Synthesis of 1-(Cyclohexylamino)-2-(aryl)pyrrolo[1,2-a]quinoline-3- carbonitrile Derivatives Using a Mild, Four-Component Reaction

Article abstract of DOI:10.1002/jhet.1913

1-(Cyclohexylamino)-2-(aryl)pyrrolo[1,2-a]quinoline-3-carbonitrile derivatives were synthesized in an efficient method from four-component condensation reaction between cyclohexyl isocyanide, quinoline, malononitrile, and aromatic aldehydes in the presence of a catalytic amount of titanium dioxide (TiO₂) in CH₂Cl₂ at ambient temperature in good yields. Silica gel column chromatography was employed for HCN elimination and then 1, 3 hydrogen shift was led to form final products 5a, 5b, 5c, 5d, 5e.

Full text of DOI:10.1002/jhet.1913

E152
Synthesis of 1-(Cyclohexylamino)-2-(aryl)pyrrolo[1,2-a]quinoline-3-
carbonitrile Derivatives Using a Mild, Four-Component Reaction
Vol 51
a
a
b
a
*
Malek Taher Maghsoodlou, Nourallah Hazeri, Khatereh Khandan-Barani, Sayyed Mostafa Habibi-Khorasani,
and Alireza Abedia
aDepartment of Chemistry, Faculty of Science, The University of Sistan and Baluchestan, PO Box 98135-674,
Zahedan, Iran
bDepartment of Chemistry, Zahedan Branch, Islamic Azad University, Zahedan, Iran
*
E-mail: mt_maghsoodlou@yahoo.com
Received May 31, 2012
DOI 10.1002/jhet.1913
Published online 18 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
1-(Cyclohexylamino)-2-(aryl)pyrrolo[1,2-a]quinoline-3-carbonitrile derivatives were synthesized in an
efficient method from four-component condensation reaction between cyclohexyl isocyanide, quinoline,
malononitrile, and aromatic aldehydes in the presence of a catalytic amount of titanium dioxide (TiO2) in
CH2Cl2 at ambient temperature in good yields. Silica gel column chromatography was employed for HCN
elimination and then 1, 3 hydrogen shift was led to form final products 5a–5e.
J. Hetercyclic Chem., 51, 152 (2014).
INTRODUCTION
(aryl)pyrrolo[1,2-a]quinoline-3-carbonitrile derivatives 5 by
a four-component condensation reaction (Scheme 1).
The rapid assembly of molecular diversity utilizing
multicomponent reactions (MCRs) has received a great
deal of attention, most notably for the construction of
heterocyclic “drug-like” libraries [1–3]. The atom economical
and convergent character, the simplicity of a one-pot
procedure, the possible structural variations, and accessi-
ble compounds are among the described advantages of
MCRs [4]. Thus, they are perfectly amenable to automation
for combinatorial synthesis [5]. Isocyanide-based multi-
component reactions (IMCRs) now occupy a position
of importance in synthetic organic chemistry, mainly
because of the contributions of Ugi and co-workers [6].
Many derivatives of quinoline have been studied for
different biological activities, such as antimicrobial [7],
anti-inflammatory [8], antileishmanial [9], antituberculosis
[10], antimalaria [11,12], cytotoxicity [13], and HIV-1 inte-
grase inhibitors [14]. Because of their biological importance,
quinoline derivatives such as pyrroloquinolines have
become synthetic targets of many organic and medicinal
chemists [15–21].
In the past years, the pharmaceutical industry has
focused more and more on diversity-oriented and biased
combinatorial libraries [22]. Furthermore, the discovery
of novel MCRs can be consider as an interesting topic for
academic research that also satisfies a practical interest of
applied science [23].
Because of the aforementioned finding and as a part of our
ongoing research program on the IMCRs [24–31], we report
herein the synthesis of substituted 1-(cyclohexylamino)-2-
RESULTS AND DISCUSSION
In this paper, the reaction between aromatic aldehydes 1,
malonitrile 2, and cyclohexyl isocyanide 3 in the presence
of quinoline 4 at room temperature with a catalytic amount
of titanium dioxide (TiO2) was led to form final products
5a–5e.
The structure of compounds 5a–5e was deduced from
IR, 1H NMR, 13C NMR, mass spectral data, and elemental
analysis. The mass spectra of these compounds 5a–5e
displayed M+ or M+ + 1 peaks at appropriate m/z values.
1
The H NMR spectrum of compound 5a exhibited three
multiplet signals at d 0.99–1.74, 2.73, and 6.92–7.71ppm
because of cyclohexyl ring, N–CH of cyclohexyl and
aromatic protons, respectively, and two singlet signals at
d 3.84 and 3.86 ppm because of methoxy group protons.
In addition, characteristic signals for two protons of quino-
line were observed at d 7.56 ppm (1H, d, J = 8.50 Hz) and
d 9.56 ppm (1H, d, J = 8.50Hz).
The 13C NMR spectrum of each compound displayed
resonances in agreement with proposed structure. The
characteristic signal because of nitrile carbon was discern-
ible at d 118.1 ppm. The carbon of pyrrole ring (C–CN)
resonated at d 92.1 ppm. Partial assignment of these
resonances is given in the experimental data.
1
The structural assignment made on the basis of the H
and 13C NMR spectra of compound 5a was supported by
© 2014 HeteroCorporation

August 2014
Synthesis of 1-(Cyclohexylamino)-2-(aryl)pyrrolo[1,2-a]quinoline-3-carbonitrile
Derivatives Using a Mild, Four-Component Reaction
E153
Scheme 1. Synthesis of 1-(cyclohexylamino)-2-(aryl)pyrrolo[1,2-a]quinoline-
Scheme 2. Proposed mechanism for synthesis of 1- (cyclohexylamino)-2-
3-carbonitrile derivatives.
(aryl)pyrrolo [1,2-a] quinoline-3-carbonitriles.
2-(aryl)pyrrolo[1,2-a]quinoline-3-carbonitrile derivatives
starting from simple and readily available precursors.
Therefore, the investigated compounds were synthesized in
an efficient method from the reaction of cyclohexyl isocya-
nide, quinoline, malononitrile, and aromatic aldehydes in
the presence of a catalytic amount of titanium dioxide
(TiO2) in CH2Cl2 at ambient temperature in good yields.
Also, we suggest the catalytic effect for silica gel in HCN
elimination to produce 1-(cyclohexylamino)-2-(aryl)pyrrolo
[1,2-a]quinoline-3-carbonitrile derivatives.
measurement of its IR spectra. The IR spectrum of 5a
showed absorption at 3341 cm–1 because of the NH
group and a strong absorption at 2209 cmÀ1 is due to
CN bond stretch. The 1H and 13C NMR spectra of
5b–5e are similar to 5a, and the results are reported in the
experimental section.
The proposed mechanism has been shown in Scheme 2.
The reaction may be rationalized with initial formation
of conjugated electron-deficient molecule 8 by standard
Knoevenagel condensation between the aromatic aldehydes
1 and malononitrile 2 in the presence of TiO2, Thus, inter-
mediate 6 can be formed and after losing a molecule of
water from 7, molecule 8 and TiO2 were afforded [32].
Then, mechanism followed by cyclohexyl isocyanide
addition to form intermediate 9, complex 9 activates the
isocyanide functional group sufficiently for further nucle-
ophilic attack by quinoline 4 to produce intermediate 10.
Subsequently, intramolecular cyclization of 10 leads to
generation of 11. Finally, pyrroloquinoline derivatives 5
are formed by using silica gel column chromatography.
Silica gel column chromatography was employed for
elimination of HCN to afford 12. Compound 12 undergoes
1,3 hydrogen shift to form product 5 (Scheme 2).
EXPERIMENTAL
2,5-Dimethoxy benzaldehyde, 2,3-dimethoxy benzaldehyde,
4-fluoro benzaldehyde, 4-nitro benzaldehyde, 3-chloro benzalde-
hyde, cyclohexyl isocyanide, malononitrile, and quinoline were
purchased from Fluka, Aldrich, and Merck and used without
further purification. Deuterochloroform, petroleum ether and
ethylacetate were purchased from Merck manufacture. Melting
points and IR spectra were measured on an Electrothermal
9100 apparatus (England) and a Shimadzu IR-460 spectrometer
(Kyoto, Japan), respectively. The 1H and 13C NMR spectra
were recorded on a Bruker DRX-250 Avance (Germany)
instrument with CDCl3 as solvent at 250.1 and 62.9 MHz,
respectively. Mass spectra were recorded on a Shimadzu GC/
MS QP 1100 EX mass spectrometer (Japan) operating at
In conclusion, this study reports four-component
condensation reaction leading to 1-(cyclohexylamino)-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E154
M. T. Maghsoodlou, N. Hazeri, K. Khandan-Barani, S. M. Habibi-Khorasani, and A. Abedi
Vol 51
an ionization potential of 70eV. Elemental analysis for C, H, and N
were performed by using a Heraeus CHN–O Rapid analyzer
(Germany).
1-(Cyclohexylamino)-2-(4-nitrophenyl)pyrrolo[1,2-a]
quinoline-3-carbonitrile (5d). Yellow powder, yield 0.36 g
(88%), mp 151–153ꢀC; IR (KBr) (nmax, cmÀ1): 3435 (NH),
1
General procedure for the synthesis of 1-(cyclohexylamino)-
2-(aryl)pyrrolo[1,2-a]quinoline-3-carbonitrile derivatives
(5a–e). The process for the preparation of 1-(cyclohexylamino)-
2-(2,5-dimethoxyphenyl)pyrrolo[1,2-a]quinoline-3-carbonitrile (5a)
is described as an example. The solution of cyclohexyl
isocyanide (0.11 g, 1 mmol) in 3 mL of CH2Cl2 solvent was
slowly added dropwise to a stirred solution of an equimolar
mixture of malononitrile (0.06 g, 1 mmol), quinoline (0.13 g,
1 mmol), and 2,5-dimethoxy benzaldehyde (0.17 g, 1 mmol)
in the presence of a catalytic amount of titanium dioxide (TiO2)
in CH2Cl2. The reaction mixture is stirred for 12 h at
room temperature. The solvent was removed under reduced
pressure, and the residue was purified by silica gel column
chromatography with the used of petroleum ether–ethylacetate
(90:10).
2209 (CN); H NMR (250.1 MHz, CDCl3): d 0.82–1.74 (10H,
m, 5CH2), 2.72–2.80 (1H, m, NCH), 7.26–7.76 (9H, m, NH
and CHarom), 8.38 (1H, d, J = 8.50 Hz, CH), 9.42 (1H, d,
J = 8.50 Hz, CH); 13C NMR (62.9 MHz, CDCl3): d 24.7, 25.4,
33.1 (3s, 5CH2 of cyclohexyl), 56.9 (s, NCH of cyclohexyl),
83.5 (C(CN)), 116.3 (CN), 117.8, 124.3, 124.4, 125.1, 125.3,
128.1, 128.8, 129.7, 133.1, 134.4, 134.6, 139.6, 146.9; ms
(m/z, %): 410 (M+, 9), 327 (25), 280 (20), 167 (10), 150
(15), 83 (48), 77 (20), 55 (100). Anal. Calcd for C25H22N4O2
(410.47): C, 73.15; H, 5.40; N, 13.65%. Found: C, 73.21; H,
5.49; N, 13.72%.
1-(Cyclohexylamino)-2-(3-chlorophenyl)pyrrolo[1,2-a]
quinoline-3-carbonitrile (5e).
Yellow powder; yield 0.36 g
(90%), mp 100–102ꢀC; IR (KBr) (nmax, cmÀ1): 3340 (NH), 2209
(CN); 1H NMR (250.1 MHz, CDCl3): d 0.63–1.73 (10H, m,
5CH2 of cyclohexyl), 2.65–2.87 (1H, m, NCH of cyclohexyl),
7.26–7.73 (9H, m, NH and CHarom), 8.10 (1H, d, J = 8.50Hz,
CH), 9.44 (1H, d, J = 8.50 Hz, CH); 13C NMR (62.9MHz,
CDCl3): d 24.5, 25.5, 34.1 (3s, 5CH2 of cyclohexyl), 53.3
(s, NCH of cyclohexyl), 87.7 (C(CN)), 116.4 (CN), 118.8,
124.6, 124.8, 125.3, 125.5, 127.4, 128.8, 129.0, 133.3, 134.8,
135.0, 138.5, 147.6; ms (m/z, %): 401 (M++2, 23), 399 (M+, 64),
364 (3), 316 (100), 289 (20), 281 (45), 128 (32), 55 (57). Anal.
Calcd for C25H22ClN3 (399.92): C, 75.08; H, 5.54; N, 10.51%.
Found: C, 75.29; H, 5.62; N, 10.59%.
1-(Cyclohexylamino)-2-(2,5-dimethoxyphenyl)pyrrolo[1,2-
a]quinoline-3-carbonitrile (5a). Yellow powder, yield 0.34 g
(80%), mp 130–132ꢀC; IR (KBr) (nmax, cmÀ1): 3341 (NH),
1
2209 (CN); H NMR (250.1 MHz, CDCl3): d 0.99–1.74 (10H,
m, 5CH2 of cyclohexyl), 2.73 (1H, m, NCH), 3.84 and 3.86 (2s,
2OCH3), 6.92–7.71 (8H, m, NH and CHarom), 7.56 (1H, d,
J = 8.50 Hz, CH), 9.56 (1H, d, J = 8.50 Hz, CH); 13C NMR
(62.9 MHz, CDCl3):
d 24.8, 25.6, 33.1 (3s, 5CH2 of
cyclohexyl), 55.9 and 57.0 (2s, 2OCH3), 56.3 (s, NCH of
cyclohexyl), 92.1 (C–CN), 113.6, 114.7, 116.5, 116.8, 118.1
(CN), 123.1, 124.5, 125.2, 127.7, 128.4, 134.9, 133.5, 150.5,
152.5, 154.2; ms (m/z, %): 425 (M+, 42), 342 (83), 311 (11),
223 (18) 165 (38), 129 (41), 77 (58), 55 (100). Anal. Calcd for
C27H27N3O2 (425.52): C, 76.21; H, 6.40; N, 9.87%. Found: C,
76.39; H, 6.49; N, 9.99%.
Acknowledgments. We gratefully acknowledge financial support
from the Research Council of University of Sistan and
Baluchestan.
1-(Cyclohexylamino)-2-(2,3-dimethoxyphenyl)pyrrolo[1,2-
a]quinoline-3-carbonitrile (5b).
Pale yellow powder, yield
0.33 g (78%), mp 138–140ꢀC; IR (KBr) (nmax, cmÀ1): 3325
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(NH), 2200 (CN); H NMR (250.1 MHz, CDCl3): d 0.83–1.84
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J = 8.50 Hz, CH), 9.47 (1H, d, J = 8.50Hz, CH); 13C NMR
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Synthesis of 1-(Cyclohexylamino)-2-(aryl)pyrrolo[1,2-a]quinoline-3-carbonitrile
Derivatives Using a Mild, Four-Component Reaction
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