Novel multicomponent synthesis of pyrido[2,3-b]indoles

Article abstract of DOI:10.1515/HC.2011.036

A series of pyrido[2,3-b]indole derivatives was synthesized via a novel multicomponent reaction catalyzed by ferric hydrogen sulfate. 2011 · Copyright by Walter de Gruyter.

Full text of DOI:10.1515/HC.2011.036

Heterocycl. Commun., Vol. 17(5-6), pp. 187–189, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.036
Novel multicomponent synthesis of pyrido[2,3-b]indoles
Saman Damavandi1,* and Reza Sandaroos2
indole-3-carbonitrile derivatives through one-pot cyclocon-
densation of substituted (triethoxymethyl)arene, 1-methyl-
1 Department of Chemistry, Sarvestan Branch, Islamic
1H-indol-2-ol and cyanoacetamide catalyzed by ferric
hydrogen sulfate, Fe(HSO4)3.
Azad University, Sarvestan, Iran
2 Department of Chemistry, Faculty of Science, Birjand
University, Birjand, Iran
Results and discussion
*Corresponding author
e-mail: saman_damavandi@yahoo.com
Treatment of (triethoxymethyl)benzene, cyanoacetamide and
1-methyl-1H-indol-2-ol in acetonitrile in the presence of 10
mol% Fe(HSO4)3 under reflux conditions furnished 2,9-di-
hydro-9-methyl-2-oxo-4-phenyl-1H-pyrido[2,3-b]indole-3-
carbonitrile in high yield (Scheme 1). Encouraged by this
success, the methodology was extended to the synthesis of a
variety of 2,9-dihydro-2-oxo-4-aryl-1H-pyrido[2,3-b]indole-
3-carbonitriles. More specifically, various derivatives of (tri-
ethoxymethyl)benzene were subjected to the reaction with
cyanoacetamide and 1-methyl-1H-indol-2-ol to furnish the
correspondingpyrido[2,3-b]indoles.Therepresentativeexam-
ples are shown in Scheme 2. The use of (triethoxymethyl)ben-
zene derivatives substituted with either electron-withdrawing
or electron-donating groups afforded the expected products in
good to high yields.
A mechanism for this reaction is proposed in Scheme 3.
The first step may involve a cross coupling between 1-meth-
yl-1H-indol-2-ol and (triethoxymethyl)benzene that results in
the formation of α,β-unsaturated compound X. Nucleophilic
attack of cyanoacetamide on the β-position of the intermedi-
ate product X, which may be activated by the catalyst, gener-
ates the intermediate product Y. Intramolecular condensation
reaction of Y leads to the final product.
Abstract
A series of pyrido[2,3-b]indole derivatives was synthesized
via a novel multicomponent reaction catalyzed by ferric
hydrogen sulfate.
Keywords: ferric hydrogen sulfate; multicomponent;
pyrido[2,3-b]indole.
Introduction
Multi-component reactions play an important role in mod-
ern synthetic organic chemistry, as they generally occur in a
single pot and exhibit a high atom-economy and selectivity
(Trost, 1995; Dömling, 2002; Toure and Hall, 2009). They
also deliver fewer by-products compared to the classical
stepwise synthetic routes (Nicolaou et al., 2006; Wang et
al., 2007). Synthesis of pyridoindole (α -carboline) deriva-
tives has attracted considerable interest due to the recent
discoveries of several naturally occurring compounds
containing this skeleton (Veale et al., 1995; Menta et al.,
2001). Among these compounds, pyrido[2,3-b]indoles have
received immense attention because of their various phar-
macological and biological activities, such as their antican-
cer activity against colon and lung cancers, central nervous
system activity in mammals and use as a biological control
agent for receptor research on bio-enzyme inhibitors (inhi-
bition of human leukocyte elastase) (Nielsch et al., 1999;
Beccalli et al., 2001; Ritzeler et al., 2001). A literature
survey has revealed that a number of pyridoindoles have
been synthesized using a wide range of reagents and meth-
ods (Meyer and Guyot, 1996; Molina et al., 1997, 1998;
Barun et al., 1999; Ryabova et al., 2001, 2009; Hostyn et
al., 2011). Nevertheless, there are no reports for a one-pot
multi-component strategy utilizing substituted (triethoxy-
methyl)arene, 1-methyl-1H-indol-2-ol and cyanoacet-
amide to synthesize pyrido[2,3-b]indoles. In connection
with our recent interest aimed at the development of effi-
cient protocols for the preparation of biologically active
heterocycles (Damavandi, 2011), we now report efficient
synthesis of 2,9-dihydro-2-oxo-4-aryl-1H-pyrido[2,3-b]
Conclusion
A novel protocol for the one-pot synthesis of 2,9-dihydro-2-
oxo-4-aryl-1H-pyrido[2,3-b]indole-3-carbonitrile derivatives
utilizing easily accessible 1-methyl-1H-indol-2-ol, substi-
tuted (triethoxymethyl)arene and cyanoacetamide in the pres-
ence of an inexpensive catalyst is described.
Experimental section
General
Chemicals were either prepared in our laboratories or purchased
from Merck, Fluka and Aldrich Chemicals. All yields refer to iso-
lated products. Infrared (IR) spectra were recorded in KBr disks on
1
a Shimadzu-IR 470 spectrophotometer. H nuclear magnetic reso-
nance (NMR) spectra were recorded in DMSO-d6 at 400 MHz on
a Bruker 400-MHz spectrometer. 13C NMR spectra were recorded
at 62.5 MHz. Flash column chromatography was performed with
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188 S. Damavandi and R. Sandaroos
O
O
O
O
CN
OH
+
NC
Fe(HSO4)3
+
NH2
N
O
CH3CN, reflux
NH
N
Scheme 1 Synthesis of 2,9-dihydro-9-methyl-4-phenyl-2-oxo-1H-pyrido[2,3-b]indole-3-carbonitrile.
Ar
CN
O
,10 mol%
Fe(HSO4)3
O
OH
Ar(OEt)3
+
NC
+
NH2
N
NH
CH3CN, Reflux
N
1-8
Ar=4-CH3OC6H4 - (1) (82%); C6H5 - (2) (80%); 4-CH3C6H4 (3) (78%); 4-BrC6H4 (4) (73%);
2-BrC6H4 - (5) (70%); 4-ClC6H4 (6) (72%); 2-ClC6H4 - (7) (67%); 4-NO2C6H4 - (8) (65%).
Scheme 2 One-pot synthesis of pyrido[2,3-b]indole derivatives 1–8.
300- and 400-mesh silica gel and thin layer chromatography (TLC)
was performed on pre-coated silica gel plates (60F-254). Elemental
analyses were performed on Thermo Finnigan EA1112 elemental
analyzer.
2,9-Dihydro-4-(4-methoxyphenyl)-9-methyl-2-oxo-1H-
pyrido[2,3-b]indole-3-carbonitrile (1) After 4 h the yield was
82%; IR: νmax 3255, 3110, 2955, 2830, 2235, 1645, 1555, 1440, 1133
1
cm-1; H NMR: δ 10.85 (1H, s, NHCO), 7.60–7.35 (2H, m, ArH),
7.28 (2H, d, J=7.1 Hz, ArH), 7.12 (2H, d, J=7.4 Hz, ArH), 6.95 (2H,
d, J=7.1 Hz, ArH), 3.80 (s, OCH3), 3.65 (3H, s, indole); 13C NMR: δ
165.8, 155.1, 150.4, 135.8, 128.2, 126.3, 124.6, 124.4, 124.2, 122.1,
121.4, 119.6, 115.3, 111.9, 112.6, 99.8, 55.8, 35.2. Anal. calcd for
C20H15N3O2: C, 72.94; H, 4.59; N, 12.76. Found: C, 72.56; H, 4.55;
N, 12.73.
General procedure for the synthesis of pyrido[2,3-b]-
indole compounds 1–8
A mixture of (triethoxymethyl)arene (1 mmol), 1-methyl-1H-indol-
2-ol (1 mmol) and cyanoacetamide (1.1 mmol) was stirred under
reflux with ferric hydrogen sulfate (0.1 mmol) in acetonitrile (6 ml)
for a period of time. The progress of the reaction was moni-
tored by TLC. After completion of the reaction, the catalyst
was recovered by filtration. The solvent was removed from the
filtrate by distillation and the residue of the crude product was
purified by column chromatography eluting with n-hexane/ethyl
acetate (5:1).
2,9-Dihydro-9-methyl-2-oxo-4-phenyl-1H-pyrido[2,3-b]indole-
3-carbonitrile (2) After 5 h the yield was 80%; IR: νmax 3250, 3120,
2965, 2833, 2230, 1642, 1551, 1431 cm-1; 1H NMR: δ 11.02 (1H, s,
NHCO), 7.55 (1H, d, J=6.3 Hz, ArH), 7.43 (1H, d, J=6.3 Hz, ArH),
7.33–7.15 (7H, m, ArH), 3.62 (3H, s, indole); 13C NMR: δ 169.3,
155.2, 138.5, 129.2, 125.5, 124.2, 123.7, 122.47, 120.4, 118.5, 118.0,
FHS
OEt
EtO
OEt
EtO
OEt
CN
CN
OEt
OEt
H+
H+
NH2
NH2
OEt
O
H
H
..
OH
OH
O
..
O
N
N
N
Fe(HSO4)3
X
OEt
CN
CN
NH
H
CN
NH
O
EtO
H+
O
H
O
NH2
..
O
N
N
OH
Fe(HSO4)3
N
Y
Scheme 3 Proposed mechanism for the synthesis of pyrido[2,3-b]indoles catalyzed by Fe(HSO4)3.
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Novel synthetic route to pyrido[2,3-b]indoles 189
117.5, 116.1, 114.6, 110.8, 96.2, 34.5. Anal. calcd for C19H13N3O:
C, 76.24; H, 4.38; N, 14.04. Found: C, 75.90; H, 4.34; N, 14.42.
References
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2,9-Dihydro-9-methyl-2-oxo-4-p-tolyl-1H-pyrido[2,3-b]indole-
3-carbonitrile (3) After 5 h the yield was 78%; IR: ν max 3254,
1
3119, 2976, 2835, 2218, 1647, 1551, 1422 cm-1; H NMR: δ 10.80
(1H, s, NHCO), 7.46 (1H, d, J=7.1 Hz, ArH), 7.57 (1H, d, J=7.1
Hz, ArH), 7.30–7.12 (6H, m, ArH), 3.52 (s, CH3, indole), 2.12 (s,
CH3); 13C NMR: δ 161.9, 156.1, 139.6, 135.5, 129.3, 128.7, 127.1,
125.9, 125.3, 124.0, 121.8, 120.1, 117.8, 115.1, 112.9, 95.2, 34.6,
24.9. Anal. calcd for C20H15N3O: C, 76.66; H, 4.82; N, 13.41. Found:
C, 76.49; H, 4.78; N, 13.38.
4-(4-Bromophenyl)-2,5-dihydro-2-oxo-1H-pyrido[3,2-b]indole-
3-carbonitrile (4) After 6 h the yield was 73%; IR: νmax 3246,
1
3125, 2983, 2826, 2217, 1656, 1509, 1452 cm-1; H NMR: δ 10.90
(1H, s, NHCO), 7.57 (1H, d, J=6.2 Hz, ArH), 7.40–7.30 (3H, m,
ArH), 7.15 (2H, d, J=6.4 Hz, ArH), 7.80 (2H, d, J=6.4 Hz, ArH),
3.55 (s, CH3, indole); 13C NMR: δ 168.5, 160.7, 139.2, 132.3, 129.5,
128.3, 127.9, 124.8, 124.1, 122.6, 121.8, 121.6, 117.3, 116.5, 111.3,
96.6, 32.7. Anal. calcd for C19H12BrN3O: C, 60.34; H, 3.20; N, 11.11.
Found: C, 60.21; H, 3.14; N, 11.05.
4-(2-Bromophenyl)-2,5-dihydro-2-oxo-1H-pyrido[3,2-b]indole-3-
carbonitrile (5) After 6 h the yield was 70%; IR: ν max 3255, 3134,
2991, 2806, 2228, 1650, 1544, 1487 cm-1; 1H NMR: δ 10.57 (1H, s,
NHCO), 7.60 (1H, d, J=7.0 Hz, ArH), 7.45–7.37 (2H, m, ArH), 7.22–
7.14 (5H, m, ArH), 3.63 (s, CH3, indole); 13C NMR: δ 163.3, 155.2,
139.7, 135.5, 132.1, 129.8, 125.9, 125.2, 124.6, 123.3, 121.9, 121.0,
118.8, 118.6, 118.1, 115.7, 94.1, 31.6. Anal. calcd for C19H12BrN3O:
C, 60.34; H, 3.20; N, 11.11. Found: C, 60.27; H, 3.13; N, 11.07.
4-(4-Chlorophenyl)-2,9-dihydro-9-methyl-2-oxo-1H-
pyrido[2,3-b]indole-3-carbonitrile (6) After 5.5 h the yield was
72%; IR: νmax 3263, 3115, 2980, 2802, 2212, 1652, 1535, 1470 cm-1;
1H NMR: δ 11.02 (1H, s, NHCO), 7.55 (1H, d, J=7.5 Hz, ArH), 7.46
(1H, d, J=7.7 Hz, ArH), 7.25–7.18 (4H, m, ArH), 7.04 (2H, d, J=7.7
Hz, ArH), 3.55 (s, CH3, indole); 13C NMR: δ 166.4, 161.1, 138.9,
135.3, 129.7, 127.4, 124.93, 124.7, 123.6, 122.1, 121.5, 120.5, 118.8,
116.7, 111.1, 93.6, 33.1. Anal. calcd for C19H12ClN3O: C, 68.37;
H, 3.62; N, 12.59. Found: C, 67.91; H, 3.53; N, 12.51.
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4-(2-Chlorophenyl)-2,9-dihydro-9-methyl-2-oxo-1H-
pyrido[2,3-b]indole-3-carbonitrile (7) After 7 h the yield was
67%; IR: νmax 3250, 3142, 2997, 2812, 2211, 1667, 1553, 1465 cm-1;
1H NMR: δ 10.92 (1H, s, NHCO), 7.50 (1H, d, J=6.5 Hz, ArH), 7.43
(1H, d, J=6.5 Hz, ArH), 7.30–7.24 (2H, m, ArH), 7.20–7.05 (4H, m,
ArH), 3.60 (s, CH3, indole); 13C NMR: δ 169.5, 158.4, 139.7, 134.4,
131.1, 128.9, 125.5, 124.2, 122.9, 122.1, 120.8, 120.1, 118.9, 118.7,
116.9, 116.3, 98.5, 34.5. Anal. calcd for C19H12ClN3O: C, 68.37; H,
3.62; N, 12.59. Found: C, 67.84; H, 3.55; N, 12.49.
2,9-Dihydro-9-methyl-4-(4-nitrophenyl)-2-oxo-1H-pyrido[2,3-
b]indole-3-carbonitrile (8) After 8 h the yield was 65%; IR: νmax
3255, 3175, 2995, 2810, 2217, 1637, 1552, 1516, 1481, 1345 cm-1;
1H NMR: δ 10.85 (1H, s, NHCO), 8.09 (2H, d, J=7.2 Hz, ArH),
7.65–7.50 (3H, m, ArH), 7.40 (1H, d, J=7.7 Hz, ArH), 7.10 (2H, d,
J=7.7 Hz, ArH), 3.62 (s, CH3, indole); 13C NMR: δ 167.7, 159.2,
154.1, 148.3, 144.4, 129.9, 127.4, 125.9, 125.2, 123.3, 122.1, 121.7,
120.4, 119.5, 115.6, 114.1, 95.5, 34.6. Anal. calcd for C19H12N4O3:
C, 66.28; H, 3.51; N, 16.27. Found: C, 66.01; H, 3.42; N, 16.16.
Received August 10, 2011; accepted September 22, 2011;
previously published online October 20, 2011
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