Novel method for the synthesis of 6,12-dihydro-2-methylindolo[2,3- b]carbazol-6-ones

Article abstract of DOI:10.1080/00397910801989535

A novel method for the synthesis of 6,12-dihydro-2-methylindolo[2,3-b] carbazol-6-ones was developed from 1-oxo-2,3,4,9-tetrahydro-1H-carbazol-1-one through methyl 6-methyl-2-(1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)oxoacetate in good yields. This metho

Full text of DOI:10.1080/00397910801989535

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Novel Method for the Synthesis of
6,12‐Dihydro‐2‐Methylindolo[2,3‐
b]Carbazol‐6‐Ones
A. Ebenezer Martin a & K. J. Rajendra Prasad a
a Department of Chemistry, Bharathiar University, Coimbatore, India
Published online: 09 May 2008.
To cite this article: A. Ebenezer Martin & K. J. Rajendra Prasad (2008): Novel Method for the Synthesis of
6,12‐Dihydro‐2‐Methylindolo[2,3‐ b]Carbazol‐6‐Ones, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:11, 1778-1783
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Synthetic Communicationsw, 38: 1778–1783, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801989535
Novel Method for the Synthesis of
6,12-Dihydro-2-Methylindolo[2,3-
b]Carbazol-6-Ones
A. Ebenezer Martin and K. J. Rajendra Prasad
Department of Chemistry, Bharathiar University, Coimbatore, India
Abstract: A novel method for the synthesis of 6,12-dihydro-2-methylindolo[2,3-
b]carbazol-6-ones was developed from 1-oxo-2,3,4,9-tetrahydro-1H-carbazol-1-one
through methyl 6-methyl-2-(1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)oxoacetate in
good yields. This method provides an alternative path for the synthesis of this
product using 2-hydroxy methylene-2,3,4,9-tetrahydro-1H-carbazol-1-one.
Keywords: 6,12-Dihydro-2-methylindolo[2,3-b]carbazol-6-ones, Fischer indole cycli-
zation, methyl 6-methyl-2-(1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)oxoacetate,
1-oxo-2,3,4,9-tetrahydro-1H-carbazol-1-one
The indolocarbazole alkaloids, rebeccamycin and staurosporine, display a
range of biological activities that make them attractive targets to synthetic
and medicinal chemists.[1–3] It was recently reported that indolo[2,3-
b]carbazole-6,12-dione, the isomeric indolo[3,2-b]carbazole-6,12-dione, and
the indolocarbazoles of type 6-formyl- and 6,12-diformyl-indolo[3,2-
b]carbazole[4,5] are extremely efficient inducers of the aryl hydrocarbon
(Ah) receptor ligands.[6] The monoformylated 6-formylindolo[3,2-
b]carbazole in particular displays an affinity for the Ah receptor in
picometer concentration, thus being more potent than the highly toxic environ-
mental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a normal Ah
receptor. In addition, recent findings show that 6-formylindolo[3,2-
Address correspondence to K. J. Rajendra Prasad, Department of Chemistry, Bhar-
athiar University, Coimbatore 641046, India. E-mail: prasad_125@yahoo.com
1778

Synthesis of 6,12-Dihydro-2- Methylindolo[2,3-b]Carbazol-6-Ones
1779
b]carbazole acts as an anticarcinogen on benzo[a]pyrene-induced mutagenesis
both in vitro and in vivo.[7,8]
We became interested in the synthesis of 6,12-dihydro-2-methylin-
dolo[2,3-b]carbazol-6-one (3), a linearly fused monoketo-indolocarbazole,
in anticipation that it might play a significant role in pharmaceutical
chemistry. We had earlier reported the synthesis of 6,12-dihydro-2-methylin-
dolo[2,3-b]carbazol-6-one (3) from 2,3,4,9-tetrahydro-1H-carbazol-1-one
via 2-hydroxymethylene-2,3,4,9-tetrahydro-1H-carbazol-1-one.[9] However,
the yield of the intermediate 2-hydroxymethylene-2,3,4,9-tetrahydro-1H-
carbazol-1-one is reduced by the concurrent formation of the side product,
1-hydroxycarbazole-2-carbaldehyde. Therefore, the overall yield of 12-
dihydro-2-methylindolo[2,3-b]carbazol-6-one (3) is low (25%). Herein we
report an efficient alternative method to obtain 3. Treatment of methyl
6-methyl-2-(1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)oxoacetate (1a)[10] with
diazotized p-toluidine in the presence of sodium acetate afforded 2a as a
red-colored solid. The conversion of 6,40-dimethyl-2-phenylhydrazono-2,3,4,9-
tetrahydro-1H-carbazol-1-one (2a) into 6,12-dihydro-2,10-dimethylindolo[2,3-
b]carbazol-6-one (3a) was effected via a Fischer-indole cyclization using
Kent’s reagent (con. HCl–gla. AcOH 1:4) as cyclizing agent. A series of
similar compounds 3b–d were obtained from respective 2b–d (Scheme 1).
In conclusion, this method provided an alternative path for the synthesis
of a possible Ah receptor, 6,12-dihydro-2-methylindolo[2,3-b]carbazol-6-one
(3), in excellent yields.
GENERAL PROCEDURE FOR THE SYNTHESIS OF 40-
METHYL-2-PHENYL HYDRAZONO-2,3,4,9-TETRAHYDRO-
1H-CARBAZOL-1-ONES (2a–d)
A diazotized p-toluidine suspension from treatment of a solution of
p-toluidine in aqueous hydrochloric acid (1.8 mL of hydrochloric acid in
Scheme 1. R1 ¼ CH3, R2 ¼ R3 ¼ H; b) R2 ¼ CH3, R1 ¼ R3 ¼ H; c) R3 ¼ CH3,
R1 ¼ R2 ¼ H; and d) R1 ¼ R2 ¼ R3 ¼ H.

1780
A. E. Martin and K. J. R. Prasad
2.12 mL of water) with cold saturated sodium nitrite (0.35 g in 0.8 mL of
water) at 0 to 58C was then added dropwise over 30 min to the ice-cold
mixture of methyl 2-(1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)oxoacetate
(8, 1 mmol) and sodium acetate trihydrate (1 g) in methanol (6 mL) with
constant stirring and kept at 0 to 58C for another 30 min. The solid thus
formed was collected, washed with water, dried and crystallized from
ethanol.
DATA
6,40-Dimethyl-2-phenylhydrazono-2,3,4,9-tetrahydro-1H-carbazol-
1-one (2a)
Red solid mass of 236 mg (75%); mp 158–160 8C (lit.[9] 155 8C). Anal. calcd.
for C20H19N3O: C, 75.69; H, 6.03; N, 13.24. Found: C, 75.69; H, 6.09; N,
1
13.19%. IR (nmax, KBr): 3271, 2922, 1649, 1598, 1481 cm21; H NMR (d,
400 MHz, DMSO-d6): 13.39 (s, 1H, C1-OH), 11.57 (b s, 1H, hydrazono
0
0
0
NH), 9.97 (b s, 1H, N9-H), 7.92–7.01 (m, 7H, C5-, C7-, C8-, C2 -, C3 -, C5 -,
0
C6 -H), 3.16–3.01 (m, 4H, C3-, C4-H2), 2.40 (s, 3H, C6-CH3), 2.26 (s, 3H,
0
C4 -CH3); mass m/z (%): 317 (43).
7,40-Dimethyl-2-phenylhydrazono-2,3,4,9-tetrahydro-1H-carbazol-
1-one (2b)
Red solid mass of 228 mg (72%); mp 134–1368C (lit.[9] 135 8C). Anal. calcd.
for C20H19N3O: C, 75.69; H, 6.03; N, 13.24. Found: C, 75.66; H, 6.04; N,
1
13.26%. IR (nmax, KBr): 3278, 2922, 1647, 1606, 1467 cm21; H NMR (d,
400 MHz, DMSO-d6): 13.37 (s, 1H, C1-OH), 11.53 (b s, 1H, hydrazono
0
0
0
NH), 9.95 (b s, 1H, N9-H), 7.60–7.00 (m, 7H, C5-, C6-, C8-, C2 -, C3 -, C5 -,
0
C6 -H), 3.14–3.11 (m, 4H, C3-, C4-H2), 2.65 (s, 3H, C7-CH3), 2.31 (s, 3H,
0
C4 -CH3); mass m/z (%): 317 (38).
8,40-Dimethyl-2-phenylhydrazono-2,3,4,9-tetrahydro-1H-carbazol-
1-one (2c)
Red solid mass of 238 mg (75%); mp 154–1568C (lit.[9] 150 8C). Anal. calcd.
for C20H19N3O: C, 75.69; H, 6.03; N, 13.24. Found: C, 75.70; H, 6.01; N,
1
13.29%. IR (nmax, KBr): 3278, 2923, 1654, 1614, 1465 cm21; H NMR (d,
400 MHz, DMSO-d6): 13.47 (s, 1H, C1-OH), 11.84 (b s, 1H, hydrazono
0
0
0
NH), 9.99 (b s, 1H, N9-H), 7.93–7.10 (m, 7H, C5-, C6-, C7-, C2 -, C3 -, C5 -,
0
C6 -H), 3.13–3.00 (m, 4H, C3-, C4-H2), 2.59 (s, 3H, C8-CH3), 2.31 (s, 3H,
0
C4 -CH3); mass m/z (%): 317 (35).

Synthesis of 6,12-Dihydro-2- Methylindolo[2,3-b]Carbazol-6-Ones
1781
40-Methyl-2-phenylhydrazono-2,3,4,9-tetrahydro-1H-carbazol-1-
one (2d)
Orange solid mass of 228 mg (75%); mp 139–141 8C (lit.[9] 142 8C). Anal.
calcd. for C19H17N3O: C, 75.22; H, 5.64; N, 13.85. Found: C, 75.30; H,
1
5.60; N, 13.81%. IR (nmax, KBr): 3282, 2927, 1645, 1601, 1450 cm-1; H
NMR (d, 400 MHz, DMSO-d6): 13.54 (s, 1H, C1-OH), 11.57 (b s, 1H,
hydrazono NH), 9.28 (b s, 1H, N9-H), 7.67–7.12 (m, 8H, C5-, C6-, C7-, C8-,
0
0
0
0
0
C2 -, C3 -, C5 -, C6 -H), 3.07–2.69 (m, 4H, C3-, C4-H2), 2.32 (s, 3H,
C4 -CH3); mass m/z (%): 303 (27).
GENERAL PROCEDURE FOR THE SYNTHESIS OF 6,12-
DIHYDRO-2-METHYLINDOLO[2,3-B]CARBAZOL-6-ONE (3a–d)
The appropriate 40-methyl-2-phenylhydrazono-2,3,4,9-tetrahydro-1H-carbazol-
1-one (2, 1 mmol) and a mixture of acetic acid (20 mL) and hydrochloric
acid (5 mL) were refluxed for 2 h at 120 8C. The contents were then cooled
to room temperature and poured into ice water and stirred for a few minutes.
The separated brown residue was collected, dissolved in a minimum amount
of warm ethyl acetate, and purified by adsorption on silica gel and passing
through a column of silica gel using petroleum ether/ethyl acetate mixture
(95:5) as an eluant to get pure 6,12-dihydro-2-methylindolo[2,3-b]carbazol-6-
one (3a–d).
DATA
6,12-Dihydro-2,10-dimethylindolo[2,3-b]carbazol-6-one (3a)
Pale white powder of 195 mg (65%); mp 182–184 8C (lit.[9] 175 8C). Anal.
calcd. for C20H16N2O: C, 79.98; H, 5.37; N, 9.33. Found: C, 79.89; H, 5.27;
1
N, 9.34%. IR (nmax, KBr): 3273, 2920, 1643, 1537, 1479 cm21; H NMR
(d, 400 MHz, DMSO-d6): 11.44 (b s, 2H, N5-, N7-H), 7.69–6.70 (m, 6H,
C1-, C3-, C4-, C8-, C9-, C11-H), 2.99 (s, 2H, C12-H2), 2.41 (s, 6H, C10-, C2-
CH3); mass m/z (%): 300 (75).
6,12-Dihydro-2,9-dimethylindolo[2,3-b]carbazol-6-one (3b)
Pale white powder of 185 mg (62%); mp 201–203 8C (lit.[9] 200 8C). Anal.
calcd. for C20H16N2O: C, 79.98; H, 5.37; N, 9.33. Found: C, 79.91; H, 5.30;
1
N, 9.31%. IR (nmax, KBr): 3213, 2927, 1616, 1508, 1460 cm21; H NMR
(d, 400 MHz, DMSO-d6): 11.56 (b s, 1H, N7-H), 11.50 (b s, 1H, N5-H),

1782
A. E. Martin and K. J. R. Prasad
7.77–6.60 (m, 6H, C1-, C3-, C4-, C8-, C10-, C11-H), 2.87 (s, 2H, C12-H2), 2.60
(s, 3H, C2-CH3), 2.35 (s, 3H, C9-CH3); mass m/z (%): 300 (63).
6,12-Dihydro-2,8-dimethylindolo[2,3-b]carbazol-6-one (3c)
Pale white powder of 185 mg (62%); mp 180–182 8C (lit.[9] 180 8C). Anal.
calcd. for C20H16N2O: C, 79.98; H, 5.37; N, 9.33. Found: C, 80.07; H, 5.27;
1
N, 9.25%. IR (nmax, KBr): 3413, 2927, 1652, 1508, 1460 cm21; H NMR
(d, 400 MHz, DMSO-d6): 11.50 (b s, 1H, N7-H), 11.43 (b s, 1H, N5-H),
8.20- 7.10 (m, 6H, C1-, C3-, C4-, C9-, C10-, C11-H), 3.23 (s, 2H, C12-H2),
2.66 (s, 4H, C2-CH3), 2.41 (s, 3H, C8-CH3); mass m/z (%): 300 (70).
6,12-Dihydro-2-methylindolo[2,3-b]carbazol-6-one (3d)
Pale white powder of 185 mg (65%); mp 208–210 8C (lit.[9] 210 8C). Anal.
calcd. for C19H14N2O: C, 79.70; H, 4.93; N, 9.78. Found: C, 79.79; H, 4.98;
1
N, 9.70%. IR (nmax, KBr): 3450, 2932, 1620, 1460, 1390 cm21; H NMR
(d, 400 MHz, DMSO-d6): 11.54 (b s, 1H, N7-H), 11.41 (b s, 1H, N5-H),
8.20–7.10 (m, 7H, C1-, C3-, C4-, C8-, C9-, C10-, C11-H), 2.91 (s, 2H, C12-
H2), 2.66 (s, 4H, C2-CH3); mass m/z (%): 286 (54).
ACKNOWLEDGMENT
The authors are grateful to IISc, Bangalore, and IICT, Hyderabad, for
providing NMR and mass spectral studies respectively.
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