Synthesis and cytotoxic activity of certain new arylazothiazole containing compounds

Article abstract of DOI:10.1002/jhet.5570390604

2-Amino-5-arylazo-4-(2-chlorophenyl)thiazoles (2a-e) were prepared by the coupling of aryldiazonium chlorides with 2-amino-4-(2-chlorophenyl) thiazole (1). The thioureas 3a-e were obtained by condensing the arylazothiazoles 2a-c with the appropriate isoth

Full text of DOI:10.1002/jhet.5570390604

Nov-Dec 2002
Synthesis and Cytotoxic Activity of Certain New Arylazothiazole
Containing Compounds
1133
1*
2
Salwa El-Meligie and Raafat A. El-Awady
1
2
Organic Chemistry Department , Faculty of Pharmacy and Pharmacology Unit, Biology Department ,
National Cancer Institute, Cairo University, Cairo, Egypt
Received November 5, 2001
2-Amino-5-arylazo-4-(2-chlorophenyl)thiazoles (2a-e) were prepared by the coupling of aryldiazonium
chlorides with 2-amino-4-(2-chlorophenyl) thiazole (1). The thioureas 3a-e were obtained by condensing the
arylazothiazoles 2a-c with the appropriate isothiocyanates. Reaction of2d with aromatic aldehydes afforded
the chalcone analogues 4a-c. The pyridone derivatives 5a,b were synthesized by reacting the ketone 2d with
different aromatic aldehydes, ethyl cyanoacetate and ammonium acetate. On the other hand, 5b was also pre-
pared by cyclizing4c with ethyl cyanoacetate and ammonium acetate. Furthermore, 6-chloroimidazo[2,1-b]-
thiazole 7 was obtained from the acid derivative 6b by treatment with POCl3. While, the imidazo[2,1-b]-
thiazolones 9a-d were produced by the cyclization of the chloroacetyl derivatives 8a-d with DMAP/pyri-
dine. Representative examples of the prepared compounds were tested for in vitro antitumor activity against
two human tumor cell lines. Some compounds showed activity against brain tumor cell lines.
J. Heterocyclic Chem., 39, 1133(2002).
A considerable number of thiazole derivatives have been
for the preparation of the pyridone 5b was via reacting the
chalcone analogue 4c with ethyl cyanoacetate and ammo-
nium acetate in 1-butanol. Although, the latter is a two-
step method yet the overall yield is higher than the former.
It is interesting to note that the one-step synthesis pro-
duced compounds 5a,b in 50-55% yield with the ketone 2d
which was detected by thin layer chromatography. Facile
removal of the starting ketone 2d was effected by silica gel
column chromatography.
A search in the literature [10-13] showed that formation
of imidazo[2,1-b]thiazoles could be obtained through
reacting a 2-aminothiazole derivative with a -halocarbonyl
compounds. It was also registered [11,13]that the reaction
started by attack of the thiazole ring nitrogen on the a -
halocarbon compound followed by cyclization.
Accordingly, treating the arylazothiazoles 2b,c with
chloroacetic acid afforded 3-carboxymethyl-2-iminothia-
found to exhibit a wide variety of biological activity [1-5].
In addition, some derivatives of 2-aminothiazoles bearing
an arylazo moiety at position 5 have shown cytostatic and
cytopathic activities [6]. Keeping this in view it was
thought of interest to synthesize certain arylazothiazole
containing compounds in a trial to obtain compounds of
anticipated antitumor value (cf. Scheme 1).
2-Amino-4-(2-chlorophenyl)thiazole (1) was prepared
[cf. 6] in 70% yield via reaction of 2-chloroacetophenone
with thiourea in the presence of iodine. This compound
was previously prepared in 49% yield by the reaction of 2-
chlorophenyldiazomethylketone with thiourea in the pres-
ence of Cu powder or CuBr [7]. Coupling 1 with some dia-
zotized arylamines furnished the required 2-amino-5-ary-
lazo-4-(2-chlorophenyl)thiazoles (2a-e). Preparation of
compound 2a has been mentioned [8] but the procedure
lacked experimental details, physical and spectral data.
Condensing 2-aminothiazoles 2a-c with some arylisothio-
cyanates brought about the thioureas 3a-e.
During this investigation attempts to obtain Schiff bases
by heating 2-aminothiazole 2a with the suitable aromatic
aldehyde at reflux temperature in ethanol, 1-butanol or
ethanol/acetic acid (3:1) for 25 hours were fruitless and the
starting 2-aminothiazole 2a was recovered. According to
these experimental findings, the required chalcones 4a-c
were obtained via condensing the ketone 2d with some
aromatic aldehydes in ethanol/acetic acid (3:1). Moreover,
a second method was undertaken for the preparation of 4a
by coupling of the diazonium salt of the prepared 1-(4-
aminophenyl)-3-(4'-bromophenyl)-2-propen-1-one [9]
with 2-aminothiazole 1. Indeed, the overall yield in the
two procedures was nearly equal.
zolines 6a,b. Reacting 6b with POCl [cf. 14] gave 6-
3
chloroimidazo[2,1-b]thiazole 7 in a poor yield. The IR
spectrum of 7 revealed the absence of the strong absorp-
tion due to NH/OH as well as the C=O function at 3450-
-1
1
2850 and 1690 cm respectively. Also, the H-NMR spec-
trum of 7 has confirmed its structure since it showed the
absence of OH and NH signals.
In this study it was decided to interact arylazothiazoles
2a-d with chloroacetyl chloride. This interaction was first
conducted in dry benzene containing a few drops of
triethylamine at room temperature but the 3-chloroacetyl
derivatives 8a-d were produced in good yields. When
equimolar amounts of the two reactants were heated under
reflux in dry benzene or dry pyridine for up to 10 hours, the
open form intermediates 8a-d (major products) alongside
the imidazo[2,1-b]thiazoles 9a-d (minor products) were
obtained (TLC). Attempts to cyclize 8a,b into the corre-
sponding imidazo[2,1-b]thiazole by refluxing in 2 M HBr
furnished 9a,b as the hydrobromide salts which were
In this work interacting 2d with the suitable aromatic
aldehyde, ethyl cyanoacetate and ammonium acetate in 1-
butanol gave rise to the pyridones 5a,b. Another approach

1134
S. El-Meligie and R. A. El-Awady
Vol. 39
Scheme 1
converted into the bases 9a,b using NH OH [cf. 13]. By the
8a-d with dimethylaminopyridine (DMAP) in dry pyridine.
The spectral data of 9a-d ascertain their structure since IR
4
application of this method ,the yield of both 9a and 9b was
considerably low (15% and 17% yield respectively).
However, the imidazo[2,1-b]thiazoles 9a-d were produced
in good yields via cyclizing the 3-chloroacetyl derivatives
-1
spectra disclosed no absorption bands at 3450-3400 cm
1
for NH. Also, the absence of the NH group signal in the H-
NMR confirmed the imidazo[2,1-b] thiazole structure.

Nov-Dec 2002
Synthesis and Cytotoxic Activity of Certain New
Arylazothiazole Containing Compounds
1135
heated until most of the solid had gone into solution and filtered
while hot. The filtrate was cooled and made alkaline with a
strong solution of ammonia. The separated solid was collected by
filtration, washed with water and recrystallized from acetone;
yield (70 %), mp: 142-44 °C [7].
In Vitro Cytotoxic Activity.
Representative members of the synthesized compounds
2a-d, 3b, 4a, 5b, 8a and 9a were screened for potential anti-
tumor activity against two human tumor cell lines namely
brain tumor (U251) and breast tumor (MCF-7) cell lines.
In routine screening each compound is tested over a
broad concentration range against every cell line. All lines
are inoculated onto a series of standard 96-well
microplates and incubated for 24 hours in humidified 5%
carbon dioxide incubator. The inoculation densities
employed depend upon the particular cell line and its
growth characteristics. Tested compounds 2a-d, 3b, 4a,
5b, 8a and 9a are routinely evaluated in range of 1-10
mg/mL solution in DMSO which is used for solubility of
the compounds. Control cells were incubated with the
same quantity of the DMSO solvent. After 24 hours of
compound incubation, the cells are assayed by the
sulphorhodamine B (SRB) assay according to the method
of Skehan and co-workers [15].
General Procedure for the Synthesis of 2-Amino-5-arylazo-4-(2-
chlorophenyl)thiazoles (2a-e).
An ice-cold solution of sodium nitrite (1.38 g; 0.02 mol) in
water (25 mL) was added slowly to a solution of the appropriate
arylamine (0.02 mol) in HCl (6 mL) at 0 °C. To a well-cooled
solution of 1 (4.21 g, 0.02 mol) and sodium acetate (10 g) in
ethanol (50 mL) was gradually added the diazonium salt solution
while stirring and cooling (-5 °C). The reaction mixture was
stirred at –5 °C for 2 hours, and then diluted with cold water (50
mL). The separated solid was collected by filtration, washed with
water and crystallized from ethanol/ether.
2-Amino-4-(2-chlorophenyl)-5-phenylazothiazole (2a).
This compound was prepared according to the general proce-
dure above in a yield of 90%, mp 174-176 °C; IR: 3400-3300 (d
of NH2), 1620 (N=N), 1585, 1470, 1340, 1020 and 810 (st. of thi-
azole nucleus); 1H-NMR (DMSO-d6): d 7.51-8.21(m, 9H, Ar-H),
8.80 (br, 2H, NH2, D2O exch.).
IC50 which is the concentration (mg/mL) that inhibits
50% of the tumor growth is the parameter used for evalua-
tion of each compound. The tested compounds will be
either active or inactive.
Anal. Calcd. for C15H11ClN4S: C, 57.23; H, 3.49; N, 17.80.
Found: C, 57.00; H, 3.70; N, 17.60.
2-Amino-4-(2-chlorophenyl)-5-(3-tolylazo)thiazole (2b).
Conclusion.
This compound was prepared according to the general proce-
dure above in a yield of 93%, mp 163-165 °C; IR: 3400-3300 (d
of NH2), 1610 (N=N), 1585, 1470, 1340, 1020 and 810 (st. of thi-
azole nucleus); 1H-NMR (DMSO-d6): d 2.38 (s, 3H, CH3), 7.37-
8.16 (m, 8H, Ar-H), 8.62 (br, 2H, NH2, D2O exch..).
The tested thiazole derivatives showed no activity
against both cell lines used even at high concentration
(10mg/mL) except compounds 8a and 9a where they
showed high activity against brain tumor cell line (U251)
since IC50 was at 1.5 and 8 mg/mL respectively. Also,
compound 2a showed activity only at high concentration
(IC50 was 10mg/mL) against the brain tumor cell line.
Anal.Calcd. for C16H13ClN4S: C, 58.44; H, 3.95; N, 17.04.
Found: C, 58.70; H, 3.90; N, 17.20.
2-Amino-4-(2-chlorophenyl)-5-(4-tolylazo)thiazole (2c).
This compound was prepared according to the general proce-
dure above in a yield of 92%, mp 183-185 °C; IR: 3400-3300 (d
of NH2), 1630 (N=N), 1585, 1470, 1340, 1020 and 810 (st. of thi-
azole nucleus); 1H-NMR (DMSO-d6): d 2.36 (s, 3H, CH3), 7.29-
8.19 (m, 8H, Ar-H), 8.62 (br, 2H, NH2, D2O exch.).
EXPERIMENTAL
Melting points were determined on a Griffin apparatus and are
uncorrected . Microanalyses were performed by the
Microanalytical Center, Cairo University, Egypt. IR spectra were
recorded as KBr discs on Shimadzu IR 435 spectrophotometer
and expressed in cm-1. 1H-NMR spectra were carried out on
Varian Gemini 200 MHz and Jeol FXQ-90 MHz spectropho-
tometers with TMS as an internal standard (chemical shift values
in ppm on d scale) and EIMS spectra on Hewlett-Packard 5988
spectrometer. The progress of the reaction was monitored by
TLC using aluminium sheets precoated with UV fluorescent sil-
ica gel (Merck 60 F254) and using benzene-methanol (8:2) as
eluant.
Anal. Calcd. for C16H13ClN4S: C, 58.44; H, 3.95; N, 17.04.
Found: C, 58.60; H, 4.20; N, 16.80.
5-(4-Acetylphenylazo)-2-amino-4-(2-chlorophenyl)thiazole
(2d).
This compound was prepared according to the general proce-
dure above in a yield of 95%, mp 244-245 °C; IR: 3400-3300 (d
of NH2), 1670 (C=O), 1630 (N=N), 1585, 1470, 1340, 1020 and
810 (st. of thiazole nucleus); 1H-NMR (DMSO-d6): d 2.50 (s, 3H,
CH3), 7.51-8.17 (m, 8H, Ar-H), 8.66 (br, 2H, NH2, D2O exch.).
Anal.Calcd. for C17H13ClN4OS : C,57.22; H, 3.64; N, 15.70.
Found: C, 56.90; H, 3.90; N, 15.80.
2-Chloroacetophenone was obtained commercially from
Aldrich fine chemicals. 1-(4-Aminophenyl)-3-(4'-bromophenyl)-
2-propen-1-one [9] was prepared according to reported procedure.
2-Amino-5-(4-carbethoxyphenylazo)-4-(2-chlorophenyl)thiazole
2-Amino-4-(2-chlorophenyl)thiazole (1).
(2e).
A mixture of 2-chloroacetophenone (15.45 g; 0.1 mol),
thiourea (15.20 g ; 0.2 mol) and iodine (25.40 g ; 0.1 mol) was
heated 12 hours on a steam bath . The mixture was cooled and
washed with ether. It was then diluted with water (200 mL),
This compound was prepared according to the general proce-
dure above in a yield of 93%, mp 260-262 °C; IR: 3400-3300 (d
of NH2), 1710 (C=O), 1640 (N=N), 1585, 1470, 1340, 1020 and
810 (st. of thiazole nucleus); 1H-NMR(DMSO-d6): d 1.33 (t, J=8

1136
S. El-Meligie and R. A. El-Awady
Vol. 39
Hz, 3H, OCH2 -CH3), 4.31 (q, J=8 Hz, 2H, OCH2CH3), 7.50-
8.25 (m, 8H, Ar-H), 8.74 (br, 2H, NH2, D2O exch.).
Anal. Calcd. for C18H15ClN4O2S: C, 55.88; H, 3.88 ; N, 14.48.
Found: C, 56.00; H, 3.70; N, 14.30.
1H, NH of NH-C6H5, D2O exch.), 11.80 (S, 1H, NH of –NHCS,
D2O exch.).
Anal. Calcd. C24H20ClN5S2: C, 60.31; H, 4.18; N, 14.65.
Found: C, 60.10; H, 4.40; N, 14.50.
General Procedure for the Synthesis of 5-Arylazo-2-(3-arylth-
ioureido)-4-(2-chlorophenyl)thiazoles (3a-e).
General Procedures for the Synthesis of 2-Amino-4-(2-
chlorophenyl)-5-[4-(substituted cinnamoyl)phenylazo]thiazoles
(4a-c).
A solution of the appropriate isothiocyanate (0.002 mol) and
the selective arylazothiazole 2a-c (0.002 mol) in benzene (20
mL) was refluxed for 13 hours on a steam bath. The solvent was
distilled off and the residue was treated with petroleum ether 40-
60 °C and then with ether. The crystalline product so obtained
was recrstallized from DMF/ethanol.
Method A: for Compounds 4a-c.
To a solution of 2d (1.07 g, 0.003 mol) in EtOH/AcOH (3:1)
(30mL), the appropriate aromatic aldehyde (0.003 mol)was
added with stirring . The reaction mixture was stirred and
refluxed for 8 hours, then cooled and poured onto cold water. The
formed precipitate was collected by filtration and crystallized
from dioxane.
4-(2-Chlorophenyl)-5-phenylazo-2-(3-phenylthioureido)thiazole
(3a).
This compound was prepared according to the general proce-
dure above in a yield of 62%, mp 114-116 °C; IR: 3450,3250
(NH); 1640 (N=N), 1370 (C=S); H-NMR (DMSO-d6): d 7.12-
8.21 (m, 14H, Ar-H), 8.38 (s, 1H, NH of NH-C6H5, D2O exch.);
EIMS for 3a: m/z 449 (1%, M+.).
Method B: for Compound 4a.
An ice-cold solution of sodium nitrite (0.14 g, 0.002 mol) in
water (2.5 mL) was added slowly to a solution of 1-(4-
aminophenyl)-3-(4'-bromophenyl)-2-propen-1-one (0.60 g,
0.002 mol) in HCl (1 mL) at 0 °C. To a well cooled solution of
compound 1 (0.42 g, 0.002 mol) and sodium acetate (1 g) in
ethanol (25 mL) was gradually added the diazonium salt solution
while stirring and cooling (-5 °C). The reaction mixture was
stirred at -5 °C for 4 hours and then diluted with cold water (30
mL). The separated solid was collected by filtration, washed with
water and crystallized from dioxane.
1
Anal. Calcd. for C22H16ClN5S2: C, 58.73; H, 3.55; N, 15.57.
Found: C,59.00; H, 3.70; N, 15.50.
4-(2-Chlorophenyl)-2-(3-phenylthioureido)-5-(3-tolylazo)-
thiazole (3b).
This compound was prepared according to the general proce-
dure above in a yield of 65%, mp 142-144 °C; IR: 3450, 3300
(NH); 1640 (N=N), 1340 (C=S); 1H-NMR (DMSO-d6): d 2.38 (s,
3H, CH3), 7.37-8.22 (m, 13H, Ar-H), 8.38 (s, 1H, NH of NH-
C6H5, D2O exch.), 11.04 (S, 1H, NH of –NHCS, D2O exch.).
Anal. Calcd. C23H18ClN5S2: C, 59.54; H, 3.88; N, 15.10.
Found: C, 59.80; H, 4.00; N, 14.80.
2-Amino-5-[4-(4-bromocinnamoyl)phenylazo]-4-(2-chloro-
phenyl)thiazole (4a).
This compound was prepared according to the general proce-
dures above in method A and method B in a yield of 80% and
78% respectively, mp 262-264 °C; IR: 3400-3300(d of NH2)
1650 (C=O); 1H-NMR (DMSO-d6): d 6.72 (d, J=18 Hz, 1H,
CH=), 7.35-7.84 (m, 12H, Ar-H), 8.00 (d, J=18 Hz, 1H, CH=),
8.40 (br, 2H, NH2, D2O exch.).
4-(2-Chlorophenyl)-2-(3-phenylthioureido)-5-(4-tolylazo)-
thiazole (3c).
This compound was prepared according to the general proce-
dure above in a yield of 63%, mp 200-201 °C; IR: 3450, 3300
(NH); 1640 (N=N), 1340 (C=S); 1H-NMR (DMSO-d6): d 2.37 (s,
3H, CH3), 7.13-8.17 (m, 13H, Ar-H), 8.38 (s, 1H, NH of NH-
C6H5, D2O exch.).
Anal. Calcd. C24H16BrClN4OS: C, 55.01; H, 3.05; N, 10.69.
Found: C, 55.30; H, 3.20; N, 10.40.
2-Amino-4-(2-chlorophenyl)-5-[4-(3-nitrocinnamoyl)phenyl-
azo]thiazole (4b).
Anal. Calcd. for C23H18ClN5S2: C, 59.54; H, 3.88; N, 15.10.
Found: C, 59.70; H, 3.60; N, 15.20.
This compound was prepared according to the general proce-
dure above in method A in a yield of 82%, mp 250-252 °C; IR:
3400-3250(d of NH2), 1660 (C=O), 1520 & 1340 (asym. & sym.
St. of NO2); 1H-NMR (DMSO-d6): d 7.75 (d, J=18 Hz, 1H,
CH=), 7.24-8.25 (m, 12H, Ar-H), 8.34 (d, J=18 Hz, 1H, CH=),
8.90 (br, 2H, NH2 , D2O exch.).
2-(3-Benzylthioureido)-4-(2-chlorophenyl)-5-(3-tolylazo)-
thiazole (3d).
This compound was prepared according to the general proce-
dure above in a yield of 58%, mp 185-186 °C; IR: 3450, 3300
(NH); 1640 (N=N), 1340 (C=S); 1H-NMR (DMSO-d6): d 2.38 (s,
3H, CH3), 4.77 (s, 2H, CH2), 7.21-8.23 (m, 13H, Ar-H), 8.38 (s,
1H, NH of NH-C6H5, D2O exch.).
Anal. Calcd. for C24H16ClN5O3S: C, 58.83; H, 3.26; N, 14.30.
Found: C, 59.10; H, 3.50; N, 14.60.
2-Amino-4-(2-chlorophenyl)-5-[4-(4-nitrocinnamoyl)phenyl-
azo]thiazole (4c).
Anal. Calcd. for C24H20ClN5S2: C, 60.31; H, 4.18; N, 14.65.
Found: C, 60.10; H, 3.90; N, 14.90.
This compound was prepared according to the general proce-
dure above in method A in a yield of 85%, mp 256-258 °C; IR:
3400-3300(d of NH2), 1660 (C=O), 1530 & 1350 (asym. & sym.
St. of NO2); 1H-NMR (DMSO-d6): d 7.75 (d, J=18 Hz, 1H,
CH=), 7.54-8.26 (m, 12H, Ar-H), 8.36 (d, J=18 Hz, 1H, CH=),
8.81 (br, 2H, NH2 , D2O exch.).
2-(3-Benzylthioureido)-4-(2-chlorophenyl)-5-(4-tolylazo)-
thiazole (3e).
This compound was prepared according to the general proce-
dure above in a yield of 55%, mp 206-207 °C; IR: 3450, 3300
(NH); 1640 (N=N), 1340 (C=S); 1H-NMR (DMSO-d6): d 2.39 (s,
3H, CH3), 4.77 (s, 2H, CH2), 7.32-8.04 (m, 13H, Ar-H), 8.38 (s,
Anal. Calcd. for C24H16ClN5O3S: C, 58.83; H, 3.26; N, 14.30.
Found: C, 59.10; H, 3.50; N, 14.10.

Nov-Dec 2002
Synthesis and Cytotoxic Activity of Certain New
Arylazothiazole Containing Compounds
1137
General Procedures for the Synthesis of 2-Amino-5-[4-(4-aryl-5-
cyano-6-oxo-1,6-dihydropyrid-2-yl)phenylazo]-4-(2-chloro-
phenyl)thiazoles (5a,b).
4.81(s, 2H, CH2), 7.14-7.94 (m, 8H, Ar-H), 9.98 (br, 1H, OH,
D2O exch.), 11.67(s, 1H, NH, D2O exch.).
Anal. Calcd. for C18H15ClN4O2S: C, 55.88; H, 3.88; N, 14.48.
Found: C, 56.10; H, 4.10; N, 14.20.
Method A: for Compounds 5a,b.
3-Carboxymethyl-4-(2-chlorophenyl)-2-imino–5-(4-tolylazo)thi-
azoline (6b).
A solution of the arylazothiazole 2d (1.07 g, 0.003 mol), the
appropriate aromatic aldehyde (0.003, mol), ethyl cyanoacetate
(0.34 g, 0.003 mol) and ammonium acetate (1.85 g, 0.024 mol) in
1-butanol (15 mL) was heated at reflux for 22 hours and then
cooled in an ice-bath. The separated solid was collected by filtra-
tion and eluted through a column, packed with silica gel, with a
mixture of benzene–ethyl acetate (9:1) in 40-60 mL fractions.
The arylazothiazole 2d was eluted at first (in fractions 3-8) fol-
lowed by the pyridone derivatives 5a,b (in fractions 12-18). A
total volume of about 200 mL was used for the elution of each
product. Eluted 1 and 2 on removal of the solvent systems under
high vacuum and at 30 °C gave 2d and 5a,b respectively.
This compound was prepared according to the general proce-
dure above in a yield of 82%, mp 214-216 °C; IR: 3450-2850
1
(NH/OH), 1690 (C=O); H-NMR (CDCl3): d 2.38 (s, 3H, CH3),
4.80 (s, 2H, CH2), 7.20 –8.21(m,8H,Ar-H), 10.08 (br, 1H, OH,
D2O exch.).
Anal. Calcd. for C18H15ClN4O2S: C, 55.88; H, 3.88; N, 14.48.
Found: 55.60; H, 4.10; N, 14.20.
6-Chloro-3-(2-chlorophenyl)–2-(4-tolylazo)imidazo[2,1-b]-
thiazole(7).
A mixture of 6b (1.16 g, 0.003 mol) and POCl3 (6 mL) was
heated under reflux for 4 hours during this time solution
occurred. The excess POCl3 was removed by evaporation under
vacuum, leaving a dark syrupy residue. This syrup was poured
with stirring into an ice-water mixture and the obtained solution
was basified with aqueous NaOH. The separated solid was col-
lected by filtration, dried and crystallized from petroleum ether
60-80 °C. Yield of 35%, mp 174-175 °C; IR: 1640 (N=N), 1630
Method B: for Compound 5b.
A solution of the chalcone analogue 4c (1.47 g, 0.003 mol),
ethyl cyanoacetate (0.34 g, 0.003 mol) and ammonium acetate
(1.85 g, 0.024 mol) in 1-butanol (10 mL) was heated at reflux for
18 hours and then cooled. The separated solid was collected by
filtration, washed with ethanol and crystallized from acetic acid.
1
Compounds 5a,b are insoluble in the available solvents of H-
NMR.
1
(C=N); H-NMR (CDCl3): d 2.39 (s, 3H , CH3), 7.21-8.16 (m,
9H, Ar-H and imidazo proton).
Anal. Calcd. for C18H12Cl2N4S: C, 55.81; H, 3.10; N, 14.47.
Found: C, 55.80; H, 3.10; N, 14.20.
2-Amino-4-(2-chlorophenyl)-5-[4-(5-cyano-6-oxo-4-phenyl-1,6-
dihydropyrid-2-yl)phenylazo]thiazole (5a).
This compound was prepared according to the general proce-
dure above in method A in a yield of 50%, mp 268-270 °C; IR:
3450-3300 (d of NH2), 3100 (NH), 2200 (CN), 1640 (C=O);
EIMS: m/z 510 (3.2%, M+2+.) & 508 (9.72%, M+.).
Anal. Calcd. for C27H17ClN6OS: C, 63.71; H, 3.34; N, 16.51.
Found: C, 63.80; H, 3.50; N, 16.30.
General Procedure for the Synthesis of 5-Arylazo-3-chloromethyl-
carbonyl-4-(2-chlorophenyl)-2-iminothiazolines (8a-d).
To a solution of the appropriate arylazothiazole 2a-d (0.005
mol) in dry benzene (10 mL) containing triethylamine (3 drops),
chloroacetyl chloride (0.57 g, 0.005 mol) in dry benzene (5 mL)
was added. The reaction mixture was stirred at room temperature
for 2 hours and then filtered. The filtrate was evaporated under
vacuum and the separated solid was crystallized from dioxane.
2-Amino-4-(2-chlorophenyl)-5-[4-(5-cyano-4-(4-nitrophenyl)-6-
oxo-1,6-dihydropyrid-2-yl)phenylazo]thiazole (5b).
This compound was prepared according to the general proce-
dures above in method A and method B in a yield of 55% and
72% respectively, mp 320-321 °C; IR: 3450-3300 (d of NH2),
3100 (NH), 2200 (CN), 1640 (C=O), 1520 & 1340 (asym. &
sym. St. of NO2); EIMS: m/z 555 (15.10%, M+2+.) & 553
(45.45%, M+.).
3-Chloromethylcarbonyl-4-(2-chlorophenyl)-2-imino-5-phenyl-
azo-thiazoline (8a).
This compound was prepared according to the general proce-
dure above in a yield of 85%, mp 210-211 °C; IR: 3400 (NH),
1
1700 (C=O); H-NMR (DMSO-d6): d 4.50 (s, 2H, CH2), 7.33-
8.26 (m, 9H, Ar-H), 13.03 (s, 1H, NH, D2O exch.).
Anal. Calcd. for C17H12Cl2N4OS: C, 52.17; H, 3.06; N, 14.32.
Found: C, 52.10; H, 3.20; N, 14.20.
Anal. Calcd. for C27H16ClN7O3S: C, 58.53; H, 2.89; N, 17.70.
Found: C, 58.80; H, 2.80; N, 17.60.
General Procedure for the Synthesis of 5-Arylazo-3-car-
3-Chloromethylcarbonyl-4-(2-chlorophenyl)-2-imino-5-(3-tolyl-
boxymethyl-4-(2-chlorophenyl)-2-iminothiazolines (6a,b).
azo)thiazoline (8b).
A mixture of the arylazothiazole 2b or 2c (0.003 mol), sodium
hydroxide (0.12 g , 0.003 mol), chloroacetic acid (0.28 g , 0.003
mol) and absolute ethanol (25 mL) was refluxed for 8 hours. The
reaction mixture was poured onto water (30 mL) and the formed
precipitate was collected by filtration, washed with water and
crystallized from dioxane.
This compound was prepared according to the general proce-
dure above in a yield of 89%, mp 186-188 °C; IR: 3400 (NH),
1720 (C=O); 1H-NMR (DMSO-d6): d 2.39 (s, 3H, CH3), 4.50 (s,
2H, CH2), 7.33-8.26 (m, 8H, Ar-H), 13.03 (s, 1H, NH, D2O exch.).
Anal. Calcd. for C18H14Cl2N4OS: C, 53.33; H, 3.45; N, 13.82.
Found: C, 53.10; H, 3.40; N, 13.70.
3-Carboxymethyl-4-(2-chlorophenyl)-2-imino–5-(3-tolylazo)-
thiazoline (6a).
3-Chloromethylcarbonyl-4-(2-chlorophenyl)-2-imino-5-(4-tolyl-
azo)thiazoline (8c).
This compound was prepared according to the general proce-
dure above in a yield of 85%, mp 190-192 °C; IR: 3450-2850
(NH/OH), 1690 (C=O); H-NMR (CDCl3): d 2.39 (s, 3H, CH3),
This compound was prepared according to the general proce-
dure above in a yield of 89%, mp 197-199 °C; IR: 3400 (NH),
1

1138
S. El-Meligie and R. A. El-Awady
Vol. 39
1700 (C=O); 1H-NMR (DMSO-d6): d 2.40 (s, 3 H, CH3), 4.48 (s,
2H, CH2), 7.37-8.25 (m, 8H, Ar-H), 12.8 (br, 1H, NH, D2O
exch.).
Anal. Calcd. for C18H14Cl2N4OS: C, 53.33; H, 3.45; N, 13.82.
Found: C, 53.20; H, 3.70; N, 14.00.
Anal. Calcd. for C18H13ClN4OS: C, 58.61; H, 3.52; N, 15.19.
Found: C, 58.90; H, 3.80; N, 15.30.
2-(4-Acetylphenylazo)-3-(2-chlorophenyl)-6H-imidazo[2,1-b]-
thiazol-5-one (9d).
This compound was prepared according to the general proce-
dure above in a yield of 82%, mp 216-218 °C; IR: 1700 (C=O),
1660(C=O); 1H-NMR (CDCl3): d 2.61(s, 3H, CH3), 4.83 (s, 2H,
CH2), 7.41-8.33 (m, 8H, Ar-H).
Anal. Calcd. for C19H13ClN4O2S: C, 57.50; H, 3.27; N, 14.12.
Found: C, 57.20; H, 3.40; N, 13.90.
5-(4-Acetylphenylazo)-3-chloromethylcarbonyl-4-(2-chloro-
phenyl)-2-iminothiazoline (8d).
This compound was prepared according to the general proce-
dure above in a yield of 88%, mp 280-281 °C; IR: 3450 (NH),
1700 (C=O); 1665 (C=O); 1H-NMR (DMSO-d6): d 2.51 (s, 3H,
CH3), 4.50 (s, 2H, CH2), 7.54-8.24 (m, 8H, Ar-H), 13.09 (s ,1H ,
NH ,D2O exch.).
REFERENCES AND NOTES
Anal. Calcd. for C19H14Cl2N4O2S: C, 52.65; H, 3.23; N,
12.93. Found: C, 52.90; H, 3.20; N, 12.80.
[1] V. K. Ahluwalia, R. P. Singh and R. P. Sing, Indian J.
Chem., 26B, 287 (1987).
[2] A.Tripathi and U. Misra, Indian J. Pharm. Sci., 56, 19
(1994); Chem. Abstr., 122, 9959q (1995).
General Procedure for the Synthesis of 2-Arylazo-3-(2-
chlorophenyl)-6H-imidazo[2,1-b]thiazol-5-ones (9a-d).
A solution of the appropriate 8a-d (0.002 mol), pyridine (0.16
g, 0.002 mol) and DMAP (0.24g, 0.002 mol) in THF (10 mL)
was stirred at room temperature for 24 hours. The formed precip-
itate of pyridinium salt was filtered off and the filtrate was evap-
orated under vacuum. The remaining residue was crystallized
from acetone.
[3] K. Yamaguchi, T. Tsuji, T. Kobori, Y. Hatanaka and K. Goda,
(Sagami Chemical Research Center , Japan) Jpn.Kokai Tokkyo koho Jp
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[4] J. A. Flygare, J. C. Jaen, P. C. Kearney, J. C. Medina and M.
Sivaraja (Tularik Inc., USA) PCT Int.Appl. WO 99 42,455 (Cl. C O7 D
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59, 375 (1982).
3-(2-Chlorophenyl)-2-phenylazo-6H-imidazo[2,1-b]thiazol-5-
one (9a).
This compound was prepared according to the general proce-
dure above in a yield of 78%, mp 110-111 °C; IR: 1700 (C=O);
1H-NMR (CDCl3): d 4.82 (s, 2H, CH2), 7.36-8.18 (m, 9H, Ar-H).
Anal. Calcd. for C17H11ClN4OS: C, 57.54; H, 3.10; N, 15.79.
Found: C, 57.20; H, 3.30; N, 15.70.
[7] W. Hampel and I. Muller,J. Prakt. Chem., 38, 320 (1968).
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Chim. France, 1277 (1966).
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Galatulas, Eur. J. Med. Chem. - Chim. Ther., 20, 93 (1985).
[12] A. Andreani, M. Rambaldi, P. Carloni, L. Greci and P. Stipa,
J.Heterocyclic Chem., 26, 525 (1989).
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El-Hawash, M. Morshedy and H. M. A. Ashour, Alex. J. Pharm. Sci.,
13, 85 (1999).
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(1969).
3-(2-Chlorophenyl)-2-(3-tolylazo)-6H-imidazo[2,1-b]thiazol-5-
one (9b).
This compound was prepared according to the general proce-
dure above in a yield of 80%, mp 144-145 °C; IR: 1700 (C=O);
1H-NMR (CDCl3): d 2.38 (s, 3H, CH3), 4.76 (s, 2H, CH2), 7.37-
8.26 (m, 8H, Ar-H).
Anal. Calcd. for C18H13ClN4OS: C, 58.61; H, 3.52; N, 15.19.
Found: C, 58.60; H, 3.50; N, 15.00.
3-(2-Chlorophenyl)-2-(4-tolylazo)-6H-imidazo[2,1-b]thiazol-5-
one (9c).
This compound was prepared according to the general proce-
dure above in a yield of 82%, mp 106-107 °C; IR: 1700 (C=O);
1H-NMR (CDCl3): d 2.37 (s, 3H, CH3), 4.75 (s, 2H, CH2), 7.23-
8.20 (m, 8H, Ar-H); EIMS: m/z 368 (1.15%, M+.).
[15] P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon,
D. Vistica, J. T. Warren, H. Bokesch, S. Kenney and M. R. Boyd; New
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