An efficient one-pot multicomponent synthesis of dihydropyridines by using succinic acid as mild organocatalyst

Article abstract of DOI:10.14233/ajchem.2013.15018

A simple, economic and mild protocol was achieved for the synthesis of 1,4-dihydropyridines catalyzed by succinic acid as a mild and effective organocatalyst at 80 C. This method furnishes better yield and associated with advantages like simple work up procedure without any toxic side products. The reusability of catalyst was also investigated. The method avoids use of toxic solvents and expensive catalysts and proceeds efficiently with the use of mild organocatalyst which makes the protocol environmentally benign.

Full text of DOI:10.14233/ajchem.2013.15018

Asian Journal of Chemistry; Vol. 25, No. 17 (2013), 9442-9446
http://dx.doi.org/10.14233/ajchem.2013.15018
An Efficient One-Pot Multicomponent Synthesis of
Dihydropyridines by using Succinic Acid as Mild Organocatalyst
1,*
1
1
2
SURESH PATIL , P.B. PAWAR , S.D. JADHAV and M.B. DESHMUKH
1Organic Research Laboratory, Department of Chemistry, Padmabhushan Dr.Vasantdada Patil College, Tasgaon-416 312, India
2Department of Chemistry, Shivaji University, Kolhapur-416 004, India
*Corresponding author: E-mail: sanyujapatil@yahoo.com
(Received: 24 December 2012;
Accepted: 1 October 2013)
AJC-14201
A simple, economic and mild protocol was achieved for the synthesis of 1,4-dihydropyridines catalyzed by succinic acid as a mild and
effective organocatalyst at 80 ºC. This method furnishes better yield and associated with advantages like simple work up procedure
without any toxic side products. The reusability of catalyst was also investigated. The method avoids use of toxic solvents and expensive
catalysts and proceeds efficiently with the use of mild organocatalyst which makes the protocol environmentally benign.
Key Words: Succinic acid, Multicomponent reaction, Dihydropyridine.
In view of the biological importance of dihydropyridines, 40
several methods for their synthesis have been reported using 41
microwaves10, ionic liquids11 and also in presence of catalysts 42
such as TMSI12,metal triflates13, I214, ceric ammonium nitrate15, 43
polymers16 and organocatalyst17. However, the use of high 44
temperatures, usage of excess organic solvents, expensive 45
metal precursors, catalysts which are unsafe for the environ- 46
ment and longer reaction times limit the use of these methods. 47
Also, some conventional Bronsted acids, such as sulfuric acid, 48
nitric acid, hydrochloric acid and hydrofluoric acid are often 49
used in organic syntheses and industrial processes. However, 50
these acid catalysts are corrosive, toxic, harmful, difficult to 51
handle, to dispose off and are difficult to remove from the reac- 52
tion mixture18. For these reasons, there is a great effort to replace 53
these conventional catalysts by new, non-toxic and efficient 54
catalysts. Development of solid acid catalysts has received great 55
INTRODUCTION
In modern synthetic organic chemistry, multicomponent
reactions (MCRs) have emerged as efficient and powerful tools
because the synthesis of complex organic molecules from
simple and readily available substrates can be achieved in a fast
and efficient manner without isolation of any intermediate1-4.
In this type of reactions three or more components are reacted
to form ideally one product, which contains the essential parts
of all the initial reactants. Nowadays, multicomponent reactions
have become important while developing environmentally
friendly processes, as they are characterized by the reduction
in number of synthetic steps, lower energy consumption as
well as less waste production. Consequently, developing new
multicomponent reactions and improving known multicom-
ponent reactions are the areas of interest for researchers in
synthetic organic chemistry.
attention in research activities and industrial processes19,20
.
56
Generally, 1,4-dihydropyridine (DHP) derivatives are
synthesized by Hantzsch reaction which involves the one pot
four-component cyclocondensation of an aldehyde with an
active methylene carbonyl compound and ammonia or
ammonium acetate5.Dihydropyridine derivatives constitute an
important class of calcium channel blockers and proved to be
valuable as they are part of an important class of drugs used
for the treatment of cardiovascular diseases, including hyper-
tension6. Recent studies have also revealed that dihydropyridine
derivatives exhibit several medicinal applications, including
neuroprotectant7, platelet antiaggregatory activity8 and as
chemo sensitizer in tumor therapy9.
Due to our interest in the synthesis of heterocyclic comp- 57
ounds, by the application of new efficient catalysts in organic 58
transformations, herein we report the synthesis of dihydro- 59
pyridines by the condensation of ethyl acetoacetate with various 60
aromatic aldehydes and ammonium acetate in ethanol:water 61
(1:1) solvent system using succinic acid as an acid catalyst 62
(Scheme-I). Succinic acid possesses high activity and results
in good yield of synthesized derivatives.
63
64
65
66
EXPERIMENTAL
All the chemicals used were obtained from commercial
source and used without purification. The reaction mixture

Vol. 25, No. 17 (2013)
Synthesis of Dihydropyridines by Using Succinic Acid as Mild Organocatalyst 9443
R
O
O
O
O
CHO
2 Me
Succinic acid (50 mol %)
1:1 EtOH:water, 80 °C
NH4OAc
OC2H5
C2H5O
Me
+
R
OC2H5
+
Me
N
H
1
3
2
5a-i
Scheme-I: Synthesis of dihydropyridine from aldehyde, ethyl acetoacetate and ammonium acetate
was heated on water bath with constant stirring which helped
the mixing and uniform heating of the reaction mixture. Melting
points were measured with DBK-programmable melting point
apparatus. The purity of products and completion of reaction
was checked by TLC on Merck silicagel 60 F254 plates. IR
spectra were obtained using potassium bromide pellets on
BrukerALPHA FTIR Spectrometer. The 1H NMR spectra were
measured with Avance-300 spectrophotometer and chemical
shifts are reported in ppm in CDCl3 with TMS as an internal
standard.
4.24 (4H, q, 2-OCH2CH3), 5. 06 (1H, s, -OH), 5.30 (1H, s,
-CH), 6.60 (1H, bs, -NH), 7.08-7.12 (2H, m, Ar-H ) 7.14-7.19
(2H, m, Ar-H ); 13C NMR (75 MHz, CDCl3, δ ppm): 14.1,
16.1, 43.5, 61.9, 102.6, 115.1, 130.8, 136.5, 150.2, 155.1,
167.5.
Diethyl-2,6-dimethyl-4-(4-methoxyphenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (5f): IR (KBr, νmax, cm-1):
3342, 3032, 2964, 1702; 1H NMR (300 MHz, CDCl3, δ ppm):
1.08 (6H, t, 2-OCH2CH3), 2.02 (6H, s, 2-CH3), 3.80 (3H, s,
-OCH3), 3.98 (4H, q, 2-OCH2CH3), 5.13 (1H, s, -CH), 7.10
(1H, bs, -NH), 7.04-7.09 (2H, m, Ar-H ) 7.12-7.14 (2H, m,
Ar-H ); 13C NMR (75 MHz, CDCl3, δ ppm): 14.1, 16.2, 45.0,
55.9, 62.4, 102.5, 115.1, 130.4, 134.6, 151.0, 157.1, 167.5.
Diethyl-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro-
pyridine- 3,5-dicarboxylate (5h): IR (KBr, νmax, cm-1):3314,
3076, 2921, 1725, 1534, 1386; 1H NMR (300 MHz, CDCl3, δ
ppm): 1.12 (6H, t, 2-OCH2CH3), 2.09 (6H, s, 2 -CH3), 4.01
(4H, q, 2-OCH2CH3), 5.12 (1H, s, -CH), 7.12 (1H, bs, -NH),
7.64 -7.69 (2H, m, Ar-H), 7.71-7.74 (2H, m, Ar-H); 13C NMR
(75 MHz, CDCl3, δ ppm): 14.6, 16.1, 44.1, 62.4, 103.1, 121.2,
130.4, 145.1, 148.4, 167.5.
General procedure: To the reaction mixture containing
benzaldehyde (1 mmol), ethyl acetoacetate (2 mmol) and
ammonium acetate (1 mmol) in 1:1 ethanol:water (2 mL),
50 mol % succinic acid was added. Then the reaction mixture
was heated at 80 ºC with constant stirring for 2 h. The progress
of reaction was monitored by TLC. The reaction mixture was
then filtered and washed with plenty of distilled water. The
solid obtained was air-dried to afford the crude product which
was recrystallized from ethyl alcohol to obtain pure product.
Yield 90 %, m.p. 157-159 ºC.
Diethyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine-
3,5-dicarboxylate (5a): IR (KBr, νmax, cm-1): 3340, 3072,
1
1704; H NMR (300 MHz, CDCl3, δ ppm): 1.28 (6H, t, 2-
Diethyl-2,6-dimethyl-4-(2-furyl)-1,4-dihydropyridine-
3,5-dicarboxylate (5i): IR (KBr, νmax, cm-1): 3346, 3082, 1700,
1650, 1488; 1H NMR (300 MHz, CDCl3, δ ppm ): 1.27 (6H, t,
2-OCH2CH3), 2.32 (6H, s, 2-CH3), 4.16 (4H, q, 2-OCH2CH3),
5.18 (1H, s, -CH), 5.92 (2H, d, furyl ring Hs) 6.20 (1H, s,
furyl ring H) 7.20 (1H, bs, -NH); 13C NMR (75 MHz, CDCl3,
δ ppm): 14.9, 15.4, 31.5, 61.1, 102.0, 107.7, 111.2, 142.5,
150.9, 152.2, 167.1.
OCH2CH3), 2.31 (6H, s, 2-CH3), 4.19 (4H, q, 2-OCH2CH3),
5.21 (1H, s, -CH), 7.27 (1H, bs, -NH), 7.49-7.52 (5H, m,
Ar-H ); 13C NMR (75 MHz, CDCl3, δ ppm) 14.7, 16.5, 42.9,
62.1, 102.1, 126.1, 128.6, 129.2, 142.9, 150.3, 167.7.
Diethyl-2,6-dimethyl-4-(2-chlorophenyl)-1,4-dihydro-
pyridine-3,5-dicarboxylate (5c): IR (KBr, νmax, cm-1): 3277,
3079, 2972, 1711; 1H NMR (300 MHz, CDCl3, δ ppm): 1.29
(6H, t, 2-OCH2CH3), 2.30 (6H, s, 2-CH3), 4.18 (4H, q, 2-
OCH2CH3), 5.20 (1H, s, -CH), 7.25 (1H, bs, -NH), 7.33-7.37
(4H, m, Ar-H ); 13C NMR (75 MHz, CDCl3, δ ppm): 14.2,
16.7, 39.9, 62.0, 102.4, 126.5, 127.9, 128.9, 130.4, 134.2,
143.4, 151.0, 167.9.
Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(phenyl)-
5(6H)-oxoquinoline-3-carboxylate (6a): IR (KBr, νmax, cm-1):
1
3050, 2940, 1715, 1630, 1605, 1460, 1375, 1215; H NMR
(300 MHz, CDCl3, δ ppm): 0.93 (3H, s, -CH3), 1.06 (3H, s,
-CH3), 1.12 (3H, t, -OCH2CH3), 2.22 (4H, m, 2 -CH2), 2.36
(3H, s, -CH3), 4.09 (2H, q, -OCH2CH3), 5.03 (1H, s, CH), 6.02
(1H, s, NH), 7.05-7.26 (5H, m, Ar-H); 13C NMR (75 MHz,
CDCl3, δ ppm): 14.62, 18.72, 21.26, 26.59, 36.05, 37.18, 59.49,
103.99, 111.54, 126.12, 127.87, 128.28, 145.40, 148.26,
151.87, 167.37, 195.11.
Diethyl-2,6-dimethyl-4-(4-chlorophenyl)-1,4-dihydro-
pyridine- 3,5-dicarboxylate (5d): IR (KBr, νmax, cm-1): 3272,
3084, 2948, 1710; 1H NMR (300 MHz, CDCl3, δ ppm): 1.35
(6H, t, 2-OCH2CH3), 2.32 (6H, s, 2-CH3), 4.20 (4H, q, 2-
OCH2CH3), 5.23 (1H, s, -CH), 7.10 (1H, bs, -NH), 7.12-7.16
(2H, m, Ar-H ) 7.21-7.26 (2H, m, Ar-H ); 13C NMR (75 MHz,
CDCl3, δ ppm): 13.9, 16.5, 42.9, 62.3, 102.9, 128.2, 130.2,
131.3, 140.6, 150.1, 167.5.
Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(2-chloro-
phenyl)-5(6H)-oxoquinoline-3-carboxylate (6c): IR (KBr,
νmax, cm-1): 3065, 2957, 1725, 1644, 1614, 1467, 1386, 1227;
1H NMR (300 MHz, CDCl3, δ ppm): 0.96 (s, 3H, -CH3), 1.06
(s, 3H, -CH3), 1.20 (t, 3H, -OCH2CH3), 2.03-2.22 (m, 4H, 2×
CH2), 2.40 (3H, s, CH3), 4.06 (2H, q, -OCH2CH3), 5.10 (1H, s,
-CH), 6.09 (1H, bs, -NH) 7.12-7.29 (4H, m, Ar-H)); 13C NMR
(75 MHz, CDCl3, δ ppm): 196.01, 167.95, 149.60, 144.59,
Diethyl-2,6-dimethyl-4-(4-hydroxhphenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (5e): IR (KBr, νmax
,
cm-1): 3312, 3054, 2952, 1705, 1455; H NMR (300 MHz,
CDCl3, δ ppm): 1.28 (6H, t, 2 -OCH2CH3), 2.21 (6H, s, 2-CH3),
1

9444 Patil et al.
Asian J. Chem.
144.35 133.57, 132.45, 130.05, 127.69, 126.70, 111.47,
105.57, 60.23, 51.16, 41.34, 36.34, 32.92, 29.78, 27.59, 19.60,
14.64.
Ar- H); 13C NMR (75 MHz, CDCl3, δ ppm): 14.65, 18.76,
26.94, 32.60, 32.54, 50.77, 59.42, 104.55, 110.59, 114.70,
128.80, 138.87, 144.86, 149.53, 155.71, 167.48, 194.86.
Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(4-chloro-
phenyl)-5(6H)-oxoquinoline-3-carboxylate (6d): IR (KBr,
νmax, cm-1): 3274, 1705; 1H NMR (300 MHz, CDCl3, δ ppm):
0.93(3H, s, -CH3), 1.08 (3H, s, -CH3), 1.19 (3H, t, -OCH2CH3),
2.11-2.30 (4H, m, 2-CH2), 2.37 (3H, S, -CH3), 4.06 (2H, q,
-OCH2CH3), 5.02 (1H, s, -CH), 5.98 (1H, bs, NH), 7.14-7.17
(2H, d, Ar-H), 7.22-7.26 ( 2H, d, Ar-H) );13C NMR (75 MHz,
CDCl3, δ ppm): 14.65, 18.76, 26.94, 32.60, 32.54, 50.77, 59.42,
104.55, 110.59, 114.70, 128.80, 138.87, 144.86, 149.53, 155.71,
167.48, 194.86.
RESULTS AND DISCUSSION
Initially, in the efforts to develop an efficient and mild
methodology for synthesis of dihydropyridine derivatives, we
initiated our studies by subjecting catalytic amount of succinic
acid for model reaction between 4-methoxy benzaldehyde,
ethyl acetoacetate and ammonium acetate in solvent free
condition at room temperature. Unfortunately, the product was
not observed on TLC plate even after 12 h of starting. To effect
the reaction, various solvent systems were screened at different
temperatures. When model reaction was carried out at room
temperature in aqueous medium there slight improvement in
the result was observed (Table-1, entry 2) even at prolonged
reaction time. Furthermore, to improve the yield and to reduce
the reaction time we have continued our efforts by employing
different organic solvents such as ethanol, acetonitrile, tetrahy-
drofuran, dichloromethane, n-hexane and chloroform (Table-
1). It is observed the reaction proceeds smoothly at 80 ºC in
EtOH:water (1:1) solvent system (Table-1, entry 9) with 94 %
yield of product in 2 h. In the case of solvents such as dichloro-
methane, n-hexane and chloroform (Table-1, entries 6-8) the
conversions were quite similar to aqueous medium. Interest-
ingly, the use of polar protic and aprotic organic solvents such
as ethanol, acetonitrile and tetrahydrofuran (Table-1, entries
3-5) afforded good results for 1,4-dihydropyridine derivatives
within 2.5-3.5 h.
Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(4-
hydroxyphenyl)-5(6H)-oxoquinoline-3-carboxylate (6e): IR
(KBr, νmax, cm-1): 3285, 1690, 1617, 1229; 1H NMR (300 MHz,
CDCl3, δ ppm): 0.95 (3H, s, -CH3), 1.19 (3H, s, -CH3), 1. 31
(3H, t, -OCH2CH3), 2.24-2.32 (4H, m, 2-CH2), 2.45 (3H, s,
-CH3) 4.45 (2H, q, -OCH2CH3), 5.24 (1H, s, -OH), 5.52 (1H,
s, -CH), 7.12-7.15 (2H, d,Ar-H), 5.72 (1H, bs, -NH).13C NMR
(75 MHz, CDCl3, δ ppm): 14.65, 18.76, 26.94, 32.60, 32.54,
50.77, 59.42, 104.55, 110. 59, 114.70, 128.80, 138.87, 144.86,
149.53, 155.71, 167.48, 194.86.
Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(4-methoxy-
phenyl)-5(6H)-oxoquinoline-3-carboxylate (6f): IR (KBr,
νmax, cm-1): 3275, 2957, 1705, 1647, 1605, 1497,1382, 1217,
1032, 766; 1H NMR (300 MHz, CDCl3, δ ppm): 0.93 (3H, s,
-CH3), 1.08 (3H, s, -CH3), 1.22 (3H, t, -OCH2CH3), 2.02-2.11
(4H, m, 2-CH2), 2.32 (3H, s, -CH3), 3.75 (3H, s, -OCH3), 4.01
(2H, q, -OCH2CH3), 4.82 (1H, s, -CH), 6.68 (2H, d, Ar-H),
7.12 (2H, d, Ar-H), 5.94 (1H, bs, -NH)); 13C NMR (75 MHz,
CDCl3, δ ppm): 196.27, 168.03, 158.19, 149.24, 143.93,
140.16, 129.36, 113.66, 112.44, 106.61, 60.19, 55.52, 51.23,
41.22, 36.17, 33.06, 29.90, 27.55, 19.65, 14.68 (Fig. 1).
TABLE-1
OPTIMIZATION OF REACTION CONDITIONS
USING VARIOUS SOLVENTSa
Entry
1
Solvent
Time (h)b
Yield (%)b
Neat
12
00
2
Water
EtOH
CH3CN
THF
8.0
42
Cl
3
2.5
87
4
3.0
73
5
3.5
71
O
6
CH2Cl2
8.0
42
COOC2H5
7
n-Hexane
8.0
32
8
Chloroform
8.0
51
N
H
9
EtOH:water (1:1)
CH3CN:water (1:1)
THF:water (1:1)
CH2Cl2:water (1:1)
n-Hexane:water (1:1)
Chloroform:water (1:1)
2.0
94
10
11
12
13
14
2.5
81
2.0
82
4.0
75
4.0
76
4.0
72
aReactions were carried out on a 1 mmol scale (2 mL of solvent) in the
molar ratio of 4-methoxy benzaldehyde:ethyl acetoacetate:ammonium
acetate:catalyst = 1:2:1:1 at 80 ºC for appropriate time. bIsolated yield
based on 4-methoxy benzaldehyde.
ppm
10
9
8
7
6
5
4
3
2
1
Fig. 1. NMR spectra of compound 6f
This can be explained in terms of a homogeneous solution
of reaction mixture with the catalyst in polar organic solvent.
In case of less polar organic solvents, the reactants were in a
different phase with the catalyst, resulting poor yields of
product. On other hand, for an aqueous medium, the reactants
were in different phases with the water-soluble catalyst succinic
acid and responsible for low reaction yield of product. Thus,
the aqueous medium reaction took a similar reaction period to
Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(4-nitro-
phenyl)-5(6H)-oxoquinoline-3-carboxylate (6g): IR (KBr,
1
νmax, cm-1): 3285, 1690, 1617, 1536, 1355, 1229; H NMR
(300 MHz, CDCl3, δ ppm): 0.92 (3H, s, -CH3), 1.22 (3H, s,
-CH3), 1.29 (3H, t, -OCH2CH3), 2.35-2.39 (4H, m, 2-CH2),
2.45 (3H, s, -CH3) 4.24 (2H, q, -OCH2CH3), 5.26 (1H, s, -CH),
6.12 (1H, bs, -NH) 7.76-7.82 (2H, d, Ar-H), 7.90-7.97 (2H, d,

Vol. 25, No. 17 (2013)
Synthesis of Dihydropyridines by Using Succinic Acid as Mild Organocatalyst 9445
less polar organic solvents. Carrying out the same reaction in
a 1:1 mixture of various organic solvents and water (Table-1,
entries 9-14) can indirectly prove this explanation. It was
observed that the reaction completed within 4 h in a hetero-
geneous 1:1 mixture of less polar organic and water solvent
systems (Table-1, entries 12 and 13). On other hand, a homo-
geneous 1:1 mixture of polar organic and water solvent systems
showed comparable results with the polar organic solvent
(Table-1, entries 9-11).
solvents, almost 100 % catalyst was easily recovered from
reaction mixture after completion of reaction.After completion
of reaction, the product was separated by filtration followed
by washing with small amount of water. The catalyst was
recovered quantitatively by concentrating the filtrate which
could be effectively used in next few cycles.
With the optimized reaction conditions in hand, we next
examined the feasibility of the succinic acid for synthesis of
dihydropyridine derivatives by condensing variously substi-
tuted aromatic aldehydes, ethyl acetoacetate and ammonium
acetate (Scheme-I) with 50 mol % succinic acid in ethanol:
water (1:1) system at 80 ºC and results were incorporated in
Table-3. The reactions proceeded efficiently to furnish the
corresponding dihydropyridines (5a-i) in good to excellent
yields. It is noteworthy that the methodology worked well even
for heterocyclic aldehydes such as 2-furfuraldehyde (Table-3,
entry 5i).
The reaction condition was then optimized by conducting
the model reaction employing different catalyts loading and
at various temperatures (Table-2). It was gratifying to observe
that similar high yield was resulted when the amount of catalyst
was reduced from 1.0 to 0.5 equiv (94 % yields, Table-2,
entry 8) within 2 h. It reveals that the reaction can also proceeds
well in a catalytic manner of 0.5 equiv of succinic acid.
However, conversion rate of reactant into product was poor
when 0.2 equiv of catalyst was used for the model reaction.
As shown in Table-2, the reaction temperature was also
affecting the results of model reaction and increasing the
reaction temperature led to a enhancement of the conversion
rate in all cases. When 0.2 equiv of catalyst was employed, at
ambient temperature, no result was observed on TLC plate,
even at increasing reaction time up to 12 h (Table-2, entries 5
and 6). But, when reaction was carried at 80 ºC temperature
with 0.2 equiv catalyst, the result was obtained with 40 %
yield of product (Table-2, entries 10 and 11).
TABLE-3
SYNTHESIS OF DIHYDROPYRIDINES
BY USING SUCCINIC ACIDa
Time Yieldb
Melting point (ºC)
Entry
R
(h)
(%)
Observed
155-157
118-120
129-130
150-151
224-226
156-157
140-141
201-202
158-160
Reported
157-15921
121-12223
130-13123
14921
227-22821
158-16021
141-14321
202-20324
160-16122
C6H5
2.5
2.0
2.5
2.5
3.0
2.0
3
90
90
89
92
92
94
88
88
89
5a
5b
5c
5d
5e
5f
4-MeC6H4
2-Cl C6H4
4-Cl C6H4
4-OHC6H4
4-OMe C6H4
C6H5 CH=CH
4-NO2 C6H4
2-Furyl
5g
5h
5i
TABLE-2
OPTIMIZATION OF REACTION CONDITIONS WITH
DIFFERENT CATALYST LOADINGS AND TEMPERATURESa
3
2.5
Yield (%)b
aReactions were carried out at 80 ºC for appropriate time using
aldehydes (1 mmol), ethyl acetoacetate (2 mmol) and ammonium
acetate (1 mmol) and succinic acid (0.5 mmol) in 2 mL ethanol:water
(1:1). bIsolated yield based on aldehydes.
Entry
Conditions
1
2
Succinic acid (1.0 equivalent), 25 ºC, 12 h
Succinic acid (0.5 equivalent), 25 ºC, 2 h
Succinic acid (0.5 equivalent), 25 ºC, 8 h
Succinic acid (0.5 equivalent), 25 ºC, 12 h
Succinic acid (0.2 equivalent), 25 ºC, 2 h
Succinic acid (0.2 equivalent), 25 ºC, 12 h
Succinic acid (1.0 equivalent), 80 ºC, 2 h
Succinic acid (0.5 equivalent), 80 ºC, 2 h
Succinic acid (0.5 equivalent), 80 ºC, 8 h
Succinic acid (0.2 equivalent), 80 ºC, 2 h
Succinic acid (0.2 equivalent), 80 ºC, 12 h
18
16
18
20
00
00
94
94
94
34
40
3
4
With these results in hand, we extend this protocol further
for unsymmetrical Hantzsch multi-component condensation
for the synthesis of dihydropyridine derivatives by condensation
of 1:1:1:1 mole ratio of substituted aromatic aldehydes, ethyl
acetoacetate, dimedone and ammonium acetate (Scheme-II)
with 50 mol % succinic acid in ethanol:water (1:1) system at
80 ºC and results were reported in Table-4. In most of the
cases, the desired dihydropyridine derivatives were obtained
in high yields. Both electron rich and electron deficient aromatic
aldehydes afforded equally good yields.
5
6
7
8
9
10
11
aThe reactions were carried out at 25-80 ºC for 2-12 h using 4-methoxy
benzaldehyde (1 mmol), ethyl acetoacetate (2 mmol) and ammonium
acetate (1 mmol) and succinic acid (0.2-1 mmol) in 2 mL ethanol:
water (1:1). bIsolated yield based on 4-methoxy benzaldehyde.
Conclusion
To assess the reusability of succinic acid, recycling
experiments were carried out with model substrates for four
times. As succinic acid is soluble in water than in organic
We have described a simple and efficient one-pot proce-
dure for Hantsch multi-component reaction for synthesis of
R
O
O
O
O
CHO
Succinic acid (50 mol %)
1:1 EtOH:water, 80 °C
NH OAc
OC2H5
Me
+
+
4
R
+
OC2H5
Me
O
O
N
H
1
2
4
3
6a-i
Scheme-II: Synthesis of dihydropyridine from aldehyde, dimedone, ethyl acetoacetate and ammonium acetate

9446 Patil et al.
Asian J. Chem.
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(1996).
TABLE-4
SYNTHESIS OF DIHYDROPYRIDINES
BY USING SUCCINIC ACIDa
Time Yieldb
Melting point (ºC)
Entry
R
Observed
201-202
259-260
204-205
243-244
232-233
253-254
238-240
202-203
245-246
Reported25
203 - 204
261-262
207-208
245-246
233-234
256-257
240-242
204-206
246-248
(h)
(%)
C6H5
2.0
2.0
2.5
2.0
3.0
2.0
2.5
3.0
3.0
92
90
90
94
92
94
92
89
90
6a
6b
6c
6d
6e
6f
4-MeC6H4
2-Cl C6H4
4-Cl C6H4
4-OHC6H4
4-OMe C6H4
4-NO2 C6H4
C6H5 CH=CH
2-Furyl
7. V. Klusa, Drugs Future, 20, 135 (1995).
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and F. Shi, J. Heterocycl. Chem., 43, 985 (2006).
6g
6h
6i
11. (a) S.J. Ji, Z.Q. Jiang, J. Lu and T.P. Loh, Synlett, 831 (2004); (b) R.
Sridhar and P.T. Perumal, Tetrahedron, 61, 2465 (2005).
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Lett., 44, 4129 (2003).
aThe reactions were carried out at 80 ºC for appropriate time using
aldehydes (1 mmol), ethyl acetoacetate (1 mmol), dimedone (1 mmol)
and ammonium acetate (1 mmol) and succinic acid (0.5 mmol) in 2
mL ethanol:water (1:1). bIsolated yield based on aldehydes.
13. L.M. Wang, J. Sheng, L. Zhang, J.W. Han, Z. Fan, H. Tian and C.T.
Qian, Tetrahedron, 61, 1539 (2005).
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(2005).
symmetrical and unsymmetrical 1,4-dihydropyridine derivatives
using catalytic amount of succinic acid as a non-toxic, non-
corrosive and inexpensive organocatalyst. The mildness of the
conversion, experimental simplicity, excellent yields make this
procedure attractive to synthesize dihydropyridine derivatives.
By recycling experiments, it is shown that succinic acid can
be quantitatively recovered and reused effectively for many
times.
15. S. Ko and C.F. Yao, Tetrahedron, 62, 7293 (2006).
16. (a) J.C. Legeay, J.Y. Goujon, J.J.V. Eynde, L. Toufet and J.P. Bazureau,
J. Comb. Chem., 8, 829 (2006); (b) A. Dondoni, A. Massi, E. Minghini
and V. Bertolasi, Tetrahedron, 60, 2311 (2004).
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18. C.R. Reddy, B. Vijayakumar, P. Iyengar, G. Nagendrappa and B.S.J.
Prakash, J. Mol. Catal. A, 223, 117 (2004).
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A, 223, 143 (2004).
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15, 118 (2004).
ACKNOWLEDGEMENTS
21. S.-X. Wang, Z.-Y. Li, J.-C. Zhang and J.-T. Li, Ultrason. Sonochem.,
15, 677 (2008).
The authors are thankful to the college authority for pro-
viding research facilities and also thankful to IICT Hyderabad
to providing spectral analysis facilities.
22. A. Debache, L. Chouguiat, R. Boulcina and B. Carbonib, Open Org.
Chem. J., 6, 12 (2012).
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24. M. Arslan, C. Faydali, M. Zengin, M. Kuc, U. Glu and H. Demirhan,
Turk. J. Chem., 33, 769 (2009).
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