Microwave-assisted synthesis of novel bis(2-thioxothiazolidin-4-one) derivatives as potential GSK-3 inhibitors

Article abstract of DOI:10.1016/j.tetlet.2012.05.088

(5Z,5′Z)-3,3′-(1,4-Phenylenebis(methylene)-bis-(5-arylidene-2- thioxothiazolidin-4-one) derivatives (5a-r) have been synthesized by the condensation reaction of 3,3′-(1,4- or 1,3-phenylenebis(methylene))bis(2- thioxothiazolidin-4-ones) (3a,b) with suitably substituted aldehydes (4a-f) or 2-(1H-indol-3-yl)2-oxoacetaldehydes (8a-c) under microwave conditions. The bis(2-thioxothiazolidin-4-ones) were prepared from the corresponding primary alkyl amines (1a,b) and di-(carboxymethyl)-trithiocarbonyl (2). The 2-(1H-indol-3-yl)-2-oxoacetaldehydes (8a-c) were synthesized from the corresponding acid chlorides (7a-c) using HSnBu₃.

Full text of DOI:10.1016/j.tetlet.2012.05.088

Tetrahedron Letters 53 (2012) 3998–4003
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted synthesis of novel bis(2-thioxothiazolidin-4-one)
derivatives as potential GSK-3 inhibitors
⇑
Sukanta Kamila, 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
(5Z,50Z)-3,30-(1,4-Phenylenebis(methylene)-bis-(5-arylidene-2-thioxothiazolidin-4-one) derivatives
(5a–r) have been synthesized by the condensation reaction of 3,30-(1,4- or 1,3-phenylenebis(methy-
lene))bis(2-thioxothiazolidin-4-ones) (3a,b) with suitably substituted aldehydes (4a–f) or 2-(1H-indol-
3-yl)2-oxoacetaldehydes (8a–c) under microwave conditions. The bis(2-thioxothiazolidin-4-ones) were
prepared from the corresponding primary alkyl amines (1a,b) and di-(carboxymethyl)-trithiocarbonyl
(2). The 2-(1H-indol-3-yl)-2-oxoacetaldehydes (8a–c) were synthesized from the corresponding acid
chlorides (7a–c) using HSnBu3.
Article history:
Received 25 April 2012
Revised 17 May 2012
Accepted 19 May 2012
Available online 26 May 2012
Keywords:
Microwave irradiation
2-Thioxothiazolidin-4-ones
2-(1H-Indol-3-yl)-2-oxoacetaldehydes
Acid chlorides
Ó 2012 Elsevier Ltd. All rights reserved.
Rhodanines
Introduction
relationship (SAR) studies suggest that substituents attached to
the N-2 of the thiadiazolidinone ring, as well as the nature of the
Glycogen synthase kinase-3 (GSK-3), a ubiquitous serine/threo-
nine kinase, plays a key role in a large number of cellular process
and diseases. GSK-3 exhibits two unique biological properties.
First, its activity is constitutive and down regulated after cell acti-
vation by phosphorylation or interaction with inhibitory proteins
and secondly, it prefers substrates that are pre-phosphorylated
by other kinases.1 Its pleiotropic but unique activities have made
GSK-3 a much sought-after target for the treatment of prevalent
human diseases,2 such as type 2 diabetes,3 Alzheimer’s disease,4
as well as CNS disorders, such as manic depressive disorders, neu-
rodegenerative diseases, and chronic inflammatory disorders.5
Today, the search for GSK-3 inhibitors is being actively pursued
in both academic and pharmaceutical laboratories.6,7 The most fre-
quent approach for discovering GSK-3 inhibitors exploits screening
programs specifically aimed at finding new ‘hits’ which exhibit
other pharmacological profiles. This is the case for kinase inhibitors
hymenialdisine,8 paullones,9 indrubines,10 maleimides,11 TDZDs,12
and thiazoles (see Fig. 1).
substituent of N-4, are important factors in inhibiting GSK-3.
Moreover, both C5 and C3 carbonyl groups may mediate favorable
interactions with the enzymes.
For the past few years, our group has also been preparing and
evaluating biologically important compounds using microwave
irradiation.14 For example, we recently prepared (Z)-5-(2-(1H-
indol-3-yl)-2-oxoethylidene)-3-(aryl/alkyl-2-ylmethyl)-2-thioxo-
thiazolidin-4-ones.14a–c Several of these compounds possess strong
neuroprotecting activities against Alzheimer’s and Parkinson’s dis-
eases. Other important heterocycles that we have prepared using
microwave heating include: novel class of rhodanine derivatives
as potential HIV-1 and JSP-1 inhibitors;14b novel functionalized
hydantoin and their conversion to 5-(Z)arylidene-4H-imida-
zoles;14c novel pyridobenzimidazoles bonded to indole or
benzo[b]thiophene structures;14d 3-methylisothiazolo[5,4-b][pyri-
dine and various 2-amino derivatives of thienyl[2,3-b]pyridine
and 1,(2-aminopyridin-3-yl).14e We have now extended our re-
search on biologically active rhodanines by successfully introduc-
ing two rhodanine core moieties to a variety of heterocyclic side
chains. We report the results herein.
Compounds 5a–r were synthesized by Knoevenagel condensa-
tion of 3,30-(1,4- or 1,3-phenylenebis(methylene)bis(2-thioxothiaz-
olidin-4-ones) (3a,b) with suitably substituted aldehydes
(4a–f) or 2-(1H-indol-3-yl)2-oxoacetaldehydes (8a–c) under micro-
wave irradiation in the presence of catalytic amounts of 2,2,6,6-tet-
ramethyl piperidine (TMP) in ethanol (Scheme 1). Although, other
bases (Table 1) can be used as catalyst [e.g., piperidine, pyridine,
Among the great diversity of chemical structures with GSK-3
inhibition that have been found,13 the 2,4-disubstituted thiadiazo-
lidinones (TDZDs) appears to be the first ATP-noncompetitive
GSK-3 inhibitors.12 These compounds are of great interest since
they do not show inhibitory activity on other kinases such as
PKA, PKC, CK-2, and CDK1/cyclin B. Preliminary structure–activity
⇑
Corresponding author. Tel.: +1 214 768 1280; fax: +1 214 768 4089.
E-mail address: ebiehl@smu.edu (E.R. Biehl).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.088

S. Kamila, E. R. Biehl / Tetrahedron Letters 53 (2012) 3998–4003
3999
H2N
N
HN
H
N
O
H
N
H
N
O
O
O
O
O
R'
R'
S
Br
HN
HN
HN
R
NH
N
R'
N
R
R
O
Paullones
Hymenialdisine
Anilino-maleimides
Bisindole-maleimides
O
X
OH
R1
X
S
R
O
N
R
R1
F
F
R
N
S
N
S
O
N
S
F
O
O
R'
O
O
Thiazole derivatives
O
TDZDs
H
N
N
H
O
Indirubin
Figure 1. Common GSK-3 inhibitors.
N-methylpiperidine (NMP), DBU], TMP proved to be superior. The
same reactions carried out under conventional reflux conditions
using ethanol as a solvent gave lower yields (Table 2), required a
longer reaction time (8 h) and/or the products required rigorous
purification. However, MW reactions reported here provided clea-
ner and faster reaction times (usually less than 30 min) and the pure
products were obtained in good to excellent yields by simple wash-
ing with cold ethanol. Optimum conditions for these MW assisted
reactions were determined by carrying out a series of reactions of
3,30-(1,4-phenylenebis(methylene))bis(2-thioxothiazolidin-4-one)
(3a) with benzaldehyde (4a). The results, which are summarized in
Table 1, show that MW irradiation at 110 °C for 30 min in ethanol is
the optimum condition for the synthesis of these molecules. The
compounds were isolated as (Z) isomers which was confirmed by
comparing the vinylic proton shift in 1H NMR with those previously
reported15,16 (around d 8.00 ppm). The starting materials 3a and 3b
attempts to prepare 3,30-(1,4-phenylenebis(methylene))bis(2-thi-
oxothiazolidin-4-one) (3a) using alkyl aldehydes under similar con-
ditions were unsuccessful.
Compounds 5a–r were obtained in 89–95% yields with most of
them being high melting solids (mp >300 °C). They are insoluble
in usual organic solvents such as, dichloromethane, ethyl acetate,
DMF, or hexane. The IR (KBr) spectra of compounds 5k–r exhibit
absorption bands due to the stretching vibrations of NH group of in-
dole cycles (ꢀ3200 cm). The spectra of compounds 5a–r display
characteristic bands of C@S group (intense bands at 1628–
1610 cmꢁ1) and C@O stretching vibrations in the 1720 cmꢁ1 range.
The 3,30-(1,4- or 1,3-phenylenebis(methylene)-bis(2-thioxothiaz-
olidin-4-ones) (3a,b) were prepared by refluxing 2.5 equiv of
di- (carboxymethyl)-trithiocarbonyl (2) with 1,4- or 1,3-phenyl-
enedimethanamine in the presence of K2CO3.17 The aldehydes
(8a–c) were synthesized (Scheme 2) by treating the corresponding
acid chlorides with HSnBu3.18 The acid chlorides were prepared by
were synthesized by
a
literature procedure.17 Unfortunately,
S
S
HOOC
O
Water
S
N
H2N
R
O
n
S
CHO
S
Reflux, 8 hr
N
NH2
S
K2CO3
O
3a, 3b
HOOC
4a-f, 8a-c
S
2
1a, 1b
m or p isomer
R = Aryl group
n = 0, 1
O
R
H
MW
n
EtOH (2ml)
S
S
110ºC, 30 min
TMP
N
O
S
N
O
S
H
O
n
5a-r
R
Scheme 1. Schematic representation for the synthesis of compounds 5a–r.

4000
S. Kamila, E. R. Biehl / Tetrahedron Letters 53 (2012) 3998–4003
acylation of indole (or substituted indole) with oxalyl chloride.19 All
compounds were characterized by 1H NMR, 13C NMR, DEPT-135, IR
(FT), and HRMS spectral methods.
Table 1
Screening of solvents, reaction time, and temperature for synthesis of 5a
Base
Condition
Temp (°C)
Time (min)
Yield
In conclusion, we have successfully developed an easy practical
access to novel series of (5Z,50Z)-3,30-(1,4-phenylenebis(methy-
lene))bis(5-arylidene-2-thioxothiazolidin-4-one) derivatives. The
mild reaction conditions and easy work up procedure allowed
the products to be produced in good to excellent yields from read-
ily available starting materials, thus rendering this reaction as an
attractive method for the preparation of these biologically impor-
tant compounds. Efforts toward the microwave assisted synthesis
of other important drug molecule with a rhodanine moiety are
ongoing in our laboratory. Also potential biological activity (anti-
bacterial, antifungal, anticancer, and neuroprotective kinase inhib-
itory activities) of these important compounds are being
investigated, the results of which will be reported in due course.
—
—
No solvent
Ethanol
Ethanol
Ethanol
No solvent
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Water
THF
n-Butanol
DME
Sulfonale
Ethanol
Ethanol
Benzene/toluene
DMF
90
90
90–110
90
90
15
15
15–30
15
15
15
30
45
30
30
30
30
30
30
30
30
30
30
30
Trace
Trace
59–61
71
Trace
78
Piperidine
TMP
TMP
TMP
TMP
TMP
DBU
DBU/piperidine
TMP
TMP
TMP
TMP
TMP
NMP
Pyridine
TMP
110
110
110
110
110
110
110
110
110
110
110
110
110
110
89
88
Trace
Trace
Trace
Trace
54
33
Trace
25
Trace
Trace
73
Acknowledgment
TMP
The authors are grateful to NIH (IRC2NS064950) for generous
financial support.
Reaction conditions: Microwave irradiation using 3a:4a (1:2 mmol, respectively),
and 1 mmol of 3a, with catalytic amount (0.5 mL) of TMP in respective solvent
(2 ml). The reactions were carried out in a capped reaction tube designed especially
for microwave reactions, which were carried out under 250 psi pressure.
Table 2
Reaction of various aldehydes with bis(2-thioxothiazolidin-4-one) derivatives
S
O
O
n
R
S
R
n
S
S
N
CHO
H
O
S
N
4a-f, 8a-c
N
O
3a
S
O
S
N
Entry
Yielda
Yieldb
O
S
S
S
S
S
N
N
H
O
n
O
O
R
3b
5a-r
S
R =
S
N
S
S
n = 0
N
O
1
2
3
3a
3b
3a
89
86
89
44
41
39
O
H
H
5a
R =
S
N
S
S
S
n = 0
N
H
H
O
O
5b
CH3
S
H3C
S
N
S
S
R =
N
O
n = 0
CH3
H
O
H
5c
CH3
H3C
CH3
S
S
R =
S
S
n = 0
4
3b
87
45
N
N
H
H
O
O
5d

S. Kamila, E. R. Biehl / Tetrahedron Letters 53 (2012) 3998–4003
4001
Table 2 (continued)
S
O
O
R
S
n
R
n
S
N
CHO
S
H
O
S
N
4a-f, 8a-c
N
O
3a
S
O
S
N
Entry
Yielda
Yieldb
O
S
S
S
S
S
N
N
H
O
n
O
O
R
3b
5a-r
F
S
F
F
S
N
S
S
R =
N
5
6
3a
3b
81
79
69
60
O
S
n = 0
F
H
O
H
5e
F
F
S
R =
S
S
n = 0
N
N
H
H
O
O
5f
S
R =
S
S
N
n = 0
S
S
S
S
7
8
9
3a
3b
3a
N
94
93
82
78
74
49
O
H
O
H
S
5g
S
R =
S
S
S
S
S
n = 0
N
N
H
H
O
S
O
S
5h
R =
S
O
N
n = 0
S
N
O
O
O
N
H
O
H
5i
O
H
O
H
R =
S
S
S
S
O
n = 0
N
10
11
3b
3a
86
89
43
47
O
O
5j
S
S
R=
N
S
S
N
HN
HN
n =0
H
N
O
H
O
H
NH
NH
5k
R=
S
S
N
H
S
S
n =0
12
3b
85
47
N
N
H
H
S
O
O
5l
S
S
R=
N
O
S
N
H
n =1
N
HN
O
O
13
3a
H
93
81
O
H
NH
5m
(continued on next page)

4002
S. Kamila, E. R. Biehl / Tetrahedron Letters 53 (2012) 3998–4003
Table 2 (continued)
S
O
O
R
S
n
R
n
S
N
CHO
S
H
O
S
N
4a-f, 8a-c
N
O
3a
S
O
S
N
Entry
Yielda
Yieldb
O
S
S
S
S
S
N
N
H
O
n
O
O
R
3b
5a-r
O
O
R =
S
S
S
S
N
H
n = 1
HN
NH
14
3b
96
80
N
N
H
H
O
S
O
5n
5o
OCH3
S
S
N
N
O
S
R =
O
O
N
H
HN
n = 1
H
O
H
15
3a
89
55
NH
OCH3
H3CO
OCH3
OCH3
H3CO
O
H
O
R =
S
S
N
H
S
S
16
3b
91
58
n = 1
HN
NH
N
N
H
O
S
O
5p
O
S
S
OCH3
N
O
S
N
HN
O
O
R =
N
H
O
O
H
17
3a
81
67
n = 1
H
NH
H3CO
H3CO
5q
O
OCH3
H3CO
O
O
OCH3
O
O
R =
S
S
S
S
18
3b
80
70
N
n = 1
H
HN
NH
N
N
H
H
O
O
5r
a
Isolated yield. All the compounds were characterized by 1H NMR, 13C NMR, IR and HRMS analyses.
Conventional heating for 8 h at 110 °C.
b
H
Cl
O
O
O
O
R2
R2
COCl
R2
Dry ether
HSnBu3
Ethylacetate
0ºC to RT
N
N
H
N
H
COCl 0ºC to RT
H
6a-c
R2 = H, OCH3, COCH3
7a-c
8a-c
Scheme 2. Synthesis of compounds 8a–c.

S. Kamila, E. R. Biehl / Tetrahedron Letters 53 (2012) 3998–4003
4003
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Supplementary data
Supplementary data (experimental details and characterization
data NMR (1H and 13C), IR, MS, HRMS, DEPT) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.05.088.
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