One pot syntheses of thiazol-2-hydrazone, pyridino[2,3-d]pyridazine, pyrazolo[3,4-d]pyridazine, and isoxazolo[4,5-d]pyridazine derivatives

Article abstract of DOI:10.1002/hc.10026

The synthesis of the heterocyclic compounds containing two rings through the use of 4-amino-5-cyano-6-oxo-1-arylpyridazine-3-hydrazidic acid derivatives was discussed. Compounds containing both the pyridazine and thiazole moieties was found to possess potential biological activities. The reactivity of 4-amino-5-cyano-6-oxo-1-phenyl-3-carbohydrazido-N-(3-phenyl-4-oxothiazolidi -n-2-ylidino)-pyridazine (6a) was discussed. The reactivity of the enaminonitrile moiety present in (6a) towards some chemical reagents was studied. The reactions of (6a) with malononitrile and ethylcyanoacetate were studied in order to acvhieve the synthesis of fused azinoazine derivatives incorporating high biological activities.

Full text of DOI:10.1002/hc.10026

Heteroatom Chemistry
Volume 13, Number 3, 2002
One Pot Syntheses of Thiazol-2-hydrazone,
Pyridino[2,3-d ]pyridazine,
Pyrazolo[3,4-d ]pyridazine, and
Isoxazolo[4,5-d ]pyridazine Derivatives
Rafat M. Mohareb1 and Daisy H. Fleita2
1Department of Chemistry, University of California, Berkeley, California 94720-1460
2Chemistry Department, American University in Cairo, 113 Kaser El-Eini Street, Cairo, Egypt
Received 4 June 2001; revised 17 September 2001
RESULTS AND DISCUSSION
ABSTRACT: Reactions of the pyridazine derivatives
1a–c with phenyl isothiocyanate followed by heterocy-
clization with ethyl chloroacetate gave the thiazolidi-
none derivatives 6a–c. The reactivity of 6a towards
The reaction of 4-amino-5-cyano-6-oxo-1-arylpyri-
dazine-3-hydrazidic acid derivatives 1a–c with
phenyl isothiocyanate (2) in dimethylformamide
containing potassium hydroxide at 70 C gave the
nonisolable intermediate potassium sulphide salts
3a–c. The latter reacted with ethyl chloroacetate (4)
to give the pyridazino-3-carbohydrazonothiazolidin-
4-one derivatives 6a–c. Formation of the latter prod-
ucts occurs via the intermediate formation of 5a–c,
followed by ethanol liberation (Scheme 1). The struc-
tures of the latter products were based on analytical
and spectral data. Thus, the 1H NMR spectrum of 6a
showed the presence of a singlet (D2O exchangeable)
at 4.58 for an NH2 group, a singlet at 6.78 for the
thiazole CH2 group, a multiplet at 7.21–7.45 for two
phenyl groups, and a singlet at 8.89 (D2O exchange-
able) for the NH group. Moreover, the 13C NMR data
showed 105.2, 128.6 (thiazole-C5, C2), 119.6 (CN),
122.0, 125.5, 127.7, 128.2, 129.5 (aromatic C), 132.6,
137.3, 140.9 (pyridazine C), 178.1, 179.5, 180.5 (3
C
some chemical reagents was studied. 2002 Wiley Pe-
riodicals, Inc. Heteroatom Chem 13:258–262, 2002; Publi-
shed online in Wiley Interscience (www.interscience.wiley.
com). DOI 10.1002/hc.10026
INTRODUCTION
Many pyridazine derivatives are reported to be useful
as antiflammatory agents, herbicides, insecticides,
and microbicides [1–4]. Also, thiazoles are known to
be highly biologically active reagents [5–8]. There-
fore, it seemed logical that compounds containing
both the pyridazine and thiazole moieties would
be expected to possess potential biological activi-
ties. Thus, we report herein the syntheses of hetero-
cyclic compounds containing the two rings through
the use of the readily available 4-amino-5-cyano-
6-oxo-1-arylpyridazine-3-hydrazidic acid derivatives
[9] 1a–c as the key starting materials.
C
O). Further confirmation for the structures of
6a–c was obtained through a study of the chemical
reactivity of 6a towards several chemical reagents
(Scheme 2). Variations in the sites of reaction have
been observed previously [10]. Thus, the reaction
of 6a with benzaldehyde gave the benzal derivative
7. On the other hand, with acetic acid/acetic anhy-
dride mixture, the N-acetylpyridazine derivative 8
is formed. The structures of compounds 7 and 8
Correspondence to: Rafat M. Mohareb; e-mail: rmmohareb@
hotmail.com.
c
2002 Wiley Periodicals, Inc.
258

One Pot Syntheses 259
SCHEME 1
were confirmed on the basis of analytical and spec-
tral data (see Experimental section). The reaction of
6a with benzenediazonium chloride gave the phenyl-
hydrazone derivative 9, not the phenylazo derivative
10. The structure of compound 9 was established
on the basis of its IR spectrum, which showed the
presence of three C O stretching bands at 1690,
tures 16a and 16b, respectively, were assigned for
these reaction products that were produced via the
intermediate formation of 15a and 15b (Scheme 3).
The IR spectrum of 16a (as an example) showed one
cyano group stretching at 2210 cm and the H
NMR spectrum showed two singlets at 4.99 and
5.88 (D2O exchangeable) due to two NH2 groups.
1
1
1
1700, 1710 cm . Also, the 1H NMR spectrum which
showed the presence of two D2O exchangeable sin-
glets at 8.78 and 9.24 for two NH groups. More-
over 13C NMR data showed 119.9 (CN), 126.2, 128.3
(thiazole-C5, C1), 121.4, 123.3, 126.9, 127.8, 129.0,
129.9 (aromatic C), 132.3, 137.0, 140.5 (pyridazine
C), 178.4, 179.0, 181.0 (3 C O).
EXPERIMENTAL
All melting points are uncorrected. IR spectra were
recorded for KBr discs on a Pye Unicam SP-1000
spectrophotometer. H NMR spectra and 13C NMR
1
spectra were measured on a Varian EM390-90 MHz
instrument in CD3SOCD3 as solvent with TMS as an
internal standard, and chemical shifts are expressed
as . Analytical data were obtained from the Micro-
analytical Data Unit at Cairo University, Giza, Egypt.
The reactivity of the enaminonitrile moiety
present in 6a towards some chemical reagents was
then studied. Thus, the reaction of 6a with each of
hydrazine hydrate and phenylhydrazine gave the
pyrazolo[3,4-d]pyridazine derivatives 12a and 12b,
respectively. Structures of the latter products were
confirmed on the basis of analytical and spectral data
(see Experimental section). Moreover, the reactions
of 6a with hydroxylamine hydrochloride in refluxing
1,4-dioxane solution containing anhydrous sodium
acetate gave the isoxazolo[5,4-d]pyridazine deriva-
tive 13. The reactions of 6a with cyanomethylene
derivatives, namely malononitrile 14a and ethyl
cyanoacetate 14b, were investigated in order to
achieve the synthesis of fused azinoazine derivatives
incorporating high biological activities [11]. Thus,
the reaction of 6a with either 14a or 14b gave, in
each case, a single product with molecular formulae
C24H17N9O3S and C24H16N8O4S, respectively. Struc-
Synthesis of Compounds 6a–c:
General Procedure
To a solution of either 1a (2.7 g, 0.01 mol), 1b (2.8 g,
0.01 mol), or 1c (3.0 g, 0.01 mol) in dimethylfor-
mamide (50 ml) containing potassium hydroxide
(0.4 g, 0.01 mol), phenyl isothiocyanate was added.
The reaction mixture was heated in a hot water bath
at 70 C for 1 h, then left to cool. Ethyl chloroacetate
(4) (1.13 g, 0.01 mol) was added to the reaction mix-
ture and the latter was stirred overnight, then poured
into an ice/water mixture. The solid product formed
upon addition of hydrochloric acid (to pH 6) was
collected by filtration.

260 Mohareb and Fleita
SCHEME 3
1
yield 66% (3.0 g), m.p. 210–213 C. IR ( /cm ) =
3470–3370 (NH2, NH), 3060 (CH aromatic), 2215
(CN), 1705, 1685, 1670 (3 C O), 1663 (exocyclic
1
C
N), 1645 (C C). H NMR = 2.01 (s, 3H, CH3),
4.58 (s, 2H, NH2), 6.88 (s, 2H, thiazole CH2), 7.05,
7.29 (m, 9H, C6H4, C6H5), 8.91 (s, 1H, NH). 13C NMR
= 29.5 (CH3), 105.3, 128.8 (thiazole-C5, C2), 120.1
(CN), 122.1, 127.2, 128.0, 132.2 (aromatic C), 132.2,
138.7, 140.2 (pyridazine C), 178.2, 179.2, 180.8 (3
C
O). Calcd for C22H17N7O3S: C. 57.52; H, 3.73; N,
21.34; S, 6.98%. Found: C, 57.34; H, 3.29; N, 21.66;
S, 6.49%.
4-Amino-5-cyano-6-oxo-1-(4-chlorophenyl)-3-car-
bohydrazido-N-(3-phenyl-4-oxothiazolidin-2-ylideno)-
pyridazine (6c). Orange crystals (from ethanol),
SCHEME 2
1
yield 50% (2.4 g), m.p. 150 C. IR ( /cm ) = 3480
4-Amino-5-cyano-6-oxo-1-phenyl-3-carbohydra-
zido-N-(3-phenyl-4-oxothiazolidin-2-ylidino)-pyrida-
zine (6a). Orange crystals (from 1,4-dioxane), yield
3366 (NH2, NH), 3078 (CH aromatic), 2225 (CN),
1700, 1695, 1670 (3 C O), 1660 (exocyclic C N),
1640 (C C). 1H NMR = 4.59 (s, 2H, NH2), 6.90 (s,
2H, thiazole CH2), 7.22–7.58 (m, 9H, C6H4, C6H5),
8.96 (s, 1H, NH). Calcd for C21H14N7O3SCl: C, 52.55;
H, 2.94; N, 20.43; S, 6.68%. Found: C, 52.64; H, 3.20;
N, 20.68; S, 6.59%.
1
78% (3.4 g), m.p. 120 C. IR ( /cm ) = 3460–3375
(NH2, NH), 3065 (CH aromatic), 2220 (CN), 1695,
1680, 1670 (3 C O), 1660 (exocyclic C N), 1645
1
(C C). H NMR = 4.58 (s, 2H, NH2), 6.78 (s, 2H,
thiazole CH2), 7.21–7.41 (m, 10H, 2Ar), 8.89 (s, 1H,
NH). 13C NMR = 105.2, 128.6 (thiazole-C5, C2),
119.6 (CN), 122.0, 125.5, 127.7, 128.2, 129.5 (aro-
matic C), 132.6, 137.3, 140.9 (pyridazine C), 178.1,
179.5, 180.5 (3 C O). Calcd for C21H15N7O3S: C,
56.62; H, 3.39; N, 22.01; S, 7.20%. Found: C, 56.44;
H, 3.29; N, 21.81; S, 6.96%.
Synthesis of 4-Amino-5-cyano-6-oxo-1-phenyl-
3-carbohydrazido-N-(5-benzal-3-phenyl-4-oxo-
thiazolidin-2-ylidino)pyridazine (7)
To a solution of 6a (4.45 g, 0.01 mol) in 1,4-dioxane
(40 ml) containing piperidine (0.5 ml), benzaldehyde
(1.06 g, 0.01 mol) was added. The reaction mixture
was heated under reflux for 2 h, then evaporated in
a vacuum. The residual product was triturated with
4-Amino-5-cyano-6-oxo-1-(4-methylphenyl)-3-N-
(3-phenyl-4-oxothiazolidin-2-ylidino)-3-carbohydraz-
idopyridazine (6b). Orange crystals (from ethanol),

One Pot Syntheses 261
3C6H5), 8.78, 9.24 (2s, 2H, NH).13C NMR = 119.9
(CN), 126.2, 128.3 (thiazole-C5, C2), 121.4, 123.3,
126.9, 127.8, 129.0, 129.9 (aromatic C), 132.3, 137.0,
140.5 (pyridazine C), 178.4, 179.0, 181.0 (3 C O).
Calcd for C27H19N9O3S: 59.01; H, 3.49; N, 22.94;
S, 5.83%. Found: C, 59.21; H, 3.42; N, 22.79; S,
5.63%.
ethanol and the formed solid product was collected
by filtration.
Yellow crystals (from 1,4-dioxane), yield 58%
1
(3.1 g), m.p. 138 C. IR: ( /cm ) = 3490–3375 (NH2,
NH), 3065 (CH aromatic), 2220 (CN), 1705, 1690,
1675 (3 C O), 1665 (exocyclic C N), 1640 (C C).
1H NMR = 4.55 (s, 2H, NH2), 6.99 (s, 1H, benzal
CH), 7.19–7.48 (m, 15H, 3C6H5), 8.99 (s, 1H, NH).
13C NMR = 116.2 (CH ), 133.6, 126.4 (thiazole-
C5, C2), 120.1 (CN), 122.3, 125.2, 128.0, 128.6, 129.4,
130.7, 131.1 (aromatic C), 132.2, 137.6, 140.4 (pyri-
dazine C), 177.6, 179.9, 180.2 (3 C O). Calcd for
C28H19N7O3S: C, 63.03; H, 3.59; N, 18.38; S, 6.01%.
Found: C, 63.14; H, 3.31; N, 18.48; S, 6.22%.
Synthesis of 12a,b: General Procedure
To a solution of 6a (4.45 g, 0.01 mol) either hydrazine
hydrate or phenylhydrazine (0.01 mol) was added.
The reaction mixture was heated under reflux for 3
h, then poured into an ice/water mixture containing
a few drops of hydrochloric acid. The formed solid
product, in each case, was collected by filtration.
Synthesis of 4-Acetylamino-5-cyano-6-oxo-1-ph-
enyl-3-carbohydrazido-N-(3-phenyl-4-oxothiazo-
lidin-2-ylidino)pyridazine (8)
6-Amino-4-hydro-1-phenyl-3-N-carbohydrazido-
(3-phenyl-4-oxothiazolidin-2-ylideno)-7-oxopyrazolo
[3,4-d]pyridazine (12a). Pale yellow crystals (from
dimethylformamide), yield 70% (3.2 g), m.p. 180 C.
To a solution of 6a (4.45 g, 0.01 mol) acetic
acid/acetic anhydride mixture (50 ml, 5:1) was
added, and the mixture was heated under reflux for
3 h, then evaporated in a vacuum. The residual prod-
uct was triturated with diethyl ether and the formed
solid product was collected by filtration.
1
IR ( /cm ) = 3490–3370 (NH2, 2NH), 3055 (CH aro-
matic), 1710, 1795, 1680 (3 C O), 1667 (exocyclic
1
C
N), 1640 (C C). H NMR = 5.68 (s, 2H, NH2),
7.32–7.49 (m, 10H, 2C6H5), 8.96, 9.33 (2s, 2H, 2NH).
13C NMR = 105.7, 126.4 (thiazole-C5, C2), 122.1,
125.6, 127.6, 128.0, 129.9, 131.4, 132.0 (aromatic C),
132.2, 138.0, 139.3, 140.4 (pyridazine C, pyrazole C),
176.9, 178.8, 180.0 (3 C O). Calcd for C21H16N8O3S:
C, 54.78; H, 3.50; N, 24.34; S, 6.96%. Found: C,
54.99; H, 3.39; N, 24.39; S, 5.67%.
Brown crystals (from 1,4-dioxane), yield 78%
1
(3.8 g), m.p. 100 C. IR: ( /cm ) = 3480–3365 (2NH),
3060 (CH aromatic), 2220 (CN), 1695, 1680, 1670,
1710 (4 C O), 1660 (exocyclic C N), 1645 (C C).
1H NMR = 2.25 (s, 3H, CH3), 6.89 (s, 2H, thia-
zole CH2), 7.23–7.42 (m, 10H, 2C6H5), 8.95, 9.46 (2s,
2H, 2NH). 13C NMR = 31.6 (CH3), 105.0, 128.8
(thiazole-C5, C2), 120.0 (CN), 121.6, 122.3, 124.9,
126.6, 127.7, 129.5 (aromatic C), 130.9, 132.2, 137.1,
140.6 (pyridazine C), 178.8, 179.9, 180.1, 183.3 (4
6-Amino-1,4-diphenyl-3-N-carbohydrazido(3-phe-
nyl-4-oxothiazolidin-2-ylideno)-7-oxopyrazolko[3,4-d]-
pyridazine (12b). Buff crystals (from dimethylfor-
C
O). Calcd for C23H17N7O4S: C, 56.67; H, 3.52; N,
1
mamide), yield 79% (4.3 g), m.p. 140 C. IR ( /cm )
20.11; S, 6.58%. Found: C, 56.61; H, 3.52; N, 19.89;
S, 6.34%.
= 3480-3360 (NH2, NH), 3066 (CH aromatic), 1700,
1690, 1675 (3 C O), 1665 (exocyclic C N), 1645
(C C). 1H NMR = 5.68 (s, 2H, NH2), 7.30–7.46
(m, 15H, 3 C6H5), 9.36 (s, 1H, NH). Calcd for
C27H20N8O3S: C, 60.44; H, 3.76; N, 20.88; S, 5.98%.
Found: C, 60.55; H, 3.36; N, 20.69; S, 5.62%.
Synthesis of 4-Amino-5-cyano-6-oxo-1-phenyl-3-
carbohydrazido-N-(3-phenyl-5-N-phenylhydrazo-
no-4-oxothiazolidin-2-ylideno)pyridine (9)
To a cold solution of 6a (4.45 g, 0.01 mol) in ethanol
(50 ml), containing sodium hydroxide (0.4 g, 0.01
mole, in 7 ml water), benzenediazonium chloride
(0.01 mol) was added with stirring. The solid prod-
uct formed upon standing at room temperature for
1 h was collected by filtration.
Synthesis of 6-Amino-1-phenyl-3-N-catbohydra-
zido-(3-phenyl-4-oxothiazolidin-2-ylideno-7-
oxoisoxazolo[3,4-d]pyridazine (13)
To a solution of 6a (4.45 g, 0.01 mol) in ethanol
(10 ml) containing sodium acetate (0.8 g, 0.01 mol),
hydroxylamine hydrochloride (0.33 g, 0.01 mol) was
added. The reaction mixture was heated under reflux
for 8 h, then poured into water and the formed solid
product was collected by filtration.
Buff crystals (from 1,4-dioxane), yield 75%
1
(4.13 g), m.p. 125 C. IR ( /cm ) = 3479–3385 (NH2,
NH), 3065 (CH aromatic), 2220 (CN), 1710, 1700,
1690 (3 C O), 1663 (exocyclic C N), 1635 (C C).
1H NMR = 4.58 (s, 2H, NH2), 7.30–7.52 (m, 15H,

262 Mohareb and Fleita
Yellowish white crystals (from ethanol), yield
7-amino-1-phenyl-6-cyano-5-hydroxy-3-N-carbo-
hydrazido-(3-phenyl-4-oxothiazolidin-2-ylideno)-8-
oxopyrido[2,3-d]pyridazine (16b). Orange crystals
(from 1,4-dioxane), yield 68% (3.40 g), m.p. 135 C.
o
1
70% (3.2 g), m.p. 130 C. IR ( /cm ) = 3480–3365
(NH2, NH), 3060 (CH aromatic), 1705, 1695, 1675
(3 C O), 1668 (exocyclic C N), 1645 (C C). 1H
NMR = 5.48 (s, 2H, NH2), 6.78 (s, 2H, thiazole
CH2), 7.32–7.49 (m, 10H, 2C6H5), 8.96 (s, 1H, NH).
13C NMR = 105.8, 126.4 (thiazole-C5, C2), 122.4,
124.5, 128.3, 128.9, 129.2, 130.3, 132.0 (aromatic C),
132.4, 137.6, 139.6, 140.3 (pyridazine C, isoxazole C),
177.6, 179.9, 180.2 (3 C O). Calcd for C21H15N7O4S:
C, 54.66; H, 3.28; N, 21.25; S, 6.95%. Found: C, 54.89;
H, 3.22; N, 21.30; S, 6.67%.
1
IR ( /cm ) = 3490–3345 (NH2, NH, OH), 3060 (CH
aromatic), 2225 (CN), 1700, 1695, 1670 (3 C O),
1662 (exocyclic C N), 1632 (C C). 1H NMR
= 5.88 (s, 2H, NH2), 6.78 (s, 2H, thiazole CH2),
7.30–7.46 (m, 10H, 2C6H5), 8.96 (s, 1H, NH), 10.30
(s, 1H, OH). Calcd for C24H16N8O4S: C, 56.25; H,
3.15; N, 21.86; S, 6.26%. Found: C, 56.61; H, 3.31;
N, 21.50; S, 6.58%.
REFERENCES
Synthesis of 16a,b: General Procedure
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To a solution of 6a (4.45 g, 0.01 mol) in dimethylfor-
mamide (30 ml) either malononitrile (14a) (0.66 g,
0.012 mol) or ethyl cyanoacetate (14b) (1.30 g, 0.01
mole) was added. The reaction mixture, in each case,
was heated under reflux for 6 h, then poured into an
ice/water mixture, neutralized with dilute hydrochlo-
ric acid (pH 7), whereby the solid product, so formed,
was collected by filtration.
[5] Amishiro, N.; Nagamura, S.; Kobayashi, E.; Gomi, K.;
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5,7Diamino-1-phenyl-6-cyano-3-N-carbohydrazi-
do(3-phenyl-4-oxothioazolidin-2-ylideno)-8-oxopyrido-
[2,3-d]pyridazine (16a). Buff crystals (from 1,4-
dioxane), yield 70% (3.57 g), m.p. 155 C. IR:
1
( /cm ) = 3495–3335 (2 NH2, NH), 3066 (CH
aromatic), 2210 (CN), 1700, 1690, 1680 (3 C O),
1665 (exocyclic C N), 1640 (C C). 1H NMR
=
4.99, 5.88 (2s, 4H, 2NH2), 6.78 (s, 2H, thiazole
CH2), 7.30–7.46 (m, 10H, 2C6H5), 8.96 (s, 1H, NH).
Calcd for C24H17N9O3S: C, 56.36; H, 3.35; N, 24.65;
S, 6.27%. Found: C, 56.69; H, 3.01; N, 24.56; S,
6.34%.