1-Methylimidazolium trifluoroacetate [Hmim]Tfa: Mild and efficient Bronsted acidic ionic liquid for Hantzsch reaction under microwave irradiation

Article abstract of DOI:10.1007/s12039-012-0306-5

One pot synthesis of 1,4-dihydropyridine derivatives was achieved via condensation of various β-ketoesters with aromatic/aliphatic aldehydes and ammonium acetate. The reaction was catalysed by a stable and reusable Bronsted acidic ionic liquid (IL), 1-methyl-imidazolium trifluoroacetate ([Hmim]Tfa), under microwave (MW) irradiation. The synergistic combination ofMWwith IL can potentially go a long way tomeet the increasing demand for chemical processes. This homogeneous catalytic procedure is simple and efficient. The catalyst can be reused at least four times with almost complete retention in its activity. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-012-0306-5

c
J. Chem. Sci. Vol. 124, No. 5, September 2012, pp. 1091–1096. ꢀ Indian Academy of Sciences.
1-Methylimidazolium trifluoroacetate [Hmim]Tfa: Mild and efficient
Brønsted acidic ionic liquid for Hantzsch reaction
under microwave irradiation
JEMIN R AVALANI, DEVJI S PATEL and DIPAK K RAVAL∗
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388 120, India
e-mail: dipanalka@yahoo.com
MS received 25 February 2012; revised 17 April 2012; accepted 30 April 2012
Abstract. One pot synthesis of 1,4-dihydropyridine derivatives was achieved via condensation of various
β-ketoesters with aromatic/aliphatic aldehydes and ammonium acetate. The reaction was catalysed by a sta-
ble and reusable Brønsted acidic ionic liquid (IL), 1-methyl-imidazolium trifluoroacetate ([Hmim]Tfa), under
microwave (MW) irradiation. The synergistic combination of MW with IL can potentially go a long way to meet
the increasing demand for chemical processes. This homogeneous catalytic procedure is simple and efficient.
The catalyst can be reused at least four times with almost complete retention in its activity.
Keywords. 1,4-Dihydropyridine; Hantzsch synthesis; [Hmim]Tfa; homogeneous catalyst; microwave;
multicomponent reaction.
1. Introduction
nuclei.7 1,4-DHPs represent an important class of bio-
logically active molecules, several of which have found
use in the treatment of cardiovascular disease.8,9 1,4-
DHPs are analogues of NADH coenzymes10,11 and an
important class of drugs which are potent blockers of
calcium (Ca2+) currents.12 Hence, the development of
new methods that lead to multisubstituted 1,4-DHPs
via an efficient and convenient procedure are of great
interest for pharmaceutical researchers.
More than a century ago, Hantzsch13 developed an
efficient method for the synthesis of 1,4-DHPs. The
classical method involves a one-pot condensation of
an aldehyde with β-ketoesters and ammonia refluxing
Current conventional methods of organic synthesis are
orders of magnitude too slow to satisfy the ever-
increasing demand for generation of organic com-
pounds.1 The efficiency of microwave (MW) heating
has resulted in remarkable reductions in reaction times
(from days and hours to minutes and seconds). The time
saved by using a MW heating approach is potentially
important in traditional organic chemistry and assembly
of heterocyclic systems.2 Not surprisingly, these fea-
tures have also recently attracted interest of the drug
discovery field and medicinal chemistry communities.3
In recent years, ionic liquids (ILs) have attracted either in acetic acid or in alcohol for a longer time,14
Up till now, numerous literature exist describing va-
rious attempts to improve the Hantzsch reaction using
alternative catalyst and greener methods.15–24 Almost
all of the new methodologies of organic reactions have
attempted to maximize reaction conversion and mini-
mize reaction time. We have already demonstrated the
efficient role of ionic liquids as dual solvent–catalysts
in Biginelli reaction.25,26 In the present study, we report
1-methyl-imidazolium trifluoroacetate ([Hmim]Tfa) as
an effective and reusable catalyst for Hantzsch pyridine
synthesis (scheme 1).
immense interest and been successfully used in a vari-
ety of catalytic reactions as dual solvents–catalysts4
due to their relatively low viscosities, low vapour pres-
sure, and high thermal and chemical stability.5 Brønsted
acidic ionic liquids consist of desired characteristics of
solid acids and mineral liquid acids and are designed to
replace customary mineral acids like HCl, H2SO4 and
HNO3.6
Heterocyclic rings containing nitrogen atoms are
abundant in nature and of great importance to life
because their structural subunit exists in many bioactive
∗For correspondence
1091

1092
Jemin R Avalani et al.
Scheme 1. General synthetic pathway for the synthesis of 1,4-dihydropyridines (1,4-DHPs).
2. Experimental
stretching of amine), 2949 (-CH stretching), 1696,
1645 (respectively due to C=O and C=C stretching of
conjugate ester), 1487, 1342, 1215;1H NMR (400 MHz,
CDCl3): δ 2.37 (s, 6H,-CH3), 3.66 (s, 6H,-OCH3), 5.12
(s, 1H,aryl –CH of C4), 5.86 (s, 1H,-NH), 7.45 (d,
J =8.8 Hz, 2H, Ar-H), 8.10 (d, J =8.8 Hz, 2H, Ar-H);
13C NMR (100 MHz, CDCl3): δ 19.63 (-CH3), 39.87,
51.14, 103.02, 123.45, 128.60, 144.91, 146.43, 154.75,
167.47 (C=O). ESI-MS: m/z: 346.9(M+H)+
2.1 General
All chemicals were of research grade and were used
as obtained. The reactions were carried out by using
700 Watt CATA-R scientific microwave system. Melt-
ing points were measured in open capillaries and are
uncorrected. TLC was performed on Silica Gel 60 F254
pre-coated plates (Merck). IR spectra were recorded on
a FT IR Perkin Elmer Spectrum 100 spectrometer, mass
spectra on a Shimadzu LCMS 2010 spectrometer, and
elemental analysis on Perkin Elmer PE 2400 elemental
analyzer. 1H NMR and 13C NMR spectra were recorded
on Bruker Avance 400 MHz instrument with TMS as
an internal standard. The IL [Hmim]Tfa was prepared
according to the procedure reported in literature.27
2.3b Diethyl
4-(furan-2-yl)-2,6-dimethyl-1,4-dihy-
dropyridine-3,5-dicarboxylate (4k): Anal.Calcd. For
C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found: C,
63.72; H, 7.01; N, 4.11. IR (KBr) cm−1: 3348 (-NH
stretching of amine), 2985 (-CH stretching), 1692,
1649 (respectively due to C=O and C=C stretching
of conjugate ester), 1486, 1209.1H NMR (400 MHz,
CDCl3): δ 1.28 (t, J=7.2 Hz, 6H, -CH2CH3), 2.34 (s,
6H, -CH3), 4.18 (m, 4H, -CH2CH3), 5.22 (s, 1H, aryl –
CH of C4), 5.84 (s, 1H, -NH), 5.95 (d, J =3.2 Hz, 1H,
Ar-H), 6.23 (dd, J = 2.8, 2 Hz, 1H, Ar-H), 7.23 (s, 1H,
Ar-H); 13C NMR (100 MHz, CDCl3): δ 14.32, 19.51,
33.43, 59.80, 100.78, 104.43, 109.98, 140.84, 145.02,
158.70, 167.46 (C=O). ESI-MS: m/z: 319.8(M+H)+
2.2 Procedure for the synthesis of 1,4-DHPs
A
mixture of aldehyde
1
(1 mmol), 1,3-
dicarbonylcompound 2 (2.1 mmol), ammonium acetate
3 (3 mmol), ethanol (1 ml) and [Hmim]Tfa (20 mol%)
were taken in a round bottom flask containing a
teflon-coated magnetic stirrer bar. It was subjected to
microwave irradiation at power level 7 (455 watt) for
an appropriate time shown in table 3. The completion
of reaction was monitored by TLC. The reaction mix-
ture was treated with cold water, extracted with diethyl
ether and dried over anhydrous Na2SO4. It was then
concentrated under reduced pressure to leave the crude
product which was crystallized in ethanol. The com-
pounds have been identified by comparison of spectral
data and mp with those reported elsewhere.
2.3c Diisopropyl 4-(furan-2-yl)-2,6-dimethyl-1,4-di-
hydropyridine-3,5-dicarboxylate
(4l): Anal.Calcd.
For C19H25NO5: C, 65.69; H, 7.25; N, 4.03. Found: C,
65.86; H, 7.57; N, 3.79. IR (KBr) cm−1: 3347 (-NH
stretching of amine), 2978 (-CH stretching), 1696,
1649 (respectively due to C=O and C=C stretching
1
of conjugate ester), 1483, 1208. H NMR (400 MHz,
CDCl3): δ 1.22 (dd, J=6,0.8 Hz, 6H, -CH3), 1.28 (dd,
J=6.4,1.2 Hz, 6H), 2.33 (s,6H), 5.05 (m, 2H), 5.2 (s,
1H), 5.76 (s,1H), 5.95 (s,1H), 6.22 (m,1H), 7.22(s,1H);
13C NMR (100 MHz,CDCl3): δ 19.52, 22.07, 33.59,
67.02, 101.15, 104.47, 109.92, 140.67, 144.54, 158.92,
167.01 C=O. ESI-MS: m/z: 347.9 (M+H)+
2.3 Spectral data for selected compounds
2.3a Dimethyl
2,6-dimethyl-4-(4-nitrophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (4d): Anal.Calcd.
For C17H18N2O6: C,58.96; H,5.24; N,8.09. Found: C,
59.30; H, 5.10; N, 7.84. IR (KBr) cm−1: 3304 (-NH

[Hmim]Tfa catalysed Hantzsch synthesis
Table 2. Effect of solvent on model reaction (4d)a.
1093
3. Results and discussion
Entry
Solvent
Time (min)c
Yield (%)b
Our first objective was to develop a set of working con-
ditions for the microwave mediated process. Initially
we optimized the reaction conditions with respect to
microwave power (P). The reaction of p-nitro ben-
zaldehyde, methyl acetoacetate and ammonium acetate
was performed as the model reaction in the presence
of catalytic amount of [Hmim]Tfa in ethanol as co-
solvent. The results are given in table 1.
1
2
3
4
5
Acetonitrile
DMF
THF
1,4-Dioxane
Ethanol
3
2
4
3
2
80
63
70
75
93
aReaction conditions: Aldehyde (1 mmol), β-ketoester
(2.1 mmol), ammonium acetate (3 mmol), [Hmim]Tfa
b
c
It could be observed that with increase in microwave
power from 280 W to 700 W, the yield of 4d is li-
nearly increased from 55% to 93%. At higher power level
(700 W) reaction completed in 3 min but resulted in
moderate yield. The optimized microwave power and
the irradiation time were 455 W and 2 min, respectively.
The model reaction was also screened to know the
effect of a range of different solvents as shown in
table 2. It was noted that in ethanol, the yield of desired
product 4d was achieved exclusively up to 93% (table 2,
entry 5). When we carried out the reaction in other sol-
vent such as acetonitrile, DMF, THF and 1, 4-dioxane
the yield of 4d was 80, 63, 70 and 75% respectively.
Above experimental results encouraged us to extend
the scope of reaction condition to apply on a range
of variously substituted aldehydes (table 3). Both
electron-deficient and electron-rich aldehydes were
well-tolerated. The reaction of heteroaromatic aldehy-
des and formaldehyde proceeded in very short reaction
time (entry 4j–4o). Ethyl acetoacetate and isopropyl
acetoacetate were also employed for the Hantzsch reac-
tion in place of methyl acetoacetate to afford appro-
priate 1,4-DHPs in good yield. All the reactions were
completed in 1–4 min. Increase in the equivalent of IL
did not improve the conversion, use of just 20 mol%
IL is found to be sufficient to accelerate the reaction
forward.
20 mol%, P = 455 W; Isolated yield; Reaction progress
was monitored by TLC
The IL, [Hmim]Tfa may promote this reaction by
virtue of its inherent Brønsted acidity conferred by the
most acidic –N–H hydrogen [chemical shift δ 10.93].
This makes the IL capable of bonding with the carbonyl
oxygen of aldehydes and β-ketoesters increasing the
reactivity of the parent carbonyl compounds. Crowhurts
et al. demonstrated that imidazolium ILs are able to act
as strong hydrogen bond acids as well as bases at the
same time.28 Many current studies have established that
hydrogen bonding can occur between the reactant and
the cationic or anionic components of ILs.29,30 Based
on this, the following mechanistic pathway has been
postulated (scheme 2).
The IR spectrum of the product showed strong
band around 3300–3350 cm−1 due to N–H stretching
and bands around 1645 and 1696 cm−1 respec-
tively due to C=C and C=O stretching of conju-
gated ester moieties where as the aromatic C=C was
found at 1483–1487 cm−1. In the H NMR spec-
1
trum, singlet was observed around δ 5.12–5.22 due
to aryl-CH moiety of the C-4 of the dihydropyri-
dine skeleton. In case of all the products described in
table 3, broad singlet appeared around δ 5.75–5.86 con-
firming the presence of N–H group. In all the aforesaid
cases, six-proton singlet was observed due to olefinic-
CH3 around δ 2.32–2.37 corroborated with the 1,4-
DHPs skeleton. In the 13C NMR spectra, peak around
δ 167.00–167.50 was due to carbonyl carbon of ester
moiety.
Table 1. Effect of the microwave power and the irradi-
ation time on the model reaction (4d)a.
Entry
Time (min)b
P (watt)
Yield (%)c
The recovery and reusability of the ionic liquid was
investigated. After completion of the reaction, ice cold
water was added to the reaction mixture and product
was extracted with diethyl ether. The aqueous layer
consisting the acidic IL, was recovered after removal
of water under reduced pressure and was reused for
subsequent reactions. It showed the same activity as
that of the fresh catalyst without any loss of acti-
vity in terms of yield and purity. The ionic liquid was
recycled and reused in the same reaction for at least
1
2
3
4
5
6
8
6
5
2
3
3
280
350
420
455
490
700
55
65
80
93
89
80
aReaction conditions: Aldehyde (1 mmol), β-ketoester
(2.1 mmol), ammonium acetate (3 mmol), ethanol (1 ml),
[Hmim]Tfa 20 mol%; bReaction progress was monitored by
TLC; cAll yields refer to isolated yield

1094
Jemin R Avalani et al.
Table 3. Synthesis of 1,4-dihydropyridines in the presence of 20 mol% [Hmim]Tfa.
Entry
R
R1
Time (Min) Yield (%) M.P. (◦C) (observed) M.P. (◦C) (reported)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
C6H5
C6H5
CH3
CH3CH2
CH3
CH3
CH3
3
3
2
2
3
3
4
4
4
1
1
1
1
1
1
90
92
86
93
82
86
85
80
82
92
90
88
90
84
80
194
156–158
198
196–198
170
162
195–19731
158–16032
196–19733
195–19634
170–17137
160–16232
123–12538
231–23235
198–19936
194–19533
166–16832
–
4-ClC6H4
4-O2NC6H4
4-FC6H5
3-O2NC6H4
3-O2NC6H4
4-OH-3-OMe-C6H3
4-OHC6H4
2-Furyl
CH3CH2
(CH3)2CHCH2
CH3
CH3CH2
CH3
CH3CH2
(CH3)2CHCH2
CH3
128
225–228
200–202
192
164–166
112–114
202–204
168–170
120–122
2-Furyl
2-Furyl
H
H
H
208–21032
170–17232
–
CH3CH2
(CH3)2CHCH2
Scheme 2. Suggested mechanism for the synthesis of 1,4-DHPs in the presence of [Hmim]Tfa.

[Hmim]Tfa catalysed Hantzsch synthesis
1095
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Supporting information
1H NMR and 13C NMR spectra of ionic liquid and some
selected compounds are available as supporting infor-
mation in the journal of Chemical Sciences Website
(www.ias.ac.in/chemsci).
Acknowledgements
Authors thank Head, Department of Chemistry, Sardar
Patel University for providing necessary research facil-
ities. DKR is grateful to authorities of Sardar Patel Uni-
versity, Vallabh Vidyanagar for allocation of research
funding in the form of seed grant-2011.

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