Synthesis of polysubstituted dihydropyridines by four-component reactions of aromatic aldehydes, malononitrile, arylamines, and acetylenedicarboxylate

Article abstract of DOI:10.1021/ol101475b

A practical and efficient procedure for the preparation of the polysubstituted dihydropyridines was developed through a unique four-component reaction of aromatic aldehydes, malononitrile, arylamines, and acetylenedicarboxylate in ethanol in the presence of triethylamine as a base promoter. This four-component reaction is atom-efficient, high-yielding, and applicable to a wide variety of four-component reactions.

Full text of DOI:10.1021/ol101475b

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3678-3681
Synthesis of Polysubstituted
Dihydropyridines by Four-Component
Reactions of Aromatic Aldehydes,
Malononitrile, Arylamines, and
Acetylenedicarboxylate
Jing Sun, Er-Yan Xia, Qun Wu, and Chao-Guo Yan*
College of Chemistry & Chemical Engineering, Yangzhou UniVersity,
Yangzhou 225002, China
cgyan@yzu.edu.cn
Received June 29, 2010
ABSTRACT
A practical and efficient procedure for the preparation of the polysubstituted dihydropyridines was developed through a unique four-component
reaction of aromatic aldehydes, malononitrile, arylamines, and acetylenedicarboxylate in ethanol in the presence of triethylamine as a base
promoter. This four-component reaction is atom-efficient, high-yielding, and applicable to a wide variety of four-component reactions.
In a Huisgen 1,4-dipolar addition, the intermediate formed
in situ by the addition of nitrogen heterocycles to electron-
deficient alkynes and reacted with different dipolarophilic
reagents leading to a considerable number of heterocyclic
compounds.1,2 In the past years, extensive interest has been
given to these interesting 1,4-dipoles, and a number of
carbon-carbon bond formation reactions and heterocyclic
constructions have been established.3 Recently, these poten-
tial 1,4-dipoles have been also widely used in multicompo-
nent reactions to develop more atom-economic and envi-
ronmental synthetic methods. A series of three-component
and four-component reactions involving nitrogen hetero-
cycles, the activated acetylenes and electrophiles or dipo-
larophiles have been developed by several research groups
such as Nair4 and Yavari5 as well as others.6-8 Quite
recently, this protocol has been broadened to employ primary
and secondary amines to replace nitrogen heterocycles to
generate the 1,4-dipolar intermediates.9-11 The multicom-
(3) (a) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899–907. (b) Nair,
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3667–3670. (c) Nair, V.; Deepth, A.; Beneesh, P. B.; Eringathodi, S.
Synthesis 2006, 1443–1446. (d) Nair, V.; Deepthi, A.; Manoj, P.; Bindu,
S.; Sreekumar, V.; Beneesh, P. B.; Mohan, R.; Suresh, E. J. Org. Chem.
2006, 71, 2313–2319. (e) Nair, V.; Sreekumar, V.; Bindu, S.; Suresh, E.
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R. Z. Chem. 1968, 8, 290–298. (c) Huisgen, R.; Morikawa, M.; Herbig,
K.; Brunn, E. Chem. Ber. 1967, 100, 1094–1106. (d) Diels, O.; Alder, K.
Liebigs Ann. Chem. 1932, 498, 16–49
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1975, 438–445. (b) Acheson, R. M.; Taylor, G. A. J. Chem. Soc. 1960,
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(5) (a) Yavari, I.; Mirzaei, A.; Moradi, L.; Khalili, G. Tetrahedron Lett.
2010, 51, 396–398. (b) Yavari, I.; Seyfi, S.; Hossaini, Z. Tetrahedron Lett.
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2009, 65, 2067–2071. (d) Yavari, I.; Mokhtarporyani-Sanandaj, A.; Moradi,
L.; Mirzaei, A. Tetrahedron 2008, 64, 5221–5225.
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10.1021/ol101475b  2010 American Chemical Society
Published on Web 07/16/2010

ponent reactions containing primary amine, acetylenedicar-
boxylate, and the third component as well as others provide
new elegant procedures for the clean synthesis of polysub-
stituted N- and N,O-heterocycles.12,13 In this letter, we wish
to report an efficient and practical synthesis of polysubstituted
dihydropyridines via the four-component reactions of aro-
matic aldehydes, arylamines, acetylenedicarboxylate, and
acetonitrile derivatives.
Table 1. Synthesis of Polysubstituted Dihydropyridines from
Reactions of Malononitrile
In an exploratory experiment, the reaction conditions of
the four-component reaction of benzaldehyde, malononitrile,
p-toluidine, and dimethyl acetylenedicarboxylate were ex-
amined, which included base catalyst, solvents, temperature,
and adding sequences of substrates. The best result was
obtained by stirring the solution of benzaldehyde, malono-
nitrile, and triethylamine in ethanol for 10 min and then
adding a solution of acetylenedicarboxylate and p-toluidine
in ethanol to it, which produced 1a in 82% yield (Table 1,
entry 1). Other solvents such as methanol and acetonitrile
and bases such as DABAO were also examined. If no base
was added, the reaction did not yield the expected product.
Afterword, with the optimized conditions in hand, we turned
our attention to examine the scope of the reaction. At first,
various aromatic aldehydes were employed, and the reaction
entry compd
Ar
Ar′
R
yield (%)
1
1a
1b
1c
1d
1e
1f
C6H5
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
82
87
85
84
80
88
95
95
94
96
82
87
88
81
87
80
91
84
76
85
81
85
80
96
2
p-CH3C6H4
p-i-PrC6H4
3
4
p-(CH3)3CC6H4 p-CH3C6H4
5
p-CH3OC6H4
p-FC6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
C6H5
6
7
1g
1h
1i
m-ClC6H4
p-ClC6H4
8
9
p-BrC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1j
1k
1l
m-NO2C6H4
p-CH3OC6H4
p-ClC6H4
m-CH3C6H4
1m
1n
1o
1p
1q
1r
1s
1t
C6H5
p-CH3OC6H4 Me
p-CH3OC6H4 Me
p-CH3OC6H4 Me
p-CH3C6H4
p-ClC6H4
p-CH3OC6H4
p-ClC6H4
o-ClC6H4
m-ClC6H4
p-ClC6H4
Me
Me
Me
p-ClC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-ClC6H4
p-CH3OC6H4 Et
m-ClC6H4
p-ClC6H4
o-CH3C6H4
o-CH3C6H4
R-Naph
Et
1u
1v
1w
1x
Et
Me
Et
p-CH3OC6H4
p-ClC6H4
(6) (a) Harju, K.; Vesterinen, J.; Yli-Kauhaluoma, J. Org. Lett. 2009,
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proceeded very well to give the corresponding polysubsti-
tuted dihydropyridines 1b-1j in 80-96% yields (Table 1,
entries 2-10). Benzaldehydes with both stronger electron-
donating and electron-withdrawing substituents all afforded
the desired products in very satisfactory yields. Then, other
arylamines and diethyl acetylenedicarboxylate were also used
in the reaction (Table 1, entries 11-24). Arylamines with
versatile substituents at o-, m-, and p-positions of the amino
group afforded the expected dihydropyridines (1k-1x) in
very good yields. Diethyl acetylenedicarboxylate also showed
very high reactivity. These results indicated that this four-
component reaction is quite general and has very broad
substrate scopes. The polysubstituted dihydropyridines
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Sridhar, B. J. Org. Chem. 2008, 73, 6857–6859. (b) Ding, H F.; Zhang,
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.
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3569–3574. (b) Bayat, M.; Imanieh, H.; Hassanzadeh, F. Tetrahedron Lett.
2010, 51, 1873–1875. (c) Terzidis, M. A.; Stephanidou-Stephanatou, J.;
Tsoleridis, C. A.; Terzis, A.; Raptopoulou, C. P.; Psycharis, V. Tetrahedron
2010, 66, 947–954. (d) Terzidis, M. A.; Stephanidou-Stephanatou, J.;
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M.; Bazhrang, R. Tetrahedron 2009, 65, 8120–8124. (f) Alizadeh, A.;
Zohreh, N.; Zhu, L. G. Tetrahedron 2009, 65, 2684–2688. (g) Kuma-
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.
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2008, 10, 4493–4496. (b) Fan, M. Q.; Yan, Z. Y.; Liu, W. M.; Liang, Y. M.
J. Org. Chem. 2005, 70, 8204–8207. (c) Naidu, B. N.; Sorenson, M. E.
1a-1x were fully characterized by H and 13C NMR, MS,
1
and IR spectra and elemental analysis, and their structures
were confirmed by single-crystal X-ray diffraction studies
performed for three representative componds 1i, 1r, and 1x.
In 1H NMR spectra, the 2-amino group usually displays one
singlet at about 4.00 ppm, and the proton at the 4-position
of dropyridine appears at 4.60 ppm. It should be pointed
Org. Lett. 2005, 7, 1391–1393
.
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.
1
out that H NMR spectra of compound 1v, 1w, and 1x
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2008, 64, 10425–10430. (d) Zewge, D.; Chen, C. Y.; Deer, C.; Dormer,
showed that they existed in two stereoiosmers, which might
be due to sterical hindrance of the o-methylphenyl and the
R-naphthyl groups in the molecules. As shown in Figure 1,
the rotation of the R-naphthyl group is restricted by 2-amino
and 6-methoxycarbonyl groups. The 4-p-chlorophenyl group
and N-R-naphthyl group existed in the diastereomeric posi-
tion.
To extend the utility of this domino reaction, the reactivity
of ethyl cyanoacetate was also explored. Under similar
reaction conditions, the four-component reaction of aromatic
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312–315. (b) Shen, Y. X.; Jiang, H. F.; Chen, Z. W. J. Org. Chem. 2010,
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Org. Lett., Vol. 12, No. 16, 2010
3679

representative single-crystal structures (2l, 2t, 2v) were
determined by X-ray diffraction. This result showed that a
domino reaction for the efficient synthesis of versatile
functionalized N-aryl dihydropyridines has been successfully
established.
Encouraged by these results, we turned our attention to
study the reactivity of pivaloylacetonitrile and cyanoaceta-
mide in this reaction. The four-component reaction involving
pivaloylacetonitrile proceeded very slowly at room temper-
ature and can be complete at the elevated temperature (60
°C) in about 24 h. Various aromatic aldehydes and amines
behaved well to give the expected polysubstituted dihydro-
pyridines 3a-3h in good yields (63-82%, Table 3, entries
Table 3. Synthesis of Dihydropyridines from Reactions of
Pivaloylacetonitrile and Cyanoacetamide
Figure 1. Molecular structure of dihydropyridine 1x.
aldehydes, ethyl cyanoacetate, arylamine, and acetylenedi-
carboxylate gave the corresponding polysubstituted dihy-
dropyridines (2a-2v) in 75-94% yields (Table 2). This
entry compd
Ar
Ar′
R
R′
yield (%)
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
p-ClC6H4
p-BrC6H4
p-ClC6H4
p-ClC6H4
Me C(CH3)3
Me C(CH3)3
Me C(CH3)3
Me C(CH3)3
Et C(CH3)3
Et C(CH3)3
Et C(CH3)3
Et C(CH3)3
Me NH2
80
82
63
80
73
75
65
78
35
46
51
33
38
42
45
36
2
Table 2. Synthesis of Polysubstituted Dihydropyridines from
Reactions of Ethyl Cyanoacetate
3
p-t-BuC6H4 p-ClC6H4
4
p-FC6H4
p-ClC6H4
p-BrC6H4
m-NO2C6H4 p-CH3C6H4
p-ClC6H4 p-ClC6H4
p-CH3C6H4 p-CH3C6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
m-NO2C6H4 p-ClC6H4
p-CH3C6H4 p-BrC6H4
p-ClC6H4
p-CH3C6H4
p-CH3C6H4
5
6
7
8
9
10
11
12
13
14
15
16
p-CH3C6H4
p-CH3OC6H4 Me NH2
m-CH3C6H4 Me NH2
m-ClC6H4
p-ClC6H4
Me NH2
entry compd
Ar
Ar’
R
yield (%)
Me NH2
Me NH2
Me NH2
Me NH2
1
2a
2b
2c
2d
2e
2f
C6H5
p-ClC6H4
p-ClC6H4
p-ClC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
86
82
87
87
86
89
82
81
88
94
80
82
85
87
84
78
79
82
75
78
92
89
2
p-CH3C6H4
p-i-PrC6H4
3
4
p-(CH3)3CC6H4 p-ClC6H4
p-CH3OC6H4
p-FC6H4
5
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
C6H5
6
7
2g
2h
2i
m-ClC6H4
p-ClC6H4
p-BrC6H4
m-NO2C6H4
p-ClC6H4
p-ClC6H4
p-CH3C6H4
p-ClC6H4
p-ClC6H4
p-(CH3)3CC6H4 p-CH3OC6H4 Et
p-FC6H4
m-ClC6H4
p-ClC6H4
p-BrC6H4
m-NO2C6H4
p-ClC6H4
1-8). It is very interesting to find that the products 3c and
3h exist not in normal enamine form (CdC-NH2) but in
tautomerial imine form (C-CdNH), which might be caused
by the larger t-butyl group in the molecule. The imino form
of 3c and 3h can be converted to enamine form in refluxing
ethanol for several hours. The molecular structures of 3e in
enamine form and 3h in imine form were successfully
determined by X-ray diffraction. On the other hand, the
reaction of cyanoacetamide is very sluggish even in refluxing
ethanol, and the expected dihydropydines 3i-3p were
prepared in 33-51% yields (Table 3, entries 9-16).
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
2j
2k
2l
m-CH3C6H4
p-CH3C6H4
2m
2n
2o
2p
2q
2r
2s
2t
p-CH3OC6H4 Me
m-ClC6H4
Me
p-CH3OC6H4 Et
p-CH3OC6H4 Et
p-CH3OC6H4 Et
p-CH3OC6H4 Et
p-CH3OC6H4 Et
2u
2v
R-Naph
Me
Lastly, the scope of this methodology was further broad-
ened by using some diamines such as 4,4′-diamino-benzene,
4,4′-diaminobiphenyl, and 4,4′-diaminodiphenyl methane in
the four-component reaction. A series of bis(dihydropy-
ridines) 4a-4f were obtained in satisfactory yields (Figure
2). The single-crystal structure of 4e was also successfully
determined by X-ray diffraction.
indicates that the substituents present on the m- and p-
positions of the aromatic ring of aldehyde and amine have
no obvious effects on the reactions. The more sterically
hindered R-naphthylamine gave the expected dihydropyridine
1
2v in 89% yields. However, its H NMR spectra clearly
indicated it existed in two diastereoisomers, which is due to
the similar reason in compounds 1v-1x. A total of 22
dihydropyridines were successfully prepared in satisfied
yields. Their structures were fully characterized, and three
To explain the mechanism of this multicomponent reac-
tion, we proposed a plausible reaction course (Scheme 1).
Knoevenagel condensation of aldehyde with malononitrile
3680
Org. Lett., Vol. 12, No. 16, 2010

Scheme 1
.
Proposed Mechanism for the Four-Component
Reaction
Figure 2. Synthesis of bis(dihydropyridines).
suitable for this four-component reaction. This protocol not
only provides a novel and effective methodology for the
preparation of functionalized dihydropyridines but also opens
a brand new way for employing the 1,4-dipole intermediate
to design new multicomponent reactions. Further expansion
of the reaction scope and synthetic applications of this
methodology are in progress in our laboratory.
and triethylamine as base catalyst yielded arylidene mal-
ononitrile (A). Arylamine added to acetylenedicarboxylate
to give the 1,3-dipole intermediate (B). Then, Michael
addition of B to arylidene malononitrile A yielded the adduct
C, which transformed to intermediate D through the migra-
tion of the hydrogen atom. In intermediate D, the intramo-
lecular addition of the amino group to the C-N triple bond
gave the cyclic intermediate (E). At last, the N-aryl dihy-
dropyridine 1 was formed by the tautomerization of the imino
group to the amino group.
Acknowledgment. This work was financially supported
by the National Natural Science Foundation of China (Grant
No. 20972132).
In conclusion, a novel domino four-component reaction
leading to selective and high-yielding polysubstituted dihy-
dropyridines is developed from readily available starting
materials involving aromatic aldehydes, arylamine, acety-
lenedicarboxylate, and substituted acetonitrile. Various al-
dehydes and amines as well as substituted acetonitrile are
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds including
crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
OL101475B
Org. Lett., Vol. 12, No. 16, 2010
3681