A convenient and facile synthesis of new thiazole derivatives

Article abstract of DOI:10.1080/10426500701724522

4-Chloro-2,3-dihydrothiazole-5-carboxaldehyde reacted with some nucleophilic reagents such as hydrazine hydrate, phenyl hydrazine, urea, thiourea, semicarbazide, cyanoacetamide, cyanothio-acetamide, cyanoacetohydrazide, 2-phenylenediamine, 2-aminophenol, 5-amino[1,2,4]triazole and 3-aminopyrazole in ethanol solution at reflux in the presence of catalytic amount of triethyl-amine afforded new polysubstituted thiazolo[4,5-c]pyrazole, thiazolo[4,5-d]-pyrimidine, thiazolo[4,5-b]-pyridine, thiazolo[4,5-b][1,5] benzodiazepine, thiazolo[4,5-b] [1,5]benzoxazepine, thiazolo[4′, 5′:6,5]-pyrimido[1,2-b][1,2,4]triazole and thiazolo[4′, 5′:6,5]pyrimido[1,2-b]pyrazole derivatives in good yields. The structure of the new compounds were confirmed based on IR, 1 H-,13C-NMR, mass spectral, and elemental analysis. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500701724522

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A Convenient and Facile
Synthesis of New Thiazole
Derivatives
Eman A. El Rady a
a Chemistry Department, Faculty of Science, South
Valley University, Aswan, Egypt
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Phosphorus, Sulfur, and Silicon, 183:1659–1671, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701724522
A Convenient and Facile Synthesis of New Thiazole
Derivatives
Eman A. El Rady
Chemistry Department, Faculty of Science, South Valley University,
Aswan, Egypt
4-Chloro-2,3-dihydrothiazole-5-carboxaldehyde reacted with some nucleophilic
reagents such as hydrazine hydrate, phenyl hydrazine, urea, thiourea,
semicarbazide, cyanoacetamide, cyanothio-acetamide, cyanoacetohydrazide, 2-
phenylenediamine, 2-aminophenol, 5-amino[1,2,4]triazole and 3-aminopyrazole
in ethanol solution at reflux in the presence of catalytic amount of triethyl-
amine afforded new polysubstituted thiazolo[4,5-c]pyrazole, thiazolo[4,5-d]-pyri-
midine, thiazolo[4,5-b]-pyridine, thiazolo[4,5-b][1,5]benzodiazepine, thiazolo[4,5-b]
[1,5]benzoxazepine, thiazolo[4ꢀ,5ꢀ:6,5]-pyrimido[1,2-b][1,2,4]triazole and thiazolo-
[4ꢀ,5ꢀ:6,5]pyrimido[1,2-b]pyrazole derivatives in good yields. The structure of the
1
13
new compounds were confirmed based on IR, H-, C-NMR, mass spectral, and
elemental analysis.
Keywords 2,3-Dihydrothiazole-5-carboxaldehyde; fused thiazole derivatives
INTRODUCTION
Thiazole derivatives have attracted a great deal of interest owing to
their antimicrobial activity,1,2 they used as antiviral, antimycobacte-
rial and showed antiproliferative.2 However, some of its derivatives
proved as agent against constipation,3 as potent and selective human
adenosine A3 receptor antagonists,4−6 as inhibitors of VEGF recep-
tors I and II,7 as vanilloid receptor I TRPVI antagonists.8 Also,
some new thiazole derivatives have been found to possess anti-
inflammatory and analgesic,9−11 as potent and selective acetyl CoA
carboxylase 2 inhibitors,12 and have potential as possible treatments
of Alzheimer’s,13 as noncovalent DNA-binding properties related to
leinamycin.14 Many thiazole derivatives have positive inotropic activity
of the novel histamine H2-receptor agonist, amthamine, on the human
Received 5 June 2007; accepted 19 June 2007.
Address correspondence to Eman A. El Rady, Chemistry Department, Faculty of Sci-
ence, South Valley University, Aswan, Egypt. E-mail: emanelradi@hotmail.com
1659

1660
E. A. El Rady
heart in vitro,15 as antitumor agents,16 as potent thrombin inhibitors,17
against thrombocytopenia.18 Moreover, thiazole derivatives well known
for their biological properties, antifungal activities19 and insecticidal
activities.20 On the other hand, fused thiazole heterocyclic compounds
play an essential role in several biological processes and have consider-
able chemical importance. In particular, thiazolopyridines were found
as histamine H3-antagonists,21 as inotropic activities.22 Furthermore,
thiazolopyrimidines can be found in a broad variety of pharmacological
properties,23 CXCR2 receptor antagonists,24 as antagonists of A1and
A2 adenosine receptors.25 However, in continuation of our interest in
the synthesis of fused heterocyclic derivatives,26−30 which might have
biological and/or medicinal effects, we report herein the utility of 4-
chloro-2,3-dihydrothiazole-5-carboxaldehyde 4 for the synthesis of sev-
eral new polysubstituted thiazole derivatives may found a medicinal
uses.
RESULTS AND DISCUSSION
Thus, the reaction of 4-bromoaniline with 3-nitrobenzaldehyde in
ethanolic piperidine solution at room temperature afforded the Schiff
base 1 which reacted with thioglycolic acid in benzene at reflux yielded
the thiazolidin-4-one derivative 3 through elimination of water from
the intermediate 2. The IR spectrum showed absorption bands at ν
1680 cm−1 due to the carbonyl of thiazolidinone. The MS of compound
1
3 showed m/z at 379 (M+, 93), 298 (30), 252 (20), 236 (39%). The H-
NMR revealed singlet signal at δ 4.5 ppm assigned for methylene and a
another singlet signal at 5.6 ppm for CH proton of thiazoldinone respec-
tively, and the multiplets protons appeared atδ 7.1–7.9 ppm. Also, the
13C-NMR showed signals at 30.2, 62.5, and 166.2 assigned for methy-
lene, CH and carbonyl carbons of thiazolidinone.
However, the Vilsmeir formylation of thiazolidin-4-one 3 afforded
4-chloro-2,3-dihydrothiazolidine-5-carboxaldehyde 4 (Scheme 1). The
IR spectrum showed bands at ν 1650 cm−1 due to CHO function. The
MS of compound 4 showed m/z at 427 (M+2, 3), 425 (M+, 10), 396
(30), 361 (20), 315 (39%). The 1H-NMR revealed a new singlet sig-
nal at δ 9.7 ppm assigned for CHO proton and the disappearance of
signal at 4.5 ppm. The 13C-NMR indicates the disappearance of ab-
sorption at 30.2 and showed new signals at 135.1 and 153.5 ppm as-
signed for C Cl and carbon of CHO group. The thiazole derivative 4
represents a versatile precursor for the synthesis of new fused thiazole
derivatives.

A Convenient and Facile Synthesis
1661
Br
NH2
OHC
+
Br
N=CH
NO2
NO2
1
SHCH2COOH
Br
HOOC
S
O
-H2O
N
HC
NH
Br
S
NO2
O2N
2
3
POCl3
DMF
Br
Cl
N
CHO
S
O2N
4
SCHEME 1
Thus, products obtained from the reaction of the carboxaldehyde 4
with hydrazine hydrate depend on the reactions conditions. So, stirring
of the reactants in ethanol at room temperature for 4 h yielded the cor-
responding Schiff base 5 in 85% yield. However, at reflux temperature
in pyridine an cyclization reaction takes place to afford thiazolo[4,5-
c]pyrazole 6 in 70% yield, (Scheme 2). It is noteworthy that, boiling of
the isolated intermediate 5 in ethanol solution containing triethylamine
yielded the compound 6 in 55% yield. The chemical structures of the
compounds 5 and 6 based on spectral and elementals analysis. The IR
spectrum of 5 showed absorption at band 3320 cm−1 due to NH2 function
with the disappearance of absorption of carbonyl function, whereas, the
IR spectrum of compound 6 showed band at 3110 cm−1due to the imino
group. The MS of compound 5 showed m/z at 441 (M+2, 10), 439 (M+,
30%) and the MS of compound 6 showed m/z at 404 (M+1, 20%). The
1H-NMR of compound 5 showed signals at 5.1 and 8.6 ppm due to NH2

1662
E. A. El Rady
Cl
Ar
N
Ar
N
NH
N
-HCl
H2N-NH2
-H2O
Ar'
Ar'
S
CH=NNH2
S
6
5
Ar
H2N-NHPh
-H2O, HCl
N
N
N
N
Ph
Ar'
S
S
7
H
N
X
Ar
Cl
Ar
X
N
H2N-C-NH2
N
X = O, S
-H2O, -HCl
Ar'
S
CHO
Ar'
8a, X = O
b, X = S
4
NH2
O
Ar
N
O
H2N-C-NH-NH2
-H2O, -HCl
N
N
Ar'
S
9
R
X
Ar
N
X
NC-CH2-C-NH-R
N
Ar'
S
CN
10a, X = O; R = H
b, X = S; R = H
c, X = O; R = NH2
Ar = 4-Br-Phenyl
Ar' = 3- NO2-Phenyl
SCHEME 2
1
and CH N protons, respectively, whereas, the H-NMR of 6 showed
singlet signal at δ 5.6 assigned for the H-2-thiazole and new singlet
signal at δ 6.8 assigned for H-6-pyrazole and lack of signal at 8.6 ppm.
The 13C-NMR of compound 5 showed new signals at 82.1 due to the car-
bon of –CH NNH2 which disappeared in the 13C-NMR of compound 6.
Also, the reaction of compound 4 with phenyl hydrazine under the same
reflux reaction conditions afforded directly the thiazolo[4,5-c]pyrazole
derivatives 7.
However, compound 4 represents a good synthon for thiazolopyrim-
idines, which found considerable interest in the medicinal and biolog-
ical field.31−33 Compound 4 reacted easily with urea and/or thiourea
in ethanol solution containing triethylamine at reflux temperature

A Convenient and Facile Synthesis
1663
to afford thiazolo[4,5-d]pyrimidine derivatives 8a,b via elimination of
H2O and hydrogen chloride (Scheme 2). The IR spectrum of 8a showed
the appearance of the characteristic absorption bands at 1690 and 3105
cm−1 assigned for carbonyl and imine functions, respectively. The MS
of compound 8a showed m/z at 431 (M+, 15%), and its 13C-NMR showed
new signal at δ 152.4 ppm due to C O.
Also, thiazolo[4,5-d]pyrimidine 9 obtained by a similar reaction
of compound 4 with semicarbazide under the same reaction condi-
tions. The chemical structures of the product based on spectral and
elemental analysis, (Scheme 2). However, a new thiazolopyridines
have been prepared via the reaction of compound 4 with cyanoac-
etamide, cyanothioacetamide and cyanoacetohydrazide in absolute
ethanol in the presence of triethylamine at reflux temperature to yield
thiazolo[4,5-b]pyridines 10 via elimination of water and hydrogen chlo-
ride, (Scheme 2). The IR spectrum of 10a revealed absorption bands at
1695 (CO), 2210 (CN), 3115 (NH) functions. The MS of 10a showed m/z
at 455 (M+, 10%). The1H-NMR of 10a showed singlet signal at δ 5.6
ppm and multiplets at δ 7.1–7.9 ppm. Also, the 13C-NMR showed signal
at 114.2 ppm for CN and at 158.4 ppm for C O.
However, the carboxaldehyde
4
reacted further with 2-
phenylenediamine in ethanol solution containing triethylamine
as catalyst, and at reflux temperature afforded a product. The IR spec-
trum of the product showed absorption band at 3340 cm−1 assigned for
amino function and revealed the lack of CHO absorption. The 1H-NMR
showed a new signal at δ 8.2 ppm for 1H. The mass measurement
showed m/z at 518 (M+2, 5), 516 (M+, 15%), which indicates that the
product is an open compound containing the chlorine atom. When the
reaction conducted in pyridine as a solvent at reflux the mass spectrum
of the product showed m/z at 479 indicating that the Schiff’s base
11 considered as an isolated intermediate for the thiazolodiazepine
derivative 12. The IR spectrum of compound 12 showed the absence of
the absorption band of amino function at 3340 cm−1 and appearance
1
of band at 3110 cm−1due to imino group. The H-NMR of 12 showed
the disappearance of the signal at δ 8.2 and showed singlet signal
at δ 5.2 ppm for H-2-thiazole and multiplets at δ 7.0–7.8 ppm. Also,
the isolated intermediate 11 was successfully transformed into 12 via
boiling in pyridine. On the other hand, in the case of 2-aminophenol the
thiazolo-1,5-benzoxapine derivative, 13 was obtained directly using
ethanol / triethylamine solution.
Finally, the reactivity of carboxaldehyde 4 towards some of amino
heterocyclic nucleophiles was also investigated. Thus, compounds
4 reacted with each of 5-amino-1H-1,2,4-triazole and 5-amino-3-
phenyl-1H-pyrazole in ethanolic triethylamine solution at reflux

1664
E. A. El Rady
NH2
NH2
Ar
Cl
Ar
NH
H2N
N
-HCl
N
-H2O
Ar'
S
CH=N
Ar'
N
S
11
12
NH2
OH
Ar
O
N
Ar
N
Cl
Ar'
N
-H2O,
S
-HCl
13
CHO
S
Ar'
HN
N
N
4
N
Ar = 4-Br-Phenyl
Ar' = 3- NO2-Phenyl
Ar
Ar
N
HN
N
N
N
H2N
-H2O
Cl
-HCl
N
N
N
S
Ar'
S
CH=N
Ar'
14
15
HN
N
Ph
N
Ph
Ar
N
HN
Ar
Cl
N
N
N
Ph
H2N
-H2O
-HCl
Ar'
N
S
S
CH=N
Ar'
16
17
SCHEME 3
temperature to give thiazolo[4ꢀ,5ꢀ:6,5]pyrimido[1,2-b]triazole 15 and
thiazolo[4ꢀ,5ꢀ:6,5]pyrimido[1,2-b]pyrazole 17, respectively via elimi-
nation of water and hydrogen chloride (Scheme 3). The structure
of 15 and 17 were established based on spectral and elemental
analysis.
EXPERIMENTAL
Melting points are uncorrected. The IR spectra (potassium bromide, ν
in cm−1) were recorded on a Pye-Unicam SP-1100 Spectrophotometer.
1H-NMR and 13C-NMR spectra (deuterodimethyl sulfoxide, δ in ppm)
were run on a Varian EM-390 Spectrometer using Tetramethylsilane
as internal standard. Mass spectra were recorded on a Varian MAT
311 A spectrometer, and the elemental analysis was determined at the
Micro-analytical Center, Cairo University, Egypt.

A Convenient and Facile Synthesis
1665
3-(4-Bromophenyl)-2-(3-nitrophenyl)thiazolidin-4-one 3
A solution of 1 (0.6 g, 2 mmol), thioglycolic acid (0.25 g, 2 mmol), in 30
ml of dry benzene was warmed at reflux for 2 h. The solid product so
formed during reflux was collected by filtration, dried and crystallized
from ethanol. M.p.: 160◦C, Yield: 90%. IR: ν 1680 (CO) cm−1; 1H NMR: δ
4.5 (s, 2H, CH2-thiaz.), 5.6 (s, H, CH-thiaz.), 7.1–7.9 (m, 8H, Ar-H); 13
C
NMR: 166.2 (C O), 123.6–135.5 (C-Phenyl), 62.5(C-2), 30.2 (C-5); MS
(70 eV) m/z (%): 379 (M+, 93). Anal. calcd. For C15H11BrN2O3S (379.23):
C, 47.51; H, 2.92; N, 7.39. Found: C, 47.59; H, 2.82; N, 7.49.
3-(4-Bromophenyl)-4-chloro-2,3-dihydro-2-(3-
nitrophenyl)thiazole-5-carboxaldehyde 4
A solution of thiazolidin-4-one 3 (0.2 mol) in DMF (50 ml) was cooled to
0◦C in an ice bath, then phosphoryl chloride (0.6 mol) was added drop-
wise at such a rate as to maintain the temperature between 10–20◦C.
The reaction mixture was then heated on water bath for an additional
three hours after completion of addition. The mixture was then poured
onto ice- water, and the resulting mixture allowed to stand overnight in
a refrigerator. The solid product thus obtained was filtered, washed well
with water, dried to give compound 4 as brown powder, and crystallized
from methanol.
M.p.: 140◦C, Yield: 46%. IR: ν 1650 (CO) cm−1; 1H NMR: δ 5.6 (s, H,
CH), 9.7 (s, H, CHO), 7.1–7.9 (m, 8H, Ar-H); 13C NMR: 153.5 (C O),
153.5 (C-5), 135.1 (C-4), 123.6–134.5 (C-Phenyl), 62.5 (C-2); MS (70 eV)
m/z (%): 427 (M+2, 3), 425 (M+, 10). Anal. calcd. For C16H10BrClN2O3S
(425.68): C, 45.15; H, 2.37; N, 6.59. Found: C, 45.19; H, 2.47; N, 6.45.
3-(4-Bromophenyl)-4-chloro-2,3-dihydro-5-methyene
hydrazine-2-(3-nitrophenyl) thiazole 5
A solution of carboxaldehyde 4 (0.4 g, 1 mmol), hydrazine hydrate (0.3
ml, excess) in 30 ml of dry ethanol was stirred at room temperature for
4 h and the solid formed was collected by filtration, washed well with 3
ml of methanol and crystallized from ethanol to give 5.
M.p.: 150◦C, Yield: 85%. IR: ν 3320 (NH2) cm−1; 1H NMR: δ 5.1 (s, 2H,
NH2), 5.5 (s, H, CH thiaz.), 7.1–7.9 (m, 8H, Ar-H), 8.6 (s, H, CH N); 13
C
NMR: 134.7 (C-4), 133.5 (C-5), 123.6–132.5 (C-Phenyl), 82.1 (CH N-),
62.2 (C-2); MS (70 eV) m/z (%): 441 (M+2, 10), 439 (M+, 30). Anal. calcd.
For C16H12BrClN4O2S (439.72): C, 43.70; H, 2.75; N, 12.74. Found: C,
43.99; H, 2.98; N, 12.64.

1666
E. A. El Rady
3-(4-Bromophenyl)-2,3-dihydro-2-(3-nitrophenyl)-4H-
thiazolo[4,5-c]pyrazole 6
A solution of carboxaldehyde 4 (0.4 g, 1 mmol), hydrazine hydrate
(0.3 ml, excess) in 20 ml of pyridine was warmed at reflux for 4 h.
The solvent was evaporated under vacuum and the residue was poured
on ice / water acidified by hydrochloric acid (1 ml HCl, 20 ml H2O). The
solid product collected by filtration and washed well with water to give
compound 6.
M.p.: 165◦C, Yield: 70%. IR: ν 3110 (NH) cm−1; 1H NMR: δ 5.6 (s, H,
CH-thiaz.), 6.8 (s, H, CH-pyraz.), 7.1–7.9 (m, 9H, Ar-H + NH); 13C NMR:
123.6–133.7 (C-Phenyl), 129.5 (C-6a), 128.7 (C-6), 127.6 (C-3a), 62.9 (C-
2); MS (70 eV) m/z (%): 404 (M+1, 20). Anal. calcd. For C16H11BrN4O2S
(403.26): C, 47.66; H, 2.75; N, 13.89. Found: C, 47.70; H, 2.98; N, 13.77.
3-(4-Bromophenyl)-2,3-dihydro-2-(3-nitrophenyl)-4-phenyl-
thiazolo[4,5-c]pyrazole 7
A solution of carboxaldehyde 4 (0.4 g, 1 mmol), phenyl hydrazine (0.15
g, 1 mmol), and 0.2 ml of triethylamine in 30 ml of dry ethanol was
refluxed for 5 h and concentrated under vacuum. The solid formed after
addition of cold diluted HCl (1 ml, 20 ml H2O) was collected by filtration,
washed well with 100 ml of cold water and crystallized from a mixture
of methanol and water (3:1) to give 7.
1
M.p.: 155◦C, Yield: 60%. H NMR: δ 5.7 (s, H, CH-thiaz.), 6.8 (s, H,
CH-pyraz.), 7.3–7.8 (m, 8H, Ar-H); MS (70 eV) m/z (%): 480 (M+1, 25).
Anal. calcd. For C22H15BrN4O2S (479.36): C, 55.12; H, 3.15; N, 11.69.
Found: C, 55.21; H, 3.29; N, 11.81.
General Procedure to Prepare Compounds 8a,b
To ethanol solution (30 ml) of carboxaldehyde 4 (0.8 g, 2 mmol), an
equimolar amount of urea (0.12 g, 2 mmol) was added and the mix-
ture was refluxed in the presence of 0.2 ml of triethylamine for 6 h.
The reaction mixture was evaporated under vacuum and the residue
poured into acidified cold water (1 ml HCl, 20 ml H2O). The solid formed
was collected by filtration, washed well with 100 ml of cold water, and
crystallized from a mixture of methanol and water (3:1) to give 8a.
Analogously, compound 4 reacted with thiourea to give 8b.
3-(4-Bromophenyl)-2,3-dihydro-2-(3-nitrophenyl)
-thiazolo[4,5-d]pyrimidine-5(4H)-one 8a
M.p.: 180◦C, Yield: 50%. IR: ν 1690 (CO), 3105 (NH) cm−1; 1H NMR: δ
5.6 (s, H, CH-thiaz.), 7.2–7.9 (m, 10H, Ar-H + NH); 13C NMR: 152.4 (CO),

A Convenient and Facile Synthesis
1667
123.6–132.7 (C-Phenyl), 129.4 (C-7a), 128.4 (C-7), 127.5 (C-3a), 62.7 (C-
2); MS (70 eV) m/z (%): 431 (M+, 15). Anal. calcd. For C17H11BrN4O3S
(431.27): C, 47.35; H, 2.57; N, 12.99. Found: C, 47.51; H, 2.76;
N, 12.80.
3-(4-Bromophenyl)-2,3-dihydro-2-(3-nitrophenyl)
-thiazolo[4,5-d]pyrimidine-5(4H)-thione 8b
1
M.p.: 165◦C, Yield: 56%. IR: ν 3100 (NH) cm−1; H NMR: δ 5.9 (s,
H, CH-thiaz.), 7.1–7.9 (m, 10H, Ar-H + NH); MS (70 eV) m/z (%): 447
(M+, 10). Anal. calcd. For C17H11BrN4O2S2 (447.34): C, 45.64; H, 2.48;
N, 12.52. Found: C, 45.90; H, 2.54; N, 12.61.
4-Amino-3-(4-bromophenyl)-2,3-dihydro-2-(3-nitrophenyl)-
thiazolo[4,5-d]pyrimidine-5-one 9
Equimolar amounts of carboxaldehyde 4 (0.8 g, 2 mmol) and semi-
carbazide (0.15 g, 2 mmol) were refluxed in ethanol containing 0.2 ml of
triethylamine for 7 h. The ethanol solution was evaporated under vac-
uum and the resulting emulsion was triturated with 5 ml of methanol
and then poured into acidified cold water (1 ml HCl, 20 ml H2O). The
solid product that formed was collected by filtration, washed well with
100 ml of cold water, and crystallized from a mixture of ethanol and
water (3:1) to give 9.
M.p.: 185◦C, Yield: 50%. IR: ν 1698 (CO), 3310 (NH2) cm−1; 1H NMR:
δ 5.7 (s, H, CH-thiaz.), 7.1–7.9 (m, 11H, Ar-H + NH2); MS (70 eV) m/z
(%): 447 (M+1, 20). Anal. calcd. For C17H12BrN5O3S (446.29): C, 45.75;
H, 2.71; N, 15.69. Found: C, 45.91; H, 2.89; N, 15.81.
General Procedure to Prepare Compounds 10a–c
A solution of carboxaldehyde 4 (0.8 g, 2 mmol), cyanoacetamide (0.16 g,
2 mmol), and 0.2 ml of triethylamine in 30 ml of dry ethanol was re-
fluxed for 5 h and concentrated under vacuum. The solid formed after
addition of cold diluted HCl (1 ml, 20 ml H2O) was collected by fil-
tration, washed well with 100 ml of cold water and crystallized from
a mixture of methanol and water (3:1) to give 10a. Analogously, com-
pound 4 reacted with equimolar amounts of cyanothioacetamide and
cyanoacetohydrazide to give 10b,c derivatives, respectively.
3-(4-Bromophenyl)-2,3,4,5-tetrahydro-2-(3-nitrophenyl)-
5-oxo-thiazolo[4,5-b]pyridine-6-carbonitrile 10a
M.p.: 170◦C, Yield: 59%. IR: ν 1695(CO), 2210 (CN), 3115 (NH)) cm−1
;
1H NMR: δ 5.6 (s, H, CH- thiaz.), 7.1–7.9 (m, 10H, Ar-H +NH); 13C
NMR: 158.4 (CO), 130.5 (C-6), 123.6–132.7 (C-Phenyl), 129.7 (C-7a),

1668
E. A. El Rady
128.7 (C-7), 126.4 (C-3a), 114.2 (CN), 62.5 (C-2); MS (70 eV) m/z (%):
455 (M+, 10). Anal. calcd. For C19H11BrN4O3S (455.30): C, 50.12; H,
2.43; N, 12.31. Found: C, 50.33; H, 2.57; N, 12.49.
3-(4-Bromophenyl)-2,3,4,5-tetrahydro-2-(3-nitrophenyl)-5-
thioxothiazolo[4,5-b]pyridine-6-carbonitrile 10b
M.p.: 190◦C, Yield: 50%. IR: ν 2225 (CN), 3123 (NH)) cm−1; 1H NMR:
δ 5.7 (s, H, CH-thiaz.), 7.1–7.9 (m, 10H, Ar-H +NH); MS (70 eV) m/z
(%): 471 (M+, 10). Anal. calcd. For C19H11BrN4O2S2(471.36): C, 48.42;
H, 2.35; N, 11.89. Found: C, 48.58; H, 2.61; N, 11.75.
4-Amino-3-(4-bromophenyl)-2,3,5-tetrahydro-2-(3-
nitrophenyl)-5-oxothiazolo[4,5-b]pyridine-6-carbonitrile 10c
M.p.: 195◦C, Yield: 56%. IR: ν 1694 (CO), 2226 (CN), 3327 (NH2))
cm−1 1H NMR: δ 5.7 (s, H, CH- thiaz.), 7.1–7.9 (m, 11H, Ar-H
;
+ NH2); MS (70 eV) m/z (%): 472 (M+2, 30). Anal. calcd. For
C19H12BrN5O3S(470.31): C, 48.52; H, 2.57; N, 14.89. Found: C, 48.77;
H, 2.75; N, 14.76.
3-(4-Bromophenyl)-4-chloro-2-(3-nitrophenyl)-5-methylene-N-
2-(phenylenediamine) thiazole 11
A solution of carboxaldehyde 4 (0.4 g, 1 mmol), 2-phenylenediamine
(0.12 g, 1 mmol), and 0.2 ml of triethylamine in 30 ml of dry ethanol
was warmed at reflux for 5 h and concentrated under vacuum. The solid
formed after addition of cold diluted HCl (1 ml, 20 ml H2O) was collected
by filtration, washed well with 100 ml of cold water and crystallized
from a mixture of methanol and water (3:1) to give 11.
M.p.: 200◦C, Yield: 60%. IR: ν 3340 (NH2) cm−1; 1H NMR: δ 5.6 (s, H,
CH-thiaz.), 7.1–7.8 (m, 14H, Ar-H + NH2), 8.2 (s, H, CH N);13C NMR:
135.4 (C-4), 123.6–132.5 (C-Phenyl), 129.1 (C-5),75.6 (CH N-), 62.5 (C-
2); MS (70 eV) m/z (%): 518 (M+2, 5%), 516 (M+, 15%). Anal. calcd. For
C22H16ClBrN4O2S(515.82): C, 51.22; H, 3.13; N, 10.86. Found: C, 51.35;
H, 3.25; N, 10.94.
3-(4-Bromophenyl)-2,3,4-trihydro-2-(3-nitrophenyl)-
thiazolo[4,5-b][1,5]benzodiazepine 12
A solution of carboxaldehyde 4 (0.4 g, 1 mmol), 2-phenylenediamine
(0.12 g, 1 mmol), in 20 ml of pyridine was warmed at reflux for 4 h
The solvent was evaporated under vacuum and the residue was poured
on ice/water acidified by hydrochloric acid (1 ml HCl, 20 ml H2O). The

A Convenient and Facile Synthesis
1669
solid product collected by filtration and washed well with water to give
compound 12.
1
M.p.: 210◦C, Yield: 56%. IR: ν 3110 (NH) cm−1; H NMR: δ 5.2 (s,
H, CH-thiaz.), 7.0–7.8 (m, 14H, Ar-H + NH);13C NMR: 123.6–132.7
(C-Phenyl), 129.4 (C-7a), 128.4 (C-7), 127.6 (C-10), 126.5 (C-4a), 126.1
(C-3a), 62.7 (C-2); MS (70 eV) m/z (%): 479 (M+, 10). Anal. calcd. For
C22H15BrN4O2S(479.36): C, 55.12; H, 3.15; N, 11.69. Found: C, 55.28;
H, 3.39; N, 11.75.
3-(4-Bromophenyl)-2,4-dihydro-2-(3-nitrophenyl)-
thiazolo[4,5-b][1,5]benzoxazepine 13
A solution of carboxaldehyde 4 (0.4 g, 1 mmol), 2-aminophenol (0.11 g,
1 mmol), and 0.2 ml of triethylamine in 30 ml of dry ethanol was
warmed at reflux for five hours and concentrated under vacuum. The
solid formed after addition of cold diluted HCl (1 ml, 20 ml H2O) was
collected by filtration, washed well with 100 ml of cold water and crys-
tallized from a mixture of methanol and water (3:1) to give 13.
1
M.p.: 205◦C, Yield: 49%. H NMR: δ 5.4 (s, H, CH-thiaz.), 7.1–7.9
(m, 13H, Ar-H); MS (70 eV) m/z (%): 480 (M+, 10). Anal. calcd. For
C22H14BrN3O3S(480.35): C, 55.01; H, 2.94; N, 8.75. Found: C, 55.22; H,
2.88; N, 8.94.
General Procedure to Prepare Compounds 15 and 17
A solution of carboxaldehyde 4 (0.8 g, 2 mmol), 5-amino-1,2,4-triazole
(0.16 g, 2 mmol), and 0.2 ml of triethylamine in 30 ml of dry ethanol
was warmed at reflux for 7 h and concentrated under vacuum. The solid
formed after addition of cold diluted HCl (1 ml, 20 ml H2O) was collected
by filtration, washed well with 100 ml of cold water and crystallized
from a mixture of methanol and water (3:1) to give compound 15. Analo-
gously, compound 4 reacted with equimolar amount of 3-aminopyrazole
to give compound 17.
3-(4-Bromophenyl)-2,3-dihydro-2-(3-nitrophenyl)-
thiazolo[4ꢀ,5ꢀ:6,5]pyrimido[1,2-b][1,2,4]triazole 15
1
M.p.: 195◦C, Yield: 56%. H NMR: δ 5.4 (s, H, CH-thiaz.), 7.1–7.8 (m,
10H, Ar-H); 13C NMR: 123.6–132.5 (C-Phenyl), 132.4 (C-6), 130.1 (C-
9a), 129.6 (C-3a), 128.8 (C-9), 62.7 (C-2); MS (70 eV) m/z (%): 455 (M+,
7). Anal. calcd. For C18H11BrN6O2S (455.30): C, 47.48; H, 2.44; N, 18.46.
Found: C, 47.56; H, 2.63; N, 18.74.

1670
E. A. El Rady
3-(4-Bromophenyl)-6-phenyl-2,3-dihydro-2-(3-nitrophenyl)-
thiazolo[4ꢀ,5ꢀ:6,5]pyrimido[1,2-b]pyrazole 17
1
M.p.: 150◦C, Yield: 56%. H NMR: δ 5.5 (s, H, CH-thiaz.), 7.1–7.9
(m, 15H, Ar-H); MS (70 eV) m/z (%): 531 (M+1, 10). Anal. calcd. For
C25H16BrN5O2S (530.41): C, 56.61; H, 3.04; N,13.21. Found: C, 56.74;
H, 3.14; N,13.77.
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