PEG400-lithium carbonate catalyzed synthesis of 1,4-dihydropyridines under solvent-free conditions

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Organic Preparations and Procedures
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PEG400-Lithium Carbonate Catalyzed
Synthesis of 1,4-Dihydropyridines under
Solvent-free Conditions
B. Palakshi Reddy a , K. Rajesh a & V. Vijayakumar a
a Organic Chemistry Division, School of Advanced Sciences, VIT
University, Vellore, 632014, India
Version of record first published: 30 Mar 2012.
To cite this article: B. Palakshi Reddy, K. Rajesh & V. Vijayakumar (2012): PEG400-Lithium Carbonate
Catalyzed Synthesis of 1,4-Dihydropyridines under Solvent-free Conditions, Organic Preparations and
Procedures International: The New Journal for Organic Synthesis, 44:2, 153-158
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Organic Preparations and Procedures International, 44:153–158, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.657562
OPPI BRIEFS
PEG400-Lithium Carbonate Catalyzed Synthesis of
1,4-Dihydropyridines under Solvent-free Conditions
B. Palakshi Reddy, K. Rajesh, and V. Vijayakumar
Organic Chemistry Division, School of Advanced Sciences, VIT University,
Vellore 632014, India
Hantzsch 1,4-dihydropyridines (1,4-DHPs) are useful as vasodilators, bronchodilator and
anti-hypertensive, hepta-protective, anti-tumor, anti-mutagenic, gero-protective and anti-
diabetic agents.1 Nifedipine, nitrendipine and nimodipine for example have found commer-
cial utility as calcium channel blockers.2–4 A number of DHP calcium antagonists have been
introduced for the treatment of congestive heart failure5,6 some DHPs have been introduced
as a neuroprotectant and cognition enhancer. In addition, a number of DHPs with platelet
anti-aggregatory activity have also been discovered.7
1,4-DHPs have been synthesized by the Hantzsch reaction8 which involves the cy-
clocondensation of aldehydes with compounds containing methylene group activated
by carbonyl groups (ethyl or methyl acetoacetate, acetylacetone) and ammonium ac-
etate/ammonia/primary amine9 under long reflux in acetic acid or ethanol. Recently, several
improved procedures for the synthesis of 1,4-DHPs have been reported by using CAN,10
silica gel/NaHSO4,11 Sc(OTf)3,12 microwave-assisted synthesis with catalysts, ionic liq-
uids, and reflux at high temperature.13–19 However, there are several drawbacks associated
with the reported methodologies. Reactions carried out under solvent-free conditions offer
several advantages such as formation of cleaner products, simpler work-up, enhanced selec-
tivity and pronounced reaction rates. Polyethylene-glycols (PEGs) are known to function
as efficient phase-transfer catalysts in a variety of organic reactions.20,21 In addition, PEGs
are non-toxic, thermally stable and inexpensive compared to conventional phase-transfer
catalysts such as crown ethers or quaternary ammonium salts. We now report a solvent-free
synthesis of 1,4-dihydropyridines using a catalytic amount of anhydrous lithium carbonate
and PEG400.
The 1,4-DHPs were synthesized from various aldehydes (including acetaldehye 6a),
ethyl and methyl acetoacetate, acetylacetone and ammonium acetate (in 1:2:1 molar ratio)
in solution as well as under solvent-free conditions using Li2CO3 and PEG400. This
Submitted June 24, 2011.
Address correspondence to V. Vijayakumar, Organic Chemistry Division, School of Advanced
Sciences, VIT University, Vellore 632014, India. E-mail: kvpsvijayakumar@gmail.com
153

154
Vijayakumar et al.
R'
O
O
O
O
R
R
PEG 400
Li2CO3
R'CHO + CH3COONH4
+
CH3
R
3
1
2
CH3
N
H
CH3
4/5/6
R = CH3, OCH3, OC2H5.
4a-l: R = OEt
5a-i: R = OMe
6a-k: R = Me
Scheme 1
reaction was optimized by varying the solvent, temperature, time, concentration of Li2CO3,
concentration of PEG400 and the results clearly revealed that the efficiency and the yield of
the reactions are much less compared to the solvent-free conditions (Table 1). The use of 5%
of Li2CO3 afforded better yields under solvent-free conditions with 5% of PEG400 at 80◦C,
while less than 5% of PEG400 is inefficient and higher percentages led only to marginally
increased yields. In general, the reaction proceeded in good yields (Table 2). Some of the
compounds were characterized by IR, NMR and Mass. Spectral data for 6i is given in Table 3
since it is not available in literature. Compound 6g was subjected to single crystal X-ray
diffraction studies (Figure 1) and the data has been deposited on CCDC [R indices (all
data) R1 = 0.0835, wR2 = 0.2689] since it has not been reported in literature.
Table 1
Synthesis of 1,4-DHPS with Li2CO3 Catalyst in Various Solventsa
Li2CO3
(mol%)
PEG400
(mol%)
Time
(min)
Entry
Solvent
Temperature
Yield %
1
2
3
4
5
6
7
8
9
Acetonitrile
DMF
Benzene
Dichloromethane
Ethanol
Toluene
Solvent-Free
Solvent-Free
Solvent-Free
Solvent-Free
Solvent-Free
Solvent-Free
RT
RT
RT
RT
RT
RT
RT
80◦C
80◦C
80◦C
80◦C
80◦C
5%
5%
5%
5%
5%
5%
5%
1%
5%
5%
5%
10%
5%
5%
5%
5%
5%
5%
5%
5%
5%
1%
10%
5%
180
150
130
240
90
100
240
150
90
60
53
74
80
81
78
84
82
88
78
89
90
10
11
12
120
90
90
aReaction conditions: benzaldehyde (5 mmol), ethyl acetoacetate (10 mmol), ammoniumacetate
(5 mmol).

Synthesis of 1,4-Dihydropyridines under Solvent-free Conditions
155
Table 2
Synthesis of 1,4-Dihydropyridines using PEG400-Li2CO3 at 80◦Ca
Entry
Rꢀ
R
Time (min)
Yieldc (%)
mp (◦C)
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
90
62
90
85
72
76
65
85
82
72
80
91
82
80
90
84
91
83
87
60
75
86
80
86
85
86
90
70
90
95
88
70
88
90
88
89
88
85
91
89
85
93
89
86
84
90
84
88
88
89
91
92
89
82
91
88
87
91
88
90
92
90
89
92
158–160 (158–160)23
145–146 (144–146)23
153–155 (158–160)23
165–167 (162–164)23
181–182 (178–180)25
188–190 (190–192)25
162–164 (162–164)26
172–173 (171–173)23
136–137 (135–138)22
227–229 (227–228)24
172–175 (180–182)25
147–148 (146–147)27
198–200 (197–198)28
210–212 (210–212)31
174–176 (174–176)31
185–186 (185–186)28
173–174 (173–174)28
194–197 (195–196)30
201–203 (200–202)29
198–199 (198–199)28
196–198 (195–196)28
155–156 (150–152)32
210–211 (210–211)32
195–197 (195–197)34
159–160 (158–159)34
169–172 (171)33
4-ClC6H4
4-CH3OC6H4
3-NO2C6H4
4-Pyridyl
3-Pyridyl
4-BrC6H4
2-Thienyl
4-CH3C6H4
4-HOC6H4
3-HOC6H4
2,5-Me2C6H3
C6H5
3-NO2C6H4
4-CH3C6H4
2-ClC6H4
4-CH3OC6H4
2-Furyl
2-Thienyl
4-HOC6H4
4-ClC6H4
CH3
3-NO2C6H4
2-NO2C6H4
2-Furyl
4j
4k
4l
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
6h
6i
Me
Me
Me
Me
Me
Me
Me
Me
2-Thienyl
3-Pyridyl
3-ClC6H4
3-CH3OC6H4
4-C2H5C6H4
4-Pyridyl
262–263 (262–263)35
222–224 (221–222)34
200–201 (196–198)32
179–181 (see Table 3)
245–246 (245–246)36
109–111 (109–111)37
6j
6k
Me
Me
4-BrC6H4
aReaction conditions: aldehyde (5 mmol), ethyl/methyl acetoacetate/acetylacetone (10 mmol),
ammonium acetate (5 mmol), Li2CO3 (0.25 mmol, 0.026 g), PEG400 (0.25 mmol, 0.1 g) at 80◦C.
Experimental Section
Melting points were determined in open capillaries and are uncorrected. IR spectra were
recorded using Thermo Nicolet AVATAR 330 equipped with DTGS detector and compared
with the literature. 1H NMR spectrum was obtained at 300 MHz using Bruker AMX-300
instrument at room temperature in CDCl3 using TMS as an internal reference. Mass spectra

156
Vijayakumar et al.
Table 3
Spectral Data for Product 6ia
mp.
(◦C)
Ir
(cm−1
1H NMR
(δ, ppm)
Mass
(HRMS)
Cmpd
)
6i
179–181 3343 (NH),
1689 (C=O).
0.88 (t, 3H, J = 7.05 Hz), 1.89
(s, 12H), 2.34 (m, 2H, J =
7.00 Hz), 4.81 (s, 1H), 6.63
(d, m, 2H, J = 7.8 Hz), 7.78
(d, o, 2H, J = 7.5 Hz).
297.1565
aAnal. Calcd. for C19H23NO2: C, 76.73; H, 7.80; N, 4.71. Found: C, 76.78; H, 7.86; N, 4.65.
were acquired using HRMS. All the reagents were purchased from Aldrich and SD-Fine
Chemicals. Liquids were purified by distillation. The reaction was monitored using TLC
silica-gel coated plates. The single crystal X-ray diffraction data was collected on a Bruker
Smart Apex CCD diffractometer using graphite monochromated MoKα radiation (k =
0.71073 A◦) at 293(2) K. A crystal with dimensions of 0.4 mm, 0.2 mm, 0.2 mm was used.
The collected data were reduced using SAINT. The structure was solved by direct methods
with the program SHELXS-97 and refined by the full matrix least squares on F2 with
SHELTL-97. The graphics tool was DIAMOND Version 3.0. All crystallographic data for
3,5-diacetyl-2,6-dimethyl-1,4-dihydro-4-(3-chlorophenyl)-3,5-pyridine are deposited with
Cambridge Crystallographic Data Centre (CCDC-683002). The data can be obtained free
Figure 1
Ortep diagram of 3,5-Diacetyl-2,6-dimethyl-1,4-dihydro-4-(3-chlorophenyl)-3,5-pyridine (6 g) and
Packing of the Molecules in the Unit cell (6 g).

Synthesis of 1,4-Dihydropyridines under Solvent-free Conditions
157
of charge at http://www.ccdc.cam.ac.uk/conts/retrieving.html [or from Cambridge Crystal-
lographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 (0)
1223-336033; e-mail: deposit@ccdc.cam. ac.uk
General Procedure for the Synthesis of 1,4-DHPs
A mixture of aldehyde (0.01 mol), ethyl acetoacetate/methyl acetoacetate/acetylacetone
(0.02 mol) and ammonium acetate (0.77 g, 0.01 mol), anhydrous Li2CO3 (0.026 g,
0.25 mmol) and PEG400 (0.1 g, 0.25 mmol) was vigorously stirred and heated at 80◦C for
the time as mentioned in Table 2. After the completion of the reaction [monitored through
TLC (pet. ether/ethyl acetate 3:2)], the mixture was cooled to room temperature. Ice cold
water was added to reaction mixture which was extracted with ethyl acetate (2 × 10 mL),
dried over anhydrous sodium sulfate and then evaporated in vacuo to afford the products
which were recrystallized from ethanol.
Acknowledgements
The authors thank VIT University for providing the basic facilities and the NMR Re-
search Centre, Indian Institute of Science, Bangalore and AIIMS, New Delhi for providing
NMR and single crystal diffraction facilities respectively.
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