An efficient and solvent-free one-pot synthesis of 1,4-dihydropyridines under microwave irradiation

Article abstract of DOI:10.1016/j.cclet.2011.05.003

An efficient synthesis of 1,4-dihydropyridines using lanthanum oxide as a catalyst from aldehydes, β-ketoester and ammonium acetate without solvent under the irradiation of microwave is described. Compared with the classical Hantzsch reaction, this new me

Full text of DOI:10.1016/j.cclet.2011.05.003

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1199–1202
www.elsevier.com/locate/cclet
An efficient and solvent-free one-pot synthesis of
1,4-dihydropyridines under microwave irradiation
*
A. Kuraitheerthakumaran, S. Pazhamalai, M. Gopalakrishnan
Department of Chemistry, Annamalai University, Annamalainagar 608002, India
Received 21 February 2011
Available online 20 July 2011
Abstract
An efficient synthesis of 1,4-dihydropyridines using lanthanum oxide as a catalyst from aldehydes, b-ketoester and ammonium
acetate without solvent under the irradiation of microwave is described. Compared with the classical Hantzsch reaction, this new
method has the advantage of good yield (90–98%) and short reaction time (40–80 s).
# 2011 M. Gopalakrishnan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Hantzsch reaction; 1,4-Dihydropyridine; Microwave; Solvent free; Lanthanum oxide
There is always something new on the old topic of the Hantzsch reaction since Arthur Hantzsch first reported it in
1882 [1]. This is mainly due to the fact that it offers an efficient way to prepare the 1,4-dihydropyridines (1,4-DHPs)
which exhibit significant biological activities in the treatment of cardiovascular disease as calcium channel blockers
[2]. A number of dihydropyridine calcium antagonists have been introduced as potential drugs for the treatment of
congestive heart failure and angina pectoris [3]. They also function as neuroprotectants, as anti-platelet treatment of
aggregators and are important in Alzheimer’s disease as anti-ischaemic agents [4]. The classical method for the
synthesis of 1,4-DHPs is one-pot condensation of aldehydes with ethyl acetoacetate and ammonia either in acetic acid
or by refluxing in ethanol. However, the yield of 1,4-DHP obtained by Hantzsch method is generally low [1]. Recently,
many synthetic methods have been developed to improve and modify this reaction by using silica gel/NaHSO4 [5],
AlCl3ꢀ6H2O [6], TMSI [7], HClO4–SiO2 [8], triphenylphosphine [9], ionic liquid [10] and 3,4,5-trifluorobenze-
neboronic acid [11]. These methods however, involve long reaction time, harsh reaction conditions, tedious work-up
procedure, give unsatisfactory yield with other side products, the use of large quantity of volatile organic solvents.
However, most of the researchers have been focused on the modification and optimization of the Hantzsch reaction
to maximize reaction conversion, minimize reaction time and offer high purity of 1,4-DHPs. Thus, the development of
an efficient and versatile method for the preparation of Hantzsch 1,4-DHPs is an active ongoing research area and there
is scope for further improvements towards short reaction time and high yield.
During the last decade, lanthanide additives (or) complexes are found to enhance the reactivity and selectivity of
many reactions, such as reduction [12], carbon–carbon bond forming reactions [13], aldol condensation [14], Friedel–
Crafts acylations [15], aza Diels–Alder reactions [16] and many diverse reactions [17]. In this letter, we would like to
* Corresponding author.
E-mail address: mgkrishnan61@gmail.com (M. Gopalakrishnan).
1001-8417/$ – see front matter # 2011 M. Gopalakrishnan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.05.003

1200
A. Kuraitheerthakumaran et al. / Chinese Chemical Letters 22 (2011) 1199–1202
report a simple effective approach to the Hantzsch reaction products using La2O3 as a catalyst under microwave
irradiation with solvent free conditions.
1. Experimental
All melting points were measured in open capillaries and are uncorrected. IR spectra were recorded using Avatar-
330 FT-IR spectrophotometer using KBr pellets. 1H and 13C NMR spectra were recorded on a BRUKER AC 300 MHz
spectrometer in CDCl3 using TMS an internal standard. Elemental analyses were performed on a Perkin Elmer 240
CHN elemental analyzer. Microwave LG MS–1947C AC–230 V/50 Hz model was used.
A mixture of aldehyde (1) (5 mmol), ethyl acetoacetate (2) (10 mmol), ammonium acetate (3) (10 mmol) and
lanthanum oxide (10 mol%) without solvent in a beaker (capacity 25 mL) kept at the center of the microwave
oven (320 W) and irradiation for a period of 10 s was maintained. After every irradiation (10 s), the reaction
vessel was removed from the microwave oven and stirred the reaction mixture. The completion of the reaction
was checked by TLC (ethylacetate:hexane, 8:2). The total period of microwave irradiation was in the range of 40–
80 s. The reaction mixture was then extracted with ethylacetate and the catalyst was separated by the filtration.
The organic layer then washed with water and dried over anhydrous Na2SO4. Organic solvent was evaporated
under reduced pressure and solid compound, which was crystallized from absolute ethanol is identified as 1,4-
1
DHPs in excellent yield. The obtained products were confirmed by FT-IR, H and 13C NMR and elemental
analysis.
2. Results and discussion
In a model reaction, benzaldehyde (1) (5 mmol), ethyl acetoacetate (2) (10 mmol), ammonium acetate (3)
(10 mmol) and La2O3 (10 mol%) are irradiated in microoven gave the product in 98% yield (Scheme 1).
We have studied the effect of catalyst by varying amount of catalyst 4, 6, 8, 10 and 12 mol% (Table 1). From the
above studies we found that 10 mol% La2O3 was to be the optimum and this amount of catalyst was fixed for all
substituents. We also screened a number of different catalysts for this reaction. The reaction was carried out in the
presence of Nafion-H, amberlite-IR-120, silica–sulfuric acid, zeolite, KH2PO4 or BF3 OEt2 under microwave
irradiation gave low yield even after prolonged reaction time. However, when the same reaction was conducted
under microwave irradiation using La2O3 as a catalyst, result in excellent yield with short reaction time (Table 2,
entry 7). Table 3 compares the efficiency of present method with the efficiency of other methods in the synthesis of
1,4-DHPs.
Encouraged by this result, a series of aldehydes were examined under optimized conditions and the results are
shown in Table 4. It is seen that several aromatic aldehydes bearing either electron-releasing or electron-withdrawing
substituents in meta and para position afford high yield. Here, we have found that the reactions of aromatic aldehydes
having electron-withdrawing groups are rapid as compared to the reaction of aldehydes having electron-donating
groups. We have not tried this method for aliphatic aldehydes.
Spectral data and elemental analysis for selected compounds:
R
4'
R
5'
3'
6'
O
2' O
1'
4
H
O
O
5
3
O
O
H3CH2CO
H3C
OCH2CH3
La2O3/solvent free
1
2
6
OCH2CH3
H3CH2CO
H3C
N1 CH3
H
MW 40−80 s
320 W
+
CH3
2
O
2
4a 4l
−
NH4OAc
3
Scheme 1. La2O3 catalyzed synthesis of 1,4-dihydropyridines under microwave irradiation.

A. Kuraitheerthakumaran et al. / Chinese Chemical Letters 22 (2011) 1199–1202
1201
Table 1
Effect of catalyst amount on model reaction.a
Entry
Catalyst (mol%)
Yieldb (%)
1
2
3
4
5
4
6
48
60
73
98
98
8
10
12
a
Reaction condition: benzaldehyde (5 mmol), ethyl acetoacetate (10 mmol), ammonium acetate (10 mmol) in the presence of La2O3 (10 mol%)
under microwave irradiation and solvent free condition.
b
Isolated yield.
Table 2
Screening of catalyst on the model reaction.a
Entry
Catalyst (mol%)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
Nafion-H
5
30
36
40
43
50
56
98
Amberlite-IR-120
Silica–sulfuric acid
Zeolite
5
5
5
KH2PO4
5
BF3.OEt2
5
La2O3
40 s
a
Reaction condition: benzaldehyde (5 mmol), ethyl acetoacetate (10 mmol), ammonium acetate (10 mmol) in the presence of La2O3 (10 mol%)
under microwave irradiation and solvent free condition.
b
Isolated yield.
Table 3
Comparison of the efficiency of La2O3 with other reported catalysts in the synthesis of 4a.
Entry
Catalyst (mol%)
Condition
Time (h)
Yield (%)
Reference
1
2
3
4
5
6
7
Silica gel/NaHSO4
CH3CN/Stirring at room temperature
EtOH/Reflux
6
85
72
90
85
83
95
98
[5]
PPh3
5
[9]
3,4,5-Trifluorobenzeneboronic acid
Stirring with ionic liquid
CH3CN/stirring at room temperature
Heating at 60 8C/solvent free
Stirring at 80 8C
4
[11]
[7]
TMSI/NaI
AlCl3ꢀ6H2O
HClO4–SiO2
La2O3
2
1
[6]
20 min
40 s
[8]
MW/solvent free at 320 W
This work
2,6-Diethyl-3,5-dicarboethoxy-4-phenyl-1,4-dihydropyridine (entry 4a): IR (KBr) cmꢁ1: 3330 (N–H str.), 1684
(C O str.); 1H NMR (CDCl3): d 7.98 (s, 1H, H-1), 7.54–7.08 (m, 5H, ArH), 4.94 (s, 1H, H-4), 4.06 (q, 4H, J = 6.6 Hz,
OCH2CH3 at C-3 and C-5), 2.32 (s, 6H, 2CH3 at C-2 and C-6), 1.21 (t, 6H, J = 6.6 Hz, 2CH3 at C-3 and C-5); 13C NMR
(CDCl3): d 167.1 (CO), 147.6 (C-10), 144.6 (C-2 and C-6), 127.1–125.1 (aromatic carbons), 102.1 (C-3 and C-5), 58.6
(COOCH2CH3 at C-3 and C-5), 39.4 (C-4), 18.0 (2CH3 at C-2 and C-6), 13.5 (2CH3 at C-3 and C-5); Anal. Calcd. for
C19H23NO4; C, 69.30; H, 6.99; N, 4.25. Found C, 69.36; H, 7.03; N, 4.29%.
2,6-Dimethyl-3,5-dicarboethoxy-4-(3,4,5-trimethoxyphenyl)-1,4-dihydropyridine (entry 4i): IR (KBr) cmꢁ1: 3359
(N–H str.), 1703 (C O str.); 1H NMR (CDCl3): d 8.29 (s, 1H, H-1), 6.50 (2H, Ar–H), 4.94 (s, 1H, H-4), 4.08 (q, 4H,
J = 6.6 Hz, OCH2CH3 at C-3 and C-5), 2.32 (s, 6H, 2CH3 at C-2 and C-6), 1.27 (t, 6H, J = 6.6 Hz, 2CH3 at C-3 and C-
5); 13C NMR (CDCl3): d 166.7 (CO), 151.5, 151.4, 144.5 (ipso carbon at C-30, C-50 and C-40), 144.4 (C-2 and C-6),
143.1 (C-10), 104.0–103.8 (aromatic carbons), 101.5 (C-3 and C-5), 59.4, 58.3, 54.9, 54.8 (OCH3 carbon), 38.8 (C-4),
17.6 (CH3 at C-2 and C-6), 13.4 (CH3 at C-3 and C-5); Anal. Calcd. for C22H28NO7; C, 63.15; H, 6.69; N, 4.29. Found
C, 63.21; H, 6.63; N, 4.34%.

1202
A. Kuraitheerthakumaran et al. / Chinese Chemical Letters 22 (2011) 1199–1202
Table 4
Synthesis of 1,4-dihydropyridines catalyzed by lanthanum oxide under microwave irradiation and solvent free condition.
Entry
R
Timea (s)
Product
Yieldb (%)
mp (8C)
Found
Reported
1
2
C6H5
40
48
40
50
62
45
65
60
65
80
4a
4b
4c
4d
4e
4f
98
94
97
93
92
96
92
90
90
90
154–156
145–147
160–162
150–152
140–142
133–135
155–157
174–176
182–184
170–172
158–160 [18]
141–143 [19]
162–164 [18]
147–148 [18]
135–137 [18]
129–131 [18]
150–152 [20]
–
3-(Cl)-C6H4
3-(NO2)-C6H4
4-(Cl)-C6H4
4-(CH3O)-C6H4
4-(NO2)-C6H4
4-(F)-C6H4
3
4
5
6
7
4g
4h
4i
8
C6H5-CH CH
3,4,5-(CH3O)-C6H2
9
–
10
4j
–
O
11
70
80
4k
4l
93
90
220–222
192–194
–
–
N
H
12
a
Reaction were continued until the TLC shown the starting materials disappeared.
Isolated yield.
b
3. Conclusion
In summary, the present method is very simple, mild and efficient for the synthesis of 1,4-DHPs. In addition, this
protocol has advantages in terms of short reaction time, solvent-free reaction, high yield, easy work-up eco-friendly
process. We believe that this method is a useful addition to the present methodology for the synthesis of 1,4-DHPs.
Acknowledgment
We wish to thank Annamalai University for supporting this work.
References
[1] A. Hantzsch, Jusfus Liebigs Ann Chem. 215 (1882) 1.
[2] R.H. Bocker, E.P. Guengerich, J. Med. Chem. 29 (1986) 1596.
[3] D. Vo, W.C. Matowe, M. Ramesh, et al. J. Med. Chem. 38 (1995) 2851.
[4] R. Boer, V. Gekker, Drugs Future 20 (1995) 499.
[5] M. Adharvana Chari, K. Syamasundar, Catal. Commun. 6 (2005) 624.
[6] S.D. Sharma, P. Hazarika, D. Konwar, Catal. Commun. 9 (2008) 709.
[7] G. Sabitha, G.S.K. Kumar Reddy, C.S. Reddy, et al. Tetrahedron Lett. 44 (2003) 4129.
[8] M. Maheswara, V. Siddaiah, Y.K. Rao, et al. J. Mol. Catal. A 260 (2006) 179.
[9] A. Debache, W. Ghalem, R. Boulcina, et al. Tetrahedron Lett. 50 (2009) 5248.
[10] L. Ming, G. Wei-Si, W.L. Rong, et al. J. Mol. Catal. A 258 (2006) 133.
[11] R. Sridhar, P.T. Perumal, Tetrahedron 61 (2005) 2465.
[12] T. Nishino, T. Watanabe, M. Okada, et al. J. Org. Chem. 67 (2002) 966.
[13] S. Kobayashi, Eur. J. Org. Chem. (1999) 15.
[14] S. Kobayashi, I. Hachiya, H. Ishitani, et al. Synlett (1993) 472.
[15] A. Kawada, S. Mitamura, S. Kobayashi, Synlett (1994) 545.
[16] Y. Makioka, T. Shindo, Y. Taniguchi, et al. Synthesis (1995) 801.
[17] T. Imamoto, Lanthanides in Organic Synthesis, Academic Press, New York, 1994.
[18] J.J. Eynde, F. Delfosse, A. Mayence, et al. Tetrahedron 51 (1995) 6511.
[19] A. Shaabani, A.H. Rezayan, A. Rahmati, Monatsh. Chem. 137 (2006) 77.
[20] B. Love, M.M. Goodman, K.M. Snader, Eur. J. Med. Chem. 17 (1974) 77.