Subscribe to RSS
DOI: 10.1055/s-2004-835667
An Efficient and General Synthesis of Indolo[2,3-a]carbazoles Using the Fischer Indole Synthesis
Publication History
Publication Date:
29 November 2004 (online)
![](https://www.thieme-connect.de/media/synlett/200501/lookinside/thumbnails/10.1055-s-2004-835667-1.jpg)
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
- 1
Bonjouklian R.Smitka TA.Doolin LE.Molloy RM.Debono M.Shaffer SA.Moore RE.Stewart JB.Patterson GML. Tetrahedron 1991, 47: 7739 -
2a
Nettleton DE.Doyle TW.Krishnan B.Matsumoto GK.Clardy J. Tetrahedron Lett. 1985, 26: 4011 -
2b
Bush JA.Long BH.Catino JJ.Bradner WT.Tomita K. J. Antibiot. 1987, 40: 668 -
3a
Tamaoki T.Nomoto H.Takahishi I.Kato Y.Morimoto M.Tomita F. Biochem. Biophys. Res. Commun. 1986, 135: 397 -
3b
Funato N.Takayanagi H.Konda Y.Toda Y.Harigaya Y.Iwai Y.Omura S. Tetrahedron Lett. 1994, 35: 1251 -
3c
Oka S.Kodama M.Takada H.Tomizuka N.Suzuki H.Agric G. Biol. Chem. 1986, 50: 2723 - 4
Moody CJ.Rahimtoola KF. J. Org. Chem. 1992, 57: 2105 -
5a
Omura S,Iwai Y, andHirano A. inventors; Japan Kokai 7,873,501. ; Chem. Abstr. 1978, 89, 178086b -
5b
Omura S,Iwai Y, andHirano 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 -
7a
Link JT.Danishefsky SJ. Tetrahedron Lett. 1994, 35: 9135 -
7b
Wood JL.Petsch DT.Stoltz BM.Hawkins EM.Elbaum D.Stover DR. Synthesis 1999, 1529 - 8
Gribble GW.Berthel SJ. Stud. Nat. Prod. Chem. 1993, 12: 365 - 9
Akinaga S.Sugiyama K.Akiyama T. Anti-Cancer Drug Des. 2000, 15: 43 - 10
Brunton RJ.Drayson FK.Plant SGP.Tomlinson ML. J. Chem. Soc. 1956, 4783 -
11a
Bhide GV.Tikotkar NL.Tilak BD. Chem. Ind. (London) 1957, 363 -
11b
Mann FG.Willcox TJ. J. Chem. Soc. 1958, 1525 -
11c
Royer H.Joseph D.Prim D.Kirsch G. Synth. Commun. 1998, 28: 1239 - 12
Pindur U.Kim Y.-S. J. Heterocycl. Chem. 1996, 33: 623 -
13a
Beccalli EM.Marchesini A.Pilati T. Tetrahedron 1993, 49: 4741 -
13b
Beccalli EM.Gelmi ML.Marchesini A. Tetrahedron 1998, 54: 6909 - 14
Merlic CA.McInnes DM. Tetrahedron Lett. 1997, 38: 7661 - 15
Somei M.Kodama A. Heterocycles 1992, 34: 1285 -
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 - 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 - 22
Gazengel JM.Lancelot JC.Rault S.Robba M. J. Heterocycl. Chem. 1990, 27: 1947
References
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.
19All 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.
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).