Ring-chain transformation of 4-aroyl-5-phenylamino-2,3-dihydrothiophene-2,3-diones: Facile and efficient synthesis of novel pyrrolo[2,3-c]pyrazol-3(2H)-ones and 1,2-dihydro-5H,6H-pyridazine-5,6-diones

Article abstract of DOI:10.1080/17415993.2019.1702664

Seven, novel pyrrolo[2,3-c]pyrazol-3(2H)-one and 1,2-dihydro-5H,6H-pyridazine-5,6-dione chromophores were synthesized by the reaction of 4-aroyl-5-phenylamino-2,3-dihydrothiophene-2,3-diones with cyanoacetohydrazide and arylhydrazines such as phenylhydrazine and 4-nitrophenylhydrazine. These derivatives were characterized by elemental analysis, IR, UV-Visible, ¹H, ¹³C NMR and mass spectroscopy. Spectral characteristics of the compounds were studied in four organic solvents of differing polarity.

Full text of DOI:10.1080/17415993.2019.1702664

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: https://www.tandfonline.com/loi/gsrp20
Ring-chain transformation of 4-aroyl-5-
phenylamino-2,3-dihydrothiophene-2,3-
diones: Facile and efficient synthesis of novel
pyrrolo[2,3-c]pyrazol-3(2H)-ones and 1,2-
dihydro-5H,6H-pyridazine-5,6-diones
Pardis Hafez Taghva & Hassan Kabirifard
To cite this article: Pardis Hafez Taghva & Hassan Kabirifard (2019): Ring-chain transformation
of 4-aroyl-5-phenylamino-2,3-dihydrothiophene-2,3-diones: Facile and efficient synthesis of novel
pyrrolo[2,3-c]pyrazol-3(2H)-ones and 1,2-dihydro-5H,6H-pyridazine-5,6-diones, Journal of Sulfur
Chemistry, DOI: 10.1080/17415993.2019.1702664
To link to this article: https://doi.org/10.1080/17415993.2019.1702664
View supplementary material
Published online: 15 Dec 2019.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=gsrp20

JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2019.1702664
Ring-chain transformation of 4-aroyl-5-phenylamino-2,
3-dihydrothiophene-2,3-diones: Facile and efficient synthesis
of novel pyrrolo[2,3-c]pyrazol-3(2H)-ones and 1,2-dihydro
-5H,6H-pyridazine-5,6-diones
Pardis Hafez Taghva and Hassan Kabirifard
Department of Chemistry, Islamic Azad University, Tehran, Iran
ABSTRACT
ARTICLE HISTORY
Received 2 November 2019
Accepted 3 December 2019
Seven, novelpyrrolo[2,3-c]pyrazol-3(2H)-oneand1,2-dihydro-5H,6H-
pyridazine-5,6-dione chromophores were synthesized by the reac-
tion of 4-aroyl-5-phenylamino-2,3-dihydrothiophene-2,3-diones
with cyanoacetohydrazide and arylhydrazines such as phenylhy-
drazine and 4-nitrophenylhydrazine. These derivatives were charac-
terized by elemental analysis, IR, UV-Visible, 1H, 13C NMR and mass
spectroscopy. Spectral characteristics of the compounds were stud-
ied in four organic solvents of differing polarity.
KEYWORDS
Ring-chain transformation;
2,3-dihydrothiophene-2,3-
dione; cyanoacetohydrazide;
arylhydrazine; pyrrolo[2,3-
c]pyrazol-3(2H)-one;
1,2-dihydro-5H,6H-
pyridazine-5,6-dione
1. Introduction
Amino or amidopyrrolo[3,4-c]pyrazoles used as inhibitors of p21-activated kinases (PAKs)
[1–5] and pyrrolo[2,3-c]pyrazoles show antidepressant activity [6]. Diverse methods
for the synthesis of pyrrolo[2,3-c]pyrazoles [6,7], pyrrolo[3,2-c]pyrazoles [8,9] and
CONTACT Hassan Kabirifard
h_kabirifard@iau-tnb.ac.ir
Department of Chemistry, Islamic Azad University,
North Tehran Branch, Tehran, Iran
Supplemental data for this article can be accessed here. https://doi.org/10.1080/17415993.2019.1702664
© 2019 Informa UK Limited, trading as Taylor & Francis Group

2
P. HAFEZ TAGHVA AND H. KABIRIFARD
Scheme 1. Synthesis of pyrrolo[2,3-c]pyrazol-3(2H)-ones 2a-c and 1,2-dihydro-5H,6H-pyridazine-5,6-
diones 3a-d.
pyrrolo[3,4-c]pyrazoles [3,10] from polyfunctionalized pyrroles or pyrazoles have been
published. With regard to the behavior of cyanoacetohydrazide with different reagents for
the synthesis of heterocyclic compounds, the attack can take place at five possible sites: the
nucleophile is able to attack carbons of the carbonyl and nitrile functional groups, while
the active methylene and amino groups are able to attack electrophiles [11].
Pyridazines and fused pyridazines are important subclasses of diaza six membered het-
erocyclic compounds that have synthetic efficiency [12–16] and biological and pharmaco-
logical activities [17–21]. Customary methods for the synthesis of pyridazine frameworks
are based on the addition of hydrazine or its derivatives to appropriate 1,4-dicarbonyls
[22–28] and different types of [2 + 4] hetero-Diels-Alder cycloaddition [29–32]. Various
other methods for the synthesis of amino-pyridazines from polyfunctionalized nitriles,
especially via the Japp-Klingemann reaction [33,34], have resulted in formation of pyri-
dazines and pyridazinones in three-component reactions between active methylenes,
benzil and hydrazine [35,36].
4-Acylated-5-substituted 2,3-dihydrothiophene-2,3-diones are versatile and useful
starting materials or intermediates for the synthesis of various substituted heterocyclic
compounds [37–39]. Earlier we found that the reactions of 4-benzoyl-5-phenylamino-
2,3-dihydrothiophene-2,3-dione (1) with N,N-dinucleophiles such as 1-aminoguanidine,
guanidine, urea, 1,2-phenylenediamine and diaminomaleonitrile provided heterocyclic
compounds that have N-phenylthiocarbamoyl group [40,41]. In continuation of our stud-
ies on thiophene-2,3-dione 1 as a key starting material for the synthesis of the nitrogen-
containing heterocycles, we report herein the ring-chain transformation of compound 1
with cyanoacetohydrazide, phenylhydrazine and 4-nitrophenylhydrazine for the formation
of substituted pyrrolo[2,3-c]pyrazol-3(2H)-ones 2 and 1,2-dihydro-5H,6H-pyridazine-
5,6-diones 3 (Schemes 1).
2. Results and discussion
The condensation reaction of 4-aroyl-5-phenylamino-2,3-dihydrothiophene-2,3-diones
(1) with cyanoacetohydrazide and arylhydrazines such as phenylhydrazine and

JOURNAL OF SULFUR CHEMISTRY
3
4-nitrophenylhydrazine under reflux condition in glacial acetic acid, gave good yield
of pyrrolo[2,3-c]pyrazol-3(2H)-one 2 and 1,2-dihydro-5H,6H-pyridazine-5,6-dione 3
derivatives (Scheme 1).
The structures of the resulting compounds were determined based on elemental analysis
data and IR, 1H, 13CNMR and mass spectra. The IR spectra of 2a-c show five character-
istic absorption bands at 3428-3404, 1741-1740, 1635-1630, 1272-1270 and 753-752 cm−1
attributable to NH, amide C=O, ketone C =O, C-O and C-S functions, respectively. In
the 1H NMR spectra of 2a-c we have observed a broad singlet at δ 1.90 ppm for the SH
proton, a set of multiplet signals at δ 7.37–7.63 ppm for aromatic protons and two broad
singlet at δ 11.49–11.58 and 13.15–13.20 ppm for NH and OH protons. The 13C NMR
spectra of 2a-c revealed two signals at δ 96.22–96.41 (=C) and 155.82–157.21 (=CNH)
ppm for ethenyl, five signals at δ 121.28–121.31 (C3a), 152.49–152.58 (C5), 154.50–154.54
(C6a), 166.27–166.39 (C4) and 172.05–172.07 (C3 =O) ppm due to the carbons of the
pyrrolopyrazol, besides eight signals at δ 122.58–138.14 ppm attributable to the aromatic
carbons and a signal at δ 195.82–195.91 ppm for the ketonic carbon. The IR spectra of
3a-d revealed the characteristic absorption bands of NH, amide C=O, ketone C =O and
thioamide C-N, NH, C=S groups at 3070-3050, 1729-1719, 1643-1613, 1521-1507, 1349-
1330 and 1218-1211 cm−1, respectively. In the 1H NMR spectra of 3a-d we had observed
a set of multiplet signals at δ 7.35–8.67 ppm for aromatic protons. Their 13C NMR spec-
tra also showed four signals at δ 120.11–120.59 (C4), 156.87–157.28 (C3), 170.06–172.35
(C6 =O) and 184.02–184.96 (C5 =O) ppm due to the carbons of the pyridazine, besides
twelve signals at δ 124.81–148.59 ppm attributable to the aromatic carbons and a signal at
δ 188.27–189.30 ppm for the thioketonic carbon.
Since, pyrrolo[2,3-c]pyrazol-3(2H)-ones 2a-c and 1,2-dihydro-5H,6H-pyridazine-5,6-
diones 3a-d due to extended resonance can be used as a potentially useful fragment in
the design of dyes, the UV-Vis absorption spectroscopic behaviors of these compounds
have been investigated. The electronic transitions of molecules in solution can depend
strongly on the polarity of solvent. For this purpose, the electronic absorption spectra of
2a-c and 3a-d were measured in several organic solvents with different polarity (DMSO,
DMF, EtOAc and 1,4-dioxane) at room temperature and concentration about 10−4 M. The
wavelengths of maximum absorbance and molar extinction coefficients of 2a-c and 3a-d
compounds are reported in Table 1.
The UV-vis absorption spectra of pyrrolo[2,3-c]pyrazol-3(2H)-ones 2a-c and 1,2-
dihydro-5H,6H-pyridazine-5,6-diones 3a-d in mentioned solvents display mainly four and
three bands, respectively. The absorptions at 230–268 nm can be assigned to the moder-
ate energy transition of the aromatic ring as a π → π∗ excitation while absorptions at
282–321 and 345–391 nm are due to low energy transitions. The absorptions in the range
595–669 nm for 2a-c can be assigned to a highly extended n → π∗ intramolecular charge
transfer electronic transition of the azomethine chromophore (Table 1). It is found that the
absorption bands generally show bathochromic shifts (positive solvatochromism) as the
polarity of solvent was increased. As the data in Table 1 indicates the charge delocalization
in 2a-c are more extended than 3a-d. The more polar solvents can stabilize the LUMO
orbitals (π*) of 2a-c more than the HOMO orbitals (n) so the excitation energy decreases
with increasing solvent polarity.
The proposed mechanisms for the synthesis of pyrrolo[2,3-c]pyrazol-3(2H)-ones 2 and
1,2-dihydro-5H,6H-pyridazine-5,6-diones 3 are shown in Scheme 2. The nucleophilic

4
P. HAFEZ TAGHVA AND H. KABIRIFARD
Table 1. Absorption spectral data of 2a-c and 3a-d in various organic solvents; λmax/nm (ꢀ/dm3 mol−1
cm−1).
Compounds
DMSO
DMF
EtOAc
1,4-Dioxane
2a
267 (14,300)
319 (16,600)
368 (11,000)
640 (600)
265 (19,900)
317 (9400)
362 (8800)
638 (1500)
263 (7100)
309 (7500)
359 (5400)
595 (800)
263 (12,900)
307 (14,900)
357 (8700)
2b
2c
262 (22,000)
318 (22,000)
368 (14,600)
669 (900)
268 (31,400)
316 (33,400)
368 (20,900)
657 (1600)
251 (17,600)
300 (15,200)
359 (9900)
611 (900)
256 (26,100)
285 (27,800)
348 (14,800)
262 (11,300)
321 (11,000)
368 (8200)
669 (1000)
268 (17,200)
318 (17,400)
365 (13,200)
658 (1300)
264 (16,300)
299 (17,200)
360 (10,700)
626 (800)
259 (21,100)
287 (23,200)
345 (11,900)
3a
3b
3c
3d
251 (3100)
291 (6900)
388 (4000)
250 (6800)
284 (11,000)
386 (4800)
247 (6900)
284 (13,100)
382 (5800)
246 (7700)
282 (9700)
383 (3600)
240 (7400)
288 (15,200)
387 (5600)
230 (5600)
282 (16,900)
385 (4100)
234 (6600)
283 (13,300)
386 (4500)
234 (3500)
283 (9000)
383 (4100)
266 (16,700)
311 (34,200)
391 (25,200)
264 (21,100)
309 (31,500)
389 (25,400)
258 (16,300(
306 (28,000)
385 (15,000)
255 (12,800)
305 (21,700)
386 (11,900)
266 (19,100)
312 (29,000)
386 (15,100)
265 (24,000)
311 (32,100)
385 (17,300)
262 (18,000)
309 (32,700)
383 (14,600)
262 (24,500)
310 (33,100)
382 (23,200)
Scheme 2. Proposed mechanism for the synthesis of pyrrolo[2,3-c]pyrazol-3(2H)-ones 2 and 1,2-
dihydro-5H,6H-pyridazine-5,6-diones 3.
attack of the active methylene of cyanoacetohydrazide at the thioesteric carboxyl group
of the thiophene-2,3-dione 1 give intermediate hexanehydrazide Ia which then undergoes
two intramolecular cyclizations to afford product 2. While, the arylhydrazines cyclize by
nucleophilic attack at the γ -ketothioesteric fragment of thiophene-2,3-dione 1 to yield
product 3. In this reaction, the primary attack occurs at the thioesteric carboxyl group
of the compound 1 because intermediate butanehydrazide Ib at room temperature and
neutral media was isolated [40].

JOURNAL OF SULFUR CHEMISTRY
5
3. Conclusion
The synthesis and characterization of pyrrolo[2,3-c]pyrazol-3(2H)-one 2a-c and 1,2-
dihydro-5H,6H-pyridazine-5,6-dione 3a-d chromophores have been studied by reaction
4-aroyl-5-phenylamino-2,3-dihydrothiophene-2,3-diones (1) with cyanoacetohydrazide,
phenylhydrazine and 4-nitrophenylhydrazine. The solvatochromic behaviors of the pre-
pared compounds in various solvents were evaluated. The results indicated that the
UV-Visible spectra of these compounds were dependent on solvent polarity.
4. Experimental
4.1. General
The chemicals were purchased from Merck and used without further purification. Melting
points were measured with an Electrothermal 9100 apparatus and are uncorrected. Ele-
mental analyses were performed using a Heraeus CHN-O-Rapid analyzer. These results
agree favorably with the calculated values. Infrared spectra were measured from KBr
disk using Thermo Nicolet 8700 and Bruker Equinox 55 FT-IR spectrometers and fre-
1
quencies were reported in cm−1. H NMR and 13C NMR spectra were recorded on a
Bruker DRX-300 AVANCE at 300 and 75 MHz instrument using TMS as internal stan-
dard and DMSO-d6 as solvent. Chemical shifts and coupling constants were reported
in ppm and Hz, respectively. Thin-layer chromatography was performed on ‘Silufol-
UV 254’ plates. Mass spectra were obtained by using an Agilent HP 5973 mass spec-
trometer operating at an ionization potential of 70 eV. Electronic spectral measurements
were carried out using Varian Cary 100 double beam spectrophotometer in the range
200–800 nm.
4.2. Material
Ethyl 4-aryl-2,4-dioxobutanoates were prepared from diethyl oxalate (6.0 mmol) and 4ꢀ-
substituted acetophenone (4.0 mmol) in the presence of sodium ethoxide (8.4 mmol)
in absolute ethanol (30 mL) under N2 atmosphere [42]. 4-Aroyl-5-phenylamino-2,3-
dihydrothiophene-2,3-diones (1) were obtained by careful addition of phenyl isothio-
cyanate (10 mmol) to ethyl 4-aryl-2,4-dioxobutanoates (10 mmol) in KOH (10 mmol)
and DMF (20 mL) with stirring at room temperature for 24 h [43]. Cyanoacetohy-
drazide was obtained by addition of hydrazine hydrate (10 mmol) to ethyl cyanoac-
etate (10 mmol) in ethanol (5 mL) and putting the resultant mixture in freezer for
10 min [36].
4.3. General procedure for the synthesis of pyrrolo[2,3-c]pyrazol-3(2H)-ones 2a-c
and 1,2-dihydro-5H,6H-pyridazine-5,6-diones 3a-d
To a stirred solution of compound 1 (1.0 mmol) in glacial acetic acid (10 mL) each
of the cyanoacetohydrazide, phenylhydrazine hydrochloride and 4-nitrophenylhydrazine
(1.0 mmol) together anhydrous sodium acetate (0.164 g, 2.0 mmol for salts) was added. The
reaction mixture was then refluxed for 4 h. The progress of the reaction was monitored by

6
P. HAFEZ TAGHVA AND H. KABIRIFARD
TLC (eluent AcOEt/hexane 2:1). The solvent was evaporated and the resulting solid was
crystallized from ethanol for 2a-c, 3c,d and 2-propanol for 3a,b and dried in air.
4.3.1. 4-Hydroxy-5-((E)-1-mercapto-3-oxo-3-phenyl-1-(phenylamino)propenyl)
pyrrolo[2,3-c]pyrazol-3(2H)-one (2a)
Dark goldenrod powder; yield: 0.25 g (63%); m.p.: 330-332°C. IR (KBr): ν¯ = 3404 (NH),
1740 (C=O, amide), 1634 (C=O, ketone), 1577 (NH), 1272 (C-O), 753 (C-S) cm−1. 1H
NMR (DMSO-d6): δ = 1.90 (1H, br s, SH), 7.37 (2H, d, J = 7.5 Hz, 2CHortho of Ph-NH),
7.41–7.53 (6H, m, 2Ph), 7.58 (2H, d, J = 7.1 Hz, CHortho of Ph-CO), 11.58, 13.15 (2H, 2br s,
NH and OH), NH proton is missing in spectrum. 13C NMR (DMSO-d6): δ = 96.22 (=C),
121.29 (C3a), 127.44, 128.87, 128.97, 129.33, 129.66, 132.22 (10C, 2Ph), 134.03 (Cipso of Ph-
CO), 138.14 (Cipso of Ph-NH), 152.58 (C5), 154.50 (C6a), 157.21 (=CNH), 166.39 (C4),
172.05 (C3 =O, amide), 195.91 (C=O, ketone) ppm. EI-MS: m/z (%) = 390 (3), 371 (42),
339 (10), 186 (3), 166 (3), 142 (20), 111 (19), 85 (39), 77 (30), 57 (100). Anal. Calcd for
C20H14N4O3S (390.42): C, 61.53%; H, 3.61%; N, 14.35%; found: C, 61.81%; H, 3.38%; N,
14.08%.
4.3.2. 5-((E)-3-(4-Chlorophenyl)-1-mercapto-3-oxo-1-(phenylamino)propenyl)-4-hyd
roxypyrrolo[2,3-c]pyrazol-3(2H)-one (2b)
Goldenrod powder; yield: 0.28 g (67%); m.p.: 305–307°C. IR (KBr): ν¯ = 3428 (NH), 1741
1
(C=O, amide), 1636 (C=O, ketone), 1596 (NH), 1271 (C-O), 752 (C-S) cm−1. H
NMR (DMSO-d6): δ = 1.90 (1H, br s, SH), 7.37 (2H, d, J = 7.4 Hz, 2CHortho of Ph-NH),
7.43–7.54 (5H, m, 2Ph), 7.62 (2H, d, J = 7.6 Hz, CHortho of Ph-CO), 11.49, 13.16 (2H,
2br s, NH and OH), NH proton is missing in spectrum. 13C NMR (DMSO-d6): δ = 96.41
(=C), 121.31 (C3a), 127.58, 128.92, 129.31, 131.64, 132.25 (9C, 2Ph), 133.84 (Cipso of Ph-
Cl), 133.97 (Cipso of Ph-CO), 136.97 (Cipso of Ph-NH), 152.50 (C5), 154.54 (C6a), 155.82
(=CNH), 166.30 (C4), 172.07 (C3 =O, amide), 195.84 (C=O, ketone) ppm. EI-MS: m/z
(%) = 426 (M·++2, 8), 424 (M·+, 21), 406 (100), 371 (13), 185 (6), 166 (11), 107 (19), 77
(66), 51 (30). Anal. Calcd for C20H13ClN4O3S (424.86): C, 56.54%; H, 3.08%; N, 13.19%;
found: C, 56.31%; H, 3.35%; N, 13.46%.
4.3.3. 5-((E)-3-(4-Bromophenyl)-1-mercapto-3-oxo-1-(phenylamino)propenyl)-4-hyd
roxypyrrolo[2,3-c]pyrazol-3(2H)-one (2c)
Light goldenrod powder; yield: 0.34 g (73%); m.p.: 323–325°C. IR (KBr): ν¯ = 3420, 3209
(NH), 1740 (C=O, amide), 1635 (C=O, ketone), 1592 (NH), 1270 (C-O), 752 (C-S)
cm−1. 1H NMR (DMSO-d6): δ = 7.37 (2H, d, J = 6.8 Hz, 2CHortho of Ph-NH), 7.43–7.57
(5H, m, 2Ph), 7.63 (2H, d, J = 8.4 Hz, CHortho of Ph-CO), 11.52, 13.20 (2H, 2br s, NH
and OH), SH and NH protons are missing in spectrum. 13C NMR (DMSO-d6): δ = 96.40
(=C), 121.28 (C3a), 122.58, 128.90, 129.29, 130.47, 131.88, 132.24 (10C, 2Ph), 133.95
(Cipso of Ph-CO), 137.33 (Cipso of Ph-NH), 152.49 (C5), 154.52 (C6a), 155.83 (=CNH),
166.27 (C4), 172.05 (C3 =O, amide), 195.82 (C=O, ketone) ppm. EI-MS: m/z (%) = 470
(M·++2, 18), 468 (M·+, 19), 451 (75), 371 (80), 185 (10), 166 (16), 107 (22), 77 (100), 51
(44). Anal. Calcd for C20H13BrN4O3S (469.31): C, 51.18%; H, 2.79%; N, 11.94%; found: C,
51.44%; H, 3.02%; N, 11.71%.

JOURNAL OF SULFUR CHEMISTRY
7
4.3.4. 5,6-Dioxo-N,2,3-triphenyl-1,2,5,6-tetrahydropyridazine-4-carbothioamide (3a)
Orange ochre cotton-like solid; yield: 0.28 g (71%); m.p.: 189–191°C. IR (KBr): ν¯ = 3438,
3070 (NH), 1719 (C=O, amide), 1640 (C=O, ketone), 1595 (NH), 1510, 1349, 1218 (C-
1
3
N, NH, C=S, thioamide) cm−1. H NMR (CDCl3): δ = 7.36 (2H, dd, J = 7.9 Hz and
4J = 1.3 Hz, 2CHortho of Ph-NH), 7.42–7.58 (10H, m, 3Ph, NH), 8.36 (2H, d, 3J = 8.1 Hz,
2CHortho of Ph-2-pyridazine), 8.52 (2H, dd, 3J = 6.5 Hz and 4J = 3.1 Hz, 2CHortho of Ph-
3-pyridazine), NH proton is missing in spectrum. 13C NMR (CDCl3): δ = 120.37 (C4),
128.27, 128.39, 128.66, 128.86, 129.14, 129.22, 129.49, 129.99, 130.22, (15C, 3Ph), 133.66
(Cipso of Ph-3-pyridazine), 138.01 (Cipso of Ph-NH), 148.59 (Cipso of Ph-2-pyridazine),
157.28 (C3), 170.06 (C6 =O), 184.96 (C5 =O), 189.30 (C=S) ppm. EI-MS: m/z (%) = 399
(8), 381 (16), 335 (7), 272 (10), 218 (42), 105 (8), 77 (100), 51 (24). Anal. Calcd for
C23H17N3O2S (399.46): C, 69.15%; H, 4.29%; N, 10.52%; found: C, 68.96%; H, 4.48%; N,
10.35%.
4.3.5. 3-(4-Chlorophenyl)-5,6-dioxo-N,2-diphenyl-1,2,5,6-tetrahydropyridazine-4-car
bothioamide (3b)
Pale orange ochre cotton-like solid; yield: 0.31 g (74%); m.p.: 242–244°C. IR (KBr): ν¯ =
3061 (NH), 1719 (C=O, amide), 1643 (C=O, ketone), 1592 (NH), 1510, 1344, 1211 (C-
N, NH, C=S, thioamide) cm−1. 1H NMR (CDCl3): δ = 7.36 (2H, d, J = 6.7 Hz, 2CHortho
of Ph-NH), 7.47–7.59 (8H, m, 3Ph), 8.35 (2H, d, J = 7.9 Hz, 2CHortho of Ph-2-pyridazine),
8.51 (2H, d, J = 8.4 Hz, 2CHortho of Ph-3-pyridazine), 2NH protons are missing in spec-
trum. 13C NMR (CDCl3): δ = 120.39 (C4), 128.46, 128.64, 128.81, 129.14, 129.23, 129.52,
129.81, 130.02 (14C, 3Ph), 133.53 (Cipso of Ph-3-pyridazine), 136.09 (Cipso of Ph-Cl),
137.92 (Cipso of Ph-NH), 147.51 (Cipso of Ph-2-pyridazine), 157.16 (C3), 170.06 (C6 =O),
184.02 (C5 =O), 189.21 (C=S) ppm. EI-MS: m/z (%) = 419 (M·++2, 18), 417 (M·+,
52), 386 (4), 306 (7), 218 (100), 105 (8), 77 (79), 51 (22). Anal. Calcd for C23H16ClN3OS
(417.91): C, 66.10%; H, 3.86%; N, 10.05%; found: C, 66.34%; H, 3.65%; N, 10.24%.
4.3.6. 2-(4-Nitrophenyl)-5,6-dioxo-N,3-diphenyl-1,2,5,6-tetrahydropyridazine-4-car
bothioamide (3c)
Goldenrod cotton-like solid; yield: 0.27 g (61%); m.p.: 267–269°C. IR (KBr): ν¯ = 3050
(NH), 1725 (C=O, amide), 1613 (C=O, ketone), 1595 (NH), 1521, 1340, 1217 (C-N,
1
3
NH, C=S, thioamide) cm−1. H NMR (CDCl3): δ = 7.35 (2H, dd, J = 6.3 Hz and
4J = 1.9 Hz, 2CHortho of Ph-NH), 7.50–7.61 (6H, m, 2Ph), 8.43 (2H, d, J = 9.3 Hz,
3
2CHortho of Ph-2-pyridazine), 8.48 (2H, dd, 3J = 6.8 Hz and 4J = 2.9 Hz, 2CHortho of Ph-
3-pyridazine), 8.67 (2H, d, J = 9.3 Hz, 2CHortho of Ph-NO2), 2NH protons are missing
in spectrum. 13C NMR (CDCl3): δ = 120.11 (C4), 124.81, 127.62, 128.07, 128.65, 128.84,
129.20, 129.36, 130.27 (14C, 3Ph), 132.89 (Cipso of Ph-3-pyridazine), 139.34 (Cipso of Ph-
NH), 141.99 (Cipso of Ph-NO2), 146.47 (Cipso of Ph-2-pyridazine), 156.87 (C3), 171.23
(C6 =O), 184.95 (C5 =O), 188.27 (C=S) ppm. EI-MS: m/z (%) = 444 (8), 426 (70), 405
(14), 263 (100), 216 (22), 114 (33), 77 (52), 51 (15). Anal. Calcd for C23H16N4O4S (444.46):
C, 62.15%; H, 3.63%; N, 12.61%; found: C, 62.41%; H, 3.37%; N, 12.89%.
4.3.7. 3-(4-Bromophenyl)-2-(4-nitrophenyl)-5,6-dioxo-N-phenyl-1,2,5,6-tetrahydro
pyridazine-4-carbothioamide (3d)
Brick red powder; yield: 0.34 g (65%); m.p.: 244–246°C. IR (KBr): ν¯ = 3062 (NH), 1729
(C=O, amide), 1640 (C=O, ketone), 1591 (NH), 1507, 1330, 1211 (C-N, NH, C=S,

8
P. HAFEZ TAGHVA AND H. KABIRIFARD
1
3
4
thioamide) cm−1. H NMR (CDCl3): δ = 7.36 (2H, dd, J = 6.1 Hz and J = 1.9 Hz,
2CHortho of Ph-NH), 7.52–7.63 (5H, m, 2Ph), 7.67 (2H, d, J = 7.5 Hz, 2CHortho of Ph-Br),
8.41 (2H, d, J = 7.6 Hz, 2CHortho of Ph-2-pyridazine), 8.44 (2H, d, J = 7.5 Hz, 2CHortho of
Ph-3-pyridazine), 8.66 (2H, d, J = 7.6 Hz, 2CHortho of Ph-NO2), 2NH protons are missing
in spectrum. 13C NMR (CDCl3): δ = 120.59 (C4), 125.12, 125.32, 128.22, 129.06, 129.32,
129.54, 129.92, 131.79 (14C, 3Ph), 133.22 (Cipso of Ph-3-pyridazine), 139.21 (Cipso of Ph-
NH), 142.27 (Cipso of Ph-NO2), 147.00 (Cipso of Ph-2-pyridazine), 157.16 (C3), 172.35
(C6 =O), 184.18 (C5 =O), 188.56 (C=S) ppm. EI-MS: m/z (%) = 524 (M·++2, 33),
522 (M·+, 34), 506 (30), 263 (100), 217 (11), 114 (28), 77 (42), 57 (20). Anal. Calcd for
C23H15BrN4O4S (523.36): C, 52.78%; H, 2.89%; N, 10.71%; found: C, 52.60%; H, 3.07%;
N, 10.96%.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Hassan Kabirifard http://orcid.org/0000-0003-2680-8051
References
[1] Rudolph J, Crawford JJ, Hoeflich KP, et al. Inhibitors of p21-activated kinases (PAKs). J Med
Chem. 2015;58(1):111–129.
[2] Grant S, Tran P, Zhang Q, et al. Discovery of a novel class of targeted kinase inhibitors that
blocks protein kinase C signaling and ameliorates retinal vascular leakage in a diabetic rat
model. Eur J Pharmacol. 2010;627(1-3):16–25.
[3] Li H, Hong Y, Nukui S, et al. Identification of novel pyrrolopyrazoles as protein kinase C b II
inhibitors. Bioorg Med Chem Lett. 2011;21(1):584–587.
[4] Guo C, McAlpine I, Zhang J, et al. Discovery of pyrroloaminopyrazoles as novel PAK inhibitors.
J Med Chem. 2012;55(10):4728–4739.
[5] Canevari G, Re Depaolini S, Cucchi U, et al. Structural insight into maternal embryonic leucine
zipper kinase (MELK) conformation and inhibition toward structure-based drug design.
Biochemistry. 2013;52(37):6380–6387.
[6] Fatahala SS, Nofal S, Mahmoud E, et al. Pyrrolopyrazoles; synthesis, evaluation and pharma-
cological screening as antidepressant agents. Med Chem. 2018;14:1–12.
[7] Abdelrazek FM, Erian AW, Hilmy KMH. Nitriles in heterocyclic synthesis. A novel synthesis
of 4-phenacylpyrazole and pyrrolo[2,3-c]pyrazole derivatives. Synthesis. 1986;(1):74–75.
[8] Nayak M, Batchu H, Batra S. Straightforward copper-catalyzed synthesis of pyrrolopyrazoles
from halogenated pyrazolecarbaldehydes. Tetrahedron Lett. 2012;53(32):4206–4208.
[9] Fahmy HM, Sharaf ME, Aboutabl MA, et al. A novel electro-organic synthesis of pyrrolopyra-
zole derivatives. J Chem Soc Perkin Trans 2. 1990;(9):1607–1613.
[10] Ead HA, Hassaneen HM, Abdallah MA. Synthesis and biological activities of some pyrrolopy-
razoles and 2-pyrazolines. Arch Pharm (Weitzheinz. 1991;324(1):35–37.
[11] Bondock S, Tarhoni AE-G, Fadda AA. Utility of cyanoacetic acid hydrazide in heterocyclic
synthesis. ARKIVOC. 2006;(ix):113–156.
[12] Coates WJ. Pyridazines and their benzo derivatives. In: Katritzky AR, Rees CW, Scriven EFV,
editor. In comprehensive heterocyclic chemistry II. Oxford: Pergamon; 1996. p. 1–91.
[13] Kolar P, Tišler M. Recent advances in the chemistry of pyridazines. In: Alan RK, editor.
Advances in heterocyclic chemistry. Vol. 75. New York: Academic Press; 1999. p. 167–241.
[14] Mátyus P, Maes BUW, Riedl Z, et al. New pathways towards pyridazino-fused ring systems.
Synlett. 2004;(7):1123–1139.

JOURNAL OF SULFUR CHEMISTRY
9
[15] Groziak MP. Six-membered ring systems: Diazines and benzo derivatives. In: Gribble GW,
Joule JA, editor. In progress in heterocyclic chemistry. Vol. 16. Oxford: Elsevier; 2005. p.
347–384.
[16] Haider N, Holzer W. Product Class 8: pyridazines. In: Yamamoto Y, editor. Science of synthe-
sis: Houben-Weyl methods of molecular transformations. Vol. 16. Stuttgart: Thieme; 2004. p.
125–313.
[17] Katrusiak A, Katrusiak A, Bałoniak S. Reactivity of 6-chloro-4- and 5-hydrazino-2-phenyl-
3(2H)-pyridazinones with Vilsmeier reagent. Tetrahedron. 1994;50(45):12933–12940.
[18] Giovannoni MP, Vergelli C, Ghelardini C, et al. [(3-chlorophenyl)piperazinylpropyl]pyrida-
zinones and analogues as potent antinociceptive agents. J Med Chem. 2003;46(6):1055–1059.
[19] Chintakunta VK, Akella V, Vedula MS, et al. 3-O-Substituted benzyl pyridazinone derivatives
as COX inhibitors. Eur J Med Chem. 2002;37(4):339–347.
[20] Rathish IG, Javed K, Bano S, et al. Synthesis and blood glucose lowering effect of novel pyridazi-
none substituted benzenesulfonylurea derivatives. Eur J Med Chem. 2009;44(6):2673–2678.
[21] Barbaro R, Betti L, Botta M, et al. Synthesis, biological evaluation, and pharmacophore gener-
ation of new pyridazinone derivatives with affinity toward α - and α -adrenoceptors. J Med
1
2
Chem. 2001;44(13):2118–2132.
[22] Fokin AS, Burgart YV, Saloutin VI, et al. Unexpected formation of pyridazine-5,6-dione
derivatives in the reactions of 3-arylhydrazono-2,4-dioxo-4-pentafluorophenylbutanoates
with hydrazines. Mendeleev Commun. 2005;15(6):252–253.
[23] Altomare C, Cellamare S, Summo L, et al. Inhibition of monoamine oxidase-b by condensed
pyridazines and pyrimidines: Effects of lipophilicity and structure-activity relationships. J Med
Chem. 1998;41:3812–3820.
[24] Ghelli S, Paola Costi M, Toma L, et al. Structures and reactivities of 1-oxo-cycloalkan-
2-ylideneacetic acids. A 1HNMR, modelling and photochemical study. Tetrahedron.
2000;56(38):7561–7571.
[25] Yoshida N, Awano K, Kobayashi T, et al. A short and efficient synthesis of a chiral pyridazinone
derivative by the chiral-pool method. Synthesis. 2004;10:1554–1556.
[26] Minetto G, Lampariello LR, Taddei M. Microwave-assisted synthesis of polysubstitutedpyri-
dazines. Synlett. 2005;18:2743–2746.
[27] Marriner GA, Garner SA, Jang H-Y, et al. Metallo-aldehyde enolates via enal hydrogenation:
Catalytic cross aldolization with glyoxal partners as applied to the synthesis of 3,5-disubstituted
pyridazines. J Org Chem. 2004;69(4):1380–1382.
[28] McIntyre CJ, Ponticello GS, Liverton NJ, et al. Pyridazinebased inhibitors of p38 MAPK. Bioorg
Med Chem Lett. 2002;12:689–692.
[29] Attanasi OA, Filippone P, Fiorucci C, et al. Reaction of some 1,2-diaza-1,3-butadienes with
activated methine compounds. A straightforward entry to 1,4-dihydropyridazine, pyridazine,
and 4,5(4H,5H)-cyclopropylpyrazole derivatives. J Org Chem. 1998;63(26):9880–9887.
[30] Attanasi OA, Filippone P, Fiorucci C, et al. Novel and convenient synthesis of 1,4-
dihydropyridazines and pyridazines from aminocarbonylazoalkenes. Synlett. 1997;12:
1361–1362.
[31] Rossi E, Abbiati G, Attanasi OA, et al. Divergent and solvent dependent reactions of 4-
ethoxycarbonyl-3-methyl-1-tert-butoxycarbonyl-1,2-diaza-1,3-diene with enamines. Tetrahe-
dron. 2007;63(45):11055–11065.
[32] South MS. Novel cyclization reactions of mono- and dichloroazodienes. A new synthesis of
substituted pyridazines. J Heterocycl Chem. 1999;36(2):301–319.
[33] Ibrahim NS, Galil FMA, Abdel-Motaleb RM, et al. Nitriles in heterocyclic synthesis: novel
synthesis of pyridazine derivatives. Heterocycles. 1986;24(5):1219–1222.
[34] Heinisch G, Holzer W, Nawwar GAM. Pyridazines. XXVI. A novel synthesis of pyrano[2,3-
d]pyridazines. J Heterocycl Chem. 1986;23(1):93–96.
[35] Zohreh N, Alizadeh A. Uncatalyzed one-pot synthesis of highly substituted pyridazines and
pyrazoline-spirooxindoles via domino SN/condensation/aza-ene addition cyclization reaction
sequence. ACS Comb Sci. 2013;15(6):278–286.

10
P. HAFEZ TAGHVA AND H. KABIRIFARD
[36] Singh P, Kumar R, Yadav BK, et al. CCSO nano catalyzed solid phase synthesis of 3-oxo-5,6-
disubstituted-2,3-dihydropyridazine-4-carbonitrile. RSC Adv. 2014;4:51239–51243.
[37] Brown DJ. Quinoxalines: Supplement II, the chemistry of heterocyclic compounds. Hoboken:
Wiley; 2004.
[38] Terpetschnig E, Ott W, Kollenz G, et al. Reaktionen mit cyclischen oxalylverbindungen, 26.
Mitt. cyclokondensation von 4,5-substituierten thiophen- bzw. N-alkylpyrrol-2,3-dionen mit
o-phenylendiamin. Monatsh Chem. 1988;119(3):367–378.
[39] Onal A, Akcamur Y, Altural B. Synthesis of some pyrazolo-pyridazine compounds. Turk J
Chem. 1996;20:159–163.
[40] Kabirifard H, Akbari S, Mousavi N, et al. Synthesis of 3-N-Phenylthiocarbamoyl-2-
butenamides from 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione in aqueous
medium at room temperature. Lett Org Chem. 2017;14(7):503–509.
[41] Moloudi M, Kabirifard H, Kabirifard R, et al. Reactions of 4-benzoyl-5-phenylamino-2,3-
dihydrothiophene-2,3-dione and diaminomaleonitrile in the presence of alcohols as reactant
and solvent. J Sulfur Chem. 2017;38:347–356.
[42] Çalışkan B, Sinoplu E, İbiş K, et al. Synthesis and cellular bioactivities of novel isoxazole deriva-
tives incorporating an arylpiperazine moiety as anticancer agents. J Enzyme Inhib Med Chem.
2018;33(1):1352–1361.
[43] Kabirifard H, Ghahremani S, Afsharpoor A. A simple and versatile protocol for the preparation
of functionalized heterocycles utilizing 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-
dione. J Sulfur Chem. 2015;36:591–605.