Ultrasound-accelerated synthesis of 1,4-dihydropyridines in an ionic liquid

Article abstract of DOI:10.1007/s00706-005-0405-9

Hantzsch 1,4-dihydropyridine compounds were synthesized efficiently in high yields at room temperature within short times in 1,1,3,3-N,N,N′,N′- tetramethylguanidinium trifluoroacetate as ionic liquid using ultrasound irradiation. The ionic liquid can be recovered conveniently and reused efficiently. Springer-Verlag 2006.

Full text of DOI:10.1007/s00706-005-0405-9

Monatshefte f€ur Chemie 137, 77–81 (2006)
DOI 10.1007/s00706-005-0405-9
Ultrasound-accelerated Synthesis
of 1,4-Dihydropyridines in an Ionic Liquid
ꢀ
and Masoumeh Sharifi
Ahmad Shaabani , Ali H. Rezayan, Abbas Rahmati,
Department of Chemistry, Shahid Beheshti University, P.O. Box 19396-4716, Tehran, Iran
Received April 4, 2005; accepted (revised) May 6, 2005
Published online January 5, 2006 # Springer-Verlag 2006
Summary. Hantzsch 1,4-dihydropyridine compounds were synthesized efficiently in high yields at
room temperature within short times in 1,1,3,3-N,N,N0,N0-tetramethylguanidinium trifluoroacetate as
ionic liquid using ultrasound irradiation. The ionic liquid can be recovered conveniently and reused
efficiently.
Keywords. 1,4-Dihydropyridine; Hantzsch reaction; Ionic liquid; Ultrasound.
Introduction
It is well known that 1,4-dihydropyridines (DHPs) exhibit a wide range of biolog-
ical activities, acting as potent vasodilators, antihypertensives, branchodilators,
antiatherosclerotics, hepatoprotective, antitumor, antimutagenic, geroprotective,
and antidiabetic agents [1, 2]. DHPs are commercially used as calcium channel
blockers for treatment of cardiovascular disease [3, 4].
1,4-Dihydropyridines are generally synthesized by the Hantzsch method [5],
which involves cyclocondensation of an aldehyde, ꢀ-ketoester, and ammonia either
in acetic acid or by refluxing in alcohols for long reaction times leading to low
yields in general [6, 7]. Recently, a number of modified methods have been
reported, but many of them suffer from drawbacks such as unsatisfactory yields,
high temperatures, long reaction times, and tedious work-up. Thus, the reaction
is carried out in two steps (the enaminoketone is used instead of ꢀ-ketoester
and ammonia) [8, 9]. Therefore the development of an efficient and room tempera-
ture one-pot synthesis of Hantzsch 1,4-dihydropyridines seemed to be of prime
importance.
In this article we demonstrate that the combination of 1,1,3,3-N,N,N0,N0-tetra-
methylguanidinium trifluoroacetate (TMGT) as ionic liquid and ultrasound irradia-
ꢀ
Corresponding author. E-mail: a-shaabani@cc.sbu.ac.ir

78
A. Shaabani et al.
Scheme 1
tion is a rapid and efficient method for the three-component condensation synthesis
of 1,4-DHPs at room temperature. In this approach the use of large volumes of
organic solvents is avoided, work-up simplified, and reaction times are consider-
ably decreased (Scheme 1).
Results and Discussion
The results of TMGT catalyzed synthesis of 1,4-DHPs using ultrasound irradiations
are given in Table 1. Using TMGT as promoter for the synthesis of Hantzsch
1,4-dihydropyridines does not only represent a dramatic improvement at room
temperature with regard to yield (84–95%) over conventional thermal heating,
but the reaction times are also considerably decreased (1.45–2.30 h) compared
to classical synthesis (6–8 h). After the reaction was completed, the reaction
mixture is simply washed with water and the ionic liquid is isolated from the
product.
To determine whether the ultrasound irradiation was an essential factor to
realize the high conversions of this condensation, the same reaction was carried
out in the ionic liquid without using ultrasound irradiation. As a result (Table 1) the
reaction time was increased by a factor of about 4. It is important to note that in
the absence of TMGT and without using ultrasound irradiation, the yield of the
reactions decreased to 22–30% (3 h at room temperature; entry 3a, 3b, and 3h in
Table 1).
To explore the scope and limitations of this reaction, we extended the reaction
of ꢀ-ketoesters with various aromatic aldehydes carrying either electron releasing
or electron withdrawing constituents in the para positions. We found that the

Ultrasound-accelerated Synthesis of 1,4-Dihydropyridines
79
Table 1. One-pot synthesis of 1,4-dihydropyridines in TMGT under classical conditions and using
ultrasound irradiation at rt
Entry Aldehyde ꢀ-Ketoester Product
Yield=% (Time=h)
mp=ꢁC Found (Reported)
Ia
IIb
1
2
3
1a
1b
1c
2a
2a
2a
3a
3b
3c
90(2)
30(3)c
83(7)
74(6.5)
79(8)
158–159
(158–160)e
157–159
(158–160)f
118–120
(120)g
88(2)
27(3)c
85(2)
88(2), 88(2.30)
87(2.30), 84(2.30)d
84(2.30)
4
5
1d
1e
2a
2a
3d
3e
84(8.30)
78(6)
135–138
139–141
(138–143)h
141–143
(142)g
95(2.15)
6
7
1f
1g
1h
1i
2a
2a
2a
2b
2b
3f
3g
3h
3i
90(1.45)
94(2)
80(6.5)
85(7)
162–164
(163–165)i
129–131
(128–130)i
193–194
(193–194)k
196–198
(197–198)k
8
92(1.45)
22(3)c
84(8.5)
83(8)
9
86(2.15)
10
1j
3j
87(1.45)
87(7.5)
a
b
In the presence of TMGT and using ultrasound irradiation; in the presence of TMGT without
c
using ultrasound irradiation; in the absence of TMGT without using ultrasound irradiation; the
d
e
same TMGT was used for each of the four runs; Ref. [12]; Ref. [13]; Ref. [14]; Ref. [15];
f
g
h
i
j
Ref. [16]; Ref. [17]; Ref. [18]
k
reaction proceeded very efficiently in all cases and that the reaction time decreased
for electron withdrawing substituents.
Hantzsch reactions have negative activation volumes owing to the condensation of three molecules
into a single reactive intermediate and reactions with negative activation volumes are accelerated with
pressure. Thus, it is well known that ultrasound irradiation [10] as well as solvophobic interactions of
ionic liquids generate a microscopic internal pressure in the solvent cavity [11]. Accordingly, it is
reasonable that these influences lead to accelerate three components Hantzsch reaction condensation.
Another advantage of the ionic liquid is that it is recyclable as reaction med-
ium. In view of environmentally friendly methodologies, recovery and reuse of the
ionic liquid is highly preferable. TMGT is easily separated from reaction medium
by washing with water and distillation of the solvent under vacuum and it can be
reused for subsequent reactions. As indicated in Table 1 (entry 3c), it showed no
loss of efficiency with regard to reaction time and yield after four successive runs.
In conclusion, we present an ultrasound-accelerated synthesis of 1,4-dihydro-
pyridines in a simple ionic liquid, TMGT. The significant improvements offered
by this procedure are: (a) fast reaction, (b) simple operation and mild reaction
conditions (room temperature), (c) high yields (84–95%), (d) cost efficiency by

80
A. Shaabani et al.
recycling of the ionic liquid, and (e) green aspects avoiding hazardous organic
solvents, toxic catalyst, and waste (atom efficiency).
Experimental
Melting points were measured on an Electrothermal 9100 apparatus. Elemental analyses were per-
formed using a Heraeus CHN–O–Rapid analyzer. The results were in agreement with the calculated
values. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at
1
an ionization potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer. H
and 13C NMR spectra were recorded on a BRUKER DRX-300 AVANCE spectrometer at 300.13 and
75.47 MHz. NMR spectra were obtained on solutions in CDCl3. All products are known compounds
(except entry 3d), which were identified by IR and 1H NMR spectral data and their melting points were
compared with literature reports.
2,6-Dimethyl-3,5-dicarboethoxy-4-(4-methylphenyl)-1,4-dihydropyridine (3d, C20H25NO4)
A mixture of 0.259 g ethyl acetoacetate (2mmol), 0.120 g 4-methylbenzaldehyde (1mmol), 0.154g
ammonium acetate (2mmol), and 0.120g TMGT (0.5mmol) was successively charged into a screw-
capped vial. The mixture was irradiated in a water bath of the ultrasonic cleaner (Eyela-92303, Tokyo
Rikakikai Co.) at 25–30ꢁC for 2.30 h. Then, the reaction mixture was washed with 25cm3 cold H2O.
The crude product was purified by column chromatography on silica gel using n-heptane:ethyl acetate
1
(7:1) as eluent to afford the pure product 3d (0.248 g, 84%). White Solid, mp 135–138ꢁC; H NMR
(CDCl3): ꢁ ¼ 1.16 (t, J ¼ 7.13 Hz, 2CH2CH3), 2.20 (s, Ph–CH3), 2.25 (s, Pyr–CH3), 4.00 (q,
J ¼ 7.15Hz, 2CH2CH3), 4.88 (s, Pyr–H), 5.64 (s, br, NH), 6.93–7.11 (m, Ph) ppm; 13C NMR (CDCl3):
ꢁ ¼ 14.28, 19.48, 39.09, 59.73, 104.03, 127.83, 128.57, 135.51, 144.13, 144.97, 167.82 ppm; IR
(KBr): ꢂꢀ¼ 3350, 2900, 1691, 1647 cmꢂ1, MS: m=z (%) ¼ 342 (Mþꢂ 1, 10), 314 (13), 252 (21),
196 (15), 109 (60), 91 (20), 69 (20), 43 (85).
Acknowledgement
We greatefully acknowledge the financial support from the Research Council of Shahid Beheshti
University.
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