Base-catalyzed three-component synthesis of 2-amino-4,5-dihydro-4- arylpyrano[3,2-b ]indole-3-carbonitriles

Article abstract of DOI:10.1515/HC.2011.032

A base-catalyzed, one-pot and facile method for the synthesis of 2-amino-4,5-dihydro-4-arylpyrano[3,2- b ]indole-3-carbonitriles is reported. This procedure includes a novel threecomponent reaction of indolin-3-one with aromatic aldehydes and malononitrile in ethanol in the presence of ammonium acetate as the catalyst. by Walter de Gruyter.

Full text of DOI:10.1515/HC.2011.032

Heterocycl. Commun., Vol. 17(3-4), pp. 125–127, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.032
Base-catalyzed three-component synthesis of 2-amino-4,5-
dihydro-4-arylpyrano[3,2-b]indole-3-carbonitriles
catalyzed by ammonium acetate. Herein, we report the details
of the study (Scheme 1).
Saman Damavandi
Department of Chemistry, Sarvestan Branch, Islamic Azad
University, Sarvestan, Iran
e-mail: Saman_Damavandi@yahoo.com
Results and discussion
In a preliminary experiment we found out that the three-
component condensation of indolin-3-one, 4-chlorobenzalde-
hyde, and malononitrile in the presence of ammonium acetate
(10 mol%) proceeded to efficiently afford 2-amino-4,5-
dihydro-4-chlorophenylpyrano[3,2-b]indole-3-carbonitrile
(compound 6 in Table 1). The catalyst has a significant effect
on the model reaction of 4-chlorobenzaldehyde.
No reaction took place in the presence of proton acids
and classical Lewis acids as catalysts, such as AlCl3, ZnCl2,
TsOH, NH2SO3H, Cu(OTf)2 and Zn(OTf)2 (Table 1, entries
1–7).
Then we examined the reaction using bases as the cata-
lysts under similar reaction conditions (Table 1, entries 8–13).
Under the base catalysis of the three-component condensation
reaction, the desired product 6 was obtained in moderate to
excellent yields (57–90%). As shown in Table 1, ammonium
acetate was found to be the most effective catalyst in terms of
reaction time and yield.
Abstract
A base-catalyzed, one-pot and facile method for the synthesis
of 2-amino-4,5-dihydro-4-arylpyrano[3,2-b]indole-3-carbo-
nitriles is reported. This procedure includes a novel three-
component reaction of indolin-3-one with aromatic aldehydes
and malononitrile in ethanol in the presence of ammonium
acetate as the catalyst.
Keywords: ammonium acetate; multicomponent;
pyrano[3,2-b]indole.
Introduction
Recently, different authors have reported the anticancer poten-
tial of indole (James et al., 2006; Singh et al., 2008; Kumar
et al., 2010a; Kumar et al., 2010b; Ziedan et al., 2010) and
a-pyrone derivatives (Marrison et al., 2002; Fairlamb et al.,
2004; Zhang et al., 2007). On the basis of these studies it was
speculated that combining the structural characteristics of both
moieties could produce substantial enhancement in the anti-
cancer activity of such compounds. Accordingly, due to their
significant biological activities as well as their wide-ranging
utility as synthetic intermediates for alkaloids, drug candidates
and clinical pharmaceuticals (Miyamoto et al., 2006), a number
of synthetic methods have been developed in pursuit of this
structure. These include intramolecular hetero-Diels-Alder
cycloaddition (Daviona et al., 2003) and cycloisomerization
(Praveen et al., 2011).
Having optimized the catalyst, we then success-
fully synthesized
a variety of 2-amino-4,5-dihydro-
4-arylpyrano[3,2-b]indole-3-carbonitrile derivatives. As
shown in Scheme 1, aromatic aldehydes carrying either
electron-donating or electron-withdrawing substituents
react efficiently giving good to excellent yields of corre-
sponding pyrano[3,2-b]indoles. The experimental proce-
dure is convenient and rapid, and a variety of functional
groups – such as methoxyl, nitro, hydroxyl and halides –
are tolerated under these reaction conditions. Steric hin-
drance of the aldehydes influences the reaction only slightly
and the corresponding pyrano[3,2-b]indoles 5, 7, 9 were
obtained in good yields.
Moreover, as there is increasing environmental conscious-
ness in chemical research and industry, the challenge has been
to create environmentally sustainable, clean procedures that
avoid using metal ions as catalysts (Su et al., 2005; Sharma
et al., 2008).
As part of a continuing effort in our laboratory toward the
development of new multi-component condensation reactions
(Damavandi, 2011), we became interested in the possibility
of developing an efficient methodology for the preparation
of 2-amino-4,5-dihydro-4-arylpyrano[3,2-b]indole-3-carbo-
nitrile derivatives through a three-component condensation
reaction of indolin-3-one, aryl aldehydes, and malononitrile
Conclusion
We have discovered an effective method for the synthesis
of 2-amino-4,5-dihydro-4-arylpyrano[3,2-b]indole-3-car-
bonitrile derivatives by a one-pot three-component reaction
of indolin-3-one, aromatic aldehydes and malononitrile in
ethanol using 10 mol% ammonium acetate as the catalyst.
The noteworthy features of this procedure are cleanness of
the reaction, an inexpensive catalyst, economical steps, high
yields and operational simplicity.
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126 S. Damavandi
OH
General procedure for the synthesis of 2-amino-
4,5-dihydro-4-arylpyrano[3,2-b]indole-3-carbonitrile
derivatives
Ar
NH4OAc
EtOH
H
ArCHO
+
CH2(CN)2
+
CN
N
N
H
O
NH2
A mixture of indolin-3-one (1 mmol), aldehyde (1 mmol), malono-
nitrile (1 mmol) and ammonium acetate (0.15 mmol) in EtOH (8 ml)
was stirred and heated under reflux. After completion of the reaction,
as indicated by TLC analysis, the mixture was cooled to room tem-
perature, treated with cold water (10 ml), and stirred for an additional
5 min. The precipitated solid was filtered off and crystallized from
EtOH–H2O (3:1). Further purification was carried out by silica gel
column chromatography eluting with n-hexane/ethyl acetate (9:1) to
afford pure products. The compounds are characterized as follows.
1-12
Ar=4-CH3OC6H4 - (1); C6H5 - (2); 4-CH3C6H4 - (3); 4-BrC6H4 - (4); 2-BrC6H4 - (5);
-
4-ClC6H4 (6); 2-ClC6H4 - (7); 4-NO2C6H4 - (8); 2-NO2OC6H4 - (9); 4-FC6H4 - (10);
2-furanyl - (11); 1-naphthyl - (12)
Scheme 1 Synthesis of pyrano[3,2-b]indole derivatives 1–12.
2-Amino-4,5-dihydro-4-(4-methoxyphenyl)pyrano[3,2-b]indole-
3-carbonitrile (1) After 3.0 h the yield was 78%; IR: ν 1,665 (NH2),
Experimental
1
2,218 (CN), 3,224 and 3,259 cm-1 (NH2); H NMR: δH 3.63 (s, 3H,
OCH3), 5.41 (s, 1H, CH), 6.89 (bs, 2H, NH2), 6.82–6.99 (m, 2 H);
7.04–7.13 (m, 4 H); 7.56 (d,1 H, J=8.0); 7.87 (d, 1 H, J=7.8), 10.14
(bs, 1H, NH). Analysis calculated for C19H15N3O2: C, 71.91; H, 4.76;
N, 13.24. Found: C, 71.75; H, 4.67; N, 13.11.
Chemicals were either prepared in our laboratories or purchased
from Merck, Fluka and Aldrich Chemical Companies. All yields
refer to isolated products. The infrared (IR) spectra were recorded
using KBr disks on a Shimadzu-IR 470 spectrophotometer. The
1H nuclear magnetic resonance (NMR) spectra were recorded on
a Bruker 250-MHz spectrometer in CDCl3 with tetramethylsilane
(TMS) as the internal standard. Flash column chromatography was
performed using 300- and 400-mesh silica gel and analytical 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-Amino-4,5-dihydro-4-phenylpyrano[3,2-b]indole-3-carbo-
nitrile (2) After 2.5 h the yield was 88%; IR: ν 1,659 (NH2); 2,214
1
(CN); 3,222 and 3,244 cm-1 (NH2); H NMR: δH 5.18 (s, 1H, CH),
6.69 (bs, 2H, NH2), 7.00–7.18 (m, 2H), 7.28–7.56 (m, 5H), 7.72 (d, 1
H, J=8.1); 8.11 (d, 1 H, J=7.0), 11.05 (bs, 1H, NH). Analysis calcu-
lated for C18H13N3O: C, 75.25; H, 4.56; N, 14.63. Found: C, 74.98;
H, 4.49; N, 14.60.
2-Amino-4,5-dihydro-4-p-tolylpyrano[3,2-b]indole-3-carbo-
nitrile (3) After 3.0 h the yield was 86%; IR: ν 1,661 (NH2), 2,224
(CN), 3,213 and 3,259 cm-1 (NH2): 1H NMR: δH 2.33 (s, 3H, CH3),
5.33 (s, 1H, CH), 6.75 (bs, 2H, NH2), 6.99–7.04 (m, 2 H), 7.20–
7.36 (m, 4 H), 7.63 (d, 1 H, J=7.9), 7.90 (d, 1 H, J=7.1), 10.42 (bs,
1H, NH). Analysis calculated for C19H15N3O: C, 75.73; H, 5.02; N,
13.94. Found: C, 74.68; H, 5.00; N, 13.79.
Table 1 One-pot synthesis of 5-amino-7-(4-chlorophenyl)-1,7-
dihydropyrano[3,2-b]pyrrole-6-carbonitrile (6) in the presence of
various catalysts.
Cl
CHO
OH
NH4OAc
H
2-Amino-4-(4-bromophenyl)-4,5-dihydropyrano[3,2-b]indole-
3-carbonitrile (4) After 2.0 h the yield was 90%; IR: ν 1,670
+
+
CH2(CN)2
CN
N
N
EtOH
H
1
(NH2), 2,226 (CN), 3,240 and 3,361 cm-1(NH2); H NMR: δH 5.50
Cl
O
NH2
(s, 1H, CH), 6.70 (bs, 2 H, NH2), 7.07–7.16 (m, 2 H); 7.30–7.44 (m,
4 H); 7.68 (d, 1 H, J=7.6); 8.01 (d, 1 H, J=7.0), 11.02 (bs, 1H, NH).
Analysis calculated for C18H12BrN3O: C, 59.03; H, 3.30; N, 11.47.
Found: C, 58.76; H, 3.27; N, 11.40.
Entry
Catalyst (10 mol%)
Yield (%)
1
2
A l C l 3
F e C l 3
0
0
2-Amino-4-(2-bromophenyl)-4,5-dihydropyrano[3,2-b]indole-
3-carbonitrile (5) After 3.0 h the yield was 82%; IR: ν 1,664
(NH2), 2,217 (CN), 3,225 and 3,252 cm-1 (NH2); 1H NMR: δH 5.43
(s, 1H, CH), 6.81 (s, 2H, NH2), 6.93 (d, 1 H, J=7.2); 7.18–7.55 (m,
6 H); 7.92 (d, 1 H, J=6.2), 9.70 (bs, 1H, NH). Analysis calculated
for C18H12BrN3O: C, 59.03; H, 3.30; N, 11.47. Found: C, 58.76; H,
3.26; N, 11.19.
3
4
5
5
6
7
8
9
10
11
12
13
Z n C l 2
0
0
0
0
0
0
5 7
6 3
82
77
57
90
C u ( O T f ) 2
Z n ( O T f ) 2
T s O H
p-TSA
N H 2SO3H
P y r i d i n e
I m i d a z o l e
Et3N
Piperidine
DBU
2-Amino-4-(4-chlorophenyl)-4,5-dihydropyrano[3,2-b]indole-3
-carbonitrile (6) After 2.0 h the yield was 90%; IR: ν 1,667 (NH2),
2,219 (CN), 3,202 and 3,244 cm-1 (NH2); 1H NMR: δH 5.49 (s, 1H,
CH), 6.68 (s, 2H, NH2), 7.21–7.42 (m, 2 H); 7.46–7.59 (m, 4 H); 7.63
(d, 1 H, J=6.7); 8.01 (d, 1 H, J=7.0), 10.54 (bs, 1H, NH). Analysis
calculated for C18H12ClN3O: C, 70.81; H, 3.96; N, 13.76. Found: C,
70.55; H, 3.90; N, 13.71.
NH4OAc
Reaction conditions: indolin-3-one (1 mmol), p-chlorobenzaldehyde
(1 mmol), malononitrile (1 mmol), EtOH (8 ml), reflux for 3 h. DBU,
diaza(1,3)bicyclo[5.4.0]undecane.
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2-Amino-4,5-dihydro-4-arylpyrano[3,2-b]indole-3-carbonitriles 127
2-Amino-4-(2-chlorophenyl)-4,5-dihydropyrano[3,2-b]indole-
References
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(NH2), 2,211 (CN), 3,222 and 3,241 cm-1 (NH2); 1H NMR: δH 5.63
(s, 1H, CH), 6.59 (bs, 2H, NH2), 6.81 (s, 1 H); 7.02–7.21 (m, 2 H);
7.29–7.38 (m, 4 H); 7.46 (d, 1 H, J=6.7), 10.39 (bs, 1H, NH).Analysis
calculated for C18H12ClN3O: C, 70.81; H, 3.96; N, 13.76. Found: C,
70.64; H, 3.89; N, 13.52.
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bonitrile (8) After 3.0 h the yield was 91%; IR: ν 1,661 (NH2), 2,211
(CN), 3,224 and 3,256 cm-1 (NH2); 1H NMR: δH 5.49 (s, 1H, CH), 6.60
(bs, 2H, NH2), 6.85 (s, 1 H); 7.02–7.20 (m, 3 H); 7.43–7.51 (m, 3 H); 7.66
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C, 65.06; H, 3.64; N, 16.86. Found: C, 64.78; H, 3.60; N, 16.79.
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3-carbonitrile (9) After 2.0 h the yield was 82%; IR: ν 1,669
(NH2), 2,225 (CN), 3,218 and 3,231 cm-1 (NH2); 1H NMR: δH 5.72
(s, 1H, CH), 6.71 (s, 2H, NH2), 7.22 (d, 1 H, J=7.76); 7.26–7.42 (m,
3 H); 7.46–7.59 (m, 2 H); 7.76 (d, 1 H, J=7.6); 7.99 (d, 1 H, J=6.9),
10.11 (bs, 1H, NH). Analysis calculated for C18H12N4O3: C, 65.06;
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CH), 6.72 (bs, 2 H, NH2), 7.01 (m, 1 H); 7.11–7.20 (m, 2 H); 7.27–
7.53 (m, 2 H); 7.64 (d, 1 H, J=6.1); 8.06 (d, 1 H, J=7.0), 10.44 (bs,
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2-Amino-4,5-dihydro-4-(naphthalen-1-yl)pyrano[3,2-b]indole-
3-carbonitrile (12) After 4.0 h the yield was 75%; IR: ν 1,656
(NH2), 2,218 (CN), 3,221 and 3,261 cm-1 (NH2); 1H NMR: δH 5.43
(s, 1H, CH), 6.65 (bs, 2H, NH2), 6.87–7.17 (m, 3 H); 7.28–7.40 (m,
6 H); 7.59 (d, 1 H, J=8.6); 7.84 (d, 1 H, J=7.8), 9.85 (bs, 1H, NH).
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Acknowledgements
The authors gratefully acknowledge partial financial support from
the Ferdowsi University of Mashhad.
Received June 30, 2011; accepted August 4, 2011
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