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

<A NAME="RU25804ST-1">1</A> Bonjouklian R. Smitka TA. Doolin LE. Molloy RM. Debono M. Shaffer SA. Moore RE. Stewart JB. Patterson GML. Tetrahedron  1991,  47:  7739 

<A NAME="RU25804ST-2A">2a</A> Nettleton DE. Doyle TW. Krishnan B. Matsumoto GK. Clardy J. Tetrahedron Lett.  1985,  26:  4011 

<A NAME="RU25804ST-2B">2b</A> Bush JA. Long BH. Catino JJ. Bradner WT. Tomita K. J. Antibiot.  1987,  40:  668 

<A NAME="RU25804ST-3A">3a</A> Tamaoki T. Nomoto H. Takahishi I. Kato Y. Morimoto M. Tomita F. Biochem. Biophys. Res. Commun.  1986,  135:  397 

<A NAME="RU25804ST-3B">3b</A> Funato N. Takayanagi H. Konda Y. Toda Y. Harigaya Y. Iwai Y. Omura S. Tetrahedron Lett.  1994,  35:  1251 

<A NAME="RU25804ST-3C">3c</A> Oka S. Kodama M. Takada H. Tomizuka N. Suzuki H. Agric G. Biol. Chem.  1986,  50:  2723 

<A NAME="RU25804ST-4">4</A> Moody CJ. Rahimtoola KF. J. Org. Chem.  1992,  57:  2105 

<A NAME="RU25804ST-5A">5a</A> Omura S, Iwai Y, and Hirano A. inventors; Japan Kokai  7,873,501.  ; Chem. Abstr. 1978, 89, 178086b

<A NAME="RU25804ST-5B">5b</A> Omura S, Iwai Y, and Hirano A. inventors; Ger. Offen.,  2,745,326.  ; Chem. Abstr. 1978, 89, 58348y

<A NAME="RU25804ST-6">6</A> Omura S. Iwai Y. Hirano A. Nakagawa A. Awaya J. Tsuchiya H. Takahashi Y. Masuma R. J. Antibiot.  1977,  30:  275 

<A NAME="RU25804ST-7A">7a</A> Link JT. Danishefsky SJ. Tetrahedron Lett.  1994,  35:  9135 

<A NAME="RU25804ST-7B">7b</A> Wood JL. Petsch DT. Stoltz BM. Hawkins EM. Elbaum D. Stover DR. Synthesis  1999,  1529 

<A NAME="RU25804ST-8">8</A> Gribble GW. Berthel SJ. Stud. Nat. Prod. Chem.  1993,  12:  365 

<A NAME="RU25804ST-9">9</A> Akinaga S. Sugiyama K. Akiyama T. Anti-Cancer Drug Des.  2000,  15:  43 

<A NAME="RU25804ST-10">10</A> Brunton RJ. Drayson FK. Plant SGP. Tomlinson ML. J. Chem. Soc.  1956,  4783 

<A NAME="RU25804ST-11A">11a</A> Bhide GV. Tikotkar NL. Tilak BD. Chem. Ind. (London)  1957,  363 

<A NAME="RU25804ST-11B">11b</A> Mann FG. Willcox TJ. J. Chem. Soc.  1958,  1525 

<A NAME="RU25804ST-11C">11c</A> Royer H. Joseph D. Prim D. Kirsch G. Synth. Commun.  1998,  28:  1239 

<A NAME="RU25804ST-12">12</A> Pindur U. Kim Y.-S. J. Heterocycl. Chem.  1996,  33:  623 

<A NAME="RU25804ST-13A">13a</A> Beccalli EM. Marchesini A. Pilati T. Tetrahedron  1993,  49:  4741 

<A NAME="RU25804ST-13B">13b</A> Beccalli EM. Gelmi ML. Marchesini A. Tetrahedron  1998,  54:  6909 

<A NAME="RU25804ST-14">14</A> Merlic CA. McInnes DM. Tetrahedron Lett.  1997,  38:  7661 

<A NAME="RU25804ST-15">15</A> Somei M. Kodama A. Heterocycles  1992,  34:  1285 

<A NAME="RU25804ST-16A">16a</A>

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.

<A NAME="RU25804ST-16B">16b</A>

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.

<A NAME="RU25804ST-17">17</A> Hughes DL. Org. Prep. Proced. Int.  1993,  25:  607 

<A NAME="RU25804ST-18">18</A>

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.

<A NAME="RU25804ST-19">19</A>

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.

<A NAME="RU25804ST-20">20</A> 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 

<A NAME="RU25804ST-21">21</A>

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).

<A NAME="RU25804ST-22">22</A> Gazengel JM. Lancelot JC. Rault S. Robba M. J. Heterocycl. Chem.  1990,  27:  1947