Versatile 2-aminothiazoles, building blocks for highly functionalised heterocycles

Article abstract of DOI:10.1002/jhet.5570400603

The reactions of quantitatively available 4-phenyl- and 4-(4-antipyrinyl)-2-aminothiazole ["4-antipyrinyl-" is used as a short-term for " 4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1-H-pyrazol-4yl)-"] with chloroacetyl chloride, acetic anhydride, ethyl cy

Full text of DOI:10.1002/jhet.5570400603

Nov-Dec 2003
963
Versatile 2-aminothiazoles, building blocks for highly
functionalised heterocycles
Gerd Kaupp [a]*, Fathy A. Amer [b], Mohamed Abbas Metwally [b]
and Ehab Abdel-latif [b]
[a] University of Oldenburg, Faculty 5, Organic Chemistry I, P.O. Box 2503, 26111 Oldenburg, Germany;
Fax: +49 441 7983409
[b] University of Mansoura, Faculty of Sciences, Egypt; Fax: +20 502246781.
Received April 10, 2003
The reactions of quantitatively available 4-phenyl- and 4-(4-antipyrinyl)-2-aminothiazole ["4-antipyrinyl-"
is used as a short-term for "4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1-H-pyrazol-4yl)-"] with
chloroacetyl chloride, acetic anhydride, ethyl cyanoacetate and carbon disulphide are reported. The products
are transformed further by Knoevenagel condensations and coupling reactions with aromatic diazonium salts.
The latter occur both at the thiazole ring and at the active methylene sites. The tautomerism of these products
is studied on the basis of density functional theory calculations at the B3LYP/6-31G* level.
J. Heterocyclic Chem., 40, 963 (2003).
Introduction.
Furthermore, secondary substitutions, cyclizations,
Knoevenagel condensations and azo couplings, the latter
to the thiazole ring and to the introduced cyanoacetamide
substituent, will be performed in order to provide numer-
ous highly functionalised heterocycles. The chromophores
that were introduced might be useful as labels or for dying
purposes of the model compounds.
The 2-aminothiazole building block is of widespread use
in chemistry [1], medicine [2-5] and pharmacology (for
example antibacterial [6] or anti-inflammatory [7] applica-
tions). A large number of 2-aminothiazoles have been sub-
stituted with different groups for pharmaceutical purposes
[8]. These syntheses are largely facilitated by the ease of
access of 2-aminothiazoles when using the new waste-free
solid-state synthesis techniques from thioureas and
α−halogenoketones [9]. We explored the synthetic capa-
bilities in view of varied and diverse reactions of 4-phenyl-
and 4-(4-antipyrinyl)-2-aminothiazol in order to point out
the versatility even in the presence of complicated func-
tionality. Actually two pharmacophores are linked together
in the latter system. The primary amino group of the
2-aminothiazoles can be substituted in various ways.
Results.
1. 2-Aminothiazoles.
4-Phenyl-2-aminothiazole (1) and related compounds
have been prepared by waste-free solid-state reaction of α-
halogenoketones and thioureas with 100% yield [9]. The
same technique could be applied to 4-(chloroacetyl)-
antipyrine (2) and thiourea (3). The product 4 (that had
been previously obtained in 92% yield by conventional
Scheme 1
Scheme 2

964
G. Kaupp, F. A. Amer, M. A. Metwally and E. Abdel-latif
Vol. 40
synthesis [8]) could now be obtained with 100% yield
from stoichiometric reactions by ball-milling followed by
the corresponding derivatives 9a, b were isolated (Scheme
4). The molecular structure of these products was con-
firmed on the basis of their spectral data.
washings with Na CO solutions (Scheme 1). This
2
3
remarkable 3-cascade reaction of substitution, cyclization
and dehydration proceeds again [9] in the solid state. The
solid-state mechanism of such unusual processes has been
amply demonstrated by nanoscopic techniques [9-10].
Numerous 2-aminothiazoles such as compound 1 have
been reacted with aliphatic or aromatic aldehydes to form
the corresponding imines (Schiff bases) and their antimi-
crobial and antifungal activities tested [11]. Numerous fur-
ther reactions of the primary amino group of the reagents 1
and 4 appear useful.
Scheme 4
2. 2-Thiazolylamides and 2-Thiazolyl-cyanoacetamides.
4. Reactions of 1 and 4 with Carbon Disulphide.
2-(N-acetylamino)-4-phenyl-thiazole and many substi-
tuted derivatives have been described [12]. Similarly,
treatment of compound 4 with acetic anhydride at 65°
yielded the mono-acetylation product 2-(N-acetylamino)-
4-(4-antipyrinyl)-thiazole (5) (Scheme 2).
The base promoted nucleophilic addition of the 2-
aminothiazoles 1 and 4 to an equimolar amount of carbon
disulphide in DMF containing potassium hydroxide
afforded the potassium sulphide salts 10 that were not iso-
lated. Subsequent treatment of the salts 10 with an
equimolar amount or an excess of methyl iodide and base
furnished the mono- or di-methylated products 11b and
12b, respectively (Scheme 5). The compounds 11a [16]
and 12a [17] are already known, the molecular structures
of 11b and 12b were secured by spectral data.
Dimethyl dithiocarbonimidates are useful precursors
for the synthesis of many important heterocyclic com-
pounds e.g. arylamino- or heteroarylamino-1,3-heteroa-
zoles [18], ß-lactams [19], 3-heteroaryl-tetrahydroquina-
zolin-2,4-diones [20], 8-arylamino- or heteroarylamino-
purines [21] and they serve as dienes in Diels-Alder
reactions [22]. We tried the reaction of 12b with 2-
aminothio-phenol in refluxing N,N-dimethylformamide
(DMF) in the presence of one equivalent of sodium
hydroxide and obtained a single product that was identi-
fied to be compound 14b, based on analytical and spec-
tral data. Heterocyclization of 10 was achieved by reac-
tion with chloroacetic acid (after neutralization with
sodium carbonate). The 3-substituted thiazolidinone-2-
thione derivatives 13a, b were obtained. The molecular
structure of 13 was confirmed by analytical and spectral
data. Thus, interesting heterocycles are easily accessible
by these routes and extensions for further reactions can
be predicted.
Reaction of compound 4 with an equimolar amount of
chloroacetylchloride in DMF containing some drops of tri-
ethylamine afforded the corresponding 4-(4-antipyrinyl)-
2-(α-chloroacetamido)-thiazole (6) (Scheme 2). The spec-
tral data of the amides 5 and 6 were consistent with their
structures. Furthermore, compound 6 reacted with 2-mer-
capto-benzothiazole, -benzoxazol and -benzimidazol in
ethanol solution containing a few drops of triethylamine to
yield the thioethers 7a-c. The structures of 7a-c were
established by spectral data (see Experimental).
Interestingly, products of the type 7 (e.g. phenyl instead of
the 4-antipyrinyl substituent) exhibited antimicrobial
activity [13] and the present compounds may be tested
accordingly.
The 2-aminothiazoles 1 and 4 reacted with ethyl cyano-
acetate and sodium ethoxide in ethanol solution and
afforded the corresponding cyanoacetamide derivatives 8
with an active methylene group for further derivatization
(see Section 3). The molecular structures of compounds 8a
[14] and 8b [15] are clearly indicated by the spectral data.
Scheme
3
5. Coupling of 8, 9 and 13 with Aryl Diazonium Salts.
The compounds 8 have two active sites for electrophilic
substitution reactions with aromatic diazonium salts. The
methylene group in compound 8a proved to be more reac-
tive toward the azo coupling reaction [23] with diazonium
salts than the free C-5 position in the thiazole ring. Thus,
an equimolar amount of aryl diazonium chlorides at 0-5 °C
reacted with compound 8a to yield the corresponding
monohydrazone derivatives 15. If two moles of aryl
3. N-(2-Thiazolyl)-2-propenamides.
The reactivity of the compounds 8 toward Knoevenagel
condensation was tested with 4-methylbenzaldehyde and

Nov-Dec 2003
Versatile 2-aminothiazoles, building blocks for highly functionalised heterocycles
965
Scheme 5
drawing electron density from the 2-amide function.
The couplings at C-5 to give 16 and 17 are unprece-
dented. Contrary to these results, no azo coupling at the
thiazole ring of 8b had previously been reported when
heterocyclic diazonium salts reacted only at the active
methylene group [15].
Scheme 7
Interestingly, the compounds 16 and 17 have both a
hydrazone and an azo moiety in the same molecule.
Density functional model calculations at the B3LYP/6-
31G* level (structure 16 but with the phenyl group and the
cyanohydrazone carbon both replaced by H and Ar = Ph)
excluded a double hydrazone structure for 16 or 17 by the
diazonium chlorides and pyridine were applied at 0-5 °C
the coupling at the thiazole ring occurred as well and the
products 16 were obtained (Scheme 6). Compound 16 was
also obtained by azo-coupling of the monohydrazone
derivatives 15. The molecular structure of the compounds
15 and 16 derives from the analytical and spectral data.
The tautomeric structure of product 15 was elucidated by
density functional calculations at the B3LYP/6-31G*
level. The most stable tautomer found exhibits the hydra-
zone structure 15 with one intramolecular hydrogen bond.
The alternative hydrazone structure 15’ was only 1.4 kcal
-1
estimated energy difference of 11.4 kcal mol .
The methylene group in the compounds 13 was not
active enough for the azo coupling. Thus, only elec-
trophilic coupling at the thiazole site was observed with
equimolar or excessive amounts of aryl diazonium chlo-
rides at 0-5° (Scheme 8). The molecular structures of the
monoazo derivatives 18 and 19 were established by analyt-
ical and spectroscopic data.
The azo coupling of compound 9 without a competing
active methylene group occurred easily, as expected, to
afford the products 20 and 21 (Scheme 9). The structure of
-1
mol worse. Therefore, both should be in equilibrium.
However, the best possible azo structure was found 13.7
-1
kcal mol higher in energy and that excludes their signifi-
cant contribution to the equilibrium.
The azo couplings of compound 8b could not avoid
the reaction at the thiazole ring. If one mole or two
moles of the diazonium salt were applied only the corre-
the highly functionalized dyes 20 and 21 was assigned on
the basis of spectral data.
Scheme 6
Scheme 8
sponding bis-azo derivatives 17 could be isolated
(Scheme 7). This fact is explained by the 4-antipyrinyl
group which donates electron density to the thiazole
13
ring (the C nmr shifts of the 5-C of 8a and 8b are
106.5 and 102.9 ppm, respectively). It appears that ini-
tial coupling to the imidazole ring enhances the reactiv-
ity of the remote methylene group by additionally with-

966
G. Kaupp, F. A. Amer, M. A. Metwally and E. Abdel-latif
Vol. 40
Scheme 9
stainless steel double-walled beaker with fittings for a heating
bath. Water of the appropriate temperature was circulated for heat-
ing or cooling. Two stainless steel balls with 12 mm diameter
were used. Ball-milling was performed at 20–25 Hz frequency.
Progress and completeness of the solid-state reactions was
checked by ir spectroscopy in potassium bromide. The product
yields were detected by weight, product purity by mp, thin layer
1
chromatography (tlc, on Merck Silica Gel 60 F plates) and H
254
nmr spectroscopy. The short-term “4-antipyrinyl-" is used for the
4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1-H-pyrazol-4-yl)-
substituent in order to improve the readability. B3LYP (basis set
6-31G*) density functional theory calculations with full geometry
optimization were performed with the program TITAN, version
1.01, of Wavefunction, Inc., Irvine, USA.
Discussion.
A large number of substituted 2-aminothiazoles has been
synthesized on useful paths. These highly functionalised
derivatives may be of interest to pharmacy and for dyeing
purposes, yet to be explored. Very high and complicated
functionality is not only achieved by coupling to the
antipyrine pharmacophore but also by further functionaliza-
tion of the substituents at the 2-amino group. Thirty two 2-
thiazolyl-amides, -cyanoacetamides, -sulfanylacetamides,
-propenamides, -arylhydrazonoacetamides, -dithiocarba-
mates, -dithiocarbonimidates, -rhodanines, -aminobenzoth-
iazoles and 5-arylazo-thiazolylamides were prepared and
characterized. All of these products exhibit unusually high
functionality with varied groups, which demonstrates the
stability of the synthetic pathways that are opened by the
waste-free access of the 2-aminothiazole building blocks.
The azo couplings at the cyanoacetamide groups and at the
thiazole ring are particularly versatile and show marked
variations in reactivity. Interesting conjugated systems arise
in compounds 15 - 21. While the absorption maxima in the
uv/visible spectra do not reach 500 nm, the dyeing proper-
ties may be favourable due to the high concentration of het-
eroatoms. These features will be explored in due time.
2-Amino-4-(4-antipyrinyl)-thiazole (4).
A mixture of 4-(chloroacetyl)-antipyrine (2) [8] (497 mg, 2.00
mmol) and thiourea (3) (152 mg, 2.00 mmol) was ball-milled at
70° for 60 minutes. After drying at 0.01 bar at 80° a quantitative
.
yield of 4 HBr (615 mg, 100%) was obtained. The free base 4
was obtained by washing the fine powder of the hydrobromide
with 5% aqueous Na CO solution followed by water and drying
2
3
at 80° in a vacuum. The yield was 530 mg (100%); mp 235-236°
-1
(Lit. [8] mp 235°); ir (KBr): 3327, 3151, 2956, 1636, 1593 cm ;
1
H nmr (DMSO-d ): δ 2.70 (s, 3H), 3.15 (s, 3H), 6.55 (s, 2H),
6
7.15 (s, 1H, thiazol proton), 7.25 – 7.50 (m, 5H, phenyl protons);
13
C nmr (DMSO-d ): δ 10.8, 33.9, 100.4, 102.7, 122.5 (2C),
6
124.8, 127.3 (2C), 133.6, 141.0, 150.6, 162.36, 165.6.
N-[4-(4-Antipyrinyl)-thiazol-2-yl]-acetamide (5).
A mixture of compound 4 (1.43 g, 5.0 mmol) and acetic anhy-
dride (3.0 ml) was heated in an oil bath at 60 - 65° for 1 hour. The
reaction mixture was allowed to cool at room temperature and
then recrystallized from ethanol to afford 1.35 g (82%) colorless
crystals, mp 227°; ir (KBr): 3185 (NH), 3094, 2964, 1689 (amide
-1
1
C=O), 1631 (pyrazole C=O), 1542, 1491, 1371, 1278 cm ; H
nmr (CDCl ): δ 2.10 (s, 3H), 2.60 (s, 3H), 3.10 (s, 3H), 7.25-7.45
3
(m, 5H, phenyl protons), 7.70 (s, thiazol proton), 10.30 (s, 1H,
13
NH); C nmr (CDCl ): δ 13.1, 23.7, 36.0, 105.2, 110.1, 125.7
3
(2C), 128.0, 129.9 (2C), 135.5, 142.1, 152.48, 157.9, 164.9,
EXPERIMENTAL
General Aspects.
+
168.8; ms: m/z (%) 328 (M ,100), 313, 286, 271, 243, 226, 194,
+
166, 138, 93, 77, 56; hrms: calcd. for C
328.0994, found 328.0983.
H
N O S (M )
16 16
4 2
Melting points were determined with a Gallenkamp melting
point apparatus (capillary method) and are uncorrected. Elemental
analyses (C, H, N; Table 1) were carried out at the Microanalytical
Unit of the Faculty of Science, Mansoura University, Egypt.
Infrared spectra (ir) were recorded with a Perkin-Elmer 1720-X
FT-IR spectrometer using potassium bromide pellets (not all fre-
quencies are reported), uv/visible spectra with a Perkin-Elmer
Lambda 551 S spectrometer. All nmr spectra were acquired using
N-[4-(4-Antipyrinyl)-thiazol-2-yl]-α-chloroacetamide (6).
Chloroacetyl chloride (1.2 ml, 15 mmol) was dropwise added
with stirring to a solution of compound 4 (2.86 g, 10.0 mmol) in
DMF (15 ml) containing triethyl amine (0.5 ml) at room temper-
ature. Stirring was continued for 4 hours and the reaction mixture
was poured to ice cooled water. The precipitate was collected by
filtration, dried and recrystallized from ethanol to obtain 2.61 g
(72%) colorless crystals, mp 208°; ir (KBr): 3282, 1700, 1615,
1590, 1549, 1487, 1455, 1410, 1322, 1260, 1155, 1082, 753
1
a Bruker WP 300 spectrometer at 300 MHz ( H) or 75.5 MHz
13
( C; in broad band mode). Deuteriochloroform/dimethylsulfox-
-1
1
ide-d (CDCl /DMSO-d ) mixtures contained up to 20% DMSO-
cm ; H nmr (CDCl ): δ 2.70 (s, 3H), 3.20 (s, 3H), 4.25 (s, 2H),
6
3
6
3
d . All δ-values are given in ppm and refer to the internal standard
tetramethylsilane (TMS), ψd in H nmr stands for an apparent
7.25-7.50 (m, 5H, phenyl protons), 7.85 (s, 1H, thiazol proton),
6
1
13
9.80 (s, 1H, NH); C nmr (CDCl ): δ 12.53, 35.40, 42.06,
3
doublet of a higher order spin system. J-Values are given in Hertz
(Hz). Mass spectra were obtained at a Finnigan MAT 212 instru-
ment by electron impact at 70 eV. For known compounds spectral
data were restricted to previously not available data. The ball-mill
for 2 mmol runs was a Retsch MM 2000 swing mill with a 10 ml
104.42, 110.11, 124.60 (2C), 127.04, 129.21 (2C), 134.91,
+
142.12, 151.95, 155.50, 163.60, 164.21; ms: m/z (%) 364 (M ),
+
362 (M ,100), 328, 313, 286, 243, 213, 194, 138, 93, 77, 56;
+
hrms: calcd. for C
362.0605.
H
ClN O S 362.0604 (M ), found
16 15
4
2

Nov-Dec 2003
Versatile 2-aminothiazoles, building blocks for highly functionalised heterocycles
967
General Procedure for the Synthesis of 2-(Azol-sulfanyl)-N-[4-
(4-antipyrinyl)-thiazol-2-yl]-acetamide Derivatives (7a-c).
3H, 2 phenyl protons and thiazol proton), 7.85 (ψd, 2H, phenyl
13
protons), 12.50 (s, 1H, NH); C nmr (CDCl ): δ 24.3, 106.5,
3
113.0, 124.2 (2C), 126.2, 127.0 (2C), 132.7, 147.9, 155.9, 159.8.
A mixture of 4-(4-antipyrinyl)-2-(α-chloroacetamido)thiazole
6 (1.08 g, 3.0 mmol) and the corresponding 2-mercaptobenzazole
(3.0 mmol) was refluxed in ethanol (50 ml) containing 5 drops of
triethyl amine for 4 hours. The precipitate upon cooling was col-
lected by filtration and crystallized from ethanol.
N-[4-(4-Antipyrinyl)-thiazol-2-yl]-cyanoacetamide (8b).
This compound was obtained as colorless crystals, mp 219-
220° (Lit. [15] mp 225-226°); yield: 5.43g (77%); ir (KBr): 3391,
3166, 3062, 2969, 2260 (CN), 1697 (C=O), 1631, 1562, 1489,
-1
1
2-(Benzothiazol-2-ylsulfanyl)-N-[4-(4-antipyrinyl)-thiazol-2-yl]-
acetamide (7a).
1407, 1340, 1271, 1155, 1049, 942, 882, 837, 750, 695 cm ; H
nmr: δ 2.70 (s, 3H), 3.20 (s, 3H), 3.80 (s, 2H), 7.30-7.50 (m, 5H,
phenyl protons), 7.70 (s, 1H, thiazol proton), 12.20 (br s, 1H,
This compound was obtained as colorless crystals, mp 120°;
yield: 920 mg (62%); ir (KBr): 3174, 3057, 2963, 1695, 1641,
1591, 1562, 1488, 1455, 1424, 1299, 1238, 1120, 1080, 1006,
13
NH); C nmr (DMSO-d ): δ 11.4, 24. 9, 34.3, 102.9, 107.8,
6
113.3, 123.7 (2C), 126.0, 128.1 (2C), 133.9, 141.2, 150.8, 155.3,
+
159.7, 163.0; ms: m/z (%) 353 (M , 100), 313, 286, 243, 194,
-1
1
796, 755 cm ; H nmr (CDCl ): δ 2.60 (s, 3H), 3.10 (s, 3H),
3
+
143, 93, 77, 56; hrms: calcd. for C
found 353.0946.
H
N O S (M ) 353.0946,
17 15
5 2
4.15 (s, 2H), 7.20-7.50 (m, 7H, phenyl protons), 7.75 (ψd, 1H,
phenyl proton), 7.85 (s, 1H, thiazol proton), 8.00 (ψd, 1H, phenyl
13
proton), 11.90 (br s, 1H, NH); C nmr (CDCl ): δ 12.4, 35.4,
3
General Procedure for the Synthesis of 2-Cyano-N-[4-
(hetero)aryl-2-thiazolyl)-3-(4-tolyl)-2-propenamides (9).
36.1, 104.5, 109.4, 121.2, 121.4, 124.4 (2C), 125.1, 125.6, 126.3,
126.8, 129.1 (2C), 134.9, 135.4, 142.0, 151.9, 156.2, 164.2,
A mixture of 8 (10 mmol) and p-methylbenzaldehyde (1.2 ml,
10 mmol) in 20 ml ethanol and two drops of piperidine was
refluxed for 2 hours. The solid products that separated on cooling
were collected by filtration, dried and crystallized from ethanol.
+
165.8, 167.1; ms: m/z (%) 493 (43, M ), 419, 327, 313 (100),
286, 243, 208, 180, 108, 77, 56; hrms: calcd. for C
(M ) 493.0701, found 493.0698.
H N O S
23 19 5 2 3
+
2-(Benzoxazol-2-ylsulfanyl)-N-[4-(4-antipyrinyl)-thiazol-2-yl]-
acetamide (7b).
2-Cyano-N-(4-phenyl-2-thiazolyl)-3-(4-tolyl)-2-propenamide
(9a).
This compound was obtained as colorless crystals, mp 182°;
yield: 960 mg (67%); ir (KBr): 3194, 3100, 2969, 1702, 1645,
1592, 1562, 1510, 1455, 1413, 1370, 1318, 1264, 1239, 1216,
This compound was obtained as light yellow crystals, mp
202°; yield: 2.35 g (68%); ir (KBr): 3378, 3115, 2213 (CN),
-1
1
1682, 1596, 1542, 1442, 1327, 1283, 1177, 816, 728 cm ; H
-1
1
1134, 1098, 1049, 755 cm ; H nmr (CDCl ): δ 2.60 (s, 3H),
3
nmr (CDCl ): δ 2.40 (s, 3H), 7.20 (s, 1H), 7.30-7.40 (m, 5H,
3
3.10 (s, 3H), 4.10 (s, 2H), 7.20-7.50 (m, 8H, phenyl protons),
phenyl protons), 7.85 (ψd, 2H, phenyl protons), 7.90 (ψd, 2H,
7.60 (ψd, 1H, phenyl proton), 7.75 (s, 1H, thiazol proton), 11.60
phenyl protons), 8.40 (s, 1H, thiazol proton), 9.70 (s, 1H, NH);
13
(br s, 1H, NH); C nmr (CDCl ): δ 12.3, 34.8, 35.2, 104.3,
3
13
C nmr (CDCl ): δ 21.9, 100.8, 108.7, 116.2, 126.1 (2C), 128.2,
3
109.4, 110.3, 118.1, 124.6 (3C), 124.7, 127.0, 129.1 (2C), 134.8,
140.8, 141.8, 151.8, 152.2, 156.1, 164.1, 164.9, 165.3; ms: m/z
128.8 (2C), 128.8, 130.2 (2C), 131.3 (2C), 134.0, 145.3, 150.5,
+
+
155.0, 156.8, 158.6; hrms: calcd. for C
345.0936, found 328.0935.
H
N OS (M )
(%) 477 (M ), 403, 313 (100), 286, 243, 192, 164, 151, 105, 78.
20 15
3
2-(1H-Benzimidazol-2-ylsulfanyl)-N-[4-(4-antipyrinyl)-thiazol-
2-yl]-acetamide (7c).
2-Cyano-N-[4-(4-antipyrinyl)-thiazol-2-yl]-3-(4-tolyl)-2-prope-
namide (9b).
This compound was obtained as colorless crystals, mp 161°;
yield: 900 mg (63%); ir (KBr): 3385, 3171, 3082, 2991, 1683,
1627, 1590, 1562, 1497, 1441, 1416, 1348, 1310, 1268, 1133,
This compound was obtained as brown shiny crystals, mp
232°; yield: 3.32 g (73%); ir (KBr): 3403, 3127, 2972, 2212
(CN), 1677, 1651, 1610, 1586, 1537, 1489, 1446, 1279, 1179,
-1
1
972, 836, 794, 746 cm ; H nmr (CDCl /DMSO-d ): δ 2.75 (s,
3
6
-1 1
1146 cm ; H nmr (CDCl ): δ 2.40 (s, 3H), 2.70 (s, 3H), 3.20 (s,
3H), 3.20 (s, 3H), 4.25 (s, 2H), 7.10-7.50 (m, 9H, phenyl protons),
7.65 (s, 1H, thiazol proton), 12.40 (br s, 2H, 2NH); ms: m/z (%)
3
3H), 7.30-7.50 (m, 7H, phenyl protons), 7.80 (s, 1H, thiazol pro-
+
ton), 7.90 (ψd, 2H, phenyl protons), 8.45 (s, 1H), 9.75 (s, 1H,
476 (M ), 442, 402, 388, 313, 286 (100), 243, 194, 118, 91, 77.
13
NH); C nmr (CDCl ): δ 12.7, 21.89, 35.3, 101.3, 103.2, 109.8,
3
General Procedure for the Synthesis of N-(Thiazol-2-yl)-cyano-
acetamides (8).
116.5, 124.6 (2C), 127.0, 129.0, 129.2 (2C), 130.2 (2C), 131.3
(2C), 134.8, 141.6, 145.1, 152.0, 154.8, 156.5, 158.9, 164.1; ms:
+
m/z (%) 455 (M , 100), 387, 353, 313, 243, 170, 115, 77; hrms:
The 2-aminothiazole 1 or 4 (20 mmol) and ethyl cyanoacetate
(2.13 ml, 20 mmol) were added to a solution of sodium ethoxide
(from 0.46 g Na, 20 mmol) in absolute ethanol (30 ml). The reac-
tion mixture was refluxed for 6 hours with stirring and the solvent
was evaporated under reduced pressure. The residue was dis-
solved in water and neutralized by 1 N HCl. The separated solid
was collected by filteration and recrystallized from ethanol.
+
calcd. for C
H
N O S (M ) 455.1416, found 455.1426.
25 21
5 2
Methyl-N-[4-(4-antipyrinyl)-thiazol-2-yl]-dithiocarbamate (11b).
To a well stirred solution of 4 (2.86 g, 10.0 mmol) in DMF (20
ml) in an ice-bath were added dropwise and successively aqueous
potassium hydroxide (0.56 g in 5 ml water), carbon disulphide
(0.60 ml, 10 mmol) and methyl iodide (0.65 ml, 10 mmol). Stirring
was continued for 3 hours and the mixture was poured into water.
The solid thus obtained was collected by filtration, washed with
water and recrystallized from ethanol to yield 1.96 g (52%) color-
less crystals, mp 198°; ir (KBr): 3441, 3082, 2908, 1626, 1615,
1592, 1479, 1397, 1331, 1288, 1234, 1216, 1163, 1088, 1001, 949,
N-(4-Phenyl-thiazol-2-yl)-cyanoacetamide (8a).
This compound was obtained as colorless crystals, mp 195° (Lit.
[14] mp 192°); yield: 3.30 g (68%); ir (KBr): 3371, 3171, 3053,
2948, 2263 (CN), 1700, 1662, 1571, 1485, 1445, 1389, 1338,
-1
1
1283, 1178 cm ; H nmr (CDCl ): δ 3.95 (s, 2H), 7.25-7.40 (m,
3

968
G. Kaupp, F. A. Amer, M. A. Metwally and E. Abdel-latif
Vol. 40
-1
1
2-[4-(4-Antipyrinyl)-thiazol-2-yl]-aminobenzothiazole (14b).
776, 693 cm ; H nmr (CDCl /CF COOD): δ 2.60 (s, 3H), 2.80
3
3
(s, 3H), 3.50 (s, 3H), 7.00 (s, 1H, thiazol proton), 7.35 (s, 2H,
phenyl protons), 7.60 (s, 3H, phenyl protons); C nmr
A solution of 2-aminothiophenol (250 mg, 2.0 mmol) in DMF
(10 ml) was heated with aqueous sodium hydroxide (0.40 g in 3
ml water) and the mixture was stirred at room temperature for 30
minutes. A solution of 12b (780 mg, 2.0 mmol) in DMF was then
added dropwise and the reaction mixture heated under reflux for
4 hours. After cooling, the mixture was poured into water and
neutralized with 1 M HCl. The precipitate thus obtained was col-
lected by filtration, washed with water, dried and recrystallized
from an ethanol-DMF mixture (1:1) to yield 470 mg (56%) color-
less crystals, mp 231°; ir (KBr): 3196, 3048, 2945, 1637, 1618,
1592, 1521, 1476, 1452, 1301, 1278, 1211, 1066, 1019, 912, 875,
13
(CDCl /CF COOD): δ 11.5, 19.0, 33.3, 94.2, 104.6, 128.3 (2C),
3
3
129.9, 130.3, 130.8 (2C), 132.3, 146.7, 159.1, 162.1, 197.4; ms:
+
m/z (%) 376 (M ), 353, 328 (100), 253, 194, 165, 135, 76; hrms:
+
calcd. for C H N OS (M ) 376.0486, found 376.0483.
16 16
4
3
Dimethyl-N-[4-(4-antipyrinyl)-thiazol-2-yl]-dithiocarbonimidate
(12b).
To a well stirred solution of 4 (2.86 g, 10 mmol) in DMF (20
ml) in an ice-bath were dropwise and successively added aqueous
potassium hydroxide (0.56 g in 5 ml water), carbon disulphide
(0.60 ml; 10 mmol), aqueous potassium hydroxide (0.56 g in 5 ml
water) and methyl iodide (1.3 ml; 21 mmol). Stirring was contin-
ued for 2-3 hours and the mixture was poured into water. The
solid that separated was collected by filtration, washed with
water and recrystallized from ethanol to yield 1.87g (48%) color-
less crystals, mp 166°; ir (KBr): 3108, 2956, 1651, 1593, 1510,
1482, 1456, 1423, 1395, 1345, 1312, 1240, 1192, 1145, 1065,
-1
1
753, 725, 700, 640 cm ; H nmr (CDCl /CF COOD): δ 2.65 (s,
3
3
3H), 3.70 (s, 3H), 7.40 (ψd, 2H, phenyl protons), 7.50 (s, 1H, thi-
azol proton), 7.60-7.75 (m, 6H, phenyl protons), 7.85 (ψd, 1H,
13
phenyl proton); C nmr (CDCl /CF COOD): δ 11.4, 33.4, 96.3,
3
3
115.0, 123.1, 124.3, 126.7, 128.7 (2C), 129.5, 129.9, 131.1 (2C),
132.2, 133.1, 135.6, 146.9, 157.8, 162.4, 166.2, 167.0; ms: m/z
+
(%) 419 (M , 100), 387, 335, 321, 286, 243, 215, 176, 135, 108,
+
91, 77; hrms: calcd. for C
419.0871.
H
N OS (M ) 419.0875, found
21 17
5
2
-1
1
1034, 977, 939, 922, 840, 787 cm ; H nmr (CDCl ): δ 2.60 (s,
3
6H), 2.80 (s, 3H), 3.15 (s, 3H), 7.25-7.45 (m, 5H, phenyl
13
General Procedure for the Synthesis of N-(4-Phenyl-thiazol-2-
yl)-2-arylhydrazono-2-cyanoacetamides (15).
protons), 8.00 (s, 1H, thiazol proton); C nmr (CDCl ): δ 12.7,
3
15.9, 35.5, 104.8, 112.7, 124.3 (2C), 126.7, 129.1 (2C), 135.1,
+
144.1, 152.4, 164.4, 167.0, 169.9; ms: m/z (%) 390 (M , 100),
A solution of sodium nitrite (0.70 g, 10.0 mmol in 10 ml water)
was gradually added to a well cooled solution of the aromatic
amine (10.0 mmol) in concentrated HCl (3 mL). The diazonium
salt solution was added with constant stirring to a cold solution of
compound 8 (10.0 mmol) in ethanol (50 ml) and sodium acetate
(4.0 g). The reaction mixture was allowed to rest at 0° for 2 hours
and the solid was collected by filtration. The monoarylazo deriv-
atives 15 thus obtained, were dried and recrystallized from an
ethanol-DMF mixture (1:1).
343, 329, 317, 296, 236, 171, 110, 77, 56; hrms: calcd. for
+
C
H
N OS (M ) 390.0643, found 390.0647.
17 18
4
3
General Procedure for the Synthesis of 3-(Thiazol-2-yl)-rhoda-
nines (13).
The reaction mixture of the 2-aminothiazole derivative 1 or 4
(10 mmol) and KOH (0.56 g in 4 ml water) and carbon disulphide
(0.60 ml, 10 mmol) was stirred in DMF (20 ml) at 0-5° till a clear
solution was obtained (about 2 hours). Simultaneously,
chloroacetic acid (945 mg, 10 mmol that was neutralized by
N-(4-Phenyl-thiazol-2-yl)-2-phenylhydrazono-2-cyanoacetamide
(15a).
K CO in 10 ml water) was added dropwise. The mixture was
2
3
poured into water and acidified by 1 M HCl. The precipitate was
collected by filtration, washed with water and recrystallized from
DMF with addition of water.
This compound was obtained as yellow crystals, mp 247°;
yield: 2.64 g (76%); uv/visible (CH OH): λ max 382 nm; ir
3
(KBr): 3387, 3213, 3102, 3068, 2222 (CN), 1672, 1605, 1537,
-1
1482, 1444, 1330, 1270, 1204, 1063, 1028, 888, 745, 691 cm ;
3-(4-Phenyl-thiazol-2-yl)-rhodanine (13a).
1
H nmr (CDCl /CF COOH):
7.30-7.65 (m, 10H, phenyl protons), 10.35 (s, 1H, NH); C nmr
δ
7.20 (s, 1H, thiazol proton),
3
3
13
This compound was obtained as colorless crystals, mp 202°;
yield: 1.87 g (64%); ir (KBr): 3115, 2945, 1682, 1594, 1568, 1518,
(CDCl /CF COOH): δ 104.3, 108.6, 109.2, 117.0 (2C), 126.6
3
3
-1 1
1452, 1408, 1325, 1238, 1175, 1013 cm ; H nmr (CF COOD): δ
(2C), 126.8, 127.9, 129.8 (2C), 130.0 (2C), 131.3, 139.6, 142.0,
3
+
4.25 (s, 2H), 7.15 (s, 1H, thiazol proton), 7.50-7.65 (m, 5H, phenyl
160.3, 162.4; hrms: calcd. for C
found 347.0843.
H
N OS (M ) 347.0840,
18 13
5
13
protons); C nmr (CF COOD): δ 37.4, 106.2, 126.6 (2C), 126.8,
3
129.9 (2C), 131.4, 141.4, 162.9, 174.1, 195.2; ms: m/z (%) 292
N-(4-Phenyl-thiazol-2-yl)-2-(p-tolylhydrazono)-2-cyanoac-
etamide (15b).
+
(M ), 264, 250, 218 (100), 203, 186, 176, 134; hrms: calcd. for
+
C H N OS (M ) 291.9799, found 291.9797.
12
8
2
3
This compound was obtained as yellow crystals, mp 230°;
3-[4-(4-Antipyrinyl)-thiazol-2-yl]-rhodanine (13b):
yield: 2.64 g (73%); uv/visible (CH OH): λ max 387 nm; ir
3
This compound was obtained as colorless crystals, mp 198°;
yield: 2.21 g (55%); ir (KBr): 3131, 2932, 1722, 1616, 1573,
(KBr): 3392, 3225, 3104, 3062, 2221 (CN), 1674, 1604, 1537,
-1
1482, 1444, 1329, 1274, 1206, 1061, 1028, 887, 814, 746 cm ;
-1
1
1
1480, 1397, 1304, 1214, 987, 776 cm ; H nmr (CF COOD): δ
H nmr (CDCl /CF COOH):
δ 2.35 (s, 3H), 7.20 (ψd, 2H,
3
3
3
2.65 (s, 3H), 3.55 (s, 3H), 4.30 (s, 2H), 7.15 (s, 1H, thiazol pro-
phenyl protons), 7.25 (s, 1H, thiazol proton), 7.45-7.65 (m, 7H,
13
13
ton), 7.35-7.70 (m, 5H, phenyl protons); C nmr (CF COOD): δ
phenyl protons), 10.35 (s, 1H, NH); C nmr (CDCl /
3
3
11.5, 33.3, 37.5, 94.3, 105.4, 128.5 (2C), 129.9, 131.0 (2C),
132.7, 146.9, 159.0, 160.7, 162.6, 173.5, 194.1; ms: m/z (%) 402
CF COOH): δ 20.9, 103.7, 108.5, 109.4, 116.9 (2C), 126.6 (2C),
3
126.9, 129.5, 129.8 (2C), 130.6 (2C), 131.3, 137.4, 138.4, 142.0,
+
+
(M ), 353, 290, 260, 265, 235 (100), 105, 78, 63, 44; hrms: calcd.
162.0; hrms: calcd. for C
361.0999.
H
N OS (M ) 361.0997, found
19 15
5
+
for C
H
N O S (M ) 402.0279, found 402.0280.
17 14
4 2 3

Nov-Dec 2003
Versatile 2-aminothiazoles, building blocks for highly functionalised heterocycles
969
N-(4-Phenyl-thiazol-2-yl)-2-(p-methoxyphenylhydrazono)-2-
cyanoacetamide (15c).
133.7, 142.7, 144.8, 147.4, 155.5, 156.4, 158.9, 159.,8; ms: m/z
(%) 511 (M ), 481, 416, 377, 335, 310 (100), 279, 229, 214, 176,
+
133, 107, 77.
This compound was obtained as yellow crystals, mp 251°; yield:
3.24 g (86%); uv/visible (CH OH): λ max 399 nm; ir (KBr): 3395,
3
N-[4-(4-Antipyrinyl)-5-phenylazo-thiazol-2-yl)-2-(phenylhydra-
zono)-2-cyanoacetamide (17a).
3192, 3107, 2222 (CN),, 1670, 1611, 1537, 1482, 1441, 1328,
-1
1
1274, 1251, 1206, 1165, 1059, 1025, 887, 826, 747 cm ; H nmr
(CDCl /CF COOH): δ 3.90 (s, 3H), 7.00 (ψd, 2H, phenyl pro-
This compound was obtained as orange crystals, mp 276-277°;
3
3
yield: 1.77 g (63%); uv/visible (CH OH): λ max 456 nm; ir
tons), 7.25 (s, 1H, thiazol proton), 7.45-7.60 (m, 7H, phenyl pro-
3
13
(KBr): 3393, 2925, 2211 (CN), 1687, 1646, 1608, 1515, 1484,
tons), 10.45 (s, 1H, NH); C nmr (CDCl / CF COOH): δ 56.0,
3
3
-1
1
1346, 1271, 1206, 1143 cm ; H nmr (CF COOD): δ 2.90 (s,
103.1, 108.5, 109.7, 115.6 (2C), 118.8 (2C), 126.6 (2C), 126.8,
129.8 (2C), 131.4, 133.9, 142.0, 158.8, 160.6, 162.4; ms: m/z (%)
3
13
3H), 3.65 (s, 3H), 7.25-7.80 (m, 15H, phenyl protons); C nmr
+
(CF COOD): δ 13.0, 33.7, 97.5, 104.4, 109.2, 117.1 (2C), 123.4
377 (M ,100), 242, 203, 176, 134, 122, 107, 77; hrms: calcd. for
3
+
C H N O S (M ) 377.0946, found 377.0946.
(2C), 128.2, 128.6 (2C), 129.5, 130.1 (2C), 130.1 (2C), 131.1
(2C), 133.1, 133.8, 136.4, 139.5, 143.4, 148.9, 150.9, 157.8,
19 15
5 2
General Procedure for the Synthesis of N-(5-Arylazo-thiazol-2-
yl)-2-arylhydrazono-2-cyanoacetamides (16 and 17).
+
160.1, 160.5; ms: m/z (%) 561 (M ), 534, 506, 457, 430, 362,
312, 286, 269, 234, 221, 169, 161, 145 (100), 91, 77, 56; hrms:
+
A solution of sodium nitrite (0.70 g, 10.0 mmol in 10 ml water)
was gradually added to a well cooled solution of the aromatic
amine (10.0 mmol) in concentrated HCl (3 ml). The diazonium
salt solution was added with constant stirring to a cold solution of
the compounds 8a or 8b (5.0 mmol) in pyridine (30 ml). The
reaction mixture was allowed to rest at 0° for 2 hours, was diluted
with water and then the solid was collected by filtration. The ary-
lazo derivatives 16 or 17 thus obtained, were dried and recrystal-
lized from an ethanol/N,N-dimethylformamide mixture (1:1).
calcd. for C
H
N O S (M ) 561.1695, found 561.1693.
29 23
9 2
N-[4-(4-Antipyrinyl)-5-(p-methyl-phenylazo)-thiazol-2-yl]-2-(p-
methyl-phenylhydrazono)-2-cyanoacetamide (17b).
This compound was obtained as orange crystals, mp 283-284°;
yield: 2.00g (68%); uv/visible (CH OH): λ max 461 nm; ir
3
(KBr): 3393, 2918, 2210 (CN), 1682, 1651, 1610, 1515, 1484,
-1
1
1413, 1273, 1212, 1070 cm ; H nmr (CDCl /CF COOH): δ
3
3
2.35 (s, 3H), 2.40 (s, 3H), 2.85 (s, 3H), 3.60 (s, 3H), 7.15-7.75
13
N-(4-Phenyl-5-phenylazo-thiazol-2-yl)-2-phenylhydrazono-2-
cyanoacetamide (16a).
(m, 13H, phenyl protons), 10.10 (s, 1H, NH); C nmr (CDCl /
3
CF COOH): δ 12.9, 20.8, 21.6, 33.7, 97.7, 104.5, 109.4, 116.6
3
(2C), 123.3 (2C), 128.5 (2C), 129.6, 130.5 (2C); 130.6 (2C),
130.8 (2C), 132.6, 136.7, 137.3, 137.9, 143.1, 144.9, 148.8,
157.8, 159.4, 159.6, 160.0.
This compound was obtained as brown crystals, mp 260-261°;
yield: 1.26 g (56%); uv/visible (CH OH): λ max 446 nm; IR
3
(KBr): 3401, 3228, 3062, 2222 (CN), 1675, 1604, 1554, 1521,
-1
1
1480, 1446, ,1327, 1272, 1073, 891, 763, 691 cm ; H nmr
(CDCl /CF COOH): δ 7.30-7.80 (m, 15H, phenyl protons),
N-[4-(4-Antipyrinyl)-5-(p-methoxyphenylazo)-thiazol-2-yl]-2-
(p-methoxy-phenylhydrazono)-2-cyanoacetamide (17c).
3
3
+
10.40 (s, 1H, NH); ms: m/z (%) 451 (M ), 416, 347, 307, 279,
242, 203 (100), 176, 134, 106, 92, 77; hrms: calcd. for
This compound was obtained as orange crystals, mp 277-278°;
+
C
H
N OS (M ) 451.1215, found 451.1214.
yield: 2.27 g (73%); uv/visible (CH OH): λ max 471 nm; ir
24 17
7
3
(KBr): 3392, 2939, 2210 (CN), 1678, 1646, 1597, 1510, 1478,
N-[4-Phenyl-5-(p-methylphenylazo)-thiazol-2-yl]-2-(p-
methylphenylhydrazono)-2-cyanoacetamide (16b).
-1
1
1436, 1246, 1146, 1068 cm ; H nmr (CDCl /CF COOH): δ
3
3
2.85 (s, 3H), 3.60 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 6.90-7.70
This compound was obtained as brown crystals, mp 241-242°;
13
(m, 13H, phenyl protons); C nmr (CDCl /CF COOH): δ 12.8,
3
3
yield: 1.51 g (63%); uv/visible (CH OH): λ max 450 nm; ir
3
33.7, 55.8, 55.9, 97.7, 103.6, 109.6, 115.5 (4C), 118.5 (2C), 126.1
(2C), 128.5 (2C), 129.5, 130.9 (2C), 132.8, 133.7, 134.6, 143.3,
145.0, 148.5, 157.7, 158.8, 159.7, 160.0, 164.1.
(KBr): 3392, 3225, 3033, 2921, 2218 (CN), 1677, 1603, 1520,
1481, 1445, 1327, 1277, 1211, 1073, 1030, 891, 816, 744, 693
-1
1
cm ; H nmr (CDCl /CF COOH): δ 2.35 (s, 3H), 2.40 (s, 3H),
3
3
General Procedure for the Synthesis of 3-(5-Arylazo-thiazol-2-
yl)-rhodanines (18 and 19).
7.20-7.85 (m, 13H, phenyl protons), 10.10 (s, 1H, NH); ms: m/z
+
(%) 479(M , 100), 446, 361, 321, 293, 266, 203 (100), 176, 134,
+
106, 92, 77; hrms: calcd. for C
479.1531.
H
N OS (M ) 479.1528, found
26 21
7
A solution of sodium nitrite (0.35 g, 5.0 mmol in 5 ml water)
was gradually added to a well cooled and stirred suspension of
the aromatic amine (5.0 mmol) in concentrated HCl (1.5 ml).
The diazonium salt solution was added with constant stirring to a
cold solution (0-5°) of compound 13 (5.0 mmol) in pyridine (30
ml). The reaction mixture was allowed to rest at 0° for 2 hours, it
was diluted with water and then the solid was collected by filtra-
tion. The solid arylazo derivatives 18 or 19 thus obtained, were
dried and recrystallized from DMF with addition of water.
N-[4-Phenyl-5-(p-methoxyphenylazo)-thiazol-2-yl]-2-(p-
methoxyphenylhydrazono)-2-cyanoacetamide (16c).
This compound was obtained as red-brown crystals, mp 248°;
yield: 1.38 g (54%); uv/visible (CH OH): λ max 468 nm; ir
3
(KBr): 3402, 3202, 3067, 2938, 2217 (CN), 1676, 1599, 1578,
-1
1
1521, 1479, 1327, 1279, 1250, 1081, 1030, 892, 827 cm ; H
nmr (DMSO-d ): δ 3.80 (s, 3H), 3.85 (s, 3H), 6.95 (ψd, 2H,
6
phenyl protons), 7.05 (ψd, 2H, phenyl protons), 7.35-7.50 (m,
3H, phenyl protons), 7.75 (m, 4H, phenyl protons), 8.25 (ψd, 2H,
phenyl protons), 12.10 (s, 1H, NH), 12.45 (s, 1H, NH); C nmr
3-(4-Phenyl-5-phenylazo-thiazol-2-yl)-rhodanine (18a).
13
This compound was obtained as brown crystals, mp 212-213°;
yield: 1.33 g (67%); uv/visible (CH OH): λ max 433 nm; ir
(DMSO-d ): δ 53.6, 53.8, 102.9, 109.2, 112.5 (2C), 112.9 (2C),
3
6
(KBr): 2918, 1694, 1592, 1567, 1516, 1458,1415, 1393, 1283,
116.8 (2C), 122.5 (2C), 126.5 (2C), 127.2, 128.0 (2C), 132.0,

970
G. Kaupp, F. A. Amer, M. A. Metwally and E. Abdel-latif
Vol. 40
-1
1
-1 1
1242, 1016, 913 cm ; H nmr (CDCl /CF COOD): δ 4.25 (s,
1381, 1322, 1302, 1282 cm ; H nmr (CF COOD): δ 2.45 (s,
3
3
3
3H), 7.35 (ψd, 2H, phenyl protons), 7.50-8.00 (m, 12H, phenyl
2H), 7.45-7.60 (m, 6H, phenyl protons), 7.80 (ψd, 2H, phenyl pro-
13
13
protons), 8.55 (s, 1H); C nmr (CF COOD): δ 22.0, 99.6, 123.8
tons), 7.90 (ψd, 2H, phenyl protons);
C nmr (CDCl /
3
3
(2C), 126.4, 128.3, 129.5 (4C), 129.6 (2C), 130.6 (2C), 132.0,
132.3 (2C), 133.3, 140.6, 142.8, 147.7, 151.6, 158.4, 161.5, 161.7
CF COOD): δ 37.4, 123.6 (2C), 126.3, 129.5 (2C), 129.7 (4C),
3
132.1, 133.2, 138.8, 140.3, 151.3, 162.6, 173.8, 195.5; ms: m/z
+
(together with a signal of the solvent), 162.7; hrms: calcd. for
(%) 396 (M ), 321 (100), 279, 173, 133, 102, 89, 77; hrms: calcd.
+
+
C
H
N OS (M ) 449.1310, found 449.1309.
for C H N OS (M ) 396.0173, found 396.0176.
26 19
5
18 12
4
3
2-Cyano-3-(p-tolyl)-N-[4-phenyl-5-(p-tolylazo)-thiazol-2-yl]-2-
propeneamide (20b).
3-[4-Phenyl-5-(p-tolylazo)-thiazol-2-yl]-rhodanine (18b).
This compound was obtained as red-brown crystals, mp 222-
This compound was obtained as orange crystals, mp 263-
223°; yield: 1.46 g (71%); uv/visible (CH OH): λ max 430 nm;
3
264°; yield: 2.04 g (88%); uv/visible (CH OH): λ max 429 nm;
ir (KBr): 2920, 1700, 1598, 1563, 1516, 1451, 1411, 1386, 1282,
3
-1
1
ir (KBr): 3063, 2919, 2227 (CN), 1646, 1604, 1561, 1484, 1444,
1240, 1208, 1014 cm ; H nmr (CDCl /CF COOD): δ 2.40 (s,
3
3
-1
1
1380, 1321, 1302, 1282 cm ; H nmr (CF COOD): δ 2.45 (s,
3H), 4.25 (s, 2H), 7.35 (ψd, 2H, phenyl protons), 7.55 (s, 3H,
3
phenyl protons), 7.75 (ψd, 2H, phenyl protons), 7.90 (ψd, 2H,
6H), 7.30-7.40 (m, 4H, phenyl protons), 7.60 (br s, 3H, phenyl
protons), 7.80 (ψd, 2H, phenyl protons), 7.95 (ψd, 4H, phenyl
protons), 8.55 (s, 1H).
13
phenyl protons); C nmr (CDCl /CF COOD): δ 21.5, 37.4,
3
3
123.6 (2C), 126.5, 129.6 (2C), 129.7 (2C), 130.5 (2C), 132.2,
140.7, 144.7, 145.0, 149.1, 162.7, 173.9, 195.4; ms: m/z (%) 410
2-Cyano-3-(p-tolyl)-N-[4-(4-antipyrinyl)-5-phenylazo-thiazol-2-
yl)-2-propeneamide (21a).
+
(M ), 393, 335 (100), 293, 173, 133, 102, 91, 65.
3-[4-(4-Antipyrinyl)-5-phenylazo-thiazol-2-yl]-rhodanine (19a).
This compound was obtained as orange-yellow crystals, mp
This compound was obtained as violet-brown crystals, mp
261-262°; yield: 2.12 g (76%); uv/visible (CH OH): λ
= 455
3
max
160-161°; yield: 1.85 g (73%); uv/visible (CH OH): λ max 440
nm; ir (KBr): 3056, 2953, 2218 (CN), 1669, 1618, 1586, 1538,
3
-1 1
nm; ir (KBr): 2970, 1727, 1617, 1578, 1478, 1419, 1284, 1247,
1495, 1424, 1370, 1320, 1301 cm ; H nmr (CF COOD): δ 2.50
3
-1
1
1191, 1146, 1048, 992 cm ; H nmr (CDCl /CF COOD): δ 2.85
(s, 3H), 3.05 (s, 3H), 3.75 (s, 3H), 7.40-7.85 (m, 12H, phenyl pro-
3
3
(s, 3H), 3.60 (s, 3H), 4.20 (s, 2H), 7.30-7.70 (m, 10H, phenyl pro-
tons), 8.00 (ψd, 2H, phenyl protons), 8.70 (s, 1H); ms: m/z (%)
13
+
tons); C nmr (CDCl /CF COOD): δ 12.9, 33.7, 37.3, 98.7,
559 (M ), 531, 480, 466, 455 (100), 388, 343, 313, 286, 243, 195,
3
3
122.8 (2C), 128.5 (2C), 129.4, 129.8 (2C), 130.8 (2C), 132.7
(2C), 139.9, 140.8, 149.3, 150.5, 156.8, 161.6, 172.5, 194.3; ms:
181, 170, 115, 93, 77, 56.
+
2-Cyano-3-(p-tolyl)-N-[4-(4-antipyrinyl)-5-(p-tolylazo)-thiazol-
2-yl)-2-propeneamide (21b).
m/z (%) 506 (M ), 430 (100), 390, 362, 338, 298, 282, 242, 240,
169, 119, 93, 77, 56.
This compound was obtained as orange crystals, mp 237-238°,
3-[4-(4-Antipyrinyl)-5-(p-tolylazo)-thiazol-2-yl]-rhodanine
(19b).
yield: 2.35 g (82%); uv/visible (CH OH): λ max 460 nm; ir
3
(KBr): 3046, 2922, 2214 (CN), 1650, 1602, 1589, 1494, 1421,
This compound was obtained as violet-brown crystals, mp
-1
1
1374, 1299, 1205, 1181 cm ; H nmr (CF COOD): δ 2.45 (s,
3
175-176°; yield: 1.51 g (58%); uv/visible (CH OH): λ max 443
3
3H), 2.50 (s, 3H), 3.00 (s, 3H), 3.70 (s, 3H), 7.30-7.75 (m, 11H,
nm; ir (KBr): 2925, 1723, 1616, 1583, 1476, 1420, 1328, 1281,
13
phenyl protons), 8.00 (ψd, 2H, phenyl protons), 8.65 (s, 1H);
C
-1
1
1247, 1144, 988, 751 cm ; H nmr (CDCl /CF COOD): δ 2.40
3
3
nmr (CF COOD): δ 13.1, 21.5, 21.8, 33.7, 97.9, 98.9, 115.5,
3
(s, 3H), 2.9 (s, 3H), 3.7 (s, 3H), 4.3 (s, 2H), 7.3-7.8 (m, 9H,
123.6 (2C), 128.5 (2C), 129.4, 130.8 (2C), 130.9 (2C), 131.2 (2C),
132.4 (2C), 133.2, 139.0, 144.0, 145.9, 148.4, 148.7, 149.2, 157.0,
13
phenyl protons); C nmr (CDCl /CF COOD): δ 12.9, 21.6,
3
3
33.7, 37.2, 98.2, 123.3 (2C), 128.5 (2C), 129.3, 130.8 (2C), 131.0
(2C), 133.0 (2C), 138.1, 140.1, 148.6, 148.8, 157.1, 162.1, 174.0,
+
159.7, 160.1, 160.5, 165.9; ms: m/z (%) 573 (M ), 545, 480, 466,
455 (100), 404, 388, 343, 313, 286, 243, 195, 170, 115, 91.
+
193.4; ms: m/z (%) 520 (M ), 466, 434, 404, 393, 328, 317, 286
(100), 213, 188, 149, 124, 106, 77, 56.
General Procedure for the Synthesis of 2-Cyano-3-(p-tolyl)-N-(5-
arylazo-thiazol-2-yl)-2-propeneamides (20 and 21).
REFERENCES AND NOTES
[1] J. V. Metzger, in Comprehensive Heterocyclic Chemistry, Vol
6, K. T. Potts, ed, Pergamon Press, Oxford, 1984, pp 235-331; R.
Barone, M. Chanon and R. Gallo, in Thiazole and its Derivatives, Vol.
34/2, J. V. Metzger, ed, Wiley, New York, 1979, p. 9ff.; L. Forlani,
Targets in Heterocyclic Systems, 1, 75 (1997).
[2] N. Amishiro, S. Nagamuro, E. Kobayashi, K. Gomi and H.
Saito, J. Med. Chem., 42, 669 (1999).
[3] K. Hattori, N. Fujii, A. Tanaka and F. Takamura, WO Patent
99/21843 to Fujisawa Pharmaceutical Co., LTD; Chem. Abstr., 130,
325140s (1999).
A solution of sodium nitrite (0.35 g, 5.0 mmol in 5 ml water)
was gradually added to a well cooled solution of the aromatic
amine (5.0 mmol) in concentrated HCl (1.5 ml). The diazonium
salt solution was added with constant stirring to a cold solution of
compound 9 (5.0 mmol) in pyridine (50 ml). The reaction mix-
ture was stirred at 0° for 3 hours and the solid product was col-
lected by filtration. The arylazo derivatives 20 or 21 were dried
and recrystallized from DMF.
2-Cyano-3-(p-tolyl)-N-(4-phenyl-5-phenylazo-thiazol-2-yl)-2-
propeneamide (20a).
[4] M. Cheung, K. C. Glennon, K. E. Lackey and M. R. Pell, WO
Patent 99/21859 to Glaxo Group LTD ; Chem. Abstr., 130, 325139y
(1999).
This compound was obtained as orange crystals, mp 241-242°;
yield: 2.04 g (91%); uv/visible (CH OH): λ max 424 nm; ir
[5] K. Yamaguchi, M. Yada, T. Tsuji, Y. Hatanaka, K. Goda and
T. Kobori, Bioorg. & Med. Chem. Lett., 9, 957 (1999).
3
(KBr): 3058, 2899, 2227(CN), 1646, 1605, 1580, 1479, 1443
,

Nov-Dec 2003
Versatile 2-aminothiazoles, building blocks for highly functionalised heterocycles
971
Table 1
Elemental Analyses of the New Compounds
Compound
Formula
N O S
C: Calc. (Found)
H: Calc. (Found)
N: Calc. (Found)
5
6
7a
7b
7c
9a
9b
C
H
58.53 (58.67)
52.96 (52.89)
55.98 (55.87)
57.86 (57.91)
57.98 (57.86)
69.56 (69.43)
65.93 (65.82)
51.06 (51.11)
52.31 (52.39)
49.31 (49.43)
50.74 (50.56)
60.14 (60.03)
62.24 (62.22)
63.16 (63.24)
60.48 (60.44)
63.86 (64.11)
65.13 (65.28)
61.05 (60.92)
62.03 (62.25)
63.16 (63.41)
59.90 (60.13)
54.54 (54.38)
55.61 (55.66)
54.54 (54.45)
55.38 (55.49)
69.49 (69.44)
69.98 (69.93)
66.55 (66.59)
67.01 (66.88)
4.88 (4.95)
4.14 (4.10)
3.85 (3.88)
3.98 (3.82)
4.20 (4.27)
4.35 (4.22)
4.61 (4.53)
4.25 (4.22)
4.61 (4.47)
2.74 (2.87)
3.48 (3.32)
4.06 (4.17)
3.74 (3.68)
4.15 (4.19)
3.98 (4.05)
3.77 (3.91)
4.38 (4.21)
4.11 (4.23)
4.10 (4.24)
4.58 (4.80)
4.35 (4.49)
3.03 (3.12)
3.41 (3.52)
3.56 (3.43)
3.84 (3.93)
4.23 (4.29)
4.53 (4.43)
4.47 (4.53)
4.71 (4.82)
17.07 (16.88)
15.45 (15.40)
14.20 (14.25)
14.67 (14.75)
17.65 (17.56)
12.17 (12.04)
15.38 (15.21)
14.89 (14.83)
14.36 (14.22)
9.59 (9.73)
13.93 (14.05)
16.70 (16.54)
20.17 (20.21)
19.39 (19.43)
18.57 (18.63)
21.73 (21.55)
20.46 (20.58)
19.18 (19.33)
22.46 (22.63)
21.39 (21.23)
20.29 (20.42)
14.14 (14.03)
13.66 (13.43)
16.60 (16.51)
16.15 (15.88)
15.59 (15.64)
15.12 (15.01)
17.53 (17.42)
17.10 (17.21)
16 16
4 2
C H ClN O S
16 15 4 2
C H N O S
23 19 5 2
3
2
2
C
C
H N O S
23 19 5 3
H N O S
23 20 6 2
C H N OS
20 15 3
C H N O S
25 21 5 2
11b
12b
13a
13b
14b
15a
15b
15c
16a
16b
16c
17a
17b
17c
18a
18b
19a
19b
20a
20b
21a
21b
C
C
C
C
C
C
C
C
H N OS
16 16 4
3
H
N OS
4
17 18
3
H N OS
12
8 2 3
H
N O S
4 2 3
17 14
H N OS
21 17 5 2
H N OS
18 13 5
H N OS
19 15 5
H N O S
19 15 5 2
C
C
H N OS
24 17 7
H N OS
26 21 7
C
C
C
C
C
C
C
C
C
C
H N O S
26 21 7 3
H
N O S
9 2
29 23
H
N O S
31 27
9 2
H
N O S
9 4
31 27
H
N OS
N OS
4
18 12
4
3
3
H
19 14
H N O S
23 18 6 2
3
H
N O S
6 2
24 20
3
H N OS
26 19 5
H N OS
27 21 5
C
C
H N O S
31 25 7 2
H
N O S
7 2
32 27
Chindris and L. Satfa, Farmacia (Bucharest), 19, 65 (1971).
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Chem. Soc., 61, 1061 (1984).
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Bhawal and A. R. A. S. Deshmukh, Tetrahedron, 58, 2215 (2002).
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