Pyridazine derivatives and related compounds, part 221: Synthesis, reactions, and insecticidal activity of 3-amino-5,6-diaryl-1h-pyrazolo[3,4-c] pyridazines

Article abstract of DOI:10.1080/10426500902758451

Starting with 3-amino-5,6-diaryl-1H-pyrazolo[3,4-c]pyridazine, the syntheses of thiourea derivatives, dithiocarbamates, ethyl carbamate, phosphoranylidene amino, and substituted acetamido derivatives are described. The products were screened for their insecticidal activity against Mucsa, domestica, and Aphid, Macrosiphum pisi. Supplemental materials are available for this article. Go to the publisher′s online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426500902758451

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Pyridazine Derivatives and Related
Compounds, Part 221: Synthesis,
Reactions, and Insecticidal Activity of
3-Amino-5,6-diaryl-1H-pyrazolo[3,4-
c]pyridazines
Ali Deeb a , Elsayed Mourad b & Diaa Elenany b
a Department of Chemistry, Faculty of Science, Zagazig University,
Zagazig, Egypt
b Central Agricultural Pesticide Laboratory, Agricultural Research
Center, El-Mansoura, Egypt
Version of record first published: 28 Dec 2009
To cite this article: Ali Deeb, Elsayed Mourad & Diaa Elenany (2009): Pyridazine Derivatives and
Related Compounds, Part 221: Synthesis, Reactions, and Insecticidal Activity of 3-Amino-5,6-diaryl-1H-
pyrazolo[3,4-c]pyridazines, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:1, 222-231
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Phosphorus, Sulfur, and Silicon, 185:222–231, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902758451
PYRIDAZINE DERIVATIVES AND RELATED COMPOUNDS,
PART 22: SYNTHESIS, REACTIONS, AND INSECTICIDAL
ACTIVITY OF 3-AMINO-5,6-DIARYL-1H-PYRAZOLO[3,4-c]
PYRIDAZINES
Ali Deeb,1 Elsayed Mourad,2 and Diaa Elenany2
1Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
2Central Agricultural Pesticide Laboratory, Agricultural Research Center,
El-Mansoura, Egypt
Starting with 3-amino-5,6-diaryl-1H-pyrazolo[3,4-c]pyridazine, the syntheses of thiourea
derivatives, dithiocarbamates, ethyl carbamate, phosphoranylidene amino, and substituted
acetamido derivatives are described. The products were screened for their insecticidal activity
against Mucsa, domestica, and Aphid, Macrosiphum pisi.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Insecticidal activity; 3-substituted amino-5,6-diaryl-1H-pyrazolo[3,4-c]pyridazine
INTRODUCTION
Pyridazines and heterocyclic annelated pyridazines have been investigated inten-
sively for their applications in agriculture, and in particular for their biological activity for
use as potential drugs.1 The recent discovery of pyridazomycin,2 a new antifungal antibi-
otic produced by Streptomyces violaceoniger and zazissine,3 a new cytotoxic guanidine
alkaloid isolated from the Mediterranean sponge Anchinoe paupertas, both containing this
heteroarene system, most likely will stimulate an even broader interest in 1,2-diazine chem-
istry. On the other hand, one of the most important classes of five-membered heterocycles is
represented by the pyrazole ring. Pyrazoles are found in a broad variety of pharmaceutical,
agrochemical, and veterinary products.4
Guided by these observations and in continuation of our earlier work5 on pyridazine
derivatives and related compounds, in this article we report the synthesis and insecticidal
activities and results of our toxicity studies of novel pyrazolo[3,4-c]pyridazines.
Received 2 June 2008; accepted 19 January 2009.
Address correspondence to Ali Deeb, Department of Chemistry, Faculty of Science, Zagazig University,
Zagazig, Egypt. E-mail: dralideeb@hotmail.com
222

PYRIDAZINE DERIVATIVES AND RELATED COMPOUNDS
223
RESULTS AND DISCUSSION
As starting substance, we used 5,6-diaryl-3-chloropyridazine-4-carbonitrile, which
reacted with hydrazine hydrate in ethanol to give 3-amino-4,5-diaryl-1H-pyrazolo[3,4-
c]pyridazine (1a,b).6
1
The structures of 1a,b were supported by their infrared, H NMR, and elemental
analyses. The infrared spectrum showed the presence of NH2 groups (3450 and 3100
cm−1). The 1H NMR spectrum of 1a showed the presence of a broad singlet 1H, NH at δ
8.1, 10H multiplet at 7.55–7.22 due to the aromatic phenyl protons, and a broad singlet 2H
at δ 4.3 due to NH2 protons.
3-Amino-5,6-diphenyl-1H-pyrazolo[3,4-c]pyridazine 1a reacted with an equimo-
lar quantity of methyl or phenyl isothiocyanate to give (N-heteroaryl)thioureas (2a,b)
(Scheme 1). Similarly the reaction of 3-amino-4,5-bis(4-chlorophenyl)-1H-pyrazolo[3,4-
c]pyridazine 1b with an equimolar amount of benzoyl isothiocyanate in situ prepared
from ammonium thiocyanate and benzoyl chloride in acetone at reflux temperature
led to the formation of N-[4,5-bis(4-chlorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]-
N‘-benzoylthiourea (3). In an analogous manner, the reaction of 1b with ethoxycar-
bonyl isothiocyanate led to the formation of N-[4,5-bis(4-chloro-phenyl)-1H-pyrazolo[3,4-
c]pyridazin-3-yl]-Nꢁ-ethoxycarbonylthiourea (4), in which the soft nucleophile amino group
attacks the isothiocyanate group, not the carbonyl group of the ethoxycarbonyl isothio-
cyanate. The structural elucidations of 3 and 4 were accomplished from their analytical and
spectroscopic data.
The reaction of 1a with aqueous 20 mol potassium hydroxide and carbon disulfide in
ethanol yielded potassium 3-N-dithiocarbamate (5), which was converted, without previous
isolation, into ethyl N-[(4,5-diphenyl)-1H-pyrazolo[3,4-c]pyridazine]-3-dithiocarbamate
(6) by reaction with diethylsulfate.
On other hand, the potassium 3-N-dithiocarbamate 5 was converted into the man-
ganese(II), zinc(II), ferrous(II), cobalt(II), and nickel(II) bis-3-N-dithiocarbamate deriva-
tives (7a–e) by reaction with manganese sulfate, zinc sulfate ferrous sulfate, cobalt sulfate,
and nickel sulfate, respectively .
Heating 1b with excess ethyl chloroformate at reflux temperature produced
3-ethoxycarbonylamino-4,5-bis(4-chlorophenyl)-1H-pyrazolo[3,4-c]pyridazine (8) as the
only product. The structure of 8 is corroborated by microanalysis, and by the mass spectra,
which show the expected molecular ion peaks at 428 and peaks for [M+ –H], and [M+
–CO2CH2CH3].
3-Diazo-4,5-diphenylpyrazolo[3,4-c]pyridazine (9) and 3-azido-4,5-diphenyl-1H-
pyrazolo[3,4-c]pyridazine (10) were prepared in excellent yields, following the conditions

224
A. DEEB ET AL.
Scheme 1
previously reported in our laboratory.7,8 Compound 9 was prepared in 96% yield as yellow
crystals (mp 135 ◦C) by diazotization of 1a with sodium nitrate in glacial acetic acid at room
temperature. Compound 10 was prepared as light yellow crystals (mp 164◦C) by addition
sodium azide portionwise to 3-diazo derivative (9) in conc. HCl at room temperature.
Compound 10 reacts in ethanol at ambient temperature with triphenylphosphine (11a)
with the evolution of nitrogen to yield 3-triphenylphosphoranylideneamino-4,5-diphenyl-
1H-pyrazolo[3,4-c]pyridaz-ine (12a). Trimethyl phosphate (11b) and triethyl phosphate
(11c) react in the same manner to furnish 12b and 12c, respectively (Scheme 2).
The reaction of 1b with an excess of chloroacetyl chloride under reflux affords
3-chloroacetylamino-4,5-bis(4-chlorophenyl)-1H-pyrazolo[3,4-c]-pyridazine (13). The
feasibility of the chlorine atom in 13 to undergo a nucleophilic displacement reaction
was proven by its reaction with morpholine and piperidine to yield 3-morpholino and

PYRIDAZINE DERIVATIVES AND RELATED COMPOUNDS
225
Scheme 2
3-piperidinoacetylamino-4,5-bis(4-chlorophenyl)-1H-pyr-azolo[3,4-c]pyridazine
and (14b) in a good yield.
(14a)
When the 3-chloroacetylamino derivative 13 was reacted with ethanolamine,
it gave a single product. The isolated product was proven to be identical in every
respect with the product 3-amino-4,5-bis(4-chlorophenyl)-1H-pyrazolo[3,4-c]pyridazine
(1b), resulting from the basic hydrolysis of the chloroacetyl group rather than the
3-ethanolaminoacetylamino derivative (14c), as shown by the analytical and spectral data.
The infrared spectrum of the product displays no absorption referred to the carbonyl group
and showed an absorption band at 3442 and 3297 cm−1, referred to the amino group and
the mass spectrum gave a molecular ion at m/z 356 (71%) in accordance with the proposed
structure.
The reaction of 3-chloroacetylamino (13) gave rise to 3-(2-imino-4-oxothiazol-3-yl)-
4,5-bis(4-chlorophenyl)-1H-pyrazolo[3,4-c]pyridazine (15) when reacted with potassium
thiocyanate in butanol. The indicated intermediate can not be isolated but can be rationalized
as follows. The 3-thiocyanoacetylamino underwent smooth cyclization to the correspond-
ing thiazolone derivative (15) (Scheme 3). The assignment of structure 15 was based on
analytical and spectral data. The IR spectrum showed the presence of NH groups at 3448,
3137 cm−1 and a strong sharp carbonyl group at 1711 cm−1. The mass spectrum gave a
1
molecular in at m/z 455 in accord with the proposed structure. The H NMR showed the
presence of a 2H singlet at δ 3.97, a 8H multiplet at δ 7.42–7.65 due to aromatic phenyl
protons, a 1H weak broad singlet at δ 11.74 due to NH, and a 1H weak broad singlet at δ
14.3 due to = NH group.
Insecticidal Activity
Out of the synthesized compounds, only compounds 1b, 2a, 2b, 3, 4, 6, 7a, 7b, 7c,
7d, 7e, 8, 12b, 12c, 13, 14, and 15 were examined for their insecticidal activity against
two insects viz. Mucsa, domestica and Aphid, Macrosiphum pisi by the dipping method9 at
2.5 × 103, 5 × 103, 10 × 103, 15 × 103, and 20 × 103 ppm concentration, and the results
are recorded in Table I (available in the Supplemental Materials online).

226
A. DEEB ET AL.
Scheme 3
EXPERIMENTAL
Melting points were determined in open-glass capillaries using a Bu¨chi 510 apparatus
and were reported uncorrected. Infrared spectra were recorded as potassium bromide disks
on a Bruker Vector 22 (Germany) spectrometer. 1H NMR spectra were obtained on a Varian
Gemini 200 MHz spectrometer, and chemical shifts are expressed in δ ppm using TMS as an
internal standard. Electron impact mass spectra were obtained at 70 eV using a GCMS-1000
EX Shimadzu spectrometer. All reactions were monitored by thin layer chromatography,
carried out on 0.2 mm silica gel 60 F-254 (Merck) plates using UV light (254 and 366 nm).
3-Amino-4,5-diaryl-1H-pyrazolo[3,4-c]pyridazine (1a,b), 3-diazo-4,5-diphenyl-
pyrazolo[3,4-c]pyridazine (9), and 3-azido-4,5-diphenyl-1H-pyr-azolo[3,4-c]pyridazine
(10) were prepared according to previously reported procedures.6–8
N-(4,5-Diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)-Nꢀ-methylthioures
(2a)
A solution of 3-amino-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (1a) (0.57 g,
2.0 mmol) and methyl isocyanate (0.15 g, 2.0 mmol) in dry benzene (20 mL) was heated
under reflux for 6 h. The reaction mixture was evaporated under reduced pressure, and the
residue was collected and recrystallized from ethanol to give 2a. Yield: 0.6 g (85.7%), mp

PYRIDAZINE DERIVATIVES AND RELATED COMPOUNDS
227
273–275◦C, IR: 3260 (NH), 3062 (CHarom.), 2828 (CHaliph.), 1057 (C S) cm−1; 1H NMR
(DMSO-d6): δ: 14.4 (s, 1H, NH), 8.80 (s, 1H, NH-C S), 8.00 (s, 1H, NHCH3), 7.60–7.20
(m, 10H, 2Ph), 2.60 (s, 3H, CH3) ppm. Anal. Calcd for C19H16N6S: C, 63.33; H, 4.48; N,
23.33. Found: C, 63.20; H, 4.40; N, 23.20.
N-(4,5-Diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)-Nꢀ-phenylthioures
(2b)
A solution of 3-amino derivative (1a) (1.7 g, 6.0 mmol) and an equimolar amount of
phenyl isothiocyanate (0.81 g, 6.0 mmol) in dry benzene (20 mL) was heated under reflux
for 5 h. The reaction mixture was evaporated under reduced pressure, and the residue was
collected and recrystallized from ethanol to give 2b. Yield 2.3 g (92%), mp 216–218 ◦C,
IR: 3376 (NH), 3062 (CHarom.), 1459 (C C), 1151 (C S) cm−1; MS: m/z (%): 422 (M+,
3.2), 330 (M+-NHPh, 13.1, ion A), 286 (ion A-CS, 99.9, ion B), 259 (ion B-HCN, 20), 245
(ion B-C(NH) N, 17.8). Anal. Calcd for C24H18N6S: C, 68.24; H, 4.29; N, 19.89. Found:
C, 68.10; H, 4.10; N, 18.70.
N-[4,5-Bis(4-chlorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]-Nꢀ-
benzoylthiourea (3)
To a stirred solution of in situ prepared benzoyl isothiocyanate (1.46 g, 9.0
mmol) in anhydrous acetone (10 mL), a solution of 3-amino-4,5-bis(4-chlorophenyl)-1H-
pyrazolo[3,4-c]pyridazine (1b) (3.20 g, 9.0 mmol) in anhydrous acetone (20 mL) was slowly
added dropwise, and the mixture was gently refluxed for 24 h. The reaction mixture was
cooled, and the solid product was collected, dried, and recrystallized from acetone to give
3. Yield: 3.0 g (65%), mp 218–220◦C, IR: 3051 (CHarom.), 2340 (NCS), 760 (C-Cl) cm−1
;
MS = m/z (%) : 521 (M+ + 2, 1.4), 411 (M+-PhCO/3H, 1.9, ion A), 353 (ion A-NCS, 4.9,
ion B), 276 (ion B-C3H3N3, 1.4). Anal. Calcd for C25H16Cl2N6OS: C, 57.81; H, 3.11; N,
16.18. Found: C, 57.70; H, 3.00; N, 16.10.
N-[4,5-Bis(4-chlorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]-Nꢀ-
ethoxy-carbonylthiourea (4)
A solution of ethoxycarbonyl isothiocyanate [prepared by mixing ethyl chloroformate
(0.66 g, 6.0 mmol) in anhydrous acetone (10 mL) with ammonium thiocyanate (0.66 g,
8.7 mmol) and heating on a water bath for 20 min] was added to a stirred solution of
compound 1b (1.4 g, 4.0 mmol) in anhydrous acetone (20 mL). The whole mixture was
heated under reflux for 5 h, and then evaporated under reduced pressure. The residue was
recrystallized from ethanol to give 4, yield 1.3 g (71%), mp 223–225 ◦C; IR: 3376, 3314
(NH), 1726 (C O), 1128 (C S) cm−1; MS = m/z (%): 487 (M+, 0.3), 486 (M+-1, 10,
ion A), 397 (ion A-NHCO2CH2CH3, 17, ion B), 354 (ion B-C S, 100). Anal. Calcd for
C21H16Cl2N6O2S: C, 51.75; H, 3.31; N, 17.25. Found: C, 51.60; H, 3.20; N, 17.00.
Ethyl N-[(4,5-diphenyl)-1H-pyrazolo[3,4-c]pyridazine]-3-dithiocarba-
mate (6)
To a vigorously stirred solution of 3-amino derivative (1a) (0.86 g, 3.0 mmol) in
ethanol (25 mL) at room temperature, carbon disulfide (0.98 g, 13.0 mmol) and aq.

228
A. DEEB ET AL.
KOH (0.9 g, 20 M) were added. After stirring for 10 min, the reaction mixture was
cooled in an ice bath (5–10◦C) and diethyl sulfate (0.6 g, 3.8 mmol) was added with
stirring. The reaction mixture was refluxed for 3 h, and thereafter the cooled reaction
mixture was poured into ice water (250 mL). The solid thus separated was filtered,
dried, and recrystallized from ethanol to afford 6 as yellow crystalline solid, yield 1.0
◦
g (91%), mp 183–184 C; IR: 3392, 3320 (NH), 2928 (CHaliph.), 1128 (C S) cm−1
.
Anal. Calcd for C20H17N5S2: C, 61.35; H, 4.38; N, 17.89. Found: C, 61.10; H, 4.20; N,
17.70.
Bis N-[(4,5-diphenyl)-1H-pyrazolo[3,4-c]pyridazine]-3-dithiocarbamate
metal salt (7a–e)
General procedure. To a vigorously stirred of 3-amino derivative (1a) (0.86 g,
3.0 mmol) in ethanol (25 mL) at room temperature, carbon disulphide (0.98 g, 13.0 mmol)
and aq. KOH (0.9 g, 20 M) were added. After stirring for 10 min, the reaction mixture was
cooled in an ice bath (5–10◦C), and metal sulfate (3.0 mmol) was added with stirring. The
reaction mixture was refluxed for 2 h. The solvent was removed under reduced pressure,
water (100 mL) was added to the residue, and the precipitate was filtered off and dried.
Manganese(II) Bis-N[-[(4,5-diphenyl)-1H-pyrazolo[3,4-c]pyridazine]-3-di-
thiocarbamate (7a). Yield: 2.2 g (95%), mp > 300 ◦C, IR: 3412 (NH), 3030 (CHarom.),
1114 (C S) cm−1
.
Zinc(II) Bis-N-[(4,5-diphenyl)-1H-pyrazolo[3,4-c]pyridazine]-3-dithio-car-
◦
bamate (7b). Yield: 2.2 g (95%), mp > 300 C, IR: 3396 (NH), 1616 (C N.), 1112
(C S) cm−1
.
Ferous(II) Bis-N-[(4,5-diphenyl)-1H-pyrazolo[3,4-c]pyridazine]-3-dithio-
carbamate (7c). Yield: 2.0 g (87%), mp > 300 ◦C, IR: 3354 (NH), 1610 (C N.), 1116
(C S) cm−1
.
Cobalt(II) Bis-N-[(4,5-diphenyl)-1H-pyrazolo[3,4-c]pyridazine]-3-dithio-
carbamate (7d). Yield: 2.1 g (91%), mp > 300 ◦C, IR: 3446 (NH), 1620 (C N.), 1116
(C S) cm−1
.
Nickel(II) Bis-N-[(4,5-diphenyl)-1H-pyrazolo[3,4-c]pyridazine]-3-dithio-
carbamate (7e). Yield: 2.2 g (96%), mp > 300 ◦C, IR: 3468 (NH), 1606 (C N.), 1096
(C S) cm−1
.
3-Ethoxycarbonylamino-4,5-bis(4-chlorophenyl)-1H-pyrazolo
[3,4-c]-pyridazine (8)
A mixture of 3-amino derivative (6b) (1.0 g, 2.8 mmol) and ethyl chloroformate
(5 mL) was refluxed for 2 h. The cooled reaction mixture was poured onto water
(100 mL) and left overnight. The separated solid product was filtered, dried, and re-
◦
crystallized from ethanol to give 8. Yield: 0.81 g (68%), mp 230–231 C; IR: 3054
(CHarom.), 2903 (CHaliph.), 1738 (C O, ester), 728 (C-Cl) cm−1; MS = m/z (%): 428
(M+, 3.9), 427 (M+-H, 9.6), 357 (M+-CO2Et, 60), 355 (M+-2H, CO2Et, 100). Anal.
Calcd for C20H15Cl2N5O2: C, 56.09; H, 3.53; N, 16.35. Found: C, 55.80; H, 3.40; N,
16.10.

PYRIDAZINE DERIVATIVES AND RELATED COMPOUNDS
229
3-Triphenylphoranylideneamino-4,5-diphenyl-1H-pyrazolo[3,4-c]pyrid-azine
(12a)
To a solution of 3-azido-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (10) (0.3 g, 0.95
mmol) in ethanol (15 mL), triphenylphosphine (0.5 g, 1.9 mmol) was added. The reaction
mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated,
and the solid product was filtered, washed with cyclohexane, dried, and recrystallized from
ethanol to give 12a. Yield: 0.4 g (77%), mp 292–294 ◦C; IR: 3320 (NH), 3090 (CHarom.),
1601 (C N) cm−1; MS = m/z (%): 547 (M+, 87), 547 (M+-1, 68), 285 (M+-PPh3, 5.7).
Anal. Calcd for C35H26N5P: C, 76.77; H, 4.79; N, 12.79. Found: C, 76.50; H, 4.60; N,
12.10.
3-Trialkoxyphosphoranylideneamino-4,5-diphenyl-1H-pyrazolo
[3,4-c]-pyridazine (12b,c)
General procedure. A mixture of 3-azido derivative (10) (0.7 g, 2.85 mmol) and
trimethylphosphite or triethylphophite (2.5 mL) was stirred at room temperature for 1 h.
Nitrogen evolution started instantly, followed by precipitation of the product. The reaction
product was filtered, dried, and recrystallized from ethanol.
3-Trimethoxyphosphoranylideneamino Derivative (12b). Yield: 1.1 g
(94%), mp 143–144 ◦C; IR: 3445 (NH), 3059 (CHarom.), 2910 (CHaliph.), 1077 (P O C)
cm−1; MS = m/z (%): 409 (M+, 10), 368 (M+-CMe2, 14, ion A), 339 (ion A N2H, 3, ion
B), 257 (ion B HPO3H, 4.9). Anal. Calcd for C20H20N5O3P: C, 58.69; H, 4.93; N, 17.11.
Found: C, 58.60; H, 4.80; N, 17.00.
3-Triethoxyphosphoranylideneamino Derivative (12c). Yield: 2.2
g
(84.6%), mp 158–160 ◦C; IR: 3322 (NH), 3151 (CHarom.), 2909 (CHaliph.), 980 (P O C)
cm−1; MS = m/z (%): 451 (M+, 13), 315 (M+-()3, 14, ion A), 286 (ion A—P, 100). Anal.
Calcd for C23H26N5O3P: C, 61.19; H, 5.81; N, 15.52. Found: C, 61.00; H, 5.70; N, 15.40.
3-Chloroacetylamino-4,5-bis(4-chlorophenyl)-1H-pyrazolo[3,4-c]pyrid-azine
(13)
A mixture of 3-amino derivative (1b) (3.56 g, 10.0 mmol) and chloroacetylchloride
(20 mL) was refluxed for 30 min. The cooled reaction mixture was poured into water
(100 mL), then the precipitate was filtered off, dried, and recrystallized from ethanol to
give 13, 4.0 g (92.5%), mp 274–275 ◦C; IR: 3062 (CHarom.), 2972 (CHaliph.), 1665 (C O,
amide), 727 (C Cl) cm−1. Anal. Calcd for C19H12Cl3N5O: C, 52.74; H, 2.80; N, 16.19.
Found: C, 52.60; H, 2.70; N, 16.00.
3-Morpholinoacetylamino-4,5-bis(4-chlorophenyl)-1H-pyrazolo
[3,4-c]-pyridazine (14a)
A mixture of 3-chloroacetylamino derivative (13) (0.4 g, 0.92 mmol) and morpholine
(6 mL) was refluxed for 2 h. The cooled reaction mixture was poured into water (100 mL).
Upon acidification with hydrochloric acid, the precipitate that was obtained was filtered,
washed several times with water, dried, and recrystallized from benzene to give 14a,

230
A. DEEB ET AL.
4.0 g (83%), mp 238–240 ◦C; IR: 3315 (NH), 3029 (CHarom.), 2820 (CHaliph.), 1688 (C O,
amide) cm−1. MS = m/z (%): 483 (M+, 0.4), 397 (M+-N(CH2CH2)2O, 0.8, ion A), 354 (ion
A COCH2, 2.5). Anal. Calcd for C23H20Cl2N6O2: C, 57.15; H, 4.17; N, 17.39. Found: C,
57.00; H, 4.10; N, 17.30.
3-Piperidinoacetylamino-4,5-bis(4-chlorophenyl)-1H-pyrazolo
[3,4-c]-pyridazine (14b)
To a solution of 3-chloroacetylamino derivative (13) (0.4 g, 0.92 mmol) in ethanol
(20 mL), piperidine (0.26 g, 3.0 mmol) was added. The reaction mixture was refluxed
for 16 h. The solvent was evaporated under reduced pressure. Water (100 mL) was added
to the residue followed by a few drops of HCl. The precipitate was filtered, dried, and
recrystallized from benzene to give 14b, 0.4 g (85%), mp 263–264◦C; IR: 3087 (CHarom.),
2933 (CHaliph.), 1690 (C O, amide), 775 (C-Cl) cm−1. Anal. Calcd for C24H22Cl2N6O: C,
59.88; H, 4.59; N, 17.46. Found: C, 59.70; H, 4.50; N, 17.30.
Reaction of 3-Chloroacetylamino derivative (13) with Ethanolamine
A mixture of 3-chloroacetylamino derivative (13) (0.4 g, 0.92 mmol) and
ethanolamine (5 mL) was refluxed for 2 h. The cooled reaction mixture was poured
onto water (100 mL). The solid product was filtered, washed several times with water,
dried, and recrystallized from ethanol to give a product that was proven to be identical
with 3-amino-4,5-bis(chlorophenyl)-1H-pyrazolo[3,4-c]pyridazine (1b) (0.4 g, 88%), mp
249–250◦C.
3-(2-Imino-4-oxothiazol-3-yl)-4,5-bis(4-chlorophenyl)-1H-pyrazolo
[3,4-c]-pyridazine (15)
A suspension of 3-chloroacetylamino derivative (13) (1.7 g, 3.93 mmol) and potas-
sium thiocyanate (0.3 g, 4.0 mmol) in n-butanol (50 mL) was heated under reflux for 40 h.
The reaction mixture was concentrated to its half volume. After cooling, the precipitate
was separated, washed with water several times, dried, and recrystallized from ethanol to
give 15, 1.5 g (84%), mp > 300◦C; IR: 3073 (CHarom.), 2931 (CHaliph.), 2366 (NCS), 1711
(C O, amide), 767 (C Cl) cm−1; 1HNMR (DMSO-d6): δ 14.30 (s, 1H, NHCO), 11.74 (s,
1H, NH), 7.27-7.65 (m, 8H, 2Ar), 3.97 (s, 2H, CH2); MS = m/z (%): 454 (M+, 11), 343
(M+-ClC6H4, 5, ion A), 246 (ion A COCNCS, 18). Anal. Calcd for C20H12Cl2N6OS: C,
52.75; H, 2.66; N, 18.46. Found: C, 52.60; H, 2.60; N, 18.20.
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