New potential fungicides pyrazole-based heterocycles derived from 2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl) acryloyl isothiocyanate

Article abstract of DOI:10.1080/17415993.2021.1909591

New series of pyrazole-based heterocyclic systems were synthesized using 2-cyanopropenoyl isothiocyanate derivative as an intermediate through treating with some nucleophilic reagents. Therefore, derivatives of carbamothioate, acylthiourea, pyrimidinethione, benzothiazole, triazolopyrimidine, pyrimidobenzothiazine, and pyrimidothiadiazepine were obtained. Structures of the obtained compounds were elucidated according to their elemental analyses and compatible spectral data. The fungicidal activity of the title compounds was evaluated against five plant pathogens belonging to both airborne and soil-borne strains using the radial growth rate method and the pyrazole derivative 13 was the most potent one that showed better fungicidal activity against F. Solani and R. Solani soil-borne fungi than the standard fungicide and moderate activity against airborne fungi. Also, pyrazole derivative 16 displayed better activity than the two standard fungicides against B. cinerea airborne fungus. Both A. Alternata and S. Sclerotiorum airborne fungi showed more resistance to the new pyrazoles than the standard fungicides. This means, fungicidal activity of the synthesized pyrazoles is remarkably diversified and affected by the heterocyclic ring or functional group attached to the core pyrazole.

Full text of DOI:10.1080/17415993.2021.1909591

Journal of Sulfur Chemistry
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New potential fungicides pyrazole-based
heterocycles derived from 2-cyano-3-(1,3-
diphenyl-1H-pyrazol-4-yl) acryloyl isothiocyanate
Sayed K. Ramadan, Nasser A. Ibrahim, Sarah A. El-Kaed & Eman A. E. El-Helw
To cite this article: Sayed K. Ramadan, Nasser A. Ibrahim, Sarah A. El-Kaed & Eman A.
E. El-Helw (2021): New potential fungicides pyrazole-based heterocycles derived from 2-
cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl) acryloyl isothiocyanate, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2021.1909591
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JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2021.1909591
New potential fungicides pyrazole-based heterocycles
derived from 2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)
acryloyl isothiocyanate
a
Sayed K. Ramadan a, Nasser A. Ibrahimb, Sarah A. El-Kaedc and Eman A. E. El-Helw
aDepartment of Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt; bCentral Agr. Pest. Lab.,
Agricultural Research Center (ARC), Dokki, Egypt; cCentral Lab. of Organic Agriculture, Agricultural Research
Center (ARC), Giza, Egypt
ABSTRACT
ARTICLE HISTORY
Received 8 February 2021
Accepted 23 March 2021
New series of pyrazole-based heterocyclic systems were synthesized
using 2-cyanopropenoyl isothiocyanate derivative as an intermedi-
ate through treating with some nucleophilic reagents. Therefore,
derivatives of carbamothioate, acylthiourea, pyrimidinethione, ben-
zothiazole, triazolopyrimidine, pyrimidobenzothiazine, and pyrim-
idothiadiazepine were obtained. Structures of the obtained com-
pounds were elucidated according to their elemental analyses and
compatible spectral data. The fungicidal activity of the title com-
pounds was evaluated against five plant pathogens belonging
to both airborne and soil-borne strains using the radial growth
rate method and the pyrazole derivative 13 was the most potent
one that showed better fungicidal activity against F. Solani and R.
Solani soil-borne fungi than the standard fungicide and moder-
ate activity against airborne fungi. Also, pyrazole derivative 16 dis-
played better activity than the two standard fungicides against B.
cinerea airborne fungus. Both A. Alternata and S. Sclerotiorum air-
borne fungi showed more resistance to the new pyrazoles than the
standard fungicides. This means, fungicidal activity of the synthe-
sized pyrazoles is remarkably diversified and affected by the het-
erocyclic ring or functional group attached to the core pyrazole.
KEYWORDS
Propenoyl isothiocyanate;
pyrimidinethione;
pyrimidothiadiazepine;
fungicidal activity; airborne
and soil-borne fungi
CONTACT Sayed K. Ramadan
sayed.karam2008@sci.asu.edu.eg
Department of Chemistry, Faculty of Science,
Ain Shams University, Cairo 11566, Egypt
Supplemental data for this article can be accessed here. https://doi.org/10.1080/17415993.2021.1909591
© 2021 Informa UK Limited, trading as Taylor & Francis Group

2
S. K. RAMADAN ET AL.
Introduction
Aroyl isothiocyanates have been extensively transformed into various nitrogen het-
erocycles in addition to thiosemicarbazide derivatives.[1–3] Also, owing to the
diverse chemotherapeutic effects, pyrazole tethered heterocycles have received great
attention.[4–16] As a result, many pharmaceutical and agrochemical active pyrazole
derivatives were published (cf. Figure 1).[11,17–27] Otherwise, fungal diseases attacking
plants are a serious problem worldwide due to their severe effect on crop quality and
yield. About 16% of annual crop losses due to plant microbial diseases, fungal diseases
represent 70-80% of these losses.[28,29] Enthused by these fascinating results and in con-
tinuation of our work on the pharmacological as well as agrochemical active heterocyclic
systems,[30–37] 2-cyano-3-pyrazolylpropenoyl isothiocyanate derivative 2 was utilized as
a key material for the synthesis of acylthiourea, pyrimidinethione, benzothiazole, tria-
zolopyrimidine, and pyrimidothiadiazepine derivatives integrated with the core pyrazole,
to may enhance its expected biological effect through the coexistence of more than one
pharmacophore. Our strategy aimed to design new pyrazole derivatives that may have bet-
ter fungicidal activity than the commercially applied fungicides that showed some resistant
problems.[38]
Results and discussion
Chemistry
Herein, the key material, 2-cyano-3-pyrazolylpropenoyl chloride derivative 1 [6,7] was
treated with ammonium thiocyanate in dry acetonitrile to produce the corresponding
isothiocyanate derivative 2 (Scheme 1). Treatment of 2 with ethanol or aminoacetic acid in

JOURNAL OF SULFUR CHEMISTRY
3
Figure 1. Some agrochemical pyrazole-based molecules.
boiling acetonitrile achieved carbamothioate and acylthiourea derivatives 3 and 4, respec-
tively (Scheme 1). IR spectrum of 3 disclosed the following bands: 3399 (NH), 2204
(C≡N), 1721 (C = O). Its 1H NMR spectrum (DMSO-d6) revealed singlet signals for NH
at δ 12.05 ppm, C5-H pyrazole at δ 9.16 ppm, the olefinic proton at δ 8.09 ppm, and quar-
tet signal for CH2 protons at δ 3.44 ppm (J = 6.9 Hz), triplet signal for CH3 protons at δ
1.06 ppm (J = 6.9 Hz), in addition to the aromatic protons at δ ∼ 8.04-7.45 ppm. IR spec-
trum of 4 displayed the absorption bands for OH, NH groups at ν 3462, 3316, 3155 cm−1
,
C≡N at ν 2225 cm−1, C = O acid at ν 1703cm−1, and C = O amide at ν 1670 cm−1. Fur-
1
ther, its H NMR spectrum supported its structure as it provided the following signals:
13.50 (br.s, 1H, COOH, exchangeable), 11.29 (br.s, 1H, NH, exchangeable), 9.60 (br.s, 1H,
NH, exchangeable), 9.17 (s, 1H, C5-H pyrazole), 8.22 (s, 1H, CH=), 8.09-7.36 (m, 10H,
Ar-H), 4.40 (s, 2H, CH2). On contrary, the interaction of 2 with benzylamine at ambi-
ent temperature furnished the acylthiourea derivative 5 in a good yield while at boiling
conditions, the pyrimidinethione derivative 6 was acquired as a mixture of cis and trans
isomers in a ratio of 1:1. Chromatography and recrystallization of the mixture obtained of
cis- and trans-isomers were not successful for their separation. IR spectrum of 5 displayed
the bands for NH, C≡N, C = O, and C = S groups at ν 3286, 2217, 1715, and 1231 cm−1
,
respectively. Further support for its structure was the 1H NMR spectrum as it exhibited a
singlet signal for methylene protons at δ 4.04 ppm, a singlet signal for C5-H pyrazole at
δ 9.06 ppm, a singlet signal for olefinic proton at δ 7.92 ppm, and an exchangeable singlet
signal at δ 8.50 ppm integrated to two protons corresponding to two NH protons, as well as
multiplet signals for the aromatic protons. The 1H NMR spectrum of 6 displayed a singlet

4
S. K. RAMADAN ET AL.
Scheme 1. Synthesis of compounds 3-7.
Scheme 2. Synthesis of compounds 8-12.
signal for the methylene protons at δ 4.84 ppm, two doublet signals for CHa, and two dou-
blet signals for CHb. Formation of pyrimidinethione derivative 6 can be extrapolated by
1,6-endo-trig cyclization of 5 via aza-Michael addition on the activated β-carbon. In a
similar manner, pyrimidinethione derivative 7 was furnished as a mixture of cis and trans
isomers in a ratio of 1:1, upon conducting 2 with 4-aminoacetophenone. Ample evidence
1
for the assigned structure of 7 was its H NMR spectrum which exhibited two doublet
signals for vicinal CH–CH protons (cf. Experimental).
Treatment of 2 with 2-aminobenzoic acid afforded a mixture of pyrimidinethione
derivative 8 and acylthiourea derivative 9 which were separated by the fractional recrystal-
lization (cf. Experimental). The 1H NMR spectrum of 8 lacked the olefinic singlet which
was conserved in compound 9. Refluxing the latter in acetic anhydride failed to produce

JOURNAL OF SULFUR CHEMISTRY
5
Scheme 3. Synthesis of compounds 13-17.
Scheme 4. A plausible pathway for compound 17.

6
S. K. RAMADAN ET AL.
Scheme 5. Reaction of [2] with 2-cyanoethanohydrazide.
quinazoline derivative 10 and achieved the pyrimidine derivative 11 (Scheme 2). The IR
spectrum of 11 displayed carbonyl functionality at ν 1656 cm−1 which ruled out the struc-
ture 10. Ample evidence for structure 11 was acquired from its 1H NMR spectrum as it
disclosed one exchangeable singlet signal at δ 11.87 ppm corresponding to the carboxylic
proton, in addition to a singlet signal in the upfield region at δ 2.13 ppm integrated for
three protons corresponding to the acetyl group. Cyclocondensation of 8 in boiling diox-
ane including triethylamine afforded pyrimidobenzothiazine derivative 12. The 1H NMR
spectrum of 12 was devoid of any labile hydrogen.
Interaction of isothiocyanate derivative 2 with 2-aminothiophenol, 2-aminoaniline,
2-hydroxybenzoylhydrazine, and thiourea in boiling acetonitrile achieved benzothia-
zole, pyrimidinethione, and acylthiourea derivatives 13-16, respectively (Scheme 3). The
IR spectrum of 13 showed NH, C≡N, and C = O absorptions at ν 3142, 2216, and
1677 cm−1, respectively. Also, its 1H NMR spectrum disclosed two singlet signals for C5-H
pyrazole (at δ 9.19 and 9.15 ppm), and two singlet signals for olefinic proton (at δ 8.32 and

JOURNAL OF SULFUR CHEMISTRY
7
8.08 ppm) which showed its existence as a mixture of E- and Z-isomers in a ratio of 1:1.
Furthermore, its mass spectrum displayed the molecular ion peak at m/z 447 (53%) and
the base peak fragment at m/z 77 corresponding to phenyl cation, as well as some impor-
tant fragments. Formation of benzothiazole derivative 13 was distinctly interpreted via
cyclization of thiourea intermediate [I] by removing gaseous hydrogen sulfide molecule,
1
as detected by the change in color of lead acetate paper into black. The H NMR spec-
trum of 14 displayed an exchangeable singlet integrated to two protons of the primary
amino group and showed its existence as a mixture of cis and trans isomers in a ratio of 1:1
by showing four doublet signals corresponding to vicinal CH–CH protons. The IR spec-
trum of 15 showed OH, NH, C≡N, and C = O absorptions at ν 3403, 3203, 2205, and
1686 cm−1, respectively. Moreover, its 1H NMR spectrum displayed four exchangeable sin-
glet signals corresponding to one OH and three NH protons at δ 12.32, 11.80, 11.20, and
10.91 ppm. The IR spectrum of 16 retained the nitrile and carbonyl functionalities. Its 1H
NMR spectrum exhibited three exchangeable singlet signals corresponding to two NH and
NH2 protons. In contrast, treating 2 with hydrazinecarbothiohydrazide at room tempera-
ture furnished the triazolopyrimidine derivative 17 which can be visualized via Scheme 4.
The IR spectrum of 17 conserved both nitrile and carbonyl functionalities. The existence
of exchangeable singlet signals for NH and NH2 protons and the absence of singlet signal
of the olefinic proton in its 1H NMR spectrum supported the assigned structure. Further-
more, its mass spectrum displayed the M+. peak at m/z 426 (6%) and a fragment at m/z 77
as a base peak corresponding to phenyl cation (cf. Experimental).
Noteworthy, the interaction of 2 with 2-cyanoethanohydrazide was dependent on
the reaction conditions. Therefore, execution of the reaction in dry acetone as a sol-
vent afforded the hydrazone derivative 18 while using acetonitrile yielded the pyrim-
idinethione derivative 21 instead of thiadiazole derivative 20 through the intermediate
19 as depicted in Scheme 5. Formation of 18 can be viewed via the first condensation
of 2-cyanoethanohydrazide with acetone to give a non-isolable hydrazone intermediate
followed by aza-Michael addition on the isothiocyanate functionality. The IR spectrum of
21 exhibited the following bands (ν, cm−1): 3227, 3121 (NH), 2260, 2224 (C≡N), 1695,
1663 (C = O). Compelling support for structure 21 was its 1H NMR spectrum as it pro-
vided the following signals (300 MHz, DMSO-d6): 12.25, 10.88 (br.s, exchangeable, 2 NH),
8.75 (s, C5-H pyrazole), 7.88-7.37 (m, Ar-H), 5.92 (d, CHa, J = 6.5 Hz), 5.43 (d, CHb,
J = 6.4 Hz), 3.47 (s, CH2). Its mass spectrum showed the M+. peak at m/z 455 (7%) and a
fragment at m/z 77 as a base peak corresponding to phenyl cation. Interestingly, boiling 21
in glacial acetic acid afforded the pyrimidothiadiazepine derivative 23 as orange crystals.
The reaction can be explained via intramolecular cyclization of 21 to give 22 which sub-
sequently underwent decarboxylation (cf. Scheme 5). The IR spectrum of 23 was devoid
of nitrile functionality. Its 1H NMR spectrum provided two exchangeable singlet signals
in the downfield region for two NH protons, in addition to a singlet signal for methylene
protons. Further support was its mass spectrum showed the molecular ion peak at m/z 428
(28%) as well as some of the important fragments (cf. Experimental).
Fungicidal activity
Most of the newly synthesized pyrazoles were evaluated for their in vitro antifungal activity
against the five targeted fungi namely, Fusarium Solani and Rhizoctonia Solani soil-borne

8
S. K. RAMADAN ET AL.
Table 1. Fungicidal activity of the synthesized pyrazoles against F. Solani and R. Solani soil-borne fungi.
Fungus
F. Solani
R. Solani
Compound No.
EC50∗(mg/L)
Slope of toxicity line
T.I∗∗
EC50∗(mg/L)
Slope of toxicity line
T.I∗∗
3
4
6
7
8
9
13
14
15
16
17
18
905.0
771.9
506.5
633.9
739.2
393.9
310.0
685.4
629.5
721.4
529.5
829.6
490.7
2.61
1.24
2.64
2.88
2.40
2.14
2.18
3.01
2.93
1.56
2.37
3.31
2.14
34.3
40.2
61.2
48.9
41.9
78.7
100.0
45.2
49.3
42.7
58.5
37.4
63.2
316.8
278.6
275.6
640.2
707.2
254.8
192.9
617.8
575.9
206.9
205.8
195.9
230.8
2.16
1.93
2.88
6.83
6.22
3.78
3.27
3.59
1.62
3.78
3.55
3.51
2.75
60.9
69.3
70.0
30.1
27.3
75.7
100.0
31.2
33.5
93.2
93.7
98.5
83.6
Pencycuron
∗ The EC50 is the effective concentration that gives 50% of the radial growth inhibition of the fungus.
∗∗ Toxicity index (T.I) is the % of EC50 of the tested compound related to the most potent one that having the lowest such
value.
fungi that cause damping-off and wilt incidence of different plants,[28] as well as, Botry-
tis cinerea, Sclerotinia Sclerotiorum, and Alternaria Alternata airborne pathogenic fungi
attacking plants and crops causing many pre- and post-harvest diseases like grey mold,
white mold, leaf blight, leaf blotch, and rust.[39–41] Data in Table 1 represent the fungicidal
activity of screened pyrazoles against F. Solani and R. Solani soil-borne fungi. Pencycuran
(Monceren 25% WP) was used as a positive control or standard fungicide. Looking closely
at the toxicity parameters (EC50 and T.I values), synthesized pyrazoles showed differenti-
ated behavior with good activities against the targeted strains. Particularly, the activities of
pyrazole derivatives 9 and 13 were found to be more active than the standard fungicide
against F. Solani fungus with EC50 values 310.0, 393.9, and 490.7 mg/L for compounds
13, 9, and standard fungicide, respectively. Besides, compounds 13, 16, 17, and 18 dis-
played high activities against R. Solani fungus whereas, their EC50 values ranged from
192.9–206.9 mg/L comparing to 230.8 mg/L of the standard fungicide. Data also show that
F. Solani fungus possessed high resistance to pyrazole derivatives 3 and 18 while, R. Solani
fungus possessed a notable resistance to pyrazoles 7, 8, 14, and 15. EC50 values of such
compounds were found to be double or more double than that of the standard fungicide.
According to the values of the toxicity index, we can descendingly arrange the activity of
the highest three potent new pyrazoles as 13, 9, and 6 against F. Solani fungus and 13, 18,
and 17 against R. Solani fungus.
Data in Tables 2 illustrate the fungi toxic effects of the screened pyrazoles against B.
cinerea, S. Sclerotiorum, and A. Alternata airborne pathogens. A perusal of activity data
indicates that all the synthesized pyrazoles have stronger activity than the standard fungi-
cide Metalaxyl against the three tested fungi, as the latter showed no inhibition activity up
to 500 mg/L treatment. As in Table 2, B. cinerea fungus was found to be highly resistant to
both standard fungicides (Metalaxyl and Mancozeb) but it showed notable sensitivity to
the tested pyrazoles especially compounds 16, 9, 4, 13, and 17. The EC50 values of these
compounds respectively are 178.4, 209.5, 240.1, 250.0, and 273.4 mg/L and their toxicity
indexes ranged from 100.0–60.3. In turn, the activity of the synthesized pyrazoles against A.
Alternata and S. Sclerotiorum fungi is higher than that of the standard fungicide Metalaxyl

JOURNAL OF SULFUR CHEMISTRY
9
but less than that of the standard fungicide Mancozeb. The most active pyrazoles against
A. Alternata fungus are 16, 9, and 13 while those against S. Sclerotiorum are 13, 16, and 9,
respectively. Introducing benzothiazole nucleus (compound 13) and thiourea group (com-
pound 16) remarkably increases the activity of pyrazole core which is compatible with the
published works.[42–46] Addition of benzothiazole nucleus increases the activity against
soil-borne fungi while linking with thiourea group increases the activity towards most of
the tested fungi especially B. cinerea fungus. Oppositely, linking the core pyrazole with
pyrimidinthione derivatives (compounds 6, 7, and 8) highly reduces the activity towards
all tested strains, especially the airborne fungi (see more details in the supplemental Tables
I–V).
Conclusion
A propenoyl isothiocyanate derivative was utilized for the synthesis of pyrimidinethione,
benzothiazole, pyrimidothiadiazepine, pyrimidobenzothiazine, and acylthiourea deriva-
tives encompassing a 1,3-diphenylpyrazole core. The synthesized compounds were evalu-
ated for their antifungal activity against five pathogenic fungi belonging to both soil-borne
and airborne strains. Generally based on data obtained, pyrazole derivative 13 is the most
potent one that showed better fungicidal activity against F. Solani and R. Solani soil-borne
fungi than the standard fungicide and moderate activity against airborne fungi. In the
same boat, pyrazole derivative 16 showed better activity than the two standard fungicides
against B. cinerea airborne fungus. Both A. Alternata and S. Sclerotiorum airborne fungi
showed more resistance to the new pyrazoles than the standard fungicides. This means,
fungicidal activity of the synthesized pyrazoles is remarkably diversified and affected by
the heterocyclic ring or functional group attached to the core pyrazole.
Experimental
Chemistry
Melting points were measured on a GALLENKAMP electric melting point apparatus
and are uncorrected. IR spectra (ν, cm−1) were run using KBr disks on Fourier Trans-
form Infrared Thermo Electron Nicolet iS10 Spectrometer (Thermo Fisher Scientific Inc.,
Waltham, MA, USA) at Chemistry Department, Faculty of Science, Ain Shams Univer-
sity. The 1H NMR and 13C NMR spectra (δ, ppm) were recorded at 300 and 75 MHz on a
Varian GEMINI (GEMINI, Manufacturing & Engineering Inc., Anaheim, CA, USA) utiliz-
ing tetramethylsilane as an internal standard in deuterated dimethyl sulfoxide (DMSO-d6)
at Faculty of Science, Cairo University. Mass spectra were carried out on direct probe
controller inlet part to single quadrupole mass analyzer in (Thermo Scientific GCMS)
MODEL (ISQ LT) using Thermo X-CALIBUR software at the regional center for mycology
and biotechnology (RCMB), Al-Azhar University, Cairo, Egypt. Elemental analyses were
recorded at Faculty of Science, Ain Shams University using Perkin-Elmer 2400 CHN ele-
mental analyzer, and satisfactory analytical data ( 0.4) were obtained for all compounds.
Reagents and solvents were purified and dried by standard techniques. The reactions were
monitored by thin-layer chromatography (TLC) using Merck Kiesel gel 60F254 obtained
from Fluka, Switzerland. The starting acid chloride 1 was previously reported by us.[6,7]

Table 2. Fungicidal activity of the newly synthesized pyrazoles against B. cinerea, S. Sclerotiorum, and A. Alternata airborne fungi.
Fungus
B. cinerea
A. Alternata
S. Sclerotiorum
Slope of
toxicity line
Slope of
toxicity line
Slope of
toxicity line
Compound No.
EC50∗ (mg/L)
T.I∗∗
EC50∗ (mg/L)
T.I∗∗
EC50∗ (mg/L)
T.I∗∗
3
4
6
7
8
9
13
14
15
16
17
18
444.8
240.1
514.7
900.8
620.4
209.5
250.0
1343.1
844.8
178.4
273.4
567.4
2.46
2.17
3.89
337
1.84
3.41
2.42
3.13
3.29
3.27
3.56
1.87
40.1
74.3
34.7
19.8
28.8
85.2
71.4
13.3
21.1
100.0
65.3
31.4
384.2
860.5
348.4
666.0
930.2
223.6
229.6
1084.3
887.2
188.9
289.3
542.8
2.03
2.63
1.29
2.58
2.30
2.09
2.08
1.44
2.11
2.25
2.02
1.84
19.2
8.6
21.2
11.1
7.9
32.9
32.1
6.8
217.5
288.6
304.9
605.0
239.3
208.8
179.6
936.8
519.8
197.3
301.1
294.1
1.91
1.99
2.20
3.72
2.56
2.27
2.40
3.81
1.90
3.07
2.77
1.90
49.8
37.6
35.6
17.9
45.3
51.9
60.4
11.6
20.9
54.9
36.0
36.9
8.3
39.0
25.5
13.6
Metalaxyl
Mancozeb
∗
∗
∗
∗
∗
∗
∗
∗
∗
73.7
3.23
100.0
108.4
4.03
100.0
∗
∗
∗
∗ The EC50 is the effective concentration that gives 50% of the radial growth inhibition of the fungus.
∗∗ Toxicity index (T.I) is the % of EC50 of the tested compound related to the most potent one that has the lowest such value.

JOURNAL OF SULFUR CHEMISTRY
11
2-Cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl Isothiocyanate (2)
Ammonium thiocyanate (5.2 mmol) was added to a stirred solution of the acid chloride
1 (5 mmol) in dry acetonitrile (10 mL), and the reaction mixture was further stirred for
20 min at room temperature to give the isothiocyanate intermediate 2 which was then used
in the following reactions.
General procedure for the synthesis of compounds 3–7
The appropriate reagent namely, ethanol, aminoacetic acid, benzylamine, and 4-
aminoacetophenone (5 mmol) was added to a suspension of isothiocyanate derivative 2
(5 mmol) in acetonitrile, prepared in situ. The reaction mixture was heated under reflux
for 2-4 h and/or stirred at an ambient temperature for 1 h in the case of benzylamine.
The deposited solid was collected and recrystallized from the suitable solvent to furnish
compounds 3-7.
O-Ethyl (2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)carbamothioate (3)
Canary-yellow crystals, mp. 178–180oC (Ethanol), yield 81%. IR: 3399 (NH), 2204 (C ≡N),
1
1721 (C = O), 1292 (C = S). H NMR (300 MHz, DMSO-d6): 12.05 (br.s, 1H, NH,
exchangeable), 9.16 (s, 1H, C5-H pyrazole), 8.09 (s, 1H, CH=), 8.04-7.45 (m, 10H, Ar-
H), 3.44 (q, 2H, CH2, J = 6.9 Hz), 1.06 (t, 3H, CH3, J = 6.9 Hz). MS, m/z (%): 404 (M+2,
3), 402 (M+., 11), 343 (100), 314 (11), 298 (21), 270 (37), 242 (7), 140 (5), 94 (4), 77 (10).
Anal. Calcd. for C22H18N4O2S (402.47): C, 65.65; H, 4.51; N, 13.92. found: C, 65.40; H,
4.39; N, 13.87%.
((2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)carbamothioyl)glycine (4)
Yellow crystals, mp. 232–234oC (Benzene), yield 62%. IR: 3462 (br.OH), 3316, 3155 (NH),
2225 (C≡N), 1703 (C = O acid), 1670 (C = O amide), 1232 (C = S). 1H NMR (300 MHz,
DMSO-d6): 13.50 (br.s, 1H, COOH, exchangeable), 11.29 (br.s, 1H, NH, exchangeable),
9.60 (br.s, 1H, NH, exchangeable), 9.17 (s, 1H, C5-H pyrazole), 8.22 (s, 1H, CH=), 8.09-
7.36 (m, 10H, Ar-H), 4.40 (s, 2H, CH2). Anal. Calcd. for C22H17N5O3S (431.47): C, 61.24;
H, 3.97; N, 16.23. found: C, 61.09; H, 3.88; N, 16.25%.
N-(Benzylcarbamothioyl)-2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acrylamide (5)
Yellow crystals, mp. 246–248oC (Ethanol), yield 84%. IR: 3286 (NH), 2217 (C ≡N), 1715
(C = O), 1231 (C = S). 1H NMR (300 MHz, DMSO-d6): 9.06 (s, 1H, C5-H pyrazole), 8.50
(br.s, 2H, NH, exchangeable), 7.92 (s, 1H, CH=), 7.91-7.38 (m, 15H, Ar-H), 4.04 (s, 2H,
CH2). Anal. Calcd. for C27H21N5OS (463.56): C, 69.96; H, 4.57; N, 15.11. found: C, 69.79;
H, 4.43; N, 15.06%.
1-Benzyl-6-(1,3-diphenyl-1H-pyrazol-4-yl)-4-oxo-2-thioxohexahydropyrimidine-5-
carbonitrile (6)
Yellow crystals, mp. 190–192oC (Ethanol), yield 78%. IR: 3228 (NH), 2225 (C ≡N), 1758
(C = O), 1227 (C = S). 1H NMR (300 MHz, DMSO-d6): (cis and trans isomers, 1:1), 9.21

12
S. K. RAMADAN ET AL.
(s, 1H, C5-H pyrazole), 8.30-7.03 (m, 15H, Ar-H), 4.84 (s, 2H, CH2); for trans isomer:
12.00 (br.s, 1H, SH thiolactim form, exchangeable), 11.46 (br.s, 1H, NH, exchangeable),
5.70 (d, 1H, CHa, J = 6.2 Hz), 5.38 (d, 1H, CHb, J = 6.3 Hz); for cis isomer: 11.98 (br.s,
1H, SH thiolactim form, exchangeable), 10.80 (br.s, 1H, NH, exchangeable), 5.50 (d, 1H,
CHa, J = 3.2 Hz), 5.22 (d, 1H, CHb, J = 3.2 Hz). MS, m/z (%): 465 (M+2, 11), 464 (M+1,
31), 463 (M+., 100), 462 (28), 461 (8), 430 (21), 403 (63), 356 (6), 299 (2), 297 (15), 231 (2),
140 (4), 106 (12), 91 (8), 77 (13). Anal. Calcd. for C27H21N5OS (463.56): C, 69.96; H, 4.57;
N, 15.11. found: C, 69.81; H, 4.44; N, 15.09%.
1-(4-Acetylphenyl)-6-(1,3-diphenyl-1H-pyrazol-4-yl)-4-oxo-2-thioxohexahydropyri
midine-5-carbonitrile (7)
Canary-yellow crystals, mp. 230–232oC (dioxane), yield 85%. IR: 3375 (NH), 2208
1
(C≡N), 1680 (C = O), 1229 (C = S). H NMR (300 MHz, DMSO-d6): (cis and trans
isomers, 1:1), 9.25 (s, 1H, C5-H pyrazole), 7.95-7.00 (m, 14H, Ar-H), 2.47 (s, 3H, CH3);
for trans isomer: 12.25 (br.s, 1H, SH thiolactim form, exchangeable), 12.16 (br.s, 1H,
NH, exchangeable), 6.22 (d, 1H, CHa, J = 6.3 Hz), 5.64 (d, 1H, CHb, J = 6.3 Hz); for cis
isomer: 12.20 (br.s, 1H, SH thiolactim form, exchangeable), 11.80 (br.s, 1H, NH, exchange-
able), 5.68 (d, 1H, CHa, J = 3.1 Hz), 5.50 (d, 1H, CHb, J = 3.2 Hz). Anal. Calcd. for
C28H21N5O2S (491.57): C, 68.42; H, 4.31; N, 14.25. found: C, 68.27; H, 4.26; N, 14.20%.
Reaction of 2 with 2-aminobenzoic acid
2-Aminobenzoic acid (5 mmol) was added to a suspension of isothiocyanate derivative 2
(5 mmol) in acetonitrile, prepared in situ. The reaction mixture was heated under reflux for
4 h. The deposited solid was collected and fractionally recrystallized from benzene to fur-
nish pyrimidine derivative 8. The insoluble part was recrystallized from ethanol to produce
compound 9.
2-(5-Cyano-6-(1,3-diphenyl-1H-pyrazol-4-yl)-4-oxo-2-thioxotetrahydropyrimidin-
1(2H)-yl)benzoic Acid (8)
Yellow crystals, mp. 228–230oC, yield 44%. IR: 3441 (br.OH), 3237 (NH), 2223 (C≡N),
1
1709 (C = O), 1280 (C = S). H NMR (300 MHz, DMSO-d6): 12.18 (br.s, 1H, COOH,
exchangeable), 11.20 (br.s, 1H, NH, exchangeable), 9.18 (s, 1H, C5-H pyrazole), 7.94-7.36
(m, 14H, Ar-H), 3.17 (d, 1H, CH-N, J = 6.3 Hz), 2.65 (d, 1H, CH-CN, J = 6.2 Hz). MS,
m/z (%): 493 (M+., 3), 461 (14), 416 (11), 338 (29), 298 (54), 270 (61), 268 (100), 242 (28),
146 (16), 138 (20), 91 (32), 77 (73). Anal. Calcd. for C27H19N5O3S (493.54): C, 65.71; H,
3.88; N, 14.19. found: C, 65.52; H, 3.74; N, 14.21%.
2-(3-(2-Cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)thioureido)benzoic Acid
(9)
Yellow crystals, mp. 258–260oC, yield 51%. IR: 3444 (br.OH,NH), 2211 (C≡N), 1695
(C = O acid), 1658 (C = O amide), 1231 (C = S). 1H NMR (300 MHz, DMSO-d6): 12.79
(br.s, 1H, COOH, exchangeable), 12.67 (br.s, 1H, NH, exchangeable), 12.43 (br.s, 1H, NH,

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13
exchangeable), 9.22 (s, 1H, C5-H pyrazole), 8.31 (s, 1H, CH=), 7.99-7.28 (m, 14H, Ar-H).
Anal. Calcd. for C27H19N5O3S (493.54): C, 65.71; H, 3.88; N, 14.19. found: C, 65.54; H,
3.77; N, 14.20%.
2-(2-(Acetylthio)-5-cyano-6-(1,3-diphenyl-1H-pyrazol-4-yl)-4-oxopyrimidin-1(4H)-
yl)benzoic Acid (11)
A suspension of compound 9 (2 mmol) in acetic anhydride (5 mL) was heated under reflux
for 2 h. The solid obtained was filtered off and recrystallized from ethanol to acquire yel-
low crystals, mp. 284–286oC, yield 81%. IR: 3441 (br.OH), 3167 (NH), 2220 (C≡N),
1
1656 (C = O), 1274 (C = S). H NMR (300 MHz, DMSO-d6): 11.87 (br.s, 1H, COOH,
exchangeable), 9.22 (s, 1H, C5-H pyrazole), 8.04-7.48 (m, 14H, Ar-H), 2.13 (s, 3H, CH3).
MS, m/z (%): 535 (M+2, 52), 534 (M+1, 22), 491 (20), 469 (22), 452 (75), 435 (100), 434
(99), 433 (56), 407 (64), 377 (53), 310 (51), 265 (83), 212 (55), 196 (59), 140 (61), 119 (34),
106 (27). Anal. Calcd. for C29H19N5O4S (533.56): C, 65.28; H, 3.59; N, 13.13. found: C,
65.14; H, 3.48; N, 13.17%.
1-(1,3-Diphenyl-1H-pyrazol-4-yl)-3,6-dioxo-3H,6H-benzo[d]pyrimido[2,1-b][1,3]
thiazine-2-carbonitrile (12)
A solution of 8 (2 mmol) in dioxane (10 mL) including triethylamine (0.1 mL) was heated
under reflux for 4 h. The solid obtained after cooling was collected and recrystallized from
ethanol to furnish dark-yellow crystals, mp. 300–302oC, yield 59%. IR: 2216 (C≡N), 1695,
1670 (C = O). 1H NMR (300 MHz, DMSO-d6): 9.05 (s, 1H, C5-H pyrazole), 8.01-7.41 (m,
14H, Ar-H). MS, m/z (%): 473 (M+., 11), 434 (17), 388 (7), 351 (8), 314 (15), 271 (26), 269
(13), 194 (8), 91 (14), 77 (100). Anal. Calcd. for C27H15N5O2S (473.51): C, 68.49; H, 3.19;
N, 14.79. found: C, 68.32; H, 3.11; N, 14.81%.
General procedure for the synthesis of compounds 13–17
The appropriate reagent namely, 2-aminothiophenol, 2-aminoaniline, 2-hydroxybenzoyl
hydrazine, thiourea, or hydrazinecarbothiohydrazide (5 mmol) was added to a suspension
of isothiocyanate derivative 2 (5 mmol) in acetonitrile, prepared in situ. The reaction mix-
ture was heated under reflux for 3-4 h or stirred at ambient temperature for 1 h in the case
of hydrazinecarbothiohydrazide. The solid obtained was collected and recrystallized from
the suitable solvent to produce compounds 13-17.
N-(Benzo[d]thiazol-2-yl)-2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acrylamide (13)
Yellow crystals, mp. 298–300oC (dioxane), yield 69%. IR: 3142 (NH), 2216 (C≡N), 1677
(C = O). 1H NMR (300 MHz, DMSO-d6): (E- and Z-isomers, 1:1), 13.40 (br.s, 1H, NH,
exchangeable), 9.19, 9.15 (s, 1H, C5-H pyrazole), 8.32, 8.08 (s, 1H, CH=), 7.93-7.31 (m,
14H, Ar-H). MS, m/z (%): 449 (M+2, 4), 448 (M+1, 57), 447 (M+., 53), 446 (96), 387 (13),
315 (29), 270 (59), 269 (66), 191 (10), 104 (43), 77 (100). Anal. Calcd. for C26H17N5OS
(447.52): C, 69.78; H, 3.83; N, 15.65. found: C, 69.61; H, 3.75; N, 15.59%.

14
S. K. RAMADAN ET AL.
1-(2-Aminophenyl)-6-(1,3-diphenyl-1H-pyrazol-4-yl)-4-oxo-2-thioxohexahydropyri
midine-5-carbonitrile (14)
Orange crystals, mp. 210–212oC (Ethanol), yield 72%. IR: 3346, 3229 (NH,NH2), 2208
(C≡N), 1679 (C = O), 1231 (C = S). 1H NMR (300 MHz, DMSO-d6): (cis and trans iso-
mers, 1:1), 8.74 (s, 1H, C5-H pyrazole), 7.94-6.61 (m, 14H, Ar-H), 5.71 (br.s, 2H, NH2,
exchangeable); for trans isomer: 12.05 (br.s, 1H, NH, exchangeable), 6.18 (d, 1H, CHa,
J = 6.4 Hz), 5.36 (d, 1H, CHb, J = 6.3 Hz); for cis isomer: 11.98 (br.s, 1H, NH, exchange-
able), 6.10 (d, 1H, CHa, J = 3.1 Hz), 5.06 (d, 1H, CHb, J = 3.1 Hz). MS, m/z (%): 464 (M+.,
18), 449 (22), 418 (13), 387 (14), 346 (16), 303 (10), 252 (20), 201 (28), 139 (50), 136 (100),
102, 92 (21), 78 (24). Anal. Calcd. for C26H20N6OS (464.55): C, 67.22; H, 4.34; N, 18.09.
found: C, 67.17; H, 4.28; N, 18.10%.
2-Cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-(2-(2-hydroxybenzoyl)hydrazine-1-
carbonothioyl)acrylamide (15)
Yellow crystals, mp. 272–274oC (dioxane), yield 77%. IR: 3403 (OH), 3203 (NH), 2205
(C≡N), 1686 (C = O), 1223 (C = S). 1H NMR (300 MHz, DMSO-d6): 12.32 (br.s, 1H,
OH, exchangeable), 11.80 (br.s, 1H, NH, exchangeable), 11.20 (br.s, 1H, NH, exchange-
able), 10.91 (br.s, 1H, NH, exchangeable), 9.19 (s, 1H, C5-H pyrazole), 8.30 (s, 1H, CH=),
7.93-6.03 (m, 14H, Ar-H). Anal. Calcd. for C27H20N6O3S (508.56): C, 63.77; H, 3.96; N,
16.53. found: C, 63.64; H, 3.88; N, 16.55%.
N-(Carbamothioylcarbamothioyl)-2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acry
lamide (16)
Yellow crystals, mp. 242–242oC (Ethanol), yield 67%. IR: 3315, 3250, 3130 (NH), 2229
1
(C≡N), 1698 (C = O), 1270, 1232 (C = S). H NMR (300 MHz, DMSO-d6): 11.28
(br.s, 1H, NH, exchangeable), 9.60 (br.s, 1H, NH, exchangeable), 9.52 (br.s, 2H, NH2,
exchangeable), 9.13 (s, 1H, C5-H pyrazole), 8.21 (s, 1H, CH=), 8.07-7.03 (m, 10H, Ar-
H). 13C NMR (75 MHz, DMSO-d6): 181.36, 163.32, 155.11, 154.14, 144.83, 141.53, 138.60,
130.94, 129.80, 129.32, 128.98, 128.28, 128.03, 127.81, 119.69, 116.96, 114.34. Anal. Calcd.
for C21H16N6OS2 (432.08): C, 58.32; H, 3.73; N, 19.43. found: C, 58.20; H, 3.65; N,
19.40%.
3-Amino-7-(1,3-diphenyl-1H-pyrazol-4-yl)-5-oxo-2-thioxo-1,2,3,5-tetrahydro-
[1,2,4]-triazolo[1,5-a]pyrimidine-6-carbonitrile (17)
Yellow crystals, mp. 224–226oC (Ethanol), yield 74%. IR: 3350, 3200 (NH,NH2), 2239
(C≡N), 1734 (C = O), 1235 (C = S). 1H NMR (300 MHz, DMSO-d6): 11.30 (br.s, 1H,
NH, exchangeable), 9.18 (s, 1H, C5-H pyrazole), 8.09-7.44 (m, 10H, Ar-H), 5.40 (br.s, 2H,
NH2, exchangeable). MS, m/z (%): 426 (M+., 6), 400 (6), 315 (40), 270 (32), 269 (20), 242
(10), 193 (8), 139 (12), 104 (13), 77 (100). Anal. Calcd. for C21H14N8OS (426.46): C, 59.15;
H, 3.31; N, 26.28. found: C, 59.01; H, 3.24; N, 26.31%.

JOURNAL OF SULFUR CHEMISTRY
15
2-Cyano-N-(1-(2-cyanoacetyl)-2-(propan-2-ylidene)hydrazine-1-carbonothioyl)-3-
(1,3-diphenyl-1H-pyrazol-4-yl)acrylamide (18)
2-Cyanoethanohydrazide (5 mmol) was added to a suspension of isothiocyanate derivative
2 (5 mmol) in dry acetone, prepared in situ. The reaction mixture was heated under reflux
for 3 h. The solid obtained was collected and recrystallized from ethanol to afford yellow
crystals, mp. 206–208oC, yield 68%. IR: 3237 (NH), 2223 (C≡N), 1708 (C = O), 1280
(C = S). 1H NMR (300 MHz, DMSO-d6): 12.15 (br.s, 1H, NH, exchangeable), 9.19 (s, 1H,
C5-H pyrazole), 8.10 (s, 1H, CH=), 8.03-7.36 (m, 10H, Ar-H), 4.04 (s, 2H, CH2), 3.17 (s,
6H, 2 CH3). MS, m/z (%): 495 (M+., 32), 477 (24), 416 (31), 377 (76), 316 (56), 270 (94),
268 (100), 237 (34), 165 (72), 131 (49), 113 (62), 104 (52), 102 (42), 74 (81). Anal. Calcd.
for C26H21N7O2S (495.56): C, 63.02; H, 4.27; N, 19.79. found: C, 62.91; H, 4.12; N, 19.72%.
2-Cyano-N-(5-cyano-6-(1,3-diphenyl-1H-pyrazol-4-yl)-4-oxo-2-thioxotetrahy
dropyrimidin-1(2H)-yl)acetamide (21)
2-Cyanoethanohydrazide (5 mmol) was added to a suspension of isothiocyanate derivative
2 (5 mmol) in dry acetonitrile, prepared in situ. The reaction mixture was further stirred
at ambient temperature for 2 h or heated under reflux for 30 min. The solid obtained was
collected and recrystallized from ethanol to produce yellow crystals, mp. 304–306oC, yield
1
81%. IR: 3227, 3121 (NH), 2260, 2224 (C≡N), 1695, 1663 (C = O), 1230 (C = S). H
NMR (300 MHz, DMSO-d6): 12.25 (br.s, 1H, NH, exchangeable), 10.88 (br.s, 1H, NH,
exchangeable), 8.75 (s, 1H, C5-H pyrazole), 7.88-7.37 (m, 10H, Ar-H), 5.92 (d, 1H, CHa,
J = 6.5 Hz), 5.43 (d, 1H, CHb, J = 6.4 Hz), 3.47 (s, 2H, CH2). MS, m/z (%): 455 (M+., 7),
454 (9), 437 (7), 355 (8), 299 (44), 298 (98), 297 (97), 296 (23), 270 (11), 269 (31), 239 (14),
140 (20), 77 (100). Anal. Calcd. for C23H17N7O2S (455.50): C, 60.65; H, 3.76; N, 21.53.
found: C, 60.52; H, 3.67; N, 21.50%.
7-(1,3-Diphenyl-1H-pyrazol-4-yl)-2-imino-2,3-dihydro-9H-pyrimido[2,1-b][1,3,4]
thiadiazepine-4,9(5H)-dione (23)
A solution of compound 19 (2 mmol) in glacial acetic acid (10 mL) was heated under reflux
for 1 h. The separated solid while hot was collected and recrystallized from dioxane to
achieve orange crystals, mp. >360oC, yield 76%. IR: 3166, 3134 (NH), 1678 (C = O).
1H NMR (300 MHz, DMSO-d6): 13.33 (br.s, 1H, NH, exchangeable), 10.52 (br.s, 1H, NH,
exchangeable), 8.17 (s, 1H, C5-H pyrazole), 8.06-7.47 (m, 11H, Ar-H + CH pyrimidine),
4.59 (s, 2H, CH2). MS, m/z (%): 428 (M+., 28), 426 (5), 387 (11), 361 (60), 358 (39), 338
(45), 309 (50), 284 (45), 280 (100), 249 (55), 223 (88), 194 (55), 176 (58), 164 (95), 115
(55), 104 (50), 90 (21), 77 (64). Anal. Calcd. for C22H16N6O2S (428.47): C, 61.67; H, 3.76;
N, 19.61. found: C, 61.54; H, 3.61; N, 19.57%.
Evaluation of the fungicidal activity
The in vitro antifungal activity of the synthesized pyrazoles against targeted fungi was eval-
uated using mycelium growth rate method. Potato-dextrose agar (PDA) was used as food
in the molten stage. Fifty milliliters of the medium were poured into 150 mL conical flasks

16
S. K. RAMADAN ET AL.
and autoclaved at 121oC for 20 min. Three drops of 25% lactic acid were added to pre-
vent bacterial contamination. Dilutions for each of the tested compounds were carried out
(v/v) by dissolving appropriate amounts of each compound in 10 mL DMSO. Equal vol-
umes of DMSO containing diluted compounds were added to sterile molten (40oC) PDA
to get a series of concentrations of 500, 400, 300, 200, and 100 mg/L for each compound in
PDA.[47] A zero (o) concentration treatment was prepared for each fungus, which contains
an equivalent volume of solvent only, and used as control. Compounds-amended PDA was
dispensed aseptically into 9 cm diameter Petri-dishes. Plugs of mycelium (4 mm diameter)
were cut from the margins of actively growing cultures of the F. Solani, R. Solani, B. cinerea,
S. sclerotiorum, and A. Alternata fungi and placed in the center of compound-amended and
unamended PDA plates with 3 replicate plates for each fungus. All plates were incubated
at 25 1oC. Colony diameter (in millimeters) was measured after complete growth of the
control (5 - 7 days). Percentages of mycelial growth inhibition were calculated from the for-
mula: Mycelial growth inhibition = [(DC-DT)/DC] ×100, where DC and DT are average
diameters of a fungal colony of control and treatment, respectively. The estimated effective
concentration (EC50) values, which give 50% inhibition of fungi radial growth, toxicity
index (T.I), and slopes of toxicity lines for each compound under investigation were cal-
culated by using the LDP line program and tabulated in Tables 1 and 2 (see more details
in the supplemental Tables I-V). Standard fungicides used are Metalaxyl (technical grade
with 95% CL), Mancozeb (Casette MZ, 69% WP formulation) and Pencycuran (Monceren,
25% WP formulation). In formulated standards, concentrations were calculated based on
the % of active ingredients and carried out in distilled water.
Disclsosure statement
The authors declare no conflict of interest.
Disclosure statement
No potential conflict of interest was reported by the author(s).
ORCID
Sayed K. Ramadan http://orcid.org/0000-0003-2743-6544
Eman A. E. El-Helw http://orcid.org/0000-0001-5104-6170
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