An improved one-pot multicomponent strategy for the preparation of thiazoline, thiazolidinone and thiazolidinol scaffolds

Article abstract of DOI:10.1039/c5ra17278k

A facile multicomponent synthesis of desirable medicinal scaffolds based on thiazoline, thiazolidinone and thiazolidinol derivatives has been disclosed. The synthesis employs the reaction of a primary amine and carbon disulphide in a microwave, to generate a symmetrical thiourea in situ. The subsequent addition of e.g. 3-bromo-1,1,1-trifluoropropan-2-one affords the desired product, in an efficient one-pot process.

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An Improved One-Pot Multicomponent Strategy for the
Preparation of Thiazoline, Thiazolidinone and Thiazolidinol
Scaffolds
Received 00th January 20xx,
Accepted 00th January 20xx
K. Appalanaidu,a Tulshiram Dadmal,a N. Jagadeesh Babub and Ravindra M. Kumbhare*a
DOI: 10.1039/x0xx00000x
A facile multicomponent synthesis of privileged medicinal scaffolds based thiazoline, thiazolidinone and thiazolidinol
derivatives has been disclosed. The reaction employs the reaction of primary amine and carbon disulphide in microwave to
generate symmetrical thiourea in situ. The subsequent addition of 3-bromo-1,1,1-trifluoropropan-2-one, affording the
desire product in an efficient one-pot process.
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cells with positive myeloperoxidase reactivity and in agriculture
Introduction
as acaricides, insecticides, plant growth regulators3,4
, inhibits
melanin production in a dose dependent manner thus acting as a
skin whitening agent5 I (KHG22394, Figure 1) and act as reversible
inhibitor of p53 mediated apoptosis and p53 dependent gene
transcription6 II (Pft-α, Figure 1). Thiazolidine-4-onethione is a five-
membered heterocyclic scaffold, also gain much attraction due to
their wide range of applications in medicinal chemistry such as
antidiabetic7, anticancer8, calcium-channel blocking9,10 V (Figure 1),
Multicomponent reactions (MCRs) are attractive progressively due
to their improved efficiency, reduced waste, atom economy,
simplicity and rapid access for the synthesis of biologically active
compounds1. Multicomponent reactions are privileged over
conventional multistep sequences owing to redeemable in the costs
of reagents, solvents and other resources required for purification
and isolation2. The greater occurrence of infectious diseases and
platelet activating factor (PAF) antagonistic11, anti-HIV activities12
,
multi-drug-resistant strains has become
a major concern in
hypnotic13,14, antitubercular15, cardiovascular16 III (Figure 1) and
cyclooxygenase (COX) inhibitory activities17 IV (Figure 1). 2-Imino-
1,3-thiazolidines are well recognised for their anti-inflammatory,
anodyne, anti-Alzheimer activity, in agriculture as pesticides and
medicinal area. Therefore, the development of new potential drugs
to counteract the advancing resistance is one of the key issues and
challenges for medicinal chemistry and related disciplines
nowadays. The current scenario highlights the need for discovery
and development of new drugs.
protective properties against γ-radiation18-20
.
In view of the fact that heterocyclic compounds in general,
thiazolines, thiazolidinone and thiazolidines exhibit a wide variety of
biological activities, the search for new approaches toward the
concluding entities with a greater degree of efficiency is of
significant importance.
The remarkable physiological activities of thiazolines,
thiazolidinone and thiazolidines inspired as target compounds in
organic synthesis. The unsaturated 2-imino-1,3-thiazolines exhibit
the great attention in pharmaceutical chemistry, due to its
important biological activities such as antimicrobial, anti-
inflammatory,
antihistaminic,
antihypertensive,
hypnotic,
anticonvulsant activity, applicability for the identification of human
Fig.1. Some biological active scaffolds in relevance of
thiazoline and thiazolidinone.
According to the literature, a number of strategies for the synthesis
of and thiazolines, thiazolidinone and thiazolidines are known. A
first approach toward the synthesis of 2-imino-1,3-thiazolines were
published more than
a
century ago, encompasses with
condensation reactions of α-haloketones with thiourea, in neutral
or basic medium, or with ammonium thiocyanate also in aqueous
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media catalysed by diammonium hydrogen phosphate or DABCO21
.
reaction at room temperature and fewer yield on conventional
In addition to 2-iminothiazolines, the condensation reaction of α- heating, may be the more time require for formation of thiourea.
haloketones with thiourea under acidic conditions gave rise to Most of the literature reports on thiourea notify more time for
variable amounts of aminothiazoles as side products.
thiourea formation. So we selected microwave method for the
Murru et al.22 reported the one pot reaction of 1,1/-(ethane-1,2- reaction. To further increase the productivity of the reaction,
diyl) dipyridinium bistribromide (EDPBT), as a brominating agent, independently, we studied the synthesis of thiourea in various
enolizable ketones and disubstituted thioureas. Several alternative conditions. We attempt the reaction of aniline (2mmol) and carbon
methods have been developed, which include use of catalyst such disulphide (1mmol) under microwave irradiation in various solvent
as copper, TiCl423-30 and other condensation as well as cycloaddition systems (Table 1). Among the various solvent, reaction proceeds
reactions. Recently, one-pot, three-component reaction of aromatic smoothly in N,N-dimethylformamide (DMF) to give the
α-bromoketones, primary amines and phenyl isothiocyanate have corresponding thiourea in 98 % yield (Table 1, Entry 2). Further,
been reported for the synthesis of thiazol-2-imines using catalytic optimization of reaction condition for thiourea synthesis, we
amount of triethylamine31
.
performed the same reaction in N,N-dimethylformamide (DMF)
The general methods for the synthesis of 2-iminothiazolidin-4-ones solvent at various conditions. Surprisingly, under microwave
includes the cyclization of thiourea with α-halocarboxylic acids, acyl condition we observed good yield (98%) of corresponding thiourea
halides, carboxylic esters or the condensation reaction of the (Table 2, Entry 3). Indication of time required for the thiourea
appropriate amine, aldehyde and mercapto acids32-39. Recently preparation has constituted the focus of our investigations
thiazolidinone derivatives have been prepared by using CuFe2O4 regarding improved strategies for further synthesis. Microwave
magnetic nanoparticles as a catalyst40
.
condition and N,N-dimethylformamide (DMF) seemed to be the
Various reports are available for the synthesis of 2- best choice.
Table 1. Solvent effect on the reaction of aniline and carbon
disulphide
iminothiazolidines, which involves the acid mediated or in the
presence of triphenylphosphine and diethyl azodicarboxylate,
intramolecular cyclization of N-(2-hydroxyethyl) thiourea41, 2-Imino-
1,3-thiazolidines have also been prepared from treatment of
aziridines with thiocyanuric acid, reaction of 2-vinylaziridine with
phenyl isothiocyanate, condensation of α- halo ketones with
thioureas, etc42-44
.
As per the literature reviews, most of the methods uses thiourea or
substituted thiourea as a substrates, while in reports of one pot
synthesis they require the use catalysts or base and harsh reaction
conditions, whereas in aqueous medium obtained the less yield. To
improve on these limitations, it is important to investigate
regarding improved strategies for the synthesis of thiazoline,
thiazolidinone and thiazolidinol derivatives.
Previously, we successfully used N,N-dimethylformamide (DMF) as
a
reaction medium and phenylisothiocyanate as substrate to
accomplish the synthesis 2-imino-4-(trifluoromethyl)thiazolidin-4-ol
derivatives45. As our on-going efforts in exploring the new route for
heterocyclic synthesis and their biological evaluation46, herein we
report an efficient, one pot synthesis of thiazolidinol, thiazolidinone
and thiazoline derivatives using carbon disulphide (CS2) as substrate
under microwave irradiation.
Results and discussion
In order to optimization the reaction condition, we have selected
the synthesis of (Z)-N-(3,4-diphenylthiazol-2(3H)-ylidene)aniline (4a)
as a model reaction (Table 3, entry a). Initially, the reaction of
aniline (1 mmol), Carbon disulphide (1mmol) and 2-bromo-1-
phenylethanone (1mmol) was performed in DMF at room
temperature but there is no progress of reaction. Later on
Table 2. Reaction condition effect on synthesis of substituted thiourea
0
conventional heating at 90 C in DMF for 2 hrs we observed fewer
yields (40%) with some side products. Subsequently, in order to
improve the reaction efficiency, we carried out the reaction under
microwave irradiation and varied the molar ratios of the reactants,
when a ratio of 2:1:1 (1:CS2:3, Scheme 1) was used, the product was
isolated in the highest yield in shorter time. The cause for no
2 | J. Name., 2012, 00, 1-3
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The possible mechanism for thiourea formation is outlined in thiourea followed by the attack of thiocarbonyl group of thiourea
scheme 2. The reaction may proceed via formation of on acetylene fragment of diethyl but-2-ynedioate affording the
phenylcarbamodithioic acid.
product 6a-i.
Table 3. Synthesis of Thiazoline derivatives.
O
R
S
N
N
Br
CS2
R
NH2
+
+
R1
R1
R
1
3a-b
4a-j
1
1 3
Product 4(a)
Entry
a
R
R
Yield %(b)
S
N
N
91
H3CO
S
N
b
H3CO
94
N
Scheme 1. Comparison of previous work with our strategy.
H3CO
N
S
N
c
88
S
N
Scheme 2. Plausible mechanism of thiourea formation.
90
86
88
d
N
N
After the optimization, further studied the scope of substrate for
this method, different amines subjected to the treatment with CS2
under microwave irradiation, followed by addition of various bromo
acylketones in N,N-dimethylformamide (DMF) and the results are
summarized in Table 3. Remarkably, several primary amines,
S
N
O
O
e
O
N
S
N
including
aniline,
benzylamine,
furan-2-ylmethanamine,
f
cyclohexalamine, substituted aniline, butylamine and 2-bromo-1-
phenylethanone, 3-(2-bromoacetyl)-2H-chromen-2-one reacted
with carbon disulphide affording the corresponding thiazoline
derivatives in the form of HBr salt, later neutralized with saturated
sodium bicarbonate and achieved desired thiazoline derivatives (4a-
j) in good to excellent yields (Table 3, entries a-j). The plausible
reaction mechanism of formation of product (4a-j) is summarized in
scheme 3. The reaction proceeds via attack of thiocarbonyl group of
thiourea on bromomethyl group of bromoacylketones followed by
cyclization and dehydration process afforded the product 4a-j.
During the synthesis of thiazolidinone derivatives, we try to
optimize the reaction conditions. The reaction of primary amine (2
mmol) and carbon disulphide (1 mmol) was subjected to microwave
irradiation for 5 min. After cooling to room temperature, DMF (3
ml) was added to the reaction mixture and then diethyl but-2-
ynedioate (or) dimethyl but-2-ynedioate (1mmol) was added. The
reaction mixture was stirred at room temperature for 10–15 min.
The reaction proceeded smoothly affording the corresponding
thiazolidinone derivatives (6a-i) in good to excellent yield (Table 4,
entries a-i). Various amines, including substituted aniline,
benzylamine, furfulamine, butylamine and diethyl but-2-ynedioate
and dimethyl but-2-ynedioate reacted with carbon disulphide to
give corresponding thiazolidinone derivatives (Table 4). This
method efficiently employed not only for aliphatic and hetero aryl
primary amines but also for aromatic primary amines. The proposed
reaction mechanism for formation of thiazolidinone derivatives is
outlined in scheme 4. The reaction proceed via is situ formation of
S
N
N
N
91
92
g
O
O
O
O
O
O
S
N
h
O
O
S
N
N
N
i
90
91
O
O
O
O
O
O
O
O
S
N
j
Reaction was performed with 2mmol of amine,1mmol CS2 and 1mmol of phenacyl bromide.
[a] All products were characterized by 1H and 13C NMR, IR and mass spectroscopy.
[b] Yield refers to pure product after column chromatography
Scheme 3. Plausible reaction mechanism of Thiazoline derivatives.
J. Name., 2013, 00, 1-3 | 3
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Table 4. Synthesis of thiazolidinone derivatives.
taking place. This might be due to the electron withdrawing effect
of trifluoromethyl group on same carbon. The proposed reaction
mechanism of formation thiazolidinol derivatives is summerized in
scheme 5. The reaction proceed via thiourea formation followed by
the attack of thiocarbonyl group of thiourea on bromomethyl group
of 1,1,1-trifluoropropan-2-one to give product 8a-h.
OR2
O
COOR2
S
N
R
NH2
CS2
N
O
COOR2
1
2
5a-b
6a-i
R2
2
Product
6[a]
Yield (%)[b]
R 1
Entry
O
O
Table 5. Synthesis of thiazolidinol derivatives.
S
N
N
85
C2H5
a
O
O
O
S
O
N
OH
CS2
2
O
NH2
R
Br
N
CF3
F3C
S
N
N
H3CO
84
b
C2H5
1
7
8a-h
8[a]
Entry
Product
Yield (%)[b]
H3CO
O
R
O
S
N
90
83
C2H5
N
O
O
c
S
N
N
OH
O
CF3
90
a
O
S
N
N
O
H3CO
C2H5
d
O
O
O
S
N
O
N
OH
S
CF3
95
91
N
N
82
89
b
H3CO
CH3
e
O
H3CO
H3CO H3CO
O
O
S
N
N
f
H3CO
CH3
OCH3
S
N
O
O
H3CO
N
OH
c
H3CO
CF3
H3CO
N
O
OCH3
S
N
91
85
F
H3CO
N
O
O
CH3
CH3
g
h
Cl
Cl
O
S
N
O
80
S
N
d
O
OH
F
N
O
CF3
O
O
Cl
O
F
S
i
90
CH3
O
F3C
N
N
S
N
F3C
N
N
OH
CF3
78
95
e
f
The reaction was perford with 2mmol of amine, 1mmol of CS2 and 1mmol of diethyl but-2-ynedioate (or) dimethyl but-2-ynedioate
[a] Product was characterized by 1H and 13C NMR, IR and mass spectroscopy. [b] isolated yield after column chromatography
F3C
S
N
OH
CF3
O
S
N
O
N
92
94
OH
g
h
CF3
O
OH
CF3
S
N
N
Reaction was performed with 2mmol of amine,1mmol CS2 and 1mmol of 3-bromo-1,1,1-
trifluoropropan-2-one. [a] All products were characterized by 1H and 13C NMR, IR and
mass spectroscopy. [b] Yield refers to pure product after column chromatography
Scheme 4. Plausible reaction mechanism of thiazolidinone
derivatives.
In case of thiazolidinol derivative synthesis, the reaction of primary
amine and carbon disulphide performed under optimized
microwave condition, followed by dropwise addition of 3-bromo-
1,1,1-trifluoropropan-2-one in DMF at room temperature, giving
the product good to excellent yield (Table 5, entries 8a-h). Scope of
the reaction was investigated for various primary amines including
benzylamine, furfulamine, butylamine and substituted anilines. In
case of thiazoline product, after cyclization tertiary hydroxyl group
in the intermediate undergoes dehydration process. But during the
formation of thiazolidinol product, dehydration process was not
Scheme 5. Pausible reaction mechanism of thiazolidinol derivatives.
4 | J. Name., 2012, 00, 1-3
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All the products were characterized by IR spectroscopy, 1Hand 13C
NMR spectroscopy, and mass spectrometry. The structure of 4j
(Table 3, entry h) was confirmed by X-ray crystallography as shown
in fig. 2. (CCDC 1410087)47. The X-ray structure shows, compound 4j
has crystallized in the form of a HBr salt, so we neutralized with
saturated sodium bicarbonate to obtained the thiazoline
derivatives.
Weinheim, Germany. doi: 10.1002/9783527678174.ch05; (c) T.
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Conclusions
In summary, we have developed a novel, one pot, and versatile
method for the synthesis of thiazoline, thiazolidinone and
thiazolidinol derivatives via three component reaction of primary
amine, carbon disulphide and various bromo acylketones or diethyl
but-2-ynedioate (or) dimethyl but-2-ynedioate using microwave
technology. The reaction used readily available, inexpensive and
harmless precursors. The procedure is extremely useful in synthetic
and medicinal chemistry as it provides the desired products in
single step process in excellent to good yield.
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Acknowledgements
We are thankful to the Director of IICT for providing facilities.
A.N., K.A. and Y.K. thank CSIR and T.D. thanks UGC, New Delhi,
for the award of a fellowship and R.M.K. thanks S.E.R.C.,
Department of Science & Technology, Government of India for
financial assistance under the Fast Track Scheme for young
scientists (SR/FTP/CS-031/2010).
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DOI: 10.1039/C5RA17278K
Graphical Abstract
An Improved One-Pot Multicomponent Strategy for the Preparation of Thiazoline,
Thiazolidinone and Thiazolidinol Scaffolds
K. Appalanaidu, Tulshiram Dadmal, N. Jagadeesh Babu and Ravindra M. Kumbhare*
A simple three component protocol towards the synthesis of a Thiazoline, Thiazolidinone and
Thiazolidinol Scaffolds have been designed and conveniently synthesized with good yield.