Multi-component synthesis of piperidines and dihydropyrrol-2-one derivatives catalyzed by a dual-functional ionic liquid

Article abstract of DOI:10.1177/1747519819883881

N,N,N’,N’-tetramethyl-N,N’-bis(sulfo)ethane-1,2-diaminium mesylate ([TMBSED][OMs]₂) was employed for the synthesis of piperidines and dihydropyrrol-2-ones via one-pot multi-component reactions in simple and green processes. This pseudo five-component reaction of aromatic aldehydes, anilines and alkyl acetoacetates was carried out under reflux conditions in ethanol to afford substituted piperidines. Also, dihydropyrrol-2-one derivatives were synthesized by means of four-component reactions of various amines, dialkyl acetylenedicarboxylates and formaldehyde in ethanol at room temperature. The present approaches have several advantages such as good yields, easy work-ups, short reaction times, and utilize mild and clean reaction conditions.

Full text of DOI:10.1177/1747519819883881

883881CHL0010.1177/1747519819883881Journal of Chemical ResearchBasirat et al.
research-article2019
Research Paper
Journal of Chemical Research
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© The Author(s) 2019
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Multi-component synthesis of piperidines
and dihydropyrrol-2-one derivatives
catalyzed by a dual-functional ionic liquid
https://doi.org/10.1177/1747519819883881
DOI: 10.1177/1747519819883881
journals.sagepub.com/home/chl
Narjes Basirat, Seyed Sajad Sajadikhah and Abdolkarim Zare
Abstract
N,N,N’,N’-tetramethyl-N,N’-bis(sulfo)ethane-1,2-diaminium mesylate ([TMBSED][OMs]2) was employed for the synthesis
of piperidines and dihydropyrrol-2-ones via one-pot multi-component reactions in simple and green processes. This
pseudo five-component reaction of aromatic aldehydes, anilines and alkyl acetoacetates was carried out under reflux
conditions in ethanol to afford substituted piperidines. Also, dihydropyrrol-2-one derivatives were synthesized by means
of four-component reactions of various amines, dialkyl acetylenedicarboxylates and formaldehyde in ethanol at room
temperature. The present approaches have several advantages such as good yields, easy work-ups, short reaction times,
and utilize mild and clean reaction conditions.
Keywords
ionic liquid, [TMBSED][OMs]2, piperidine, dihydropyrrol-2-ones, multi-component reactions
Date received: 31 May 2019; accepted: 1 October 2019
well as ability to catalyze numerous types of organic
reactions, their ability to be used in solvent-free or solution
Introduction
In recent years, ionic liquids (ILs) have been extensively
used and have attracted remarkable research interest as
catalysts for the green synthesis of the organic compounds
due to their tunable physical and chemical properties.1 ILs
have also been employed because of their advantages,
including high thermal and chemical stability, low vapor
pressure, non-flammability, and good ionic conductivity, as
Department of Chemistry, Payame Noor University (PNU), Tehran, Iran
Corresponding author:
Seyed Sajad Sajadikhah, Department of Chemistry, Payame Noor
University (PNU), P.O. Box 19395-3697, Tehran, Iran.
Email: sssajadi@pnu.ac.ir

2
Journal of Chemical Research 00(0)
conditions, the ease of changing the cation or anion in their
structures to modify their physical and chemical properties,
and their ability to dissolve in many organic and inorganic
materials.2–5
Piperidine derivatives, as a valuable class of nitrogen-
containing heterocycles, have received much attention
owing to their properties such as anti-hypertensive,6 neuro-
toxic activity,7 anti-bacterial,8 treatment of Alzheimer’s
diseases,9 anticonvulsant, anti-inflammatory,10 anticancer,11
and antimalarial.12 Recently, multicomponent reactions
(MCRs) have been employed for the synthesis of substi-
tuted piperidines.13–22
In addition, dihydropyrrol-2-ones are important in organic
synthesis due to their wide spectrum of activity which includes
anti-microbiological,23,24 antitumor,25,26 anti-inflammatory,27
antimalarial,28 antifungal,29 antidiabetics,30 and antibiotic
properties.31 Therefore, many methodologies have been
developed to synthesize these practical heterocycles.32–38
However, some of the above-mentioned methods for the
synthesis of both those types heterocycles have disadvan-
tages such as long reaction times, low or moderate yields,
and environmental pollution. Hence, the development of
beneficial and environmentally friendly methods for the
preparation of these compounds is still in demand.
In this work, N,N,N’,N’-tetramethyl-N, N’-bis(sulfo)
ethane-1,2-diaminium mesylate ([TMBSED][OMs]2) was
used as an effective dual-functional IL for the synthesis of
substituted piperidines and dihydropyrrol-2-one deriva-
tives via one-pot MCRs in ethanol as a green solvent
(Scheme 1).
Scheme 1. Synthesis of piperidines 4 and dihydropyrrol-2-
ones 9 in the presence of ([TMBSED][OMs]2).
Table 1. Optimization of the reaction conditions for the
synthesis of 4a.
Entry Catalyst (mol%) Temp (oC) Time (min) Yield (%)a
1
2
3
4
5
6
7
8
9
5
10
15
5
10
15
5
rt
rt
rt
50
50
50
reflux
reflux
reflux
100
100
100
80
75
65
60
55
55
―
25
32
59
62
62
80
93
94
10
15
Results and discussions
aIsolated yield.
[TMBSED][OMs]2 was synthesized according to the our
previously reported work.39 To optimize the amount of the
catalyst for the synthesis of substituted piperidines, the
reaction of aniline (2 mmol), methyl acetoacetate (1 mmol),
and benzaldehyde (2 mmol) was selected as a model sys-
tem. Next, 5, 10, and 15 mol% of [TMBSED][OMs]2 were
examined at ambient temperature, 50°C, and reflux condi-
tions in EtOH. According to the results in Table 1, 10 mol%
of the IL catalyst afforded methyl 1,2,5,6-tetrahydro-1,2,6-
triphenyl-4-(phenylamino)pyridine-3-carboxylate (4a) in
93% yield under reflux conditions in 55 min as the best
result (Table 1, entry 8).
Next, the pseudo five-component reaction of anilines 1
(2 mmol), methyl/ethyl acetoacetate 2 (1 mmol) and aro-
matic aldehydes 3 (2 mmol) was investigated under the
optimized conditions for the preparation of functionalized
piperidines 4a-j (Table 2). A wide range of substituted and
structurally diverse aldehydes and anilines was utilized to
give the corresponding products in high to excellent yields
using the acidic IL. Next, we examined n-heptanal and
n-heptylamine as examples of aliphatic aldehydes and
amines instead of benzaldehyde and aniline, respectively.
However, the desired products were not obtained (Table 2,
entries 11 and 12). This may be due to the tendency of ali-
phatic aldehydes to produce enamines rather than imines
and that these condense with any remaining aldehyde. In
addition, in the presence of n-heptylamine, the higher
basicity of the aliphatic amine compared to aniline can lead
to salt formation with the catalyst.40
Based on the literature,14–16 the proposed mechanism
for this pseudo five-component reaction is displayed in
Scheme 2. It was assumed that the aniline 1 reacts with the
β-ketoester 2 to give enamine A in the presence of
[TMBSED][OMs]2 and that it also reacts with aldehyde 3
to give imine B with elimination of water. Afterwards, the
reaction of enamine A and activated imine B via an inter-
molecular Mannich-type reaction led to intermediate C.
The reaction of intermediate C with a second molecule of
the aldehyde produces intermediate D, which undergoes
tautomerization to afford intermediate D. Following an
intramolecular Mannich-type reaction to form intermediate
E, deprotonation and tautomerization provided the corre-
sponding functionalized piperidine 4.
To demonstrate the applicability of the presented work,
it can be compared with several reported results in the lit-
erature. The results show that the reactions were performed
in short times and gave excellent yields in the presence of
[TMBSED][OMs]2 when compared to other catalysts
(Table 3).
We next synthesized dihydropyrrol-2-ones 9 using the
[TMBSED][OMs]2 catalyst. First, optimization studies
were performed using aniline (2 mmol), dimethyl

Basirat et al.
3
Table 2. Preparation of functionalized piperidines 4a-j in the presence of [TMBSED][OMs]2..
Entry
Ar
Ar’
R1
Product
Time (min)
Yield (%)a
M.p. (°C)
Found
Reported
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Me
Me
Et
Et
Et
Me
Me
Et
Me
Me
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
55
60
60
60
70
55
60
60
93
94
87
81
95
88
88
90
89
52
―
―
180–182
188–189
224–226
219–221
169–171
194–196
161–162
196–198
205–207
234–236
―
185–18615
186–18815
228–23115
221–22416
169–17122
190–19220
160–16312
196–19822
202–20312
239–24212
―
4-MeO-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
Ph
4-Br-C6H4
Ph
Ph
4-MeO-C6H4
4-Me-C6H4
4-Me-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Cl-C6H4
Ph
9
55
10
11
12
4-O2N-C6H4
Ph
n-heptanal
4j
―
―
120
24 h
24 h
n-heptylamine
Ph
Et
―
―
aIsolated yield.
[OMs]2 produces imine H. Reaction between intermediate
G and imine H then generates intermediate I. Cyclization
of intermediate I leads to intermediate J, which in the final
step tautomerizes to give the corresponding dihydropyrrol-
2-one 9.
A comparison the results obtained with [TMBSED]
[OMs]2 and some reported catalysts for the synthesis of
product 9c shows that [TMBSED][OMs]2 can act as effec-
tive and efficient catalyst with respect to the reaction time
and yield (Table 5).
Conclusion
Scheme 2. The proposed mechanism for the preparation of
piperidine derivatives.
In summary, we have developed efficient one-pot proce-
dures for the synthesis of functionalized piperidines and
dihydropyrrol-2-one derivatives using [TMBSED][OMs]2
as a catalyst. These methods offered several advantages
such as short reaction times, good to high yields, simplicity
in operation, no need for column chromatography, and a
green aspect by using ethanol as the solvent.
acetylenedicarboxylate (1 mmol) and formaldehyde (1.5
mmol) in EtOH as a model reaction. The reaction was car-
ried out with 10, 20, and 30 mol% of the catalyst at room
temperature over 2.5–3 h and the corresponding product 9a
was obtained in yields of 80%, 95%, and 96%. Increasing
the amount of catalyst to 30 mol% did not increase the reac-
tion yield further. Therefore, the substrate scope of the reac-
tion was investigated utilizing a range of structurally
diverse aliphatic and aromatic amines and dimethyl/ethyl
acetylenedicarboxylates in the presence of 20 mol% of
[TMBSED][OMs]2. The corresponding dihydropyrrol-
2-ones 9a-j were synthesized in good to high yields in short
reactions times (Table 4).
Experimental
Materials
All chemicals were obtained from Merck, Fluka and Sigma-
Aldrich and were used without subsequent purification. The
nuclear magnetic resonance (NMR) spectra were recorded
with a Bruker DRX-400 AVANCE instrument (400 MHz for
1H, 100 MHz for 13C) in dimethyl sulfoxide (DMSO)-d6 as
solvent. Melting points were measured on an Electro ther-
mal 9100 apparatus. Please see the supplemental material
for the spectral data of some selected compounds.
A possible reaction mechanism for the preparation of
dihydropyrrol-2-ones 9 is presented in Scheme 3.34 First,
the reaction of amine 5 with dialkyl acetylenedicarboxylate
6 leads to intermediate G. Second, condensation between
amine 7 and formaldehyde 8 in the presence of [TMBSED]

4
Journal of Chemical Research 00(0)
Table 3. Comparison the results of [TMBSED][OMs]2 with other catalysts in the synthesis of compound 4a.
Entry
Catalyst (mol%)
Conditions
Time
Yield (%)a [Ref]
1
2
3
4
5
6
7
Iodine (10 mol%)
ZrOCl2.8H2O (20 mol%)
TBATB (10 mol%)
[Hpyro][HSO4] (15 mol%)
Al(H2PO4)3 (0.1 g)
CAN (15 mol%)
MeOH, rt
EtOH, reflux
EtOH, rt
EtOH, reflux
EtOH, rt
8 h
8115
3.5 h
24 h
8 h
12 h
20 h
55 min
8013
7414
7721
8020
MeCN, rt
EtOH, reflux
8216
[TMBSED][OMs]2 (10 mol%)
93 (present work)
aYields refer to isolated pure products based on the reaction of aniline (2 mmol), methyl acetoacetate (1 mmol) and benzaldehyde (2 mmol).
Table 4. Preparation of dihydropyrrol-2-one derivatives in the presence of [TMBSED][OMs]2..
Entry
R2
R3
Ar″
Product
Time (h)
Yield (%)a
M.p. (°C)
Found
Reported
1
2
3
4
5
6
7
8
9
10
Ph
Me
Me
Me
Et
Et
Et
Me
Et
Me
Me
Ph
9a
9b
9c
9d
9e
9f
9g
9h
9i
2.5
2
2.5
3
95
93
91
90
85
89
90
92
94
90
152–154
171–173
175–177
134–136
152–154
76–77
92–94
94–96
143–145
137–138
155–15634
173–17434
177–17834
138–14033
152–15420
78–7933
4-Cl-C6H4
4-Me-C6H4
Ph
4-MeO-C6H4
n-C3H7
n-C4H9
n-C4H9
Ph-CH2
Ph-CH2
4-Cl-C6H4
4-Me-C6H4
Ph
4-MeO-C6H4
Ph
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4
Ph
3
2.5
2.5
2.5
2
92–9438
94–9635
144–14638
139–14034
9j
2
aIsolated yield.
General procedure for the synthesis of
piperidines 4
A solution of aromatic amine 1 (2 mmol) and alkyl acetoac-
etate 2 (1 mmol) in ethanol (10 mL) was stirred for 30 min
in the presence of [TMBSED][OMs]2 (10 mol%) at room
temperature. Next, the aromatic aldehyde 3 (2 mmol) was
added and the reaction mixture was allowed to stir for the
appropriate amount of time under reflux. The progress of
the reaction was monitored by thin layer chromatography
(TLC). After completion of the reaction, the mixture was
cooled to room temperature. The resulting precipitate was
collected by filtration and washed with EtOH (3 × 2 mL)
to give the pure product.
Scheme 3. The proposed mechanism for the synthesis of
dihydropyrrol-2-ones 9.
Table 5. Comparison the results of [TMBSED][OMs]2 with
other catalysts in the synthesis of compound 9c.
Entry Catalyst
Conditions Time (h) Yield (%)a
[Ref]
1
2
Iodine (10 mol%) MeOH, rt
1
7834
8032
General procedure for the preparation of
dihydropyrrol-2-ones 9
Nano-TiCl4/
SiO2(0.08 g)
EtOH, 70°C 2.5
3
4
5
p-TsOH·H2O (15 MeOH, rt
mol%)
3
6
8338
9137
A mixture of amine 5 (1 mmol) and dialkyl acetylenedi-
carboxylate 6 (1 mmol) in EtOH (10 mL) was stirred for
30 min. Next, amine 7 (1 mmol), formaldehyde 8 (1.5 mmol)
and [TMBSED][OMs]2 (20 mol%) were added successively.
The reaction mixture was allowed to stir at room tempera-
ture for the appropriate amount of time. After completion of
the reaction (monitored by TLC), the solid precipitate was
Cu(OAc)2·H2O
(80 mg)
MeOH, rt
[TMBSED][OMs]2 EtOH, rt
(20 mol%)
2.5
91 (present
work)
aYields refer to isolated pure products.

Basirat et al.
5
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filtered off and washed with EtOH (3 × 2 mL) to give the
pure product 9.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
19. Mukhopadhyay C, Rana S, Butcher RJ, et al. Tetrahedron
Lett 2011; 52: 5835.
Funding
20. Sajadikhah SS, Hazeri N, Maghsoodlou MT, et al. J Iran
Chem Soc 2013; 10: 863.
21. Sajadikhah SS, Hazeri N, Maghsoodlou MT, et al. J Chem
Res 2012; 36: 463.
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
work was financially supported by the Research Council of
Payame Noor University.
22. Sajadikhah SS, Maghsoodlou MT, Hazeri N, et al. Chin
Chem Lett 2012; 23: 569.
23. Chitra S, Devanathan D and Pandiarajan K. Eur J Med Chem
2010; 45: 367.
24. Liu J, Li J, Zhang L, et al. Tetrahedron Lett 2012; 53: 2469.
25. Wei F, Zhao BX, Huang B, et al. Bioorg Med Chem Lett
2006; 16: 6342.
ORCID iD
Seyed Sajad Sajadikhah
-5325
https://orcid.org/0000-0002-4415
Supplemental material
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Supplemental material for this article is available online.
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