An efficient one-pot synthesis of 2-amino-5-arylidenethiazol-4-ones catalyzed by MgO nanoparticles

Article abstract of DOI:10.1002/jccs.201300425

A mild and efficient protocol for the synthesis of 2-amino-5-arylidene-1,3- thiazol-4(5H)-ones is reported by three component reaction of aldehydes, rhodanine and secondary amines in the presence of magnesium oxide nanoparticles as heterogeneous nanocatalyst in good yields and short reaction times. A mild and efficient protocol for the synthesis of 2-amino-5-arylidene-1,3-thiazol- 4(5H)-ones is reported by three component reaction of aldehydes, rhodanine and secondary amines in the presence of magnesium oxide nanoparticles as heterogeneous nanocatalyst in good yields and short reaction times. Copyright

Full text of DOI:10.1002/jccs.201300425

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
An Efficient One-pot Synthesis of 2-Amino-5-arylidenethiazol-4-ones Catalyzed by
MgO Nanoparticles
Narges Shariati and Robabeh Baharfar*
Department of Chemistry, University of Mazandaran, Babolsar, Iran
(Received: Aug. 16, 2013; Accepted: Nov. 2, 2013; Published Online: Dec. 19. 2013; DOI: 10.1002/jccs.201300425)
A mild and efficient protocol for the synthesis of 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones is reported
by three component reaction of aldehydes, rhodanine and secondary amines in the presence of magnesium
oxide nanoparticles as heterogeneous nanocatalyst in good yields and short reaction times.
Keywords: Multicomponent reaction; Rhodanine; MgO nanoparticles; Knoevenagel condensation;
2-Amino-5-arylidene-thiazol-4-one.
INTRODUCTION
4-Thiazolidinones are considered as privileged struc-
Preparation of 2-amino-5-arylidenethiazol-
4-ones
Scheme I
tures in the medicinal chemistry field.1-3 Particularly 2-ami-
no-5-arylidene-1,3-thiazol-4(5H)-ones have been widely
investigated for a range of pharmacological activities such
as antibacterial,4,5 antiviral,6 cardiotonic7,8 and anti-inflam-
matory activities.9,10 Numerous synthetic routes11-21 have
been developed in order to obtain this heterocyclic core,
but these described routes require additional steps with ex-
tended reaction times, high temperatures, and laborious
work-up. In recent years, Anderluh et al. reported an acid
catalyzed microwave assisted three component synthesis
of 2-amino-5-alkylidenethiazol-4-ones,22 which requires
high temperature (~150 °C) microwave heating and double
equivalent of aldehydes for good yield. Therefore, this
method is no longer a green methodology.
model reaction of benzaldehyde (1 mmol), rhodanine (1
mmol), and morpholine (1 mmol) was optimized under a
variety of conditions and the results are summarized in Ta-
ble 1. The reaction was first tried under catalyst free condi-
tions and the result indicated that presence of catalyst is
necessary for this transformation (Table 1, entry 1). Then,
the reaction was examined in the presence of different base
catalysts under diffrerent conditions. The optimal result
was obtained when 30 mol% of MgO-NPs had been used in
aqueous ethanol at 50 °C (Table 1, entry 9). After optimiza-
tion of the model reaction, a variety of 2-amino-5-aryli-
denethiazol-4-ones were synthesized with three-compo-
nent reaction of rhodanine (1 equiv, 1 mmol), secondary
amines (1 equiv, 1 mmol), and some benzaldehydes with
various functionalities (1 equiv, 1 mmol) in according to
Scheme II. The products were obtained in excellent yields
with high purity (Table 2). The structures of products were
Metal oxide nanoparticles have been found excellent
applications as catalysts in the synthesis of organic com-
pounds.23-25 Their high reactivity is due to their limited size
and a high density of corner or edge surface sites.26,27
Among them, magnesium oxide nanoparticle (MgO-NPs)
is most widely used as heterogeneous catalyst and exhibits
high activities in numerous base-catalyzed organic reac-
tions.28-30 In continuation of our previous works for the
synthesis of novel biologically interested heterocyclic
compounds,31-33 we report herein a novel, efficient and
convenient one-pot synthesis of a variety of 2-amino-5-
alkylidene-thiazol-4-ones using MgO-NPs as heterogene-
ous catalyst (Scheme I).
1
confirmed by IR, H and 13C NMR spectroscopy, mass
spectrometry, and elemental analysis, and were found to be
identical with the data described in the literature.19-22 The
reaction was also examined in the presence of some aliphatic
aldehydes, but the desired products were not obtained.
RESULTS AND DISCUSSION
In order to determine the best reaction conditions, the
* Corresponding author. Tel: +981125342358; Fax: +981125342350; Email: baharfar@umz.ac.ir
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337

Article
Shariati and Baharfar
Table 1. Optimization of reaction conditions[a]
Proposed mechanism of preparation of 2-
amino-5-arylidene-thiazol-4-ones
Scheme II
Entry Catalyst (mol%)
Solvent
Time (min) Yield (%)
1
2
3
4
5
6
7
8
-
H2O+EtOH
H2O+EtOH
H2O+EtOH
H2O+EtOH
H2O+EtOH
H2O+EtOH
H2O+EtOH
H2O+EtOH
H2O+EtOH
H2O+EtOH
Dry EtOH
THF
250
30
25
10
10
10
15
61
58
52
95
95
82
68
47
71
65
NaOH (50)
K2CO3 (50)
DBU (50)
35
ZnO-NPs (50)
TiO2-NPs (50)
Bulk MgO (50)
MgO-NPs (50)
MgO-NPs (30)
MgO-NPs (20)
MgO-NPs (30)
MgO-NPs (30)
MgO-NPs (30)
MgO-NPs (30)
150
140
170
110
120
140
210
165
110
120
9
10
11
12
13
14
H2O
DCM
materials will be in the homogeneous phase of aqueous eth-
anol. This three-component reaction proceeds via dual acti-
vation of substrates by MgO-NPs which have a number of
anionic oxidic Lewis basic (O2–/O–) and hydroxylic Bronsted
basic (OH) sites along with Mg2+ as Lewis acid site.28 The
Lewis base moiety of the catalyst activates the methylene
group of rhodanine. The carbonyl oxygen of aldehyde co-
ordinates with the Lewis acid moiety increasing the elec-
trophilicity of the carbonyl carbon and thereby making it
possible to carry out the reaction in short time.
[a] Reaction and conditions: rhodanine (1 equiv, 1 mmol),
benzaldehyde (1 equiv, 1 mmol), morpholine (1 equiv, 1 mmol),
different catalysts, 50 °C, stirring.
A plausible mechanism for the formation of products
is given in Scheme II. During the process, the Knoevenagel
condensation between aldehyde and rhodanine should first
take place as evidenced by the isolation of an 5-arylidene
thiazol-4-one intermediate after the reaction proceeding
for a few minutes. The quenching of the reaction could sim-
ply be done by removing the catalyst from the reaction mix-
ture through filtration. Since the catalyst is heterogeneous,
it remains outside the homogeneous phase, and the starting
In conclusion we have developed an efficient proto-
col for the three-component synthesis of 2-amino-5-aryli-
denethiazol-4-ones from rhodanine, amines and aldehyde
in the presence of MgO-NPs as heterogeneous catalyst.
This new method offers several advantages such as excel-
Table 2. Preparation of 2-amino-5-arylidenethiazol-4 ones[a]
Entry Product
Aldehyde
Amine
Time (min) Melting point (°C) Yield (%)[b]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
PhCHO
PhCHO
PhCHO
piperidine
pyrrolidine
morpholine
piperidine
pyrrolidine
morpholine
morpholine
piperidine
piperidine
piperidine
piperidine
piperidine
morpholine
pyrrolidine
pyrrolidine
95
45
105
120
100
50
120
100
85
110
95
100
110
75
90
80
213-215
219-220
194-196
192-194
256-260
271-273
236-238
207-209
163-165
152-154
197-199
162-164
234-236
210-212
236-238
228-230
91
80
95
82
78
76
90
89
84
93
81
89
94
85
87
87
4-CN-PhCHO
4-CN-PhCHO
4-CN-PhCHO
4-Cl-PhCHO
4-Cl-PhCHO
2-MeO-PhCHO
4-Me-PhCHO
4-OMe-PhCHO
2-Br-PhCHO
2-Br-PhCHO
2-Br-PhCHO
2-Cl-PhCHO
9
10
11
12
13
14
15
16
4-(NMe2)-PhCHO pyrrolidine
[a] Reaction and conditions: benzaldehyde derivatives (1 equiv, 1 mmol), rhodanine (1 equiv, 1
mmol), amines (1 equiv, 1 mmol), MgO-NPs (0.3 eq, 0.15 mmol), H2O + EtOH (1:1), 50 °C, stirring.
[b] Isolated yield.
338
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of 2-Amino-5-arylidenethiazol-4-ones
lent yields, short reaction times, mild conditions and easy
work-up.
= 5.1 Hz, 2H, CH2), 3.78-3.85 (m, 4H, 2CH2), 4.07 (t, J = 4.8 Hz,
2H, CH2), 7.40-7.47 (m, 4H, 4CHarom.), 7.72 (s, 1H, CH); 13
C
NMR (100 MHz, CDCl3): d 49.1, 66.3, 66.4, 128.6, 129.1, 130.0,
130.7, 132.6, 135.5, 175.0, 180.5; MS: m/z 310 (M+.+1), 308
(M+.); Anal. Calcd for C14H13ClN2O2S (308.78): C, 54.46; H,
4.24; N, 9.07; S, 10.38. Found: C, 54.22; H, 4.29; N, 9.15; S,
10.27.
EXPERIMENTAL
General: All chemicals and reagents were purchased from
Fluka and Merck and used without further purification. Magne-
sium Oxide nanoparticles (20 nm diameters, SSA: >60 M2/g)
were obtained from US Research Nanomaterials, Inc. (USA).
Melting points were measured on an Electrothermal 9100 appara-
tus. NMR spectra were recorded with a Bruker DRX-400 AVANCE
instrument (400.1 MHz for 1H, 100.6 MHz for 13C) with CDCl3
or DMSO-d6 as solvent. IR spectra were recorded on an FT-IR
Bruker vector 22 spectrometer. Mass spectra were recorded on a
Finnigan-Matt 8430 mass spectrometer operating at an ionization
potential of 70 eV. Elemental analyses were carried with a
Perkin-Elmer 2400II CHNS/O Elemental Analyzer. General
procedure for the synthesis of 2-amino-5- arylidenethiazol-4-
ones: A mixture of rhodanine (1 mmol), amine (1 mmol), alde-
hyde (1 mmol) and 12 mg (30 mol %) of MgO-NPs in 4 mL aque-
ous ethanol (50:50) were stirred in 50 °C until the reaction is com-
pleted. The completion of the reaction was indicated by the disap-
pearance of the starting material in thin layer chromatography.
After completion of the reaction, the crude product was filtered
and the residue was taken in DCM and filtered again to separate
the product as filtrate from the catalyst. The product was further
purified by recrystallization in EtOAc/DCM (equal volume). Iso-
lation of 5-arylidene thiazol-4-one intermediate: A mixture of
rhodanine (1 mmol), amine (1 mmol), aldehyde (1 mmol) and 12
mg (30 mol %) of MgO-NPs in 4 mL aqueous ethanol (50:50)
were stirred in 50 °C. After 5-10 minutes, the reaction mixture
was filtered and the residue was taken in DCM and filtered again
to separate the product as filtrate from the catalyst. Finally, the
solvent was evaporated from the product in a rotary evaporator.
Data of selected products are represented below. 5-Benzylidene-
2-(piperidin-1-yl)thiazol-4(5H)-one (4a): Yield 849 mg, 91%;
yellow powder; mp 213-215 °C; IR (KBr, cm-1) nmax: 2939, 1700,
1673, 1612, 1560; 1H NMR (400 MHz, CDCl3): d 1.69-1.81 (6H,
m, 3CH2), 3.59 (2H, br s, CH2), 4.01-4.04 (2H, m, CH2), 7.36-
ACKNOWLEDGEMENTS
This research was supported by the Research Council
of the University of Mazandaran, Iran.
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