A one-pot four-component synthesis of pyrrolo[1,2-a]quinolines

Article abstract of DOI:10.3184/174751914X14031091272010

A facile one-pot, four-component reaction for the synthesis of pyrrolo[1,2-a]quinolines is described. Knoevenagel condensation reaction of malononitrile and aromatic aldehydes gave 2-arylmethylidenemalononitriles which on treatment with quinoline and cycl

Full text of DOI:10.3184/174751914X14031091272010

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 JULY, 423–426
RESEARCH PAPER 423
A one-pot four-component synthesis of pyrrolo[1,2-a]quinolines
Mehdi Adiba*, Marjan Azimzadeha, Mehdi Rahimi-Nasrabadib and Long-Guan Zhuc
aSchool of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
bDepartment of Chemistry, Imam Hossein University, Tehran, Iran
cChemistry Department, Zhejiang University, Hangzhou 310027, P.R. China
A facile one-pot, four-component reaction for the synthesis of pyrrolo[1,2-a]quinolines is described. Knoevenagel condensation
reaction of malononitrile and aromatic aldehydes gave 2-arylmethylidenemalononitriles which on treatment with quinoline and
cyclohexyl isocyanide under solvent-free conditions afforded 1-(cyclohexylamino)-2-arylpyrrolo[1,2-a]quinoline-3-carbonitriles
in good yields.
Keywords: four-component reactions, pyrrolo[1,2-a]quinolines, 2-arylmethylidenemalononitriles, cyclohexyl isocyanide
Bridgehead nitrogen heterocycles are of interest because
they constitute an important class of natural and non-natural
products, many of which exhibit useful biological activity.
Pyrrolo[1,2-a]quinolines (benzo analogues of indolizines),
tricyclic-fused 6:6:5 systems, have attracted much synthetic
attention. The interest in these heterocycles stems from the
H
occurrence of some saturated and partially saturated derivatives
H
in many biologically active compounds.1–3 For example,
gephyrotoxin (Fig. 1), a natural alkaloid with a saturated
pyrrolo[1,2-a]quinoline skeleton, has shown activity as a
muscarinic antagonist.4,5 In addition, some pyrroloquinolines
have been used as pesticides, light-sensitive and photographic
materials and in electroluminescent devices.6–11
N
H
OH
One of the most powerful methods for the synthesis of
pyrrolo[1,2-a]quinolines is 1,3-dipolar cycloaddition of
quinolinium N-methylides with different dipolarophiles such
as active alkenes and alkynes.3,12 Recently, various metal-
catalysed cyclisations have been developed.13–15
Fig. 1 Structure of gephyrotoxin.
1
Full characterisation involving IR, H NMR and 13C NMR
spectroscopy, mass spectrometry and elemental analysis
demonstrated the identity of the isolated products. The IR
spectrum of 5a showed the stretching bands for the amine and
nitrile functionalities at 3325 and 2210 cm–1, respectively. The
mass spectrum of 5a displayed the molecular ion [M+] peak
at m/z=365, which was consistent with the 1:1:1:1 adduct
of benzaldehyde, malononitrile, quinoline and cyclohexyl
In 2003, Mironov et al.16 defined a new three-component
reaction between isoquinoline, gem-dicyanoalkenes and
isocyanides. They assigned 1,10b-dihydropyrrolo[2,1-a]
isoquinoline-2,2(3H)-dicarbonitriles as the structures of
the isolated products. In 2011, Li and coworkers17 developed
this reaction to phenanthridine and reported the synthesis of
2,3-dihydropyrrolo[1,2-fꢀ]phenanthridines. Recently, four-
component versions of this reaction have been developed for the
preparation of pyrrolo[1,2-a][1,10]phenanthrolines,18,19 2-Aryl-
1-(cyclohexylimino)-1,2-dihydropyrrolo[1,2-a]quinoline-
3,3(3aH)-dicarbonitriles,20 and 2-aryl-3-(cyclohexylimino)-2,3-
dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitriles.21
Due to the unique properties of pyrrolo[1,2-a]quinolines,
the development of synthetic methods which enable facile
access to these useful entities are desirable. As part of our
studies on the development of efficient and facile methods
for the preparation of biologically active heterocyclic
compounds from readily available building blocks,22–25 we
now report an efficient four-component synthesis of 2-aryl-
1-(cyclohexylamino)-pyrrolo[1,2-a]quinoline-3-carbonitriles.
Thus, heating a mixture of an aldehyde 1 and malononitrile
2 at 70 °C for 40 min under solvent-free conditions gave
2-arylmethylidenemalononitriles 6. After nearly complete
conversion to 6 as was indicated by TLC monitoring, quinoline
3 and cyclohexyl isocyanide 4 were added to the reaction
mixture and stirring was continued at 70 °C for 35 min under
solvent-free conditions to afford 1-(cyclohexylamino)-2-
arylpyrrolo[1,2-a]quinoline-3-carbonitriles 5a–f in 78–94%
yields (Schemes 1 and 2).
1
isocyanide with the loss of H2O and HCN molecules. The H
NMR spectrum of 5a consisted of multiplet signals for the eleven
protons of the cyclohexyl ring at δ 0.84–1.75 and δ 2.66–2.85
[CH(CH2)5]. A broadened doublet was seen for the amine NH
group (δ 3.95, J=8.1 Hz) because of coupling with the adjacent
CH group along with characteristic signals with appropriate
chemical shifts and coupling constants for the eleven aromatic
H-atoms. The H decoupled 13C NMR spectrum of 5a showed
1
21 distinct resonances in agreement with the assigned structure.
Single-crystal X-ray analysis of 5a confirmed conclusively its
structure, and by analogy, those of the other isolated products.
An ORTEP diagram of 5a is shown in Fig. 2. Selected X-ray
crystallographic data for compound 5a are summarised in
Table 1.
A mechanistic rationalisation for this reaction is provided
in Scheme 2. The first step is the formation of dicyanostyrene
6 by the Knoevenagel condensation reaction of aromatic
aldehyde 1 and malononitrile 2. The electrophilic carbon
atom of dicyanostyrene may undergo nucleophilic addition
of isocyanide 4 leading to the highly reactive zwitterionic
intermediate 7. 1,3-Dipolar cycloaddition reaction of the
zwitterion with quinoline 3 as dipolarophile gives the
1,2-dihydropyrrolo[1,2-a]quinoline intermediate 8. Subsequent
elimination of hydrogen cyanide and tautomerisation affords the
pyrrolo[1,2-a]quinoline 5.
* Correspondent. E-mail: madib@khayam.ut.ac.ir

424 JOURNAL OF CHEMICAL RESEARCH 2014
O
_
C
solvent-free
70 oC
+
N
CN
N
Ar
H
+
+
NC
CN
+
N
N
Ar
H
4
2
1
3
5
5
Ar
Yield of 5 (%)a
5a
5b
5c
5d
5e
5f
Ph
94
83
90
80
78
88
3-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
aYields of isolated products.
Scheme 1 Reaction between aldehydes, malononitrile, quinoline, and cyclohexyl isocyanide.
Cy
3
O
N
Ar
CN
CN
+
_
H2O
N
NC
CN
+
Ar
H
CN
_
_
+
C
Cy N
1
2
6
Ar
CN
4
7
H
CN
CN
_
HCN
CN
N
N
Cy
N
Cy N
Ar
Ar
H
H
8
5
Scheme 2 Proposed mechanism for the formation of pyrrolo[1,2-a]quinolines 5.
Table 1 Crystallographic data and refinement parameters for 5a.
Empirical formula
C25H23N3
Crystal system
Space group
Monoclinic
P21/n
a/Å
b/Å
c/Å
β/°
V/Å3
Z
7.0339(3)
15.2876(7)
18.4356(9)
96.537(4)
1969.52(9)
4
Dc/g cm–3
µ/mm–1
1.232
0.073
Observed reflections
T/K
R1, wR2 [I>2σ (I)]
R1, wR2 [all data]
2564
295(2)
0.040, 0.111
0.063, 0.142
Fig. 2 ORTEP diagram of the molecular structure of 5a.

JOURNAL OF CHEMICAL RESEARCH 2014 425
(br s, 1H, NH), 7.28 (d, J=9.1 Hz, 1H, ArH), 7.37 (d, J=8.5 Hz, 2H,
2ArH), 7.44–7.50 (m, 2H, 2ArH), 7.57 (td, J=7.7, 1.5 Hz, 1H, ArH),
7.64 (d, J=8.5 Hz, 2H, 2ArH), 7.71 (dd, J=7.7, 1.3 Hz, 1H, ArH), 9.43
(d, J=8.5 Hz, 1H, ArH). 13C NMR (62.9 MHz, CDCl3): δ 24.8, 25.5,
33.1, 56.7, 83.6, 116.3, 116.5, 117.9, 121.2, 121.8, 123.7, 124.8, 125.3,
127.9, 128.6, 130.7, 131.6, 132.3, 132.7, 133.8, 134.7. EI-MS: m/z
(%)=445 (M+ 81Br, 48), 443 (M+ 79Br, 47), 362 (100), 360 (97), 281 (80),
242 (9), 128 (76), 101 (15), 83 (21), 55 (76). Anal. calcd for C25H22BrN3
(444.37): C, 67.57; H, 4.99; N, 9.46; found: C, 67.49; H, 5.12, N, 9.40%.
1-(Cyclohexylamino)-2-(4-methylphenyl)pyrrolo[1,2-a]quinoline-
3-carbonitrile (5d): Pale yellow crystals; yield: 0.30 g (80%), m.p.
179–181 °C. IR (KBr) (νmax/cm–1): 3333 (NH), 2199 (CN), 1606, 1538,
In summary, we have developed a facile one-pot and
four-component reaction between malononitrile, aromatic
aldehydes, quinoline and cyclohexyl isocyanide for the
preparation of pyrrolo[1,2-a]quinolones of potential synthetic
and pharmacological interest. Solvent-free conditions, good
to excellent yields of the products, use of simple and readily
available starting materials, and fairly short reaction times are
the main advantages of this method.
Experimental
All the chemicals were obtained from Merck (Germany), and were
used without further purification. Melting points were measured
on an Electrothermal 9100 apparatus. IR spectra were recorded on
a Shimadzu IR-460 spectrometer. Elemental analyses for C, H and
N were performed using a Heraeus CHN-O-rapid analyser. Mass
spectra were recorded on an Agilent Technologies (HP) 5973 mass
spectrometer operating at an ionisation potential of 20 eV. 1H and
13C NMR spectra were measured using Bruker DPX-250 Avance (at
250.1 and 62.9 MHz) and Bruker DRX-300 Avance (at 300.1 MHz)
spectrometers using CDCl3 solvent with TMS as an internal
standard. X-ray crystallography was performed on a Bruker SMART
diffractometer equipped with a CCD area detector with graphite
monochromatised Mo‑Kα radiation. Chromatography columns were
prepared from Merck silica gel 60 mesh.
1
1503, 1440, 1406, 1347, 1190, 1079, 803, 746. H NMR (250.1 MHz,
CDCl3): δ 0.81–1.73 [m, 10H, CH(CH2)5], 2.42 (s, 3H, CH3), 2.63–2.82
(br m, 1H, CH), 3.86–3.98 (br s, 1H, NH), 7.23 (d, J=9.1 Hz, 1H,
ArH), 7.30 (d, J=8.0 Hz, 2H, 2ArH), 7.40–7.43 (m, 3H, 3ArH), 7.47 (d,
J=9.1 Hz, 1H, ArH), 7.54 (td, J=7.7, 1.5 Hz, 1H, ArH), 7.69 (dd, J=7.7,
1.3 Hz, 1H, ArH), 9.44 (d, J=8.5 Hz, 1H, ArH). 13C NMR (62.9 MHz,
CDCl3): δ 21.4, 24.9, 25.6, 33.0, 56.6, 84.0, 116.3, 116.9, 117.9, 122.3,
123.2, 124.6, 125.3, 127.7, 128.5, 129.0, 129.7, 129.8, 132.8, 133.6,
134.8, 137.3. EI-MS: m/z (%)=379 (M+, 67), 296 (100), 281 (36), 269
(15), 241 (4), 128 (65), 101 (10), 83 (24), 55 (55). Anal. calcd for C26H25N3
(379.50): C, 82.29; H, 6.64; N, 11.07; found: C, 82.26; H, 6.66, N,
10.97%.
1-(Cyclohexylamino)-2-(4-methoxyphenyl)pyrrolo[1,2-a]quinoline-
3-carbonitrile (5e): Pale yellow crystals; yield: 0.31 g (78%), m.p.
159–160 °C. IR (KBr) (νmax/cm–1): 3371 (NH), 2196 (CN), 1611, 1567,
Synthesis of 5a–f; general procedure
A mixture of the appropriate aldehyde (1, 1.0 mmol) and malononitrile
(2, 1.2 mmol) was stirred at 70 °C for 40 min. After complete
conversion to the 2-arylmethylidenemalononitrile, as was indicated
by TLC monitoring, the mixture was allowed to cool to ambient
temperature. Then quinoline (3, 1.0 mmol) was added, followed by
addition of cyclohexyl isocyanide (4, 1.0 mmol) and stirred at 70 °C for
35 min. After cooling to room temperature, the product was purified by
column chromatography using 10:1 n-hexane-EtOAc as eluent.
1-(Cyclohexylamino)-2-phenylpyrrolo[1,2-a]quinoline-3-
carbonitrile (5a): Pale yellow crystals; yield: 0.34 g (94%), m.p.
153–155 °C. IR (KBr) (νmax/cm–1): 3325 (NH), 2210 (CN), 1603, 1546,
1
1540, 1442, 1284, 1245, 1173, 1142, 1031, 831, 798, 748. H NMR
(250.1 MHz, CDCl3): δ 0.83–1.73 [m, 10H, CH(CH2)5], 2.64–2.83 (br
m, 1H, CH), 3.76–3.88 (br s, 1H, NH), 3.88 (s, 3H, OCH3), 7.04 (d,
J=8.8 Hz, 2H, 2ArH), 7.25 (d, J=9.1 Hz, 1H, ArH), 7.40 (d, J=8.8 Hz,
2H, 2ArH), 7.41–7.43 (m, 1H, ArH), 7.48 (d, J=9.1 Hz, 1H, ArH),
7.52 (td, J=7.6, 1.3 Hz, 1H, ArH), 7.69 (d, J=7.7 Hz, 1H, ArH), 9.45
(d, J=8.5 Hz, 1H, ArH). 13C NMR (62.9 MHz, CDCl3): δ 24.8, 25.6,
33.0, 55.3, 56.6, 84.0, 114.6, 116.4, 116.8, 117.8, 122.1, 123.1, 124.6,
124.9, 125.3, 127.7, 128.5, 130.3, 132.7, 133.5, 134.8, 159.0. EI-MS: m/z
(%)=395 (M+, 84), 312 (100), 297 (9), 281 (16), 268 (23), 242 (15), 128
(41), 101 (7), 83 (18), 55 (60). Anal. calcd for C26H25N3O (395.50): C,
78.96; H, 6.37; N, 10.62; found: C, 78.88; H, 6.29, N, 10.57%.
1
1497, 1448, 1414, 1346, 1075, 793, 743, 692. H NMR (300.1 MHz,
CDCl3): δ 0.84–1.75 [m, 10H, CH(CH2)5], 2.66–2.85 (br m, 1H, CH),
3.95 (d, J=8.1 Hz, 1H, NH), 7.28 (d, J=9.1 Hz, 1H, ArH), 7.42–7.61 (m,
8H, 8ArH), 7.72 (d, J=7.7 Hz, 1H, ArH), 9.47 (d, J=8.6 Hz, 1H, ArH).
13C NMR (62.9 MHz, CDCl3): δ 24.8, 25.5, 33.0, 56.6, 83.9, 116.4, 116.7,
117.9, 122.2, 123.3, 124.7, 125.3, 127.6, 127.7, 128.6, 129.1, 129.2, 132.6,
132.9, 133.7, 134.8. EI-MS: m/z (%)=365 (M+, 53), 282 (100), 255 (21),
128 (64), 97 (14), 84 (79), 69 (24), 55 (42). Anal. calcd for C25H23N3
(365.48): C, 82.16; H, 6.34; N, 11.50; found: C, 82.05; H, 6.42, N,
11.39%.
2-(3-Chlorophenyl)-1-(cyclohexylamino)pyrrolo[1,2-a]quinoline-
3-carbonitrile (5b): Pale yellow crystals; yield: 0.33 g (83%), m.p.
197–198 °C. IR (KBr) (νmax/cm–1): 3321 (NH), 2208 (CN), 1599, 1558,
1485, 1446, 1410, 1346, 1072, 888, 791, 745, 678. 1H NMR (250.1 MHz,
CDCl3): δ 0.84–1.74 [m, 10H, CH(CH2)5], 2.68–2.80 (m, 1H, CH), 3.81
(br s, 1H, NH), 7.27 (d, J=9.1 Hz, 1H, ArH), 7.35–7.49 (m, 6H, 6ArH),
7.57 (td, J=7.6, 1.3 Hz, 1H, ArH), 7.71 (dd, J=7.7, 1.1 Hz, 1H, ArH),
9.43 (d, J=8.5 Hz, 1H, ArH). 13CNMR (62.9 MHz, CDCl3): δ 24.8,
25.5, 33.0, 56.7, 83.7, 116.2, 116.4, 117.8, 120.9, 123.7, 124.8, 125.2,
127.4, 127.7, 127.9, 128.6, 128.9, 130.3, 132.9, 133.8, 134.5, 134.7, 134.8.
EI-MS: m/z (%)=401 (M+ 37Cl, 19), 399 (M+ 35Cl, 57), 316 (100), 281
(82), 128 (67), 101 (13), 83 (23), 55 (66). Anal. calcd for C25H22ClN3
(399.92): C, 75.08; H, 5.54; N, 10.51; found: C, 75.15; H, 5.58, N,
10.42%.
2-(4-Chlorophenyl)-1-(cyclohexylamino)pyrrolo[1,2-a]quinoline-
3-carbonitrile (5f): Pale yellow crystals; yield: 0.35 g (88%), m.p.
206–207 °C. IR (KBr) (νmax/cm–1): 3380 (NH), 2204 (CN), 1601, 1536,
1
1493, 1443, 1406, 1347, 1137, 1089, 1012, 889, 802, 755. H NMR
(250.1 MHz, CDCl3): δ 0.82–1.73 [m, 10H, CH(CH2)5], 2.65–2.79 (m,
1H, CH), 3.80 (d, J=7.5 Hz, 1H, NH), 7.27 (d, J=9.1 Hz, 1H, ArH),
7.41–7.51 (m, 6H, 6ArH), 7.57 (td, J=7.6, 1.5 Hz, CH, ArH), 7.71
(dd, J=7.6, 1.1 Hz, 1H, ArH), 9.43 (d, J=8.5 Hz, 1H, ArH). 13C NMR
(62.9 MHz, CDCl3): δ 24.8, 25.5, 33.1, 56.7, 83.7, 116.3, 116.5, 117.9,
121.2, 123.7, 124.8, 125.3, 127.9, 128.6, 129.3, 130.4, 131.2, 132.8, 133.6,
133.8, 134.7. EI-MS: m/z (%)=401 (M+ 37Cl, 7), 399 (M+ 35Cl, 22), 318
(35), 316 (99), 281 (57), 253 (6), 128 (86), 101 (17), 83 (38), 55 (100).
Anal. calcd for C25H22ClN3 (399.92): C, 75.08; H, 5.54; N, 10.51; found:
C, 74.89; H, 5.57, N, 10.46%.
CCDC 965834 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif
This research was supported by the Research Council of
University of Tehran.
2-(4-Bromophenyl)-1-(cyclohexylamino)pyrrolo[1,2-a]quinoline-
3-carbonitrile (5c): Pale yellow crystals; yield: 0.40 g (90%), m.p.
214–216 °C. IR (KBr) (νmax/cm–1): 3350 (NH), 2202 (CN), 1537, 1491,
1443, 1408, 1349, 1137, 1075, 1008, 801, 754. H NMR (250.1 MHz,
CDCl3): δ 0.83–1.74 [m, 10H, CH(CH2)5], 2.68–2.76 (m, 1H, CH), 3.80
Received 12 March 2014; accepted 4 June 2014
Paper 1402521 doi: 10.3184/174751914X14031091272010
Published online: 12 July 2014
1

426 JOURNAL OF CHEMICAL RESEARCH 2014
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