An Efficient Three-Component Synthesis of Benzimidazo[1,2- a ]-quinoline-6-carbonitriles

Article abstract of DOI:10.1055/s-0035-1561939

An efficient three-component synthesis of benzimidazo[1,2-a]quinoline-6-carbonitriles is described. Condensation reaction of a benzene-1,2-diamine and a cyclohexane-1,3-dione gave an enamine intermediate, which on treatment with an arylidenemalononitrile

Full text of DOI:10.1055/s-0035-1561939

SYNLETT
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2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
M. Adib et al.
Letter
Synlett
An Efficient Three-Component Synthesis of Benzimidazo[1,2-a]
quinoline-6-carbonitriles
Mehdi Adib*a
Mohsen Zainalia
Il Kimb
R'
H O–EtOH (1:1), 70 °C, 1 h
1)
2)
2
R'
CN
R' R'
O
R
R
NH2
NH2
Ar
CN
Ar
CN
R
R
+
N
N
a School of Chemistry, College of Science, University of Tehran,
P. O. Box 14155-6455, Tehran, Iran
tBuOK (10 mol%), 70 °C, 3 h
O
O
3) HCl (1 equiv), 70 °C, 3 h
madib@khayam.ut.ac.ir
b BK21 PLUS Center for Advanced Chemical Technology,
Department of Polymer Science and Engineering,
Pusan National University, Pusan 609-735, Korea
12 examples
45–85% yield
R = H, Me
R' = H, Me
Ar = Ph, 2-furyl, 4-O2NC6H4,
3-O2NC6H4, 4-ClC6H4,
4-BrC6H4, 4-MeC6H4
Received: 30.11.2015
O
NH
N
Accepted after revision: 01.03.2016
Published online: 30.03.2016
DOI: 10.1055/s-0035-1561939; Art ID: st-2015-d0927-l
_
Cl
+
NH 10
N
Abstract An efficient three-component synthesis of benzimidazo[1,2-
a]quinoline-6-carbonitriles is described. Condensation reaction of a
benzene-1,2-diamine and a cyclohexane-1,3-dione gave an enamine in-
termediate, which on treatment with an arylidenemalononitrile in wa-
ter–ethanol (1:1) afforded the title compounds in good to excellent
yields.
9
N
N
CN
N
2
H
1
(mixture of 9- and 10-isomers)
N
N
CN
Key words benzene-1,2-diamines, cyclohexane-1,3-diones, arylidene-
malononitriles, benzimidazo[1,2-a]quinoline-6-carbonitriles, multicom-
ponent reactions
O
O
H2N
CN
NH2
3
Figure 1 Examples of antitumor benzimidazo[1,2-a] quinolines
Compounds containing benzimidazo[1,2-a]quinoline
core structure have been shown to possess antitumor activ-
ity against various cancer cells such as breast and pancre-
as.1–3 For example, the imidazolyl-substituted benzimid-
azo[1,2-a]quinoline hydrochloride 1 (Figure 1) inhibits to-
poisomerase II and induces strong G2/M cell cycle arrest on
colon carcinoma cells.2a 2-N-Acetamidobenzimidazo[1,2-
a]quinoline-6-carbonitrile (2, Figure 1) has exhibited no-
ticeable antiproliferative activity and in vitro inhibition on
growth of five tested tumor cell lines.3 1-Amino-2,4-dicy-
anopyrido[1,2-a]benzimidazole (3) has been reported as a
direct inhibitor of the lytic activity of perforin in cells.4
Due to the great pharmaceutical importance of benzim-
idazo[1,2-a]quinolines, several synthetic approaches have
been reported for the preparation of these heterocycles in-
cluding condensation of benzaldehydes with benzimidaz-
ole-2-acetonitrile followed by photochemical cyclization of
the corresponding arylidene-1H-benzimidazol-2-ylacetoni-
I2/O2,1,2 reaction of coumarins with o-phenylenediamine in
the presence of polyphosphoric acid,7 condensation of cy-
clohexane-1,3-diones and dimethylformamide dimethylac-
etal followed by treatment of the adduct with benzimidaz-
ole-2-acetonitriles under microwave irradiation,8 reaction
of 2-fluorobenzoyl chlorides with 2-benzoylmethylbenzim-
idazoles,9 and aromatic nucleophilic substitution reaction
between 2-methylbenzimidazoles and 2-fluorobenzalde-
hydes followed by an intramolecular Knoevenagel conden-
sation reaction.10
In continuation of our attempts toward the synthesis of
biologically active organic compounds,11 herein, we de-
scribe an efficient synthetic route leading to quinoline-
fused benzimidazoles. Thus, a mixture of benzene-1,2-di-
amines 4, cyclohexane-1,3-diones 5, and arylidenemalono-
nitriles 6 underwent a 1:1:1 addition reaction to afford the
corresponding 4-oxo-tetrahydro[1,3]benzimidazo[1,2-a]quin-
oline-6-carbonitriles 7a–l in 45–85% yields (Scheme 1). The
reactions were carried out by condensation reaction be-
tween benzene-1,2-diamines 4 and cyclohexane-1,3-di-
5
triles in the presence of I2/O2 or under thermal condi-
tions,2b,6 condensation of cinnamaldehyde or cinnamic acid
derivatives with o-phenylenediamines followed by photo-
chemical cyclization of 2-styryl-1H-benzimidazoles with
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
M. Adib et al.
Letter
Synlett
R'
N
R'
CN
CN
O
then:
1)
6
Ar
Ar
CN
R
R
tBuOK (10 mol %), 70 oC, 3 h
2) HCl (1 equiv), 70 °C, 3 h
R' R'
N
R
R
NH2
NH2
7
H2O–EtOH (1:1)
70 °C, 1 h
CN
R'
+
6
R'
O
O
H
Ar
CN
N
R
R
5
4
AcOH (20 mol %)
70 °C, H2O–EtOH (1:1), 1 h
(by losing a malononitrile)
O
N
H
Ar
8
Scheme 1 Synthesis of 4-oxo-tetrahydro[1,3]benzimidazo[1,2-a]quinoline-6-carbonitriles 7 and 1,5-benzodiazepines 8
ones 5 in H2O–EtOH (1:1) at 70 °C for one hour. After nearly
complete conversion into the corresponding enamines, as
was indicated by TLC monitoring, arylidenemalononitriles
6 and t-BuOK (10 mol%) were added to the mixture which
was stirred for a further three hours at 70 °C. Next, an
equivalent amount of HCl was added to the mixture and
stirring was continued for further three hours at 70 °C. All
the reactions went to completion within seven hours. TLC
and NMR analysis of the reaction mixtures clearly indicated
the formation of the corresponding 4-oxo-tetrahy-
dro[1,3]benzimidazo[1,2-a]quinoline-6-carbonitriles 7 in
good to excellent yields (Scheme 1 and Table 1).12
It must be noted that when the reaction was performed
in the presence of acetic acid (20 mol%), the 1,5-benzodiaz-
epines 8 were produced by the loss of a malononitrile
(Scheme 1). These compounds have been reported by Tu
and co-workers via a three-component reaction between
benzene-1,2-diamines, cyclohexane-1,3-diones, and aro-
matic aldehydes under microwave irradiation.13
trum of 7c showed the stretching bands for the carbonyl
and nitrile functionalities at 1677 and 2230 cm–1, respec-
tively. The mass spectrum of 7c displayed the molecular ion
[M+] peak at m/z = 382, which was 35 mass units (H2O +
NH3) less than that of the 1:1:1 adduct of benzene-1,2-di-
amine, cyclohexane-1,3-dione, and 4-nitrobenzylidene-
malononitrile. The 1H NMR spectrum of 7c exhibited a
quintet signal (δ = 2.31 ppm, J = 6.7 Hz) for the middle CH2
and two triplets (δ = 2.61 and 3.92 ppm, J = 6.7 and 6.3 Hz,
respectively) for the two side CH2 groups of the trimethy-
lene moiety of the cycloxexenone ring. The characteristic
signals with appropriate chemical shifts and coupling con-
stants were observed in the region of δ = 7.5–8.6 ppm of the
spectrum for the nine H atoms of the 4-nitrosubstituted
1
phenyl ring and phenylene moiety. The H-decoupled 13C
NMR spectrum of 7c showed characteristic signals at
δ = 19.8, 28.9 and 37.2 ppm for the trimethylene moiety, a
fairly shielded signal at δ = 99.9 ppm due to the C–CN, at
δ = 116.1 ppm for the nitrile, at δ = 193.6 ppm arising from
the carbonyl as well as other 14 signals (6 ´ CH and 8 ´ C) in
agreement with the proposed structure.12
The structures of the isolated products were deduced
on the basis of their IR, 1H NMR, and 13C NMR spectroscopy,
mass spectrometry, and elemental analysis. The IR spec-
O
H
Ar
CN
CN
H
+
_
NH2
NH2
O
N
NH
NC
Ar
CN
+
– H2O
6
O
O
NH2
NH2
4
10
5
9
O
O
O
O
Ar
Ar
Ar
Ar
NH
N
N
[O]
N
CN
7
CN
N
NH2
NH
NH2
– NH3
CN
NH2
CN
N
H
13
N
H
11
12
14
Scheme 2 Proposed mechanism for the formation of benzimidazo[1,2-a]quinoline-6-carbonitriles 7
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
M. Adib et al.
Letter
Synlett
Table 1 (continued)
Table 1 Synthesis of Benzimidazo[1,2-a]quinoline-6-carbonitriles 7a–l
Product 7 Structure
Mp (°C)
Yield (%)a
Product 7 Structure
Mp (°C)
Yield (%)a
O
O
7j
230–232
70
NO2
7a
243–245
80
N
N
N
N
CN
CN
O
O
O
NO2
7k
242–243
265–267
80
45
7b
7c
7d
7e
7f
280–282
266–269
288–291
286–289
284–286
218–220
270–272
65
85
76
68
80
80
80
N
N
N
N
CN
CN
O
O
Cl
7l
NO2
N
N
N
N
CN
CN
a Isolated yields.
O
Cl
A mechanistic rationalization for this reaction is provid-
ed in Scheme 2. At first, benzene-1,2-diamine 4 condenses
with cyclohexane-1,3-dione 5 to produce the enamine in-
termediate 9,14 followed by its Michael addition to the
arylidenemalononitrile 6 and a proton transfer to give in-
termediate 11 via 10. Then, one of the nitrile groups may
undergo nucleophilic attack by the two nitrogen atoms of
the benzene-1,2-diamine moiety to form the cyclized inter-
mediate 13, through 12, from which an ammonia may be
removed to form intermediate 14. Finally, 14 may undergo
an aerial oxidation under the reaction conditions to afford
benzimidazo[1,2-a]quinoline-6-carbonitrile 7. It seems
that nucleophilic attacks (conjugate addition of 9 on 6 and
conversion of 11 into 13) and elimination of NH3 molecule
(conversion of 13 into 14), can be accelerated by the added
base and acid, respectively. These roles are in agreement
with the proposed mechanism.
In conclusion, we have developed an efficient approach
for the synthesis of 4-oxo-tetrahydro[1,3]benzimidazo[1,2-
a]quinoline-6-carbonitriles from a three-component reac-
tion between benzene-1,2-diamines, cyclohexane-1,3-di-
ones, and arylidenemalononitriles. Considering the avail-
ability of the starting materials, the simple and one-pot
procedure, easy workup, and high yields of the products,
this approach provides a straightforward route to construct
these fused benzimidazoles. The products synthesized in
the present study may find useful applications in synthetic
organic and medicinal chemistry.
N
N
CN
O
N
N
NO2
CN
O
Br
N
N
CN
O
7g
7h
N
N
CN
O
N
N
CN
O
7i
160–163
85
N
N
CN
Acknowledgement
This research was supported by the Research Council of the University
of Tehran.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
M. Adib et al.
Letter
Synlett
Supporting Information
was stirred at 70 °C for 1 h. After nearly complete conversion
into the corresponding enamine, as was indicated by TLC moni-
toring, benzylidenemalononitrile (0.154 g, 1 mmol) and t-BuOK
(0.011 g, 0.1 mmol), were added to the mixture and stirring was
continued for further 3 h at 70 °C. Next, HCl (37%, 1 mmol) was
added, and the mixture was allowed to stir for more 3 h at
70 °C. After completion of the reaction as was indicated by TLC
monitoring, the reaction mixture was cooled and stirring was
continued for 15 min at ambient temperature. The resulting
precipitate was filtered, washed with EtOH–H2O (1:1), and
dried to afford the pure product 7a.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561939.
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References and Notes
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4-Oxo-5-phenyl-1,2,3,4-tetrahydro[1,3]benzimidazo[1,2-
a]quinoline-6-carbonitrile (7a)
Yield 0.270 g, (80%); pale yellow solid; mp 243–245 °C. IR (KBr):
2229 (CN), 1686 (C=O), 1580, 1500, 1446, 1410, 1380, 1356,
1306, 1249, 1193, 1123, 1019, 937, 757, 703 cm–1
(300.1 MHz, DMSO-d6): δ = 2.30 (quin, J = 6.6 Hz,
.
1H NMR
H,
2
CH2CH2CH2), 2.60 (t, J = 6.7 Hz, 2 H, CH2C=O), 3.89 (t, J = 6.0 Hz,
2 H, CCH2), 7.31–7.36 (m, 2 H, 2 × CH), 7.43–7.50 (m, 3 H, 3 ×
CH), 7.54 (t, J = 7.8 Hz, 1 H, CH), 7.70 (t, J = 7.6 Hz, 1 H, CH), 8.02
(d, J = 8.0 Hz, 1 H, CH), 8.47 (d, J = 8.6 Hz, 1 H, CH). 13C NMR
(75.5 MHz, DMSO-d6): δ = 20.9, 28.9 and 37.5 (3 × CH2), 99.8 (C–
CN), 114.6 (C), 116.7 (CN), 117.1, 119.9, 122.9 and 126.9 (4 ×
CH), 127.8 (2 × CH), 127.9 (2 × CH), 128.2 (CH), 130.2, 137.6,
145.3, 145.8, 150.1 and 156.1 (6 × C), 193.5 (C=O). MS: m/z
(%) = 337 (100) [M+], 312 (58), 299 (4), 280 (43), 255 (19), 140
(13), 127 (19), 115 (18), 102 (30), 91 (32), 77 (49), 55 (26), 41
(24). Anal. Calcd for C22H15N3O (337.38): C, 78.32; H, 4.48; N,
12.45. Found: C, 78.26; H, 4.54; N, 12.37.
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5-(4-Nitrophenyl)-4-oxo-1,2,3,4-tetrahydro[1,3]benzimid-
azo[1,2-a]quinoline-6-carbonitrile (7c)
Yield 0.325 g (85%); pale yellow solid; mp 267–269 °C. IR (KBr):
2230 (CN), 1677 (C=O), 1581, 1511, 1494, 1449, 1416, 1376,
1337, 1303, 1247, 1198, 1128, 1017, 930, 850, 766, 730, 691
cm–1. 1H NMR (400.1 MHz, DMSO-d6): δ = 2.31 (quin, J = 6.7 Hz,
2 H, CH2CH2CH2), 2.61 (t, J = 6.7 Hz, 2 H, CH2C=O), 3.92 (t, J = 6.3
Hz, 2 H, CCH2), 7.58 (t, J = 7.8 Hz, 1 H, CH), 7.66 (d, J = 9.0 Hz, 2
H, 2 × CH), 7.73 (t, J = 7.8, Hz, 1 H, CH), 8.05 (d, J = 8.2, Hz, 1 H,
CH), 8.35 (d, J = 9.0 Hz, 2 H, 2 × CH), 8.50 (d, J = 8.6 Hz, 1 H, CH).
13C NMR (75.5 MHz, DMSO-d6): δ = 19.8, 28.9 and 37.2 (3 × CH2)
99.9 (C–CN), 114.2 (C), 116.1 (CN), 117.2 and 120.0 (2 × CH),
123.16 (2 × CH), 123.17 and 127.2 (2 × CH), 129.3 (2 × CH),
130.2, 144.9, 145.3, 145.4, 147.2, 147.8 and 156.4 (7 × C), 193.6
(C=O). MS: m/z (%) = 382 (15) [M+], 352 (9), 334 (5), 308 (6), 291
(32), 263 (28), 232 (17), 208 (18), 173 (28), 153 (19), 135 (38),
115 (54), 105 (50), 93 (82), 77 (100), 65 (91), 55 (71), 41 (86).
Anal. Calcd for C22H14N4O3 (382.38): C, 69.10; H, 3.69; N, 14.65.
Found: C, 69.03; H, 3.75; N, 14.63.
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56, 1933. (b) Adib, M.; Soheilizad, M.; Zhu, L. G.; Wu, J. Synlett
2015, 26, 177. (c) Adib, M.; Soheilizad, M.; Rajai-Daryasarei, S.;
Mirzaei, P. Synlett 2015, 26, 1101. (d) Adib, M.; Bayanati, M.;
Soheilizad, M.; Janatian Ghazvini, H.; Tajbakhsh, M.; Amanlou,
M. Synlett 2014, 25, 2918. (e) Mahernia, S.; Mahdavi, M.; Adib,
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(12) General Procedure for the Preparation of Product 7a–l,
Exemplified with 7a
A mixture of benzene-1,2-diamine (0.108 g, 1 mmol) and cyclo-
hexane-1,3-dione (0.112 g, 1 mmol) in EtOH–H2O (1:1, 3 mL)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D