaffer SA. Moore RE. Stewart JB. Patterson GML. Tetrahedron  1991,  47:  7739 
    CrossrefGoogle Scholar
  • 2a Nettleton DE. Doyle TW. Krishnan B. Matsumoto GK. Clardy J. Tetrahedron Lett.  1985,  26:  4011 
    Google Scholar
  • 2b Bush JA. Long BH. Catino JJ. Bradner WT. Tomita K. J. Antibiot.  1987,  40:  668 
    Google Scholar
  • 3a Tamaoki T. Nomoto H. Takahishi I. Kato Y. Morimoto M. Tomita F. Biochem. Biophys. Res. Commun.  1986,  135:  397 
    Google Scholar
  • 3b Funato N. Takayanagi H. Konda Y. Toda Y. Harigaya Y. Iwai Y. Omura S. Tetrahedron Lett.  1994,  35:  1251 
    Google Scholar
  • 3c Oka S. Kodama M. Takada H. Tomizuka N. Suzuki H. Agric G. Biol. Chem.  1986,  50:  2723 
    Google Scholar
  • 4 Moody CJ. Rahimtoola KF. J. Org. Chem.  1992,  57:  2105 
    CrossrefGoogle Scholar
  • 5a Omura S, Iwai Y, and Hirano A. inventors; Japan Kokai  7,873,501.  ; Chem. Abstr. 1978, 89, 178086b
  • 5b Omura S, Iwai Y, and Hirano A. inventors; Ger. Offen.,  2,745,326.  ; Chem. Abstr. 1978, 89, 58348y
  • 6 Omura S. Iwai Y. Hirano A. Nakagawa A. Awaya J. Tsuchiya H. Takahashi Y. Masuma R. J. Antibiot.  1977,  30:  275 
    Google Scholar
  • 7a Link JT. Danishefsky SJ. Tetrahedron Lett.  1994,  35:  9135 
    Article in Thieme ConnectGoogle Scholar
  • 7b Wood JL. Petsch DT. Stoltz BM. Hawkins EM. Elbaum D. Stover DR. Synthesis  1999,  1529 
    Article in Thieme ConnectGoogle Scholar
  • 8 Gribble GW. Berthel SJ. Stud. Nat. Prod. Chem.  1993,  12:  365 
    Google Scholar
  • 9 Akinaga S. Sugiyama K. Akiyama T. Anti-Cancer Drug Des.  2000,  15:  43 
    Google Scholar
  • 10 Brunton RJ. Drayson FK. Plant SGP. Tomlinson ML. J. Chem. Soc.  1956,  4783 
    Google Scholar
  • 11a Bhide GV. Tikotkar NL. Tilak BD. Chem. Ind. (London)  1957,  363 
    CrossrefGoogle Scholar
  • 11b Mann FG. Willcox TJ. J. Chem. Soc.  1958,  1525 
    CrossrefGoogle Scholar
  • 11c Royer H. Joseph D. Prim D. Kirsch G. Synth. Commun.  1998,  28:  1239 
    CrossrefGoogle Scholar
  • 12 Pindur U. Kim Y.-S. J. Heterocycl. Chem.  1996,  33:  623 
    Google Scholar
  • 13a Beccalli EM. Marchesini A. Pilati T. Tetrahedron  1993,  49:  4741 
    CrossrefGoogle Scholar
  • 13b Beccalli EM. Gelmi ML. Marchesini A. Tetrahedron  1998,  54:  6909 
    CrossrefGoogle Scholar
  • 14 Merlic CA. McInnes DM. Tetrahedron Lett.  1997,  38:  7661 
    CrossrefGoogle Scholar
  • 15 Somei M. Kodama A. Heterocycles  1992,  34:  1285 
    Google Scholar
  • 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 
    CrossrefGoogle Scholar
  • 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 
    Google Scholar
  • 22 Gazengel JM. Lancelot JC. Rault S. Robba M. J. Heterocycl. Chem.  1990,  27:  1947 
    CrossrefGoogle Scholar
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.

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).