One-step synthesis of polysubstituted benzene derivatives by multi-component cyclization of α-bromoacetate, malononitrile and aromatic aldehydes

Article abstract of DOI:10.1039/b718171j

Polysubstituted benzene derivatives with an unprecedented substitution pattern are produced in a novel one-pot multi-component cyclization reaction from pyridine, ethyl α-bromoacetate, malononitrile and aromatic aldehyde in refluxing acetonitrile. The Royal Society of Chemistry.

Full text of DOI:10.1039/b718171j

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
One-step synthesis of polysubstituted benzene derivatives by
multi-component cyclization of a-bromoacetate, malononitrile and
aromatic aldehydesw
Chao Guo Yan,*a Xiao Kai Song,a Qi Fang Wang,a Jing Sun,a Ulrich Siemeling*b
and Clemens Bruhnb
Received (in Cambridge, UK) 23rd November 2007, Accepted 8th January 2008
First published as an Advance Article on the web 25th January 2008
DOI: 10.1039/b718171j
Polysubstituted benzene derivatives with an unprecedented sub-
stitution pattern are produced in a novel one-pot multi-compo-
nent cyclization reaction from pyridine, ethyl a-bromoacetate,
malononitrile and aromatic aldehyde in refluxing acetonitrile.
ditions to give the corresponding polysubstituted benzene
derivatives 1b–1h in moderate yields. Benzaldehydes with
substituents of moderate electronic influence such as bromo,
chloro, methyl and tert-butyl afforded the desired products
(Table 1). In contrast, benzaldehydes with stronger electron-
donating groups such as methoxy, hydroxyl and dimethyl-
amino or with stronger electron-withdrawing groups such as
the nitro group did not give the polysubstituted benzenes,
affording only gummy materials whose structure could not be
elucidated. The polysubstituted benzenes 1a–1h were fully
characterized by 1H and 13C NMR, MS, IR spectra and
elemental analysis, and their structures were confirmed by
single-crystal X-ray diffraction studies performed for 1a, 1b,
1c, and 1h.9,12 As an example the structure of 1h is shown in
Fig. 1. The most unusual feature of the structure of 1a–1h is
the fact that the two aryl substituents are in ortho position,
which has not been observed to date in any of the known
cyclization reactions of malononitrile with formation of
carbocyclic and heterocyclic compounds.10–13
Multicomponent reactions are one-pot processes in which
several easily accessible components react to form a single
product. They offer significant advantages over conventional
linear-type syntheses due to their flexible, convergent and
atom efficient nature and have become an important area of
research in organic, medicinal and combinatorial chemistry.1–3
According to current synthetic requirements, effective and
environmentally benign multicomponent procedures are par-
ticularly welcome.4 Malononitrile is an exceptionally versatile
compound in this context and is therefore used extensively as a
reactant or reaction intermediate. It exhibits unique reactivity
since the strongly electron-withdrawing cyano groups activate
the methylene group (pKa = 11.2), their polar multiple bond is
suitable for nucleophilic addition and is also a good leaving
group for substitution.5 The methylene group and either one
or both cyano groups can take part in condensation reactions
to give a variety of addition products and heterocyclic com-
pounds.6 This exceptional behavior makes malononitrile an
important candidate for the design of new practical multi-
component reaction procedures in research and in medicinal,
industrial and agricultural chemistry. In fact there are a lot of
multicomponent reaction procedures with malononitrile to
prepare carbocyclic and heterocyclic compounds.6–8 Herein
we wish to report our investigation of a new multicomponent
reaction which involves malononitrile, aromatic aldehyde,
pyridine and ethyl a-bromoacetate for the synthesis of poly-
substituted benzene compounds (Scheme 1).z
To optimize the reaction conditions for the formation of the
polysubstituted benzenes, the influences of base catalyst,
solvent and the ratio of the components were investigated
using the reaction of p-chlorobenzaldehyde as an example.
Ethyl a-bromoacetate can be replaced by ethyl a-chloro-
acetate, affording 1c in ca. 47% yield. In addition to the one-
pot four-component procedure described above, combinations
containing plausible reaction intermediates were also tested,
viz. (1) a mixture of previously prepared N-ethoxycarbonyl-
methylpyridinium bromide, p-chlorobenzaldehyde and malo-
nonitrile; (2) pyridine, ethyl a-bromoacetate and previously
prepared p-chlorobenzylidene malononitrile; (3) N-ethoxycar-
bonylmethylpyridinium bromide and p-chlorobenzylidenema-
lononitrile. Similar results were observed in each case and
nearly the same yield of 1c was produced in these three
reactions. These findings clearly show that the final polysub-
stituted benzene derivative 1c results from the reactions of
When a mixture of malononitrile, benzaldehyde, ethyl a-
bromoacetate and an excess of pyridine was heated in aceto-
nitrile for several hours, the unexpected polysubstituted ben-
zene derivative 1a (ethyl 3-amino-2,4-dicyano-5,6-diphenyl-
benzoate) was isolated in 31% yield after workup. Similarly,
various aromatic aldehydes reacted well under the same con-
a College of Chemistry & Chemical Engineering Yangzhou University,
Yangzhou 225002, China
b Institute of Chemistry University of Kassel Heinrich-Plett-Strasse
40, D-34132 Kassel. E-mail: cgyan@yzu.edu.cn
w Electronic supplementary information (ESI) available: experimental
methods, characterization of compounds and crystal data. See DOI:
10.1039/b718171j
Scheme 1 One-pot multi-component reaction affording polysubsti-
tuted benzene derivatives.
ꢀc
This journal is The Royal Society of Chemistry 2008
1440 | Chem. Commun., 2008, 1440–1442

View Article Online
Table 1 One-pot four component reactions for the synthesis of 1a–1h
Entry
Comp Ar
T (h) Yield (%)
Mp. (1C)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
18
24
12
12
12
12
12
12
31
37
53
45
44
36
31
46
151–152
190–191
231–232
201–202
252–253
187–188
171–172
184–185
p-CH3C6H4
p-ClC6H4
m-ClC6H4
p-BrC6H4
m-BrC6H4
o-BrC6H4
p-tert-BuC6H4
1g
1h
N-ethoxycarbonylmethylpyridinium bromide with p-chloro-
benzylidenemalononitrile, which are both formed in situ.
To explain the mechanism of this one-pot multicomponent
tandem reaction, we propose a plausible reaction course,
which is illustrated in Scheme 2. The first step is the formation
of the two reaction intermediates already identified by the
experiments described in the preceding paragraph, namely the
N-ethoxycarbonylmethylpyridinium salt (A) formed from the
addition of ethyl a-bromoacetate to pyridine and the arylide-
nemalononitrile (B) formed by the Knoevenagel condensation
of the respective aromatic aldehyde with malononitrile. The
second step is a Michael addition of a pyridinium ylide (C)
which is formed by deprotonation of the N-ethoxycarbonyl-
methylpyridinium species (A) by excess pyridine to the aryli-
denemalononitrile (B) to afford a cyclopropane derivative (D).
The third step is initiated by deprotonation and leads to the
ring-opening of the activated cyclopropane (D) to form a 1,3-
dipolar intermediate (E), which in turn reacts with a second
equivalent of arylidenemalononitrile (B) with concomitant
intramolecular addition of the cyano-stabilized carbanion to
one of the cyano groups to give a six-membered carbon ring
system (F). The final step is an aromatization process to form
the polysubstituted benzene product 1 by elimination of one
hydrogen cyanide molecule. Here the key step is that the ring-
opened intermediate (E) undergoes a reaction formally analo-
gous to 1,3-dipolar additions to double bonds due to inherent
strain and unique electron features, which now have been
utilized to synthesize valuable five- and six-membered hetero-
cycles of potential biological relevance.14 The unique proper-
ties of the two cyano groups in malononitrile are a crucial
factor in the reaction sequence, especially in the final steps,
where the cyano group acts as a strongly electron-withdrawing
Scheme 2 Proposed mechanism for the formation of polysubstituted
benzenes 1.
substituent, as a leaving group and as a polar triple bond for
nucleophilic addition.
In order to probe the credibility of our proposed mechan-
istic scheme and shed more light on the formation of the
polysubstituted benzenes 1, further experiments were carried
out. Firstly, when the four-component reaction was conducted
at lower temperature with triethylamine as base catalyst the
cyclopropane derivatives D (ethyl 2,2-dicyano-3-aryl cyclopro-
panecarboxylate) turned out to be formed in high yield. For
example p-chlorobenzaldehyde and o-bromobenzaldehyde
give D1 (Ar = p-ClC6H4, 85%) and D2 (Ar = o-BrC6H4,
75%), respectively.15 donor–acceptor-substituted cyclopro-
panes of this type, which correspond to the proposed inter-
mediate D in Scheme 2, were previously prepared by
cyclopropanation reactions of phosphorus,16 sulfur,17 ammo-
nium18 and also pyridinium ylides.19–20
Secondly, when a mixture of cyclopropane derivative D1
and p-chlorobenzylidenemalononitrile was heated in acetoni-
trile in the presence of pyridine, the expected polysubstituted
benzene 1c was obtained in 52% yield. This fact clearly shows
that the ring-opening process of the cyclopropane intermediate
(D in Scheme 2) is a key step in the multicomponent reaction.
When the bulkier p-tert-butylbenzaldehyde was used in the
reaction and the refluxing time was shortened to five hours, the
six-membered ring system intermediate (F, Ar = p-tert-
BuC6H4) could be isolated in 22% yield.21 Quantitative con-
version of this compound to 1h proved to be possible by
prolonged heating in a mixture of acetonitrile and pyridine.
Fortuitously, we have been able to obtain the crystal struc-
tures of representative examples of the cyclopropane inter-
mediate (D) and the six-membered ring system intermediate
Fig. 1 Molecular structure of 1h in the crystal.
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 1440–1442 | 1441

View Article Online
7 (a) D. Xue, Y. C. Chen, Q. W. Wang, L. F. Cun, J. Zhu and J. G.
Deng, Org. Lett., 2005, 7, 5293–5296; (b) D. Xue, J. Li, Z. T.
Zhang and J. G. Deng, J. Org. Chem., 2007, 72, 5443–5445; (c) R.
Pratap and V. J. Ram, J. Org. Chem., 2007, 72, 7402–7405.
8 (a) S. Marchalin, B. Baumlova, P. Baran, H. Oulyadi and A.
Daich, J. Org. Chem., 2006, 71, 9114–9127; (b) T. Inokuma, Y.
Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2006, 128,
9413–9419; (c) M. N. Elinson, A. N. Vereshchagin, S. K. Fedu-
covich, T. A. Zaimovskaya, Z. A. Starikova, P. A. Belyakov and
G. I. Nikishin, Tetrahedron Lett., 2007, 48, 6614–6619.
9 1a: CCDC 663309; 1b: CCDC 663310; 1c: CCDC 663311; 1h
CCDC 663312.
10 (a) C. N. O’Callaghan, T. Brian and H. McMurry, J. Chem. Res.,
1999, 458–459; (b) T. Shintani, H. Kadono, T. Kikuchi, T.
Schubert, Y. Shogase and M. Shimazaki, Tetrahedron Lett.,
2003, 44, 6567–6569; (c) K. Guo, M. J. Thompson, T. R. K.
Reddy, R. Mutter and B. Chen, Tetrahedron, 2007, 63, 5300–5311;
(d) X. S. Wang, M. M. Zhang, Q. Li, C. S. Yao and S. J. Tu,
Tetrahedron, 2007, 63, 5265–5273.
11 (a) L. Zhou and T. Hirao, Tetrahedron Lett., 2000, 41, 8517–8521;
(b) F. E. Goda, A. M. Abdel-Azizb and O. A. Attefc, Bioorg. Med.
Chem., 2004, 12, 1845–1852; (c) P. Victory, A. Alvarez-Larena, G.
Germain, R. Kessels, J. F. Piniella and A. Vidal-Ferran, Tetra-
hedron, 1995, 51, 235–242; (d) Z. Yu and D. Velasco, Tetrahedron
Lett., 1999, 40, 3229–3232.
12 (a) B. C. Ranu, R. Jana and S. Sowmiah, J. Org. Chem., 2007, 72,
3152–3154; (b) N. M. Evdokimov, A. S. Kireev, A. A. Yakovenko,
M. Yu, I. V. Magedov and A. Kornienko, J. Org. Chem., 2007, 72,
3443–3453; (c) N. M. Evdokimov, I. V. Magedov, A. S. Kireev and
A. Kornienko, Org. Lett., 2006, 8, 899–902; (d) A. M. Shestopalov,
Y. M. Emeliyanova, A. A. Shestopalov, L. A. Rodinovskaya, Z. I.
Niazimbetova and D. H. Evans, Tetrahedron, 2003, 59, 7491–7496.
13 (a) X. Y. Lu, Z. Lua and X. X. Zhang, Tetrahedron, 2006, 26,
457–460; (b) D. Q. Shi, S. J. Tu, X. S. Wang, C. S. Yao, C. X. Yu
and Y. C. Wang, Chin. J. Struct. Chem., 2001, 20, 501–504; (c) T.
S. Jin, Y. Yi, L. B. Liu, Y. Zhao and T. X. Zhao, Chin. J. Org.
Chem., 2007, 27, 261–265; (d) S. L. Cui, X. F. Lin and Y. G. Wang,
J. Org. Chem., 2005, 70, 2866–2869.
Fig. 2 Molecular structure of intermediate F in the crystal.
(F,21 Fig. 2) as well as the final polysubstituted benzenes 1. The
mechanism proposed in Scheme 2 is strongly supported by the
isolation of key intermediates, which were structurally char-
acterized by X-ray diffraction.
This work was financially supported by the National Nat-
ural Science Foundation of China (Grant No. 20672091).
Notes and references
z Typical procedure: A mixture of pyridine (20.0 mmol, 1.58 g), ethyl
a-bromoacetate (4.0 mmol, 0.668 g), p-chlorobenzaldehyde (4.0 mmol,
0.562 g) and malononitrile (4.0 mmol, 0.264 g) in acetonitrile (20 mL)
was refluxed for 12 h. The solvent was removed by evaporation and
the residue was titrated with ethanol (10 mL) to give the crude
product, which is recrystallized in ethanol to give light yellow solid
1c (0.458 g, 53%): Mp. 231–232 1C. 1H NMR (600 MHz, CDCl3) d
7.26 (d, J = 7.8, 2H, p-ClC6H4), 7.16 (d, J = 8.4, 2H, p-ClC6H4), 6.99
(d, J = 7.8, 2H, p-ClC6H4), 6.86 (d, J = 8.4, 2H, p-ClC6H4), 5.42 (s,
2H, NH2), 4.13 (q, J = 7.2, 2H, CH2), 1.05 (t, J = 7.2, 3H, CH3) ppm.
13C NMR (CDCl3, 150 MHz) d 162.8, 148.8, 147.1, 139.5, 132.4, 132.4,
129.6, 129.5, 129.2, 126.7, 125.2, 121.6, 120.3, 112.4, 111.7, 97.5, 92.9,
60.7, 11.4; IR(KBr) n 3469, 3351, 3244, 2221, 1743, 1642, 1557, 1493,
1447, 1375, 1276, 1218, 1016, 789, 743 cmꢁ1; Anal. Calcd for
C23H15Cl2N3O2: C 63.32, H 3.47, N 9.63; Found: C 63.09, H 3.22,
N 9.54%.
14 For examples of cyclopropanes as building blocks in the synthesis,
see: (a) Y. B. Kang, X. L. Sun and Y. Tang, Angew. Chem., Int.
Ed., 2007, 46, 3918–3921; (b) Z. G. Zhang, Q. Zhang, S. G. Sun
and T. Xiong Q. Liu, Angew. Chem., Int. Ed., 2007, 46, 1726–1729;
(c) V. K. Yadav and V. Sriramurthy, Angew. Chem., Int. Ed., 2004,
43, 2669–2671; (d) I. Nakamura, R. Nagata, T. Nemoto, M.
Terada, Y. Yamamoto, T. Spath and A. de Meijere, Eur. J. Org.
Chem., 2007, 4479–4482.
¨
15 D1: CCDC 663313; D2: CCDC 663314w.
16 (a) H. Lebel, J. F. Marcoux, C. Molinaro and A. B. Charette,
Chem. Rev., 2003, 103, 977–1050; (b) V. K. Aggarwal, E. Alonso,
G. Fang, M. Ferrara, G. Hynd and M. Porcelloni, Angew. Chem.,
Int. Ed., 2001, 40, 1433–1436; (c) W. W. Lioa, K. Li and Y. J.
Tang, J. Am. Chem. Soc., 2003, 125, 13030–13031.
1 (a) A. Domling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39,
¨
3168–3210; (b) D. J. Ramon and M. Yus, Angew. Chem., Int. Ed.,
2005, 44, 1602–1634.
2 L. F. Tietze, Chem. Rev., 1996, 96, 115–136.
3 G. Balme, E. Bossharth and N. Monteiro, Eur. J. Org. Chem.,
2003, 4101–4111.
4 (a) R. V. A. Orru and M. de Greef, Synthesis, 2003, 1471–1499;
(b) L. Weber, K. Illgen and M. Almstetter, Synlett, 1999,
366–374.
5 (a) F. Freeman, Chem. Rev., 1969, 69, 591–624; (b) A. J. Fatiadi,
Synthesis, 1978, 241–282; (c) A. Saikia, Synlett, 2004, 2247–2248.
6 (a) L. Rodinovskaya, A. Shestopalov, A. Gromova and A. Shes-
topalov, Synthesis, 2006, 2357–2370; (b) V. Nair, A. Deepthi, P. B.
Beneesh and S. Eringathodi, Synthesis, 2006, 1443–1446; (c) S.
Balalaie, M. Bararjanian, A. M. Amani and B. Movassagh,
Synlett, 2006, 263–266; (d) T. S. Jin, A. Q. Wang, X. Wang, J. S.
Zhang and T. S. Li, Synlett, 2004, 871–873; (e) F. Fringuelli, O.
Piermatti and F. Pizzo, Synthesis, 2003, 2331–2334.
17 J. Gosselk and G. Schmidt, Tetrahedron Lett., 1969, 2615–2618.
18 (a) C. D. Papageorgiou, S. V. Ley and M. J. Gaunt, Angew. Chem.,
Int. Ed., 2003, 42, 828–831; (b) N. Bremeyer, S. C. Smith, S. V. Ley
and M. J. Gaunt, Angew. Chem., Int. Ed., 2004, 43, 2681–2684; (c)
C. D. Papageorgiou, M. A. C. de Dios, S. V. Ley and M. J. Gaunt,
Angew. Chem., Int. Ed., 2004, 43, 4641–4644.
19 (a) M. N. Elinson, T. L. Lizunova, B. I. Ugrak, M. Dekaprilevich,
G. I. Nikishin and Y. T. Struchkov, Tetrahedron Lett., 1993, 34,
5195–5198; (b) S. Kojima, K. Hiroikea and K. Ohkata, Tetrahe-
dron Lett., 2004, 45, 3565–3568; (c) S. Kojima, K. Fujitomo, Y.
Shinohara, M. Shimizu and K. Ohkata, Tetrahedron Lett., 2000,
41, 9847–9851; (d) S. Yamada, J. Yamamoto and E. Ohta, Tetra-
hedron Lett., 2007, 48, 855–858; (e) N. N. Vo, C. J. Eyermann and
C. N. Hodge, Tetrahedron Lett., 1997, 38, 7951–7954.
20 F. Al-Omran, A. A. El-Klair and M. H. Elnagdi, Org. Prep.
Proced. Int., 1998, 30, 211–214.
21 F: CCDC 663315w.
ꢀc
This journal is The Royal Society of Chemistry 2008
1442 | Chem. Commun., 2008, 1440–1442