A comparative study using conventional methods, ionic liquids, microwave irradiation and combinations thereof for the synthesis of 5-trifluoroacetyl-1,2,3,4-tetrahydropyridines

Article abstract of DOI:10.1016/j.tetlet.2018.01.059

This study reports a comparison between conventional methods, ionic liquids, microwave (MW) irradiation, and combinations thereof for the synthesis of a series of fourteen 1-aryl-2-arylamino-5-trifluoroacetyl-1,2,3,4-tetrahydropyridines. In all of the reactions tested, the products were obtained at very good yields (87–97%), but the reaction times were very different, depending on the method used. Comparing to other methods, the time decreased to 1 min when [BMIM]BF₄ under MW irradiation was used, thus evidencing a synergic effect.

Full text of DOI:10.1016/j.tetlet.2018.01.059

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A comparative study using conventional methods, ionic liquids,
microwave irradiation and combinations thereof for the synthesis
of 5-trifluoroacetyl-1,2,3,4-tetrahydropyridines
Valquiria P. Andrade, Mateus Mittersteiner, Márcio M. Lobo, Clarissa P. Frizzo, Hélio G. Bonacorso,
⇑
Marcos A.P. Martins, Nilo Zanatta
Núcleo de Química de Heterociclos (NUQUIMHE), Universidade Federal de Santa Maria, Santa Maria, RS 97105-900, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
This study reports a comparison between conventional methods, ionic liquids, microwave (MW) irradi-
ation, and combinations thereof for the synthesis of a series of fourteen 1-aryl-2-arylamino-5-trifluo-
roacetyl-1,2,3,4-tetrahydropyridines. In all of the reactions tested, the products were obtained at very
good yields (87–97%), but the reaction times were very different, depending on the method used.
Comparing to other methods, the time decreased to 1 min when [BMIM]BF4 under MW irradiation was
used, thus evidencing a synergic effect.
Received 1 November 2017
Revised 15 January 2018
Accepted 20 January 2018
Available online xxxx
Keywords:
Heterocycles
Ó 2018 Elsevier Ltd. All rights reserved.
Tetrahydropyridin-2-arylamines
Ionic liquids
Microwave irradiation
Introduction
disease.14–16 Recently, three tetrahydropyridines—NUNL02,
NUNL09, and NUNL10 (Fig. 1)—were able to inhibit ethidium bro-
17
Functionalized piperidines or tetrahydropyridines are crucial
building blocks for the synthesis of numerous natural products
and other classes of nitrogen heterocyclic compounds.1 The
synthetic procedures reported for the preparation of this class of
compounds involve difficult reaction work-up or purification, the
usage of toxic organic solvents under high temperatures, long
reaction periods, and multi-step reactions.2–7 Tetrahydropyridines
can be prepared from a large range of known reactions, but due to
extensive synthetic routes, they usually furnish the products at low
yields.8 On the other hand, 6-ethoxy-3-trifluoroacetyl-4,5-dihydro-
6H-pyran (1), although, little explored for organic synthesis, was
demonstrated to be a suitable building block for the construction
of libraries of 6-alkoxy-1-alkyl(aryl)-3-trifluoroacetyl-1,4,5,6-
tetrahydropyridines and 1-alkyl(aryl)-6-amino-3-trifluoroacetyl-
1,4,5,6-tetrahydropyridines,9,10 and oxa- and aza-condensed
tetrahydropyridines.11 In its turn, tetrahydropyrimidines with
structure similar to the target compounds of this study were rarely
reported.12,13
mide efflux in the Escherichia coli strains AG100 and AG100TET.
In the past few years, ionic liquids (ILs) have become com-
pounds of great interest in the replacement of organic solvents,
mainly because of their unique properties—non-flammability,
non-volatility, possibility of reuse, high thermal stability, chemical
factors such as stabilization of charges formed during the course of
the reaction and the promotion of catalysis are some of the advan-
tages that have been widely reported.18–20 Their use as reaction
media has been reported to be an efficient and practical alternative
to the use of volatile and toxic organic solvents, and they lead to a
reduction in reaction time and higher yields.21 The combination of
ILs with microwave (MW) irradiation is a technique that has been
widely explored.22,23 This combined system is very efficient in the
synthesis of different heterocycles—given that ILs are polar and
ionic, they promote a more effective interaction with the MW than
regular solvents. In our previous studies,9 we reported the synthe-
sis of
a series of 1-aryl-2-arylamino-5-trifluoroacetyl-1,2,3,4-
tetrahydropyridines by conventional method, which resulted in
long reaction times and difficulties in obtaining products with cer-
tain substituents (Scheme 1). In this study we focused on the reac-
tions with arylamines because with other primary amines such as
alkyl, benzyl, and phenethyl, for example, reactions are much
The biological activity of these six-membered nitrogen hetero-
cycles has been widely reported; for example, 1-methyl-4-phenyl-
1,2,5,6-tetrahydropyridine is a neurotoxin that induces Parkinson’s
faster.10 Additionally, the reaction of enone
1 with some
⇑
Corresponding author.
E-mail address: nilo.zanatta@ufsm.br (N. Zanatta).
https://doi.org/10.1016/j.tetlet.2018.01.059
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Andrade V.P., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.01.059

2
V.P. Andrade et al. / Tetrahedron Letters xxx (2018) xxx–xxx
IL mediated synthesis
The optimization of the reaction conditions was carried out
using aniline as the arylamine, since there were no influences from
any substituent group. The results obtained for these tests are
reported in Table 1. All the ILs furnished the product at very good
yields and at different optimal times. It is important to highlight
that [EMIM]BF4 and [OMIM]BF4 furnished more enone than the
product in the thin layer chromatography analysis for reaction
times less than 3 h. For the control reactions done in the absence
of the IL, no formation of the product was detected. Once the best
reaction time for each IL was established for the aniline, several
arylamines were used for each IL. When the reaction was kept
longer than the ideal time, a decrease of yield was observed prob-
ably due to decomposition of the product. Table 2 shows the yields
for the products 3a–n and a comparison with the previously
reported data.
Fig. 1. Tetrahydropyridines which exhibited drug efflux inhibition.
Table 2 shows the significant changes in the reaction time.
Under the best conditions, the time was reduced from 24 h to 1 h
when using [HMIM]OTs, and the product was obtained at the same
reported yield (entry 7). The isolated yields of the known products
suffered no significant changes, although it is important to high-
light entries 8, 9, 11, 12, and 14, in which the products could not
be obtained using the methodology proposed in Ref. 9. When com-
paring the ILs, the performance of [HMIM]OTs stands out due to
the addition acidity—this IL can be considered to be a Bronsted
acid, which increases the electrophilicity of the carbonyl group.
This is due to the complexation of IL with the oxygen atom, which
results in a more efficient attack of the nucleophile at the b-carbon
and, therefore, a shorter reaction time compared to the other ILs.
To verify the efficiency of [HMIM]OTs, an attempt was made to
prepare product 3a using HCl (Bronsted acid) and boron trifluoride
(Lewis acid). The reaction was carried out under the same experi-
mental conditions, but the IL was replaced by the aforementioned
Scheme 1. Synthetic route adopted for the synthesis of 1,2,3,4-tetrahydropyridines.
Table 1
Optimization of the reactions conditions, using ILs to obtain product 3a.
arylamines could not be obtained by conventional methods and
the reason for this remains unclear.
Given the long reaction time and difficulties in obtaining the
expected products with some arylamines, when conventional
methods were used, we decided to use alternative methods. ILs,
microwave irradiation, and combinations thereof were used in
order to explore new and more efficient methodologies that would
reduce the reaction time, extend the scope of the reaction, and fur-
ther improve the reaction yields. The strategy was quite successful
because it yielded a series of fourteen 1-aryl-2-arylamino-5-triflu-
oroacetyl-1,2,3,4-tetrahydropyridines: seven of these compounds
had already been prepared by the conventional method,9 and
seven were newly synthesized products that could not be obtained
by conventional methods.
Entry
ILa
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[EMIM]BF4
[EMIM][BF4
[EMIM]BF4
[OMIM]BF4
[OMIM]BF4
[OMIM]BF4
[HMIM]OTs
[HMIM]OTs
[HMIM]OTs
1
3
5
6
7
3
4
5
3
4
5
1
2
3
–
c
94
88
85
90d
87
72
96d
90
84
90e
75
50
Results and discussion
The synthetic route adopted for this work is outlined in
Scheme 1, part b. The cyclic enone 1 was obtained in accordance
with the previously described procedure.9 The reaction between
enone 1 and the different arylamines (2a–n) was carried out using
a molar ratio of 1:2 (enone:arylamine) at different reaction times
and in the presence of the following ILs: 1-butyl-3-methylimida-
zolium tetrafluoroborate ([BMIM]BF4), 1-ethyl-3-methylimida-
zolium tetrafluoroborate ([EMIM]BF4), 1-methyl-3-octylimidazolium
tetrafluoroborate ([OMIM]BF4), and 1H-3-methylimidazolium
p-toluenesulfonate ([HMIM]OTs).
9
10
11
12
13
14
a
b
c
Reaction conditions: enone 1 (1.0 mmol), aniline (2.0 mmol), ILs (1.0 mmol), r. t.
Isolated yield.
Enone was not completely consumed.
Enone was not completely consumed in 1 or 2 h.
Enone was not completely consumed in 0.5 h.
d
e
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V.P. Andrade et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Table 2
Isolated yields of different tetrahydropyridines, varying the IL.
Entry
Arylaminea (2a–n)
Solvent
Ethanolb
[BMIM]BF4
[EMIM]BF4
[OMIM]BF4
[HMIM]OTs
Product
1
2
3
4
5
6
7
8
C6H5
81
94
81
99
83
80
68
85
92
80
86
95
93
98
94
90
83
87
77
90
95
80
87
98
81
89
93
91
95
96
87
92
89
94
90
81
90
79
97
91
88
96
94
90
87
96
85
89
85
94
94
85
90
88
95
92
90
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
2-F-C6H4
92
65c
87
88c
93
94
d
d
9
10
11
12
13
14
82
d
d
3-F-C6H4
4-F-C6H4
4-Br-C6H4
98
d
a
b
c
Reaction conditions: enone (1.0 mmol), arylamine (2.0 mmol), IL (1 mmol) and optimized time for each IL ([BMIM]BF4, 5 h; [EMIM]BF4 3 h; [OMIM]BF4 3 h; [HMIM]OTs 1 h).
According to Ref. 9.
New obtained compounds.
Compounds not obtained at the given conditions.
d
Table 3
Table 4
Optimization of reaction conditions for the synthesis of 3a under MW irradiation.
Preparation of different tetrahydropyridines using the EtOH/MW and [BMIM]BF4/MW
methods.
Entry
Solventa
Time (min)
Yield (%)
Entry
Arylamine
EtOH/MW Yield (%)a
IL/MW Yield (%)b
Product
1
2
3
4
5
6
[BMIM]BF4
EtOH
EtOH
EtOH
EtOH
1
1
5
25
30
60
97
b
1
2
3
4
5
6
7
8
C6H5
63
70
75
90
80
87
72
78
60
86
68
54
68
77
97
95
91
89
92
90
95
94
90
95
87
89
94
96
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
b
b
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
2-F-C6H4
63
60
EtOH
a
Reaction conditions: enone 1 (1 mmol), arylamine 2a (2 mmol), ethanol (2 mL)
or IL (1 mmol), MW, 50 °C.
b
Low formation of the product followed by TLC.
9
10
11
12
13
14
acids. No product formation was observed, which demonstrates
the efficiency of the IL as a reaction medium.
3-F-C6H4
4-F-C6H4
4-Br-C6H4
IL/microwave mediated synthesis
Reaction conditions:
a
Enone 1 (1 mmol), arylamine 2a (2 mmol), ethanol (2 mL), MW 50 °C, 30 min.
[BMIM][BF4] (1 mmol), MW, 50 °C, 1 min.
The results observed with the use of different ILs were promis-
ing due to the high yields of the isolated products; however, the
reaction times were still long for some of the ILs tested. For this
reason, [BMIM]BF4, which had the longest reaction time, was cho-
sen to evaluate systems combining ILs and MW, with the aim of
obtaining the 1,2,3,4-tetrahydropyridines faster. In order to opti-
mize the reactions, enone 1 and arylamine 2a were used at 50 °C
under MW irradiation. The temperature was also varied, but
decomposition of the product was observed at temperatures above
50 °C. In Table 3, under the same experimental conditions, the
results are compared to when ethanol was used as solvent.
From the data presented in Table 3, we can see that the [BMIM]
BF4/MW system was much more effective than the ethanol/MW
system in relation to both reaction yield and time. However, when
[HMIM]OTs/MW was used, only the starting materials were recov-
ered while with [OMIM]BF4/MW and [EMIM]BF4/MW a complex
mixture of compounds was obtained.
b
high purity and at elevated yields. As a comparison with other
heterocycles prepared using IL/MW systems, several quinolines
were prepared by Prola et al. in excellent yields.25
Conclusion
In summary, we presented new methodologies for the synthesis
of a series of 1-aryl-2-arylamino-5-trifluoroacetyl-1,2,3,4-tetrahy-
dropyridines, in which organic solvents were replaced by ILs. The
combination of ILs with MW irradiation furnished products with
high yields and short reaction times (1 min). Under this methodol-
ogy, new derivatives that could not be synthesized through the usual
procedure were obtained at high yields. We expect that this syn-
thetic protocol could be very useful for synthesis of various
1,2,3,4-tetrahydropyridine derivatives in an effective and
fast manner.
Given these results, the 1,2,3,4-tetrahydropyridines 3a–n were
prepared by both methods and the results obtained are shown in
Table 4.
The results from Table 4 indicate that the IL/MW system is more
efficient than the ethanol/MW system. According to Martinez-
Palou,24 the combined effects of MW and ILs in promoting the
efficient synthesis of heterocycles is due to the ionic and polar
character of the media being more efficient than regular organic
solvents most of the times, thus furnishing the final products at
Experimental section
General information
Unless otherwise indicated, all commercial reagents and sol-
vents were obtained from commercial suppliers and used without
Please cite this article in press as: Andrade V.P., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.01.059

4
V.P. Andrade et al. / Tetrahedron Letters xxx (2018) xxx–xxx
further purification. Thin-layer chromatography (TLC) was per-
formed using silica gel plates GF254, 0.25 mm thickness. For visual-
ization, TLC plates were placed under ultraviolet light. All melting
points were determined on a Reichert Thermovar apparatus and
are uncorrected. Elemental analyses were performed on a Vario
EL Elementar Analysensysteme. 1H and 13C spectra were recorded
on a Bruker DPX 400 spectrometer (1H at 400.13 MHz and 13C at
100.62 MHz) in CDCl3 as deuterated solvent using TMS as the inter-
nal reference. GC–MS analyses could not be performed because the
compounds decomposed in the column during the experiment. The
MW experiments were performed in a Discover CEM using the
simultaneous cooling operation mode. 2-Ethoxy-5-trifluo-
roacetyl-3,4-dihydro-2H-pyran was obtained from the acylation
reaction of 2-ethoxy-3,4-dihydro-2H-pyran with trifluoroacetic
anhydride in accordance with the methodology developed in our
laboratory.9
1 min for the reactions with IL, and 30 min for the reactions with
EtOH as solvent. After the reaction period, the mixture was
extracted with water (3 Â 10 mL) and dichloromethane (10 mL),
and the organic layers were then combined, dried over Na2SO4,
filtered and concentrated under reduced pressure.
Acknowledgments
The authors are grateful for financial support from the
Fundação de Amparo a Pesquisa do Estado do Rio Grande do Sul
(FAPERGS/CNPq – PRONEX – Grant No. 16/2551-0000477-3) and
fellowships from CAPES (V. P. A. and M. M.).
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.01.059.
Conventional synthetic procedure
References
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organic layer was dried over Na2SO4 and then filtered and concen-
trated under reduced pressure. When necessary, the products were
purified by recrystallization in hexane.9
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Please cite this article in press as: Andrade V.P., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.01.059