A facile one-pot synthesis of 2-amino-4-arylbenzo[h]quinoline-3- carbonitrile derivatives without catalyst

Article abstract of DOI:10.1002/jhet.5570440337

(Chemical Equation Presented) A series of 2-amino-4-arylbenzo[h]quinoline- 3-carbonitrile derivatives were synthesized by one-pot condensation of aromatic aldehyde, α-naphthylamine and malononitrile in ethanol without catalyst. This multicomponent reaction has the notable advantages of short route, high yield and convenient operation.

Full text of DOI:10.1002/jhet.5570440337

May-Jun 2007
735
A Facile One-pot Synthesis of 2-Amino-4-arylbenzo[h]quinoline-3-
carbonitrile Derivatives without Catalyst
Shujiang Tu,* Runhong Jia, Junyong Zhang, Yan Zhang, Bo Jiang.
Department of Chemistry, Xuzhou Normal University, Key Laboratory of Biotechnology on Medical
Plant, Xuzhou; Jiangsu, 221116, P. R. China
Received July 6, 2006
Ar
NH2
H
NC
CN
CN
EtOH
+
O
Ar
C
+
H2N
N
1
2
3
4
A series of 2-amino-4-arylbenzo[h]quinoline-3-carbonitrile derivatives were synthesized by one-pot
condensation of aromatic aldehyde, ꢀ-naphthylamine and malononitrile in ethanol without catalyst. This
multicomponent reaction has the notable advantages of short route, high yield and convenient operation.
J. Heterocyclic Chem., 44, 735 (2007).
amine and malononitrile as starting materials has not been
reported yet. In order to enlarge the libraries of 4-
arylbenzo[h]quinoline and explore the new classes of
biological active compounds, herein we report a facile
three-component one-pot synthesis of 2-amino-4-aryl-
benzo[h]quinoline-3-carbonitrile derivatives by the
reaction of aromatic aldehyde, ꢀ-naphthylamine and
malononitrile in ethanol (Scheme 1).
INTRODUCTION
The rapid assembly of molecular diversity is an
important goal of synthetic organic chemistry and one of
the key paradigms of modern drug discovery. One
approach to address this challenge involves the
development of multicomponent reactions (MCRs), in
which three or more reactants are combined together in a
single reaction flask to generate a product incorporating
most of the atoms contained in the starting materials. In
addition to the intrinsic atom economy and selectivity
underlying such reactions, simpler procedures and
equipment, time and energy savings, as well as
environmental friendliness have all led to a sizable effort
to design and implement MCRs in both academia and
industry [1-4].
RESULTS AND DISCUSSION
Choosing an appropriate solvent is of importance for
successful synthesis. In order to search for the optimum
solvent, the reaction of 4-chlorophenyl aldehyde 1a, ꢀ-
naphthylamine 2 and malononitrile 3 was examined using
glycol, DMF, glacial acetic acid and ethanol as solvent
respectively at 80 °C. The results were summarized in
Table 1, which showed that the reaction using ethanol as
solvent resulted in higher yield and shorter reaction time
(Entry 4 of Table 1). Therefore, ethanol was chosen as the
optimum solvent.
The products were synthesized by equimolecular
amounts of aromatic aldehyde, ꢀ-naphthylamine and
malononitrile without catalyst in ethanol. After refluxing
for 5-8 hours at 80 °C, the 2-amino-4-arylbenzo[h]quin-
oline-3-carbonitrile derivatives were obtained in high
yields (80-96%). The results are listed in Table 2.
The quinoline ring system exists in natural products,
especially alkaloids [5-7], and much attention has still been
paid to the synthesis of quinoline derivatives because of
their pharmacological properties. Especially, the benzo-
quinoline skeleton is found in many substances with
industrial applications or biological activity [8-10].
Furthermore, they are effective against infectious microbes,
have produced some improvements in Alzheimer’s disease,
and display good antipsychotic activity. Besides, benzo-
quinoline derivatives have marked anti-Parkinson activity
and are used in the chemotherapy of the mind [11].
This reaction may occur via
a
condensation,
Synthesis of compounds of benzoquinoline series has
been well documented [12-15]. Anderson and co-workers
synthesized benzoquinoline by the condensation of
malononitrile with aromatic aldehydes and alkyl ketones
in the presence of ammonium acetate [16,17]. Chkanikov
and co-workers synthesized dihydrobenzoquinoline by ꢀ-
naphthylamine and 1,1-dicyano-2,2-bis(trifluoromethyl)
ethylene [18]. However, the synthesis of 4-arylbenzo-
quinoline derivatives using aromatic aldehyde, naphthyl-
elimination, addition, cyclization, dehydrogenization
mechanism (Scheme 2). The condensation between
aromatic aldehyde 1 and ꢀ-naphthylamine 2 gives Schiff
base 5 which further undergoes in situ Michael addition
reaction with malononitrile 3 to yield intermediate 6,
followed by the elimination of ꢀ-naphthylamine to form
the intermediate product 7 which undergoes inter-
molecular cyclization, isomerisation, dehydrogenization,
finally affords 4.

736
S. Tu, R. Jia, J. Zhang, Y. Zhang, B. Jiang
Vol 44
Table 1
Solvent Optimization of synthesis 4a at 80 °C
Entry
Solvent
Time (h)
Y ield (%)[a]
1
2
3
4
glycol
HOAc
DMF
6
7
7
5
67
72
74
85
EtOH
[a] Yields of isolated compounds.
Table 2
Synthesis of 4
Product
Ar
Time (h)
Yield (%)[a]
Mp (ꢀꢁꢂꢃꢄ
ꢅ
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-ClC6H4
4-BrC6H4
4-FC6H4
5
8
5
7
5
6
8
8
5
85
80
89
92
90
90
95
95
96
236-239
244-246
194-196
239-242
246-249
298-300
247-248
280-283
273-274
2-ClC6H4
3,4-Cl2C6H3
2,4-Cl2C6H3
4-NO2C6H4
3-NO2C6H4
3-NO2-4-OHC6H3
[a] Yields of isolated compounds; [b] Melting points are uncorrected.
Scheme 1
Ar
NH2
H
NC
EtOH
CN
CN
3
+
Ar
C
O
+
H2N
N
1
2
4
Scheme 2
Ar
C
Ar
H
CN
CN
H
C
CH
H2N
CN
CN
NH2
N
HN
H
C
Ar
C
H
C
+
CN
Ar
O
+
CN
3
1
2
5
6
7
2
Ar
N
Ar
Ar
Ar
NC
NC
NC
NC
HN
-H2
N
C
H2N
H2N
N
N
H
H
H2N
4
9
8
10
To test the mechanism described above, the reaction of
Schiff base 5a and malononitrile 3 was carried out in EtOH
under identical conditions (Scheme 3). The target compound
4a was obtained with yield similar to the one-pot reaction.
However, when the reaction of the intermediate product 7a
and ꢀ-naphthylamine 2 was carried out in EtOH under
identical conditions, the yield was lower than the one-pot
reaction. This result supported the proposed mechanism.
The procedure is easy to carry out and the workup
procedure is simple. In this experiment, we found that this
Scheme 3
Cl
Cl
CH
N
NC
H2N
CN
EtOH
+
CN
N
5a
3
4

May-Jun 2007
A Facile One-pot Synthesis of 2-Amino-4-arylbenzo[h]quinoline-3-carbonitrile Derivatives
737
C20H12BrN3: C, 64.19; H, 3.23; N, 11.23. Found: C, 64.25; H,
3.31; N, 11.29.
protocol could be applied to aromatic aldehydes with
electron-withdrawing groups, but not to aromatic
aldehydes with electron-donating groups. Therefore, we
concluded that the electronic nature of the substituent of
aldehyde has an effect on this reaction. In order to obtain
4-unsubstituted benzo[h]quinoline and 4-alkyl benzo[h]-
quinoline, the aromatic aldehyde was replaced by
formaldehyde and aliphatic aldehydes (such as pentanal
and butyraldehyde), unfortunately, the anticipated product
were not obtained. When the ꢀ-naphthylamine was
replaced by ꢁ-naphthylamine prepared by the reaction of
aromatic aldehyde and malononitrile under the same
reaction conditions, unfortunately, the anticipated result
were not attained.
2-Amino-4-(4-fluorophenyl)benzo[h]quinoline-3-carbo-
nitrile (4c). This compound was obtained as yellow solid
(alcohol); ir (potassium bromide): 3488, 3375, 2219, 1628,
1507,1450, 1420, 1405, 1294, 1228, 1160, 1096, 848, 823, 802,
1
770 cm-1; H nmr (DMSO-d6): ꢂ 9.05 (d, 1H, J = 8.0 Hz, ArH),
7.92 (d, 1H, J = 7.2 Hz, ArH), 7.76-7.68 (m, 2H, ArH), 7.63-
7.46 (m, 5H, ArH), 7.20 (s, 2H, NH2), 7.17 (d, 1H, J = 8.8 Hz,
ArH). Anal. Calcd. for C20H12FN3: C, 76.67; H, 3.86; N, 13.41.
Found: C, 76.70; H, 3.81; N, 13.49.
2-Amino-4-(2-chlorophenyl)benzo[h]quinoline-3-carbo-
nitrile (4d). This compound was obtained as yellow solid
(alcohol); ir (potassium bromide): 3488, 3352, 2230, 1627,
1507, 1451, 1417, 1405, 1296, 1142, 1050, 826, 801, 768, 758
1
cm-1; H nmr (DMSO-d6): ꢂ 9.04 (d, 1H, J = 7.6 Hz, ArH), 7.92
(d, 1H, J = 7.2 Hz, ArH), 7.78-7.55 (m, 7H, ArH), 7.31 (s, 2H,
NH2), 6.93 (d, 1H, J = 9.2 Hz, ArH). Anal. Calcd. for
C20H12ClN3: C, 72.84; H, 3.67; N, 12.74. Found: C, 72.89; H,
3.59; N, 12.84.
In conclusion, we have disclosed a facile method for the
synthesis of benzo[h]quinoline-3-carbonitrile derivatives.
Although the reaction has some limitations, it offered a
new method with the notable advantages of short route,
high yield and easy workup procedure for the synthesis of
benzoquinoline scaffold.
2-Amino-4-(3,4-dichlorophenyl)benzo[h]quinoline-3-car-
bonitrile (4e). This compound was obtained as yellow solid
(alcohol); ir (potassium bromide): 3489, 3369, 2221, 1626,
1506, 1453, 1422, 1406, 1361, 1294, 1253, 1159, 1130, 1031,
1
923, 879, 827, 816, 802, 766 cm-1; H nmr (DMSO-d6): ꢂ 9.04
EXPERIMENTAL
(d, 1H, J = 7.6 Hz, ArH), 7.94-7.92 (m, 2H, ArH), 7.91 (s, 1H,
ArH), 7.78-7.55 (m, 2H, ArH), 7.58-7.56 (m, 2H, ArH ), 7.28 (s,
2H, NH2), 7.16 (d, 1H, J = 9.2 Hz, ArH). Anal. Calcd. for
C20H11Cl2N3: C, 65.95; H, 3.04; N, 11.54. Found: C, 65.87; H,
3.12; N, 11.66.
2-Amino-4-(2,4-dichlorophenyl)benzo[h]quinoline-3-car-
bonitrile (4f). This compound was obtained as yellow solid
(alcohol); ir (potassium bromide): 3478, 3349, 2229, 1626,
1499, 1450, 1421, 1409, 1382, 1294, 1139, 1099, 1048, 826,
800, 764 cm-1; 1H nmr (DMSO-d6): ꢂ 9.03 (s, 1H, ArH), 7.92 (s,
1H, ArH), 7.81-7.74 (m, 5H, ArH), 7.58 (d, 1H, J = 7.2 Hz,
ArH), 7.36 (s, 2H, NH2), 6.96 (d, 1H, J = 6.4 Hz, ArH). Anal.
Calcd. for C20H11Cl2N3: C, 65.95; H, 3.04; N, 11.54. Found: C,
65.85; H, 3.18; N, 11.67.
2-Amino-4-(4-nitrophenyl)benzo[h]quinoline-3-carbo-
nitrile (4g) This compound was obtained as yellow solid
(alcohol); ir (potassium bromide): 3487, 3376, 2218, 1628,
1505, 1450, 1420, 1405, 1349, 1295, 1265, 860, 801, 770 cm-1;
1H nmr (DMSO-d6): ꢂ 9.05 (d, 1H, J = 7.6 Hz, ArH), 8.49 (d,
2H, J = 8.8 Hz, ArH), 7.94-7.87 (m, 3H, ArH), 7.76-7.72 (m,
2H, ArH), 7.57 (d, 1H, J = 8.8 Hz, ArH), 7.33 (s, 2H, NH2), 7.09
(d, 1H, J = 9.2 Hz, ArH). Anal. Calcd. for C20H12N4O2: C, 70.58;
H, 3.55; N, 16.46. Found: C, 70.66; H, 3.48; N, 16.39.
2-Amino-4-(3-nitrophenyl)benzo[h]quinoline-3-carbo-
nitrile (4h). This compound was obtained as yellow solid
(alcohol); ir (potassium bromide): 3489, 3372, 2218, 1612,
1505, 1451, 1407, 1348, 1293, 1245, 1146, 1086, 884, 807, 769
cm-1; 1H nmr (DMSO-d6): ꢂ 9.05 (d, 1H, J = 7.6 Hz, ArH), 8.50-
8.44 (m, 2H, ArH), 8.05 (d, 1H, J = 8.0 Hz, ArH), 7.97 (s, 1H,
ArH), 7.95-7.92 (m, 1H, ArH), 7.78-7.70 (m, 2H, ArH), 7.57 (d,
1H, J = 9.2 Hz, ArH), 7.32 (s, 2H, NH2), 7.14 (d, 1H, J = 8.8 Hz,
ArH). Anal. Calcd. for C20H12N4O2: C, 70.58; H, 3.55; N, 16.46.
Found: C, 70.64; H, 3.59; N, 16.48.
Melting points were determined in open capillaries and are
uncorrected. The IR spectra were recorded on a TENSOR 27
spectrometer in KBr. 1H NMR spectra were measured on a DPX
400 spectrometer operating at 400 MHz, using DMSO-d6 as
solvent and TMS as internal standard. Elemental analyses were
determined by using a Perkin-Elmer 240c elemental analysis
instrument.
General procedure for 2-amino-4-arylbenzo[h]quinoline-
3-carbonitrile derivatives (4). A mixture of the appropriate
aromatic aldehyde 1 (2 mmol), ꢀ-naphthylamine 2 (2 mmol),
malononitrile 3 (2 mmol) was refluxed in ethanol (8 mL) and
stirred at 80 °C (oil bath temperature) for 5-8 hours in a
ventilating arrangement. Upon completion, monitored by
TLC, the reaction mixture was cooled to room temperature,
after 8 hours, filtered to give the crude product, which was
further purified by recrystallization from EtOH (4a-4i). All
the products were characterized by IR, 1H NMR and
elemental analysis.
2-Amino-4-(4-chlorophenyl)benzo[h]quinoline-3-carbo-
nitrile (4a). This compound was obtained as yellow solid
(alcohol); ir (potassium bromide): 3482, 3376, 2219, 1628,
1506, 1450, 1419, 1291, 1090, 1014, 840, 823, 768 cm-1; 1H nmr
(DMSO-d6): ꢂ 9.04 (d, 1H, J = 8.0 Hz, ArH), 7.92 (d, 1H, J = 7.6
Hz, ArH), 7.76-7.69 (m, 4H, ArH), 7.24 (s, 2H, NH2), 7.19 (t,
3H, J = 8.8 Hz, ArH), 7.16 (d, 1H, J = 8.8 Hz, ArH). Anal.
Calcd. for C20H12ClN3: C, 72.84; H, 3.67; N, 12.74. Found: C,
72.91; H, 3.72; N, 12.81.
2-Amino-4-(4-bromophenyl)benzo[h]quinoline-3-carbo-
nitrile (4b). This compound was obtained as yellow solid
(alcohol); ir (potassium bromide): 3487, 3376, 2218, 1627,
1505, 1449, 1419, 1391, 1290, 1238, 1073, 1010, 836, 822, 800,
1
766 cm-1; H nmr (DMSO-d6): ꢂ 9.04 (d, 1H, J = 8.0 Hz, ArH),
2-Amino-4-(4-hydroxy-3-nitrophenyl)benzo[h]quinoline-3-
carbonitrile (4i). This compound was obtained as yellow solid
(alcohol); ir (potassium bromide): 3487, 3368, 3267, 2220,
1625, 1508, 1452, 1411, 1365, 1320, 1248, 1167, 1081, 838,
7.92 (d, 1H, J = 7.6 Hz, ArH), 7.85 (d, 2H, J = 8.4 Hz, ArH),
7.75-7.72 (m, 2H, ArH), 7.57-7.50 (m, 3H, ArH), 7.24 (s, 2H,
NH2), 7.16 (d, 1H, J = 8.8 Hz, ArH). Anal. Calcd. for

738
S. Tu, R. Jia, J. Zhang, Y. Zhang, B. Jiang
Vol 44
807, 764 cm-1; 1H nmr (DMSO-d6): ꢀ 11.59 (s, 1H, OH), 9.03 (d,
1H, J = 7.6 Hz, ArH), 8.10 (s, 1H, ArH), 7.93 (d, 1H, J = 7.6 Hz,
ArH), 7.76-7.69 (m, 3H, ArH), 7.58 (d, 1H, J = 9.2Hz, ArH),
7.37 (d, 1H, J = 8.8 Hz, ArH), 7.26 (d, 1H, J = 7.2 Hz, ArH),
7.24 (s, 2H, NH2). Anal. Calcd. for C20H12N4O3: C, 67.41; H,
3.39; N, 15.72. Found: C, 67.49; H, 3.31; N, 15.68.
Acknowledgments. We are grateful to the financial support
from the National Natural Science Foundation of China (No.
20672090), Natural Science Foundation of the Jiangsu Province
(No. BK2006033)ꢀSix Kinds of Professional Elite Foundation
of the Jiangsu Province (No. 06-A-039).
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