La2O3/TFE: An efficient system for room temperature synthesis of Hantzsch polyhydroquinolines

Article abstract of DOI:10.1016/j.cclet.2014.03.037

Lanthanum oxide (La₂O₃) in combination with 2,2,2-trifluoroethanol (TFE) was found to be an efficient system for the one-pot, four-component synthesis of Hantzsch polyhydroquinoline derivatives from aromatic aldehydes, dimedone, ethy

Full text of DOI:10.1016/j.cclet.2014.03.037

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Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
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Original article
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La2O3/TFE: An efficient system for room temperature synthesis of
Hantzsch polyhydroquinolines
Q1 Sunil U. Tekale a, Vijay P. Pagore a, Sushama S. Kauthale b, Rajendra P. Pawar b,
*
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a Department of Chemistry, Shri Muktanand College, Gangapur 431109, India
b Department of Chemistry, Deogiri College, Aurangabad 431005, India
A R T I C L E I N F O
A B S T R A C T
Article history:
Lanthanum oxide (La2O3) in combination with 2,2,2-trifluoroethanol (TFE) was found to be an efficient
system for the one-pot, four-component synthesis of Hantzsch polyhydroquinoline derivatives from
aromatic aldehydes, dimedone, ethyl acetoacetate and ammonium acetate at ambient temperature. The
catalyst is heterogeneous and reusable, hence can be separated easily and reused. The present method is
featured by mild reaction conditions, use of heterogeneous catalyst, non-chromatographic purification,
short reaction time and high yields, which make it an attractive route for the synthesis of
polyhydroquinolines.
Received 12 November 2013
Received in revised form 3 March 2014
Accepted 12 March 2014
Available online xxx
Keywords:
Hantzsch polyhydroquinolines
ß 2014 Rajendra P. Pawar. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
La2O3
TFE
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1. Introduction
These facts reflect the remarkable pharmacological and medicinal 32
potential of 1,4-dihydropyridines and polyhydroquinolines as drug 33
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During the past decade, multi-component reactions (MCRs)
have become an area of prime interest in synthetic organic
chemistry due to their ability in converting more than two
components in a single step to complex molecules. MCRs have
emerged as efficient, atom economic, time saving and powerful
tools in modern synthetic organic chemistry for the synthesis of
pharmacologically and biologically important targets as they
increase the efficiency of the reaction and avoid the multiple steps
along with saving solvents and chemicals. Such reactions allow the
formation of new bonds resulting in diverse molecular complexity
in a single step [1]. MCRs play a prominent role in modern drug
discovery processes [2]. Thus the study of MCRs has become one of
the most attractive synthetic strategies preferred by organic
chemists in industry and academia.
Derivatives of 1,4-dihydropyridine and polyhydroquinoline
heterocyclic scaffolds are important classes of well known Ca2+
channel blockers and constitute the skeletons of drugs used in the
treatment of hypertension and cardiovascular diseases [3]. These
compounds possess a variety of biological activities including
antidiabetic, antitumor, vasodilator, bronchodilator, geroprotec-
tive and anti-atherosclerotic properties [4]. They are also explored
as antiischemics and in the treatment of Alzheimer’s disease [5].
candidates of therapeutic significance and as intermediates in 34
organic synthesis. Thus the synthesis of these heterocyclics has 35
become an area of great interest.
36
Traditionally 1,4-dihydropyridine and polyhydroquinolines are 37
synthesized by refluxing aldehydes with 1,3-dicarbonyl compound 38
and ammonium acetate catalyzed by acidic or basic catalysts. 39
Literature survey reveals the availability of numerous methods for 40
the synthesis of polyhydroquinoline derivatives using catalysts 41
such as HClO4–SiO2 [6], ZnO [7], CuO [8], nano-Ni [9], t-BuOK [10], 42
Yb(OTf)3 [11], Sc(OTf)3 [12], GuHCl [13], TiO2 [14], scolecite [15], 43
morpholine [16], Zn-VCO3 hydrotalcite [17], magnetic Fe3O4 44
nanoparticles [18], Mn(III) complex [19], etc. The synthesis in 45
aqueous medium [20] without catalyst although successful, 46
requires longer reaction time (2.25–8 h). Thus many of the existing 47
strategies suffer from harsh reaction conditions, use of stoichio- 48
metric and/or relatively expensive reagents, long reaction time, 49
unsatisfactory yield of products, etc. Some of these methods, for 50
example microwave or ultrasound assisted synthesis [21], require 51
additional equipment such as a microwave oven or a soniccation Q252
bath. Ionic liquids [22] have also been used for clean chemical 53
reactions replacing volatile organic solvents. But they suffer from 54
inherent problems in separation and tedious workup is often 55
involved. Consequently, research continues in the development of 56
novel and facile protocols for the synthesis of polyhydroquinolines 57
with improved operational simplicity, economic viability, reus- 58
*
Corresponding author.
ability and milder reaction conditions.
59
E-mail address: rppawar@yahoo.com (R.P. Pawar).
http://dx.doi.org/10.1016/j.cclet.2014.03.037
1001-8417/ß 2014 Rajendra P. Pawar. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: S.U. Tekale, et al., La2O3/TFE: An efficient system for room temperature synthesis of Hantzsch
polyhydroquinolines, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.037

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S.U. Tekale et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
Scheme 1. Synthesis of Hantzsch polyhydroquinoline derivatives by using La2O3/TFE.
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Recently, the characteristic features of fluorinated solvents such
as high polarity, strong hydrogen accepting ability and low boiling
points prompted their applications in organic synthesis. 2,2,2-
Trifluoroethanol (TFE) is a low boiling (bp 74 8C), colorless and
water miscible organic solvent. It has become one of the more
widely used fluorinated solvents. It exhibits stronger acidic
character and higher stability than the non-fluorinated alcohol
due to the presence of the electronegative trifluoromethyl group.
TFE is commonly used as a fluorinated alcohol on commercial scale
manufacture processes. TFE has been used as an alternative to
metal-assisted syntheses including several multi-component
reactions such as the synthesis of dibenzo[c,e]azepinones, 1,3,4-
trisubsituted pyrazoles, reductive alkylation, etc. [23].
Several inorganic metal oxides, such as ZnO, CuO, Al2O3, TiO2,
etc. act as efficient heterogeneous catalysts due to their Lewis acid–
base characters and ability to provide large surface area for
adsorption of organic molecules [24]. Lanthanum oxide (La2O3),
also known as Lanthana, is a white, odorless, and large band gap
(5.5 eV) rare earth metal oxide with a high dielectric constant
polyhydroquinoline derivatives were confirmed on the basis of
spectral data and comparison of their physical constants to those
reported in literature. Melting points were measured in
capillaries open at one end and were uncorrected. The progress
of reaction was monitored by thin-layer chromatography (TLC)
analysis in 30% EA: Hexane. 1H NMR spectra were recorded in
CDCl3 on a 400 MHz Varian spectrophotometer using tetra-
methylsilane (TMS) as an internal standard. Infrared (IR) spectra
were recorded on a Shimadzu FTIR spectrometer using KBr
pellets. Samples were analyzed for exact mass on a Shimadzu
mass analyzer.
General procedure for the synthesis of Hantzsch polyhydro-
quinoline derivatives: in a typical condensation reaction, a mixture
of aldehyde (1 mmol), dimedone (1 mmol), ethyl acetoacetate
(1.2 mmol), ammonium acetate (1.5 mmol) and La2O3 (10 mol%) in
TFE (2 mL) was magnetically stirred at room temperature for
appropriate time as specified in Table 1. After the completion of the
reaction as monitored by TLC (30% EA: Hex) analysis, the reaction
mixture was diluted with hot TFE, and the catalyst was filtered off.
The filtrate was concentrated and the crude was purified by
recrystallization from ethanol to afford the pure polyhydroquino-
line derivatives.
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(e = 27). It is thermally stable (melting point 2315 8C), cheap,
readily available and insoluble in water. Consequently it can be
employed in organic synthesis as an effective heterogeneous
catalyst. In recent years, lanthanum oxide and its composites came
into limelight as catalysts in organic synthesis such as carbonyla-
tion of glycerol [25], C–N coupling reactions [26], Heck reaction
[27], Wittig reaction [28], etc. In continuation of our efforts in the
development of new synthetic routes for the synthesis of
heterocyclic compounds using reusable heterogeneous catalysts
[29], we report the combination of TFE/La2O3 as an efficient tool for
the one-pot, four-component synthesis of polyhydroquinolines at
room temperature in excellent yields (Scheme 1).
The structures of the synthesized products were confirmed by
comparison of their melting points with authentic values reported
in literature and spectral techniques-1H NMR, IR, elemental
analysis and ESMS. The spectral data of representative compounds
are described below:
Ethyl-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-4-phenyl-
quinoline-3-carboxylate (5a): Faint yellow solid, Mp. 202–
122
123
124
125
126
127
128
129
204 8C, 1H NMR (400 MHz, CDCl3):
d
0.95 (s, 3H, CH3), 1.1 (s, 3H,
CH3), 1.2 (t, 3H, CH3), 2.15–2.35 (m, 4H), 2.4 (s, 3H), 4.05 (q, 2H),
5.03 (s, 1H), 6.02 (brs, 1H, NH), 7.1–7.4 (m, 5H). IR (KBr, cmÀ1):
3285.88, 3082.38, 2954.11, 1697.43, 1609.67. Anal. Calcd. for
21H25NO3: C, 74.31, H, 7.42, N, 4.13. Found: C, 72.43, H, 7.029,
91
2. Experimental
n
92
93
All the chemicals were purchased from SD fine chemicals
Ltd and used without further purification. The synthesized
C
N, 3.97.
Table 1
TFE mediated La2O3 catalyzed synthesis of polyhydroquinoline derivatives.
Entry
R
Product
Time (min)
Yield (%)a
Mp. (8C) [Ref.]
1
2
H
5a
5b
5c
5d
5e
5f
60
60
70
65
70
70
85
90
90
90
80
70
90
90
95
88
92
94
86
87
89
91
86
89
88
87
202–204 [6]
244–246 [6]
259–261 [20]
209–211 [20]
240–242 [8]
260–262 [16]
241–243 [6]
230–232 [9]
208–210 [9]
287–289 [20]
246–248 [6]
183–185 [8]
261–263 [6]
4-Cl
3
4-OMe
4
3,4-Methylene dioxy
4-SMe
5
6
4-Me
7
4-NO2
5g
5h
5i
8
4-OH
9
4-OH-3-OMe
3,4(OMe)2
2-Furyl
4-F
10
11
12
13
5j
5k
5l
4-NMe2
5m
a
Reactions conditions: aldehyde (1 mmol), dimedone (1 mmol), ethyl acetoacetate (1.2 mmol) and ammonium acetate (1.5 mmol), La2O3 (10 mol %) in TFE (2 mL), room
temperature.
Please cite this article in press as: S.U. Tekale, et al., La2O3/TFE: An efficient system for room temperature synthesis of Hantzsch
polyhydroquinolines, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.037

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Table 2
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153
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155
156
Ethyl-4-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-tri-
Solvent screening for La2O3 catalyzed synthesis of polyhydroquinolines.
methyl-5-oxoquinoline-3-carboxylate (5b): Yellow solid,
Mp 244–246 8C, 1H NMR (400 MHz, CDCl3):
d 0.92 (s, 3H),
Entry
Solvent
Time (h)
Yield (%)a
1.07 (s, 3H), 1.2 (t, 3H), 2.15–2.30 (m, 4H), 2.4 (s, 3H), 4.04 (q,
1
2
3
4
5
6
7
8
9
No catalyst, no solvent
24
3
27
26
2H), 5.03 (s, 1H), 5.82 (brs, 1H, NH), 7.15–7.20 (d, 2H, J = 8.4 Hz),
DMSO
7.20–7.30 (d, 2H, J = 8.4 Hz) IR (KBr, cmÀ1):
n 3274.31, 3077.56,
DMF
4
17
EtOH
2.5
2.5
2.5
3.5
2
67
2958.93, 1705.15, 1647.28, 1602.91. Anal. Calcd. for
C21H24ClNO3: C, 67.46, H, 6.47, N, 3.75. Found: C, 67.55, H,
6.38, N, 3.68, ES-MS: 396.03 [M+Na]+.
50% EtOH:H2O
THF:H2O (1:1)
H2O
58
53
32
Ethyl-4-(benzo[d][1,3]dioxol-6-yl)-1,4,5,6,7,8-hexahydro-
2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5d): Faint yel-
ACN
56
89b, 95
TFE
1
low solid, Mp 209–211 8C, 1H NMR (400 MHz, CDCl3):
d 0.93 (s,
a
Isolated yield.
b
Reaction carried in the absence of catalyst under reflux in TFE for 5 h.
3H, CH3), 1.07 (s, 3H, CH3), 1.23 (t, 3H), 2.13–2.35 (m, 4H), 2.35
(s, 3H), 4.07 (q, 2H), 4.98 (s, 1H), 5.87 (s, 2H), 6.08 (brs, 1H, NH),
6.6–6.83 (m, 3H), IR (KBr, cmÀ1):
n 3273.34, 3077.56, 3198.11,
1696.47, 1604.84, 1031.00, 884. Anal. Calcd. for C22H25NO5: C,
68.91, H, 6.57, N, 3.65. Found: C, 66.54, H, 6.415, N, 3.34, ES-MS:
406.04 [M+Na]+.
or DMF at ambient temperature resulted in low yield of the 181
corresponding polyhydroquinolines after 3–4 h. Binary solvent 182
systems such as EtOH:H2O (1:1) or THF:H2O (1:1) could not 183
improve the results. Acetonitrile could accomplish moderate yield 184
(56%). From the literature survey, ethanol is a common solvent 185
employed for the synthesis of 1,4-dihydropyridine and polyhy- 186
droquinolines. When the reaction was carried in ethanol, the yield 187
was improved and the reaction time was shortened to some extent. 188
However, excellent yields with short reaction time were possible 189
with the use of 2,2,2-trifluoroethanol (TFE). To study the 190
temperature effect in the TFE-mediated synthesis of polyhydro- 191
quinolines, a reaction was carried in the absence of catalyst by 192
simply refluxing a mixture of 4-chlorobenzaldehyde, dimedone, 193
ethyl acetoacetate and ammonium acetate in which a good yield of 194
the corresponding polyhydroquinoline (89%) was obtained but the 195
reaction required 5 h for completion. Furthermore, to determine 196
the amount of the catalyst in this reaction, the reactions were 197
carried with different concentrations of La2O3. The rise in catalyst 198
concentration from 10 to 15 or 20 mol% could neither enhance the 199
yield of product nor reduce the time to below 1 h. Thus, excellent 200
results were obtained with 10 mol% of La2O3 in TFE at room 201
temperature in terms of yield as well as time. The scope and 202
generality of the one-pot, four-component synthesis of polyhy- 203
droquinoline derivatives through the Hantzsch reaction was 204
verified with different aldehydes under these optimized condi- 205
tions. Almost all aldehydes, possessing both electron-donating as 206
well as electron withdrawing groups along with heterocyclic 207
aldehydes reacted smoothly with clean reaction profile to afford 208
Ethyl-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-4-(4-(methylthio)
phenyl)-5-oxoquinoline-3-carboxylate (5e): Yellow solid, Mp
240–242 8C, 1H NMR (400 MHz, CDCl3):
d 0.92 (s, 3H, CH3), 1.1
(s, 3H, CH3), 1.21 (t, 3H), 2.1–2.3 (m, 4H), 2.38 (s, 3H), 2.42 (s,
3H), 4.07 (q, 2H), 5.0 (s, 1H), 6.02 (brs, 1H, NH), 7.05–7.20 (d, 2H,
J = 7.2 Hz), 7.20–7.35 (d, 2H, J = 7.2 Hz) IR (KBr, cmÀ1):
3277.20, 3077.56, 2958.93, 1700.32, 1601.95, 1487.18, 1367.59,
1279.82, 1231. Anal. Calcd. for C22H27NO3S: C, 68.54, H, 7.06, N,
3.63. Found: C, 68.47, H, 6.917, N, 3.53, ES-MS: 408.02 [M+Na]+.
n
157
3. Results and discussion
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The acidic nature of fluorinated organic solvents primarily
arises from the fluorine atoms. The presence of an electronegative
trifluoromethyl group in TFE affords it strong acidic character.
Lanthanum oxide has temperature dependent crystal structure
[30]. At ambient temperature, it has a hexagonal crystal structure
in which the La3+ ion (Lewis acid) is surrounded by 7 co-ordinate
group of O2À ions (Fig. 1).
At higher temperature, it becomes a cubic crystal. These basic
structural features prompted us to use the combination of these
two in organic synthesis for the construction of heterocyclic
compounds such as Hantzsch polyhydroquinoline derivatives. To
optimize the reaction conditions and select proper solvent, the
reaction of 4-Cl-benzaldehyde (1 mmol), dimedone (1 mmol),
ethyl acetoacetate (1.2 mmol) and ammonium acetate (1.5 mmol)
using La2O3 (10 mol%) catalyst in 2 mL of respective solvent was
chosen as the model condensation reaction whose results are
summarized in Table 2.
the corresponding polyhydroquinoline derivatives.
209
No significant substituent effect was observed in terms of 210
reaction time and yield of the product. Furthermore, reusability 211
study of the catalyst showed good results. 4-Chlorobenzaldehyde 212
gave 95%, 91%, 88%, 85% yield of the ethyl 4-(4-chlorophenyl)- 213
1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carbox-
ylate after fresh, 1st, 2nd and 3rd run, respectively. The catalyst can 215
be recycled and reused several times without much loss of catalytic 216
Initially the reaction was tried at room temperature in the
absence of any catalyst and solvent. When the reaction was carried
at room temperature in the absence of catalyst, it could not
complete even after a long time (24 h) (Table 2, entry 1). Then we
continued to optimize the model condensation using various
solvents and their combinations. The use of solvents such as DMSO
214
activity (Table 3).
217
Thus, the present protocol tolerates different functional groups, 218
such as methoxy, hydroxyl, halide, etc., and smoothly affords the 219
polyhydroquinolines in short reaction time at room temperature in 220
excellent yields. A comparative study of the effect of La2O3/TFE 221
combination with some of the literature methods for the synthesis 222
of polyhydroquinolines is summarized in Table 4.
223
Table 3
Reusability of La2O3 catalyst.
Run
Fresh
95
I
II
III
Yield (%)a
91
88
85
a
Fig. 1. Structure of La2O3.
Yields in case of 4-chlorobenzaldehyde.
Please cite this article in press as: S.U. Tekale, et al., La2O3/TFE: An efficient system for room temperature synthesis of Hantzsch
polyhydroquinolines, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.037

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S.U. Tekale et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
Table 4
Comparison of La2O3/TFE combination with literature methods for the synthesis of polyhydroquinolines.
Entry
Catalyst
Conditions
Yield (%)
Reference
1
2
3
4
5
6
7
HClO4–SiO2 (50 mg/mmol)
ZnO (10 mol%)
90 8C, neat, 8–20 min
80 8C, 1 h
EtOH, r.t., 2–8 h
81–96
81–94
85–95
85–95
81–95
90–99
86–95
[6]
[7]
Yb(OTf)3 (5 mol%)
Sc(OTf)3 (5 mol%)
Scolecite (100 mg/mmol)
No catalyst
[11]
EtOH, r.t., 2–6 h
[12]
EtOH, reflux, 35–60 min
H2O, reflux, 2.25–8 h
TFE, r.t., 1–1.5 h
[15]
[20]
La2O3 (10 mol%)
Present work
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4. Conclusion
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Thus inthe present work, we have demonstrated the utilityof the
combination of lanthanum oxide and trifluoroethanol (La2O3/TFE)
for the synthesis of Hantzsch polyhydroquinolines from aromatic
aldehydes, dimedone, ethylacetoacetate and ammonium acetate at
room temperature. The presence of Lewis acidic sites (La3+) in the
catalyst and trifluoromethyl group in TFE increased Lewis acidity of
the combination of La2O3/TFE system, which was sufficient enough
to catalyze the reaction at ambient temperature affording high yield
of products in short reaction time. Use of heterogeneous catalyst,
tolerance to various substituents, easy separation, short reaction
time and high yield are the significant advantages associated with
the present protocol, which make it an attractive strategy for the
synthesis of polyhydroquinolines. Thus, the present protocol
highlights and explores not only the applications of 2,2,2-
trifluoroethanol as a powerful solvent in organic synthesis but also
the emerging utility of La2O3 as a heterogeneous catalyst for the
synthesis of heterocyclic compounds. We strongly believe that
the combination will find extensive applications in future for the
synthesis of heterocyclic compounds.
244
Acknowledgments
245
246
247
Authors are thankful to the Principal, Shri Muktanand College,
Gangapur (MS) India and Principal, Deogiri College Aurangabad
(MS) India for encouraging us to carry out this work. One of the
248 Q3 authors (SUT) thanks University Grants Commission for Financial
249
assistance under a Minor Research Project [No. 47-283/12(WRO)].
250
References
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Please cite this article in press as: S.U. Tekale, et al., La2O3/TFE: An efficient system for room temperature synthesis of Hantzsch
polyhydroquinolines, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.037