A novel and green method for the synthesis of indeno[2,1-c]pyridine derivatives in ionic liquid catalyzed by malononitrile

Article abstract of DOI:10.1055/s-2008-1072722

1-Aryl-9H-indeno[2,1-c]pyridine-4-carbonitrile derivatives were unexpectedly obtained from the reaction of 2-(2,3-dihydroinden-3-ylidene) malononitrile, benzaldehyde and malononitrile in ionic liquid at 90°C. Modification of the novel reaction protocol re

Full text of DOI:10.1055/s-2008-1072722

LETTER
1185
A Novel and Green Method for the Synthesis of Indeno[2,1-c]pyridine
Derivatives in Ionic Liquid Catalyzed by Malononitrile
S
ynthesis of Inden
i
o[2,1-
c
a
]pyridine
D
n
erivativesin
g
Ionic
L
iquid-Shan Wang,*a,b Jian-Rong Wu,a Qing Li,a Chang-Sheng Yao,a Shu-Jiang Tua,b
a
School of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou, Jiangsu 221116, P. R. of China,
The Key Laboratory of Biotechnology for Medical Plants, Xuzhou, Jiangsu 221116, P. R. of China
Fax +86(516)83500065; E-mail: xswang1974@yahoo.com; E-mail: xswang@xznu.edu.cn
b
Received 2 January 2008
NH2
NC
NC
Abstract: 1-Aryl-9H-indeno[2,1-c]pyridine-4-carbonitrile deriva-
tives were unexpectedly obtained from the reaction of 2-(2,3-dihy-
droinden-3-ylidene) malononitrile, benzaldehyde and malononitrile
in ionic liquid at 90 °C. Modification of the novel reaction protocol
resulted in a two-component reaction between 2-(2,3-dihydroinden-
3-ylidene) malononitrile, and benzaldehyde catalyzed by 10 mol%
malononitrile. A 1,5-hydrogen transfer was proposed to occur in the
formation of the product.
CN
NC
CN
Ar CHO
CN
Ar
IL
1
+
90 °C
CN
N
3
CN
Ar
Key words: indeno[2,1-c]pyridine, ionic liquids, malononitrile,
1,5-hydrogen transfer, synthesis
2
4
Scheme 1
Molecules with heterocyclic substructures are attractive
targets for synthesis since they often exhibit diverse and
important biological properties,1 such as indenopyridine
derivatives. They have been reported to possess insecti-
cidal, phosphodiesterase inhibiting, antifungal, antisper-
matogenic, antifertility, antagonistic, and antiarrhythmic
activity.2 Accordingly, novel strategies for the synthesis
of indenopyridines continue to receive considerable atten-
tion in the field of synthetic organic chemistry.3 The effi-
ciency of heterocycle formation is important not only
because it affects the cost for the desired products, but
also the environmental impact associated with waste dis-
posal, conservation of source materials like petroleum
stocks, and energy consumption. The rate of increase in
molecular intricacy as one progress from simple starting
materials to the final product can serve as a measure of ef-
ficiency.4 At one end of the continuum, a highly complex
or novel heterocyclic product can be obtained by a single
synthetic step from an inexpensive material. Domino re-
actions are organic reactions where multiple carbon–car-
bon bond formation is achieved in a single operation
without any troublesome experimental procedures. The
procedures are advantageous both environmentally and
economically and should have broad practical applica-
tions.5
vapor pressure also ensure their utility in environmentally
friendly technologies. They have been used as solvents for
a large number of organic transformations.7 To the best of
our knowledge, little attention has been paid to the synthe-
sis of indeno[2,1-c]pyridine derivatives.8 As part of a con-
tinuing effort in our laboratory toward the development of
new methods for the expeditious synthesis of biologically
relevant heterocyclic compounds in ionic liquids,9 herein,
we would like to report a novel domino reaction of 2-(2,3-
dihydroinden-3-ylidene)malononitrile and benzaldehydes
containing 1,5-hydrogen transfer in the synthesis of 1-
aryl-9H-indeno[2,1-c]pyridine-4-carbonitrile derivatives.
We have previously reported an improved synthesis of
highly substituted fluorene and phenanthrene derivatives
in water.10 However, the desired 2,6-dicyanoaniline moi-
eties were not detected in this TEBAC (triethylbenzylam-
monium chloride)–water system. In order to obtain these
acceptor–donor–acceptor systems in a multicomponent
reaction, we performed the same reaction by performing a
three-component reaction of benzaldehyde, malonodini-
trile, and 2-(2,3-dihydroinden-3-ylidene)malononitrile in
ionic liquid at 90 °C. Unexpectedly, it produced 1-aryl-
9H-indeno[2,1-c]pyridine-4-carbonitrile rather than the
fluorene derivative (Scheme 1).
Ionic liquids have attracted increasing interest in the con-
text of green synthesis in recent years. They were initially
introduced as alternative green reaction media because of
their unique chemical and physical properties of nonvola-
tility, nonflammability, thermal stability, and controlled
miscibility.6 The possibility of recycling them and the low
It was obviously that the malononitrile fragment was not
incorporated into the product and we suggested that mal-
ononitrile may act as a catalyst in the reaction. Therefore
we repeated the reaction without malononitrile through a
two-component reaction of the benzaldehyde and 2-(2,3-
dihydroinden-3-ylidene)malononitrile in ionic liquid at
the same reaction conditions (Scheme 2). As expected,
product 4 was not found and hence we concluded that ma-
lononitrile acted as a catalyst in this reaction.
SYNLETT 2008, No. 8, pp 1185–1188
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072722; Art ID: W00208ST
© Georg Thieme Verlag Stuttgart · New York

1186
X.-S. Wang et al.
LETTER
NC
NC
NC
NC
CN
CN
N
N
2 (10 mol%)
IL
Ar CHO
Ar CHO
+
+
90 °C
IL, 90 °C
Ar
Ar
1
3
1
3
4
Scheme 2
Scheme 3
Table 1 Synthesis of 4a under Different Reaction Conditionsa
Table 2 Malononitrile-Catalyzed Reactions of Benzaldehyde and
2-(2,3-Dihydroinden-3-ylidene)malononitrile in Ionic Liquida,b
Entry
Amount of 2
(mol%)
Ionic liquidb
Temp (°C) Yield
(%)c
Entry
1
Ar
Product
4a
Time (h) Yields (%)c
1
2
10
10
5
[bmim+][BF4 ]
r.t.
50
90
90
90
90
90
90
90
90
0
–
4-MeC6H4
4-ClC6H4
12
11
8
89
84
83
84
90
83
84
85
90
82
84
80
79
–
[bmim+][BF4 ]
65
78
89
89
82
83
82
85
85
2
4b
4c
3
[bmim+][BF4 ]
–
3
4-O2NC6H4
4-BrC6H4
–
[bmim+][BF4 ]
4
4d
4e
12
8
4
10
20
10
10
10
10
10
–
[bmim+][BF4 ]
5
2-O2NC6H4
furan-2-yl
5
[emim+]Br–
[pmim+]Br–
[bmim+]Br–
6
4f
8
6
7
thiophen-2-yl
2,3-(Cl)2C6H3
2-ClC6H4
4g
8
7
8
4h
4i
10
10
14
10
10
14
8
9
[emim+][BF4 ]
–
9
–
[pmim+][BF4 ]
10
11
12
13
4-MeOC6H4
3-O2NC6H4
2,4-(Cl)2C6H3
3,4-(MeO)2C6H3
4j
10
a Reaction conditions: ionic liquid (1 mL), 4-methyl benzaldehyde (2
mmol), and 2-(2,3-dihydroinden-3-ylidene)malononitrile (2 mmol).
b bmim = 1-butyl-3-methylimidazolium; emim = 1-ethyl-3-meth-
ylimidazolium; pmim = 1-methyl-3-propylimidazolium.
c Isolated yields.
4k
4l
4m
a Reaction conditions: ionic liquid (1 mL), benzaldehyde (2 mmol),
and 2-(2,3-dihydroinden-3-ylidene)malononitrile (2 mmol).
b See ref. 11 for experimental details.
Subsequently, optimizations of the reaction conditions,
including reaction temperature, solvents, and amount of 2,
were investigated using 4-methylbenzaldehyde and 2-
(2,3-dihydroinden-3-ylidene)malononitrile as model re-
actants. As summarized in Table 1, the results show that
at room temperature no reaction took place (Table 1, entry
1). To our delight, the reaction proceeded smoothly in
high yield at 90 °C. Similar reactions were then carried
out in the presence of 5 mol%, 10 mol% and 20 mol% of
malononitrile. The results from Table 1 (entries 3, 4, and
5) show that 10 mol% malononitrile at 90 °C in ionic liq-
uid gave the best yield. Higher loading of the catalyst had
no significant influence on the reaction yield. Thus, the
optimal reaction conditions are 90 °C and 10 mol% malo-
nonitrile. Moreover, different ionic liquids were further
tested as reaction medium and it was observed that
c Isolated yields.
for other reactions with different substrates, it was washed
with ethyl acetate, followed by evaporation at 80 °C in
vacuo for three hours. Investigations by using 4-methyl-
benzaldehyde and 2-(2,3-dihydroinden-3-ylidene)malo-
nonitrile as model substrates proved the successful
reusability of the ionic liquid. Even in the fourth cycle, the
yield of product 4a (84%) was still fairly high.
According to the optimized conditions, we next examined
the utility of this process (Scheme 3) to synthesize a range
of indeno[2,1-c]pyridines 4. Various arylaldehydes 1,
bearing either electron-withdrawing groups (such as ha-
lide, nitro) or electron-donating groups (such as alkyl
group, or alkoxyl group), were subjected to react with 3 to
give the corresponding 1-aryl-9H-indeno[2,1-c]pyridine-
4-carbonitriles 4 in high yields (Table 2).
–
[bmim+][BF4 ] was the best ionic liquid for the reaction.
After the reaction was completed, the reaction mixtures
were cooled to room temperature. Water (5 mL) was then
added to the mixture and the solid was isolated by filtra-
tion. The water in the filtrate was removed by evaporation
at reduced pressure, and the ionic liquid in the filtrate
could be recycled easily at 80 °C in vacuo for four hours.
The recovered ionic liquid could be directly used for the
same reactions. Alternatively, if the ionic liquid was used
Although the detailed mechanism of the above reaction
has not been clarified yet, the formation of 4 could be ten-
tatively explained by a domino reaction containing 1,5-
hydrogen transfer (Scheme 4). A sequential reaction of
the Knoevenagel condensation and Michael addition reac-
tion took place to give I, followed by the lost of a mole-
cule of 2 to produce a,b-unsaturated cyclodinitrile II.
Synlett 2008, No. 8, 1185–1188 © Thieme Stuttgart · New York

LETTER
Synthesis of Indeno[2,1-c]pyridine Derivatives in Ionic Liquid
1187
Ar CHO
1
N
NC
CN
NC
CN
Ar
CN
Knoevenagel
condensation
–CH(CN)2
3
CN
– CH2(CN)2
Ar
CN
Michael
addition
H
Ar
I
II
CN
NH
CN
CN
Ar
NC
CN
2
NC
N
CN
NC
NC
NC
III
CN
NH
Ar
CN
NC
NC
NC
Ar
NH2
..
NH
Ar
4
[1,5]-H
transfer
Ar
VI
V
IV
Scheme 4
Me
ionic liquid using 10 mol% malononitrile as catalyst. The
noteworthy features of this procedure are mild reaction
conditions, one pot, high yield, operational simplicity and
the environmentally friendly procedure. Meanwhile,
CN
CN
IL
CN
Me
CHO
+
CN
H
5
–
[bmim+][BF4 ] could be reused for several rounds without
3
IL
significant loss of activity.
NC
Acknowledgment
N
We are grateful to the Foundation (04KJB150139) of the Education
Committee of Jiangsu Province for financial support.
4a
Me
References and Notes
Scheme 5
(1) Comprehensive Heterocyclic Chemistry; Katritzky, A. R.;
Rees, C. W.; Scriven, E. F. V., Eds.; Elsevier Science:
Oxford, UK, 1996.
Malononitrile then attacked one of the cyano groups to af-
ford III, which then isomerized to yield IV. Subsequently,
the intramolecular nucleophilic addition between amino
group and a,b-unsaturated dinitriles took place to obtain
V. An interesting 1,5-hydrogen transfer occurred in the
partially saturated six-membered pyridine moiety to form
VI, and VI finally lost a molecule of malononitrile to
yield product 4.
(2) (a) Crawford, S. D.; Rowley, E. G.; Eldridge, J. R.; Schuler,
F.; Roush, D. M.; Lyga, J. W.; Frank, B.; Sehgel, S. WO
2006089038 A2, 2006; Chem. Abstr. 2006, 145, 243208.
(b) Heintzelman, G. R.; Averill, K. M.; Dodd, J. H.;
Demarest, K. T.; Tang, Y.; Jackson, P. F. WO 2003088963
A1, 2003; Chem. Abstr. 2003, 139, 350637. (c) Cook, C. E.;
Sloan, C. D.; Thomas, B. F.; Navarro, H. A. US 2004147539
A1, 2004; Chem. Abstr. 2004, 141, 157039. (d) Hild, S. A.;
Meistrich, M. L.; Blye, R. P.; Reel, J. R. Biol. Reprod. 2001,
65, 165. (e) Upton, C.; Osborne, R. H.; Jaffar, M. Bioorg.
Med. Chem. Lett. 2000, 10, 1277. (f) Safak, C.; Simsek, R.;
Altas, Y.; Boydag, S.; Erol, K. Bull. Chim. Farm. 1997, 136,
665. (g) Ellefson, C. R.; Woo, C. M.; Cusic, J. W. J. Med.
Chem. 1978, 21, 340.
(3) (a) Tu, S. J.; Jiang, B.; Jia, R.; Zhang, J.; Zhang, Y.
Tetrahedron Lett. 2007, 48, 1369. (b) Tu, S. J.; Jiang, B.;
Zhang, J.; Zhang, Y.; Jia, R.; Li, C.; Zhou, D.; Cao, L.; Shao,
Q. Synlett 2007, 480. (c) Smith, N. D.; Hayashida, J.;
Rawal, V. H. Org. Lett. 2005, 7, 4309. (d) El-Taweel, F. M.
A.; Sofan, M. A.; Abu El-Maati, T. M.; Elagamey, A. A. .
(e) Van Emelen, K.; De Wit, T.; Hoornaert, G. J.;
To verify the mechanism, we performed each separate
step of the reaction. The Knoevenagel condensation prod-
uct, 4-methylphenylidenemalonodinitrile (5) was ob-
tained in 92% yield. When compound 5 was treated with
2-(2,3-dihydroinden-3-ylidene)malononitrile (3) in ionic
liquid (Scheme 5), the corresponding 1-(4-methylphen-
yl)-9H-indeno[2,1-c]pyridine-4-carbonitrile (4a) was ob-
tained in 82% yield. This result suggested that a
Knoevenagel condensation took place during the reaction.
In conclusion, we have disclosed a green and effective
method to synthesize 1-aryl-9H-indeno[2,1-c]pyridine-4-
carbonitrile through a domino reaction of arylaldehyde
and 2-(2,3-dihydroinden-3-ylidene)malononitrile in an
Compernolle, F. Tetrahedron 2002, 58, 4225. (f) Abdel-
Gawad, I. I.; Kaddah, A. M.; Khalil, A. M.; Habib, O. M. O.;
Synlett 2008, No. 8, 1185–1188 © Thieme Stuttgart · New York

1188
X.-S. Wang et al.
LETTER
Al-Rifai, H. Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem. 1982, 21, 37. (g) Van Emelen, K.; De Wit, T.;
Hoornaert, G. J.; Compernolle, F. Org. Lett. 2000, 2, 3083.
(h) Catoen-Chackal, S.; Facompré, M.; Houssin, R.;
Pommery, N.; Goossens, J. F.; Colson, F.; Bailly, C.;
Hénichart, J. P. J. Med. Chem. 2004, 47, 3665. (i) Deady,
L. W.; Desneves, J.; Kaye, A. J.; Thompson, M.; Finlay, G.
J.; Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 1999,
7, 2801. (j) Quintela, J. M.; Arcas, R. M.; Veiga, M. C.;
Peinador, C.; Vilar, J.; Ojea, V. Heterocycles 1996, 43, 53.
(k) Manpadi, M.; Uglinskii, P. Y.; Rastogi, S. K.; Cotter, K.
M.; Wong, Y. C.; Anderson, L. A.; Ortega, A. J.;
Slambrouck, S. V.; Steelant, W. F. A.; Rogelj, R.; Tongwa,
P.; Antipin, M. Y.; Magedov, I. V.; Kornienko, A. Org.
Biomol. Chem. 2007, 5, 3865. (l) Hassanein, A. E. B.; Zeid,
A. Synth. Commun. 2000, 30, 3883. (m) Krause, A.;
Liepins, E.; Dubur, G. Khim. Geterotsikl. Soedin. 1990, 115.
(8) (a) Young, S. D.; King, S. W.; Remy, D. C. Heterocycles
1987, 26, 3081. (b) Jump, J. M.; McPhail, A. T.; Cook, C. E.
Tetrahedron Lett. 1997, 38, 3691. (c) Belanger, P. C.;
Williams, H. W. R. J. Chem. Soc., Perkin Trans. 1 1986,
1027.
(9) (a) Wang, X. S.; Zhang, M. M.; Jiang, H.; Shi, D. Q.; Tu, S.
J.; Wei, X. Y.; Zong, Z. M. Synthesis 2006, 4187.
(b) Wang, X. S.; Zhang, M. M.; Jiang, H.; Yao, C. S.; Tu, S.
J. Tetrahedron 2007, 63, 4439.
(10) Wang, X. S.; Zhang, M. M.; Jiang, H.; Yao, C. S.; Tu, S. J.
Tetrahedron 2007, 63, 5265.
(11) General Procedure for the Syntheses of 1-Aryl-9H-
indeno[2,1-c]pyridine-4-carbonitrile Derivatives
A dry 50 mL flask was charged with benzaldehyde (2.0
mmol), malononitrile (0.2 mmol), 2-(2,3-dihydroinden-3-
ylidene)malononitrile (2.0 mmol), and ionic liquid of
–
[bmim+][BF4 ] (1 mL). The reaction mixture was stirred at
(4) Fuchs, P. L. Tetrahedron 2001, 57, 6855.
90 °C for 3–8 h. Then, H2O (5 mL) was added to the mixture,
the solid was isolated by filtration. The water in the filtrate
was removed by evaporation at reduced pressure, and the
ionic liquid could be recovered easily 80 °C in vacuo for 4 h.
The crude yellow products were washed with H2O and
purified by recrystallization from DMF to give 4.
(5) (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131. (b) Bunce, R. A. Tetrahedron 1995, 51,
13103. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(6) (a) Welton, T. Chem. Rev. 1999, 99, 2071. (b) Dupont, J.;
de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102,
3667. (c) Lu, J.; Ji, S. J.; Teo, Y. C.; Loh, T. P. Tetrahedron
Lett. 2005, 46, 7435. (d) Huang, J. Y.; Lei, M.; Wang, Y. G.
Tetrahedron Lett. 2006, 47, 3047.
(7) (a) Carmichael, A. J.; Earle, M. J.; Holbrey, J. D.;
McCormac, P. B.; Seddon, K. R. Org. Lett. 1999, 1, 997.
(b) Shen, Z. L.; Ji, S. J.; Loh, T. P. Tetrahedron Lett. 2005,
46, 3137. (c) Ren, R. X.; Wu, J. X. Org. Lett. 2001, 3, 3727.
(d) Chen, S. L.; Ji, S. J.; Loh, T. P. Tetrahedron Lett. 2004,
45, 375. (e) Chiappe, C.; Capraro, D.; Conte, V.; Pieraccini,
D. Org. Lett. 2001, 3, 1061. (f) Tao, X. L.; Lei, M.; Wang,
Y. G. Tetrahedron Lett. 2007, 48, 5143.
1-(4-Methylphenyl)-9H-indeno[2,1-c]pyridine-4-
carbonitrile (4a): mp 201–203 °C. 1H NMR (400 MHz,
CDCl3): d = 2.43 (s, 3H, CH3), 4.02 (s, 2H, CH2), 7.29 (d,
J = 8.0 Hz, 2H, ArH), 7.44–7.52 (m, 4H, ArH), 7.58–7.60
(m, 1H, ArH), 8.31 (s, 1H, ArH), 8.59 (d, J = 8.0 Hz, 1H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): d = 167.2, 147.3,
141.1, 137.5, 136.6, 135.7, 134.3, 132.4, 130.9, 129.8,
128.2, 126.0, 125.3, 115.4, 115.1, 112.4, 37.4, 21.6 ppm.
HRMS (EI): m/z calcd for C20H14N2 [M+]: 282.1157; found:
282.1151. IR (KBr): n = 3052, 2215, 1619, 1603, 1523,
1414, 1331, 1314, 1218, 1188, 1164, 1122, 1105, 1019, 942,
896, 848, 806, 770, 720 cm–1.
Synlett 2008, No. 8, 1185–1188 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.