Synthesis of novel N-substituted 2-(hetero)arylimino-1,3-thiazolidin-4-ones

Article abstract of DOI:10.1055/s-0030-1257867

The preparation of new N-substituted 2-arylimino-1,3-thiazolidin-4-ones from 5-substituted-3-aminothiophenes using an easy three-step procedure is described.

Full text of DOI:10.1055/s-0030-1257867

PAPER
3319
Synthesis of Novel N-Substituted 2-(Hetero)arylimino-1,3-thiazolidin-4-ones
Synthesis of
N
-Sub
e
stituted 1, 3
r
-Thiaz
o
m
lidin-4-ones ain Revelant, Stéphanie Hesse,* Gilbert Kirsch
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol, FR CNRS 2843, 1 Boulevard Arago,
57070 Metz, France
Fax +33(3)87325801; E-mail: hesse@univ-metz.fr
Received 2 June 2010; revised 15 June 2010
described:4 3-aminothiophenes were transformed into the
Abstract: The preparation of new N-substituted 2-arylimino-1,3-
corresponding chloroacetamide derivatives and reacted
thiazolidin-4-ones from 5-substituted-3-aminothiophenes using an
with ammonium thiocyanate (Scheme 1).9
easy three-step procedure is described.
Key words: 5-substituted 3-aminothiophenes, isothiocyanates,
thioureas, N-substituted 1,3-thiazolidin-4-ones
R1
S
R1
R2
O
R2
NH2
Thiazolidinone moiety belongs to an important family of
heterocyclic scaffold,1 as evidenced by the common struc-
tural motif with the glitazone class of PPAR-g agonists
(e.g., rosiglitazone). 2-Imino-4-thiazolidinones have also
been investigated for their pharmacological properties.
For example, darbufelone shows anti-inflammatory activ-
ity (Figure 1).2 2-Heteroarylimino-1,3-thiazolidin-4-ones,
especially thiazolylimino and benzothiazolylimino deriv-
atives, were described as antifungal or antibacterial com-
pounds.3,4
ClCH2COCl
R1
R2
S
R1
NH4SCN
S
H
O
N
R2
N
Cl
HN
O
S
Scheme 1
In our ongoing project to study 2-aryliminothiazolidino-
nes as PPAR-g agonists, we were also interested in intro-
ducing more diversity on this core (especially region A,
Figure 2). However, the precedent pathway does not en-
able a substitution on the nitrogen atom. We, therefore,
describe here the preparation of N-substituted 2-thie-
nylimino-1,3-thiazolidin-4-ones starting from 3-ami-
nothiophenes via thienylthioureas (Scheme 2).
S
Me
O
N
N
N
O
O
H
rosiglitazone
t-Bu
HO
S
NH
N
H
O
t-Bu
A
darbufelone
R2
N
N
Figure 1 Rosiglitazone and darbufelone
O
R1
S
S
A common pathway for the synthesis of iminothiazolidi-
nones relies on the cyclization of thiourea derivatives with
a-halo esters or acids in polar solvents in the presence of
an inorganic base.5 Alternatively, these compounds can be
synthesized starting from thioureas with a gem-dicyano
epoxide6 or from thioureas with an aldehyde in the pres-
ence of chloroform.7
B
Figure 2 Regions A and B of 2-aryliminothiazolidinones
Several aminothiophenes and two aminoben-
zo[b]thiophenes were first treated with thiophosgene in
the presence of sodium bicarbonate to give the corre-
sponding isothiocyanates10 in good yields (58–80%).
These highly reactive compounds were next stirred with a
primary amine (p-anisidine in our case) in anhydrous
dichloromethane to yield the thioureas (35–78%). The cy-
clization to thiazolidinones was performed by refluxing
the thiourea and ethyl chloroacetate in the presence of dry
sodium acetate in anhydrous N,N-dimethylformamide11
(Scheme 2).
Since many years, our lab has developed methodologies
in heterocyclic chemistry; especially, we have worked on
the synthesis and functionalization of polysubstituted
thiophenes.8 Recently, the preparation of 2-thienylimino-
1,3-thiazolidin-4-ones using Vicini’s procedure has been
SYNTHESIS 2010, No. 19, pp 3319–3324
x
x.
x
x
.
2
0
1
0
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1257867; Art ID: Z14110SS
© Georg Thieme Verlag Stuttgart · New York

3320
G. Revelant et al.
PAPER
R2
R1
NH2
R2
R1
NCS
(Table 1). In spite of their structural proximity, these com-
pounds could be separated by chromatography on silica
gel using a convenient eluting system. We have noticed
that regioisomers 4a–e were always solid compounds
whereas regioisomers 4¢a–e (which were the first one to
be eluted) were always oils. However, the two regioiso-
mers obtained from the benzothienyl thioureas 3f and 3g
were structurally too near to be separated (same spot on
TLC) and are not described here.
i
S
S
2a–g
1a–g
ii
R2
H
H
N
N
R1
S
OMe
We then performed NMR studies to define the structure of
each product. Most of the time, when alkyl aryl ureas were
cyclized, identification of the two regioisomers was based
on HMBC correlation5e or on important changes in chem-
ical shifts.13 In our case, one phenyl and one thienyl group
are present on the thiazolidinone ring so that it is difficult
to distinguish the protons or carbons of the thiazolidinone
ring from those of the substituents. Indeed, 1H NMR spec-
tra of the two isomers 4 and 4¢ were almost the same with
only some very small differences on few chemical shifts.
The 13C NMR spectra showed more significant differenc-
es with a modification of the global distribution of the sig-
nals. We also tried to use the spectra from compounds
synthesized in our previous work9 (i.e., 2-thienylimino-
1,3-thiazolidin-4-ones without substituent on nitrogen) to
assign the correct structure to each isomer. By comparing
the 13C NMR spectra of our compounds 4 and 4¢ with
those previously obtained for molecules without substitu-
tion on the nitrogen, we noticed a lot of similarities only
with one of the two spectra. It led us to consider that it cor-
responds to the N-(4-methoxyphenyl) compound 4. The
same comparison for each couple of isomers a–e enabled
us to assign the spectra to each structure and to character-
ize all the products. Moreover, to be sure of our structure’s
assignment, we performed an alternative synthesis of
compound 4b. This pathway establishes the structure of
4b in an unambiguous fashion (Scheme 3). p-Anisidine
was reacted with chloroacetyl chloride to give compound
5. Condensation of 5 with thienyl isothiocyanate 2b al-
lowed formation of 4b in 30% yield.
S
3a–g
iii
R1
S
OMe
R2
R2
+
N
N
N
O
R1
N
S
S
S
O
MeO
4a–e
4'a–e
Scheme 2 Reagents and conditions: i. CSCl2, NaHCO3, CHCl3, r.t.,
2 h; ii. p-anisidine, anhyd CH2Cl2, r.t., 18 h; iii. ClCH2CO2Et, NaOAc,
anhyd DMF, reflux, 24 h.
The first two steps gave only the targeted compounds 2
and 3 with high purity (no purification needed), but as it
might be expected, condensation of the thiourea 3 with
ethyl chloroacetate provided 4 as a mixture of two regio-
isomers. It has been shown that, for unsymmetrical thio-
ureas, the regioselectivity in cyclization was influenced
by electronic factors that predispose electron-withdraw-
ing susbtituents to maintain conjugative stabilization with
the imine nitrogen. It was reported in literature12 that a
thiourea bearing one aryl and one alkyl substituent gave
the more stable arylimino isomer. Ottana et al. have also
noted that the nature of the solvent used in the cyclization
step as well as the reaction time may modify the ratio be-
tween the two isomers.13 In this study, the thienylarylthio-
ureas always led to the two regioisomers 4 and 4¢ without
particular selectivity whatever the conditions used
Table 1 N-Aryl-2-arylimino-1,3-thiazolidin-4-ones Prepared
Thiophene 1
Thiazolidinone 4
Yield (%) Thiazolidinone 4¢
Yield (%)
32
O
C6H4(4-OMe)
NH2
S
N
O
N
N
22
Ph
Ph
S
N
C6H4(4-OMe)
Ph
S
S
S
4a
4¢a
O
C6H4(4-OMe)
NH2
S
N
N
N
N
46
30
O
4-MeC6H4
S
4-MeC6H4
S
S
4-MeC6H4
C6H4(4-OMe)
S
4b
4¢b
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Synthesis of N-Substituted 1,3-Thiazolidin-4-ones
3321
Table 1 N-Aryl-2-arylimino-1,3-thiazolidin-4-ones Prepared (continued)
Thiophene 1
Thiazolidinone 4
Yield (%) Thiazolidinone 4¢
Yield (%)
O
C6H4(4-OMe)
NH2
S
N
N
O
N
45
25
30
10
4-ClC6H4
S
4-ClC6H4
S
N
S
4-ClC6H4
C6H4(4-OMe)
S
4c
4¢c
O
C6H4(4-OMe)
NH2
S
N
N
O
N
30
4-MeOC6H4
S
4-MeOC6H4
S
N
S
4-MeOC6H4
C6H4(4-OMe)
S
4d
4¢d
C6H4(4-OMe)
O
NH2
N
O
S
N
N
30
S
N
C6H4(4-OMe)
S
S
S
4¢e
4e
O2N
C6H4(4-OMe)
O
O2N
O2N
NH2
S
N
O
N
a
a
N
–
–
S
N
C6H4(4-OMe)
S
S
S
4f
4¢f
O
C6H4(4-OMe)
NH2
S
N
O
N
a
N
a
–
–
S
N
C6H4(4-OMe)
S
S
S
4g
4¢g
a Compounds 4f and 4¢f (as well as compounds 4g and 4¢g) could not be separated by column chromatography.
recorded on a Perkin-Elmer FTIR Baragon 1000PC spectrometer
equipped with the Spectrum (Perkin-Elmer) software version 5.3.1.
ClCH2COCl
DMF
MeO
MeO
O
r.t., 2 h
Cl
3-Aminothiophenes 1a–e were synthesized from b-chloroacryloni-
trile, prepared from b-chloropropenal, as described previously.9 3-
Aminobenzo[b]thiophenes 1f–g were synthesized by the same way
starting from the commercially available 2-chlorobenzonitriles.14
Petroleum ether (PE) used refers to the fraction boiling in the range
35–60 °C.
NH2
N
H
5 (85%)
OMe
2b, K2CO3
MeCN
40 °C, 24 h
Isothiocyanatothiophenes 2a–g; General Procedure
O
N
S
To a stirred mixture of NaHCO3 (10 mmol) in CHCl3/H2O (8:6 mL)
was added CSCl2 (575 mg, 5 mmol), followed by dropwise addition
of a solution of the corresponding aminothiophene 1 (5 mmol) in
CHCl3 (15 mL). The mixture was stirred at r.t. for 2 h. The layers
were separated and the organic layer was washed with H2O (15
mL), dried (MgSO4), and evaporated. The residue was poured into
PE (15 mL), filtered, and evaporated.
N
S
4b (30%)
Scheme 3
3-Isothiocyanato-5-phenylthiophene (2a)
Yield: 40%; green solid; mp 58 °C.
1H NMR (250 MHz, DMSO-d6): d = 7.40 (m, 3 H, 3 CH), 7.66 (m,
3 H, 3 CH), 7.77 (d, J = 1.5 Hz, 1 H, CH).
13C NMR (62.9 MHz, DMSO-d6): d = 121.2, 121.3, 125.2, 126.3,
128.5, 129.2, 132.4, 132.9, 143.5.
Structural modifications of the CH2 group of the thiazoli-
dinone moiety (region B of Figure 2) are currently under
investigation and evaluation of their biological activity
will be reported in due course.
Melting points were determined on a Stuart SMP3 apparatus and are
uncorrected. 1H and 13C NMR spectra were recorded on a AC Bruk-
er 250 MHz spectrometer in CDCl3 or DMSO-d6. Mass spectra
were recorded on a MicroTof-Q 98 spectrometer. IR spectra were
HRMS (APCI): m/z calcd for [C11H7NS2 + H]+: 218.0093; found:
218.0117.
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3322
G. Revelant et al.
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3-Isothiocyanato-5-(4-methylphenyl)thiophene (2b)
Yield: 58%; brown solid; mp 56 °C.
1H NMR (250 MHz, DMSO-d6): d = 2.30 (s, 3 H, CH3), 7.22 (d,
J = 7.8 Hz, 2 H, 2 CH), 7.52 (s, 1 H, CH), 7.55 (d, J = 7.8 Hz, 2 H,
2 CH), 7.70 (s, 1 H, CH).
13C NMR (62.9 MHz, DMSO-d6): d = 20.7, 120.5, 120.7, 123.1,
125.1, 126.3, 129.6, 132.8, 138.1, 143.7.
HRMS (APCI): m/z calcd for [C12H9NS2 + H]+: 232.0249; found:
Thioureas 3a–g; General Procedure
To a stirred solution of the appropriate isothiocyanate 2 (2 mmol) in
anhyd CH2Cl2 (6 mL) was added p-anisidine (246 mg, 2 mmol). The
mixture was stirred at r.t. for 16 h. PE (6 mL) was added and then
the precipitate was filtered, washed, with H2O (10 mL) and PE (10
mL), and dried.
N-(4-Methoxyphenyl)-N¢-(5-phenyl-3-thienyl)thiourea (3a)
Yield: 75%; grey solid; mp 149 °C.
1H NMR (250 MHz, DMSO-d6): d = 3.31 (s, 3 H, CH3), 6.90 (d,
J = 8.75 Hz, 2 H, 2 CH), 7.29–7.33 (m, 3 H, 3 CH), 7.41 (t, J = 8
Hz, 2 H, 2 CH), 7.52 (s, 1 H, CH), 7.58–7.61 (m, 3 H, 3 CH), 9.56
(s, 1 H, NH), 9.78 (s, 1 H, NH).
232.0220.
5-(4-Chlorophenyl)-3-isothiocyanatothiophene (2c)
Yield: 60%; green solid; mp 86 °C.
1H NMR (250 MHz, DMSO-d6): d = 7.48 (d, J = 8.75 Hz, 2 H, 2
CH), 7.68 (d, J = 8.75 Hz, 2 H, 2 CH), 7.69 (d, J = 1.5 Hz, 1 H,
CH), 7.78 (d, J = 1.5 Hz, 1 H, CH).
13C NMR (62.9 MHz, DMSO-d6): d = 121.7, 121.8, 126.5, 126.9,
129.1, 131.3, 132.9, 133.2, 142.1.
13C NMR (62.9 MHz, DMSO-d6): d = 55.1, 112.2, 113.6, 120.6,
124.9, 126.1, 127.7, 129.1, 131.9, 133.5, 138.1, 140.7, 156.6, 179.2.
HRMS (APCI): m/z calcd for [C18H16N2OS2 + H]+: 341.0777;
found: 341.0785.
HRMS (APCI): m/z calcd for [C11H6ClNS2 + H]+: 251.9703; found:
251.9719.
N-(4-Methoxyphenyl)-N¢-[5-(4-methylphenyl)-3-thienyl]thio-
urea (3b)
Yield: 45%; pale brown solid; mp 152 °C.
1H NMR (250 MHz, DMSO-d6): d = 2.30 (s, 3 H, CH3), 3.77 (s, 3
H, OCH3), 6.90 (d, J = 9 Hz, 2 H, 2 CH,), 7.21 (d, J = 9 Hz, 2 H, 2
CH), 7.31 (d, J = 9 Hz, 2 H, 2 CH), 7.46 (s, 1 H, CH), 7.48 (d, J = 9
Hz, 2 H, 2 CH), 7.58 (s, 1 H, CH), 9.61 (s, 1 H, NH), 9.84 (s, 1 H,
NH).
3-Isothiocyanato-5-(4-methoxyphenyl)thiophene (2d)
Yield: 80%; brown solid; mp 105 °C.
1H NMR (250 MHz, DMSO-d6): d = 3.79 (s, 3 H, CH3), 6.97 (d,
J = 8.5 Hz, 2 H, 2 CH), 7.51 (s, 1 H, CH), 7.58 (d, J = 8.5 Hz, 2 H,
2 CH), 7.66 (s, 1 H, CH).
13C NMR (62.9 MHz, DMSO-d6): d = 20.7, 55.2, 111.6, 113.6,
119.9, 124.8, 126.1, 129.6, 130.7, 132.0, 137.1, 138.1, 140.8, 156.5,
179.2.
HRMS (APCI): m/z calcd for [C19H18N2OS2 + H]+: 355.0933;
found: 355.0940.
13C NMR (62.9 MHz, DMSO-d6): d = 55.2, 114.5, 119.9, 120.1,
125.1, 125.2, 126.2, 126.6, 143.6, 159.5.
HRMS (APCI): m/z calcd for [C12H9NOS2 + H]+: 248.0198; found:
248.0209.
3-Isothiocyanato-4,5-dihydronaphtho[1,2-b]thiophene (2e)
Yield: 62%; orange oil.
1H NMR (250 MHz, DMSO-d6): d = 2.76 (t, J = 7.5 Hz, 2 H, CH2),
2.96 (t, J = 7.5 Hz, 2 H, CH2), 7.21–7.38 (m, 4 H, 4 CH), 7.67 (s, 1
H, CH).
13C NMR (62.9 MHz, DMSO-d6): d = 21.5, 28.3, 117.1, 122.5,
126.5, 127.3, 127.8, 128.5, 130.4, 133.5, 134.5, 136.3.
HRMS (APCI): m/z calcd for [C13H9NS2 + H]+: 244.0249; found:
244.0281.
N-[5-(4-Chlorophenyl)-3-thienyl]-N¢-(4-methoxyphenyl)thio-
urea (3c)
Yield: 70%; pale brown solid; mp 167 °C.
1H NMR (250 MHz, DMSO-d6): d = 3.73 (s, 3 H, OCH3), 6.90 (d,
J = 9 Hz, 2 H, 2 CH), 7.30 (d, J = 9 Hz, 2 H, 2 CH), 7.46 (d, J = 9
Hz, 2 H, 2 CH), 7.56 (s, 1 H, CH), 7.60–7.63 (m, 3 H, 3 CH), 9.58
(s, 1 H, NH), 9.78 (s, 1 H, NH).
13C NMR (62.9 MHz, DMSO-d6): d = 55.1, 112.9, 113.6, 121.2,
126.1, 126.6, 129.1, 131.9, 132.1, 132.4, 138.3, 139.3, 156.6, 179.3.
HRMS (APCI): m/z calcd for [C18H15ClN2OS2 + H]+: 371.0882;
found: 371.0875.
3-Isothiocyanato-5-nitrobenzo[b]thiophene (2f)
Yield: 60%; green solid; mp 179 °C.
1H NMR (250 MHz, DMSO-d6): d = 8.26 (s, 1 H, CH), 8.26–8.29
(m, 1 H, CH), 8.36 (d, J = 8.75 Hz, 1 H, CH), 8.56 (d, J = 2 Hz, 1
H, CH).
13C NMR (62.9 MHz, DMSO-d6): d = 115.9, 119.7, 125.2, 127.4,
131.7, 133.9, 134.4, 143.3, 144.7
HRMS (APCI): m/z calcd for [C9H4N2O2S2 + H]+: 235.9709; found:
235.9712.
N-(4-Methoxyphenyl)-N¢-[5-(4-methoxyphenyl)-3-thienyl]thio-
urea (3d)
Yield: 48%; pale brown solid; mp 176 °C.
1H NMR (250 MHz, DMSO-d6): d = 3.73 (s, 3 H, OCH3), 3.77 (s, 3
H, OCH3), 6.90 (d, J = 9 Hz, 2 H, 2 CH), 6.97 (d, J = 9 Hz, 2 H, 2
CH), 7.30 (d, J = 9 Hz, 2 H, 2 CH), 7.39 (s, 1 H, CH), 7.52 (m, 3 H,
3 CH), 9.55 (s, 1 H, NH), 9.78 (s, 1 H, NH).
13C NMR (62.9 MHz, DMSO-d6): d = 54.8, 55.2, 111.1, 113.6,
3-Isothiocyanatobenzo|b]thiophene (2g)
Yield: 36%; orange solid; mp 175 °C.
1H NMR (250 MHz, DMSO-d6): d = 7.47–7.58 (m, 2 H, 2 CH), 7.80
(d, J = 8.5 Hz, 1 H, CH), 8.02 (s, 1 H, CH), 8.07 (d, J = 8.5 Hz, 1 H,
CH).
13C NMR (62.9 MHz, DMSO-d6): d = 120.2, 120.6, 123.4, 123.8,
124.2, 125.5, 125.9, 133.5, 137.2.
114.5, 119.4, 126.0, 126.2, 132.0, 137.9, 140.8, 156.5, 158.9, 179.2.
HRMS (APCI): m/z calcd for [C19H18N2O2S2 + H]+: 375.0387;
found: 375.0392.
N-(4-Methoxyphenyl)-N¢-(4,5-dihydronaphtho[1,2-b]-3-thien-
yl)thiourea (3e)
Yield: 90%; brown solid; mp 136 °C.
HRMS (APCI): m/z calcd for [C9H5NS2 + H]+: 190.9858; found:
190.9858.
1H NMR (250 MHz, DMSO-d6): d = 2.70 (t, J = 7.5 Hz, 2 H, CH2),
2.88 (t, J = 7.5 Hz, 2 H, CH2), 3.73 (s, 3 H, OCH3), 6.87 (d, J = 7.5
Hz, 2 H, 2 CH), 7.15 (d, J = 7.5 Hz, 2 H, 2 CH), 7.22 (d, J = 7.5 Hz,
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Synthesis of N-Substituted 1,3-Thiazolidin-4-ones
3323
2 H, 2 CH), 7.29 (d, J = 7.5 Hz, 2 H, 2 CH), 9.29 (s, 1 H, NH), 9.60
HRMS (ESI): m/z calcd for [C20H16N2O2S2 + Na]+: 403.0545;
(s, 1 H, NH).
found: 403.0549.
13C NMR (62.9 MHz, DMSO-d6): d = 22.0, 27.9, 55.2, 113.6, 121.9,
126.0, 126.1, 127.0, 127.1, 128.1, 130.9, 132.1, 133.6, 133.8, 134.3,
135.9, 156.5, 180.1.
HRMS (APCI): m/z calcd for [C20H18N2OS2 + H]+: 367.0933;
found: 367.0933.
3-(4-Methoxyphenyl)-2-[5-(4-methylphenyl)-3-thienyl)imino]-
1,3-thiazolidin-4-one (4b)
Yield: 46%; pale brown solid; mp 183 °C.
1H NMR (250 MHz, CDCl3): d = 2.36 (s, 3 H, CH3), 3.84 (s, 3 H,
OCH3), 4.01 (s, 2 H, CH2), 6.70 (s, 1 H, CH), 7.02–7.05 (m, 3 H, 3
CH), 7.17 (d, J = 7.75 Hz, 2 H, 2 CH), 7.28 (d, J = 9 Hz, 2 H, 2 CH),
7.46 (d, J = 7.75 Hz, 2 H, 2 CH).
13C NMR (62.9 MHz, CDCl3): d = 21.2, 32.9, 60.4, 109.9, 114.7,
119.4, 125.4, 127.3, 129.1, 129.5, 131.4, 137.6, 143.9, 146.8, 155.7,
159.7, 171.6.
N-(4-Methoxyphenyl)-N¢-(5-nitrobenzo[b]-3-thienyl)thiourea
(3f)
Yield: 78%; brown solid; mp 197 °C.
1H NMR (250 MHz, DMSO-d6): d = 3.74 (s, 3 H, OCH3), 6.92 (d,
J = 7.8 Hz, 2 H, 2 CH), 7.38 (d, J = 7.8 Hz, 2 H, 2 CH), 8.18–8.30
(m, 3 H, 3 CH), 8.72 (s, 1 H, CH), 9.88 (s, 1 H, NH), 9.96 (s, 1 H,
NH).
HRMS (ESI): m/z calcd for [C21H18N2O2S2 + Na]+: 417.0702;
found: 417.0707.
13C NMR (62.9 MHz, DMSO-d6): d = 55.2, 113.7, 116.7, 118.6,
2-[(4-Methoxyphenyl)imino]-3-[5-(4-methylphenyl)-3-thienyl]-
1,3-thiazolidin-4-one (4¢b)
120.7, 124.5, 125.9, 131.8, 132.1, 134.6, 143.5, 144.6, 156.7, 180.1.
HRMS (ESI): m/z calcd for [C16H13N3O3S2 + Na]+: 382.0291;
found: 382.0299.
Yield: 30%; yellow oil.
1H NMR (250 MHz, CDCl3): d = 2.36 (s, 3 H, CH3), 3.84 (s, 3 H,
OCH3), 4.01 (s, 2 H, CH2), 6.70 (s, 1 H, CH), 7.02–7.05 (m, 3 H, 3
CH), 7.17 (d, J = 7.75 Hz, 2 H, 2 CH), 7.28 (d, J = 9 Hz, 2 H, 2 CH),
7.46 (d, J = 7.75 Hz, 2 H, 2 CH).
13C NMR (62.9 MHz, CDCl3): d = 21.2, 32.5, 55.4, 114.4, 120.7,
120.9, 121.9, 125.7, 129.6, 131.1, 131.7, 137.9, 141.1, 143.7, 153.9,
156.8, 170.9.
N-(Benzo[b]-3-thienyl)-N¢-(4-methoxyphenyl)thiourea (3g)
Yield: 40%; brown solid; mp 136 °C.
1H NMR (250 MHz, DMSO-d6): d =3.72 (s, 3 H, OCH3), 6.90 (d,
J = 7.8 Hz, 2 H, 2 CH), 7.35–7.44 (m, 3 H, 3 CH), 7.81–8.03 (m, 2
H, 2 CH), 9.77 (s, 1 H, NH), 9.80 (s, 1 H, NH).
13C NMR (62.9 MHz, DMSO-d6): d = 60.4, 118.8, 119.8, 126.3,
128.3, 129.2, 129.9, 131.4, 136.3, 137.3, 139.9, 142.6, 161.8, 185.4.
HRMS (ESI): m/z calcd for [C16H14N2OS2 + Na]+: 337.0440; found:
HRMS (ESI): m/z calcd for [C21H18N2O2S2 + Na]+: 417.0702;
found: 417.0706.
337.0466.
2-[(5-(4-Chlorophenyl)-3-thienyl)imino]-3-(4-methoxyphenyl)-
1,3-thiazolidin-4-one (4c)
Thiazolidin-4-ones 4a–e and 4¢a–e; General Procedure
To a stirred solution of the appropriate thiourea 3 (0.5 mmol) and
NaOAc (205 mg, 2.5 mmol) in anhyd DMF (6 mL) was added ethyl
chloroacetate (123 mg, 1 mmol) dropwise via a syringe. The mix-
ture was refluxed overnight, cooled to r.t., and then poured into H2O
(25 mL). The mixture was extracted with EtOAc (2 × 10 mL), the
combined organic layers were dried (MgSO4), and evaporated. The
two isomers were separated by chromatography on silica gel (cyclo-
hexane–EtOAc, 7:3) (Table 1).
Yield: 45%; pale brown solid; mp 155 °C.
1H NMR (250 MHz, CDCl3): d = 3.74 (s, 3 H, OCH3), 4.01 (s, 2 H,
CH2), 6.75 (d, J = 1.25 Hz, 1 H, CH), 7.01–7.05 (m, 3 H, 3 CH),
7.28 (d, J = 8.75 Hz, 2 H, 2 CH), 7.32 (d, J = 8.75 Hz, 2 H, 2 CH),
7.48 (d, J = 8.75 Hz, 2 H, 2 CH).
13C NMR (62.9 MHz, CDCl3): d = 32.9, 55.5, 110.8, 114.3, 120.3,
127.0, 127.3, 129.1, 129.5, 132.7, 133.5, 142.4, 147.0, 155.1, 159.8,
171.5.
HRMS (ESI): m/z calcd for [C20H15ClN2O2S2 + Na]+: 437.0156;
found: 437.0172.
3-(4-Methoxyphenyl)-2-[(5-phenyl-3-thienyl)imino]-1,3-thiazo-
lidin-4-one (4a)
Yield: 22%; orange solid; mp 123 °C.
3-[5-(4-Chlorophenyl)-3-thienyl]-2-[(4-methoxyphenyl)imino]-
1,3-thiazolidin-4-one (4¢c)
1H NMR (250 MHz, CDCl3): d = 3.84 (s, 3 H, OCH3), 4.02 (s, 2 H,
CH2), 6.74 (d, J = 1 Hz, 1 H, CH), 7.01–7.07 (m, 3 H, 3 CH), 7.27–
7.39 (m, 5 H, 5 CH), 7.57 (d, J = 6.75 Hz, 2 H, 2 CH).
13C NMR (62.9 MHz, CDCl3): d = 32.9, 55.4, 110.5, 114.7, 119.8,
121.9, 125.5, 127.7, 128.9, 128.9, 134.1, 143.8, 146.9, 155.8, 159.7,
171.6.
Yield: 25%; orange oil.
1H NMR (250 MHz, CDCl3): d = 3.74 (s, 3 H, OCH3), 3.96 (s, 2 H,
CH2), 6.89–6.91 (m, 4 H, 4 CH), 7.35 (d, J = 8.75 Hz, 2 H, 2 CH),
7.44 (d, J = 1.5 Hz, 1 H, CH), 7.50 (d, J = 1.5 Hz, 1 H, CH), 7.52
(d, J = 8.75 Hz, 2 H, 2 CH).
HRMS (ESI): m/z calcd for [C20H16N2O2S2 + Na]+: 403.0545;
found: 403.0558.
13C NMR (62.9 MHz, CDCl3): d = 32.5, 55.4, 114.5, 121.6, 121.9,
127.1, 129.1, 131.9, 132.3, 133.8, 141.0, 142.1, 153.8, 156.8, 167.4,
170.8.
2-[(4-Methoxyphenyl)imino]-3-(5-phenyl-3-thienyl)-1,3-thiazo-
lidin-4-one (4¢a)
Yield: 32%; orange oil.
HRMS (ESI): m/z calcd for [C20H15ClN2O2S2 + Na]+: 437.0156;
found: 437.0173.
1H NMR (250 MHz, CDCl3): d = 3.79 (s, 3 H, OCH3), 3.96 (s, 2 H,
CH2), 6.87–6.91 (m, 4 H, 4 CH), 7.29–7.40 (m, 3 H, 3 CH), 7.46 (d,
J = 5.5 Hz, 2 H, 2 CH), 7.59 (d, J = 5.5 Hz, 2 H, 2 CH).
3-(4-Methoxyphenyl)-2-{[5-(4-methoxyphenyl)-3-thienyl]imi-
no}-1,3-thiazolidin-4-one (4d)
Yield: 30%; orange solid; mp 142 °C.
13C NMR (62.9 MHz, CDCl3): d = 32.5, 55.5, 114.5, 121.2, 121.4,
121.9, 125.8, 127.9, 128.9, 131.8, 133.8, 141.1, 143.5, 156.8, 167.8,
170.3.
1H NMR (250 MHz, CDCl3): d = 3.82 (s, 3 H, OCH3), 3.84 (s, 3 H,
OCH3), 4.01 (s, 2 H, CH2), 6.67 (d, J = 1.25 Hz, 1 H, CH), 6.86–
6.95 (m, 3 H, 3 CH), 7.03 (d, J = 9 Hz, 2 H, 2 CH), 7.28 (d, J = 9
Hz, 2 H, 2 CH,), 7.49 (d, J = 9 Hz, 2 H, 2 CH).
Synthesis 2010, No. 19, 3319–3324 © Thieme Stuttgart · New York

3324
G. Revelant et al.
PAPER
13C NMR (62.9 MHz, CDCl3): d = 32.9, 55.4, 55.7, 109.5, 114.3,
114.8, 118.8, 121.9, 126.7, 127.2, 129.1, 143.7, 146.8, 155.6, 159.3,
159.7, 171.6.
Acknowledgment
We are grateful to I. Abdillahi for providing the starting compounds
and V. Poddig for NMR studies.
HRMS (ESI): m/z calcd for [C21H18N2O3S2 + Na]+: 433.0651;
found: 433.0661.
References
3-[5-(4-Methoxyphenyl)-3-thienyl]-2-[(4-methoxyphenyl)imi-
no]-1,3-thiazolidin-4-one (4¢d)
Yield: 30%; orange oil.
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1H NMR (250 MHz, CDCl3): d = 3.79 (s, 3 H, OCH3), 3.83 (s, 3 H,
OCH3), 3.95 (s, 2 H, CH2), 6.89–6.93 (m, 6 H, 6 CH), 7.32 (d,
J = 1.5 Hz, 1 H, CH), 7.40 (d, J = 1.5 Hz, 1 H, CH), 7.51 (d, J = 8.85
Hz, 2 H, 2 CH).
13C NMR (62.9 MHz, CDCl3): d = 32.7, 55.3, 55.4, 114.3, 114.9,
120.2, 120.5, 121.9, 126.8, 127.2, 131.6, 141.1, 143.9, 153.9, 156.8,
159.5, 170.9.
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Zani, F. Bioorg. Med. Chem. 2006, 14, 3859. (b) Vicini, P.;
Geronikaki, A.; Incerti, M.; Zani, F.; Dearden, J.; Hewitt, M.
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J.; Suchár, G.; Kristian, P.; Sillanpää, R.; Pihlaja, K. Eur. J.
Chem. 2002, 1248. (e) St.Laurent, D. R.; Gao, Q.; Wu, D.;
Serrano-Wu, M. H. Tetrahedron Lett. 2004, 45, 1907.
(6) Majcen le Maréchal, A.; Robert, A.; Leban, I. Tetrahedron
1990, 46, 453.
HRMS (ESI): m/z calcd for [C21H18N2O3S2 + Na]+: 433.0651;
found: 433.0670.
3-(4-Methoxyphenyl)-2-[(4,5-dihydronaphtho[1,2-b]-3-thien-
yl)imino]-1,3-thiazolidin-4-one (4e)
Yield: 30%; yellow solid; mp 92 °C.
1H NMR (250 MHz, CDCl3): d = 2.58 (t, J = 7.5 Hz, 2 H, CH2),
2.90 (t, J = 7.5Hz, 2 H, CH2), 3.85 (s, 3 H, OCH3), 4.02 (s, 2 H,
CH2), 6.66 (s, 1 H, CH), 7.04 (d, J = 9.25 Hz, 2 H, 2 CH), 7.16–7.21
(m, 3 H, 3 CH), 7.30 (d, J = 9.25 Hz, 2 H, 2 CH), 7.36 (m, 1 H, CH).
13C NMR (62.9 MHz, CDCl3): d = 21.9, 28.8, 32.9, 55.5, 108.0,
114.7, 122.5, 126.9, 126.9, 127.3, 128.0, 129.0, 131.6, 132.7, 134.9,
136.0, 144.7, 156.0, 159.7, 171.6.
(7) Blanchet, J.; Zhu, Z. Tetrahedron Lett. 2004, 45, 4449.
(8) (a) Thomae, D.; Perspicace, E.; Henryon, D.; Xu, Z.;
Schneider, S.; Hesse, S.; Kirsch, G.; Seck, P. Tetrahedron
2009, 65, 10453. (b) Hesse, S.; Perspicace, E.; Kirsch, G.
Tetrahedron Lett. 2007, 48, 5261. (c) Thomae, D.; Kirsch,
G.; Seck, P. Synthesis 2007, 2153.
(9) Abdillahi, A.; Revelant, G.; Datoussaid, Y.; Kirsch, G.
Synthesis 2010, 2543 and references cited therein for the
synthesis of 3-aminothiophenes.
(10) Santagati, A.; Longmore, J.; Guccione, S.; Langer, T.;
Tonnel, E.; Modica, M.; Santagati, M.; Monsù Scolaro, L.;
Russo, F. Eur. J. Med. Chem. 1997, 32, 973.
(11) Zhou, H.; Wu, S.; Zhai, S.; Liu, A.; Sun, Y.; Li, R.; Zhang,
Y.; Ekins, S.; Swaan, P. W.; Fang, B.; Zhang, B.; Yan, B.
J. Med. Chem. 2008, 51, 1242.
HRMS (ESI): m/z calcd for [C22H18N2O2S2 + Na]+: 429.0702;
found: 429.0703.
2-[(4-Methoxyphenyl)imino]-3-(4,5-dihydronaphtho[1,2-b]-3-
thienyl)-1,3-thiazolidin-4-one (4¢e)
Yield: 10%; yellow oil.
1H NMR (250 MHz, CDCl3): d = 2.69 (t, J = 7.5 Hz, 2 H, CH2), 2.98
(t, J = 7.5 Hz, 2 H, CH2), 3.79 (s, 3 H, OCH3), 4.01 (s, 2 H, CH2),
6.86 (s, 4 H, 4 CH), 7.16–7.22 (m, 3 H, 3 CH), 7.28 (s, 1 H, CH),
7.35–7.39 (m, 1 H, CH).
13C NMR (62.9 MHz, CDCl3): d = 22.7, 28.6, 32.7, 55.4, 114.3,
120.7, 121.9, 122.5, 126.9, 127.3, 128.0, 130.7, 131.1, 133.9, 134.6,
136.6, 141.0, 153.3, 156.8, 170.8.
HRMS (ESI): m/z calcd for [C22H18N2O2S2 + Na]+: 429.0702;
found: 429.0712.
(12) Mandhare, P. N.; Rindhe, S. S.; Patil, L. R.; Mane, R. A.
Indian J. Heterocycl. Chem. 2003, 12, 209.
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Cuzzocrea, S.; Vigorita, M. G. Bioorg. Med. Chem. 2005,
13, 4243.
(14) Abdillahi, I.; Kirsch, G. Synthesis 2010, 1428.
Synthesis 2010, No. 19, 3319–3324 © Thieme Stuttgart · New York