The Reactivity of Dimethyl Acetylenedicarboxylate and Heterocyclization of Hydrazinecarbothioamides to 1,3-Thiazolidin-4-ones

Article abstract of DOI:10.1002/jhet.2392

(Chemical Equation Presented) 2-Substituted hydrazinecarbothioamides and N,2-disubstituted hydrazinecarbothioamides react, in high yields with dimethyl acetylenedicarboxylate to give 4-oxo-Z-(thiazolidin-5-ylidene)acetate derivatives. Several mechanistic options involving interaction are presented. The structures of thiazolidin-4-ones have been unambiguously confirmed by single crystal X-ray crystallography.

Full text of DOI:10.1002/jhet.2392

Month 2014 The Reactivity of Dimethyl Acetylenedicarboxylate and Heterocyclization
of Hydrazinecarbothioamides to 1,3-Thiazolidin-4-ones
a
a
a
a
b
c
Alaa A. Hassan, * Nasr K. Mohamed, Kamal M. A. El-Shaieb, Hendawy N. Tawfeek, Stefan Bräse, and Martin Nieger
a
Chemistry Dept, Faculty of Science, Minia University, El-Minia 61519, Egypt
b
Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe 76131, Germany
c
Laboratory of Inorganic Chemistry, Department of Chemistry, University of Helsinki, Helsinki 00014, Finland
*
E-mail: alaahassan2001@mu.edu.eg
Additional Supporting Information may be found in the online version of this article.
Received August 12, 2014
DOI 10.1002/jhet.2392
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
2
-Substituted hydrazinecarbothioamides and N,2-disubstituted hydrazinecarbothioamides react, in high
yields with dimethyl acetylenedicarboxylate to give 4-oxo-Z-(thiazolidin-5-ylidene)acetate derivatives. Sev-
eral mechanistic options involving interaction are presented. The structures of thiazolidin-4-ones have been
unambiguously confirmed by single crystal X-ray crystallography.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
RESULTS AND DISCUSSION
The reaction of hydrazinecarbothioamides with elec-
tron deficient compounds is a convenient method for the
synthesis of various heterocyclic compounds, such as
pyrazolo[1,2-c]-1,3,4-thiadiazoles [1], spiro(indolone-3,2′-
We report here the results of our investigations on the
reaction of hydrazinecarbothioamides 6a–e with 2. These
results are compared with those obtained in Scheme 1 [23].
As shown in Scheme 2, the synthesis of thiazolidin-4-ones
7 and 8 was simply affected by the nucleophilic active
centers in hydrazinecarbothioamides 6a–e and an electro-
philic acetylenic ester (DMAD, 2). The reaction proceeds
smoothly, without using catalyst, by treatment of 6a–e
with one molar equivalent of DMAD (2) in ethanol at
reflux temperature to give the products 7a,b and 8a–c in
78–89% yields (Scheme 2).
[1,3,3]thiadiazole)-2-ones [2], indazoles [3], and
thiadiazines [3].
Thiazoles are synthetic intermediates and common
substructures in numerous other biologically active com-
pounds [4–9]. Owing to the various physiological activi-
ties of thiazolidinones, many thiazolidinone derivatives
have been prepared, and several new methods for the
preparation of substituted thiazolidin-4-ones have been
reported [9,10].
Elemental analyses and mass spectra clearly revealed
that the products were formed by the addition of equimolar
amounts of DMAD (2) and 6a–e with the elimination of
one molecule of methanol. There are different possibilities
for the formation of various isomers, which would behave
spectroscopically very similar. Hydrazinecarbothioamides,
Thiazolidin-4-one compounds display antimicrobial
[
11,12], antimycobacterial [13,14], anti-HIV [15,16], anti-
inflammatory [17], and anticancer [18,19]. Moreover, they
have been studied extensively because of their ready acces-
sibility, diverse chemical reactivity, and broad spectrum of
pharmacological activities [20]. Furthermore, 2-
iminothiazolidin-4-ones have been found to have anti-
fungal activity [21].
1
2
3
N , N , N , and sulfur atom are the nucleophilic sites in
compounds 6a–e. Thus, several options for the interaction
between 6a–e and 2 may be envisaged. It is probable that
all the products observed are formed from one of the five
labile (1:1) adducts (A–E) (Fig. 1).
Methyl
[3-aryl-4-oxo-1-(phenylthiocarbamoyl)-4,5-
dihydro-pyrazol-5-ylidene]ethanoates were formed from
the reaction of arenealdehyde 4-phenylthiosemi-carbazones
with dimethyl acetylenedicarboxylate (DMAD, 2) [22],
whereas 1,2,4-triazepine-3-thiones 4a–c and 5a–d were
formed via conventional and microwave irradiation of 4-
substituted thiosemicarbazides 1a–c and 2,4-disubstituted
thiosemicarbazides 3a–d with DMAD, 2 (Scheme 1) [23].
To elucidate the tautomeric states and structure of the
products as well as to characterize the products, we use
1
13
IR, H NMR, and C NMR as well as mass spectrometry.
Rigorous structure proof comes from the single crystal
X-ray structural analyses of 7b (Fig. 2) and 8b (Fig. 3).
To illustrate the structure elucidation of compounds 7a,
b, we choose 7b as an example. Thus, IR spectrum showed
©
2014 HeteroCorporation

A. A. Hassan, N. K. Mohamed, K. M. A. El-Shaieb, H. N. Tawfeek, and M. Nieger
Vol 000
Scheme 1. Reactions of hydrazinecarbothioamides 1a–c and 3a–d with
dimethyl acetylenedicarboxylate 2.
Figure 2. Molecular structure of 7b in the crystal (displacement parame-
ters are drawn at 50% probability level). The crystallographic numbering
does not reflect the systematic IUPAC numbering.
Scheme 2. Reaction of hydrazinecarbothioamides 6a–e with dimethyl
acetylenedicarboxylate.
proton at δ = 6.85 and NH at δ = 8.27. In addition its
H
H
13
C NMR spectrum showed five downfield lines at
1
68.12, 166.64, 145.94, 140.22, and 115.73 ppm, because
of (C¼O, ester), (C-4), (C¼N), (C-5) and vinyl-CH,
1
13
respectively. Full H NMR and C NMR data are given
in the experimental part.
Moreover, the structure of Z-methyl-2-[(Z)-4-oxo-2-(2-
tosylhydrazono)-thiazolidin-5-ylidene]acetate 7b has been
unambiguously confirmed by a single crystal X-ray struc-
ture analysis (Fig. 2 and Tables S1–7 in the supplementary
data), which confirms a cisoid geometry with respect to
C¼C and C¼N double bonds. Also, the vinyl-CH is in cis
form with the cyclic C¼O. The thiazolidine moiety is
planar.
On the other hand, refluxing a solution of equimolar
amounts of 6c–d and 2 in absolute EtOH (25 mL) for 6–
8
h furnished the new thiazolidine-4-ones 8a–c, as the only
reaction product. The structures of 8a–c were confirmed
for the reaction products on the basis of their elemental
and spectral data. Their IR spectra showed two carbonyl
two carbonyl absorption bands at 1745, 1685 (C¼O) and a
ꢀ
1
band at 1615 cm that assigned to C¼N vibration. Broad
ꢀ
1
bands at 3310 and 3160cm are due to NH-groups.
ꢀ
1
1
absorption bands about 1690–1725 cm , and an absorption
The H NMR spectrum of 7b showed one methoxy
group at δ = 3.86, methyl group at δ = 2.24ppm, one
H
H
phenyl group in the range of δ = 6.85–7.24, one vinylic
H
Figure 3. Molecular structure of 8b in the crystal (displacement parame-
ters are drawn at 50% probability level). The crystallographic numbering
does not reflect the systematic IUPAC numbering.
Figure 1. Expected adducts (1:1) (A–E) through interactions between
6a–e and 2.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Dimethyl Acetylenedicarboxylate and Heterocyclization
ꢀ
1
band between 1635 and 1655cm that was assigned to a
CONCLUSION
ꢀ
1
C¼N vibration. A broad band at 3295–3320cm is due
Reaction of 2-substituted hydrazinecarbothioamides 6a,b
and N,2-disubstituted hydrazinecarbothioamides 6c-e with
DMAD (2) can involve possible competition between
nucleophilic addition of several sites (N , N , N , and SH
of hydrazinecarbothioamide group) to the triple bond of
activated acetylenic ester. Thioheterocyclic N-C-S+C2
mode of cyclization is favored.
1
to NH group. H NMR revealed a vinyl-CH singlet be-
tween 6.50–6.65 ppm, and a methoxy singlet at about
.85–3.90 ppm. In all cases, the IR and C NMR confirmed
the disappearance of a thione group. C NMR showed sig-
1
3
3
1
2
3
1
3
nals at 166.28–166.64 (C¼O, ester), 162.24–162.99 (C-4),
1
45.46–145.77 (C¼N), 138.78–140.51 (thiazolidine-C-5)
and 115.05–115.36 (vinyl-CH), in addition to the aromatic
carbons.
1
The H-NMR spectrum of 8c clearly indicated the pres-
EXPERIMENTAL
ence of an allyl group, which appeared as three multiplets
All melting points were determined using open capillaries on a
Gallenkamp melting point apparatus. The IR spectra were
recorded with a Shimadzu 408 instrument using potassium bro-
centered at 4.15, 5.12, and 5.92ppm due to (allyl-CH N),
2
(
allyl-CH ¼), and (allyl-CH¼), respectively. The presence
2
13
1
13
of the allyl group was also proved by the C-DEPT-NMR
mide. The 400 MHz H NMR and 100 MHz C NMR spectra
were observed on a Bruker AM 400 spectrometer with
tetramethylsilane as the internal standard, br = broad, s = singlet,
spectrum, exhibiting positive signals at 133.72 (allyl-CH¼)
and negative signal at 45.24 and 117.15 due to (allyl-CH N)
2
13
d = doublet, t = triplet, q = quartet, m = multiplet. The C NMR
signals were assigned on the basis of DEPT 135/90 spectra. The
mass spectra (70 eV, electron impact mode) were recorded on
Finnigan MAT instrument. Elemental analyses are carried out at
the Microanalytical Center, Cairo University, Egypt. Preparative
layer chromatography (plc) used air dried 1.0 mm thick layers of
slurry applied silica gel (Merck Pf254) on 48 cm wide and 20 cm
high glass plates using the solvents listed. Zones were detected
by quenching of indicator fluorescence upon exposure to
and (allyl-CH ¼), respectively.
2
Unambiguous support for products 8a–c came from the
X-ray structure analysis of (Z)-methyl-2-[(Z)-2-(ethylimino)-
4
-oxo-3-(phenylamino)thiazolidin-5-ylidene)]acetate 8b
(
Fig. 3 and Tables S8–14, in the supplementary data). A
cisoid geometry with respect to C¼C and C¼N double
bonds and the thiazolidine moiety is planar.
A rationale for the formation of products 7a,b and 8a–c
is depicted in (Scheme 3). Nucleophilic attack of SH of
2
54 nm light and eluted with acetone.
Starting materials. 2-Substituted hydrazinecarbothioamides
a,b and N,2-disubstituted hydrazinecarbothioamides 6c–e were
6
a–e on the triple bond of 2 through the intermediate (C),
6
followed by intramolecular nucleophilic attack of the NH2
of 6a,b at α-ester carbonyl group, the products 7a,b would
be isolated, where via the intermediate (D) and nucleophilic
attack of SH on the triple bond of 2 with elimination of one
molecule of MeOH during the attack of N-hydrazine-
carbothioamide at the carbonyl ester, the thiazolidin-4-ones
prepared according to the literature: 6a [24], 6b [25], 6c [26], 6d
[
26], and 6e [27]. DMAD (2) was bought from Fluka.
Reaction of substituted hydrazinecarbothioamides 6a–e
with dimethyl acetylenedicarboxylate (2).
A mixture of
substituted hydrazinecarbothioamides 6a–e (1 mmol) and
DMAD (2) (0.142 g, 1 mmol) in absolute ethanol (30 mL) was
refluxed for 6–10 h and was cooled to room temperature. Yellow
crystals from 7a,b were precipitated, filtered, and washed with a
small amount of cold ethanol and recrystallized from listed
solvents. The reaction mixture between 6c–e and 2 was pre-
concentrated, applied to chromatographic plates, and developed
using toluene/ethyl acetate (Qr = 10:1) to give only one zone
containing compounds 8a–c. The products so obtained were
recrystallized.
8
a–c would be formed.
Scheme 3. The mechanism for the formation of products 7a,b and 8a–c.
(
Z)-Methyl-2-[(Z)-4-oxo-2-(2-phenylhydrazno)-thiazolidin-
5
2
1
-ylidene]acetate (7a). Yellow crystals (0.246 g, 89%), mp
22–224°C (acetonitrile); IR (KBr) v = 3288, 3252 (NH), 1692,
ꢀ
1
1
668 (CO), 1640 (C¼N), 1605 cm
(Ar–C¼C); H NMR
(
400 MHz, CDCl ): δ = 3.85 (s, 3H, OCH ), 6.85 (m, 2H, Ar-
3 H 3
H and vinyl-CH), 7.24 (m, 4H, Ar-H), 8.27 (br, 1H, NH),
1
3
1
1.27 (br, s, 1H, thiazolidine-NH); C NMR (100 MHz,
CDCl ): = 52.71 (OCH ), 116.12 (vinyl-CH), 122.81,
27.19, 129.67 (Ar-CH), 140.12 (thiazolidine-C5), 142.88 (Ar-
C), 146.12 (thiazolidine-C2), 166.73 (thiazolidine-C4), 168.19
3
δ
C
3
1
+
(
(
CO-ester); MS (70 eV): m/z = 277 (M , 100), 246 (12), 218
19), 145 (22), 105 (39), 92 (54), 77 (62), 65 (42), 59 (21). Anal.
Calcd. for C12
S, 11.56. Found: C, 52.11; H, 3.88; N, 15.06; S, 11.74.
Z)-Methyl 2-[(Z-4-oxo-2-(2-tosylhydrazono)thiazolidin-5-
ylidene] acetate (7b). Yellow crystals (0.290 g, 82%), mp
11 3 3
H N O S (277.05): C, 51.98; H, 4.00; N, 15.15;
(
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. A. Hassan, N. K. Mohamed, K. M. A. El-Shaieb, H. N. Tawfeek, and M. Nieger
Vol 000
2
1
34–236°C (acetonitrile); IR (KBr) v = 3310, 3160 (NH), 1745,
radiation (λ = 0.71073 Å). Direct methods (SHELXS-97) [28]
were used for structure solution, and refinement was carried out
using SHELX-97 [28], (full-matrix least-squares on F2).
Hydrogen atoms were localized by difference electron density
determination and refined using a riding model (H(N) free). An
extinction correction was applied for 7b and a semi-empirical
absorption correction was applied for 8b.
ꢀ
1
1
685 (CO), 1615 (C¼N), 1590 cm
(Ar–C¼C); H NMR
(
400 MHz, CDCl ): δ = 2.24 (s, 3H, CH ), 3.86 (s, 3H, OCH ),
3 H 3 3
6
.80 (s, 1H, vinyl-CH), 6.90–7.00 (m, 2H, Ar-H), 7.28 (m, 2H,
Ar-H), 8.45 (br, 1H, NH), 11.16 (br, 1H, thiazolidine-NH);
13
C
NMR (100 MHz, CDCl3): δC = 22.16 (CH3), 52.75
(
(
(
OCH ), 115.73 (vinyl-CH), 129.29, 129.53 (Ar-CH), 138.12
Ar-C), 140.22 (thiazolidine-C5), 143.42 (Ar-C), 145.94
thiazolidine-C2), 166.64 (thiazolidine-C4), 168.12 (CO-ester);
3
ꢀ1
Compound 7b.
C
13
H
13
N
3
O
5
S
2
, M = 355.38 gmol , yellow
crystals, crystal size 0.50 × 0.45 × 0.40 mm, orthorhombic,
space group Pbca (No. 61), a = 13.8883(3)Å, b = 12.8134(4)
+
MS (70 eV): m/z = 355 (M , 21), 324 (12), 200 (100), 155 (11),
1
4
17 (23), 91 (37). Anal. Calcd. for C13
H
13
N
3
O
5
S
2
(355.04): C,
3
Å,
D
c = 16.8953(5) Å,
V = 3006.63(14) Å ,
Z = 8,
3.93; H, 3.69; N, 11.82; S, 18.04. Found: C, 44.14; H, 3.78;
ꢀ3
ꢀ1
calcd = 1.570 Mgm , μ = 0.384 mm , T = 123(2) K, 14529
N, 11.67; S, 17.91.
Z)-Methyl-2-[(Z)-4-oxo-3-(phenylamino)-2-(phenyl-imino)
thiazolidin-5-ylidene]acetate (8a). Yellow crystals (0.286g,
1%), mp 183–185°C (acetone); IR (KBr) v = 3295 (NH),
o
reflection, 3424 unique [Rint = 0.019], 2θmax = 55 , 217
parameters, two restraints, R [for 3198 I › 2σ (I)]= 0.028, wR2
all data) = 0.074, S = 1.12, largest diff. peak and hole= 0.385/
(
1
(
8
1
ꢀ3
ꢀ
0.347 e A
.
ꢀ
1
1
690, 1710 (CO), 1635 (C¼N), 1595, 1605 cm (Ar–C¼C); H
ꢀ1
Compound 8b.
14 15 3 3
C H N O S, Mr =305.35gmol , yellow
NMR (400, MHz, CDCl ): δ = 3.90 (OCH ), 6.65 (vinyl-
3
H
3
crystal, crystal size 0.50 × 0.30 × 0.20 mm, monoclinic, space
CH), 6.85 (m, 3H, Ar-H), 7.28 (m, 3H, Ar-H, and NH), 7.50
group P21/n (no. 14), a = 7.3170(2) Å, b= 10.8893(3) Å,
1
3
(
(
m, 5H, Ar-H);
OCH ), 115.13 (vinyl-CH), 121.03, 126.90, 127.61, 128.74,
C NMR (100 Hz, CDCl ): δ = 52.67
ꢀ3
3
C
c = 17.6717(5) Å, β = 96.992(1) Å, V = 1397.56(7) A
,
Z = 4,
ꢀ
3
ꢀ1
3
Dcalcd =1.451 Mgm
reflection, 3144 unique [Rint = 0.012], 2θmax = 55 , 194 parameters,
one restraint, R [for 2967 I › 2σ (I)] = 0.028 WR2(all data)
0.072, S = 1.04, largest diff. peak and hole = 0.370/ꢀ0.232e A
,
μ =0.246mm
,
T= 120(2) K, 11545
o
1
1
29.52 (Ar-CH), 133.99 (Ar-C), 140.23 (thiazolidine-C5),
42.33 (Ar-C), 145.46 (thiazolidine-C2), 162.99
1
ꢀ
3
(
(
thiazolidine-C4), 166.64 (CO-ester); MS (70 eV): m/z = 353
M , 100), 322 (12), 135 (81), 92 (28). Anal. Calcd. For
=
.
+
C
18
H
15
N
3
O
3
S (353.08): C, 61.18; H, 4.28; N, 11.89; S, 9.07.
Found: C, 61.29, H, 4.19; N, 12.02; S, 8.92.
Z)-Methyl-2-[(Z)-2-(ethylimino)-4-oxo-3-(phenylamino)-
thiazolidin-5-ylidene]acetate (8b). Yellow crystals (0.256g,
4%), mp 151°C (acetone); IR (KBr): v = 3310 (NH), 1695, 1725
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(
[
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8
ꢀ
1 1
(
CO), 1655 (C¼N), 1615 (Ar–C¼C) cm ; H NMR (400 MHz,
CDCl ): δ = 1.15 (t, 3H, J = 7.6 Hz, CH ), 3.40 (m, 2H, CH
.85 (s, 3H, OCH ), 6.50 (s, 1H, vinyl-CH), 6.73 (m, 2H, Ar-H),
.92 (m, 2H, Ar-H), 7.20 (m, 2H, Ar-H and NH); C NMR
): δ = 15.67 (CH ), 47.21 (CH ), 52.65 (OCH ),
15.05 (vinyl-CH), 116.82, 122.82, 129.23 (Ar-CH), 138.78
3
H
3
2
)
4
3
6
3
13
2
(
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2
3
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(
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+
(
thiazolidine-C4), 166.28 (CO-ester); MS (70 eV): m/z = 305 (M ,
00), 290 (11), 274 (18), 247 (11), 134 (38), 106 (21), 92 (16).
Anal. Calcd. For C14 S (305.08): C, 55.07; H, 4.95; N,
3.76; S, 10.50. Found: C, 54.97; H, 5.02; N, 13.85; S, 10.39.
Z)-Methyl-2-[(Z)-2-(allyimino)-4-oxo-3-(phenylamino)-
thiazolidin-5-ylidene]acetate (8c). Yellow crystals (0.247g,
8%), mp 129°C (acetone); IR (KBr): v = 3320 (NH), 1710, 1695
[
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(
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7
(
ꢀ
1
1
CO), 1650 (C¼N), 1605 cm (Ar–C¼C); H NMR (400 MHz,
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3
H
3
2
(
m, 2H, allyl-CH ¼), 5.92 (m, 1H, allyl-CH¼), 6.60 (s, 1H,
2
[
vinyl-CH), 6.85 (m, 1H, Ar-H), 7.0 (m, 2H, Ar-H), 7.3 (m, 2H,
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13
Ar-H and NH); C NMR (100 MHz, CDCl
): δ
3 C
= 45.24 (allyl-
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CH N), 52.61(OCH ), 115.36 (vinyl-CH), 117.15 (allyl-CH ¼),
2
3
2
1
(
1
(
22.85, 129.26, 129.26 (Ar-CH), 133.72 (allyl-CH=), 140.51
thiazolidine-C5), 141.46 (Ar-C), 145.61 (thiazolidine-C2),
62.92 (thiazolidine-C4), 166.56 (CO-ester); MS (70 eV): m/z = 317
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+
M , 100), 286 (13), 258 (9), 225 (14), 92 (33). Anal. Calcd. For
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15 15 3 3
C H N O
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8
b.
Suitable crystals were obtained by recrystallization from
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acetonitrile. The single crystal X-ray diffraction study was
carried out on a Bruker-Nonius ApexII diffractometer at 123 (2)
K (7b) or a Bruker Apex Duo at 120(2) K (8b) using MoKα
[
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