Synthesis of novel 5-aryl/hetarylidenyl 3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-ones

Article abstract of DOI:10.3987/COM-13-S(S)36

The synthesis of a variety of novel 5-substituted titled compounds containing a priviledged rhodanine scaffold is described. The synthesis involves a microwave (MW) assisted Knoevenagel condensation of 3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one with suitably substituted aromatic aldehydes. However, these condensations fail with aliphatic aldehydes. The 2-thioxothiazolidin-4-one (rhodanine) precursor was prepared by the condensation of 2-thioxothiazolidin-4-one-di-(carboxymethyl)trithiocarbonyl and 4,5,6,7-tetrahydrobenzo[4,5]thienyl[2,3-d]-2-methylpyrimidin-4-amine in the presence of K₂CO₃.

Full text of DOI:10.3987/COM-13-S(S)36

See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/256095242
SYNTHESIS OF NOVEL 5-ARYL/HETARYLIDENYL
3-(2-METHYL- 5, 6,7,8-
TETRAHYDROBENZO[4,5]THIENO[2,3-
d]PYRIMIDIN-4-YL)- 2-THIOXOTHIAZOLIDIN-
4-ONES
ARTICLE in HETEROCYCLES · AUGUST 2013
Impact Factor: 0.91 · DOI: 10.3987/COM-13-S(S)36
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HETEROCYCLES, Vol. , No. , , pp. -. © The Japan Institute of Heterocyclic Chemistry
Received, , Accepted, , Published online,
DOI: 10.3987/COM- (Please do not delete.)
.
SYNTHESIS OF NOVEL 5-ARYL/HETARYLIDENYL 3-(2-METHYL-
5, 6,7,8-TETRAHYDROBENZO[4,5]THIENO[2,3-d]PYRIMIDIN-4-YL)-
2-THIOXOTHIAZOLIDIN-4-ONES
Kimberly Mendoza, Sukanta Kamila, and Edward R. Biehl* Chemistry
Department, Southern Methodist University, Dallas, TX 75275 U. S. A. Email:
ebiehl@smu.edu
.
Abstract - The synthesis of a variety of novel 5-substituted titled compounds containing a
priviledged rhodanine scaffold is described. The synthesis involves a microwave (MW)
assisted Knoevenagel condensation of 3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5)]thieno[2,3-d]-
pyrimidin-4-yl)-2-thioxothiazolidin-4-one with suitably substituted aromatic aldehydes.
However, these condensations fail with aliphatic aldehydes. The 2-thioxothiazolidin-4-one
(rhodanine) precursor was prepared by the condensation of 2-thioxothiazolidin-4-one-di-
(carboxymethyl)trithiocarbonyl and 4,5,6,7-tetrahydrobenzo[4,5]thienyl[2,3-d]-2-methylpyr-
imidin-4-amine in the presence of K2CO3.
Thienopyrimidines are biologically important heterocycles that have been attracting attention in medicinal
chemistry research over the last two decades due to their diverse range of biological activities. An
intensive literature review reveals that several thienopyrimidines possess a wide range of biological
activities such as antitumor, antimicrobial, anti inflammatory, and bronchodilatory activities1-3 as well as
inhibitors of enzymes like VEGFR-2 kinase,4 tyrosine kinase and phosphodiesterases; several of these
drugs have been patented.5 Currently, benzothiophenes in combination with other ring systems are being
used extensively in pharmaceutical applications such as antiallergic6 and analgesic agents.7 Raloxifene, a
polyhydroxyphenylbenzo[b]thiophene antiestrogen, has been approved by the U.S food and Drug
Administration for the prevention and treatment of postmenopausal osteoporosis.8 In addition,
benzo[b]thiophenes containing a nitrogen ring system (compound A in Figure 1) are potent metabotropic
glutamate receptors (mGluRs).9 Rhodanines10 that possess a substituted ring-nitrogen atom are paten-
ted as fungicides while those containing an unsubstituted ring nitrogen atom11 are patented as pesticides.
Additionally, 2-aryl-5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)-furans, (Compound B in
Figure 1) which possess a rhodanine core, exhibits anti-HIV-1 activity,12 and 5-benzylidine-

3-phenyl-2-thioxothiazolidin-4-one (Compound C in Figure 1) inhibits jun NH2-terminal kinase (jnk)
stimulatory phosphatase-1 (jsp-1).13
O
HO
O
OH
R2
S
N
S
S
R1
N
N
S
N
N
O
N
O
O
S
OMe
O
C
A
B
Figure 1. Structures of biologically active benzothiophenes containing a nitrogen ring system (A) and
heterocycles containing a rhodanine core (B and C)
In addition, rhodanine-based compounds are popular small molecule inhibitors of numerous targets such
as HCVNS3 protease,14a aldose reductase,14b,c β-lactamase,14d UDP-N-acetylmuramate/L-alanine ligase,14e
and histidine decarboxylase,14f and can also behave as antidiabetic agents14g and cathepsin D receptors.14h
For the past few years, our group has been carrying out microwave assisted reactions for the preparation
of potentially biologically important heterocycles.15a-j Several of these compound exhibit strong
neuroprotecting properties.16 We have now extended the scope of microwave assisted reactions to include
the incorporation of potentially biologically active rhodanine cores into a variety of heterocyclic side
chains and report the result herein.
As shown in Scheme 1, compounds (8a-o) were obtained by a four-step reaction sequence. The first step
O
H2N
CN
N
N
Me
O
H
Et3N
NH2
MeCN
S8
N
N
N
MW
o
S
EtOH
reflux
S
110 C
4
2
3
1
5
45 min
1,4-dioxane
COOH
S
K2CO3
R
S
S
S
S
COOH
6
N
N
N
N
O
O
RCHO
Me
Me
N
N
piperidine
S
S
EtOH
o
7
8a-o
R = aromatic group
MW/100 C
25 min
Scheme 1. Four-step preparation of titled compounds (8a-o).
involves the reaction of cyclohexanone (1) and malononitrile (2) in presence of sulphur (3)17 to give
2-amino-4,5,6,7-tetrahydro[1]benzo[b]thiolophene-3-carbonitrile (4) in 92% yield. 2-Methyl-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine (5) is next prepared by a microwave assisted

intramolecular cyclization of compound 4 with acetontrile in 1,4-dioxane.18 The pentultimate step
involves preparing 7 by treating 4,5,6,7-tetrahydro-3-(2-methylthieno[2,3-d]pyrimidin-4-yl) (5) and
diacid 6 in the presence of K2CO3.17,18 Lastly, the titled compounds 8a-o are obtained via the Knoe-
venagel condensation of 3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl) 2-thi- oxo
thiazolidin-4-one (7) with suitably substituted aromatic/heteroaromatic aldehydes using microwave
heating. In this step the condensation involves the addition of the 5-carbon of the 2-thioxo-
thiazolidin-4,5-enolate to the C=O of the aldehyde.
In order to maximize yields of compounds (8a-o), optimum reaction conditions were determined by
carrying out a series of reactions of compound 7 and benzaldehyde using various bases. The results,
which are summarized in Table 1, indicate that optimum conditions for these reactions involved MW
heating at 100 °C for 25 min in ethanol in the presence of a catalytic amount of piperidine.
Table 1. Determination of optimum conditions for synthesis of compound 8a
Base
Condition
Temp (oC)
Time (min)
Yield (%)
----
----
no solvent
90
15
trace
EtOH
90
15
trace
59-65
60-65
trace
trace
89
triethylamine
TMP
EtOH
90-110
90-110
90-110
90-110
100
15-30
15-30
15-30
25
EtOH
TMP
no solvent
no solvent
EtOH
piperidine
piperidine
piperidine
DBU
25
EtOH
110
25-30
25
85-89
35
EtOH
100
NMP
EtOH
100
25
15
piperidine
piperidine
piperidine
piperidine
piperidine
DBU
water
100
25
trace
41
THF
100
25
1,4-dioxane
100
25
45
benzene/toluene 100
25
10
DMF
EtOH
100
100
25
61
25
81
piperidine
pyridine
NMP
EtOH
100
100
25
25
55
THF/water
Trace
The results of synthesis of compounds 8a-o using MW irradiation and conventional heating are shown in
Scheme 2. As shown, the microwave assisted reactions affords compounds 8a-o in excellent yields
(89-94%). The crude products were readily purified by washing with ethyl acetate and hexane (20:80 v/v).
The same reaction using conventional refluxing in ethanol solvent gave compounds 8a-o in lower yields
(56-71%), required a longer reaction time (5h), and the crude products required rigorous purification.

OMe
Cl
Cl
MeO
MeO
O2N
S
S
S
S
S
S
S
S
N
N
N
N
N
O
N
N
O
O
N
O
Me
Me
Me
Me
N
N
N
N
S
S
S
S
8a (89a/55b) [8.58ppm]c 8b (90a/70b) [8.83ppm]c 8c(89a/54b) [8.92ppm]c
8d (96a/66b)[8.67ppm]c
N
NH
O
NH
O
S
NH
Me
S
S
S
S
S
S
N
S
S
N
N
N
N
N
O
Me
Me
Me
N
N
O
N
N
N
Me
S
S
S
N
S
8e (88a/41b) [8.29ppm]c
8f (91a/43b) [8.06ppm]c
8g (93a/68b) [8.83ppm]c 8h (88a/61b) [8.61ppm]
OH
Me
N
Me
O
N
S
S
S
S
S
N
S
N
N
O
S
S
N
Me
N
O
NH
N
Me
O
N
N
Me
N
N
O
S
N
Me
S
S
N
S
8i (96a/66b) [8.67ppm]c
8j (85a/42b) [8.20ppm]c
8k (86a/39b) [8.36]c
8l (84a/37b)[7.15]c
S
S
S
S
Me
N
S
S
N
N
S
NH
N
N
O
O
N
N
NH
O
Me
Me
N
Me
N
N
N
S
S
S
8m (92a/71b) [7.26]c
8n (88a/52b)[7.73]c
8o (95a/55b[[7.55]c
a. Isolated yield from microwave heating b. Isolated yield from conventional heating for 5h at 100 °C. c. δ of C=CH
Scheme 2. Structures, % yields, δ of C=CH compounds 8a-o using microwave and conventional heating.
Attempts to carryout Knoevenagel condensations with alkyl aldehydes under similar conditions were
unsuccessful.
The structures of purified compounds 8a-o were established by LC/MS, GC/MS and NMR analysis. As

shown in Scheme 2, compounds 8a-k were assigned Z configurations and 8l-o were assigned E
1
configurations. The configuration about their C-C double bond was assigned on the basis of H-NMR
analysis of the vinyl hydrogen chemical shifts. As shown in Scheme 2, the chemical shift of vinyl hydrogen
of 8a-k appears in the range of δ 8.06-8.92 ppm whereas that of 8l-m is seen in the range of δ 7.15-7.73 ppm.
The downfield shift of the former vinyl hydrogens can be explained by the anisotropic effect of the carbonyl
group located at carbon atom C-4 of the rhodanine core which is only possible for Z but not for
E-configured pyrimidin-4-ylthioxothiazolidin-4-ones. Similar results have been observed and so
rationalized for certain indolones,16 thiaindirubin-N-glycosides,19 and selenoindirubins and
selenoindirubin-N-glycosides.20 With the exception of the furan derivative 8k, the preference of the Z over
the E configurational structure is most likely a steric effect i.e. less steric hindrance in the Z isomer than
in the E isomer. The E isomers are however structured in such as way to allow intramolecular
stabilization via resonance interaction of the heteroatom of the five-membered ring and the oxygen atom
of the 4-keto group of the rhodanine core. Thus, in the case of the thiophene derivative 8o, shown in
Figure 2, stabilization of the E configuration most likely involves resonance delocalization of the lone
pair sulfur electrons (probably d electrons) onto the 4-keto group of the rhodanine core in which the
resulting resonance hybrid possesses a favorable electron donor/electron acceptor attraction.
Figure 2. Stabilization of E-configuration of 8o by resonance induced electron donor/ electron acceptor
attraction.
The pyrrole 8m and imidazole dervatives 8l most likely adopt E configuration due to intramolecular
hydrogen bonding between the NH group of the nitrogen heterocycles and oxygen atom of the O=C group
on C-4 of the rhodanine ring. Such NH.....O=C interactions have been recently found to be crucial in
inducing a high degree of stereochemical control in aza-Morita-Baylis-Hillman reactions.21 However,
the vinyl-H chemical shift of the furan derivative 8c occurs at 8.36 ppm indicting it most likely exist in
the Z-configuration. Since oxygen is more electronegative than sulfur, its ability to be an electron
acceptor in stabilizing the E configuration is decreased to such an extent that the molecule adopts the Z
configuration where the two potential interacting oxygen atoms are removed from each.

Additional support for the necessary of intramolecular stabilization of E isomer comes by noting that
indol-3-yl 8e, 5-methyl-1-H-imidazol-3-yl, 8f benzothiophene-3-ylmethylene 8g derivatives shown in
Figure 3 cannot be stabilized by electron- donor/electron acceptor interactions due to geometrical
constraints. Furthermore, 8a-d and 8h-j lack functionality needed to interact with the O=C group attached
to C-4 of the rhodanine ring to form E configured compounds.
Figure 3. Lack of intramolecular stabilization of E isomers ( 8e, 8f, and 8g) due to geometrical
constraints
We currently are attempting confirm E and Z isomers assigned structures for selective compounds by
X-ray structural analysis. In addition, computational chemical studies on the energetics of E and Z
conformers of titled compounds are being carried out. The results of these studies will be reported in due
course.
In conclusion, we have successfully developed an easy practical access to novel thieno[2,3-d]pyrimidine
derivatives. The mild reaction conditions and easy work up procedure allow the products to be produced
in good to excellent yields from readily available starting materials, thus rendering this reaction as an
attractive method for the preparation of these biologically important compounds. Efforts towards the
microwave-assisted synthesis of other rhodanine moiety are ongoing in our laboratory. Also potential
biological activity (anti-bacterial, antifungal, anticancer, and neuroprotective kinase inhibitory activities)
of these important compounds are being investigated, the results of which will be reported in due course.
EXPERIMENTAL
1
General information. The H and 13CNMR spectra were recorded on a 500-MHz Jeol multinuclear
NMR spectrometer and chemical shifts were referenced to tetramethylsilane (TMS) as internal standard.
Melting points were taken on a Meltemp apparatus. MW reactions were carried out in CEM DiscoverTM
microwave oven which comprises a mono mode (single mode) microwave cavity that operates at a
frequency of 2.45 GHz with continuous irradiation power from 0-300 W. The reaction temperature in the
microwave cavity was measured by an IR captor (infrared thermometry) and a software algorithm
regulates the microwave output power so that the preselected maximum temperature can be maintained

during the reaction. High-resolution mass spectra (HRMS) were obtained from Washington University; St.
Louis, MO. Column chromatography was carried out on Combi-Flash instrument using pre-packed silica
gel columns. Mass analysis of products were carried out by Ommscientific Inc, Dallas, Texas.
Materials. All chemicals and reagents were purchased from commercial sources and used as received.
2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (4),18 4,5,6,7-tetrahydrobenzo[b]thieno- [2,3
-d]-2-methylpyrimidin-4-amine (5)18 and 3-(2-methyl-5,6,7,8-hydrobenzo[4,5]-thieno[2,3-d] pyrimidin
-4-yl)-2-thioxothiazolidin-4-one (7)17 were prepared by literature procedures.
General microwave-assisted synthesis of 5-aryl/hetarylidenyl-3-(2-methyl-5,6,7,8- tetrahydrobenzo-
[4,5]thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-ones (8a-o):
3-(2-Methyl-5,6,7,8-hydrobenzo[4,5]- thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one 7 (0.2 g,
(0.60 mmol, 1 equiv) and aromatic aldehyde (0.77 mmol, 1.3 equiv). were thoroughly mixed then placed
into a specially designed microwave test tube containing 5 mL EtOH and three drops of piperidine. The
°
charged tube was heated for 25 min at 100 C and 250 psi pressure. After cooling, the solid mass was
placed in 50 mL cold EtOH and crushed. The slurry was filtered to give a solid that was washed several
times with EtOH/hexane mix (20%, v/v), then dried under vacuum to give the corresponding 5-aryl/
hetaryl-2-thiocothiazolidine-4- one (8a-o) whose structures were identified by IR, LC/MS, GC/MS and
NMR analysis. The physical and spectral properties of these compounds are shown later in the experi-
mental section.
General synthesis of compound (8o-m) using conventional heating. Compound 7 (0.2g, 0.60 mmol)
and aromatic aldehyde (0.77 mmol, 1.3 equiv) were thoroughly mixed and place in 25 mL flask
containing 10 mL EtOH and three drops of piperidine, then the charged tube was refluxed for 8 h. After
cooling, the solid mass was filtered and the filtrate was discarded. After several washing with
EtOH/hexane mix (20%, v/v), the crude product 8 was dried under vacuum was then purified by column
chromatography carried out on a Combi-Flash instrument using a pre-packed silica gel column and
MeOHl/DCM, 10% (v/v) as elutant.
Physical and spectral data for compounds (8a-8o):
(5Z)-5-Benzylidene-3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-2-thioxo-
°
thiazolidin-4-one (8a): Isolated as a light orange solid, mp 122.0-122.8 C; IR (KBr): 1716, 1615 cm-1.
1H NMR (DMSO-d6): δ 8.58 (s, 1H, vinyl-H), 7.92 (d, J= 7.6 Hz, 2H, Ar-CH), 7.55-7.49 (m, 3H, Ar-CH),
2.64-2.52 (m, 2H, CH2), 2.46 (s, 3H, CH3), 1.75-1.73 (m, 2H, CH2). 13C NMR (DMSO-d6): δ 195.6 (C=S),
166.1 (C=O), 161.0 (C), 155.1 (C), 142.5 (C), 143.3 (CH), 137.3 (C), 135.2 (C), 133.3 (CH), 129.7 (CH),
129.5 (CH), 127.1 (C), 122.1 (C), 114.6 (C), 25.1 (CH2), 24.2 (CH3), 23.0 (CH2), 21.9 (CH2), 21.3
(CH2).95: HRMS: m/z calculated for C21H17N3OS3: 423.0534. Found: 424.0544 (M++1).
(5Z)-5-[(2,3-Dichlorophenyl)methylene])-3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyri-

°
midin-4-yl)-2-thioxothiazolidin-4-one (8b): Isolated as a golden yellow solid, mp 209.7-211.0 C; IR
1
(KBr): 1700, 1611 cm-1. H NMR (CDCl3): δ 8.83 (s, 1H, vinyl-H), 8.26 (d, J = 7.5 Hz, 1H, Ar-CH),
7.55 (d, J = 7.5 Hz, 1H, Ar-CH), 7.30 (dd, J = 7.5, 7.8 Hz, 1H, Ar-CH), 2.71-2.66 (m, 4H, CH2), 2.43 (s,
3H, CH3), 1.87-1.85 (m, 4H, CH2). 13C NMR (CDCl3): δ 195.6 (C=S), 166.3 (C=O), 165.3 (C), 154.6 (C),
145.2 (C), 143.2 (CH), 142.5 (C), 137.2 (C), 135.6 (C), 133.4 (CH), 127.7 (C), 127.5 (CH), 125.3 (CH),
113.2 (C), 118.8 (C), 25.4 (CH2), 24.3 (CH2), 24.0 (CH3), 23.0 (CH2), 22.1 (CH2), 22.0 (CH2). HRMS:
m/z calculated for C21H15Cl2N3OS3: 490.9754. Found: 491.9764 [M++1].
5Z)-3-(2-Methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-2-thioxo-5-[(2-nitrophen-
yl)methylene]-2-(thioxotiazolidin-4-one (8c): Isolated as a dark brown fine powder, mp 165.1- 167.0 °C.
IR (KBr): 1717, 1620 cm-1. 1H NMR (CDCl3): δ 8.92 (C, 1H, vinyl-H), 8.45 (d, J = 7.8 Hz, 1H, Ar-CH),
8.04 (d, J = 7.8 Hz, 1H, Ar-CH), 7.63 (dd, J = 7.8, 3.1 Hz, 1H, Ar-CH), 7.62 (dd, J = 7.8, 3.0 Hz, 1H,
Ar-CH), 2.72-2.66 (m, 4H, Ar-CH2), 2.49 (s, 3H CH3), 1.86-1.84 (m, 4H, CH2). 13C NMR (CDCl3):
δ 195.6 (C=S), 166.2 (C=O), 160.2 (C), 158.4 (C), 149.3 (C), 143.2 (CH), 137.1 (C), 135.7 (CH), 130.0
(CH), 129.7 (CH), 127.2 (C), 124.9 (C), 123.1 (CH), 116.2 (C), 114.2 (C). HRMS: m/z calculated for
C21H16N4O3S3: 468.0385. Found: 469.0397 [M++1].
(5Z)-3-(2-Methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-2-thioxo-5-[(2,3,4-tri-
methoxyphenyl)methylene)-2-thiazothiazolidin-4-one (8d): Isolated as a bright yellow solid powder,
°
1
mp 159.5- 160.1 C. IR (KBr): 1719,1620 cm-1. H NMR (CDCl3): δ 8.67 (s, 1H, vinyl-H), 7.98 (d, J =
8.0 Hz, 1H, Ar-CH), 6.74 (d, J = 8.0 Hz, 1H, Ar-CH), 3.97 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.87 (s,
3H, OCH3), 2.67-2.64 (m, 4H, CH2), 2.43 (s, 3H, CH3), 1.86-1.84 (m, 4H, CH2). 13C NMR (CDCl3):
δ 197.9 (C=S), 168.3 (C=O), 165.9 (C), 157.6 (C), 155.0 (C), 154.8 (C), 145.2 (C), 143.1 (CH), 141.7 (C),
137.9 (C), 131.6 (C), 123.9 (CH), 121.8 (C), 108.5 (CH), 62.2 (OCH3), 61.0 (OCH3), 56.2 (OCH3), 25.2
(CH2), 24.4 (CH2), 24.1 (CH3), 23.2 (CH2), 21.1 (CH2), 22.0 (CH2). HRMS: m/z calculated for
C24H23N3O4S3, 513.0851. Found: 514.0868 [M++1].
(5Z)-3-(2-Methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidn-4yl)-5-(1H-pyrrolo[2,3[b]pyri-
dine-3-ylmethylene)-2-thioxothiazolidin-4-one (8e): Isolated as a mustard yellow fine shiny powder,
°
1
mp 288.3-289.7 C. IR (KBr) 3200, 1716, 1615 cm-1. 1H NMR (DMSO-d6): δ 12.64 (brs, H, NH), 8.61
1
(dd, J = 7.5 Hz, 2.5 Hz, H, Ar-CH), 8.33 (dd, J = 7.5, 2.5 Hz, 1H, Ar-CH), 8.29 (s, 1H, vinyl-H),
7.9-7.27 (m, 2H, Ar-CH), 2.62-2.51 (m, 4H, CH2), 2.41 (s, 3H, CH3), 1.75-1.75 (m, 4H, CH2). 13C NMR
(DMSO-d6): δ 198.2 (C=S), 165.9 (C=O), 163.2 (C), 155.8 (C), 145.3 (C), 148.3 (C), 143.3 (CH), 142.1
(CH), 137.2 (C), 128.3 (CH), 127.3 (C), 124.3 (C), 122.1 (C), 118.5 (CH), 118.1 (C), 25.1 (CH2), 24.1
(CH3), 23.0 (CH2), 22.0 (CH2), 21.3 (CH2). HRMS: m/z calculated for C22H17N5OS3: 463.0595. Found:
464.0598 [M++1].

(5Z)-5-[(1H-Indol-3-yl)methylene]-3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3,-d]pyrimidin-
4-yl)-2-thioxothiazolidin-4-one (8f): Isolated as a dark brown solid with tints of purple, mp
204.9-205.4 °C; IR (KBr): 3213, 1718, 1615 cm-1. 1H NMR (DMSO-d6): δ 12.07 (brs, 1H, NH), 8.65 (s,
1H, Ar-CH), 8.36 (dd, J = 7.8, 2.9 Hz, 1H, Ar-CH), 8.15 (s, 1H, vinyl-H), 7.47 (dd, J = 7.8, 3.0 Hz, 1H,
Ar-CH), 7.24-7.21 (m, 2H, Ar-CH), 3.10 (s, 3H, CH3), 2.59-2.46 (m, 4H, CH2), 1.73-1.72 (m, 4H, CH2).
13C NMR (DMSO-d6): δ 198.3 (C=S), 166.9 (C=O), 166.3 (C), 163.5 (C), 145.8 (C), 143.2 (CH), 138.0
(C), 137.1 (C), 129.8 (CH), 127.5 (C), 127.1 (C), 124.0 (CH), 122.6 (C), 122.3 (CH), 115.5 (C), 114.8
(CH), 112.9 (CH), 103.1 (C), 25.0 (CH2), 24.3 (CH3), 23.1 (CH2), 22.1 (CH2), 21.1 (CH2). Anal. HRMS:
m/z calculated for C23H18N4OS3: 462.0643. Found 463.0652 [M++1].
(5Z)-5-[(Benzothiophen-3-yl)methylene]-3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyr-
imidin-4-yl)-2-thioxothiazolidin-4-one (8g): Isolated as a bright yellow powder, mp 137.1-138.0 °C. IR
1
(KBr): 1700, 1616 cm-1. H NMR (DMSO-d6): 8.90 (d, J = 7.5 Hz, 1H, Ar-CH), 8.79 (s, 1H, Ar-CH),
8.65 (s, 1H, vinyl-H), 8.06 (d, J = 7.5 Hz, 1H, Ar-CH), 7.51-7.46 (m, 2H, Ar-CH), 2.63-2.52 (m, 4H,
CH2), 2.43 (s, 3H, CH3), 1.76-1.73 (m, 4H, CH2). 13C NMR (DMSO-d6): 196.8 (C=S), 166.5 (C=O),
165.2 (C), 155.7 (C), 145.2 (C), 143.2 (CH), 141.7 (C), 140.8 (C), 135.8 (C), 134.7 (C), 126.4 (C), 125.5
(C), 124.2 (CH), 123.7 (CH), 122.8 (CH), 114.9 (CH), 25.1 (CH2), 24.2 (CH3), 23.0 (CH2), 22.01 (CH2),
22.0 (CH2). Anal. HRMS: m/z calculated for C23H17N3OS4: 479.0254. Found 480.0259 [M++1
(5Z)-5-[(5-Methy-1H-Indol-3-ylmethylene)-3-(2-methy-5,6,7,8-tetrahydro[4,5]thieno[2,3-d]-pyrimid
in-4-yl)-2-thioxothiazolidin-4-one (8h): Isolated as a dark yellow flakey solid, mp 207.6- 209.3 °C. IR
(KBr): 3312, 1701, 1618 cm-1. 1H NMR (DMSO-d6): δ 11.93 (brs,1H, NH), 8.61 (s, 1H, vinyl-H), 8.02 (d,
J = 7.8 Hz, 2H, Ar-CH), 7.81 (s, 1H, Ar-CH), 7.36 (d, J = 3.5 Hz, 1H, Ar-CH), 6.84 (d, J = 7.8 Hz, 1H,
Ar-CH), 3.79 (s, 3H, CH3), 2.55-2.47 (m, 4H, CH2), 2.49 (s, 3H, CH3), 1.71-1.70 (m, 4H, CH2). 13C NMR
(DMSO-d6): δ 195.5 (C=S), 168.0 (C=O), 163.2 (C), 155.9 (C), 145.2 (C), 143.2 (CH), 136.6 (C), 132.6
(C), 129.7 (CH), 127.2 (C), 126.0 (C), 122.0 (C), 115.5 (CH), 114.7 (CH), 113.5 (CH), 25.0 (CH2), 24.3
(CH2), 24.1 (CH3), 22.1 (CH2), 22.0 (CH2), 19.08 (CH3). HRMS: m/z calculated for
C24H20N4OS3: 476.0799. Found: 477.0787) [M++1].
(5Z)-5-[(1-Methyl-1H-indol-3-yl)methylene)-3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno-2,3-d]
pyrimidin-4yl-2-thioxothiazolidin-4-one (8i): Isolated as a orange brown solid powder, mp 171.4-
172.8 °C. IR (KBr): 1719, 1619 cm-1. 1H NMR (CDCl3): δ 8.55 (dd, J = 7.8, 3.1 Hz, 1H, Ar-CH), 8.50 (s,
1H, vinyl- H), 7.49 (s, 1H, Ar-CH), 7.35-7.31 (m, 3H, Ar-CH), 3.81 (s, 3H, CH3), 2.66-2.63 (m, 4H, CH2),
2.43 (s, 3H, CH3), 1.85-1.84 (m, 4H CH2). 13C NMR (CDCl3): δ 195.9 (C=S), 168.3 (C=O), 166.3 (C),
153.2 (C), 145.2 (C), 144.1 (CH), 138.2 (C), 136.5 (C), 134.3 (C), 129.6 (CH), 127.2 (C), 123.9 (CH),
123.2 (CH), 122.7 (C), 115.4 (CH), 114.1 (C), 109.7 (CH), 33.6 (CH3), 25.2 (CH2), 24.4 (CH3), 23.3
(CH2), 22.2 (CH2), 21.9 (CH2). HRMS: m/z calculated for C24H20N4OS3: 476.0799. Found: 477.0823

[M++1].
5Z)-5–[4-[(2-Hydroxyethyl)(methyl)amino]pheny]methylene)-3-(2-methyl--5,6,7,8-tetrahydrobenzo
[4,5][2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one (8j): Isolated as a orange solid, mp 145.1-
146.3 °C. IR (KBr): 3400, 1717, 1618 cm-1. 1H NMR (CDCl3): 8.20 (s, 1H, vinyl-H), 7.72 (d, J = 7.8 Hz,
2H, Ar-CH), 6.69 (d, J = 7.8 Hz, 2H, Ar-CH), 3.82-3.81 (m, 2H, CH2), 3.57-3.56 (m, 2H, CH2), 3.07 (s,
3H, CH3), 2.64-2.60 (m, 4H, CH2), 2.44 (s, 3H, CH3), 1.82-1.81 (m, 4H, CH2). 13C NMR (CDCl3):
196.8 (C=S), 166.8 (C=O), 166.2 (C), 159.0 (C), 152.6 (C), 144.1 (CH), 134.5 (C), 131.6 (CH), 130.2
(CH), 127.2 (C), 123.1 (C), 116.1 (C), 115.3 (C), 113.2 (C), 111.7 (CH), 60.1 (CH2), 54.5 (CH2) 39.2
(CH3), 25.2 (CH2), 24.4 (CH3), 23.2 (CH2), 22.1 (CH2), 22.0 (CH2). HRMS: m/z calculated for
C24H24N4O2S3, 496.1061. Found: 497.1069 [M++1]k
(5Z)-[(5-Furan-2-yl)]methylene)-3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-
°
4-yl)-2-thioxothiazolidin-4-one (8k): Isolated as a yellow fine solid powder, mp 153.3-154.9 C; IR
(KBr): 1716, 1616 cm-1. 1H NMR (DMSO-d6): δ 8.36 (s, 1H, vinyl-H), 8.02 (d, J = 3.5 Hz, 1H, Ar-CH),
7.29 (d, J = 3.5 Hz, 1H, Ar-CH), 6.74 (d, J = 3.5 Hz, 1H Ar-CH), 2.64-2.63 (m, 4H, CH2), 2.47 (s, 3H,
CH3), 1.75-1.76 (m, 4H, CH2). 13C NMR (DMSO-d6): δ 193.5 (C=S), 166.9 (C=O), 166.3 (C), 156.1 (C),
151.1 (C), 148.9 (C), 148.1 (CH), 146.1 (CH), 135.0 (C), 132.9 (C), 122.5 (C), 121.6 (CH), 113.9 (CH),
25.1 (CH2), 24.2 (CH3), 23.0 (CH2), 22.0 (CH2), 21.9 (CH2). HRMS: m/z calculated for C19H15N3O2S3:
413.0326. Found: 414.0326) [M++1].
(5-E)-3-(2-Methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-5-(1H-pyrrol-2-yl)met-
0
hylene)-2-thioxothiazolidin-4-one (8l): Isolated as a dark brown solid, mp 192.1-193.0 C; IR (KBr):
3215, 1718, 1620 cm.-1 1H NMR (DMSO-d6): δ 11.18 (brs, 1H, NH), 8.23 (s, 1H, Ar-CH), 7.15 (s, 1H,
vinyl-H), 6.87 (s, 1H, Ar-CH), 6.25 (d, J = 3.5 Hz, 1H, Ar-CH), 2.59 (brs, 4H, CH2), 2.48 (s, 3H, CH3),
1.73-1.72 (m, 4H, CH2). 13C NMR (DMSO-d6): δ 195.6 (C=S), 166.3 (C=O), 162.5 (C), 150.8 (C), 145.3
(C), 137.3 (C), 134.5 (CH), 129.8 (C), 127.5 (C), 122.8 (C), 120.2 (CH), 111.6 (CH), 102.7 (CH), 24.9
(CH2), 24.3 (CH2), 24.1 (CH3), 23.1 (CH2), 22.1 (CH2). HRMS: m/z calculated for C19H16N4OS3:
412.0486. Found: 413.0582 [M++1].
(5E)-5-(1H-Imidazol-2-yl)methylene)-3-(2-methy,5,6,7,8-tetrahydro[4,5]lthieno[2,3-d]pyrimidin-4-
yl)-2thioxothiazolidin-4-one (8m): Isolated as a bright yellow colored solid powder, mp 248.4-249.0 °C;
1
IR (KBr): 3216, 1721, 1638 cm-1. H NMR (DMSO-d6): δ 12.44 (brs, 1H, NH), 8.30 (s, 1H, Ar-CH),
7.42 (s, 1H, Ar-CH), 7.26 (s, 1H, vinyl-H), 2.63-2.62 (brs, 4H, CH2), 2.52 (s, 3H, CH3), 1.74-1.73 (m, 4H,
13
CH2). C NMR (DMSO-d6): δ 192.8 (C=S), 166.3 (C=O), 166.2 (C), 160.0 (C), 150.3 (C), 143.9 (CH),
135.4 (C), 135.1 (CH), 135.0 (CH), 127.8 (C), 122.0 (C), 25.0 (CH2), 24.3 (CH3), 23.0 (CH2), 22.1 (CH2),
21.9 (CH2). HRMS: m/z calculated for C18H15N5OS3: 413.0439. Found: 427.0428) [M++1].
(5E)-5-[(4-Methyl-1H-imidazol-5-yl)methylene)-3-(2-methyl,5,6,7,8-tetrahydro[4,5]thieno[2,3-d]pyri

°
-midin-4-yl)-2-thioxothiazolidin-4-one (8n): Isolated as a dark yellow solid, mp 268.1-269.9 C. IR
(KBr): 3318, 1715, 1617 cm-1. 1H NMR (DMSO-d6): δ 12.98 (brs, 1H, NH), 8.37 (s,1H, Ar-CH), 7.73 (s,
1H, vinyl-H), 2.61-2.50 (m, 4H, CH2), 2.47 (s, 3H, CH3), 2.44 (s, 3H, CH3), 1.74-1.64 (m, 4H, CH2). 13C
NMR (DMSO-d6): δ 198.3 (C=S), 166.9 (C=O), 166.3 (C), 156.3 (C), 145.3 (C), 144.3 (C), 137.3 (C),
136.1 (CH), 131.0 (CH), 127.2 (C), 122.1 (C), 115.3 (C), 113.3 (C), 25.0 (CH2), 24.3 (CH3), 23.1 (CH2),
22.0 (CH2), 21.0 (CH2), 16.3 (CH3). HRMS: m/z: calculated for C19H17N5OS3: 427.0595. Found:
428.0605.
(5E)-3-(2-Methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-5-(2-thienylmethylene)-2
°
-thioxothiazolidin-4-one (8o): Isolated as a yellow powder, mp 121.9-123.0 C; IR (KBr) 1700, 1592
cm-1. 1H NMR (DMSO-d6): δ 8.59 (s, 1H, Ar-CH), 8.30 (d, J = 5.5 Hz, 1H, Ar-CH), 7.67 (dd, J = 2.5, 5.5
1
Hz, H, Ar-CH), 7.55 (s, 1H, vinyl-H), 2.64-2.52 (m, 2H, CH2), 2.53-2.47 (m, 2H, CH2), 2.41 (s, 3H,
CH3), 1.75-1.74 (m, 2H, CH2). 13C NMR (DMSO-d6): δ 196.1 (C=S), 166.2 (C=O), 161.0 (C), 156.1 (C),
143.9 (C), 143.0 (CH), 139.7 (C), 135.2 (C), 130.1 (CH), 128.9 (CH), 128.3 (CH), 122.1 (C), 25.0 (CH2),
24.2 (CH3), 23.0 (CH2), 22.0 (CH2), 21.5 (CH2). HRMS: m/z calculated for C19H15N3OS4: 429.0098.
Found: 430.0102. [M++1].
ACKNOWLEDGEMENTS
The authors are grateful for generous financial support provided by NIH Grant (IRC2NS064950) and the
Hamilton Family SMU Undergraduate Research Scholarship Fund.
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