A facile synthesis of novel 3-(aryl/alkyl-2-ylmethyl)-2-thioxothiazolidin- 4-ones using microwave heating

Article abstract of DOI:10.1016/j.tetlet.2012.02.064

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-(aryl/alkyl-2-ylmethyl) -2-thioxothiazolidin-4-ones (7a-w) have been synthesized by the Knoevenagel condensation reaction of 3-(aryl/alkyl-2-ylmethyl)-2-thioxothiazolidin-4-ones (3a-d) with suitably substituted 2-(1H-indol-3-yl)2-oxoacetaldehydes (6a-g) under microwave conditions. The thioxothiazolidin-4-ones were prepared from the corresponding aryl/alkyl amines (1a-d) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-g) were synthesized from the corresponding acid chlorides (5a-g) using HsnBu₃.

Full text of DOI:10.1016/j.tetlet.2012.02.064

Tetrahedron Letters 53 (2012) 2195–2198
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile synthesis of novel 3-(aryl/alkyl-2-ylmethyl)-2-thioxothiazolidin-4-ones
using microwave heating
⇑
Sukanta Kamila, Haribabu Ankati, Emily Harry, Edward R. Biehl
Department of Chemistry, Southern Methodist University, Dallas, TX 75275, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-(aryl/alkyl-2-ylmethyl)-2-thioxothiazolidin-4-ones (7a–w)
have been synthesized by the Knoevenagel condensation reaction of 3-(aryl/alkyl-2-ylmethyl)-2-thioxo-
thiazolidin-4-ones (3a–d) with suitably substituted 2-(1H-indol-3-yl)2-oxoacetaldehydes (6a–g) under
microwave conditions. The thioxothiazolidin-4-ones were prepared from the corresponding aryl/alkyl
amines (1a–d) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a–g) were synthesized from
the corresponding acid chlorides (5a–g) using HsnBu3.
Received 24 January 2012
Revised 10 February 2012
Accepted 14 February 2012
Available online 24 February 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Microwave irradiation
2-Thioxothiazolidin-4-onse
2-(1H-Indol-3-yl)-2-oxoacetaldehydes
Acid chlorides
Rhodanines
O
X
OH
R1
X
S
S
Introduction
R
R1
F
R
N
N
S
F
S
F
O
O
5-Benzylidene-3-phenyl-2-thioxothiazolidine-4-ones (rhoda-
nine derivatives) represent privileged scaffolds in drug discovery.
A survey of recent papers dealing with the pharmacological prop-
erties of such compounds reveals that they display a wide range of
O
O
B
A
activities.
For
example
2-aryl-5-(4-oxo-3-phenethyl-2-thi-
Figure 1. Competitive inhibitor of HIV-1 and JSP-1.
oxothiazolidinylidene methyl)furans (A) with molecular weight
ꢀ500 Da exhibit anti-HIV-1 activity1 as seen in Fig. 1. In a later
study, the same group found that 5-((arylfuran/1H-pyrrol-2-yl)-
methylene)-2-thioxo-3-(3-(trifluromethyl)phenyl)-thiazolidin-4-
ones (B) exhibited a high potency against infection by laboratory-
adapted and primary HIV-1 strains with EC50 at low nanomolar
levels and inhibiting HIV-1-mediated cell–cell fusion and the trans
membrane subunit gp41 six-helix bundle formation.2 Various 5-
substituted rhodanine derivatives have been shown to prevent
mildew formation3 and to exhibit antifungicidal4 and antipesticid-
al5 activities. The 5-benzylidine-3-phenyl-2-thioxo-thiazolidin-4-
one core has been shown to inhibit the Jun NH2-terminal kinase
(Jnk) stimulatory phosphatetase-1 (JSP-1).6 In addition, rhoda-
nine-based molecules have become the popular small-molecule
inhibitors of numerous targets such as HCV NS3 protease,7a aldose
The use of microwave irradiation in the synthesis of small bio-
molecules is growing in importance.8 The major benefits of per-
forming reactions under microwave condition are: significant
rate enhancements and higher product yields as compared to reac-
tions which run under conventional heating. A key advantage of
modern, scientific microwave apparatus is their ability to control
reaction conditions precisely, by monitoring temperature/pressure,
and reaction times. Since quick reaction times for the synthesis of
potentially active biological molecules is crucial to the medicinal
community, the use of microwave technology has grown rapidly.9
For the past few years, our group has also been preparing and
evaluating biologically important compounds using microwave
heating.10 For example, we recently prepared several 5-(2-(1H-in-
dol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-ones
in 89–96% yields using microwave radiation for 10 min at 90 °C.
Several of these compounds possessed strong neuroprotecting
activity against Alzheimer and Parkinson diseases.10a
reductase,7b,c b-lactamase,7d UDP-N-acetylmuramate/
L-alanine
UDP-N-acetylmuramate/L
-alanine ligage,7e antidiabetic agent,7f
Cathepsin D,7g and histidine decarboxylase.7h
With these promising results, we have extended our research
on biologically active rhodanines for the design and preparation
⇑
Corresponding author.
E-mail address: ebiehl@smu.edu (E.R. Biehl).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.064

2196
S. Kamila et al. / Tetrahedron Letters 53 (2012) 2195–2198
Table 1
Previously, Knoevenagel condensation reactions have used organic
base such as CH3CO2Na14 or piperidene,11 however our previous
experience has shown 2,2,6,6-tetramethyl piperidine to be a supe-
rior base in these condensation reactions10a and thus was used in
the optimizing experiments. As shown in Table 1, optimal micro-
wave-assisted reaction conditions were obtained using a power
of 200 W, a pressure of 250 psi, and a ratio of 1/1.2 rhodanine/alde-
hyde in the presence of a catalytic amount of 2,2,6,6-tetramethyl
piperidine in 2 mL of ethanol.
Screening of solvents, reaction time, and temperature
Solvent
Condition
Time (min)
Yield%
No solvent
No solvent
No solvent
Ethanol
Ethanol
Ethanol
Acetonitrile
DMF
Water
Toluene
Isopropanol
THF
n-Butanol
DME
1:1; 3a/6a, 80 °C
1:1.2; 3a/6a, 80 °C
1:1.2; 3a/6a, 90 °C
1:1; 3a/6a, 80 °C
1:1; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
1:1.2; 3a/6a, 90 °C
10
10
15–20
15
40
41
45–50
68
90
98
75
49
Trace
Trace
45
38
30
Trace
Trace
Trace
Trace
30
15
15
15
15
15
15
15
15
15
15
15
15
15
15
Using these microwave optimal conditions, the synthesis of
titled compounds (7a–w) by a microwave assisted Knoevenagel
condensation of (3a–c) with suitably substituted 2-(1H-indol-3-
yl)-2-oxoacetaldehydes (6a–g) was carried out (Scheme 1). The
starting 3-(aryl/alkyl-2-ylmethyl)-2-thioxothiazolidin-4-one (3a–
d) derivatives were prepared from the literature procedures17a–c
which involved refluxing equimolar quantities of suitably substi-
tuted amines and di-(carboxymethyl)-trithiocarbonyls in the pres-
ence of 0.5 equiv of potassium carbonate. The 2-(1H-Indol-3-yl)2-
oxoacetaldehydes (6a–g) were synthesized by treating corre-
Sulfolane
NMP
Dimethylsulfone
Acetone
18
sponding acid chlorides with HSnBu3.. The acid chlorides were
prepared by the acylation of indole (or substituted indole) with
of novel (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(alkyl/aryl-
2-ylmethyl)rhodanines and report the results herein. We have fo-
cused our attention on introducing side-chain linkers attached to
N-atom of the rhodanine core and substituting the benzene ring
with thiophene, furan, and tetrahydrofuran moieties with the
hopes of developing rhodanine compounds possessing inhibitory
properties against HIV-1 and neuroprotecting ability in the low mi-
cro-molar range. We should mention that there is a plethora of lit-
erature precedence for Knoevenagel condensation with aryl
aldehydes or rhodanine derivatives however, most of the methods
suffer from one or other limitations such as requiring harsh reac-
tion conditions, low moderate yields, relatively long reaction time,
and a cumbersome experimental process. Among these reported
methods, the Knoevenagel reaction has been performed in the
presence of a catalyst with various solvents: piperidine in etha-
nol,11 tetrabutylammonium bromide in water,12 sodium acetate
in glacial acetic acid,13 or ethanol14 and piperidinium benzoate in
toluene.15 The use of microwave irradiation has also been em-
ployed with solid inorganic support (Al2O3 or KSF) in a domestic
microwave oven (multimode cavity)16 with a complete lack of con-
trol of the reaction temperature.13
oxalylchloride.19
As shown in Table 2, the rhodanine derivatives (7a–w) were
prepared in excellent yields ranging from 85% to 98% using alde-
hydes carrying either electron-donating and/or electron-with-
drawing groups. On the other hand, yields of 7a–w using
conventional heating for 3 h at 90 °C were significantly lower,
ranging from 43% to 80%. The solvent plays an important role in
this MW assisted reaction. It is found that ethanol is the best sol-
vent for these types of reaction, may be due to the stabilization
of the final product through H-bonding. In addition the starting
materials are also soluble in ethanol which makes it a better sol-
vent than water, isopropanol or n-butanol. The products 7a–w
were isolated as stable Z-isomers which were confirmed by noting
that vinyl proton shift in the 1H NMR spectrum occurred around
8 Hz which is similar to those previously reported.10a The struc-
tures of compounds 7a–w were further substantiated by, 13C
NMR, DEPT-135, HRMS, (see Supplementary data) and IR analyses.
For example, IR(KBr) spectra of 7a–w exhibited absorption bands
due to the stretching vibrations of NH group of indole cycles
(3200 cmÀ1 range) and displayed characteristic absorption bands
of the C@S group (intense band at 1628–1610 cmÀ1 range) and
two C@O groups (1720 cmÀ1 range).
We determined optimum microwave conditions by studying
the reaction of 3-(thiophen-2-ylmethyl)-2-thioxo-thiazolidin-4-
one 3a with 2-(1H-indol-3-yl)-2-oxoacet-aldehyde (6a) using a
series of solvents at different reaction times and temperatures.
In conclusion we have designed and prepared several rhodadine
derivatives (7a–w) by a microwave-assisted Knoevenagel reaction
O
Water
H2OOCH2C
S
N
NH2
R1
S
R1
X
X
Reflux, 8 hr
S
HOOCH2C
X = S, O
X = S, O
Y
R1 = H, CH3
N
1a-c
3a-c
2
R2
R3
MW (250 psi/200 W)
EtOH (2 mL)
H
N
O
O
o
S
90 C, 20 min
R1
X
S
H
Cl
O
O
Y = H, CH3
R2
R3
R2
R2 = H, CH3, OCH3
O
O
R1
COCl
R2
R1
Dry ether
Cl, COCH3
R3 = H, CN
Bu3SnH
o
Ethylacetate
N
Y
N
Y
N
Y
COCl 0 C to RT
o
0 C to RT
4a-g
6a-g
7a-w
5a-g
Scheme 1. Schematic representation for the syntheses of 7a–w.

S. Kamila et al. / Tetrahedron Letters 53 (2012) 2195–2198
2197
Table 2
Reaction of various indole based aldehydes with rhodanine derivatives
O
H
Y
O
N
R2
S
N
R2
O
R1
R1
X
R3
S
H
N
Yielda
Yieldb
N
Y
O
O
S
Z
S
Z =
Z =
Z =
Z =
Z =
Z =
Z =
Z =
Z =
Z =
Z =
Z =
Z =
Z =
1
R1 = H, X = S
R1 = H, X = S
R1 = H, X = S
R1 = H, X = S
R1 = H, X = S
R1 = H, X = S
R1 = H, X = S
R1 = H, X = O
R1 = H, X = O
R1 = H, X = O
R1 = R2 = H, Y = H
98
95
98
95
90
93
85
95
91
98
96
89
83
98
92
93
97
96
66
56
45
48
44
56
43
67
70
80
80
70
67
55
60
44
80
61
S
7a
2
R1 = R2 = H, Y = CH3
S
7b
3
R1 = CH3, R2 = H, Y = H
R1 = OCH3, R2 = H, Y = H
R1 = Cl, R2 = H, Y = = H
R1 = COCH3, R2 = H, Y = H
R1 = = H, R2 = CN, Y = H
R1 = R2 = H, Y = H
S
7c
4
S
7d
5
S
7e
6
S
7f
7
S
7g
8
O
7h
9
R1 = R2 = H, Y = CH3
O
7i
10
11
12
13
14
15
16
17
18
R1 = CH3, R2 = H, Y = H
R1 = OCH3, R2 = H, Y = H
R1 = Cl, R2 = H, Y = H
R1 = H, R2 = CN, Y = H
R1 = COCH3, R2 = H, Y = H
R1 = R2 = H, Y = H
O
7j
R
1 = H, X = O
1 = H, X = O
O
7k
R
O
7l
R1 = H, X = O
R1 = H, X = O
O
7m
O
7n
Z = H3C
Z = H3C
Z = H3C
Z = H3C
Z = H3C
R1 = CH3, X = O
O
7o
7p
7q
7r
R1 = CH3, X = O
R1 = CH3, X = O
R1 = CH3, X = O
R1 = R2 = H, Y = CH3
O
O
O
R1 = CH3, R2 = H, Y = H
R1 = OCH3, R2 = H, Y = H
19
R1 = CH3, X = O
R1 = Cl, R2 = H, Y = H
81
51
O
7s
(continued on next page)

2198
S. Kamila et al. / Tetrahedron Letters 53 (2012) 2195–2198
Table 2 (continued)
O
H
Y
O
N
R2
S
R2
N
O
R1
R1
X
R3
S
H
N
Yielda
Yieldb
N
Y
O
O
S
Z
S
Z = H3C
20
21
22
R1 = CH3, X = O
R1 = H, X = O
R1 = H, X = O
R1 = H, X = O
R1 = COCH3, R2 = H, Y = H
R1 = R2 = H, Y = H
95
93
94
89
55
79
49
60
O
7t
Z =
O
7u
Z =
O
R1 = OCH3, R2 = H, Y = H
R1 = COCH3, R2 = H, Y = H
7v
Z =
O
23
7w
a
Isolated yield. All the compounds were characterized by 1H NMR, 13C NMR, IR, and HRMS analyses.
Conventional heating for 3 h at 90 °C.
b
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in excellent yields using a reaction time of only 15 min at 90 °C.
The mild workup conditions, good to excellent yields, and easily
available substrates make this reaction an attractive method for
the preparation of these biologically important molecules. We
are currently investigating the synthesis of a number of other rho-
danine based drug molecules by this method. Detailed biological
activity studies (antibacterial, antifungal, anticancer, and neuro-
protective kinase inhibitor activity) of these important compounds
are being carried out. Preliminary results indicate that many of
these compounds exhibit excellent neuroprotective properties.
Their biological properties will be published in due course.
Acknowledgment
The authors are grateful to NIH (IRC2NS064950) for generous
financial support.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.064.
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