Synthesis of thiazolidin-4-ones from substituted (Ylidene) hydrazinecarbothioamides and dimethyl acetylenedicarboxylate

Article abstract of DOI:10.1002/jhet.1642

Conjugated substituted (ylidene)hydrazinecarbothioamides react in high yield with dimethyl acetylenedicarboxylate to give substituted [(ylidene)hydrazono)-4-oxothiazolidin-5-ylidene]acetates; several mechanistic options involving nucleophilic interaction

Full text of DOI:10.1002/jhet.1642

674
Synthesis of Thiazolidin-4-ones from Substituted
Vol 51
(Ylidene)hydrazinecarbothioamides and Dimethyl Acetylenedicarboxylate
a
a
a
a
b
c
*
Alaa A. Hassan, Ashraf A. Aly, Kamal M. A. El-Shaieb, Tarek M. I. Bedair, Stefan Bräse, and Alan B. Brown,
aChemistry Department, Faculty of Science Minia University, 61519 El-Minia, Egypt
bInstitute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
cChemistry Department, Florida Institute of Technology, 150 W University Blvd, Melbourne, Florida 32901
*
E-mail: alaahassan2001@yahoo.com
Received August 3, 2011
DOI 10.1002/jhet.1642
Published online 2 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
H3CO2C
S
H
H
N
H
N
MeOH
Reflux
+
H3CO2C
CO2CH3
O
R
N
R'
S
N
N
N
R
R'
Conjugated substituted (ylidene)hydrazinecarbothioamides react in high yield with dimethyl
acetylenedicarboxylate to give substituted [(ylidene)hydrazono)-4-oxothiazolidin-5-ylidene]acetates; several
mechanistic options involving nucleophilic interaction are presented.
J. Heterocyclic Chem., 51, 674 (2014).
INTRODUCTION
mass spectra clearly revealed that the products were
formed by the addition of one molecule of DMAD to one
molecule of 4a–r with elimination of one molecule of
methanol. There are possibilities for the formation of
various isomers 6–9 and 11–14 that would behave spectro-
scopically very similar (Schemes 2–5).
In recent years, there has been considerable interest in
reactivity of nitrogen-containing and sulfur-containing com-
pounds with dimethyl acetylenedicarboxylate (DMAD, 2)
[1–13]. The reaction of thioureas and thiosemicarbazide
derivatives with DMAD is a convenient and effective method
to prepare heterocycles possessing important biological ac-
tivities. For instance, thiazolidin-4-ones represent privileged
scaffolds in drug discovery [14,15]. A survey of recent
articles dealing with the pharmacological properties of such
compounds reveals that they display a wide range of activities
[16]. Also, compounds containing 5-ylidene-1,3-thiazolidin-
4-one moiety are reported to have antiviral [15], antimicrobial
[17], cardiotonic [18], and anticancer activities [19–22].
Recently, we reported that the reaction of arenecarbaldehyde
4-phenylthiosemicarbazones 1a–f with 2 gave methyl [3-aryl-
4-oxo-1-(phenylthiocarbamoyl)-4,5-dihydro-1H-pyrazol-5-
ylid-ene]ethanoates 3 (Scheme 1) [13].
If the reaction took place through N2 and either the
azomethine-CH or the SH of 4, the most likely products
would be 6 and 7, respectively (Scheme 2).
If N2 attacked the triple bond of 2 followed by intramolec-
ular nucleophilic attack of N4 at the a-ester and b-ester
groups, the products 8 and 9 would be observed (Scheme 3).
If SH attacked the triple bond of 2 followed by intramolec-
ular nucleophilic attack of N2 or N4 at the b-ester carbonyl,
the products 11 and 12 would be observed (Scheme 4).
The products 13 and 14 would be isolated if the reaction
involve the participation of SH and N4 or N2, respectively
(Scheme 5).
The IR spectra of the isolated compounds from the reac-
tion of 2 with 4a–r showed two carbonyl absorption bands
about 1728–1715 and 1705–1692 cmꢀ1, and a band between
1648 and 1605 cmꢀ1 that was assigned to a C═N vibration.
RESULTS AND DISCUSSION
These intriguing transformations led us to investigate the
reactions of thiosemicarbazones 4a–r bearing a selection
of aryl, alkyl, and alkenyl substituents with 2 (Fig. 1).
Compounds 4a–r may react either with their sulfur atom,
N2 or N4 as nucleophilic sites. On the other hand, it has been
reported that the azomethine carbon and N2 of 1 had taken
part in the heterocyclization [13]. The methine carbon of 4
had to act as a nucleophile in the sense of an “umpolung”
[13]. Thus, several options for interaction between 4a–r
and 2 may be expected as will be outlined later.
1
The H NMR spectra revealed a vinyl-CH singlet between
6.94–6.80 ppm and a methoxy singlet at about 3.91–3.78.
The 1H NMR signal of CH═N- is downfield shifted
(d = 8.3–7.6 ppm) because of the anisotropy of the N(sp2)
atom [23].
In all cases, the 13C NMR spectra show five downfield
lines at 166.22–163.93, 165.70–163.07, 159.92–157.75,
142.52–139.58, and 116.56–113.24 because of (C═O,
ester), (C-4), (C═N), (C-5), and vinyl-CH, respectively. Full
1H NMR and 13C NMR data are given in the experimental
part. The following additional remarks are necessary: the
1H NMR spectrum of 13c (R0═trans-CH═CH-Ph) shows
Treatment of 4a–r with one molar equivalent of DMAD
(2) in methanol at reflux resulted in the formation of single
products 13a–r in 72–89% yield. Elemental analyses and
© 2013 HeteroCorporation

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Synthesis of Thiazolidin-4-ones
675
Scheme 1
H
N
+
MeO2C
- MeOH
CO2Me
X
N
Ar
1a-f
2
O
CO2Me
H
Ar
N
N
X
3
1,3: a, Ar = C6H5; b, Ar = 4-MeO-C6H4; c, Ar = 4-Cl-C6H4;
d, Ar = 2-HO-C6H4; e, Ar = 2-Thienyl; f, Ar = 2-Furyl
X = Ph-NH-CS
two doublets at dH = 7.03–7.07 ppm because of CH═CH. In
its 13C NMR spectrum, the ethenyl (-CH═CH-) resonates at
142.69 (C-30) and 125.17 (C-20). The 1H NMR of R group in
13c resonated at 4.54, 5.31–5.26, and 5.92 ppm because of
(allyl-CH2N), (allyl-CH2═), and (allyl-CH═), respectively.
The presence of allyl group is also evident from the 13C
DEPT-135 spectrum exhibiting a positive signal at 130.22
(allyl-CH═) and negative signals at 45.34 and 118.88
because of allyl-CH2N and allyl-CH2═, respectively.
Figure 1. Substituted (ylidene)hydrazinecarbothioamides.
Scheme 2
The mass spectra showed the following four fragments
common to all products [M+ ꢀ 31], [M+ ꢀ R0CH═N2], RNCO,
m/z=59 (CO2Me).
For the compound 13c.
Structures 6–9 can be
immediately ruled out: the four C═X 13C chemical shifts
are all too far upfield for a C═S. These signals must
represent two C═O, one C═N, and C-5. The methoxyl
protons are distinctive at dH = 3.86; this signal gives HSQC
correlation with the attached carbon at dC = 52.61 and
HMBC correlation with the ester carbonyl at dC = 166.22
(Table 1). The signal (dC = 164.65) giving strong HMBC
correlation to vinyl-CH (dH = 6.89) is assigned as the
lactam carbonyl C-4. Under gated decoupling, this carbon
couples to vinyl-CH with J = 5.6 Hz, a value that requires a
three-bond not two-bond coupling [24]; thus, structures 11
and 12 can also be ruled out. The magnitude of this
coupling further argues that C-4 and vinyl-CH are mutually
cis [24a], as depicted in structures 13c and 14c. C-4 also
couples to and gives HMBC correlation with the allylic
methylene protons (dH = 4.54). This is consistent with
structure 13c but excludes structure 14c: it would be a
three-bond coupling in 13c but a five-bond coupling in
14c. The allylic methylene carbon appears in the coupled
spectrum as a well-resolved double-double-double-triplet,
with three different long-range C-H coupling constants.
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676
A. A. Hassan, A. A. Aly, K. M. A. El-Shaieb, T. M. I. Bedair, S. Bräse, and A. B. Brown
Vol 51
Scheme 3
Scheme 5
Scheme 4
The rest of the correlations and couplings are consis-
tent with the assigned structure [25]. The long-range C-H
couplings of C-m and C-o make these assignments un-
ambiguous: C-m (dC = 128.90) shows only doublet
coupling to H-m (dH = 7.39) on the opposite side, whereas
C-o (dC = 127.44) shows doublet coupling not only to the
“other” H-o (dH = 7.52) but also to H-p (dH = 7.34) and
H-30 (dH = 7.032). With the other cinnamylidene vinylic
protons H-10 and H-20 (dH = 8.255 and 7.072, respec-
tively), H-30 gives a classic ABX pattern [26], in which
J12 = 15.9 Hz; this value establishes the stereochemistry
between C-20 and C-30 as trans.
The spectral data of 13k show methoxy protons at
dH = 3.87; this signal gives HSQC correlation with the
attached carbon at dC = 52.52 and HMBC correlation with
the ester carbonyl at dC = 166.32. The signal (dC = 164.71)
giving HMBC correlation to vinyl-CH (dH = 6.94) is
assigned as the lactam carbonyl C-4. There is no direct
coupling or correlation between C-4 and the phenyl ring,
so it is assigned as 13k by analogy (Table 2).
In conclusion, all spectral data listed previously, espe-
cially the 13C chemical shifts for the ring carbonyl atoms
(C-100), C═N and thiazolidine-C-5 support the formation
of structures 13a–r as the reaction products.
The NMR spectra showed that only one stereoisomer
was present for all products, indicating that the reaction is
stereoselective. From these data, it follows that the
RNHCS group was changed; thus, the thioxo sulfur reacted
as a nucleophile. One ester group was converted into a
The carbon (dC = 116.05) giving HSQC correlation to
vinyl-CH is assigned as vinyl-CH. One other carbon
(dC = 141.57) gives HMBC correlation to vinyl-CH
(albeit weak) and is assigned as C-5 (Table 1).
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Synthesis of Thiazolidin-4-ones
677
Table 1
Spectroscopic data of compound 13c.
1H NMR (CDCl3)
1H-1H COSY
Assignment
8.26 (ABX, J = 10.0, ꢀ1.8; 1H)
7.52 (dd, J = 7.0, 1.2; 2H)
7.39 (dd, J = 7.2, 7.2; 2H)
7.34 (t, J = 7.1; 1H)
7.07 (ABX, J = 15.9, 10.0; 1H)
7.03 (ABX, J = 15.9, ꢀ1.8; 1H)
6.89 (s; 1H)
7.07, 7.03
7.39, 7.34
7.52, 7.34
7.52, 7.39
8.26
H-10
H-o
H-m
H-p
H-20
8.26
H-30
Vinyl-CH
Allyl-CH═
Allyl-CH2═ (cis)
Allyl-CH2═ (trans)
Allyl-CH2N
OCH3
5.92 (ddt, Jd = 16.7, 10.7, Jt = 6.0; 1H)
5.31 (dd, J = 17.1, 1.0; 1H)
5.26 (dd, J = 10.2, 0.8; 1H)
4.54 (d, J = 5.8; 2H)
5.31, 5.26, 4.54
5.92, 5.26, 4.54
5.92, 5.31, 4.54
5.92, 5.31, 5.26
3.86 (s; 3H)
13C NMR (CDCl3)
HSQC
HMBC
3.86
6.89, 4.54
7.03
Assignment
CO2CH3
C-4
166.22 (dq, Jd = 1.5, Jq = 3.5)
164.65 (dt, Jd = 5.6, Jt = 2.9)
161.88 (ddd, J = 162.2, 6.8, 1.4)
158.64 (bt, J = 3.4)
142.69 (bd, J = 154.9)
141.57 (s)
8.26
7.03
C-10
8.26
C-2
8.26, 7.52, 7.39, 7.07
6.89
C-30
C-5
135.72 (dt, Jd = Jt = 6.8)
7.52, 7.39, 7.07
Ar-C
130.22 (ddt, Jd = 159.3, 3.3, Jt = 5.6)
129.50 (dt, Jd = 161.3; Jt = 7.4)
128.90 (dd, J = 160.9, 7.5)
127.44 (dddd, J = 159.1, 6.7, 6.7, 4.1)
125.17 (ddd, J = 159.3, 9.3, 3.4)
118.88 (ddt, Jd = 160.6, 155.2, Jt = 5.4)
116.05 (d, J = 172.3)
5.92
7.34
7.39
7.52
7.07
5.31, 5.26
6.89
3.86
Allyl-CH═
C-p
C-m
7.52, 7.39
7.39, 7.34, 7.03
8.26, 7.032
4.54
C-o
C-20
Allyl-CH2═
Vinyl-CH
OCH3
Allyl-CH2N
3.86
52.47 (q, J = 147.6)
45.34 (dddt, Jd = 13.4, 8.0, 5.5, Jt = 142.3)
4.54
5.92, 5.31, 5.26
lactam carbonyl, and neither the azomethine carbon nor N1
took part in the heterocyclization.
The yield percentages of the obtained products increase
in the presence of aromatic moiety. On the other hand,
the thiazolidinone derivative 13q gives a lower yield, and
the reaction requires more time compared with the other
derivatives.
EXPERIMENTAL
General. Melting points were determined with a Gallenkamp
melting point apparatus (Weiss-Gallenkamp, Loughborough, UK)
and were uncorrected. The IR spectra were recorded with a
Shimadzu 408 instrument (Shimadzu Corporation, Kyoto, Japan)
using potassium bromide pellets. A 400 MHz 1H NMR and
100 MHz 13C NMR spectra were recorded on a Bruker AM 400 or
AV 400 spectrometer (Bruker BioSpin, Karlsruhe, Germany, and
Billerica, MA). Chemical shifts are expressed as d (ppm) with
reference of tetramethylsilane as internal standard; br, broad; s,
singlet; d, doublet; t, triplet; and m, multiplet. 13C assignments
(q, quaternary carbon atoms) were made with the aid of DEPT 135/
90 HMBC and HMQC experiments. The mass spectra (70 eV,
electron impact mode) were recorded on a Finnigan MAT instrument
(Thermo Finnigan, San Jose, CA). Elemental analyses were
carried out at the Microanalytical Center, Cairo University, Egypt.
CONCLUSION
Reactions of DMAD (2) with substituted (ylidene)
hydrazinecarbothioamides 4a–r having multiple bonds
conjugated with the thioamide moiety should be consid-
ered separately, taking into account possible competition
between nucleophilic addition of the SH group at the triple
bond of the activated acetylenic compound and the
methine carbon that act as a nucleophile in the sense of
an “umpolung”. The sulfur atom can be incorporated in
the ring, and the thiaheterocycles, S-C-N + C2 or N-CS-
N + C2 mode of cyclization, are favored with thiocarbohy-
drazides characterized by increased negative charge on sul-
fur atom. Comparison of 13C NMR chemical shifts as well
as HMBC measurements for the possible sets of isomers
may serve as a useful supplementary tool in finding the
correct structure of a heterocycle.
Starting materials.
General procedure. A solution of an aldehyde (1.0 mmol) in
5 mL dimethylsulfoxide was added dropwise with stirring at room
temperature to a solution of 4-substituted thiosemicarbazide
(1.0mmol) in the same solvent containing two drops of acetic
anhydride. The mixture was stirred for 3 h and left overnight. The
reaction mixture was poured into 250mL ice/water and then
filtered, and the precipitates recrystallize from ethanol to give
4a–r as colorless crystals.
N-Phenyl-2-(E)-3-phenylallylidene)hydrazinecarbothioamide
(4a). This compound was obtained as colorless crystals, mp
173–175ꢁ. (Lit. 175–176ꢁ) [27]. 1H NMR (DMSO-d6): 9.95 (1H,
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Vol 51
Table 2
Spectroscopic data of compound 13k.
1H NMR (CDCl3)
7.94 (d, J = 9.4; 1H)
1H-1H COSY
Assignment
6.37
H-10
7.51 (dd, J = 7.4, 7.4; 2H)
7.45 (t, J = 7.3; 1H)
7.38 (dd, J = 7.3, 1.4; 2H)
6.94 (s; 1H)
6.37 (ddd, J = 15.5, 9.5, 1.3; 1H)
6.24 (dq, Jd = 15.4, Jq = 6.7; 1H)
3.87 (s; 3H)
7.45, 7.38
7.51, 7.38
7.51, 7.45
H-m
H-p
H-o
Vinyl-CH
7.94, 6.24, 1.91
6.37, 1.91
H-20
H-30
OCH3
1.91 (dd, J = 6.6, 0.9; 3H)
6.37, 6.24
H-40
13C NMR (CDCl3)
166.32 (q, J = 3.6)
164.71 (d, J = 5.7)
162.32 (dd, J = 161.9, 8.0)
159.25 (s)
HSQC
HMBC
3.87
6.94
Assignment
CO2CH3
C-4
7.94
6.24
6.37, 6.24, 1.91
7.94
7.94, 6.37, 1.91
6.94
C-10
C-2
142.55 (ddq, Jd = 155.4, 7.5, Jq = 4.0)
141.50 (s)
C-30
C-5
133.92 (t, J = 9.4)
7.51, 7.45, 7.38
7.51
C-ipso
C-m
129.30 (dd, J = 163.4, 8.1)
129.16 (dt, Jd = 161.8, Jt = 7.6)
128.96 (dddq, Jd = 160.8, 9.6, 6.3, Jq = 3.2)
127.64 (ddd, J = 164.0, 7.6, 5.7)
116.24 (d, J = 172.6)
7.51
7.45
6.37
7.38
6.94
3.87
1.91
7.38
C-p
7.94, 6.24, 1.91
7.45, 7.38
3.87
C-20
C-o
Vinyl-CH
OCH3
C-40
52.52 (q, J = 147.7)
18.89 (ddq, Jd = 6.0, 4.0, Jq = 127.1)
6.37, 6.24
br, NH), 8.02 (1H, d, J = 9.41, CH═N), 7.65–6.9 (12H, m, Ar-H
and CH═CH). 13C NMR (DMSO-d6): 175.32 (C═S), 144.92
(CH═N), 139.29 and 138.92 (Ar-C), 135.85, 128.91, 128.07,
127.76, 126.94, 125.03 (Ar-CH and CH═CH). MS (EI): m/z
(%) = 281 [M+] (91), 151 (93), 135 (33), 115 (43), 91 (100), 77 (90).
N-Benzyl-2-(E)-3-phenylallylidene)hydrazinecarbothioamide
cmꢀ1. 1H NMR (DMSO-d6): 9.95 (1H, br, NH), 8.0 (1H, d, J = 9.4,
CH═N), 7.60–7.58 (3H, m, Ar-H), 7.35–7.32 (3H, m, Ar-H), 7.17–
7.14 (2H, m, Ar-H), 7.10–6.90 (3H, m, CH═CH and Ar-H), 3.90
(3H, s, CH3). 13C NMR (DMSO-d6): 175.24 (C═S), 156.42 (Ar-
C-O), 145.83 (CH═N), 138.09, 134.43 (Ar-C), 130.43, 128.03,
127.80, 125.79, 124.94, 124.82, 124.13 (Ar-CH), 120.77, 110.61
(CH═CH), 55.54 (CH3). MS (EI): m/z (%) = 311 [M+] (100), 280
(11), 135 (36), 91 (28), 77 (21). Anal. Calcd for C17H17N3OS
(311.40): C, 65.57; H, 5.50; N, 13.49; S, 10.30. Found: C, 65.65;
H, 5.41; N, 13.60; S, 10.17.
N-Benzyl-2-(E)-3-[(2-methoxyphenyl)allylidene)hydrazine-
carbothioamide (4e). This compound was obtained as colorless
crystals, mp 210–212ꢁ. IR (KBr): 3367, 3165 (NH), 2992 (Ali-CH),
1614, 1596 (Ar-C═C), 1356, 983 (C═S, C-N str.) cmꢀ1. 1H NMR
(DMSO-d6): 8.80 (1H, br, NH), 7.98 (1H, d, J=9.4, CH═N),
7.58–7.55 (1H, m, Ar-H), 7.30–7.20 (8H, m, Ar-H), 7.15–6.90
(2H, m, CH═CH), 4.83 (2H, s, CH2-Ph), 3.85 (3H, s, CH3). 13C
NMR (DMSO-d6): 177.01 (C═S), 156.88 (Ar-C-O), 145.44
(CH═N), 139.26, 133.97 (Ar-C), 130.21, 128.14, 127.51, 127.40,
126.76, 125.80, 124.13 (Ar-CH), 120.73, 111.57 (CH═CH), 55.52
(CH3), 46.52 (CH2-Ph). MS (EI): m/z (%) = 325 [M+] (100), 294
(22), 149 (32), 91 (40). Anal. Calcd for C18H19N3OS (325.12): C,
66.43; H, 5.88; N, 12.91; S, 9.85. Found: C, 66.28; H, 5.94; N,
13.11; S, 10.09.
(4b).
This compound was obtained as colorless crystals, mp
182–184ꢁ. IR: 3365, 3133 (NH), 2995 (Ali-CH), 1625, 1579 (Ar-
C═C), 1359, 971 (C═S, C-N str.) cmꢀ1. H NMR (DMSO-d6):
1
8.82 (1H, br, NH), 8.0 (1H, d, J = 9.39, CH═N), 7.62–7.60 (2H,
m, Ar-H), 7.50–7.25 (8H, m, Ar-H), 7.05–6.85 (2H, m,
CH═CH), 4.85 (2H, s, CH2-Ph). 13C NMR (DMSO-d6): 177.11
(C═S), 144.56 (CH═N), 138.86, 138.78 (Ar-C), 135.86, 129.35,
128.87, 128.17, 127.69, 127.42 (Ar-CH), 126.65, 125.05
(CH═CH), 46.55 (CH2-Ph). MS (EI): m/z (%) = 295 [M+] (20),
181 (36), 149 (21), 91 (100), 77 (17). Anal. Calcd for C17H17N3S
(295.11): C, 69.12; H, 5.80; N, 14.22; S, 10.85. Found: C, 68.97;
H, 5.91; N, 14.17; S, 11.03.
N-Allyl-2-(E)-3-phenylallylidene)hydrazinecarbothioamide
(4c). This compound was obtained as colorless crystals, mp 166–
1
167ꢁ. (Lit. 165–166ꢁ) [28]. H NMR (DMSO-d6): 8.46 (1H, br,
NH), 7.95 (1H, d, J=9.4, CH═N), 7.60–7.57 (2H, m, Ar-H),
7.43–7.30 (3H, m, Ar-H), 7.09–6.86 (2H, m, CH═CH), 5.93–5.90
(1H, m, allyl-CH═), 5.19–5.15 (2H, m, allyl-CH2═), 4.22–4.20
(2H, m, allyl-CH2N). 13C NMR (DMSO-d6): 176.86 (C═S),
144.40 (CH═N), 138.77 (Ar-C), 135.88 (allyl-CH═), 128.86,
128.79, 127.67 (Ar-CH), 126.87, 125.05 (CH═CH), 115.70 (allyl-
CH2═), 45.66 (allyl-CH2N). MS (EI): m/z (%) = 245 [M+] (19),
146 (22), 130 (81), 115 (100), 77 (31), 41 (86).
2-(E)-3-[(2-Methoxyphenyl)allylidene)-N-phenylhydrazine-
carbothioamide (4d). This compound was obtained as colorless
crystals, mp 190–192ꢁ. IR (KBr): 3315, 3236 (NH), 3123 (Ar-CH),
2983 (Ali-CH), 1619, 1594 (Ar-C═C), 1362, 983 (C═S, C-N str.)
N-Allyl-2-(E)-3-[(2-methoxyphenyl)allylidene)hydrazinecarbo-
thioamide (4f). This compound was obtained as colorless crystals,
mp 168–170ꢁ. IR (KBr): 3336, 3147 (NH), 3043 (Ar-CH), 2986
(Ali-CH), 1618, 1597 (Ar-C═C), 1358, 993 (C═S, C-N str.) cmꢀ1
.
1H NMR (DMSO-d6): 8.40 (1H, br, NH), 7.95 (1H, d, J=9.4,
CH═N), 7.57–7.55 (1H, m, Ar-H), 7.36–7.33 (3H, m, Ar-H),
7.10–6.90 (2H, m, CH═CH), 5.92–5.90 (1H, m, allyl-CH═), 5.15–
5.12 (2H, m, allyl-CH2═), 4.22–4.20 (2H, m, allyl-CH2N), 3.85
(3H, s, CH3). 13C NMR (DMSO-d6): 176.76 (C═S), 156.86 (Ar-C-
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Synthesis of Thiazolidin-4-ones
679
O), 145.30 (CH═N), 134.88 (allyl-CH═), 133.87 (Ar-C), 130.19,
129.06, 128.85, 125.81 (Ar-CH), 115.64 (allyl-CH2═), 120.73,
111.55 (CH═CH), 55.70 (CH3), 45.65 (allyl-CH2N). MS (EI): m/z
(%) = 275 [M+] (18), 160 (37), 130 (100), 115 (42), 91 (28), 77
(22). Anal. Calcd for C14H17N3OS (275.37): C, 61.06; H, 6.22; N,
15.26; S, 11.64. Found: C, 60.86; H, 6.29; N, 15.11; S, 11.81.
2-(E)-2-Methyl-3-phenylallylidene)-N-phenyl hydrazinecarbo-
(DMSO-d6): 175.38 (C═S), 145.21 (CH═N), 141.24 (═CH(3)),
138.90 (Ar-C), 128.39, 127.99, 127.72 (Ar-CH), 125.91 (═CH
(2)), 18.51 (CH3). MS (EI): m/z (%) = 219 [M+] (12), 192 (14),
151 (18), 135 (12), 77 (15), 41 (100).
2-(E)-Benzyl-2-(E)-but-2-enylidenehydrazinecarbothioamide
(4l).
This compound was obtained as colorless crystals, mp
150–152ꢁ. IR (KBr): 3257, 3150 (NH), 2997 (Ali-CH), 1644 (Ar-
1
thioamide (4g).
This compound was obtained as colorless
C═C), 1328, 970 (C═S, C-N str.) cmꢀ1. H NMR (DMSO-d6):
1
crystals, mp 187–189ꢁ. (Lit. 185–185.5ꢁ) [29]. H NMR (DMSO-
d6): 9.85 (1H, br, NH), 8.0 (1H, s, CH═N), 7.59–7.18 (10H, m,
Ar-H), 6.85 (1H, s, CH═), 2.20 (3H, s, CH3). 13C NMR (DMSO-
d6): 175.62 (C═S), 148.50 (CH═N), 138.98, 137.23 (Ar-C),
136.32 (═C-CH3), 134.32, 129.35, 128.45, 128.05, 127.73, 125.53
(Ar-CH), 125.22 (CH═), 12.85 (CH3). MS (EI): m/z (%) = 295
[M+] (16), 280 (7), 135 (17), 115 (22), 91 (100), 77 (66).
8.70 (1H, br, NH), 7.75 (1H, d, J=9.3, CH═N), 7.38–7.20 (5H, m,
Ar-H), 6.17-6.15 (2H, m, CH═CH), 4.80 (2 H, s, CH2-Ph), 1.83
(3H, dd, J=6.6, CH3). 13C NMR (DMSO-d6): 177.15 (C═S),
146.84 (═CH(3)), 144.78 (CH═N), 138.41 (Ar-C), 128.36, 127.52,
127.35 (Ar-CH), 126.62 (═CH(2)), 46.45 (CH2-Ph), 18.44 (CH3).
MS (EI): m/z (%) = 233 [M+] (10), 205 (5), 149 (15), 91 (100).
Anal. Calcd for C12H15N3S (233.33): C, 61.77; H, 6.48; N, 18.01;
S, 13.74. Found: C, 61.84; H, 6.35; N, 17.86; S, 13.89.
2-(E)-Hex-2-enylidene-N-phenylhydrazinecarbothioamide
(4h).
152–154ꢁ. IR (KBr): 3292, 3142 (NH), 2988 (Ali-CH), 1644,
1595 (Ar-C═C), 1324, 983 (C═S, C-N str.) cmꢀ1 1H NMR
This compound was obtained as colorless crystals, mp
N-Allyl-2-(E)-but-2-enylidenehydrazinecarbothioamide
(4m).
This compound was obtained as colorless crystals, mp
.
125–126ꢁ. IR (KBr): 3354, 3149 (NH), 2938 (Ali-CH), 1375, 997
1
(DMSO-d6): 9.85 (1H, br, NH), 7.85 (1H, d, J = 9.4, CH═N),
7.63–7.60 (2H, m, Ar-H), 7.30–7.28 (2H, m, Ar-H), 7.17–7.15
(1H, m, Ar-H), 6.22 (m, 2H, CH═CH), 2.24–2.20 (2H, m, CH2),
1.45 (2H, m, CH2), 0.85 (3H, t, J = 7.6, CH3). 13C NMR (DMSO-
d6): 175.37 (C═S), 145.21 (CH═N), 143.62 (═CH(3)), 138.96
(Ar-C), 127.98, 127.25, 124.88 (Ar-CH), 124.82 (═CH(2)), 34.38
(CH2), 21.29 (CH2), 13.51 (CH3). MS (EI): m/z (%) =247 [M+]
(100), 151 (76), 135 (64), 110 (51), 91 (48), 77 (41). Anal. Calcd
for C13H17N3S (247.36): C, 63.12; H, 6.93; N, 16.99; S, 12.96.
Found: C, 62.97; H, 7.07; N, 17.14; S, 12.79.
(C═S, C-N str.) cmꢀ1. H NMR (DMSO-d6): 8.25 (1H, br, NH),
7.73 (1H, d, J=9.3, CH═N), 6.18–6.15 (2H, m, CH═CH), 5.93–
5.90 (1H, m, allyl-CH═), 5.15–5.10 (2H, m, allyl-CH2═), 4.15
(2H, s, allyl-CH2N), 1.85 (3H, dd, J= 6.63, CH3). 13C NMR
(DMSO-d6): 176.88 (C═S), 144.62 (CH═N), 141.71 (═CH(3)),
134.95 (allyl-CH═), 128.37 (═CH(2)), 115.52 (allyl-CH2═), 45.57
(allyl-CH2N), 18.43 (CH3). MS (EI): m/z (%) 183 [M+] (18), 115
(100), 81 (17), 41 (55). Anal. Calcd for C8H13N3S (183.27): C,
52.43; H, 7.15; N, 22.93; S, 17.50. Found: C, 52.62; H, 7.06; N,
23.14; S, 17.36.
N-Benzyl-2-(E)-hex-2-enylidenehydrazinecarbothioamide
(4i). This compound was obtained as colorless crystals, mp 165–
167ꢁ. IR (KBr): 3342, 3149 (NH), 3003 (Ar-CH), 2956 (Ali-CH),
2-(2-Methylpropylidene)-N-phenylhydrazinecarbothioamide
(4n).
This compound was obtained as colorless crystals, mp
144–146ꢁ. IR (KBr): 3301, 3151 (NH), 3064 (Ar-CH), 2998 (Ali-
CH), 1599 (Ar-C═C), 1379, 981 (C═S, C-N str.) cmꢀ1. 1H NMR
(DMSO-d6): 9.70 (1H, br, NH), 7.63–7.60 (2H, m, Ar-H and
CH═N), 7.52–7.50 (1H, m, Ar-H), 7.35–7.33 (2H, m, Ar-H),
7.18–7.15 (1H, m, Ar-H), 2.57–2.55 (1H, m, CH), 1.12 (6H, d,
J = 6.5, 2CH3). 13C NMR (DMSO-d6): 175.65 (C═S), 152.45
(CH═N), 138.94 (Ar-C), 129.47, 128.56, 125.86 (Ar-CH), 30.84
(CH), 19.89, 19.56 (CH3). MS (EI): m/z (%) = 221 [M+] (14), 178
(28), 151 (11), 135 (12), 91 (21), 77 (26), 43 (100). Anal. Calcd
for C11H15N3S (221.10): C, 59.69; H, 6.83; N, 18.99; S, 14.49.
Found: C, 59.82; H, 6.74; N, 19.22; S, 14.34.
1642 (Ar-C═C), 1352, 995 (C═S, C-N str.) cmꢀ1 1H NMR
.
(DMSO-d6): 8.75 (1H, br, NH), 7.80 (1H, d, J=9.4, CH═N), 7.32–
7.21 (5H, m, Ar-H), 6.15 (2H, m, CH═CH), 4.80 (2H, s, CH2-Ph),
2.50 (2H, m, CH2), 1.45 (2H, m, CH2), 0.9 (3H, t, J= 7.63, CH3).
13C NMR (DMSO-d6): 177.15 (C═S), 144.76 (CH═N), 142.94
(═CH(3)), 139.31 (Ar-C), 128.10, 127.37, 127.35 (Ar-CH), 126.62
(═CH(2)), 46.45 (CH2-Ph), 34.31 (CH2), 21.27 (CH2), 13.48 (CH3).
MS (EI): m/z (%) = 261 [M+] (12), 151 (16), 149 (12), 91 (51), 77
(42), 43 (100). Anal. Calcd for C14H19N3S (261.39): C, 64.33; H,
7.33; N, 16.08; S, 12.27. Found: C, 64.12; H, 7.44; N, 15.96; S, 12.15.
N-Allyl-2-(E)-hex-2-enylidenehydrazinecarbothioamide
N-Benzyl-2-(2-methylpropylidene)hydrazinecarbothioamide
(4o). This compound was obtained as colorless crystals, mp 152–
154ꢁ (Lit. 154–156ꢁ) [31]. 1H NMR (DMSO-d6): 8.60 (1H, br, NH),
7.46–7.22 (6H, m, Ar-H and CH═N), 4.85 (2H, s, CH2-Ph), 2.57–
2.54 (1H, m, CH), 1.03 (6H, d, J=6.5, 2CH3). 13C NMR (DMSO-
d6): 177.39 (C═S), 151.82 (CH═N), 139.46 (Ar-C), 128.11,
127.28, 126.69 (Ar-CH), 46.42 (CH2-Ph), 30.77 (CH), 19.60
(CH3). MS (EI): m/z (%) = 235 [M+] (18), 192 (19), 149 (10), 77
(37), 43 (100).
N-Allyl-2-(2-methylpropylidene)hydrazinecarbothioamide
(4p). This compound was obtained as colorless crystals, mp 127–
128ꢁ. IR (KBr): 3366, 3163 (NH), 2964 (Ali-CH), 1379, 962 (C═S,
C-N str.) cmꢀ1. 1H NMR (DMSO-d6): 8.16 (1H, br, NH), 7.35 (1H,
d, J= 9.3, CH═N), 5.94–5.90 (1H, m, allyl-CH═), 5.14–5.10
(2H, m, allyl-CH2═), 4.23–4.20 (2H, m, allyl-CH2N), 2.53–2.50
(1H, m, CH), 1.02 (6H, d, J =6.5, 2CH3). 13C NMR (DMSO-d6):
177.09 (C═S), 151.58 (CH═N), 135.11 (allyl-CH═), 115.43
(allyl-CH2═), 45.53 (allyl-CH2N), 30.74 (CH), 19.58, 19.50
(CH3). MS (EI): m/z (%) = 185 [M+] (100), 170 (11), 142 (22),
115 (38), 99 (22). Anal. Calcd for C8H15N3S (185.29): C, 51.86;
(4j).
This compound was obtained as colorless crystals, mp
130–132ꢁ. IR (KBr): 3352, 3147 (NH), 2956 (Ali-CH), 1365, 998
(C═S, C-N str.) cmꢀ1. H NMR (DMSO-d6): 8.30 (1H, br, NH),
1
7.78 (1H, d, J = 9.4, CH═N), 6.18–6.15 (2H, m, CH═CH), 5.94–
5.90 (1H, m, allyl-CH═), 5.13–5.10 (2H, m, allyl-CH2═), 4.15
(2H, s, allyl-CH2N), 2.17–2.15 (2H, m, CH2), 1.48–1.45 (2H, m,
CH2), 0.9 (3H, t, J = 7.65, CH3). 13C NMR (DMSO-d6): 176.87
(C═S), 142.87 (═CH(3)), 134.94 (allyl-CH═), 127.22 (═CH(2)),
115.52 (allyl-CH2), 45.57 (allyl-CH2), 34.31 (CH2), 21.28 (CH2),
13.48 (CH3). MS (EI): m/z (%)= 211 [M+] (11), 182 (5), 115
(38), 99 (20), 41 (100). Anal. Calcd for C10H17N3S (211.33): C,
56.83; H, 8.11; N, 19.88; S, 15.17. Found: C, 57.04; H, 8.21; N,
20.06; S, 14.95.
2-(E)-But-2-enylidene-N-phenylhydrazinecarbothioamide
(4k).
This compound was obtained as colorless crystals, mp
1
144–146ꢁ (Lit. 141–143ꢁ) [30]. H NMR (DMSO-d6): 9.80 (1H,
br, NH), 7.82 (1H, d, J = 9.3, CH═N), 7.58–7.55 (2H, m, Ar-H),
7.38–7.35 (2H, m, Ar-H), 7.17–7.15 (1H, m, Ar-H), 6.26–6.23
(2H, m, CH═CH), 1.85 (3H, dd, J = 6.6, CH3). 13C NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

680
A. A. Hassan, A. A. Aly, K. M. A. El-Shaieb, T. M. I. Bedair, S. Bräse, and A. B. Brown
Vol 51
H, 8.16; N, 22.68; S, 17.31. Found: C, 52.07; H, 8.06; N, 22.54; S,
17.47.
(Z)-Methyl 2-((Z)-3-allyl-4-oxo-2-{(E)-[(E)-3-phenylallylidene]-
hydrazono}thiazolidin-5-ylidene)acetate (13c). This compound
was obtained as yellow crystals; mp 150ꢁ. IR (KBr): 1715 (CO),
2-(2-Methylbutylidene)-N-phenylhydrazinecarbothioamide
(4q). This compound was obtained as colorless crystals, mp 80ꢁ.
IR (KBr): 3303, 3156 (NH), 2958 (Ali-CH), 1377, 981 (C═S, C-N
str.) cmꢀ1.1H NMR (DMSO-d6): 9.70 (1H, br, NH), 7.60–7.55 (2H,
m, Ar-H), 7.38–7.32 (1H, d, J = 9.3, CH═N), 7.30–7.27 (2H, m,
Ar-H), 7.18–7.15 (1H, m, Ar-H), 2.35–2.32 (1H, m, CH), 1.57–
1.38 (2H, m, CH2), 1.14–1.10 (3H, d, J = 6.6, CH3), 0.95–0.89
(3H, t, J = 7.65, CH3). 13C NMR (DMSO-d6): 175.58 (C═S),
152.01 (CH═N), 138.93 (Ar-C), 128.50, 127.98, 125.04 (Ar-CH),
37.40 (CH), 26.83 (CH2), 17.01 (CH3), 11.40 (CH3). Anal. Calcd
for: C12H17N3S (235.35): C, 61.24; H, 7.28; N, 17.85; S, 13.62.
Found: C, 61.33; H, 7.15; N, 18.02; S, 13.81.
1700 (COO), 1630 (C-2) and 1605 (Ar-C═C) cmꢀ1 1H NMR
.
and 13C NMR (see Table 1). MS (EI): m/z (%)= 355 [M+] (100),
324 (6), 280 (12), 211 (16), 168 (10), 144 (8), 130 (36), 116 (46),
83 (11), 77 (13), 59 (7), 41 (12). Anal. Calcd for C18H17N3O3S
(355.41): C, 60.83; H, 4.82; N, 11.82; S, 9.02. Found: C, 61.03;
H, 4.74; N, 12.01; S, 8.87.
(Z)-Methyl 2-((Z)-2-{(E)-[(E)-3-(2-methoxy-phenyl)allylidene]-
hydrazono}-4-oxo-3-phenylthiazolidin-5-ylidene)acetate (13d).
This compound was obtained as yellow crystals; mp 278–280ꢁ. IR
(KBr): 1722 (CO), 1700 (COO), 1615 (C-2) and 1600 (Ar-C═C)
1
cmꢀ1. H NMR (CDCl3): 8.18 (1H, d, J=9.9, CH═N), 7.61–7.39
(9H, m, Ar-H), 6.97 (2H, d, J= 15.9, CH═CH), 6.89 (1H, s, cyclic-
CH), 3.90 (3H, s, CH3), 3.87 (3H, s, OCH3). 13C NMR (CDCl3):
166.03 (CO-ester), 164.77 (C-4), 161.34 (CH═N), 157.85 (Ar-C-
O), 157.55 (C-2), 141.23 (C-5), 138.42 (═CH(3)), 134.99 (Ar-C),
130.73 (Ar-C), 129.80, 129.17, 127.88, 127.64, 125.56 (Ar-CH),
120.83 (═CH(2)), 115.62 (cyclic-CH), 55.51, 51.63 (CH3). MS
(EI): m/z (%) = 421 [M+] (19), 390 (48), 356 (7), 261 (5), 247 (8),
146 (6), 119 (8), 103 (6), 91 (10), 77 (9), 59 (54), 44 (100). Anal.
Calcd for C22H19N3O4S (421.47): C, 62.69; H, 4.54; N, 9.97; S,
7.61. Found: C, 62.54; H, 4.43; N, 10.11; S, 7.77.
2-Decylidene-N-phenylhydrazinecarbothioamide (4r).
This
compound was obtained as colorless crystals, mp 95ꢁ. IR (KBr):
3342, 3150 (NH), 2956–2926 (Ali-CH), 1352, 995 (C═S, C-N
str.) cmꢀ1.1H NMR (DMSO-d6): 9.73 (1H, br, NH), 7.63–7.55
(3H, m, Ar-H and CH═N), 7.35–7.30 (2H, m, Ar-H), 7.15–7.13
(1H, m, Ar-H), 2.3–2.26 (2H, m, CH2), 1.45–1.40 (2H, m, CH2-
CH3), 1.20–1.10 (12H, m, 6CH2), 0.94–.90 (3H, t, J = 7.6, CH3).
13C NMR (DMSO-d6): 175.44 (C═S), 148.12 (CH═N), 138.96
(Ar-C), 129.36, 128.20, 125.96 (Ar-CH), 31.49, 28.91, 28.79,
28.67, 28.37, 28.07, 25.91, 22.08 (CH2), 13.92 (CH3). Anal.
Calcd for: C17H27N3S (305.48): C, 66.84; H, 8.91; N, 13.76; S,
10.50. Found: C, 67.03; H, 9.05; N, 13.63; S, 10.62.
(Z)-Methyl 2-((Z)-3-benzyl-2-{(E)-[(E)-3-(2-methoxyphenyl)-
allylidene]hydrazono}-4-oxothiazolidin-5-ylidene)acetate (13e).
This compound was obtained as yellow crystals; mp 192–194ꢁ. IR
(KBr): 1720 (CO), 1700 (COO), 1620 (C-2) and 1600 (Ar-C═C)
Products.
1
cmꢀ1. H NMR (CDCl3): 8.3 (1H, d, J=9.9, CH═N), 7.55–7.30
General procedure.
A mixture of substituted (ylidene)
hydrazinecarbothioamide 4a–r (1mmol) and DMAD (2, 1 mmol)
in methanol was refluxed for 30 min (for compounds 4a–m) and
2 h (for compounds 4n–r). The solvent was evaporated, and the
solid residue was recrystallized from ethanol to give 13a–r.
(Z)-Methyl 2-((Z)-4-oxo-3-phenyl-2-{(E)-[(E)-3-phenyl-allylidene]
(9H, m, Ar-H), 7.0–6.92 (2H, d, J= 15.9, CH═CH), 6.9 (1H, s,
cyclic-CH), 5.10 (2H, s, CH2), 3.9 (3H, s, CH3), 3.88 (3H, s, OCH3).
13C NMR (CDCl3): 165.73 (CO-ester), 164.47 (C-4), 162.44
(CH═N), 157.75 (Ar-C-O), 157.06 (C-2), 141.21 (C-5), 137.5 (═CH
(3)), 134.77 (Ar-C), 130.19 (Ar-C), 128.40, 128.09, 127.61, 127.29,
127.56, 125.11 (Ar-CH), 120.34 (═CH(2)), 115.42 (cyclic-CH),
55.01, 51.93 (CH3), 46.05 (CH2). MS (EI): m/z (%) = 435 [M+] (41),
404 (92), 376 (4), 345 (8), 275 (9), 261 (12), 174 (5), 133 (14), 91
(44), 59 (39), 44 (100). Anal. Calcd for C23H21N3O4S (435.13): C,
63.43; H, 4.86; N, 9.65; S, 7.63. Found: C, 63.61; H, 4.94; N, 9.48;
S, 7.49.
(Z)-Methyl 2-((Z)-3-allyl-2-{(E)-[(E)-3-(2-methoxyphenyl)-
allylidene]hydrazono}-4-oxothiazo-lidin-5-ylidene)acetate (13f).
This compound was obtained as yellow crystals; mp 208–210ꢁ. IR
(KBr): 1715 (CO), 1700 (COO), 1630 (C-2) and 1605 (Ar-C═C)
cmꢀ1. 1H NMR (CDCl3): 8.25 (1H, d, J =9.9, CH═N), 7.68–7.30
(4H, m, Ar-H), 7.0–6.92 (2H, d, J= 15.9, CH═CH), 6.90 (1H, s,
cyclic-CH), 5.90 (1H, m, allyl-CH═), 5.3 (2H, m, allyl-CH2═),
4.58 (2H, m, allyl-CH2N), 3.9 (3H, s, CH3), 3.88 (3H, s, OCH3).
13C NMR (CDCl3): 166.06 (CO-ester), 164.61 (C-4), 162.18
(CH═N), 156.69 (C-2), 141.01 (C-5), 137.86 (═CH(3)), 134.22
(Ar-C), 130 (Ar-C), 129.44 (allyl-CH═), 129.49, 127.06, 124.88,
123.93 (Ar-CH), 120.68 (═CH(2)), 118.12 (allyl-CH2═), 115.12
(cyclic-CH), 54.77, 51.69 (CH3), 44.58 (allyl-CH2N). MS (EI): m/z
(%) = 385 [M+] (76), 354 (100), 278 (6), 211 (5), 174 (4), 144 (7),
128 (11), 83 (9), 59 (13), 44 (33). Anal. Calcd for C19H19N3O4S
(385.44): C, 59.21; H, 4.97; N, 10.90; S, 8.32. Found: C, 59.38; H,
5.08; N, 11.02; S, 8.23.
hydrazono}thiazolidin-5-ylidene)acetate (13a).
was obtained as yellow crystals; mp 263–265ꢁ. IR (KBr): 1722 (CO),
1695 (COO), 1630 (C-2) and 1600 (Ar-C═C) cmꢀ1 1H NMR
This compound
.
(CDCl3): 8.1 (1H, d, J= 10.0, CH═N), 7.5–7.28 (10H, m, Ar-CH),
6.98 (2H, d, J= 15.9, CH═CH), 6.90 (1H, s, cyclic-CH), 3.82 (3H, s,
OCH3). 13C NMR (CDCl3): 166.30 (CO-ester), 164.67 (C-4), 162.24
(CH═N), 159.84 (C-2), 142.58 (═CH(3)), 141.18 (C-5), 135.63,
133.89 (Ar-C), 129.77, 129.23, 128.90, 127.74, 125.09 (Ar-CH),
125.05 (═CH(2)), 116.48 (cyclic-CH), 52.56 (OMe). MS (EI): m/z
(%) = 391 [M+] (82), 363 (19), 332 (4), 324 (16), 247 (12), 119 (8),
116 (42), 103 (5), 77 (10), 59 (39), 44 (100). Anal. Calcd for
C21H17N3O3S (391.44): C, 64.43; H, 4.38; N, 10.73; S, 8.19. Found:
C, 64.29; H, 4.47; N, 10.89; S, 8.25.
(Z)-Methyl 2-((Z)-3-benzyl-4-oxo-2-{(E)-[(E)-3-phenyl-allylidene]
hydrazono}thiazolidin-5-ylidene)acetate (13b).
was obtained as yellow crystals; mp 206–208ꢁ. IR (KBr): 1718
(CO), 1705 (COO), 1630 (C-2) and 1595 (Ar-C═C) cmꢀ1 1H
This compound
.
NMR (CDCl3): 8.2 (1H, d, J = 9.9, CH═N), 7.45–7.20 (10H, m,
Ar-H), 7.02 (2H, dd, J = 15.9, CH═CH), 6.80 (1H, s, cyclic-CH),
5.02 (2H, s, CH2), 3.8 (3H, s, OCH3). 13C NMR (CDCl3): 166.22
(CO-ester), 164.98 (C-4), 161.94 (CH═N), 158.89 (C-2), 142.75
(═CH(3)), 141.57 (C-5), 135.74, 135.27 (Ar-C), 129.83, 128.99,
128.64, 128.17, 127.78, 127.46 (Ar-CH), 125.19 (═CH(2)),
116.13 (cyclic-CH), 52.49 (OMe), 46.60 (CH2). MS (EI): m/z
(%) = 405 [M+] (100), 374 (10), 346 (5), 302 (10), 272 (18), 261
(34), 219 (25), 144 (14), 133 (26), 91 (58), 59 (36), 44 (61). Anal.
Calcd for C22H19N3O3S (405.47): C, 65.17; H, 4.72; N, 10.36; S,
7.91. Found: C, 64.97; H, 4.81; N, 10.52; S, 8.04.
(Z)-Methyl 2-((Z)-2-{(E)-[(E)-2-methyl-3-phenylallylidene]-
hydrazono}-4-oxo-3-phenylthiazol-idin-5-ylidene)acetate (13g).
This compound was obtained as yellow crystals; mp 230–232ꢁ. IR
(KBr): 1718 (C-4), 1700 (COO), 1605 (C-2) and 1600 (Ar-C═C)
cmꢀ1
.
1H NMR (CDCl3): 8.1 (1H, J =9.8, CH═N), 7.58–7.4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Synthesis of Thiazolidin-4-ones
681
(10H, m, Ar-CH), 6.94 (1H, s, cyclic-CH), 6.80 (1H, s, CH attached
to phenyl), 3.88 (3H, s, OCH3), 2.55 (3H, s, CH3). 13C NMR
(CDCl3): 166.08 (CO-ester), 165.54 (CH═N), 164.74 (C-4),
159.92 (C-2), 140.62 (C-5), 136.35, 134.89 (Ar-C), 133.92 (C-
CH3), 129.62, 129.34, 129.21, 128.42, 128.12, 127.64 (Ar-CH),
116.14 (cyclic-CH), 52.55 (OMe), 13.17 (CH3). MS (EI): m/z
(%) = 405 [M+] (100), 377 (11), 346 (52), 328 (13), 261 (11), 142
(16), 119 (32), 103 (6), 59 (34), 44 (92). Anal. Calcd for
C22H19N3O3S (405.47): C, 65.17; H, 4.72; N, 10.36; S, 7.91.
Found: C, 64.97; H, 4.83; N, 9.51; S, 7.56.
(%) = 329 [M+] (52), 314 (100), 257 (6), 210 (10), 119 (8), 77 (9),
59 (8), 44 (16). C16H15N3O3S (329.37): Calcd: C, 58.34; H, 4.59;
N, 12.76; S, 9.74. Found: C, 58.19; H, 4.67; N, 12.91; S, 9.63.
(Z)-Methyl 2-((Z)-3-benzyl-2-{(E)-[(E)-but-2-enylidene]-
hydrazono}-4-oxothiazolidin-5-ylidene)acetate (13l).
This
compound was obtained as yellow crystals; mp 149–150ꢁ. IR
(KBr): 1718 (C-4), 1700 (COO), 1640 (C-2) and 1610 (Ar-C═C)
1
cmꢀ1. H NMR (CDCl3): 8.0 (1H, d, J =9.8, CH═N), 7.40–7.2
(5H, m, Ar-CH), 6.80 (1H, s, cyclic-CH), 6.29 (2H, m, CH═CH),
5.04 (2H, s, CH2-Ph), 3.80 (3H, s, OCH3), 1.87 (3H, d, J=6.55,
CH3). 13C NMR (CDCl3): 166.22 (CO-ester), 164.48 (C-4), 161.48
(CH═N), 158.12 (C-2), 142.66 (═CH(3)), 141.05 (C-5), 135.39
(Ar-C), 129.08, 128.83, 128.59 (Ar-CH), 128.10 (═CH(2)), 116.20
(cyclic-CH), 52.45 (OMe), 46.51 (CH2-Ph). MS (EI): m/z
(%) = 343 [M+] (36), 328 (9), 273 (6), 261 (12), 130 (11), 119 (6),
91 (83), 65 (8), 59 (36), 44 (100). Anal. Calcd for C17H17N3O3S
(343.40): C, 59.46; H, 4.99; N, 12.24; S, 9.34. Found: C, 59.63; H,
5.07; N, 12.38; S, 9.19.
(Z)-Methyl-2-((Z)-2-{(E)-[(E)-hex-2-enyl-idene]hydrazono}-
4-oxo-3-phenylthiazolidin-5-ylidene)acetate (13h). This
compound was obtained as yellow crystals; mp 198-200ꢁ. IR (KBr):
1722 (C-4), 1695 (COO), 1645 (C-2) and 1608 (Ar-C═C) cmꢀ1
.
1H NMR (CDCl3): 7.9 (1H, d, J=9.8, CH═N), 7.48–7.30 (5H, m,
Ar-CH), 6.89 (1H, s, cyclic-CH), 6.30–6.15 (2H, m, CH═CH), 3.80
(3H, s, OCH3), 2.15 (2H, m, CH2), 1.4 (2H, m, CH2), 0.85 (3H, t,
J=7.6, CH3). 13C NMR (CDCl3): 166.31 (CO-ester), 164.71 (C-4),
162.49 (CH═N), 159.19 (C-2), 147.68 (═CH(3)), 141.49 (C-5),
133.33 (Ar-C), 129.29, 129.19, 127.87, 127.50 (Ar-CH and ═CH
(2)), 116.44 (cyclic-CH), 52.52 (OMe), 35.09 (CH2), 21.68 (CH2),
13.66 (CH3). MS (EI): m/z (%) = 357 [M+] (26), 326 (4), 314 (100),
261 (5), 211 (8), 119 (9), 103 (6), 77 (12), 59 (8), 44 (16). Anal.
Calcd for C18H19N3O3S (357.43): C, 60.49; H, 5.36; N, 11.76; S,
8.97. Found: C, 60.31; H, 5.47; N, 11.65; S, 9.14.
(Z)-Methyl 2-((Z)-3-allyl-2-{(E)-[(E)-but-2-enylidene]-
hydrazono}-4-oxothiazolidin-5-ylidene)-acetate (13m). This
compound was obtained as yellow crystals; mp 158–159ꢁ. IR
(KBr): 1712 (CO), 1695 (COO), 1645 (C-2) and 1605 (Ar-C═C)
1
cmꢀ1. H NMR (CDCl3): 8.0 (1H, d, J= 9.94, CH═N), 6.82 (1H,
s, cyclic-CH), 6.35–6.20 (2H, m, CH═CH), 5.8 (1H, m, allyl-
CH═), 5.23–5.15 (2H, m, allyl-CH2═), 4.47 (2H, m, allyl-CH2N),
3.79 (3H, s, OCH3), 1.89 (3H, d, J=6.6, CH3). 13C NMR (CDCl3):
166.92 (CO-ester), 164.67 (C-4), 161.92 (CH═N), 158.03 (C-2),
142.32 (═CH(3)), 141.26 (C-5), 129.02 (allyl-CH═), 130.22 (═CH
(2)) 118.38 (allyl-CH2═), 115.84 (cyclic-CH), 52.44 (OMe), 45.37
(allyl-CH2N), 18.32 (CH3). MS (EI): m/z (%) = 293 [M+] (100), 278
(97), 262 (6), 225 (12), 211 (16), 170 (6), 83 (14), 59 (36), 44 (95).
Anal. Calcd for C13H15N3O3S (293.34): C, 53.23; H, 5.15; N,
14.32; S, 10.93. Found: C, 53.39; H, 5.06; N, 14.19; S, 11.11.
(Z)-Methyl 2-{(Z)-2-[(E)-(2-methylpropylidene)hydrazono]-
4-oxo-3-phenylthiazolidin-5-ylidene}acetate (13n). This
compound was obtained as yellow crystals; mp 182–184ꢁ. IR
(KBr): 1722 (C-4), 1700 (COO), 1638 (C-2) and 1620 (Ar-C═C)
cmꢀ1. NMR (CDCl3): 7.6 (1H, d, J = 9.8, CH═N), 7.45–7.30
(5H, m, Ar-CH), 6.9 (1H, s, vinyl-CH), 3.8 (3H, s, OCH3), 2.55
(1H, m, CH), 1.05 (6H, d, J = 6.5, 2CH3). 13C NMR (CDCl3):
169.81 (CH═N), 166.06 (C-ester), 164.0 (C-4), 159.35 (C-2),
141.75 (C-5), 133.88 (Ar-C), 129.35, 129.05, 128.44 (Ar-CH),
116.12 (vinyl-CH), 52.52 (OMe), 31.90 (CH), 19.46 (CH3). MS
(EI): m/z (%) = 331 [M+] (68), 316 (24), 303 (25), 288 (9), 261
(38), 212 (10), 119 (33), 103 (8), 77 (13), 59 (35), 44 (100). Anal.
Calcd for C16H17N3O3S (331.39): C, 57.99; H, 5.17; N, 12.68; S,
9.68. Found: C, 58.14; H, 5.11; N, 12.53; S, 9.79.
(Z)-Methyl 2-((Z)-3-benzyl-2-{(E)-[(E)-hex-2-enylidene]-
hydrazono}-4-oxothiazolidin-5-ylidene)acetate (13i). This
compound was obtained as yellow crystals; mp 108ꢁ. IR (KBr):
1715 (C-4), 1700 (COO), 1648 (C-2) and 1608 (Ar-C═C) cmꢀ1
.
1H NMR (CDCl3): 8.02 (1H, d, J = 9.8, CH═N), 7.40 (2H, m, Ar-
CH), 7.20 (3H, m, Ar-H), 6.83 (1H, s, cyclic-CH), 6.3 (2H, m,
CH═CH), 5.02 (2H, s, CH2-Ph), 3.78 (3H, s, OCH3), 2.18 (2H,
m, CH2), 1.43 (2H, m, CH2), 0.85 (3H, t, J = 7.6, CH3). 13C NMR
(CDCl3): 166.23 (CO-ester), 164.79 (C-4), 162.61 (CH═N),
158.77 (C-2), 147.81 (═CH(3)), 141.75 (C-5), 135.47 (Ar-C),
128.84, 128.10, 127.72 (Ar-CH), 116.3 (cyclic-CH), 52.43
(OMe), 46.79 (CH2-Ph), 35.11 (CH2), 21.70 (CH2), 13.12 (CH3).
MS (EI): m/z (%) = 371 [M+] (56), 343 (7), 328 (44), 302 (6), 261
(11), 119 (6), 103 (7), 91 (100), 65 (8), 59 (18), 44 (16). Anal.
Calcd for C19H21N3O3S (371.45): C, 61.44; H, 5.70; N, 11.31; S,
8.63. Found: C, 61.26; H, 5.81; N, 11.47; S, 8.50.
(Z)-Methyl 2-((Z)-3-allyl-2-{(E)-[(E)-hex-2-enylidene]-
hydrazono}-4-oxothiazolidin-5-ylidene)acetate (13j). This
compound was obtained as yellow crystals; mp 122ꢁ. IR (KBr):
1720 (CO), 1695 (COO), 1640 (C-2) and 1610 (Ar-C═C) cmꢀ1
.
NMR (CDCl3): 8.0 (1H, d, J = 9.8, CH═N), 6.80 (1H, s, vinyl-
CH), 6.25 (2H, m, CH═CH), 5.85 (1H, m, allyl-CH═), 5.20 (2H,
m, allyl-CH2═), 4.47 (2H, m, allyl-CH2N), 3.80 (3H, s, OCH3),
2.18 (2H, m, CH2), 1.42 (2H, m, CH2), 0.9 (3H, t, J = 7.6, CH3).
13C NMR (CDCl3): 164.62 (CO-ester), 163.07 (C-4), 160.24
(CH═N), 158.39 (C-2), 145.09 (═CH(3)), 142.52 (C-5),128.65
(allyl-CH═), 126.11 (═CH(2)) 117.30 (allyl-CH2═), 114.84
(vinyl-CH), 52.43 (OMe), 43.67 (allyl-CH2N), 32.31 (CH2), 20.13
(CH2), 18.0 (CH3). MS (EI): m/z (%) = 321 [M+] (41), 293 (10),
278 (100), 252 (5), 211 (7), 83 (8), 59 (16), 44 (58). Anal. Calcd
for C15H19N3O3S (321.39): C, 56.06; H, 5.96; N, 13.07; S, 9.98.
Found: C, 55.89; H, 6.09; N, 12.91; S, 10.13.
(Z)-Methyl 2-{(Z)-3-benzyl-2-[(E)-(2-methylpropylidene)-
hydrazono]-4-oxothiazolidin-5-ylidene}acetate (13o). This
compound was obtained as yellow crystals; mp 119ꢁ. IR (KBr):
1715 (C-4), 1700 (COO), 1642 (C-2) and 1620 (Ar-C═C) cmꢀ1
.
1H NMR (CDCl3): 7.76 (1H, d, J = 9.8, CH═N), 7.40–7.20 (5H,
m, Ar-CH), 6.80 (1H, s, cyclic-CH), 5.0 (2H, s, CH2-Ph), 3.78
(3H, s, OCH3), 2.6 (1H, m, CH), 1.08 (6H, d, J = 6.5, 2CH3). 13
C
NMR (CDCl3): 169.54 (CH═N), 166.40 (CO-ester), 165.07 (C-
4), 158.39 (C-2), 142.03 (C-5), 133.29 (Ar-C), 128.87, 128.59,
128.02 (Ar-CH), 115.30 (cyclic-CH), 52.99 (OMe), 46.45 (CH2-
Ph), 37.89 (CH), 19.58 (CH3). MS (EI): m/z (%)= 345 [M+] (58),
302 (100), 275 (12), 212 (8), 133 (11), 117 (9), 91 (61), 65 (10),
59 (13), 44 (27). Anal. Calcd for C17H19N3O3S (345.42): C,
59.11; H, 5.54; N, 12.17; S, 9.28. Found: C, 58.93; H, 5.48; N,
11.98; S, 9.39.
(Z)-Methyl 2-((Z)-2-{(E)-[(E)-but-2-enylidene]hydrazono}-4-
oxo-3-phenylthiazolidin-5-ylidene)acetate (13k).
This
compound was obtained as yellow crystals; mp 210–212ꢁ. IR
(KBr): 1718 (C-4), 1692 (COO), 1645 (C-2) and 1605 (Ar-C═C)
cmꢀ1 1H NMR and 13C NMR (see Table 2). MS (EI): m/z
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

682
A. A. Hassan, A. A. Aly, K. M. A. El-Shaieb, T. M. I. Bedair, S. Bräse, and A. B. Brown
Vol 51
[3] Csomös, P.; Fodor, L.; Bernäth, G.; Sinkkonen, J.; Salminen,
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Tetrahedron Lett 2008, 49, 2815.
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P. F.; Robertson, J. G.; Stock, D.; Sun, Y.; Walsh, A. W. Bioorg Med
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L. L. J Am Chem Soc 2004, 126, 10532.
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R.; Chiericozzi, M.; Galatulas, I.; Salvatore, G. Eur J Med Chem 1996,
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R.; Mani, S. Curr Med Chem Anti Canc Agents 2003, 3, 217.
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Gross, J. D.; Yuan, J.; Wagner, G. J Am Chem Soc 2002, 124, 1234.
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Harbinski, F.; Luus, L.; Christ, W.; Aktas, H.; Halperin, J. A. Bioorg
Med Chem Lett 2004, 14, 5401.
(Z)-Methyl 2-{(Z)-3-allyl-2-[(E)-(2-methylpropylidene)-
hydrazono]-4-oxothiazolidin-5-ylidene}acetate (13p). This
compound was obtained as yellow crystals; mp 149ꢁ. IR (KBr): 1720
(CO), 1690 (COO), 1640 (C-2) and 1615, 1590 (Ar-C═C) cmꢀ1. 1H
NMR (CDCl3): 7.73 (1H, d, J=9.8, CH═N), 6.80 (1H, s, cyclic-
CH), 5.85 (1H, m, allyl-CH═), 5.20 (2H, m, allyl-CH2═), 4.42 (2H,
m, allyl-CH2N), 3.79 (3H, s, OCH3), 2.55 (1H, m, CH), 1.1 (6H, d,
J=6.5, 2CH3). 13C NMR (CDCl3): 167.08 (CO-ester), 163.93 (C-4),
161.31 (CH═N), 158.62 (C-2), 139.58 (C-5), 127.74 (allyl-CH═),
116.12 (allyl-CH2═), 113.35 (cyclic-CH), 50.07 (OMe), 42.77 (allyl-
CH2N), 29.46 (CH), 17.63 (CH3). MS (EI): m/z (%) = 295 [M+] (61),
280 (12), 252 (100), 225 (34), 212 (44), 116 (12), 83 (17), 59 (9), 41
(35). Anal. Calcd for C13H17N3O3S (295.36): C, 52.86; H, 5.80; N,
14.23; S, 10.86. Found: C, 53.03; H, 5.71; N, 14.06; S, 11.05.
(Z)-Methyl 2-{(Z)-2-[(E)-(2-methylbutylidene)hydrazono]-
4-oxo-3-phenylthiazolidin-5-ylidene}acetate (13q). This
compound was obtained as yellow crystals; mp 172–174ꢁ. IR
(KBr): 1722 (C-4), 1700 (COO), 1640 (C-2) and 1590 (Ar-C═C)
cmꢀ1. 1H NMR (CDCl3): 7.65 (1H, d, J = 9.8, CH═N), 7.53–7.40
(5H, m, Ar-CH), 6.94 (1H, s, cyclic-CH), 3.9 (3H, s, OCH3), 2.38
(1H, m, CH), 1.38 (2H, m, CH2), 1.1 (3H, d, J = 6.5, CH3), 0.9
(3H, t, J = 7.68, CH3). 13C NMR (CDCl3): 168.57 (CH═N),
165.59 (CO-ester), 163.91 (C-4), 158.63 (C-2), 140.90 (C-5),
132.91 (Ar-C), 128.46, 128.29, 126.12 (Ar-CH), 11.20 (cyclic-
CH), 52.52 (OMe), 37.69 (CH), 26.31 (CH2), 16.31 (CH3), 10
(CH3). MS (EI): m/z (%)= 345 [M+] (44), 330 (32), 303 (61), 261
(22), 247 (6), 119 (16), 103 (8), 77 (12), 59 (40), 44 (100). Anal.
Calcd for C17H19N3O3S (345.42): C, 59.11; H, 5.54; N, 12.17; S,
9.28. Found: C, 58.96; H, 5.61; N, 11.99; S, 9.41.
(Z)-Methyl 2-{(Z)-2-[(E)-decylidenehydrazono]-4-oxo-3-
phenylthiazolidin-5-ylidene}acetate (13r). This compound was
obtained as yellow crystals; mp 132ꢁ. IR (KBr): 1728 (C-4), 1700
(COO), 1642 (C-2) and 1620, 1590 (Ar-C═C) cmꢀ1 1H NMR
.
(CDCl3): 7.70 (1H, d, J=9.8, CH═N), 7.45–7.30 (5H, m, Ar-CH),
6.90 (1H, s, cyclic-CH), 3.8 (3H, s, OCH3), 2.3 (2H, m, CH2), 1.50
(2H, m, CH2), 1.19 (12H, m, CH2), 0.8 (3H, t, J=7.6, CH3). 13C
NMR (CDCl3): 166.59 (CH═N), 165.66 (CO-ester), 164.58 (C-4),
159.05 (C-2), 141.66 (C-5), 129.26, 128.06, 127.35 (Ar-CH),
116.56 (cyclic-CH), 52.50 (OMe), 32.38, 31.88, 29.88, 29.38,
29.29, 29.01, 26.12, 22.52 (CH2), 14.12 (CH3). MS (EI): m/z
(%) = 415 [M+] (59), 330 (8), 303 (100), 261 (12), 119 (10), 77 (7),
59 (16), 44 (58). Anal. Calcd for C22H29N3O3S (415.55): C, 63.59;
H, 7.03; N, 10.11; S, 7.72. Found: C, 63.73; H, 6.94; N, 9.92; S, 7.87.
[23] Sohár, P. Nuclear Magnetic Resonance Spectroscopy; CRC
Press: Boca Raton, FL, 1983; Vol 2, p 89.
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M. D. Helv Chim Acta 1978, 61, 607. (b) Danilkina, N. A.; Mikhailov,
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Badertscher, M. Structure Determination of Organic Compounds, 4th
ed.; Springer: Berlin, 2009; pp 80–84, 93–100.
[26] Abraham, R. J.; Fisher, J.; Loftus, P. Introduction to NMR
Spectroscopy; John Wiley & Sons: Chichester, 1988; pp 72–80.
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Acknowledgment. Purchase of the AV-400 NMR spectrometer
was assisted by the National Science Foundation (CHE03-42251).
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Brown, A. B. J Heterocycl Chem 2008, 45, 521.
[2] Fodor, L.; Bernäth, G.; Sohár, P.; Gröschl, D.; Meier, H.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet