Application of the β-cyclodextrin supramolecules as a green accelerator hosts in one-step preparation of highly functionalised rhodanine scaffolds

Article abstract of DOI:10.1080/10610278.2014.890200

β-Cyclodextrin (β-CD) supramolecule was found to be a convenient, green and economical tool in one-pot synthesis of rhodanine scaffolds as a highly efficient mediating agent in aqueous media in which the reaction accelerated to complete in 15 min and room

Full text of DOI:10.1080/10610278.2014.890200

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Application of the β-cyclodextrin supramolecules as
a green accelerator hosts in one-step preparation of
highly functionalised rhodanine scaffolds
Sadegh Rostamniaa, Esmail Doustkhaha & Asadollah Hassankhanib
a Organic and Nano Group (ONG), Department of Chemistry, University of Maragheh, P.O.
Box 55181-83111, Maragheh, Iran
b Department of Materials Science, International Center for Science, High Technology &
Environmental Sciences, P.O. Box 76315-117, Kerman, Iran
Published online: 26 Mar 2014.
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To cite this article: Sadegh Rostamnia, Esmail Doustkhah & Asadollah Hassankhani (2015) Application of the β-cyclodextrin
supramolecules as a green accelerator hosts in one-step preparation of highly functionalised rhodanine scaffolds,
Supramolecular Chemistry, 27:1-2, 1-3, DOI: 10.1080/10610278.2014.890200
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Supramolecular Chemistry, 2015
Vol. 27, Nos. 1–2, 1–3, http://dx.doi.org/10.1080/10610278.2014.890200
Application of the b-cyclodextrin supramolecules as a green accelerator hosts in one-step
preparation of highly functionalised rhodanine scaffolds
Sadegh Rostamniaa*, Esmail Doustkhaha and Asadollah Hassankhanib
aOrganic and Nano Group (ONG), Department of Chemistry, University of Maragheh, P.O. Box 55181-83111, Maragheh, Iran;
bDepartment of Materials Science, International Center for Science, High Technology & Environmental Sciences, P.O. Box 76315-117,
Kerman, Iran
(Received 20 December 2013; accepted 29 January 2014)
b-Cyclodextrin (b-CD) supramolecule was found to be a convenient, green and economical tool in one-pot synthesis of
rhodanine scaffolds as a highly efficient mediating agent in aqueous media in which the reaction accelerated to complete in
15 min and room temperature. In this work, amines reacted with equimolar ratio of CS2 (not excess ratio of CS2) and then
with activated acetylenes in the presence of b-CD in aqueous media.
Keywords: cyclodextrin; supramolecule; rhodanine; multicomponent reaction
Introduction
b-cyclodextrin supramolecules as a green accelerator
hosts in the economical and convenient synthetic approach
of rhodanines.
One of the main objectives of organic and medicinal
chemistry is the design, synthesis and production of
molecules having value as human therapeutic agents (1).
The rhodanine scaffold is a central part of bioactive
compounds with various applications and uses (1–3).
Rhodanine-based molecules, in particular, are known to
possess multiple biological activities including the
inhibition of numerous targets such as HCV NS3 protease
and b-lactamase (4–5). As part of our ongoing research in
multicomponent reactions leading to the synthesis of
heterocyclic compounds, and based on our previous study
of the synthesis of rhodanine (6), we became interested in
the development of a practical method to synthesise
potential pharmacologically and biologically interesting
rhodanines. Hence, many synthetic ways including
different reactants, medium, catalysis and solvents
are suggested (3–6). One of them is the one-pot three-
component strategy which our research group has
extensively studied. In this manner, CS2 and amines with
a third component are usually variable (Scheme 1).
Previously, we synthesised rhodanines aqueous media for
1 h (6a). However, this method requires more equivalent
amount of CS2 and more reaction time when compared to
other methods. Thus, we reported it with g-Fe2O3 as a
heterogeneous catalyst (6b). In spite of its efficiency, the
catalyst was not very high stable in the long term. On other
hand, cyclodextrins (CDs) as green and eco-friendly
biomimetic materials are readily available. Recently,
CDs supramolecules, especially b-CD, have been
found as potent catalysing agent in the organic
reactions (3–5, 7–9). Thus, here, we wish to report the
Results and discussion
In continuation of our ongoing program aiming at the
development of efficient methods for the synthesis of
bioactive heterocycles (10), we took a simple one-pot
strategy for synthesis of rhodanine scaffolds by macromol-
ecular b-CD as an eco-friendly catalyst in aqueous media
through its host capability. In order to evaluate the efficiency
of the b-CD, synthesis of 3a (the reaction of benzyl amine 1,
CS2 and dimethyl acetylenedicarboxylate 2) as a model
reaction was carried out in aqueous medium with a catalytic
amount of b-CD. Surprisingly, reaction in water with no
catalyst or additives proceeded only 15% in 10 min,
meanwhile the b-CD-mediated synthesis of rhodanine
resulted in 95% yield within 15min in optimised condition
(Table 1). b-CD molecules are able to form host–guest
complexes with organic small molecules, given the unique
nature imparted by their structure. b-CDs act as a small cage
or supramolecular reactor for organic processes via
encapsulation effects. Here, the b-CD molecules act as a
green accelerator hosts in one-step preparation of the
rhodanines.
Solvent study was also studied in this work by model
reaction. Water, THF, acetonitrile and ethanol were selected
to investigate the solvent effect and finally water was
selected either as green or efficient solvent in this reaction.
Based on the biological interest of rhodanines, and
after selection of the ideal reaction conditions b-CD,
*Corresponding author. Email: rostamnia@maragheh.ac.ir; srostamnia@gmail.com
q 2014 Taylor & Francis

2
S. Rostamnia et al.
Table 2. Synthesis of rhodanines using b-CD supramolecule.a
S
COOR
E
R
S
N
S
β–CD
CS2
+
+
RNH2
(10 mol%)
R
N
S
3
E
E
–ROH
R
NH2
CS2
+
+
H2O, r,t.
O
E
1
2
O
E
Scheme 1. Synthetic components of rhodanines.
3
R
R0
Time (min) Yield (%)b
Table 1. Effect of reaction conditions on model synthesis of 3a.a
3a
C6H5CH2
CO2Me
CO2Me
CO2Me
CO2Et
15
17
15
15
15
15
15
20
95
93
95
93
91
90
92
90
3b p-Cl–C6H4CH2
3c o-Cl–C6H4CH2
3d o-Cl–C6H4CH2
3e
3f
S
CO2CH3
NH2
Cyclodextrin
N
C6H5CH(CH3)
CH3CH(CH3)CH2 CO2Me
CO2Me
S
CS2
+
+
H2O
O
CO2CH3
CO2CH3
2a
3 g CH2vCHCH2
3 h CH3CH(CH3)
CO2Me
CO2Me
1a
3a
a Reaction conditions: 2 mmol amine derivative, 2 mmol CS2, 10 mol%
b-CD in 5 ml H2O at room temperature for appropriate time.
b Isolated yield.
CD
Temp (8C)
mol%
Time (min)
Yield %b
b-CD
b-CD
b-CD
b-CD
b-CD
a-CD
a-CD
–
r.t.
40
r.t.
r.t
r.t.
r.t.
r.t.
r.t.
5
5
10
10
10
15
15
15
10
10
31
56
77
95
90
75
79
15
10
10
15
10
15
–
residual product and dried under vacuum and reused in a
subsequent reaction.
A proposed mechanism for the b-CD-mediating
synthesis of rhodanines is shown in Scheme 2. We suggest
that the reaction occurs by initial formation of the
dithiocarbamate by CD supramolecule-host catalysed
reaction between the amine and CS2 (6). The dithiocarba-
mate then adds to the acetylene by S-addition of the
dithiocarbamate to acetylene followed bynucleophilic attack
of the dithiocarbamate nitrogen at the ester carbonyl and
eliminationofalcoholtoformtherhodaninering(Scheme 2).
Bold values are optimized condition.
a Reaction conditions: benzyl amine (2 mmol), CS2 (2 mmol), DMAD
(2 mmol) in 5 ml H2O.
b Isolated yield.
10 mol% in room temperature), we extended this reaction
to the synthesis of other derivatives of rhodanine to
demonstrate the generality of our method. The results are
summarised in Table 2. These results support the proposed
catalytic function of the b-CD.
Experimental
Chemicals and apparatus
The recycling possibility and ability of the CD
supramolecule catalyst, the model reaction in the presence
of b-CD was studied (Figure 1). During this study, when
the reaction was completed, after the adding of CH2Cl2
(DCM) as solvent, the catalyst was easily separated from
the product by separatory funnel. The remaining catalyst
was washed with DCM and diethyl ether to remove
All reagents were obtained from Merck (Tehran, Iran) and
Fluka (Tehran, Iran) and were used without further
purification. IR spectra were recorded on a Shimadzu IR-
460 spectrometer (Shimadzu Analytical India Pvt. Ltd,
India). Melting points were measured on an Electro-
thermal 9100 apparatus (Electrothermal 9100, China).
Figure 1. (Colour online) Reusing and separation method of b-CD-accelerate rhodanine synthesis.

Supramolecular Chemistry
3
E
O
CO2R'
E
R
NH2
+
CS2
+
N
S
R
β–CD
H2O
S
H2O
OH
–R'OH
H2O
HO
OH
OH
H2O
H2O
H2O
H2O
O
HO
O
O
O
O
O
HO
O
HO
O
O
HO
H2O
OH
OH HO
OH
HO
OH
OH
OH
OH
O
HO
O
H2O
O
O
OH
H2O
O
H2O
O
OH
HO
O
HO
O
OH
HO
S
HO
O
OH
S
RNH2
O
OH
O
R
O
E
S
HO
O
OH
CS2
N
H
S H
NHR
HO
O
OH
HO
HO
O
OH
HO
H2O
HO
E
E
+
OH
O
OH
OH
O
E
E
O
H2O
R'O
H2O
O
HO
H2O
HO
H2O
OH
HO
OH
HO
HO
OH
O
O
OH
O
HO
O
HO
O
O
O
O
O
OH
O
OH
O
HO
O
OH
HO
HO
H2O
HO
HO
H2O
H2O
H2O
O
HO
HO
H2O
H2O
O
O
OH
OH
OH
Scheme 2. (Colour online) Proposed mechanism for synthesis of rhodanines in the presence of CD supramolecule.
General procedure for synthesis of rhodanine derivatives
by simple mixing of the starting materials during 15 min
the products can be separated by simple extraction.
The amine derivative (2 mmol) and carbon disulphide
(2 mmol) were added to a solution of b-CD (10 mol%) in
H2O (5 ml) and the mixture was stirred at room temperature
for 30 s. Then 2 mmol of activated acetylene was added to
the mixture dropwise and then the mixture stirred to
appropriate time (Table 2). After completion (TLC), the
reaction mixture was extracted with CH2Cl2 (4 £ 10 ml)
and dried over anhydrous MgSO4 and evaporated to give
the rhodanine. All the products were previously reported (6)
and were characterised by direct comparison of their IR and
physical data.
References
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thiazolan-5-yliden]ethanoate (3b)
Orange powder, m.p. 114–1188C. IR (KBr) (nmax, cm21):
1
1728 (CvO), 1649 (CvC), 1310 and 1177 (CvS); H
NMR (500.1 MHz, CDCl3): dH ¼ 3.87 (3H, s, OMe), 5.24
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3
3JHH ¼ 8.4 Hz, 2CH of Ar), 7.37 (2H, d, JHH ¼ 8.4 Hz,
2CH of Ar) ppm; 13C NMR (125.7 MHz, CDCl3):
dC ¼ 46.62 (OMe), 52.89 (CH2Ph), 117.16 (CvCH),
128.86 (2CH of Ar), 130.49 (2CH of Ar), 132.79 (Cipso of
Cl), 134.36 (Cipso of NCH2), 141.82 (CvCH), 165.45
(CON), 166.46 (CO2 Me), 195.43 (CvS) ppm.
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Conclusion
In the present work, we have described a green, simple
supramolecular-mediated route through b-CD for the
synthesis of rhodanine derivatives which are potentially,
pharmacologically and biologically interesting. Another
scope this work was its echo-friendly green procedure in
which, the reaction is performed under neutral conditions