Synthesis of new pyridazin-6-ones, pyridazin-6-imines, 4-pyridazinals, and pyridines

Article abstract of DOI:10.1081/SCC-120002134

3-Dimethyl-1-[3-methyl-(4H)-5-phenylimidazol[2,1-b]thiazol-2-yl]prop-2-enone 4 couples smoothly with benzenediazonium chloride to yield propanal 5 which is a key intermediate for the synthesis of pyridazinones 9-13, 16 and pyridazine-6-imine 8, 19. Pentadienonitrile 18 was converted into pyridine-3-carbonitrile 20 on refluxing in ethanolic sodium ethoxide solution. Pyrazole 24 was synthesized from the reaction of 5 with 1-chloro-2-phenylhydrazono propan-2-one 22.

Full text of DOI:10.1081/SCC-120002134

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SYNTHESIS OF NEW PYRIDAZIN- 6-ONES,
PYRIDAZIN-6-IMINES, 4-PYRIDAZINALS, AND
PYRIDINES
Samia M. Sayed a , Mohamed A. Khalil a , Maghraby A. Ahmed b & Mohamed A. Raslan a
a Department of Chemistry, Faculty of Science, University of South Valley, Aswan, 81528,
Egypt
b Department of Chemistry, Faculty of Science, University of South Valley, Qena, Egypt
Version of record first published: 16 Aug 2006.
To cite this article: Samia M. Sayed , Mohamed A. Khalil , Maghraby A. Ahmed & Mohamed A. Raslan (2002): SYNTHESIS
OF NEW PYRIDAZIN- 6-ONES, PYRIDAZIN-6-IMINES, 4-PYRIDAZINALS, AND PYRIDINES, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:3, 481-495
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SYNTHETIC COMMUNICATIONS, 32(3), 481–495 (2002)
SYNTHESIS OF NEW PYRIDAZIN-
6-ONES, PYRIDAZIN-6-IMINES,
4-PYRIDAZINALS, AND PYRIDINES
Samia M. Sayed,1, Mohamed A. Khalil,1
*
Maghraby A. Ahmed,2 and Mohamed A. Raslan1
1Department of Chemistry, Faculty of Science,
University of South Valley, 81528 Aswan, Egypt
2Department of Chemistry, Faculty of Science,
University of South Valley, Qena, Egypt
ABSTRACT
3-Dimethyl-1-[3-methyl-(4H)-5-phenylimidazol[2,1-b]thiazol-
2-yl]prop-2-enone 4 couples smoothly with benzenediazonium
chloride to yield propanal 5 which is a key intermediate for
the synthesis of pyridazinones 9–13, 16 and pyridazine-
6-imine 8, 19. Pentadienonitrile 18 was converted into
pyridine-3-carbonitrile 20 on refluxing in ethanolic sodium
ethoxide solution. Pyrazole 24 was synthesized from the reac-
tion of 5 with 1-chloro-2-phenylhydrazono propan-2-one 22.
Key Words: Azo compounds; Active methylene; Hydra-
zonoyl chloride
*Corresponding author.
481
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
482
SAYED ET AL.
The biological and medicinal activity of pyridazines has stimulated
considerable interest in the chemistry of the ring system.1–8 As a part of
our program aimed at developing the synthesis of functionally substituted
heteroaromatices from readily obtainable starting materials, we have devel-
oped several novel and efficient syntheses of pyridazine derivatives from the
readily obtainable 2-arylhydrazonoketones.9,10 In conjunction with this
work, we now report the synthesis of new, otherwise not readily obtainable
pyridazinones and pyridazin-6-imines needed for the evaluation of their
potential as new biodegradable agrochemicals.
Thus, we have found that 5-acetyl-2-amino-4-methylthiazole 1 readily
reacts with phenacyl bromide 2 to afford 5-phenylimidazo[2,1-b]thiazol 3.
The formation of 3 was suggested to proceed through the intermolecular
quaternization of phenacyl bromide on the thaizole ring nitrogen atom
followed by dehydration to afford an intermediate which converted directly
into anhydro base11 5-phenylimidazo[2,1-b]thiazol 3. Compound 3 con-
densed readily with dimethylforamamide dimethylacetal as has been
described earlier12 affording 3-aminoenone derivative 4. Compound 4
coupled smoothly with benzenediazonium chloride in the presence of
sodium hydroxide13 to yield the 2-phenylhydrazonopropanal 5. Although
the reactivity of methyl ketones toward nucleophilic reagents has been
extensively studied,14–16 to our knowledge this is first reported reaction of
C-2 in 3-aminoenone derivatives 4 with electrophiles.
2-Phenylhydrazonopropanal 5 condensed readily with malononitrile
6a to yield products that can be formulated as 7 or isomeric cyclic 8.
Structure 8 was established for the reaction products based on its stability
under conditions reported to effect cyclization of compounds of struc-
ture similar to that of 7.17,18 For example, condensation product 8 was
recovered unchanged after extensive reflux in acetic acid. Similar to the
formation of pyridazine-6-imine 8, compound 5 readily reacted with
benzoylacetonitrile 6c and cyanoacetamide 6d to yield pyridazine-6-imines
10 and 11, respectively. In contrast to the behaviour of 5 towards 6c,d,
treatment of 5 with ethyl cyanoacetate 6b gave pyridazinone 9.
Treatment of 5 with diethyl malonate 6e in ethanol at room tempera-
ture in the presence of dimethylamine gave phenylazopyrane-2-one 12; upon
refluxing in ethanolic sodium ethoxide, the latter compound isomerized to
13 which was obtained directly from the reaction of 5 with 6e in refluxing
pyridine.
Compound 5 readily reacted with hippuric acid 6f in refluxing acetic
anhydride to yield products that can be formulated as 2-phenyl-2-oxazolin-
5-one 15a or pyridazinone isomeric 16a. Thus, initial cyclization of hippuric
acid would generate in situ the oxazolone 14a. This then condenses with 5
yielding the phenylhydrazone 15a. This phenylhydrazone rearranges into

ORDER
REPRINTS
SYNTHESIS OF PYRIDAZINE DERIVATIVES
483
Scheme 1.
Scheme 2.

ORDER
REPRINTS
484
SAYED ET AL.
the pyridazinone 16a via attack of the hydrazone moiety at the ring carbonyl
group. Structure 16a was preferred over 15a based on the fact that the
reaction product was recovered unchanged after extensive reflux under con-
ditions reported to effect ring-opening19 of 2-oxazolin-5-one. Similar to the
formation of 5-benzoyl-aminopyridazine-6-one 16a, compound 5 readily
reacted with glycine 6g in refluxing acetic anhydride to yield 5-acetylamino-
pyridazin-6-one 16b.
Scheme 3.
1-[3-Methyl-( 4H )-5-phenylimidazo[ 2,1-b ]thiazol-2-yl]-2,2-dicyano-1-
methylvinyl 17 was prepared by condensing 6a with imidazo[2,1-b]thiazolyl
methyl ketone 3 in boiling dry benzene containing ammonium acetate and
acetic acid using a Dean-stark water separator. Compound 17 reacted
smoothly with dimethylformamide dimethylacetal in dioxane or with mix-
ture of dimethylformamide/triethylorthoformate to afford pentadienonitrile
18. The observation that C-2 in 4 couples with benzenediazonium chloride
prompted us to investigate the behaviour of the enamine 18 toward benzene-
diazonium chloride to yield the pyridazinal 19. Hydrolysis of the enamine 18
by the action of acetic acid/hydrochloric acid mixture afforded the pyridi-
none 21,20 but refluxing 18 in ethanolic sodium ethoxide solution afforded
ethoxypyridine 20.21
Nitrilimines, generated by the action of bases on hydrazonoyl halides
have been reported to added to a,b-unsaturated carbonyl compounds to
yield mixtures of isomeric pyrazolines.22 In the present work, the reaction
of nitrilimine 23 (generated in situ from 1-chloro-2-phenylhydrazono

ORDER
REPRINTS
SYNTHESIS OF PYRIDAZINE DERIVATIVES
485
Scheme 4.
Scheme 5.

ORDER
REPRINTS
486
SAYED ET AL.
propan-2-one 22 and triethylamine) with 5 has afforded only one pyrazole
derivative by cycloaddition and dimethylamine elimination. The derivative
may be formulated as 24 or its isomer 25. Structure 24 was established based
on recovering unaffected after fused or long reflux with hydrazine hydrate.
These finding provide firm support for structure 24. Clearly the pyra-
zolo[3,4-d ] pyridazine 26 could be obtained only from reaction of 25 and
hydrazine hydrate.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded in KBr
disks using a Perkin-Elmer 1650 FT-IR Spectrometer. 1H NMR spectra were
measured on a Varian (200 MHz) Spectrometer with DMSO-d6 as solvent
and TMS as internal standard, chemical shifts are reported in d units (ppm).
Mass spectra were obtained by electron impact method. Microanalyses were
obtained from the Microanalytical Data Unit at Cairo University. Com-
pound 110 and 2223 were prepared according to literature procedures.
2-Acetyl-3-methyl-(4H)-5-phenylimidazo[2,1-b]thiazole (3): Equimolar
amount of 2-amino-5-acetyl-4-methylthiazole 1 (1.56 g, 10 mmol) and
phenacyl bromide (1.99 g, 10 mmol) in butanol (30 ml) were refluxed on
water bath for 6–12 h, (TLC control). The solvent was evaporated under
reduced pressure and the product obtained was triturated with ether,
collected by filtration and crystallized from DMF.
Yield: 1.8 g (70%); mp 220–222ꢀC; IR (KBr): n ¼ 1708 cmÀ1 (C¼O);
1H NMR (DMSO-d6): d ¼ 2.51 (s, 3H, CH3), 2.72 (s, 3H, COCH3),
7.23–7.92 (m, 5Harom), 8.5 (s, 1Himidazo); MS: m/z ¼ 256 (Mþ).
C
H
N
S
C14H12N2OS
(256.31)
Calc.
Found
65.60
65.57
4.72
4.70
10.93
10.82
12.51
12.38
3-Dimethylamino-1-[3-methyl-(4H)-5-phenylimidazo[2,1-b]thiazol-2-yl]-
prop-2-enone (4): The procedure used earlier was adopted.12 An equimolar
amount of dimethylformamide dimethylacetal (1.19 g, 10 mmol) was added
to the thiazolyl methyl ketone 3 (2.56 g, 10 mmol) in p-xylene (50 ml), and
the reaction mixture was refluxed for 4–6 h, (TLC control). The removal of
solvent under reduced pressure yielded the crude product, which was crys-
tallized from EtOH.

ORDER
REPRINTS
SYNTHESIS OF PYRIDAZINE DERIVATIVES
487
Yield: 2.5 g (81%); mp 194–195ꢀC; IR (KBr): n ¼ 1672 cmÀ1 (C¼O);
1H NMR (DMSO-d6): d ¼ 2.35 (s, 3H, CH3), 2.81 (s, 6H, -N(CH3)2), 5.61 (d,
1H, -CH¼CH-N, J ¼ 13 Hz), 7.13–7.93 (m, 6H 5Harom and -COCH¼CH-),
8.51 (s, 1Himidazo); MS: m/z ¼ 311 (Mþ).
C
H
N
S
C17H17N3OS
(311.40)
Calc.
Found
65.57
65.51
5.50
5.46
13.49
13.39
10.30
10.19
3-Oxo-2-phenylhydrazono-3-[3- methyl-(4H)-5-phenylimidazo[2,1-b]-
thiazol-2-yl]propanal (5): A cold solution of benzenediazonium chloride
(10 mmol) was prepared as described earlier17 was stirring. The resulting
solution of the benzenediazonium chloride was then added to a cold solu-
tion of enaminone 4 (3.11 g, 10 mmol) in ethanol (50 ml) containing sodium
hydroxide (550 mg, 12.5 mmol, in (5 ml) water). The reaction mixture was
stirred at room temperature for 3 h, crushed ice was added the solid sepa-
rated was filtered off and crystallized from EtOH.
Yield: 3 g (77%); mp. 160–162ꢀC; IR (KBr): n ¼ 3335–3450 (NH),
1
1662 cmÀ1 (C¼O); H NMR (DMSO-d6): d ¼ 2.43 (s, 3H, CH3), 7.16–7.98
(m, 10Harom), 8.49 (s, 1Himidazo), 9.85 (s, 1H, CHO), 11.16 (brs, 1H, NH);
MS: m/z ¼ 389 (Mþ þ 1).
C
H
N
S
C21H16N4O2S
(388.443)
Calc.
Found
64.93
64.85
4.15
4.11
14.42
14.32
8.25
8.16
5-Substituted-1,6-dihydro-3-[2-(3-methyl-(4H)-5-phenylimidazo[2,1-b]-
thiazoloyl]-6-imino-1-phenylpyridazines (8, 10, 11); General Procedure: A
mixture of 3-oxo-2-phenylhydrazono-3-[3-methyl-(4H)-5-phenylimidazo-
[2,1-b]thiazol-2-yl]propanal 5 (3.88 g, 10 mmol) malononitrile, benzoylaceto-
nitrile and/or cyanoacetamide (10 mmol) and a few drops of piperidine
(0.5 ml) in absolute ethanol (50 ml) were refluxed for 4–6 h. (TLC control).
The reaction mixture was cooled to room temperature, evaporated till dry-
ness and the residue redissolved in cold water (25 ml) containing dilute
HCl (if necessary) and kept over night. The solid product, so formed, was
collected by filtration and crystallized from EtOH.

ORDER
REPRINTS
488
SAYED ET AL.
1,6-Dihydro-3-[2-(3-methyl-(4H)-5-phenylimidazo[2,1-b]thiazoloyl]-6-
imino-1-phenylpyridazine-5-carbonitrile (8): Yield: 3.2 g (73.5%); mp 175–
176ꢀC; IR (KBr): n ¼ 3295 (NH), 2225 (CN), 1668 cmÀ1 (C¼O); H NMR
1
(DMSO-d6): d ¼ 2.45 (s, 3H, CH3), 7.16–8.46 (m, 12H, 10Harom; 4-H and
1Himidazo), 10.27 (brs, 1H, NH); MS: m/z ¼ 436 (Mþ).
C
H
N
S
C24H16N6OS
(436.49)
Calc.
Found
66.04
65.94
3.69
3.62
19.25
19.19
7.34
7.26
5-Benzoyl-1,6-dihydro-3-[2-(3-methyl-(4H)-5-phenylimidazo[2,1-b]thia-
zoloyl]-6-imino-1-phenylpyridazine (10): Yield: 3.1 g (60%); mp 201–203ꢀC;
1
IR (KBr): n ¼ 3380 (NH), 1662, 1645 cmÀ1 (C¼O); H NMR (DMSO-d6):
d ¼ 2.45 (s, 3H, CH3), 7.21–8.76 (m, 17H, 15Harom; 4-H and 1Himidazo), 9.98
(brs, 1H, NH); MS: m/z ¼ 516 (Mþ þ 1).
C
H
N
S
C30H21N5O2S
(515.59)
Calc.
Found
69.89
69.86
4.11
4.13
13.58
13.51
6.22
6.15
5-Amino-1,6-dihydro-3-[2-(3-methyl-(4H)-5-phenylimidazo[2,1-b]thiazo-
loyl]-6-imino-1-phenylpyridazine (11): Yield: 3.3 g (72%); mp 194–195ꢀC; IR
(KBr): n ¼ 3246, 3125 (NH and NH2), 1673 (C¼O), 1640 cmÀ1 (amide
C¼O); 1H NMR (DMSO-d6): d ¼ 2.51 (s, 3H, CH3), 7.22–8.46 (m,
14H, 10Harom; 4-H and 1Himidazo and NH2), 9.72 (brs, 1H, NH); MS:
m/z ¼ 454 (Mþ).
C
H
N
S
C24H18N6O2S
(454.505)
Calc.
Found
63.42
63.39
4.00
3.98
18.49
18.35
7.05
6.91
1,6-Dihydro-3-[2-(3-methyl-(4H)-5-phenylimidazo[2,1-b]thiazoloyl]-6-
imino-5-oxo-1-phenylpyridazine (9): To a suspension of 5 (3.88 g, 10 mmol)
in dioxane (35 ml), ethyl cyanoacetate (1.13 g, 10 mmol), a few drops of

ORDER
REPRINTS
SYNTHESIS OF PYRIDAZINE DERIVATIVES
489
triethylamine were added. The reaction mixture was refluxed for 4–6 h
(TLC control), then concentrated to half of its volume, poured into
crushed ice containing dilute HCl (if necessary). The solid product,
so formed on standing was collected by filtration and crystallized
from DMF.
Yield: 3 g (68.5%); mp 215–216ꢀC; IR (KBr): n ¼ 2198 (CH),
1693 (C¼O), 1635 cmÀ1 (ring C¼O); 1H NMR (DMSO-d6): d ¼ 2.51 (s,
3H, CH3), 7.25–8.48 (m, 12H, 10Harom; 4-H and 1Himidazo); MS:
m/z ¼ 437 (Mþ).
C
H
N
S
C24H15N5O2S
(437.47)
Calc.
Found
65.89
65.87
3.46
3.45
16.01
15.89
7.33
7.26
Ethyl 2-Oxo-5-phenylazo-6-[3-methyl-(4H)-5-phenylimidazo[2,1-b]thia-
zol-2-yl]-4H-pyrane-3-carboxylate (12): To stirred solution of 5 (3.88 g,
10 mmol) in ethanol (30 ml) containing dimethylamine diethyl malonate
6e (1.6 g, 10 mmol) was added. The reaction mixture was kept under stirring
for 24 h, at room temperature during which the solid formed was filtered and
washed with ethanol and crystallized from methanol.
Yield: 3.6 g (75%); mp 124–125ꢀC; IR (KBr): n ¼ 1732 (ester CO),
1644 cmÀ1 (ring C¼O); 1H NMR (DMSO-d6): d ¼ 1.35 (t, 3H, J ¼ 8 Hz,
CH3), 2.47 (s, 3H, CH3), 4.34 (q, 2H, J ¼ 8 Hz, OCH2), 7.34–8.52 (m,
12H, 10Harom; 4-H and 1Himidazo); MS: m/z ¼ 484 (Mþ).
C
H
N
S
C26H20N4O4S
(484.53)
Calc.
Found
64.45
64.41
4.16
4.12
11.56
11.48
6.62
6.58
Ethyl 1,6-Dihydro-3-[2-(3-methyl-(4H)-5-phenylimidazo[2,1-b]thiazo-
loyl]-6-oxo-1-phenylpyridazine-5-carboxylate (13) Method A: To a suspen-
sion of 5 (3.88 g, 10 mmol) in pyridine (35 ml), diethyl malonate (1.6 g,
10 mmol) was added. The reaction mixture was refluxed for 3–6 h, (TLC
control), then concentrated to half of its volume, poured into crushed ice
containing dilute HCl (if necessary). The solid product, so formed on stand-
ing was collected by filtration and crystallized from EtOH.

ORDER
REPRINTS
490
SAYED ET AL.
Yield: 3.3 g (68%); mp 170–172ꢀC; IR (KBr): n ¼ 1728 (ester CO),
1665 (C¼O), 1634 cmÀ1 (ring C¼O); 1H NMR (DMSO-d6): d ¼ 1.32 (t,
3H, J ¼ 8.6 Hz, CH3), 2.47 (s, 3H, CH3), 4.31 (q, 2H, J ¼ 8 Hz, OCH2),
7.34–8.58 (m, 12H, 10Harom; 4-H and 1Himidazo); MS: m/z ¼ 485 (Mþ þ 1).
C
H
N
S
C26H20N4O4S
(484.53)
Calc.
Found
64.45
64.38
4.16
4.14
11.56
11.47
6.62
6.53
Method B: A solution of 12 (4.84 g, 10 mmol) in absolute ethanol
(50 ml) was treated with sodium ethoxide (0.25 mmol). The reaction mix-
ture was heated for 4 h, then allow to cool to room temperature and acid-
ified with dilute HCl. The solid product thus formed was collected by
filtration and crystallization from ethanol to afford a compound identical
in all respects (mp, mixed mp and spectral data) with that obtained by
Method A.
5- Substituted-1,6- dihydro-3-[2-(3-methyl-(4H)-5-phenylimidazo[2,1-b]-
thiazoloyl]-6-oxo-1-phenylpyridazine (16a,b): General procedure: A solution
of 5 (3.88 g, 10 mmol) and hippuric acid (1.79 g, 10 mmol) or glycine (0.8 g,
10 mmol) in dry acetic anhydride (45 ml) was refluxed for 3–5 h, left to cool
then poured into water. After complete decomposition of excess acetic
anhydride the remaining was triturated with methanol, collected by filtra-
tion and crystallized from EtOH.
5-Benzoamido-1,6-dihydro-3-[2-(3-methyl-(4H)-5-phenylimidazo[2,1-b]-
thiazoloyl]-6-oxo-1-phenylpyridazine (16a): Yield: 4.3 g (81%); mp
288–289ꢀC; IR (KBr): n ¼ 3375 (NH), 1698 (CO), 1675 (ring C¼O),
1660 cmÀ1 (amide C¼O); 1H NMR (DMSO-d6): d ¼ 2.49 (s, 3H, CH3),
7.31–8.52 (m, 17H, 15Harom; 4-H and 1Himidazo), 10.11 (brs, 1H, NH);
MS: m/z ¼ 531 (Mþ).
C
H
N
S
C30H21N5O3S
(531.59)
Calc.
Found
67.78
67.87
3.98
3.78
13.17
13.01
6.03
5.92
5-Acetamido-1,6-dihydro-3-[2-(3-methyl-(4H)-5-phenylimidazo[2,1-b]-
thiazoloyl]-6-oxo-1-phenylpyridazine (16b): Yield: 3.4 g (72%);

ORDER
REPRINTS
SYNTHESIS OF PYRIDAZINE DERIVATIVES
491
mp 145–147ꢀC; IR (KBr): n ¼ 3315 (NH), 1692 (CO), 1679 (ring CO),
1
1656 cmÀ1 (amide CO); H NMR (DMSO-d6): d ¼ 2.28 (s, 3H, CH3), 2.51
(s, 3H, CH3), 7.38–8.63 (m, 12H, 10Harom; 4-H and 1Himidazo), 9.98 (brs, 1H,
NH); MS: m/z ¼ 470 (Mþ þ 1).
C
H
N
S
C25H19N5O3S
(469.52)
Calc.
Found
63.95
63.87
4.08
3.98
14.92
14.79
6.83
6.72
1-(3-Methyl-(4H)-5-phenylimidazo[2,1-b]thiazol-2-yl]ethylidenemalono-
nitrile (17): A suspension of 3 (2.56 g, 10 mmol) in dry benzene (30 ml),
ammonium acetate (0.5 g) and acetic acid (2 ml) was treated with malononi-
trile (0.67 g, 10 mmol). The reaction mixture was heated under reflux using a
Dean-stark water separator until water ceased to be collected. The solid
product obtained was crystallized from EtOH.
Yield: 2.5 g (82%); mp 207–209ꢀC; IR (KBr): n ¼ 2210 cmÀ1 (CN);
1H NMR (DMSO-d6): d ¼ 2.51 (s, 3H, CH3), 2.75 (s, 3H, CH3), 7.32–7.96
(m, 5Harom), 8.45 (s, 1Himidazo); MS: m/z ¼ 304 (Mþ).
C
H
N
S
C17H12N4S
(304.37)
Calc.
Found
67.09
66.98
3.98
3.68
18.41
18.19
10.53
10.42
2-Cyano-5-(N,N-dimethylamino)-3-[3-methyl-(4H)-5-phenylimidazo[2,1-b]-
thiazol-2-yl]-2,4-pentadienonitrile (18) Method A: A suspension of each of 17
(3.04 g, 10 mmol) was treated with N,N-dimethyl-formamide (15 ml) and
triethylorthoformate (15 ml). The reaction mixture was refluxed for 4–6 h,
then poured into water. The oily product thus formed was triturated with
methanol and left aside for two days. The solid product was filtered off and
crystallized from dioxane.
Method B: A suspension of each of 17 (3.04 g, 10 mmol) in dioxane
(35 ml), dimethylformamide dimethylacetal (1.19 g, 10 mmol) was added.
The reaction mixture was refluxed for 3 h, (TLC control). The solid product
thus formed was collected by filtration and crystallized from dioxane to
afford a compound identical in all respects (mp, mixed mp and all spectra
data) with that obtained by Method A.

ORDER
REPRINTS
492
SAYED ET AL.
Yield: 2.4 g (67%); mp 200–201ꢀC; IR (KBr): n ¼ 2225 cmÀ1 (CN);
1H NMR (DMSO-d6): d ¼ 2.48 (s, 3H, CH3), 3.10 (s, 3H, NCH3), 3.19 (s,
3H, NCH3), 5.68 (d, 1H, -CH¼CH-N, J ¼ 13 Hz), 7.23–8.52 (m, 7H, 5Harom
and –COCH¼CH-, 1Himidazo). MS: m/z ¼ 359 (Mþ).
C
H
N
S
C20H17N5S
(359.45)
Calc.
Found
66.83
66.81
4.77
4.58
19.48
19.21
8.92
8.82
1,6-Dihydro-3-formyl-6-imino-4-[3-methyl-(4H)-5-phenylimidazo-[2,1-
b]thiazol-2-yl]-1-phenylpyridazine-5-carbonitrile (19): A solution of 2-cyano-
5-(N,N-dimethylamino)-3-[3-methyl-(4H)-5-phenylimidazo[2,1-b]- thiazol-2-
yl]- 2,4-pentadienonitrile 18 (3.59 g, 10 mmol) in ethanol (50 ml) containing
sodium hydroxide solution (0.5 g, in (10 ml) water) was treated with a cold
solution of benzenediazonium chloride (10 mmol) prepared according to
literature.13 The reaction mixture was stirred at room temperature for
48 h, crushed ice was added (50 g), the solid separated was filtered and
crystallization from EtOH.
Yield: 2.7 g (63%); mp 140–142ꢀC; IR (KBr): n ¼ 3395 (NH), 2225
(CN), 1695 cmÀ1 (C¼O); 1H NMR (DMSO-d6): d ¼ 2.51 (s, 3H, CH3),
7.92–8.62 (m, 11H, 10Harom, 1Himidazo), 8.72 (s, 1H, CHO), 8.98 (brs, 1H,
NH); MS: m/z ¼ 436 (Mþ).
C
H
N
S
C24H16N6OS
(436.49)
Calc.
Found
66.04
66.12
3.69
3.62
19.25
19.01
7.34
7.21
2-Ethoxy-4-[3-methyl-(4H)-5-phenylimidazo[2,1-b]thiazol-2-yl]pyridine-
3-carbonitrile (20): solution of 18 (3.59, 10 mmol) in absolute
A
ethanol (50 ml) was treated with the sodium ethoxide (0.25 mmol). The
reaction mixture was heated for 4 h, then allowed to cool to room temp-
erature and triturated with cold water containing dilute HCl. The
solid product thus formed was collected by filtration and crystallized from
ethanol.

ORDER
REPRINTS
SYNTHESIS OF PYRIDAZINE DERIVATIVES
493
Yield: 2 g (58%); mp 222–223ꢀC; IR (KBr): n ¼ 2218 cmÀ1 (CN);
1H NMR (DMSO-d6): d ¼ 1.40 (t, 3H, J ¼ 8 Hz, CH3), 2.43 (s, 3H, CH3),
4.71 (q, 2H, J ¼ 8 Hz, OCH2), 7.92–8.62 (m, 6H, 5Harom, pyridyl H-5), 8.53
(m, 2H, 1Himidazo pyridyl H-6); MS: m/z ¼ 361 (Mþ þ 1).
C
H
N
S
C20H16N4OS
(360.43)
Calc.
Found
66.65
66.61
4.47
4.42
15.54
15.41
8.89
8.82
1,2-Dihydro-2-oxo-4-[3-methyl-(4H)-5-phenylimidazo[2,1-b]thiazol-2-yl]-
pyridine-3-carbonitrile (21): A solution of 18 (3.59 g, 10 mmol) in acetic acid/
hydrochloric acid (3/1) mixture (30 ml) was refluxed for 4 h, then poured
into water. The solid product thus formed was collected by filtration and
crystallized from dioxane.
Yield: 2.4 g (72%); mp 194–196ꢀC; IR (KBr): n ¼ 3298 (NH), 2226
(CN), 1658 cmÀ1 (amide CO): 1H NMR (DMSO-d6): d ¼ 2.48 (s, 3H,
CH3), 6.34 (d, 1H, pyridyl H-5), 7.24–7.98 (m, 6H, 5Harom, pyridyl H-6),
8.51 (s, 1Himidazo), 12.51 (brs, 1H, NH); MS: m/z ¼ 332 (Mþ).
C
H
N
S
C18H12N4OS
(332.38)
Calc.
Found
65.05
64.88
3.64
3.58
16.86
16.49
9.64
9.58
3-Acetyl-1-phenyl-5-[2-(3-methyl-(4H)-5-phenylimidazo[2,1-b]thiazo-
loyl]pyrazole (24): A solution of 5 (3.88 g, 10 mmol) in ethanol (30 ml) and 22
(1.96 g, 10 mmol) in ethanol (30 ml) was treated with triethylamine (2 ml).
The solution was left over night under stirring, then reflux for 4 h. The
solvent was then evaporated and the remaining product was triturated
with methanol. The product that formed, was collected by filtration and
crystallized from ethanol.
Yield: 2.5 g (58%); mp 235–236ꢀC; IR (KBr): n ¼ 1693, 1662 cmÀ1
1
(C¼O); H NMR (DMSO-d6): d ¼ 2.49 (s, 3H, CH3), 2.63 (s, 3H, CH3),
7.14–8.06 (m, 10Harom), 8.49 (s, 1Himidazo), 8.92 (s, 1H, H-5); MS:
m/z ¼ 426 (Mþ).

ORDER
REPRINTS
494
SAYED ET AL.
C
H
N
S
C24H18N4O2S
(426.49)
Calc.
Found
67.59
67.31
4.25
4.58
13.14
13.11
7.52
7.46
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Received in the USA March 19, 2001

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