New approaches for the synthesis of thiazoles and their fused derivatives with antimicrobial activities

Article abstract of DOI:10.1002/jccs.200800167

The 2-ethoxy carbonyl methylene thiazol-4-one (3) reacts with acetophenone (4) to give the ethyl 2-(4-oxo-4,5-dihydro-thiazol-2-yl)-3-phenyl-2-butenoate (5). The reactivity of the latter product towards aromatic aldehydes 6a-d, cyanomethylene reagents 9a,

Full text of DOI:10.1002/jccs.200800167

Journal of the Chinese Chemical Society, 2008, 55, 1133-1144
1133
New Approaches for the Synthesis of Thiazoles and Their Fused
Derivatives with Antimicrobial Activities
Wagnat W. Wardkhan,a,* Mohamed A. Youssef,b Faten I. Hameda and Salama A. Ouf c
aNational Organization for Drug Control & Research, P. O. 29, Cairo, A. R. Egypt
bDepartment of Chemistry, Faculty of Science, Helwan University, Cairo, A. R. Egypt
cDepartment of Botany, Faculty of Science, Cairo University, Giza, A. R. Egypt
The 2-ethoxy carbonyl methylene thiazol-4-one (3) reacts with acetophenone (4) to give the ethyl 2-
(4-oxo-4,5-dihydro-thiazol-2-yl)-3-phenyl-2-butenoate (5). The reactivity of the latter product towards
aromatic aldehydes 6a-d, cyanomethylene reagents 9a,b, aromatic aldehydes 13a-d, phenylisothiocya-
nate (16), elemental sulfur and aromatic amines (20a-c) was studied to give arylidene, pyridine, thiophene
and anilide derivatives. Some of the newly synthesized derivatives were used to synthesize fused deriva-
tives. The antimicrobial activities of the newly synthesized products were tested in vitro for antimicrobial
activity against two bacterial isolates, one saprophytic (Escherichia coli) and the other parasitic (Xantho-
monas citri) and for antifungal activity against one saprophytic (Aspergillus fumigatus) and two
phytopathogenics (Rhizoctonia solani and Fusarium oxysporum).
Keywords: Thiazole; Pyrazole; Pyridazine; Antimicrobial.
INTRODUCTION
Thiazoles play a prominent role in nature. For exam-
densation product 5. The structure of compound 5 was
based on analytical and spectral data. Thus, the 1H NMR
spectrum showed a triplet at d 1.12 corresponding to ester
CH3, a singlet at d 2.50 for CH3 group, a quartet at d 4.22
for the ester CH2, a singlet at d 5.41 for CH2 group and a
multiplet at d 7.33-7.40 for phenyl protons. Moreover, the
13C NMR spectrum showed d at 14.28, 19.99 (2 CH3);
32.37, 59.25 (2 CH2); 87.39, 88.38 (2 CH); 121.58 (C-
Phenyl); 126.74, 128.95 (2 CH); 142.45, 146.39 (2 C=C);
166.26 (C=N); 167.01 (C=O); 174.21 (C=O). 13C NMR d
(DMSO) (DEPT), up lines: 14.28 (CH3); 19.99 (CH3);
87.39 (CH); 88.38 (CH), 126.74 (CH); 128.95 (CH), down
lines: 32.37 (CH2); 59.25 (CH2).
ple, the thiazolium ring present in vitamin B1 serves as an
electron sink and its coenzyme form is important for the
decarboxylation of a-keto acids.1 Various pesticides pos-
sessing a thiazole nucleus are well known in agriculture.
Large numbers of thiazole derivatives have emerged as ac-
tive pharmaceutical ingredients in several drugs for their
potential anti-inflammatory,2 anti-tumour,3 anti-hyperlip-
idemic,4 anti-hypertensive5 and several other biological
properties.6 Besides, thiazoles are also synthetic intermedi-
ates and common substructures in numerous biologically
active compounds.7-14 Thus, the thiazole nucleus has been
much studied in the field of organic and medicinal chemis-
try.
The reaction of compound 5 with aromatic aldehydes
was studied to give arylidine derivatives with potential bio-
logical activities. Thus, compound 5 reacts with either benz-
aldehyde (6a), 4-chlorobenzaldehyde (6b), 4-methoxy-
benzaldehyde (6c) or salicylaldehyde (6d), in each case a
single product with molecular formula C22H19NO3S,
C22H18NO3SCl, C23H21NO4S and C22H19NO4S, respec-
tively. Two possible isomeric structures were considered
for the reaction products, either 7a-d or 8a-d. The possibil-
ity of compounds 7a-d was ruled out on the basis of 13C
NMR which showed in the case of 8c (as an example) d at
RESULTS AND DISCUSSION
In this work we describe the uses of 2-ethoxy car-
bonyl methylene thiazol-4-one (3), which was obtained
earlier,15,16 through the reaction of ethyl cyanacetate (1)
with thioglycollic acid (2) in the presence of ethanol and
triethylamine in many heterocyclic transformations. Com-
pound 3 reacts with acetophenone (4) in the presence of
ammonium acetate at 140 °C to give the Knoevenagel con-
* Corresponding author. E-mail: wagnatward@hotmail.com

1134 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Wardkhan et al.
14.3 (CH3), 43.5 (ester CH2), 55.3 (CH3), 55.46 (OCH3),
59.5 (CH2), 89.48, 114.8 (2 CH); 120.4 (C=C), 126.1,
129.3, 131.8 (3CH), 152.1 (C=C); 160.4 (C=N); 166.8,
167.1 (2 C=O). 13C NMR d (DMSO) (DEPT): Up lines;
14.3 (CH3); 55.3 (CH3); 55.4 (OCH3); 89.4 (CH); 114.8
(CH); 126.1 (CH); 129.3 (CH); 131.8 (CH). Down lines;
43.5 (CH2); 59.5 (CH2). The reaction of compound 8a with
either malononitrile (9a) or ethyl cyanoacetate (9b) gave
the polyfunctionally substituted pyrano[2,3-d]thiazole de-
rivatives 11a,b. The reaction took place via the intermedi-
ate formation of 10a,b (see Scheme I). Structures of com-
pounds 11a and 11b were established on the basis of analyt-
ical and spectral data. Thus, the 1H NMR spectrum of 11a
showed a triplet at d 1.21 corresponding to the CH3 ester
group, a singlet at d 2.66 for the CH3 group, quartet at d
4.24 for the ester CH2 group, a singlet at d 5.43 for the NH2
group, and a multiplet at d 7.37-7.58 for the phenyl and
pyran protons. Further confirmation for structures 11a,b
was obtained through the synthesis of these compounds us-
ing other reaction routes. Thus, the reaction of compound 5
with either a-cyano cinmamonitrile (12a) or ethyl a-cya-
nocinmamate (12b) (Scheme I) in the presence of 1,4-diox-
an and a catalytic amount of triethylamine gave the same
polyfunctionally substituted pyrano[2,3-d]thiazole deriva-
tives 11a and 11b, respectively (finger print IR spectrum,
m.p. and mixed m.p.).
products are in agreement with the proposed structures.
Thus, the 1H NMR spectrum of 18a showed a triplet at d
1.16 corresponding to the ester CH3 group, a singlet at d
2.59 for the CH3 group, a quartet at d 4.22 for the ester CH2
group, a singlet (D2O exchangeable) at d 4.88 for the NH2
group, a singlet at d 5.99 for the pyran H-3 and a multiplet
at d 7.35-7.47 for the phenyl and pyran protons and a sin-
glet (D2O exchangeable) at d 8.92 for the NH group. The
reaction of compound 5 with elemental sulfur in 1,4-dioxan
containing triethylamine gave thiophene derivative 19 (see
Scheme III). On the other hand, the reaction of compound 5
with either aniline (20a), 2-amino-3-cyano-4,5,6,7-tetra-
hydro-benzo[b]thiophene (20b) or ethyl-2-amino-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (20c) in an oil
bath at 140 °C gave the anilide derivatives 21a-c, respec-
tively. The structures of the latter products were established
on the basis of analytical and spectral data (see Scheme III).
Compound 21a reacts with either benzaldehyde (6a),
p-chlorobenzaldehyde (6b), p-methoxybenzaldehyde (6c)
or salicyaldehyde (6d) to give the arylidene derivatives
22a-d, respectively. On the other hand, the reaction of com-
pound 21a with either malononitrile (9a), or ethylcyano-
acetate (9b) gave the substituted pyrano[2,3-d]thiazole de-
rivatives 23a,b.
It is convenient to notice that compounds, 5, 8a-d,
11a,b, 14a-d, 18a-d, 21a-c, 22a-d and 23a,b can exist in
either Z or E structures. However, according to the concept
of push-pull alkenes that was reviewed by Sandstrom,17
where the physicochemical properties and chemical reac-
tivity of numerous functionalized compounds of that type
have been extensively studied,18-23 and the recent studies
which showed that the 4-oxothiazolidines with one and two
exocyclic double bonds attached to a thiazolidine ring, re-
spectively, exemplify typical push-pull compounds which
can exist in Z/E equilibrium depending on temperature and
the nature of the solvent.24 One can say that compounds 5,
8a-d, 11a,b, 14a-d, 18a,b, 21a-c, 22a-d and 23a,b are ex-
amples of push-pull conjugated alkenes which are existing
in a Z/E equilibrium mixture. Moreover, the resonance ef-
fect existing in these compounds due to the presence of the
phenyl-diene moiety enhances such equilibrium.
The reaction of compound 5 with either benzenedi-
azonium chloride (13a), 4-chlorobenzenediazonium chlo-
ride (13b), 4-methybenzenediazonium chloride (13c) or
4-methoxybenzenediazonium chloride (13d) gave aryl-
hydrazone derivatives 14a-d, respectively. The analytical
and spectral data of the latter products are consistent with
the proposed structures (see experimental section). Com-
pounds 14a-d underwent ready cyclization when heated
under reflux in ethanolic/NaOH solution to give the 4-thi-
azol-2-yl-pyridazine derivatives 15a-d, respectively. The
reaction of compound 5 with phenylisothiocyanate (16) in
1,4-dioxan containing triethylamine gave the 3-thiazol-2-
yl-pyridine derivative 17, the structure of which was based
on analytical and spectral data. Thus, the 1H NMR spec-
trum showed a singlet at d 3.89 corresponding to pyridine
CH2, a singlet at d 5.77 for the thiazole CH2 and a multiplet
at d 7.29-7.38 corresponding to the phenyl protons. The re-
action of compound 5 with either malononitrile (9a) or
ethyl cyanoacetate (9b) gave the polyfunctionally substi-
tuted pyrano[2,3-d]thiazole derivatives 18a and 18b, re-
spectively. The analytical and spectral data of the latter
Biological Activity
The diverse biological activities of thiazoles and their
fused derivatives encouraged us to test and study the bio-
logical activities of some newly synthesized products. The
antibacterial and antifungal activities were tested.

Synthesis of Thiazoles and Their Fused Derivatives
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 1135
Scheme I

1136 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Wardkhan et al.
Scheme II
H
N
-
+
HC
N
Ar-X
Ph
N
NCl
+
X-Ar
5
C2H5OOC
13a, X = H
b, X = 4-Cl
c, X = 4-CH3
N
S
O
d, X = 4-OCH3
14a-d
Ar-X
O
N
N
Et-OH/NaOH
14a-d
N
Ph
S
O
15a, X = H
b, X = 4-Cl
c, X = 4-CH3
d, X = 4-OCH3
Ph
S
1,4-dioxan/Et3N
5
PhNCS
+
N
Ph
N
16
O
S
O
17
CH3
Ph
Et3N
H2C
R
CN
C2H5OOC
N
5
+
S
O
9a, R = CN
b, R = COOEt
Y
H2N
18a, Y = NH
b, Y = O
OH
S
5
+
OC2H5
S
N
Ph
S
O
19

Synthesis of Thiazoles and Their Fused Derivatives
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 1137
Scheme III
CH3
Ph
+
5
NH2
R
RHN
C
N
20a, R = Ph
CN
O
S
=
b, R
O
S
COOEt
c, R =
21a-c
S
CH3
Ph
PhHN
C
N
CHO
+
21a
O
S
O
X
CH
6a, X = H
b, X = 4-Cl
22a, X = H
b, X = 4-Cl
X
c, X = 4-OCH3
d, X = 2-OH
c, X = 4-OCH3
d, X = 2-OH
CH3
Ph
+
21a
H2C
R
CN
PhHN
C
O
N
S
O
9a, R = CN
b, R = COOEt
X
H2N
23a, X = NH
b, X = O
Biological Screening
of the bacterium or 7-day-old culture of spore suspension
of the fungus. The solutions of the tested compounds at 25
ug/mL in dimethylformamide (DMF) were placed sepa-
rately in the cup (8 mm diameter). The plates were incu-
bated at 28 °C and the resulting inhibition zones were
measured.
All described compounds were tested in vitro for
antimicrobial activity against two bacterial isolates, one
saprophytic (Escherichia coli) and the other parasitic
(Xanthomonas citri) and for antifungal activity against one
saprophytic (Aspergillus fumigatus) and two phytopatho-
genics (Rhizoctonia solani and Fusarium oxysporum).
The culture medium was the nutrient agar for bacteria
and Czapek’s Dox agar medium for fungi. The sterile me-
dium was inoculated with the test organism so that each
100 mL of the medium received 1 mL of a 24-hour culture
DMF as a blank exhibited no antimicrobial activity
against any of the tested organisms used.
As can be seen from the results, most of the synthe-
sized compounds showed antibacterial and/or antifungal
activities. Compounds 5, 8a, 8d, 11a, 16, 21b, 22c, 22d,

1138 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Wardkhan et al.
23a and 23b were highly active against Escherichia coli
and Xanthomonas citri, whereas 8b, 8c, 11b and 17 showed
moderate activity against this microorganism. And 14a and
22b showed the lowest activities. Compounds 8a, 8d, 14c
and 14d were highly active against A-fumigatus, com-
pounds 5, 14b, 17, 21b, 22a, 22d, 23a and 23b showed
moderate activity against A. fumigatus, R. solani and F.
oxysparum and compounds 8b, 8c and 19 were not active
against either R. solani or F. oxysparum. The bacterial iso-
lates were more susceptible to the synthesized compounds
than isolated fungals. The recorded inhibition zones are
summarized in Table 1.
Table 1. Inhibition zones in mm for some of the synthesized
compounds at a concentration level of 25 ug/mL
Compound E.coli X.citri A.fumigatus R.solani F.oxysporum
5
26
28
18
16
28
26
21
13
18
32
28
34
22
34
28
32
11
26
12
38
26
26
26
26
26
10
12
29
26
16
12
20
34
30
30
15
14
26
30
11
18
10
28
28
20
20
12
19
06
08
30
16
05
06
16
32
28
18
14
12
16
17
04
14
08
18
15
14
16
10
17
05
00
15
18
03
05
04
20
18
14
14
06
15
16
05
13
08
16
18
16
13
12
13
00
04
18
19
00
04
04
17
18
18
18
00
16
18
04
18
08
16
16
17
17
8a
8b
8c
8d
11a
11b
14a
14b
14c
14d
16
Compounds 14c and 14d which have 4-methyl or 4-
methoxy instead of 4-chloro on the benzene ring, showed
higher activity than the corresponding compounds 14a and
14b. Compound 14c showed the highest activity against
the two bacteria, E. coli, X. citri and also towards the three
fungi A. fumigatums, R. solani, and F. oxysporum.
17
19
21a
21b
21c
22a
22b
22c
22d
23a
23b
EXPERIMENTAL
All melting points are uncorrected. IR spectra were
recorded for (KBr) discs on a Pye Unicam SP-1000 Spec-
trophotometer. 1H NMR Spectra were measured on a Var-
ian EM-390-200 MHz and Bruker AVANCE DRX-500-
300 MHz in CD3SOCD3 as solvent, using TMS as internal
standard, and chemical shifts are expressed as d. 13C NMR
spectra were measured on a Bruker AVANCE DRX-500.
Analytical data were obtained from the Micro Analytical
Data Unit at Cairo University, Giza, Egypt.
128.95 (2 CH), 142.45, 146.39 (2 C=C), 166.26 (C=N),
167.01 (C=O), 174.21 (C=O). 13C NMR d (DMSO) (DEPT):
Up lines: 14.28 (CH3), 19.99 (CH3), 87.39 (CH), 88.38
(CH), 126.74 (CH), 128.95 (CH). Down lines: 32.37 (CH2),
59.25 (CH2). Calculated for C15H15NO3S (289.35): C,
62.26; H, 5.23; N, 4.84; S, 11.08. Found: C, 62.10; H, 5.26;
N, 5.02; S, 10.88.
Ethyl 2-(4,5-dihydro-4-oxothiazol-2-yl)-3-phenyl-2-
butenoate (5)
Ethyl 2-(5-benzylidene-4,5-dihydro-4-oxothiazol-2-yl)-
3-phenyl-2-butenoate (8a), ethyl 2-[5-(4-chlorobenzyli-
dene)-4,5-dihydro-4-oxothiazol-2-yl]-3-phenyl-2-bu-
tenoate (8b), ethyl 2-[5-(4-methoxybenzylidene)-4,5-
dihydro-4-oxothiazol-2-yl]-3-phenyl-2-butenoate (8c),
ethyl 2-[5-(2-hydroxy-benzylidene)-4,5-dihydro-4-oxo-
thiazol-2-yl]-3-phenyl-2-butenoate (8d), 5-benzylidene-
4,5-dihydro-4-oxothiazol-2-yl)-N,3-diphenylbut-2-en-
amide (22a), 5-(4-chlorobenzylidene)-4,5-dihydro-4-
oxothiazol-2-yl)-N,3-diphenylbut-2-enamide (22b),
5-(4-methoxybenzylidene-4,5-dihydro-4-oxothiazol-2-
yl)-N,3-diphenylbut-2-enamide (22c), 5-(2-hydroxy-
benzylidene-4,5-dihydro-4-oxothiazol-2-yl)-N,3-diphen-
ylbut-2-enamide (22d)
Procedure for the Synthesis of (5)
To a dry mixture of compound 3 (0.01 mol, 1.87 g),
acetophenone (1.20 g, 0.01 mol) was added in the presence
of ammonium acetate (2.0 g). The reaction mixture was
heated in an oil bath (at 140 °C) for 1 h, then left to cool.
The solid product formed after boiling in ethanol was col-
lected by filtration.
Compound 5
Yellow crystals from ethanol, yield 76% (2.19 g) and
m.p. 130 °C. IR (u/cm-1) = 2994-2899 (CH3, CH2), 1715 (2
C=O), 1677 (C=N), 1630 (C=C). MS: m/z (%) = 289
(20.8%), 243 (44.6%), 148 (100%), 103 (11.2%). 1H NMR
d = 1.12 (t, 3H, J = 7.61 Hz, CH3), 2.50-2.61 (s, 3H, CH3),
4.22 (q, 2H, J = 7.61 Hz, CH2), 5.41 (s, 2H, CH2), 7.33-7.40
(m, 5H, C6H5). 13C NMR d = 14.2, 19.9 (2 CH3), 32.37,
59.2 (2 CH2), 87.3, 88.3 (2 CH), 121.58 (C-phenyl), 126.74,
General procedure
An equimolar amount of either compound 5 (0.01

Synthesis of Thiazoles and Their Fused Derivatives
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 1139
mol, 2.89 g) or 21a (3.36 g, 0.01 mol), in ethanol (30 mL)
containing pipridine (0.5 mL) either benzaldehyde (0.01
mol, 1.06 mL), p-chlorobenzaldehyde (1.40 g, 0.01 mol),
p-methoxy-benzaldhyde (1.36 g, 0.01 mol), or salicylalde-
hyde (1.22 g, 0.01 mol) was added. The reaction mixture
was heated under reflux for 3 h. then poured into an ice/wa-
ter mixture containing a few drops of hydrochloric acid.
The solid product formed, in each case, was collected by
filtration.
Compound 8d
Yellow crystals from ethanol, yield 53.6% (2.3 g) and
m.p. 175 °C. IR (u/cm-1) = 3056 (CH aromatic), 2932, 2835
1
(CH3, CH2), 1685 (C=O), 1660 (C=N), 1592 (C=C). H
NMR d = 1.38 (t, 3H, J = 5.99 Hz, CH3), 2.54 (s, 3H, CH3),
4.24 (q, 2H, J = 5.99 Hz, CH2), 7.28-7.38 (m, 10H, C6H5,
C6H4, CH), 10.01 (s, 1H, OH). 13C NMR (DMSO) d (ppm)
= 14.3, 18.9 (2 CH3), 55.3 (CH3), 55.46 (OCH3), 59.56
(CH2), 89.48, 114.86 (2 CH), 120.49 (C=C), 126.18,
129.38, 131.82 (3CH), 152.19 (C=C), 160.46 (C=N),
166.83, 167.14 (2 C=O).13C NMR d (DMSO) (DEPT): Up
lines: 14.32 (CH3), 55.3 (CH3), 55.46 (OCH3), 89.48 (CH),
114.86 (CH), 126.18 (CH), 129.38 (CH), 131.82 (CH).
Down lines: 59.56 (CH2). Calculated for C22H19NO4S
(393.46): C, 67.16; H, 4.87; N, 3.56; S, 8.15. Found: C,
67.63; H, 4.80; N, 3.87; S, 7.99.
Compound 8a
Yellow crystals from ethanol, yield 61% (2.3 g), m.p.
106-108 °C. IR (u/cm-1) = 3056 (CH aromatic), 2976-2869
(CH3, CH2), 1690, 1685 (2 C=O), 1668 (C=N), 1633 (C=C).
1H NMR d = 1.36 (t, 3H, J = 7.02), 2.66 (s, 3H, CH3), 4.21
(q, 2H, J = 7.02 Hz, CH2), 7.28-7.39 (m, 11H, C6H4, C6H5,
CH). 13C NMR d = 13.6, 14.6 (2 CH3), 60.8 (CH2), 120.6,
122.8, 124.7, 126.4, 126.8, 128.0, 135.8, (2 C6H5), 155.8,
156.8, 158.2 (C=C), 166.1 (C=N), 169.7, 188.9 (2 C=O).
Calculated for C22H19NO3S (377.11): C, 70.00; H, 5.07; N,
3.71; S, 8.50. Found: C, 69.76; H, 4.95; N, 4.02; S, 8.73.
Compound 8b
Compound 22a
Pale yellow crystals from 1,4-dioxan, yield 70%
(2.96 g), m.p. 201-204 °C. IR (u/cm-1) = 3465-3321 (NH),
3053 (CH aromatic), 2860 (CH3), 1688, 1687 (2 C=O),
1655 (C=N), 1638 (C=C). 1H NMR d = 2.66 (s, 3H, CH3),
7.26-7.38 (m, 16H, 3C6H5, CH), 8.26 (s, 1H, NH). 13C
NMR d = 16.3 (CH3), 120.8, 121.8, 122.7, 122.8, 124.4,
126.6, 126.9, 127.8, 129.0, 129.3, 136.7, 146.1 (3C6H5),
157.3, 158.1, 159.6 (C=C), 166.4 (C=N), 171.4, 186.9 (2
C=O). Calculated for C26H20N2O2S (424.51): C, 73.56; H,
4.75; N, 6.60; S, 7.55. Found: C, 73.85; H, 4.88; N, 6.31; S,
7.73.
Yellow crystals from ethanol, yield 67% (3.0 g), m.p.
180 °C. IR (u/cm-1) = 3060 (CH aromatic), 2939-2862
1
(CH3, CH2), 1685 (C=O), 1660 (C=N), 1593 (C=C). H
NMR d = 1.36 (t, 3H, J = 6.59 Hz, CH3), 2.49 (s, 3H, CH3),
4.22 (q, 2H, J = 6.59 Hz, CH2), 7.25-7.46 (m, 10H, C6H4,
Ph, CH). 13C NMR d = 13.8, 14.9 (2 CH3), 61.3 (CH2),
122.6, 123.3, 123.9, 126.0, 127.1, 127.5, 134.6, 144.9 (2
C6H5), 156.5, 157.2, 159.9 (C=C), 166.8 (C=N), 170.6,
187.4 (2 C=O). Calculated for C22H18ClNO3S (411.90). C,
64.15; H, 4.40; N, 3.40; S, 7.78. Found: C, 64.15; H, 4.54;
N, 3.73; S, 8.02.
Compound 22b
Yellow crystals from 1,4-dioxan, yield 64% (2.93 g),
m.p. 222-225 °C. IR (u/cm-1) = 3473-3327 (NH), 3060 (CH
aromatic), 2880 (CH3), 1689, 2685 (2 C=O), 1657 (C=N),
1622 (C=C). 1H NMR d = 2.67 (s, 3H, CH3), 7.29-7.43 (m,
15H, 2C6H5, C6H4, CH), 8.29 (s, 1H, NH). 13C NMR d =
16.7 (CH3), 120.4, 120.9, 121.6, 122.6, 123.8, 125.3,
126.6, 127.3, 129.1, 129.7, 138.9, 147.9 (3C6H5), 157.0,
158.8, 159.8 (C=C), 166.7 (C=N), 170.9, 186.4 (2 C=O).
Calculated for C26H19ClN2O2S (458.96). C, 68.04; H, 4.17;
N, 6.10; S, 6.99. Found: C, 68.33; H, 4.24; N, 5.83; S, 7.32.
Compound 22c
Compound 8c
Yellow crystals from ethanol; yield 86% (3.5 g) and
m.p. 180 °C. IR (u/cm-1) = 3056 (CH aromatic), 2932-2835
1
(CH3, CH2), 1685 (C=O), 1660 (C=N), 1592 (C=C). H
NMR d = 1.40 (t, 3H, J = 7.01 Hz, CH3), 2.51, 3.04 (2s, 6H,
2CH3), 4.22 (q, 2H, J = 7.01 Hz, CH2), 7.32-7.44 (m, 10H,
C6H4, Ph, CH). 13C NMR d = 14.3, 18.6 (2 CH3), 43.5 (ester
CH2), 55.3 (CH3), 55.4 (OCH3), 59.5 (CH2), 89.4, 114.8 (2
CH), 120.4 (C=C), 122.5, 124.9, 126.1, 129.3, 131.8
(C6H5, C6H4), 152.1 (C=C), 160.4 (C=N), 166.8, 167.1 (2
C=O). 13C NMR d (DEPT): Up lines: 14.3 (CH3), 55.3
(CH3), 55.4 (OCH3), 89.4, 114.8, 124.9, 126.1, 129.3 (CH
aromatic); 131.8 (CH). Down lines: 59.5 (CH2). Calculated
for C23H21NO4S (407.48): C, 67.79; H, 5.19; N, 3.44; S,
7.87. Found: C, 67.91; H, 5.43; N, 3.71; S, 8.22.
Orange crystals from acetic acid; yield 72% (3.27 g)
and m.p. 170-174 °C. IR (u/cm-1) = 3469-3331 (NH), 3059
(CH aromatic), 2896 (CH3), 1689, 1687 (2 C=O), 1658
(C=N), 1633 (C=C). 1H NMR d = 2.58, 3.16 (2s, 6H, 2CH3),
7.29-7.40 (m, 15H, 2C6H5, C6H4, CH), 8.33 (s, 1H, NH).
13C NMR d = 16.4, 22.9 (2 CH3), 121.3, 121.9, 122.0,
122.3, 123.2, 124.9, 126.5, 127.1, 128.5, 129.3, 139.2,

1140 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Wardkhan et al.
146.4 (3C6H5), 156.8, 158.4, 159.5 (C=C), 166.9 (C=N),
169.5, 187.2 (2 C=O). Calculated for C27H22N2O3S (454.54):
C, 71.34; H, 4.88; N, 6.16; S, 7.05. Found: C, 71.65; H,
5.21; N, 6.37; S, 6.7.
C), 154.9, 167.9 (C=C), 166.4 (C=N), 169.9 (C=O). Calcu-
lated for C25H21N3O3S (443.52): C, 67.70; H, 4.77; N, 9.47;
S, 7.23. Found: C, 67.52; H, 4.50; N, 9.31; S, 7.07.
Compound 11b
Compound 22d
Yellow crystals from ethanol, yield 56% (2.53 g) and
m.p. 90 °C. IR (u/cm-1) = 3575-3163 (OH), 3065 (CH, aro-
matic), 2989, 2899 (CH3, CH2), 2195 (CN), 1677 (C=O),
1650 (C=N), 1633(C=C). 1H NMR d = 1.02-1.14 (t, 3H, J =
5.44 Hz, CH3), 3.30 (s, 3H, CH3), 4.23 (q, 2H, J = 5.44 Hz,
CH2), 7.12-7.51 (m, 11H, 2C6H5, pyrane H-4), 8.56 (s, 1H,
OH). 13C NMR d = 16.0, 18.6 (2 CH3), 60.4 (CH2), 59.0,
80.6 (pyran C-3, C-4), 116.6 (CN), 119.0, 121.8, 122.4,
122.9, 123.0, 123.4, 124.3, 124.7, 125.5, 127.6, 128.0,
129.3, 129.9, 133.5, 138.7, 140.9, 156.6 (2 C6H5, thiazole
C), 154.7, 167.3 (C=C), 166.0 (C=N), 169.5 (C=O). Calcu-
lated for C25H20N2O4S (444.11): C, 67.55; H, 4.54; N, 6.30;
N, 7.21. Found: C, 67.34; H, 4.28; N, 6.57; N, 7.48.
Ethyl 2-(4-oxo-4,5-dihydro-thiazol-2-yl)-3-phenyl-4-
(phenyl-hydrazono)-2-butenoate (14a). Ethyl 4-[(4-
chloro-phenyl)-hydrazono]-2-(4-oxo-4,5-dihydro-thi-
azol-2-yl)-3-phenyl-2-butenoate (14b). Ethyl 2-(4-oxo-
4,5-dihydro-thiazol-2-yl)-3-phenyl-4-(p-tolyl-hydrazo-
no)-2-butenoate (14c). Ethyl 4-[(4-methoxy-phenyl)-
hydrazono]-2-(4-oxo-4,5-dihydro-thiazol-2-yl)-3-phen-
yl-2-butenoate (14d)
Yellow crystals from ethanol/1,4-dioxan mixture,
yield 52% (2.28 g) and m.p. 150 °C. IR (u/cm-1) = 3473-
3329 (NH), 3050 (CH aromatic), 2946 (CH3) 1688, 1686 (2
C=O), 1654 (C=N), 1623 (C=C). 1H NMR d = 2.66 (s, 3H,
CH3), 7.32-7.42 (m, 15H, 2C6H5, C6H4, CH), 8.23 (s, 1H,
NH), 10.26 (s, 1H, OH). 13C NMR d = 16.4 (CH3), 120.0,
122.3, 122.9, 122.1, 123.8, 123.9, 125.8, 127.1, 127.3,
127.2, 138.2, 148.4 (3 C6H5), 156.8, 158.4, 159.5 (C=C),
166.9 (C=N), 169.5, 187.2 (2 C=O). Calculated for
C26H20N2O3S (440.51): C, 70.89; H, 4.58; N, 6.36; S, 7.28.
Found: C, 71.16; H, 4.83; N, 6.87; S, 7.07.
Ethyl 2-(5-amino-6-cyano-7-phenyl-7H-pyrano[2,3-d]-
thiazol-2-yl)-3-phenyl-2-butenoate (11a) and Ethyl
2-(6-cyano-5-hydroxy-7-phenyl-7H-pyrano[2,3-d]thi-
azol-2-yl)-3-phenyl-2-butenoate (11b)
General procedure: Method A
To a solution of compound 8a (0.01 mol, 3.77 g) in
ethanol (30 mL) containing triethylamine (0.5 mL), either
malononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate
(1.13 g, 0.01 mol) was added; the reaction mixture was
heated under reflux for 4 h. The solid product formed upon
pouring onto ice/water mixture was collected by filtration.
Method B
General Procedure
To a cold solution (0-5 °C) of compound 5 (2.89 g,
0.01 mol g) in acetic acid/ethanol (1:4) (50 mL) containing
sodium hydroxide (5 mL, 10%) either benzenediazonium
chloride (0.01 mol), 4-chlorobenzene-diazonium chloride
(0.01 mol), 4-methylbenzenediazonium chloride (0.01
mol) or 4-methoxy-benzenediazonium chloride (0.01 mol)
[prepared by adding sodium nitrite (0.02 mol, 1.38 g) solu-
tion to a cold solution (0-5 °C) of aniline (0.93 g, 0.01 mol),
4-chloroaniline (1.27 g, 0.01 mol), 4-methylaniline (1.07 g,
0.01 mol) or 4-methoxyaniline (1.23 g, 0.01 mol) contain-
ing the appropriate amount of hydrochloric acid with con-
tinuous stirring] was added with stirring. The reaction mix-
ture was left at 0-5 °C for 4 h and the formed solid product,
in each case, was collected by filtration.
To a solution of compound 5 (0.01 mol, 2.89 g) in eth-
anol (30 mL) containing triethylamine (0.5 mL), either a-
cyanocinnamonitrile (1.70 g, 0.01 mol) or ethyl a-cyano-
cinnamate (1.97 g, 0.01 mol) was added. The reaction mix-
ture was heated under reflux for 5 h and then the reaction
mixture was poured onto an ice/water mixture containing a
few drops of hydrochloric acid and the formed solid prod-
uct was collected by filtration.
Compound 11a
Orange crystals from ethanol, yield 56% (2.5 g) and
m.p. 164-166 °C. IR (u/cm-1) = 3455-3379 (NH2); 3059
(CH aromatic), 2931-2897 (CH3, CH2), 2197 (CN), 1694
(C=O); 1641 (C=N), 1595 (C=C). 1H NMR d = 1.21 (t, 3H,
J = 6.32 Hz, CH3), 2.66 (s, 3H, CH3), 4.24 (q, 2H, J = 6.32
Hz, CH2), 5.43 (s, 2H, NH2), 7.37-7.58 (m, 11H, 2C6H5,
pyran H-4). 13C NMR d = 16.3, 18.9 (2 CH3), 60.8 (CH2),
59.2, 80.3 (pyran C-3, C-4), 116.9 (CN), 119.3, 120.8,
122.6, 122.8, 123.2, 123.6, 124.6, 125.5, 127.8, 128.3,
129.0, 129.9, 133.5, 138.9, 141.2, 146.4 (2 C6H5, thiazole
Compound 14a
Red crystals from ethanol, yield 84% (3.30 g) and
m.p. 92 °C. IR (u/cm-1) = 3450-3325 (NH), 3066 (CH aro-
matic), 2993, 2900 (CH3, CH2), 1684, 1674 (2 C=O), 1660
(C=N), 1633 (C=C). 1H NMR d = 1.36 (t, 3H, J = 6.41 Hz,
CH3), 4.23 (q, 2H, J = 6.41 Hz, CH2), 5.33 (s, 2H, thiazole
CH2), 6.34 (s, 1H, CH=N), 7.32-7.41 (m, 10H, 2C6H5),

Synthesis of Thiazoles and Their Fused Derivatives
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 1141
8.21 (s, 1H, NH). 13C NMR d = 19.0 (CH3), 39.8 (thiazole
CH2), 60.8 (CH2), 119.8, 120.3, 122.9, 123.9, 124.0, 124.2,
125.3, 126.6, 128.0, 129.0, 134.9, 138.9, 140.0, 143.2 (2
C6H5, thiazole C-2), 153.7, 166.4 (C=C), 159.3, 163.1 (2
C=N), 169.3, 198.5 (2 C=O). Calculated for C21H19N3O3S
(393.46): C, 64.10; H, 4.87; N, 10.68; S, 8.15. Found: C,
63.87; H, 4.76; S, 8.44.
C22H21N3O4S (423.48): C, 62.40; H, 5.00; N, 9.92; S, 7.57.
Found: C, 62.14; H, 5.35; N, 10.27; S, 7.79.
4-(4,5-Dihydro-4-oxothiazol-2-yl)-2,5-diphenylpyrida-
zin-3(2H)-one (15a), 4-(4,5-dihydro-4-oxothiazol-2-yl)-
2-(4-chlorophenyl)-5-phenylpyridazin-3(2H)-one (15b),
4-(4,5-dihydro-4-oxothiazol-2-yl)-2-(4-methylphenyl)-5-
phenylpyridazin-3(2H)-one (15c) and 4-(4,5-dihydro-
4-oxothiazol-2-yl)-2-(4-methoxyphenyl)-5-phenylpyr-
idazin-3(2H)-one (15d)
Compound 14b
Dark brown powder from ethanol, yield 70% (2.89
g), m.p. 155 °C. IR (u/cm-1) = 3460-3326 (NH), 3066 (CH
aromatic), 2970, 2900 (CH3, CH2), 1687, 1679 (2 C=O),
1650 (C=N), 1632 (C=C). 1H NMR d = 1.34 (t, 3H, J = 7.05
Hz, CH3), 4.21 (q, 2H, J = 7.05 Hz, CH2), 5.31 (s, 2H,
thiazole CH2), 6.22 (s, 1H, CH=N), 7.24-7.38 (m, 9H,
C6H5, C6H4), 8.29 (s, 1H, NH). 13C NMR d = 18.8 (CH3),
39.1 (thiazole CH2), 60.5 (CH2), 119.6, 120.8, 121.3,
123.3, 124.6, 124.9, 126.2, 128.1, 129.6, , 137.3, 142.4,
148.7 (2 C6H5, thiazole C-2), 153.5, 166.8 (C=C), 159.1,
163.3 (2 C=N), 169.7, 198.0 (2 C=O). Calculated for
C21H18ClN3O3S (427.90): C, 58.94; H, 4.24; N, 9.82; S,
7.49. Found: C, 58.89; H, 4.69; N, 9.67; S, 7.82.
General procedure
A solution of either 14a (3.93 g, 0.01 mol), 14b (4.27
g, 0.01 mol), 14c (4.07 g, 0.01 mol) or 14d (4.23 g, 0.01
mol) in ethanol (50 mL) containing sodium hydroxide
(0.50 g) was heated under reflux for 4 h. The formed solid
product, upon pouring onto ice/water mixture containing
hydrochloric acid (till pH 6), was collected by filtration.
Compound 15a
Pale yellow crystals from 1,4-dioxane, yield 66%
(2.29 g) and m.p. 177 °C. IR (u/cm-1) = 3054 (CH aro-
matic), 2876 (CH2), 1685, 1682 (2 C=O), 1659 (C=N),
1630 (C=C). 1H NMR d = 5.36 (s, 2H, thiazole CH2), 6.29
(s, 1H, pyridine H-6), 7.35-7.40 (m, 10H, 2 C6H5). 13C
NMR d = 39.5 (thiazole CH2), 120.2, 120.6, 121.8, 122.6,
124.0, 124.7, 126.0, 127.6, 137.3, 142.5, 148.1 (2 C6H5,
pyridazine C, thiazole C-2), 154.5, 164.9 (2 C=N), 165.3,
198.6 (2 C=O). Calculated for C19H13N3O2S (347.39): C,
65.69; H, 3.77; N, 12.10; S, 9.23. Found: C, 65.44; H, 4.01;
S, 9.01.
Compound 14c
Brown crystals from ethanol, yield 76% (3.10 g),
m.p. 162 °C. IR (u/cm-1) = 3448-3321 (NH), 3066 (CH aro-
matic), 2969, 2908 (CH3, CH2), 1688, 1680 (2 C=O), 1661
(C=N), 1638 (C=C). 1H NMR d = 1.33 (t, 3H, J = 7.33 Hz,
CH3), 3.01 (s, 3H, CH3), 4.25 (q, 2H, J = 7.33 Hz, CH2),
5.42 (s, 2H, thiazole CH2), 6.28 (s, 1H, CH=N), 7.26-7.35
(m, 9H, C6H5, C6H4), 8.32 (s, 1H, NH). 13C NMR d = 18.6,
24.8 (2 CH3), 39.0 (thiazole CH2), 60.7 (CH2), 119.4,
120.4, 123.6, 125.8, 126.1, 128.3, 128.9, 130.2.6, 137.6,
144.4, 148.9 (C6H5, C6H4, thiazole C-2), 153.2, 166.3
(C=C), 159.0, 163.8 (2 C=N), 168.2, 198.6 (2 C=O). Cal-
culated for C22H21N3O3S (407.49): C, 64.85; H, 5.19; N,
10.31; S, 7.87. Found: C, 64.60; H, 5.10; N, 10.55; S, 8.16.
Compound 14d
Compound 15b
Yellowish brown crystals from ethanol, yield 66%
(2.51 g), m.p. 186-189 °C. IR (u/cm-1) = 3052 (CH aro-
matic), 2877 (CH2), 1689, 1681 (2 C=O), 1656 (C=N),
1638 (C=C). 1H NMR d = 5.35 (s, 2H, thiazole CH2), 6.27
(s, 1H, pyridine H-6), 7.28-7.35 (m, 9H, C6H5, C6H4). 13
C
NMR d = 39.8 (thiazole CH2), 120.8, 121.6, 121.9, 122.2,
123.8, 124.5, 126.7, 132.3, 134.0, 140.6, 147.8 (2 C6H5,
pyridazine C, thiazole C-2), 153.6, 163.7 (2 C=N), 163.7,
198.9 (2 C=O). Calculated for C19H12ClN3O2S (381.84):
C, 59.76; H, 3.17; N, 11.00; S, 8.40. Found: C, 60.03; H,
2.89; N, 10.83; S, 8.27.
Brown crystals from ethanol, yield 89% (3.76 g) and
m.p. 148 °C. IR (u/cm-1) = 3466-3321 (NH), 3067 (CH aro-
matic), 2970, 2900 (CH3, CH2), 1677 (C=O), 1650 (C=N),
1588 (C=C). 1H NMR d = 1.19 (t, 3H, J = 6.52 Hz, CH3),
3.22 (s, 3H, CH3), 4.28 (q, 2H, J = 6.49 Hz, CH2), 5.46 (s,
2H, CH2), 6.26 (s, 1H, CH=N), 7.32-7.41 (m, 9H, C6H4,
C6H5), 8.67 (s, 1H, NH). 13C NMR d = 18.6, 29.3 (2 CH3),
39.2 (thiazole CH2), 60.8 (CH2), 119.1, 120.6, 123.8,
125.9, 126.2, 128.6, 128.9, 130.2, 137.8, 144.0, 149.4
(C6H5, C6H4, thiazole C-2), 153.1, 166.2 (C=C), 159.2,
163.6 (2 C=N), 168.1, 198.3 (2 C=O). Calculated for
Compound 15c
Brown crystals from 1,4-dioxane, yield 79% (2.85 g),
m.p. 162 °C. IR (u/cm-1) = 3053 (CH aromatic), 2908
(CH2), 1689, 1683 (2 C=O), 1655 (C=N), 1636 (C=C). 1H
NMR d = 5.39 (s, 2H, thiazole CH2), 6.29 (s, 1H, pyrid-
azine H-6), 7.26-7.39 (m, 9H, C6H5, C6H4). 13C NMR d =
20.8 (CH3), 39.6 (thiazole CH2), 119.6, 121.0, 122.6,

1142 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Wardkhan et al.
123.3, 123.8, 124.2, 125.7, 126.7, 139.2, 143.6, 149.0 (2
C6H5, pyridazine C, thiazole C-2), 155.5, 165.0 (2 C=N),
166.4, 198.2 (2 C=O). Calculated for C20H15N3O2S
(361.42): Calcd: C, 66.46; H, 4.18; N, 11.63; S, 8.87.
Found: C, 66.78; H, 3.89; N, 11.57; S, 8.69.
poured onto ice/water mixture containing a few drops of
hydrochloric acid. The solid product formed, in each case,
was collected by filtration.
Compound 18a
Yellow crystals from methanol yield 65% (2.34 g),
m.p. 148-150 °C. IR (u/cm-1) = 3480-3321 (NH2, NH),
3054 (CH aromatic), 2987, 2880 (CH3, CH2), 1688 (C=O),
1666 (C=N); 1638 (C=C). 1H NMR d = 1.16 (t, 3H, J = 6.69
Hz, CH3), 2.59 (s, 3H, CH3), 4.22 (q, 2H, J = 6.69 Hz, CH2),
4.88 (s, 2H, NH2), 5.99 (s, 1H, pyran H-3), 7.35-7.47 (m,
5H, C6H5), 8.92 (s, 1H, NH). 13C NMR d = 16.3, 24.1 (2
CH3), 56.8 (CH2), 119.2, 122.4, 123.0, 124.9, 130.1, 143.5
(C6H5, thiazole C), 162.8 (C=N), 168.8 (C=O). Calculated
for C18H17N3O3S (355.41): Calcd: C, 60.83; H, 4.82; N,
11.82; S, 9.02. Found: C, 60.75; H, 5.04; N, 12.21; S, 8.84.
Compound 18b
Compound 15d
Yellow crystals from dimethylformamide, yield 69%
(2.55 g) and m.p. 220-224 °C. IR (u/cm-1) = 3061 (CH aro-
matic), 2893 (CH2), 1689, 1681 (2 C=O), 1658 (C=N),
1633 (C=C). 1H NMR d = 3.01 (s, 3H, CH3), 5.53 (s, 2H,
CH2), 6.28 (s, 1H, pyridazine H-6), 7.27-7.38 (m, 9H,
C6H4, C6H5). 13C NMR d = 24.6 (CH3), 39.8 (thiazole CH2),
119.8, 120.2, 120.8, 121.9, 123.8, 124.0, 125.7, 126.7,
139.6, 143.5, 149.3 (2 C6H5, pyridazine C, thiazole C-2),
155.8, 165.2 (2 C=N), 166.6, 198.1 (2 C=O). Calculated
for C20H15N3O3S (377.42): Calcd: C, 63.65; H, 4.01; N,
11.13; S, 8.50. Found: C, 63.83; H, 4.35; N, 11.27; S, 8.42.
5,6-dihydro-3-(4,5-dihydro-4-oxothiazol-2-yl)-1,4-di-
phenyl-6-thioxopyridin-2(1H)-one (17)
Yellow crystals (from ethanol), yield 53% (1.9 g) and
m.p. 145-148 °C. IR (u/cm-1) = 3058 (CH aromatic), 2990,
2876 (CH3, CH2), 1685, 1679 (2 C=O), 1661 (C=N), 1633
(C=C). 1H NMR d = 1.14 (t, 3H, J = 5.77 Hz, CH3), 2.33 (s,
3H, CH3), 4.26 (q, 2H, J = 5.77 Hz, CH2), 4.68 (s, 2H,
NH2), 5.87 (s, 1H, pyran H-2), 7.32-7.42 (m, 5H, C6H5).
13C NMR d = 16.0, 24.5 (2 CH3), 56.3 (CH2), 120.5, 122.9,
123.7, 124.1, 132.6, 143.8 (C6H5, thiazole C), 166.3, 168.0
(C=O). Calculated for C18H16N2O4S (356.43): C, 60.66; H,
4.53; N, 7.86; S, 9.00. Found: C, 60.87; H, 4.44; N, 8.04;
8.79.
Equimolar amounts of compound 5 (2.89 g, 0.01
mol), and phenylisothiocyanate (1.35 g, 0.01 mol), in 1,4-
dioxan (30 mL) containing triethylamine (0.50 mL), were
heated under reflux for 3 hr. The reaction mixture was
poured onto an ice/water mixture containing a few drops of
hydrochloric acid. And the formed solid product was col-
lected by filtration.
Compound 17
Orange crystals from ethanol, yield 78% (2.94 g) and
m.p. 180-184 °C. IR (u/cm-1) = 2894 (CH2), 1689, 1682 (2
C=O); 1659 (C=N), 1636 (C=C). 1H NMR d = 3.89 (s, 2H,
pyridine CH2), 5.77 (s, 2H, thiazole CH2), 7.29-7.38 (m,
10H, 2 C6H5). 13C NMR d = 39.6 (thiazole CH2), 120.5,
121.6, 122.8, 123.1, 123.8, 125.0, 126.1, 134.3, 136.2,
141.1, 143.6 (2 C6H5, pyridazine C, thiazole C-2), 166.4
(C=N), 163.5, 197.9 (2 C=O). Calculated for C20H14N2O2S2
(378.47): C, 63.47; H, 3.73; N, 7.40; S, 16.94. Found: C,
63.36; H, 3.89; N, 7.65; S, 17.25.
2-(2-ethoxy-2,5-dihydro-2-hydroxy-4-phenylthiophen-
3-yl)thiazol-4-(5H)-one (19)
An equimolar amount of compound 5 (2.89 g, 0.01
mol) in 1,4-dioxan (30 mL) containing triethylamine (0.5
mL) and elemental sulfur (0.32 g, 0.01 mol) was added.
The reaction mixture was heated under reflux for 3 h. The
reaction mixture was poured onto ice/water mixture con-
taining a few drops of hydrochloric acid. The solid product
formed was collected by filtration.
Compound 19
Ethyl 2-(7-amino-5-imino-5H-pyrano[2,3-d]thiazol-2-
yl)-3-phenyl-2-butenoate (18a) and ethyl 2-(7-amino-
5-oxo-5H-pyrano[2,3-d]thiazol-2-yl)-3-phenyl-2-bu-
tenoate (18b)
Orange crystals (from ethanol), yield 56% (1.80 g)
and m.p. 170 °C. IR (u/cm-1) = 3444 (OH), 3064 (CH aro-
matic), 2991-2899 (CH3, CH2), 1683 (C=O), 1640 (C=N),
1588 (C=C). 1H NMR d = 1.36 (t, 3H, J = 6.11 Hz, CH3),
4.24 (q, 2H, J = 6.11 Hz, CH2), 4.84, 5.31 (2s, 4H, thiazole
CH2, thiophene CH2), 7.34-7.41 (m, 5H, C6H5), 10.13 (s,
1H, OH). 13C NMR: d = 16.7 (CH3), 27.4 (thiophene CH2),
38.8 (thiazole CH2), 112.0 (thiophene C-2), 117.8, 122.3,
123.9, 125.3, 127.1, 128.0, 128.8 130.9, 133.4 (C6H5,
thiophene C-3, C-4), 165.2 (C=N). Calculated for
General Procedure
An equimolar amount of compound 5 (2.89 g, 0.01
mol) in ethanol (20 mL) containing triethylamine (0.5 mL)
and either malononitrile (0.66 g, 0.01 mol) or ethylcyano-
acetate (1.13 g, 0.01 mol) was added. The reaction mixture
was heated under reflux for 6 h, and then the mixture was

Synthesis of Thiazoles and Their Fused Derivatives
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 1143
C15H15NO3S2 (321.41): Calcd: C, 56.05; H, 4. 70; N, 14.93;
S, 19.95. Found: C, 55.93; H, 4.83; N, 15.21; S, 20.26.
Ethyl 2-(4-oxo-4,5-dihydro-thiazol-2-yl)-3-phenyl-but-
2-enoic acid phenylamide (21a). 2-(4-Oxo-4,5-dihydro-
thiazol-2-yl)-3-phenyl-but-2-enoic acid-(3-cyano-
4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-amide (21b).
Ethyl 2-[2-(4-oxo-4,5-dihydro-thiazol-2-yl)-3-phenyl-
but-2-enoyl amino]-4,5,6,7-tetrahydrobenzo[b]thio-
phene-3-carboxylate (21c)
Compound 21c
Yellow crystals yield 68% (3.29 g), m.p. 178 °C. IR
(u/cm-1) = 3053 (CH aromatic), 2941, 2885 (CH3, CH2),
1689, 1682 (2 C=O), 1665 (C=N), 1631 (C=C). 1H NMR d
= 1.16 (t, 3H, J = 7.01 Hz, CH3), 2.04-2.24 (s, 4H, 2 CH2),
2.30-2.37 (m, 4H, CH2), 2.73 (s, 3H, CH3), 4.22 (q, 2H, J =
7.01 Hz, CH2), 5.31 (s, 2H, thiazole CH2), 7.30-7.39 (m,
5H, C6H5), 8.31 (s, 1H, NH). 13C NMR d = 14.0, 22.6 (2
CH3), 19.3 (thiazole CH2), 20.1, 23.0, 23.1, 24.0 (cyclo-
hexene CH2), 60.9 (ester CH2), 119.9, 123.7, 124.9, 126.2,
128.0, 129.6 (C6H5), 154.6, 155.9 (C=C), 166.3 (C=N),
165.8, 198.6 (2 C=O). Calculated for C24H24N2O4S2
(468.59): Calcd: C, 61.52; H, 5.16; N, 5.98; S, 13.69.
Found: C, 61.75; H, 5.44; N, 6.06; S, 13.99.
General Procedure
An equimolar amount of compound 5 (2.89 g, 0.01
mol), in dimethylformamide (30 mL), either aniline (0.93
g, 0.01 mol), 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo-
[b]thiophene (1.80 g, 0.01 mol) or ethyl-2-amino-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (2.38 g, 0.01
mol) was added. The reaction mixture was heated under re-
flux for 2 h and then the reaction mixture was poured onto
an ice/water mixture containing a few drops of hydrochlo-
ric acid. The solid product formed, in each case, was col-
lected by filtration.
2-(7-Amino-5-imino-5H-pyrano[2,3-d]thiazol-2-yl)-N,3-
diphenylbut-2-enamide (23a) and 2-(7-Amino-5-oxo-
5H-pyrano[2,3-d]thiazol-2-yl)-N,3-diphenylbut-2-en-
amide (23b)
General Procedure
An equimolar amount of compound 21a (3.36 g, 0.01
mol) in ethanol (20 mL) containing triethylamine (0.5 mL)
and either malononitrile (0.66 g, 0.01 mol) or ethyl cyano-
acetate (1.13 g, 0.01 mol) was added. The reaction mixture
was heated under reflux for 6 h, and then the mixture was
poured onto an ice/water mixture containing a few drops of
hydrochloric acid. The solid product formed, in each case,
was collected by filtration.
Compound 21a
Yellow crystals (from ethanol), yield 71% (2.34 g),
m.p. 190 °C. IR (u/cm-1) = 3058 (CH aromatic), 2924, 2870
(CH3, CH2), 1688, 1682 (3C=O), 1658 (C=N), 1623 (C=C).
1H NMR d = 2.78 (s, 3H, CH3), 5.31 (s, 2H, thiazole CH2),
7.31-7.37 (m, 10H, C6H5), 8.28 (s, 1H, NH). MS: m/z = 336
(18%), 289 (33.9%), 243 (58.8%), 148 (100%), 93 (52.2%).
13C NMR d = 13.8 (CH3), 40.1 (thiazole CH2), 119.6,
124.8, 125.7, 126.4, 126.8, 128.6, 128.8, 135.6, 139.0 (2
C6H5), 154.9, 156.5 (C=C), 166.5 (C=N), 164.7, 198.9 (2
C=O). Calculated for C19H16N2O2S (336.41): C, 67.84; H,
4.79; N, 8.33; S, 9.53. Found: C, 67.61; H, 4.86; N, 8.03; S,
9.72.
Compound 23a
Pale brown crystals from 1,4-dioxane, yield 59%
(3.53 g), m.p. 166 °C. IR (u/cm-1) = 3480-3311 (NH2, NH),
3058 (CH aromatic), 2971, 2880 (CH3, CH2), 1683 (C=O),
1668 (C=N), 1634 (C=C). 1H NMR d = 2.77 (s, 3H, CH3),
4.61 (s, 2H, NH2), 5.48 (s, 1H, pyrane H-3), 7.30-7.37 (m,
10H, 2 C6H5), 8.22, 8.36 (2s, 2H, 2NH). 13C NMR d = 14.3
(CH3), 122.8, 124.9, 125.0, 125.6, 125.7, 126.4, 126.7,
128.4, 128.7, 134.3, 139.6, 140.1 (2 C6H5), 153.9, 156.2
(C=C), 160.1, 164.6 (2 C=N), 171.9 (C=O). Calculated for
C22H18N4O2S (402.47): Calcd: C, 65.65; H, 4.51; N, 13.92;
S, 7.97. Found: C, 65.81; H, 4.81; N, 14.22; S, 8.27.
Compound 23b
Compound 21b
Orange-red crystals from acetic acid yield 63% (2.75
g), m.p. 108 °C. IR (u/cm-1) = 3058 (CH aromatic), 2944,
2875 (CH3, CH2), 1686, 1680 (2 C=O), 1655 (C=N), 1624
(C=C). 1H NMR d = 2.02-2.22 (s, 4H, 2CH2), 2.31-2.36 (m,
4H, CH2), 2.73 (s, 3H, CH3), 5.31 (s, 2H, thiazole CH2),
7.30-7.39 (m, 5H, C6H5), 8.31 (s, 1H, NH). 13C NMR d =
14.2 (CH3), 19.1 (thiazole CH2), 20.1, 23.0, 23.1, 24.0
(cyclohexene CH2), 116.3 (CN), 120.5, 123.7, 124.0,
126.2, 128.0, 128.3 (C6H5), 154.2, 156.8 (C=C), 166.1
(C=N), 165.3, 199.0 (2 C=O). Calculated for C22H19N3O2S2
(421.54): C, 62.68; H, 4.54; N, 9.97; S, 15.21. Found: C,
62.41; H, 4.56; N, 10.27; S, 14.85.
Pale brown crystals from 1,4-dioxan, yield 59% (3.53
g), m.p. 166 °C. IR (u/cm-1) = 3440-3321 (NH2, NH), 3053
(CH aromatic), 2978, 2883 (CH3, CH2), 1686, 1683 (2
C=O), 1655 (C=N), 1636 (C=C). 1H NMR d = 2.77 (s, 3H,
CH3), 4.68 (s, 2H, NH2), 5.48 (s, 1H, pyrane H-3), 7.30-
7.37 (m, 10H, 2 C6H5), 8.36 (s, 1H, NH). 13C NMR d = 14.0

1144 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Wardkhan et al.
Chem. 1996, 31, 1017.
(CH3), 120.3, 122.6, 124.8, 125.0, 125.2, 125.9, 126.2,
127.9, 128.7, 134.0, 139.3, 141.8 (2 C6H5), 153.9, 156.2
(C=C), 160.6 (C=N), 166.4, 169.8 (2 C=O). Calculated for
C22H17N3O3S (403.45): Calcd: C, 65.49; H, 4.25; N, 10.42;
S, 7.95. Found: C, 65.81; H, 4.81; N, 10.33; S, 8.77.
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