One-pot synthesis of thiazoles from pyridazin-3-hydrazidic acid derivatives

Article abstract of DOI:10.1080/10426500214556

Several new thiazole derivatives have been synthesized; the reactivity of these compounds toward amines, aldehydes, and hydroxyl amine are reported. New syntheses of pyrimidino[5,4:3,4]pyrazolo[4,3:5,6]pyridazine derivatives also have been achieved.

Full text of DOI:10.1080/10426500214556

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
One-Pot Synthesis of Thiazoles from Pyridazin-3-
hydrazidic Acid Derivatives
Waganat W. Wardakhan & Yehya M. Elkholy
To cite this article: Waganat W. Wardakhan & Yehya M. Elkholy (2002) One-Pot Synthesis of
Thiazoles from Pyridazin-3-hydrazidic Acid Derivatives, Phosphorus, Sulfur, and Silicon and the
Related Elements, 177:11, 2661-2673, DOI: 10.1080/10426500214556
To link to this article: http://dx.doi.org/10.1080/10426500214556
Published online: 27 Oct 2010.
Submit your article to this journal
Article views: 34
View related articles
Citing articles: 6 View citing articles
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gpss20
Download by: [University of Nebraska, Lincoln]
Date: 11 June 2016, At: 02:31

Phosphorus, Sulfur and Silicon, 2002, Vol. 177:2661–2673
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290110883
ONE-POT SYNTHESIS OF THIAZOLES FROM
PYRIDAZIN-3-HYDRAZIDIC ACID DERIVATIVES
Waganat W. Wardakhana and Yehya M. Elkholyb
National Organization for Drug Control and Research, Cairo,
Egypta and Chemistry Department, Faculty of Science,
Helwan University, Cairo, Egyptb
(Received December 31, 2001; accepted March 14, 2002)
Several new thiazole derivatives have been synthesized; the reactivity
of these compounds toward amines, aldehydes, and hydroxyl amine are
reported. New syntheses of pyrimidino[5,4:3,4]pyrazolo[4,3:5,6]pyri-
dazine derivatives also have been achieved.
Keywords: Bromoethylcyanoacetate; phenylisothio cyanate; pyridazin-
3-hydrazidic acid derivatives; thioglycollic acid
Pyridazine derivatives comprise a very interesting class of compounds
4
because of their significant biological and pharmaceutical activities.1
As part of our studies aimed at developing simple and efficient synthesis
of polyfunctionally heteroaromatics from readily obtainable starting
materials,5 7 we report herein the synthesis of heterocyclic compounds
containing both thiazole and pyridazine moieties through the use of the
readily available 4-amino-5-cyano-6-oxo-1-arylpyridazine-3-hydrazidic
acid derivatives8 1a–c as the starting materials.
The reaction of 4-amino-5-cyano-6-oxo-1-arylpyridazine-3-hydra-
zidic acid derivatives 1a–c with phenylisothiocyanate 2 in dimethyl
fomamide containing potassium hydroxide at 70 C yielded the non-
isolable potassium sulphide salts 3a–c (Scheme 1). The latter re-
acted with bromoethyl cyanoacetate9 to yield the 5-hydroxy thiazole-
4-carbonitrile derivatives 7a–c, not the thiazol-5-one derivatives 6a–c.
The reaction probably took place via the intermediate formation of
5a–c followed by ethanol elimination. Assignment of structures 7a–c
for the reaction products was based on analytical and spectral data.
Address correspondence to Y. M. Elkholy, Chemistry Department, Faculty of Science,
Helwan University, Ain-Helwan, Cairo, Egypt. E-mail: y elkholy@yahoo.com
2661

2662
W. W. Wardakhan and Y. M. Elkholy
SCHEME 1

One-Pot Synthesis of Thiazoles
2663
Thus, the IR spectrum of the reaction product showed OH, NH2, NH
1
stretchings at 3534–3490 cm and two CN groups stretching at 2225
and 2220 cm 1. The mass spectrum of 7a shows m/z = 470 (M+) for
C22H14N8O3S. Moreover, the 1H NMR spectrum showed no CH stretch-
ing for thiazole H-5 present in structures 6a–c and the appearance of a
broad singlet at 10.42 for one OH group also was indicative of the forma-
tion of 7a–c, which was confirmed by studying their reactivity toward
various chemical reagents. Thus, the ∝-hydroxy nitrile moiety present
in 7a–c showed greater reactivity over the enamino nitrile moiety as the
latter exists in the nonactive anionic form. The reaction of 7a–c with
either hydrazine hydrate or phenyl hydrazine gave the pyrazolo[3,4-
d]thiazole derivatives 8a and 8b respectively (cf. Scheme 1).
The reaction took place via first addition of NH2 group of the hy-
drazine to CN group of thiazole followed by water elimination. The
reaction of 7a with malononitrile gave the 2-thiazolo[4,5-b]pyran-2-one
derivative 11 (fingerprint IR, m.p., and mixed m.p.). The reaction likely
took place through the intermediate formation of 10 followed by cycliza-
tion. Two pathways for cyclization are considered, in case of the reac-
tion with malononitrile. The intermediate 2-iminothiazolo[4,5-b]pyran
is formed followed by hydrolysis and ammonia liberation to give 11
(cf. Scheme 2).
The reaction of 7a with thioglycollic acid 12 gave 5-thiazolylthiazole
derivative 13 and the reaction of 7a with hydroxylamine hydrochlo-
ride gave the isoxazolo[5,4-d]thiazole derivative 14 (Scheme 2). The
use of excess amount of hydroxylamine hydrochloride gives a mixture
of products.
The reaction of 3a–c with phenacyl bromide 15 gave the thiazole
derivatives 16a–c, the structures of which were established based on
1
analytical and spectral data (Scheme 3). Thus, the H NMR spectrum
of 16a (as an example) showed a singlet (D2O exchangeable) at 4.55
for one NH2 group, a singlet at d 6.78 for thiazole H-5, a multiplet at
7.21–7.45 for three phenyl protons, and a singlet (D2O exchangeable)
at 8.97 for one NH group. Thus, the reaction of 16a with formalde-
hyde or benzaldehyde gave a single product in each case with molecu-
lar formula C28H17N7O2S and C34H21N7O2S, respectively, to which the
structures of the pyrimidino[4,5-c]pyridazine derivatives 17a and 17b,
respectively, were assigned (Scheme 3). The 1H NMR spectrum of 17a,
showed beside the expected signals, two singlets at 6.89 and 7.02 corre-
sponding to thiazole H-5 and pyrimidine H-2 respectively. The mass
spectrum of 17a shows m/z = 515 (M+) for C28H17N7O2S. Thus, the
reaction of 17a and 17b with hydrazine hydrate or phenylhydrazine
gave the pyrimidino[5,4:3,4]-pyrazolo[4,3:5,6]pyridazine derivative
18a,b and 19a,b respectively. On the other hand, the reaction of

2664
W. W. Wardakhan and Y. M. Elkholy
SCHEME 2

One-Pot Synthesis of Thiazoles
2665
SCHEME 3
17a and 17b with hydroxylamine hydrochloride gave the pyrim-
idino[5,4:3,4]isoxazolo[4,3:5,6]pyridazine derivatives 21a and 21b
respectively (Scheme 4). Formation of the latter products can be ex-
plained in terms of the formation of the first intermediate 20a,b, fol-
lowed by nucleophilic addition of the OH group to the cyano group
to form the final products 21a,b respectively. The Imino function
present in the latter products is hydrolyzed when these products were
heated under reflux in ethanolic/NaOH solution to form the corre-
sponding fused 3-oxoisoxazolo derivatives 22a,b (Scheme 4). Structures

2666
W. W. Wardakhan and Y. M. Elkholy
SCHEME 4
21a,b and 22a,b were established based on analytical and spectral
data.
EXPERIMENTAL
All melting points reported were uncorrected. IR spectra were recorded
1
for KBr discs on a Pye Unicam SP-1000 spectrophotometer. H NMR
spectra were measured on a Varian EM 390-90 MHz in CD3SOCD3 as
solvent using TMS as an internal standard. Chemical shifts are ex-
pressed as ppm. Mass spectra were measured on a Shimadzu GCMS-
QP 1000 Ex massspectrometer at 70 eV. Analytical data were obtained
from the Microanalytical Data Unit at Cairo University, Giza, Egypt.
Synthesis of compounds 7a--c and 16a--c
General Procedure
To a solution of either la (2.7 g, 0.01 mmol) or lb (2.8 g, 0.01 mmol) or
lc (3.0 g, 0.01 mmol) in dimethylformamide (50 ml) containing potas-
sium hydroxide (0.4 g, 0.01 mmol) was added phenylisothiocyanate.

One-Pot Synthesis of Thiazoles
2667
The reaction mixture was heated in a boiling water bath at 70 C for
1 h and then left to cool. Bromoethyl cyanoacetate 4 (2.0 g, 0.01 mmol)
or phenacyl bromide 15 (2.00 g, 0.01 mmol) were added to the reac-
tion mixture, and the latter was stirred overnight and then poured into
an ice-water mixture. The solid product, formed upon addition of hy-
drochloric acid (up to pH 6), was collected by filtration.
4-Amino-5-cyano-6-oxo-1-phenyl-3-carbohydrazido-
N-(5-cyano-3-phenyl-4-hydroxythiazolidin-
2-ylideno)pyridazine (7a)
7a: Yellow crystals (3.7 g, 78%), m.p. 125 C (from ethanol),
1
max/cm 3534–3490 (OH, NH2, NH), 3060 (CH aromatic), 2225, 2220
(2 CN), 1705, 1695 (2 C O), 1665 (exocyclic C N), 1645 (C C). 1H NMR:
4.57 (s, 2H, NH2), 7.30–7.45 (m, 10H, aromatic protons), 8.99 (s, 1H,
NH), 10.42 (s, 1H, OH) MS (EI, 70 ev):m/z = 470 (M+). Anal. requires
for C22H14N8O3S (470.4) C, 56.17; H, 3.00; N, 23.82; S, 6.82. Found: C,
56.34; H, 3.20; N, 23.62; S, 6.48.
4-Amino-5-cyano-6-oxo-1-(4-methylphenyl)-
3-carbohydrazido-N-(-5-cyano-3-phenyl-
4-hydroxythiazolidin-2-ylideno)pyridazine (7b)
7b: Orange crystals (3.2 g, 72%), m.p. 160 C (from ethanol),
1
max/cm
3585–3330 (OH, NH2, NH), 3065 (CH aromatic), 2225,
2218 (2 CN), 1705, 1695 (2 C O), 1667 (exocyclic C N), 1643 (C C).
1H NMR: 2.29 (s, 3H, CH3), 4.58 (s, 2H, NH2), 7.25–7.45 (m, 9H, aro-
matic protons), 8.91 (s, 1H, NH), 10.45 (s, 1H, OH). Anal. requires for
C23H16N8O3S (484.43) C, 57.02; H, 3.30; N, 23.13; S, 6.62. Found: C,
57.24; H, 3.49; N, 23.21; S, 6.39.
4-Amino-5-cyano-6-oxo-1-(4-chlorophenyl)-
3-carbohydrazido-N-(5-cyano-3-phenyl-
4-hydroxythiazolidin-2-ylideno)pyridazine (7c)
7c: Orange crystals (2.9 g, 63%), m.p. 140 C (from 1,4-dioxane),
1
max/cm 3550–3336 (OH, NH2, NH), 3065 (CH aromatic), 2225, 2220
1
(2 CN), 1706, 169O (2 C O), 1663 (exocyclic C N), 1643 (C C). H
NMR: 4.57 (s, 2H, NH2), 7.32–7.48 (m. 9H, aromatic protons), 8.97 (s,
1H, NH), 10.32 (s, 1H, OH). Anal. requires for C22H13N8O3SCl (504.84):
C, 57.83; H, 2.87; N, 24.52; S, 7.02. Found: C, 57.24; H, 3.49; N, 24.21;
S, 6.39.
4-Amino-5-cyano-6-oxo-1-phenyl-3-carbohydrazido-
N-(3,4-diphenylthiazolo 2-Ylideno)pyridazine (16a)
16a: Yellow crystals (3.2 g, 63%), m.p. 70 C (from ethanol),
max/cm 1 3450–3345 (NH2, NH), 3050 (CH aromatic), 2225 (CN), 1695,

2668
W. W. Wardakhan and Y. M. Elkholy
1689 (2 C O), 1665 (exocyclic C N), 1634 (C C). 1H NMR: 4.55 (s, 2H,
NH2), 6.78 (s, 1H, thiazole H-5), 7.21–7.45 (m, 15H, aromatic protons),
8.97 (s, 1H, NH). Anal. requires for C27H19N7O2S (505.49): C, 64.15; H,
3.79; N, 19.40; S, 6.34. Found: C, 64.22; H, 3.64; N, 19.32; S, 6.39.
4-Amino-5-cyano-6-oxo-1-(4-methylphenyl)-
3-carbohydrazido-N-(3,4-diphenylthiazol-
2-ylideno)pyridazine (16b)
16b: Yellow crystals (3.5 g, 68%), m.p. l40 C (from ethanol),
1
max/cm
3455–3338 (NH2, NH), 3065 (CH aromatic), 2220 (CN),
1
1695, 1680, (2 C O), 1665 (exocyclic C N), 1638 (C C). H NMR:
2.09 (s, 3H, CH3), 4.58 (s, 2H, NH2), 6.79 (s, 1H, thiazole H-5), 7.27–
7.48 (m, 14H, aromatic protons), 8.99 (s, 1H, NH). Anal. requires for
C28H21N7O2S (519.51): C, 64.73; H, 4.07; N, 18.87; S, 6.17. Found: C,
64.53; H, 3.94; N, 19.19; S, 6.30.
4-Amino-5-cyano-6-oxo-1-(4-chlorophenyl)-
3-carbohydrazido-N-(3,4-diphenylthiazol-
2-ylideno)pyridazine (16c)
16c: Yellow crystals (2.8 g, 52%), m.p. 165 C (from ethanol),
1
max/cm
3520–3342 (NH2, NH), 3058 (CH aromatic), 2222 (CN),
1693, 1687, (2 C O), 1660 (exocyclic C N), 1635 (C C). 1H NMR: 4.48
(s, 2H, NH2), 7.02 (s, 1H, thiazole H-5), 7.20–7.55 (m, 14H, aromatic pro-
tons), 8.99 (s, 1H, NH). Anal. requires for C27H18N7O2SCl (539.94): C,
60.04; H, 3.36; N, 18.15; S, 5.94. Found: C, 60.34; H, 3.51; N, 18.23; S,
6.20.
Synthesis of 8a,b Derivatives
General Procedure
To a solution of 7a (4.7 g, 0.01 mmol) in dimethylformamide (5 ml),
was added hydrazine hydrate or phenylhydrazine (0.01 mmol). The
reaction mixture, in each case, was heated under reflux for 3 h,
and then poured into an ice-water mixture containing few drops of
hydrochloric acid. The solid product in each case was collected by
filtration.
3-Amino-6-phenyl-5-[4-amino-5-cyano-1-phenyl-
6-oxopyridazin-3-(carbohydrazido-N-ylideno)]
Thiazolo[4,5-c]pyrazole (8a)
8a: Orange crystals (2.8 g, 58%), m.p. 165 C (from ethanol),
1
max/cm 3490–3360 (2 NH2, 2 NH), 3050 (CH aromatic), 2222 (CN),
1695, 1683 (2 C O), 1665 (exocyclic, C N), 1640 (C C). 1H NMR:

One-Pot Synthesis of Thiazoles
2669
4.86, 5.48 (2s, 4H, 2NH2), 7.30–7.41 (m, 10H, aromatic protons) 8.88,
9.01 (2s, 2H, 2NH). Anal. requires for C22H16N10O2S (484.45): C, 54.54;
H, 3.33; N, 28.91; S, 6.82. Found: C, 54.60; H, 3.09; N, 28.90; S, 6.68.
3-Amino-l,6-diphenyl-5-[4-amino-5-cyano-l-phenyl-
6-oxopyridazin-3-(carbohydrazido-N-ylideno)]
Thiazolo[4,5-c]pyrazole (8b)
8b: Reddish brown crystals (3.3 g, 58%), m.p. 115 C (from ethanol),
1
max/cm 3475–3334 (2NH2, NH), 3050 (CH aromatic), 2220 (CN),
1695, 1680 (2 C O), 1660 (exocyclic C N), 1645 (C C). 1H NMR:
4.79, 5.54 (2s, 4H, 2NH2), 7.28–7.39 (m, 15H, aromatic protons), 8.09
(s, 1H, 2NH). Anal. requires for C28H20N10O2S (560.54): C, 59.36;
H, 3.56; N, 24.72; S, 5.66. Found: C, 59.60; H, 3.09; N, 24.90; S, 5.98.
Synthesis of Compounds 14 and 21a,b
General Procedure
The solution of 7a (4.7 g, 0.01 mmol), 17a (5.16 g, 0.01 mmol) or 17b
(5.91 g, 0.01 mol) in ethanol (10 ml) containing sodium acetate (0.8 g,
0.01 mol), hydroxylamine hydrochloride (0.33 g, 0.01 mmol) was added.
The reaction mixture was heated under reflux for 8 h then poured into
water and the solid product in each case was collected by filtration.
3-Amino-6-phenyl-5-[4-amino-5-cyano-1-phenyl-
6-oxopyridazin-3-(carbohydrazido-N-ylideno)]-
isoxazolo[5,4-d]thiazole (14)
14: Yellowish white crystals (2.9 g, 40%), m.p. l40 C (from ethanol),
1
max/cm 3478–3343 (2NH2, NH), 3050 (CH aromatic), 1690, 1685
1
(2 C O), 1670 (exocyclic C N), 1635 (C C). H NMR: 4.92, 5.51 (2s,
4H, 2NH2), 7.32–7.46 (m, 10H, aromatic protons), 8.69 (s, 1H, NH).
Anal. requires for C22H15N9O3S (485.47): C, 49.85; H, 3.11; N, 25.97; S,
6.60. Found: C, 49.52; H, 3.49; N, 25.52; S, 6.94.
7-Imino-3-oxo-4(3,4-diphenylthiazolidin-2-ylideno)-
1-phenylpyrimidino[5,4:3,4]isoxazolo[4,3:5,6]pyridazine
(21a)
21a: Yellow crystals (4.25 g, 80%), m.p. l65–168 C (from l,4- dioxane),
1
max/cm 3650–3375 (NH), 3055 (CH aromatic), 1700 (C O), 1670
(exocyclic; C N), 1640 (C C). 1H NMR: 6.99 (s, 1H, thiazole CH), 7.30–
7.42 (m, 16H, aromatic protons, pyrimidine H-2), 9.00 (s, 1H, NH). Anal.
requires for C28H18N8O2S (530.48): C, 63.40; H, 3.42; N, 21.12; S, 6.04.
Found: C, 63.39; H, 3.36; N, 21.07; S, 6.16.

2670
W. W. Wardakhan and Y. M. Elkholy
1,5-Diphenyl-7-imino-3-oxo-4-(3,4-diphenylthiazolidin-
2-ylideno)-pyrimidino[5,4:3,4]isoxazolo[4,3:5,6]-
pyridazine (21b)
21b: Yellow crystals (4.98 g, 82%), m.p. 260–263 C (from,4-dioxane),
1
max/cm 3570–3340 (NH), 3060 (CH aromatic), 1700 (C O), 1673
(exocydic C N), 1642 (C C). 1H NMR: 6.99 (s, 1H, thiazole CH), 7.30–
7.42 (m, 20H, aromatic protons), 9.01 (s, 1H, NH). Anal. requires for
C34H22N8O2S (606.58) C, 67.32; H, 3.66; N, 18.47; S, 5.29. Found: C,
67.39; H, 3.36; N, 18.07; S, 6.16.
Synthesis of Compound 11
To a solution of 7a (4.7 g, 0.01 mmol) in dimethylformamide, malononi-
trile 9 (0.66 g, 0.01 mmol) was added. The reaction mixture was heated
under reflux for 6 h then poured into an ice-water mixture, neutralized
with dilute hydrochloric acid (pH-7), and the solid product was collected
by filtration and crystallized from dioxane.
4-Amino-3-cyano-6-[1-phenyl-6-oxopyridazin-
3-(carbonhydrazido-N-ylideno)]-2-oxo-7-phenyl Thiazolo
[4,5-b]pyrane (11)
11: Orange crystals (3.8 g, 71%), m.p. 155 C (from l,4-dioxane),
1
max/cm 3480–3330 (2 NH2, NH), 3050 (CH aromatic), 2225, 2220
(CN), 1720, 1685–1670 (3 C O), 1666 (exocyclic C N), 1638 (C C).
1H NMR: 4.67, 5.80 (s, 4H, 2NH2), 7.33–7.39 (m, 10H, aromatic pro-
tons), 8.39 (s, 1H, NH). Anal. requires for C25H15N9O4S (537.44) C,
55.86; H, 2.81; N, 23.45; S, 5.97. Found: C, 55.61; H, 3.11; N, 23.51;
S, 6.29.
4-Amino-5-cyano-1-phenyl-3-carbohydrazido-N-ylidine-
4-hydroxy-3-phenyl-5-(4-oxo-5H Thiazol-2-ylideno)]-
6-oxopyridazine (13)
To a solution of 7a (4.7 g, 0.01 mmol) in acetic acid (40 ml), thiogly-
collic acid 12 (0.92 g, 0.01 mmol) was added. The reaction mixture was
heated under reflux for 2 h then left to cool. The solid product formed
upon pouring into ice/water mixture was collected by filtration.
13: Orange crystals (3.8 g, 70%), m.p. 235 C (from l,4-dioxane),
1
max/cm 3520–3300 (OH, NH2, NH), 3060 (CH aromatic), 2220 (CN),
1700, 1690, 1680 (3 C O), 1668 (exocyclic; C N),1640 (C C). 1H NMR:
4.77, 5.80 (s, 2H, NH2), 6.89 (s, 2H, thiazole CH2), 7.29–7.35 (m, 10H,
aromatic protons), 8.34 (s, 1H, NH). 10.21 (s, 1H, OH) Anal. requires
for C24H16N8O4S2 (544.49): C, 52.94; H, 2.96; N, 20.58; S, 11.78. Found:
C, 52.69; H, 3.01; N, 20.56; S, 11.34.

One-Pot Synthesis of Thiazoles
2671
Synthesis of Compound 17a,b Derivatives
General Procedure
To a solution of 16a (5.1 g, 0.01 mmol) in 1,4-dioxane (40 ml) contain-
ing piperdine (0.5 ml) was added either formaldehyde (0.3 g, 0.01 mmol)
or benzaldehyde (1.06 g, 0.01 mmol). The reaction mixture, was heated
under reflux for 4 h, then left to cool. The solid product so formed upon
pouring into an ice-water mixture containing few drops of hydrochloric
acid was collected by filtration.
7-Cyano-3,8-dioxo-4-N-(3,4-diphenylthiazolidin-
2-ylideno)-1-phenylpyrimidino[4,5-c]pyridazine (17a)
17a: Yellow white crystals (3.5 g, 68%), m.p. 165 C (from dimethyl-
1
formamide), max/cm 3050 (CH aromatic), 2220 (CN) 1710, 1695,
(2 C O), 1660 (exocydic C N), 1668 (C N), 1632 (C C). 1H NMR: 6.89
(s, 1H, thiazole C H), 7.23–7.39 (m, 16H, aromatic protons , pyrimidine
H-2)- MS (EI, 70 ev): m/z = 515 (M+) - Anal. requires for C28H17N7O2S
(515.49): C, 65.2; H, 3.32: N, 19.02; S, 6.22. Found: C, 65.12; H, 3.09
N, 19.50; S, 6.34.
7-Cyano-3,8-dioxo-4-N-(3,4-diphenylthiazolidin-
2-ylideno)-1,5-diphenylpyrimidino[4,5-c]pyridazine (17b)
17b: Yellow white crystals (4.4 g, 74%), m.p. 178–180 C (dimethyl-
1
formamide), max/cm 3075 (CH aromatic), 2220 (CN), 1705, 1690
1
(2 C O), 1665 (C N), 1663 (exocyclic C N), 1665 (C C). H NMR:
6.99 (s, 1H, thiazole C H), 7.20–7.51 (m, 20H, aromatic protons) Anal.
requires for C34H21N7O2S (591.59): C, 69.02; H, 3.58 N, 16.57; S, 5.42.
Found: C, 69.23; H, 3.39 N, 16.29; S, 5.39.
Synthesis of Compound 18a,b and 19a,b Derivatives
General Procedure
To a solution of either 17a (5.16 g, 0.01 mmol) or 17b (5.91 g, 0.01
mmol)in dimethylformamide (5 ml) was added either hydrazine hydrate
(0.5 g, 0.01 mmol) or phenyl hydrazine (1.08 g, 0.01 mmol). The reaction
mixture was heated under reflux for 4 h then pouring into an ice-water
mixture containing few drops of hydrochloric acid. The solid product
was collected by filtration.
7-Amino-3-oxo-4-N-(3,4-diphenylthiazolo-2-ylideno)-
1-phenylpyrimidino[5,4:3,4]pyridazine-
[4,3:5,6]pyridazine (18a)
18a: Yellow crystals (4.03 g, 76%), m.p. 300 C (from 1,4-dioxane),
1
max/cm 3455, 3338 (NH2), 3065 (CH aromatic), 1695 (C O), 1675

2672
W. W. Wardakhan and Y. M. Elkholy
(exocyclic C N), 1638 (C C). 1H NMR: 5.31 (s, 2H, NH2), 6.99 (s, 1H,
thiazole C H), 7.26–7.39 (m, 16H, aromatic protons, pyrimidine H-2),
Anal. requires for C28H19N9OS (529.53): C, 63.50; H, 3.62: N, 23.80; S,
6.05. Found: C, 63.29; H, 3.41 N, 23.76; S, 6.26.
7-Amino-3-oxo-4-N-(3,4-diphenylthiazolidin-2-ylideno)-
1,4-diphenylpyrimidino[5,4:3,4]pyrazolo
[4,3:5,6]pyridazine (18b)
18b: Yellow crystals (3.88 g, 64%), m.p. 230 C (from 1,4-dioxane),
1
max/cm 3474, 3337 (NH2) 3060 (CH aromatic), 1689, (C O), 1670,
(exocyclic C N), 1640 (C C). 1H NMR: (s, 2H, NH2), 6.99 (s, 1H,
thiazole CH), 7.23–7.75 (m, 20H, aromatic protons). Anal. requires for
C34H23N9OS (605.63): C, 67.42; H, 3.83 N, 20.81; S, 5.29. Found: C,
67.43; H, 3.67 N, 20.69; S, 5.26.
7-Imino-3-oxo-4-N-(3,4-diphenylthiazolidin-2-ylideno)-
1-phenylpyrimidino[5,4:3,4]pyrazolo
[4,3:5,6]pyridazine (19a)
19a: Yellow crystals (4.42 g, 73%), m.p. 199–201 C (from 1,4-
dioxane), max/cm 1 3466–3335 (NH) 3066 (CH aromatic), 1680 (C O),
1670 (exocyclic C N), 1642 (C C). 1H NMR: 6.99 (s, 1H, thiazole CH),
7.29–7.48 (m, 21H, aromatic protons, pyrimidine H-2), 9,30 (s, 1H, NH).
Anal. requires for C34H23N9OS (605.63): C, 67.42; H, 3.83: N, 20.81; S,
5.29. Found: C, 67.28; H, 3.80 N, 21.09; S, 5.08.
7-Imino-3-oxo-4-N-(3,4-diphenylthiazolidin-2-ylideno)-
1,4-diphenylpyrimidino[5,4:3,4]pyrazolo
[4,3:5,6]pyridazine (19b)
19b: Yellow crystals (4.43 g, 65%), m.p. 220 C (from 1,4-dioxane),
1
max/cm 3458–3300 (NH) 3060 (CH aromatic), 1688 (C O), 1673
(exocyclic C N), 1637 (C C). 1H NMR: 6.99 (s, 1H, thiazole CH),
7.31–7.59 (m, 25H, aromatic protons ), 9.30 (s, 1H, NH). Anal. requires
for C40H27N9OS (681.72): C, 70.47; H, 3.99: N, 18.49; S, 4.70. Found: C,
70.18; H, 4.21 N, 18.63; S, 4.98.
Synthesis of Compound 22a,b Derivatives
General Procedure
The solution of either 21a (5.31 g, 0.01 mmol) or 21b (6.07 g,
0.01 mmol) in ethanol (50 ml) containing solid sodium hydroxide (0.4 g,
0.01 mmol) was heated under reflux for 1 h, then poured into an ice-
water mixture containing few drops of hydrochloric acid (till pH 6). The
solid product formed upon stirring for 1 h was collected by filtration.

One-Pot Synthesis of Thiazoles
2673
3,7-Dioxo-4-N-(3,4-diphenylthiazolidin-2-ylideno)-
1-phenylpyrimidino[5,4:3,4]pyridazo[6,5:3,4]isoxazole
(22a)
22a: Yellow crystals (3.62 g, 68%), m.p. 148 C (from 1,4-dioxane),
1
max/cm
3060 (CH aromatic), 1705, 1685 (2 C O), 1673 (exo-
6.89 (s, 1H, thiazole CH),
cyclic C N), 1645 (C C). 1H NMR:
7.22–7.39 (m, 16H, aromatic protons, pyrimidine H-2). Anal. requires
for C28H17N7O3S (531.48): C, 63.27; H, 3.22: N, 18.45; S, 6.03. Found:
C, 63.29; H, 3.41 N, 23.76; S, 6.26.
1,5-Diphenyl-3,7-dioxo-4-N-(3,4-diphenylthiazolidin-
2-ylideno)-pyrimidino[4,5:3,4]pyridazo[6,5:3,4]isoxazole
(22b)
22b: Yellow crystals (4.44 g, 73%), m.p. 204–206 C (from 1,4-
1
dioxane), max/cm 3060 (CH aromatic), 1703, 1690 (2 C O), 1675
(exocyclic C N), 1638 (C C). 1H NMR: 6.93 (s, 1H, thiazole CH),
7.30–7.42 (m, 20H, aromatic protons) Anal. requires for C34H21N7O3S
(607.58): C, 67.21; H, 3.48: N, 16.14; S, 5.28. Found: C, 67.41; H, 3.40 N,
16.06; S, 6.26.
REFERENCES
[1] T. Yamasaki, E. Kawamiinami, F. Uchimura, Y. Okamoto, T. Okamwara, and M.
Furkawa, J. Heterocycl. Chem., 29, 835 (1992).
[2] K. Kaji, H. Nagoshima, S. Nagao, K. Tabashi, and H. Oda, Chem. Pharm. Bull., 30,
1030 (1982).
[3] T. Tamasaki, Y. Y. Yoshihara, Y. Okamoto, T. Okaara, and M. Furakawa, J. Heterocycl.
Chem., 29, 1313 (1992).
[4] S. Cehm and R. P. Panzica, J. Org. Chem., 46, 2467 (1981).
[5] A. W. Erian, Y. M. Elkholy, E. E. Alarab, and M. H. Elnagdi, Phosph., Sulfur, and
Silicon, 122, 133 (1997).
[6] Y. M. Elkholy, F. A. Abo-Shanb, and A. W. Erian, Phosph., Sulfur, and Silicon, 167,
151 (2000).
[7] Y. M. Elkholy, Phosph., Sulfur, and Silicon, 177, 1 (2001) .
[8] S. M. Fahmy, N. M. Abed, R. M. Mohareb, and M. H. Elnagdi, Synthesis, 390 (1982).
[9] B. C. Vicentini, S. Manfredini, M. Monfrini, R. Bazzanine, C. Musiu, M. Putsolu, G.
Perra, and E. M. Marongiu, Arch. Pharm. Wienheim (Ger.) 331, 269 (1998).