Synthesis, crystal structure, characterization and antifungal activity of 3,4-diaryl-1H-Pyrazoles derivatives

Article abstract of DOI:10.1016/j.molstruc.2017.07.106

A series of 3,4-diaryl-1H-pyrazoles derivatives were designed and synthesized by the reaction of 3-heteroarylchromones and 3-phenylchromones with hydrazine hydrate in good yields. All of those compounds were characterized by ¹H NMR, ¹³C NMR, IR, and HRMS. Moreover, 3-(2,4-dihydroxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrazole and 3-(2,4-dihydroxy phenyl)-4-(4-methoxyphenyl)-1H-pyrazole were further conformed by the single crystal X-ray diffraction. In addition, the antifungal activity against five phytopathogenic fungi (Cytospora sp., Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani and Fusarium solani) of 3,4-diaryl-1H-pyrazoles were evaluated. 3-(2-Hydroxy-4-isopropoxyphenyl)-4-phenyl-1H-pyrazole was more better and broader inhibitory effect on Cytospora sp., C. gloeosporioides, A. solani and Fusarium solani with IC₅₀ values of 26.96, 28.84, 16.77 and 22.10 μg/mL, respectively. 4-(4-Fluorophenyl)-3-(2-hydroxy-4-methoxyphenyl)-1H-pyrazole exhibited fairly effective antifungal activity against Cytospora sp., C. gloeosporioides and A. solani with IC₅₀ values of 11.91, 14.92 and 16.98 μg/mL, respectively.

Full text of DOI:10.1016/j.molstruc.2017.07.106

Accepted Manuscript
Synthesis, crystal structure, characterization and antifungal activity of 3,4-diaryl-1H-
Pyrazoles derivatives
Jin Zhang, Da-Jin Tan, Tao Wang, Si-Si Jing, Yang Kang, Zun-Ting Zhang
PII:
S0022-2860(17)31050-5
10.1016/j.molstruc.2017.07.106
MOLSTR 24133
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 6 April 2017
Revised Date: 28 July 2017
Accepted Date: 29 July 2017
Please cite this article as: J. Zhang, D.-J. Tan, T. Wang, S.-S. Jing, Y. Kang, Z.-T. Zhang, Synthesis,
crystal structure, characterization and antifungal activity of 3,4-diaryl-1H-Pyrazoles derivatives, Journal
of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.07.106.
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Graphical abstract:
Synthesis, Crystal Structure, Characterization and Antifungal Activity
of Pyrazolo[1,5-a]pyrimidines Derivatives
Jin Zhang, Da-Jin Tan, Tao Wang, Si-Si Jing, Yang Kang and Zun-Ting Zhang*
Fourteen 3,4-diaryl-1H-pyrazoles (4 and 5) derivatives were designed and synthesized by
the reaction of chromone with hydrazine hydrate in good yields. The synthesized
compounds were characterized by the method of 1H NMR, 13C NMR, IR and HRMS and
were evaluated their antifungal properties against five phytopathogenic fungi.

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Highlights
•
Fourteen 3,4-diaryl-1H-pyrazoles (4 and 5) derivatives were designed and synthesized by
the reaction of chromone with hydrazine hydrate in good yields, and they were
characterized by the spectroscopy of 1H NMR, 13C NMR, IR and HRMS.
The crystal structure of 3-(2,4-dihydroxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrazole (4b)
and 3-(2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-1H-pyrazole (4c) was determined.
The experimental results showed that 3,4-diaryl-1H-pyrazoles (4 and 5) derivatives
existed two tautomeric forms in DMSO-d6.
•
•
•
The synthesized compounds were evaluated their antifungal abilities against five
phytopathogenic fungi (Cytospora sp., Colletotrichum gloeosporioides, Botrytis cinerea,
Alternaria solani and Fusarium solani).

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Synthesis, Crystal Structure, Characterization and Antifungal
Activity of 3,4-Diaryl-1H-Pyrazoles Derivatives
Jin Zhang, Da-Jin Tan, Tao Wang, Si-Si Jing, Yang Kang, Zun-Ting Zhang*
Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical
Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude
Drugs in Northwest of China, and School of Chemistry and Chemical Engineering, Shaanxi
Normal University, Xi’an 710062, P.R. China.
ABSTRACT
A series of 3,4-diaryl-1H-pyrazoles derivatives were designed and synthesized by the
reaction of 3-heteroarylchromones and 3-phenylchromones with hydrazine hydrate in good
1
yields. All of those compounds were characterized by H NMR, 13C NMR, IR, and HRMS.
Moreover, 3-(2,4-dihydroxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrazole and 3-(2,4-dihydroxy
phenyl)-4-(4-methoxyphenyl)-1H-pyrazole were further conformed by the single crystal X-ray
diffraction. In addition, the antifungal activity against five phytopathogenic fungi (Cytospora sp.,
Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani and Fusarium solani) of
3,4-diaryl-1H-pyrazoles were evaluated. 3-(2-Hydroxy-4-isopropoxyphenyl)-4-phenyl-1H-
pyrazole was more better and broader inhibitory effect on Cytospora sp., C. gloeosporioides, A.
solani and Fusarium solani with IC50 values of 26.96, 28.84, 16.77 and 22.10 ꢀg/mL, respectively.
4-(4-Fluorophenyl)-3-(2-hydroxy-4-methoxyphenyl)-1H-pyrazole exhibited fairly effective
antifungal activity against Cytospora sp., C. gloeosporioides and A. solani with IC50 values of
11.91, 14.92 and 16.98 ꢀg/mL, respectively.
Keywords: 3,4-Diaryl-1H-pyrazoles, the single crystal X-ray diffraction, phytopathogens fungi,
antifungal activity.
1．Introduction
Pyrazole and its derivatives is a kind of important nitrogenous five-membered heterocyclic
compounds, and they are showed unique biological and pharmaceutical activities such as
anti-inflammatory [1, 2], antipyretic [3], analgesic [4], antidepressant [5] and antiobesity activity

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[6]. In addition, they also can be used as herbizide, insecticide and fungicide [7-9]. Nowadays,
many pyrazole derivatives as fungicide have been commercialized, for examples furametpyr and
penthiopyrad. Furametpyr has been used to control rice sheath blight in the agriculture field due to
it could inhibited the aspirate and glutamate synthesis [10]. Penthiopyrad exhibits activity on
strobilurin and DMI resistant diseases, which were caused by powdery mildew, gray mold, rusts,
and Botrytis [11]. As we all know, phytopathogenic fungi are very hard to control and easily infect
many crops [12, 13]. Apart from the yield losses of crop production, phytopathogenic fungi can
also be severely harmful to consumers, because they produce dangerous mycotoxins [14, 15].
3,4-Diaryl-1H-pyrazoles exhibited antibodies to heat-shock protein 70 and anticancer [16-18].
In our previous work [19], 3,4-diaryl-1H-pyrazoles derivatives were synthesized and the
antioxidant of them was tested. In 2017, the antifungal activities of 3-arylpyrazoles,
3-aryl-4-halogenatepyrazoles and 2,3-diarylpyrazoles were evaluated by us [20]. It indicated that
3-arylpyrazoles, 3-aryl-4-halogenatepyrazoles and 2,3-diarylpyrazoles showed better and broader
spectrum antifungal properties. Based on our previous works [19, 21-22], in this paper, a series of
3,4-diaryl-1H-pyrazoles were designed and synthesized (Scheme 1), and their antifungal activities
in vitro against phytopathogenic fungi Cytospora sp., Colletotrichum gloeosporioides, Botrytis
cinerea, Alternaria solani and Fusarium solani were evaluated. In addition,
3-(2,4-dihydroxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrazole
(5b)
and
3-(2,4-dihydroxy
phenyl)-4-(4-methoxyphenyl)-1H-pyrazole (5c) were further conformed by the single crystal
X-ray diffraction, and other new products were fully characterized by 1H NMR, 13C NMR, IR and
HRMS.
Scheme 1. General synthetic route for compounds 4 and 5.

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2ꢀExperimental
2.1.1 Instruments
All starting materials were obtained from commercial sources and used without purification.
Melting points were measured using X-5 melting point apparatus and were uncorrected. NMR
spectra were recorded on a Bruker AM 400 or 600 instrument using either CDCl3 or DMSO-d6 as
the solvent. The crystal diffraction data were collected on a Bruker Smart-1000 CCD
diffractometer. High-resolution mass spectrometry (HRMS) was recorded using electron-spray
ionization quadrupole-time of flight (ESI-Q-TOF) technique and IR spectra were recorded on a
Nicollet 170SX FT-IR spectrophotometer with KBr pellets. Thin-layer chromatography (TLC)
used silica gel 60 GF254 plate. The silica gel (size 200-300 mesh) used for the column
chromatography was purchased from Qingdao Haiyang Chemistry Plant (China).
2.1.2 Fungal Materials
Fungi Cytospora sp., Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani and
Fusarium solan were all kindly provided by the Institute of Pesticides, Northwest A&F University.
The strains were inoculated and cultured on potato dextrose agar (PDA) at 28 ± 1 °C for 1 week
by the general fungi culture technique [20, 23].
2.2 General procedure for the synthesis of the intermediates (2) and (3)
According to the literature method [24], the intermediate 3-iodochromones (1) were prepared.
3-Heteroarylchromones (2) were obtained via a photochemical reaction with furan, 2-methylfuran,
thiophene and 1-N-methylpyrrole and 3-iodochromones (1) in 60-83% yields [22].
3-Phenylchromones (3) were got via the Negishi cross-coupling reactions of aryl zinc reagents and
3-iodochromones (1) in 68-81% yields [21, 24].
2.3 General procedure for the synthesis of 3-phenyl-4-heteroaryl-1H-pyrazoles (4) and
3,4-diphenyl-1H-pyrazoles (5)
Compound 2 or 3 (1 mmol) and hydrazine hydrate (2 mmol) were refluxed in ethanol (15 mL)
for about 2 h. All reactions were monitored by TLC until the 3-heteroarylchromones was fully
consumed. After that the mixture was poured into ice water (100 mL) and was adjusted to pH =
6-7 with 10% HCl. The white precipitate formed was filtered and purified via column

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chromatography on silica gel (dichloromethane) gave product 4 in 75%-94% yields and 5 in
91%-96% yields. 4a-4g were new compounds.
2.3.1. 4-(Furan-2-yl)-3-(2-hydroxyphenyl)-1H-pyrazole (4a)
White solid; mp 123-125 °C; IR (KBr), ν (cm-1): 3414, 2028, 1625, 1389, 1151, 1075, 750,
622, 482; 1H NMR (600 MHz, CDCl3) δ (ppm) 6.39 (m, 1H), 6.46 (m, 1H), 6.84 (m, 1H), 7.05 (d,
1H, J = 7.8 Hz), 7.23 (m, 1H), 7.41 (dd, 1H, J = 7.8, 1.2 Hz), 7.48 (d, 1H, J = 1.2 Hz), 7.77 (s, 1H),
10.33 (br, 2H). 13C NMR (150 MHz, DMSO-d6) δ(ppm) 108.2, 111.0, 111.2, 116.7, 116.9, 119.5,
128.3, 129.9, 130.7, 141.9, 146.4, 146.7, 155.3. HRMS (ESI): m/z [M + H]+ calculated for
C13H11N2O2: 227.0820; found: 227.0824.
2.3.2. 4-(Furan-2-yl)-3-(2-hydroxy-4-methoxyphenyl)-1H-pyrazole (4b)
Yellow solid; mp 115-117 °C; IR (KBr), ν (cm-1): 3415, 2028, 1624, 1391, 1283, 1155, 622,
482; 1H NMR (600 MHz, CDCl3) δ (ppm) 3.80 (s, 3H, OMe), 6.40 (m, 2H), 6.46 (m, 1H), 6.59 (d,
1H, J = 2.4 Hz), 7.28 (m, 1H), 7.47 (d, 1H, J = 1.2 Hz), 7.75 (s, 1H), 9.38 (br, 2H). 13C NMR (150
MHz, CDCl3) δ(ppm) 55.3, 101.8, 106.1, 108.3, 109.6, 110.5, 111.2, 128.9, 130.2, 141.9, 146.4,
147.5, 157.2, 160.9. HRMS (ESI): m/z [M + H]+ calculated for C14H13N2O3: 257.0926; found:
257.0933.
2.3.3. 3-(2-Hydroxy-4-methoxyphenyl)-4-(5-methylfuran-2-yl)-1H-pyrazole (4c)
Yellow solid; mp 139-141 °C; IR (KBr), ν (cm-1): 3415, 2028, 1625, 1284, 1160, 1086, 846,
1
622, 482; H NMR (600 MHz, CDCl3) δ (ppm) 2.33 (s, 3H), 3.79 (s, 3H), 6.03 (m, 1H), 6.25 (d,
1H, J = 2.4 Hz), 6.40 (dd, 1H, J = 8.4, 2.4 Hz), 6.58 (d, 1H, J = 2.4 Hz), 7.38 (d, 1H, J = 8.4 Hz),
7.71 (s, 1H), 9.10 (br, 2H). 13C NMR (150 MHz, CDCl3) δ(ppm) 13.7, 55.4, 101.8, 106.1, 107.2,
109.2, 109.9, 111.0, 129.1, 130.2, 144.6, 147.2, 151.8, 157.2, 161.0. HRMS (ESI): m/z [M + H]+
calculated for C15H15N2O3: 271.1082; found: 271.1091.
2.3.4. 3-(2-Hydroxyphenyl)-4-(thiophen-2-yl)-1H-pyrazole (4d)
Yellow solid; mp 143-145 °C; IR (KBr), ν (cm-1): 3460, 3247, 2013, 1616, 1541, 1458, 1377,
1296, 1223, 1016, 974, 822, 760, 611; 1H NMR (600 MHz, CDCl3) δ (ppm) 6.72 (m, 1H), 7.03 (m,
2H), 7.06 (m, 1H), 7.19 (m, 1H), 7.33 (dd, 1H, J = 7.8, 1.2 Hz), 7.38 (dd, 1H, J = 7.8, 1.2 Hz),
7.65 (s, 1H), 10.47 (br, 2H). HRMS (ESI): m/z [M + H]+ calculated for C13H11N2OS: 243.0592;
found: 243.0598. 13C NMR (150 MHz, CDCl3) δ(ppm) 113.3, 116.6, 117.1, 119.4, 125.9, 127.5,

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127.7, 128.4, 129.8, 131.1, 133.7, 147.3, 155.7. HRMS (ESI): m/z [M + H]+ calculated for
C13H11N2OS: 243.0592; found: 243.0598.
2.3.5. 3-(2-Hydroxy-4-methoxyphenyl)-4-(thiophen-2-yl)-1H-pyrazole (4e)
Yellow solid; mp 117-119 °C; IR (KBr), ν (cm-1): 3414, 3240, 2028, 1625, 1387, 1199, 1153,
624, 482; 1H NMR (600 MHz, CDCl3) δ (ppm) 3.78 (s, 3H), 6.32 (m, 1H), 6.59 (m, 1H), 7.03 (m,
1H), 7.08 (m, 1H), 7.28 (m, 1H), 7.34 (m, 1H), 7.65, 9.95 (br, 2H). 13C NMR (150 MHz, CDCl3)
δ(ppm) 55.4, 102.0, 106.0, 109.8, 112.7, 125.9, 127.6, 129.1, 131.0, 133.9, 147.5, 157.4, 160.9.
HRMS (ESI): m/z [M + H]+ calculated for C14H13N2O2S: 273.0697; found: 273.0705.
2.3.6. 3-(2-Hydroxyphenyl)-4-(1-methyl-1H-pyrrol-2-yl)-1H-pyrazole (4f)
Yellow solid; mp 96-98 °C; IR (KBr), ν (cm-1): 3415, 3240, 2028, 1625, 1392, 1246, 1152,
1
622, 482; H NMR (400 MHz, CDCl3) δ (ppm) 3.26 (s, 3H), 6.20 (dd, J = 3.3, 1.8 Hz, 1H), 6.26
(m, 1H), 6.71 (m, 1H), 6.79 (m, 1H), 6.89 (dd, 1H, J = 8.1, 1.8 Hz), 7.04 (d, J = 8.1 Hz, 1H), 7.18
(m, 1H), 7.63 (s, 1H), 10.83 (br, 2H). 13C NMR (150 MHz, CDCl3) δ(ppm) 34.2, 108.0, 110.1,
111.1, 116.9, 117.1, 119.7, 123.0, 124.1, 126.7, 129.5, 131.0, 149.2, 156.1. HRMS (ESI): m/z [M
+ H]+ calculated for C14H14N3O: 240.1137; found: 240.1143.
2.3.7. 3-(2-Hydroxy-4-methoxyphenyl)-4-(1-methyl-1H-pyrrol-2-yl)-1H-pyrazole (4g)
1
White solid; mp 155-156 °C; IR (KBr), ν (cm-1): 3415, 2028, 1625, 1392, 1077, 622, 482. H
NMR (600 MHz, CDCl3) δ (ppm) 3.26 (s, 3H), 3.77 (s, 3H), 6.18 (m, 1H), 6.25 (m, 1H), 6.28 (dd,
1H, J = 8.8, 2.6 Hz), 6.57 (d, 1H, J = 2.6 Hz), 6.76 (d, 1H, J = 8.8 Hz), 6.77 (m, 1H), 7.59 (s, 1H),
10.14 (br, 2H). 13C NMR (150 MHz, CDCl3) δ(ppm) 34.2, 55.4, 101.9, 106.4, 108.0, 110.2, 110.4,
122.9, 124.2, 127.5, 130.7, 149.5, 157.8, 160.7. HRMS (ESI): m/z [M + H]+ calculated for
C15H15N3O2: 270.1242; found: 270.1243.
2.3.8. 3-(2-Hydroxyphenyl)-4-phenyl-1H-pyrazole (5a) [25]
1
White solid; mp 113-115 °C; H NMR (400 MHz, DMSO-d6) δ (ppm) 6.80 (s, 1H), 6.01 (s,
1H), 7.09-7.32 (m, 5H), 7.34(d, J = 7.3 Hz, 2H), 7.89 (s, 1H), 9.87 (s, 1H), 12.98 (s, 1H). HRMS
(ESI): m/z [M + H]+ calculated for C15H13N2O: 237.1028; found: 237.1026.
2.3.9. 3-(2,4-Dihydroxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrazole (5b) [19]

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White solid; mp 252-254 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 6.28 (m, 2H), 6.89 (m,
5H), 7.63 (s, 1H), 9.24-10.50 (m, 3H), 12.55 (s, 1H). HRMS (ESI): m/z [M + H]+ calculated for
C15H13N2O3: 269.0926; found: 269.0921.
2.3.10. 3-(2,4-Dihydroxyphenyl)-4-(4-methoxyphenyl)-1H-pyrazole (5c) [19]
White solid; mp 210-211; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.72 (s, 3H), 6.22 (s, 1H),
6.40 (s, 1H), 6.88 (m, 3H), 7.21 (d, 2H, J = 8.4 Hz), 7.70 (s, 1H), 9.48-10.34 (s, 2H), 12.62 (s, 1H).
HRMS (ESI): m/z [M + H]+ calculated for C16H14N2O3: 283.1082; found: 283.1077.
2.3.11. 3-(2-Hydroxy-4-isopropoxyphenyl)-4-phenyl-1H-pyrazole (5d) [19]
White solid; mp 129-131 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 1.26 (d, 6H, J = 6.0 Hz),
4.54 (m, 1H), 6.36 (s, 1H), 6.46 (s, 1H), 6.99 (d, 1H, J = 8.4 Hz), 7.16 (s, 1H), 7.29 (s, 4H), 7.78
(s, 1H), 9.72 (s, 1H), 12.74 (s, 1H). HRMS (ESI): m/z [M + H]+ calculated for C18H19N2O2:
295.1447; found: 295.1443.
2.3.12. 3-(2-Hydroxy-4-isopropoxyphenyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrazole (5e) [26]
White solid; mp 110-112 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 1.27 (d, 6H, J = 5.6 Hz),
4.54 (m, 1H), 6.49 (m, 2H), 7.08 (d, 1H, J = 7.5 Hz), 7.51 (d, 2H, J = 7.4 Hz), 7.59 (m, 2H), 7.90
(s, 1H), 9.80 (s, 1H), 12.97 (s, 1H). HRMS (ESI): m/z [M + H]+ calculated for C19H18F3N2O2:
363.1320; found: 363.1313.
2.3.13. 3-(2-Hydroxy-4-methoxy-6-methylphenyl)-4-phenyl-1H-pyrazole (5f) [26]
1
White solid; mp 141-142 °C; H NMR (400 MHz, DMSO-d6) δ (ppm) 1.84 (s, 3H), 3.73 (s,
3H), 6.36 (s, 2H), 7.17 (m, 6H), 7.92 (s, 1H), 12.54 (s, 1H). HRMS (ESI): m/z [M + H]+ calculated
for C17H17N2O2: 281.1290; found: 281.1287.
2.3.14. 4-(4-Fluorophenyl)-3-(2-hydroxy-4-methoxyphenyl)-1H-pyrazole (5g) [26]
1
White solid; mp 173-175 °C; H NMR (400 MHz, DMSO-d6) δ (ppm) 3.72 (s, 3H), 6.41 (d,
1H, J = 8.4 Hz), 6.49 (s, 1H), 7.02 (d, 1H, J = 8.4 Hz), 7.10 (m, 2H), 7.29 (m, 2H), 7.82 (s, 1H),
9.83 (s, 1H), 12.80 (s, 1H). HRMS (ESI): m/z [M + H]+ calculated for C16H14FN2O2: 285.1039;
found: 285.1035.
2.4 Crystal data and structure determination
Data collections for 5b and 5c were performed on a Bruker Smart-1000 CCD diffractometer

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meter. Both diffractometers were equipped with graphite-monochromated Mo-Ka radiation (λ =
0.71073 A°) and intensity data for all compounds were collected by the narrow frame method at
room temperature. All data sets were corrected for absorption by the ψ-ω Method. All structures
were solved by the direct method and refined by full matrix least-squares fitting on F2 by
SHELX-97. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were added
at calculated position and refined using a riding model. Crystallographic data and structural
refinements for 5b and 5c were summarized in Table 1.
Table 1.
Crystal and structure refinement data for 5b and 5c.
Crystal Data
5b
5c
CCDC
886075
1528616
Empirical formula
Formula weight
Temperature
C15H14N2O4
C16H14N2O3
286.28
286.29
296(2) K
296(2) K
Wavelength
0.71073 Å
0.71073 Å
Crystal system
Space group
Hexagonal
Monoclinic
R-3
P2(1)/c
Unit cell dimensions
a = 31.4958(12) Å
b = 31.4958(12) Å
c = 7.1857(6) Å
alpha = 90 deg.
beta = 90 deg.
gamma = 120 deg.
6173.1(6)
a = 14.6062(16) Å
b = 7.0612(8) Å
c = 13.7484(15) Å
alpha = 90 deg.
beta = 110.890(2) deg.
gamma = 90 deg.
1324.8(3)
Volume (Å3)
Z, Calculated density (mg/m3)
Absorption coefficient (mm-1)
F (000)
18, 1.386
4, 1.415
0.102
0.099
2700
592
Crystal size, mm
0.42 × 0.30 × 0.18
2.24-25.09 deg.
-37≤h≤36, -37≤k≤36, -8≤l≤8
10506 / 2449 [R(int) = 0.0285]
100.0%
0.46 × 0.29 × 0.24
2.99-25.10 deg.
-17≤h≤15, -8≤k≤8, -16≤l≤15
6387 / 2366 [R(int) = 0.0201]
99.7%
Theta range for data collection
Limiting indices
Reflections collected / unique
Completeness to theta
Max. and min. transmission
Refinement method
0.9816 and 0.9582
Full-matrix least-squares on F2
2449 / 2 / 202
0.9765 and 0.9557
Full-matrix least-squares on F2
2366 / 0 / 194
Data / restraints / parameters

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Goodness-of-fit on F2
1.088
1.086
Final R indices [I>2sigma(I)]
R indices (all data)
R1 = 0.0453, ωR2 = 0.1277
R1 = 0.0591, ωR2 = 0.1375
R1 = 0.0407, ωR2 = 0.1259
R1 = 0.0485, ωR2 = 0.1315
0.515 e.A-3
0.583 and −
0.517 e.A-3
Largest diff. peak and hole
0.556 and
−
2.5 Antifungal Bioassay
According to the literature [22, 23], compounds 4 and 5 were tested for their antifungal
performance against five phytopathogenic fungi, such as Cytospora sp., Colletotrichum
gloeosporioides, Botrytis cinerea, Alternaria solani, and Fusarium solani. These strains were
incubated and cultured on potato dextrose agar (PDA), and prepared in the sterilized Petri dishes
to get new mycelium for 7 days at 28 oC. Then, 4 and 5 dissolved in acetone at the concentrations
of 100, 50, 25, 12.5, 6.25 ꢀg/mL and mixed with sterile molten PDA agar medium. Every kind of
mycelium was cut to 4.5 mm diameter size and incubated in the center of the dishes on PDA with
the sterile conditions at 28 oC for 4 days. Each sample was performed three times. The commercial
fungicide hymexazol and acetone were used as positive control and negative control, respectively.
After the mycelia grew completely, the inhibition rate for the mycelia growth was measured using
the following formula:
Inhibition rate (%) = (C − T)/(C − 4.5 mm) × 100%
Where C is the average diameter of mycelia in the negative control test, and T is the average
diameter of mycelia on other treated PDA.
3ꢀResults and discussion
3.1 Chemistry
In our initial investigation, 4a was prepared according to our previous reports [19, 22-23]. The
condensation of 4-furan-3-phenyl-1H-pyrazole and hydrazine hydrate in the different solvents
such as MeOH, EtOH, MeCN, Hexane, THF, t-BuOH and DMF under refluxing were optimized
(Table 2). The results showed that the yield of 4a was the highest (90%) using EtOH as the solvent
and refluxing for 2 h.
Table 2.
Solvent effects on the condensation of 4-furan-3-phenyl-1H-pyrazole 2a with hydrazine hydratea

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O
O
N2H4 H2O
HO
EtOH
N
O
O
N
H
2a
4a
Entry
Solvent
CH3OH
T (oC)
Time (h)
yield (%)b
68
79
3.0
2.0
2.5
4.5
4.0
3.0
1.5
78
90
65
58
55
80
50
1
2
3
4
5
6
7
CH3CH2OH
CH3CN
Hexane
THF
80
69
68
t-BuOH
DMF
83
153
aAll reactions were carried out on 1 mmol scale of 2a and 2 mmol scale of hydrazine hydrate in 15 mL solvent.
Isolated yield on the basis of 2a and the reaction was monitored by TLC until 2a was fully consumed.
With the suitable reaction conditions, 3-phenyl-4-heteroaryl-1H-pyrazoles (4) and
3,4-diphenyl-1H-pyrazoles (5) were synthesized by the condensation of compound 2 or 3 and
hydrazine hydrate. As depicted in Table 3, compound 3 bearing more hydroxyl groups gave the
corresponding products in lower yields. For example, product 5a was obtained in 90% yield, and
the yield of 5b was 81%. When substrates carried electron-donating groups, the corresponding
products were obtained in higher yields than those with electron-withdrawing groups. For example,
5g carried the electron-withdrawing substituent –F, the yield of 4g (86%, Table 3) was lower than
5f (95%, Table 3). On the contrary, when a methoxy group was introduced at the para-position of
the phenyl ring located at 3-position of the pyrazole, the yield of the corresponding product 4 was
1
obviously decreased (4a vs 4b and 4d vs 4e). All new products were fully characterized by H
NMR, 13C NMR spectra, IR and HRMS.
Table 3.
Synthesis of 3-phenyl-4-heteroaryl-1H-pyrazoles (4) and 3,4-diphenyl-1H-pyrazoles (5) a

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aAll reactions were carried out on 1 mmol scale of compound 2 or 3 and 2 mmol scale of hydrazine hydrate in 15
mL ethanol and monitored by TLC until compound 2 or 3 were fully consumed. Isolated yield on the basis of
compound 2 and 3.
3.2 Tautomeric forms of 3-phenyl-4-heteroaryl-1H-pyrazoles (4) and 3,4-diphenyl-1H-pyrazoles
(5)
According to the literature reported [19, 27], compounds 4 and 5 exist in tautomeric forms
(Scheme 2). For 1H NMR of 5a, with DMSO-d6 as solvent, two neighboring proton peaks at 13.31
ppm and 12.98 ppm were appeared simultaneously in the aromatic region; when D2O was added
to DMSO-d6, those two proton peaks disappeared and the spectra was simplified via the deuterium
(2H)-exchange experiments. The experimental results showed that 3,4-diphenyl-1H-pyrazoles
existed two tautomeric forms at the same time and their integral areas of two proton peaks (12-14
ppm) at N atom have different proportion. For examples, the ratio of tautomers is 4 : 5 in 5a and 1 :
2 in 5e. Interestingly, when CDCl3 was as the solvent, compounds 4 and 5 were all absent
tautomeric forms and have a single structure.

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Scheme 2. Alternative tautomeric forms of 5.
3.3 Crystal structure of 5b and 5c
The molecular structure of compounds 5b and 5c are illustrated in Fig. 1. Single-crystal X-ray
diffraction analysis has been performed for the two crystals to determine their structures. The
investigations revealed that 5b and 5c have a similar structural feature including a pyrazole ring
and two phenyl rings. Meanwhile, compound 5b contains one solvent water molecule and three
hydroxyls. Compound 5c contains a methoxyl group and two hydroxyls. The atom of 5b and 5c
composed of ring A/B(C1-C6/C10-C15) and pyrazole ring (C7-C9/N1-N2) are not coplanar. The
torsion angle of the ring A and pyrazole ring of 5b and 5c are 126.4° and 70.9°. The torsion angle
of the ring B and pyrazole ring of 5b and 5c are 143.0° and 156.0°. To avoid steric conflicts, the
dihedral angle between ring A and B of 5b and 5c are 129.6° and 76.8°. In the crystal structure of
5c, the methoxyl groups at C13 is nearly coplanar with its attached ring, indicative of the torsion
angle C16-O3-C13-C14 = 7.9°.
5b
5c
A
B
C
Fig. 1 Molecular structure of 5b and 5c
As shown Fig. 2 (a), an obturated center-hollowed ring was generated by 12 hydrogen bonds
which formed by six lattice water molecules and six pyrazole skeletons. The bond lengths and
angles of O1-H1…O4, O4-H4B…O2(i) [symmetry code (i): x-y+1/3, x-1/3, -z+5/3] were 1.93 Å,
2.00(4) Å and 163.0°, 159(3)°, respectively. Meanwhile, within the obturated center-hollowed ring,
a regular hexagon was linked by the six same aromatic hydrogen bonds C15-H15…Cg(ii) with
bond length and angle were 2.92 nm and 135°, where the Cg(ii) was the centroid of ring (C10-C15)

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at symmetry code (ii): (y+1/3, -x+y+2/3, -z+5/3). The obturated center-hollowed ring was linked
into an along ab sheet through hydrogen bonds, which formed by lattice water molecules and other
pyrazole skeletons.
Furthermore, Fig. 2 (b) shows how a centrosymmetric dimer is formed through paired
N1-H1A…O(i) hydrogen bonds at the inversion position. Within the dimer π–π stacking
interactions exist between the two pyrazole skeletons. The two stacking molecules arrange in a
centro-symmetric fashion with Cg-Cg(i) = 3.658 Å, where Cg and Cg(i) are the centre of two
phenyl ring (C1-C6) of the pyrazole skeleton at (x, y, z) and (1-x, -y, 1-z), respectively. These
dimers are linked by aromatic hydrogen bonds C12—H12ꢁCg(ii) [symmetry code (ii): x, y, 1+z].
Other parts of the four molecules interacted by the same way along axis c. Meanwhile, hydrogen
bonds O1—H1ꢁO4, O4—H4BꢁO4 and O4—H4BꢁO2 formed by lattice water and lattice
water, lattice water and pyrazole skeleton are also existed between the dimmers. Thus, compound
5b is assembled to a three-dimensional networking structure by hydrogen bonds and aromatic
stacking interactions.
a
b
O1
C15
Cg
H1
H15
Cg(ii)
C15(ii)
H15(ii)
O4
H4B
O2(i)
H15(i)
C15(i)
Cg(iii)
Fig. 2. (a) 2D network of 5b by C―H···π and H-bonds connections. Symmetry code: (i): x-y+1/3, x-1/3, -z+5/3;
(ii): y+1/3, -x+y+2/3, -z+5/3. (b) 3D network of 5b by C―H···π, H-bonds and π···π connections. Symmetry code:
(i): 1-x, -y, 1-z; (ii): x, y, 1+z.
As illustrated in Fig. 3 (a), compound 5c contains two different C―H…π stackings interaction,
and the distances of the H6 to CgC(i) [symmetry code (i): x, 1+y, z] and H16B to CgA(ii)
[symmetry code (ii): 1-x, 1-y, 3/2-z] are 2.789 nm and 2.872 nm, which are in the normal range of
the C-H···π stacking. Furthermore, two adjacent 5c molecules also is linked by

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O1(iii)—H1(iii) ꢁO2 intermolecular hydrogen bonds [symmetry code (iii): x, y-1, z]. Thus, one
molecule interacts other three adjacent molecules by intermolecular hydrogen bonds and two
different C―Hꢁπ aromatic hydrogen bonds, and compound 5c is assembled to a columnar
structure along axis-b. In addition, compound 4c also contains two intermolecular hydrogen bonds
(Fig. 3 (b)). Among them, atom N1 and O1(i) acted as acceptor, via H2(ii) and H2B, to O2(ii) and N2
from the neighboring molecules, which are observed for O2(ii)—H2(ii) ꢁN1 [symmetry code (ii): x,
1/2-y, -1/2+z] and N2—H2BꢁO1(i) [symmetry code (i): -x, 1/2+y, 1/2-z]. The distance of
O2(ii) ꢁN1 and N2ꢁO1(i) are 2.652 Å and 2.758 Å. The angle of O2(ii)—H2(ii) ꢁN1 and
N2—H2B…O1(i) are 163o and 153o. (Details of hydrogen bond lengths and angles are given in
Table 4). Compound 5c is assembled to a three-dimensional networking structure by hydrogen
bonds and aromatic stacking interactions.
a
b
Fig. 3. (a) The C―H···π and H-bonds of compound 5c. Symmetry code: (i): x, 1+y, z; (ii): 1-x, 1-y, 3/2-z; (iii): x,
-1+y, z. (b) Three kinds of hydrogen bonds of 5c. Symmetry code: (i): -x, 1/2+y, 1/2-z; (ii): x, 1/2-y, -1/2+z; (iii): x,
-1+y, z.
Table 4.
Hydrogen bond lengths (Å) and bond angles (o).
∠
D—H···A
D—H···A
D—H
H···A
D—A
Symmetric code
5b
O1—H1…O4
N1—H1A…O1
O2—H2…N2
O4—H4B…O2
O4—H4C…O4
0.82
0.88
0.836
0.84
0.84
1.93
2.12
1.94
2.00
2.03
2.727 (3)
2.968 (2)
2.752 (4)
2.801 (3)
2.864 (3)
163
163
167
159
174
2/3-x, 1/3-y, 1/3-z
2/3-x+y, 1/3-x, 1/3+z
x-y, x, 1-z
1/3-x+y, 2/3-x, -1/3+z

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5c
O1—H1…O2
O2—H2…N1
N2—H2B…O1
0.92
0.90
0.86
1.91
1.78
2.15
2.758 (2)
2.652 (2)
2.957 (2)
153
163
155
x, -1+y, z
x, 1/2-y, -1/2+z
-x, 1/2+y, 1/2-z
3.4 Antifungal activity
Fourteen 3,4-diaryl-1H-pyrazoles derivatives (4a-4g, 5a-5g) were screened for their antifungal
activity at a concentration of 100 ꢀg/mL in vitro against Cytospora sp., Colletotrichum
gloeosporioides, Botrytis cinerea, Alternaria solani, and Fusarium solani (Table 5). Most of those
compounds exhibited effectively antifungal performance. Among them, the inhibition rates of
compounds 4c-4e, 4g, 5a and 5d-5g over 70% were selected to obtain their IC50 (half-maximal
inhibitory concentration) values (Table 6).
Table 5
Preliminary antifungal activities of compounds 4 and 5 at 100 ꢀg/mLa
Average values of antifungal rate (%)
Compd.
C.s.
C.g.
B.c.
A.s.
F.s.
62.90
67.02
68.46
76.37
78.76
37.30
68.17
87.36
9.30
68.59
69.04
83.11
92.39
91.70
40.31
74.71
100
26.45
31.91
25.35
25.96
31.77
26.50
29.05
15.87
2.30
60.85
53.59
77.29
67.54
74.45
33.5
46.7
45.75
68.38
87.66
84.04
26.74
70.74
89.29
21.13
24.53
80.80
73.00
74.7
4a
4b
4c
4d
4e
4f
69.94
83.70
34.01
63.96
84.20
64.46
76.22
79.40
55.17
4g
5a
5b
5c
5d
5e
5f
25.52
68.6
69.59
84.55
65.32
93.86
78.22
28.06
19.10
23.20
15.53
28.49
28.03
100
74.66
74.19
70.71
88.45
38.01
29.81
5g
60.1
Hy
a C.s. Cytospora sp.; C.g., Colletotrichum gloeosporioides; B.c., Botrytis cinerea; A.s. Alternaria
solani; F.s., Fusarium solani; Hy, hymexazol.
As outlined in Table 6, compounds 4 and 5 showed different antifungal activities against the
five tested fungi. Most of them exhibited better antifungal activities than the positive control

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hymexazol against Cytospora sp., Colletotrichum gloeosporioides, Alternaria solani and
Fusarium solani. They were all almost inactive against Botrytis cinerea.
In case of compounds 4, 4c with a methyl group at the ortho-position of the furan group showed
an effective antifungal activity against C. gloeosporioides with IC50 values of 29.52 ꢀg/mL. When
a thiophene group was introduced to the 4-position of the pyrazole ring, compounds 4d and 4e
selectively inhibited the growth of Cytospora sp. and C. gloeosporioides. Especially, 4d exhibited
effective inhibition rate against C. gloeosporioides with IC50 values of 12.86 ꢀg/mL, which was
far more superior to the positive control hymexazol (IC50 > 100 ꢀg/mL).
In case of compounds 5, compound 5a with a hydroxyl group at the ortho-position of the
phenyl ring located at 3-position of the pyrazole, showed effective inhibitory activity against
Cytospora sp. and C. gloeosporioides with IC50 values of 19.59 and 20.53 ꢀg/mL. When a
methoxy group and fluorine atom were simultaneously introduced to the para-position of the
phenyl ring located at 3- and 4-position of the pyrazole, the antifungal activity and broad-spectrum
antifungal property enhanced dramatically. For example, 5g exhibited fairly good antifungal
activity against Cytospora sp., C. gloeosporioides and A. solani with IC50 values of 11.91, 14.92
and 16.98 ꢀg/mL, respectively. Moreover, compound 5d, having a isopropoxy group fixing the
para-position of the phenyl ring located at 3-position of the pyrazole, was more better and broader
inhibitory effect on Cytospora sp., C. gloeosporioides, A. solani and Fusarium solani with IC50
values of 26.96, 28.84, 16.77 and 22.10 ꢀg/mL, respectively. Compared with our previous work
[20], compounds 4c, 4d, 4e, 5d, and 5g exhibited better and more selectivity antifungal activities.
Table 6
Antifungal activity of selected compounds
IC50 ± SD/ (ꢀg/mL)
Compd.
C.s.
C.g.
B.c.
A.s.
F.s.
4c
4d
4e
4g
5a
5d
5e
5f
—
29.52 ± 1.57
12.86 ± 6.21
30.28 ± 2.49
35.36 ± 2.82
20.53 ± 1.75
28.84 ± 5.39
55.13 ± 5.77
56.76 ± 4.99
—
49.05 ± 2.11
—
—
36.82 ± 2.86
24.87 ± 1.02
—
—
62.81 ± 0.72
53.23 ± 5.19
57.73 ± 6.12
44.99 ± 6.48
22.10 ± 0.43
55.31 ± 0.50
39.93 ± 3.43
—
36.71 ± 2.09
—
—
—
19.59 ± 0.89
26.96 ± 2.12
—
35.77 ± 1.47
16.77 ± 0.88
—
43.57 ± 2.16
—
37.7 ± 1.56
70.37 ± 4.57
41.42 ± 0.54

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5g
11.91 ± 0.51
>100
14.92 ± 1.14
>100
—
16.98 ± 0.50
18.41 ± 0.40
—
Hy
7.23 ± 0.33
37.42 ± 3.50
a — : IC50 values was not determined.
4ꢀConclusions
In summary, we have designed and synthesized fourteen 3,4-diaryl-1H-pyrazoles
derivatives (4 and 5) by the reaction of 3-heteroarylchromones and 3-phenylchromones with
hydrazine hydrate in good yields (75-96%). The structure of 3-(2,4-dihydroxyphenyl)-4-(4-
hydroxyphenyl)-1H-pyrazole (5b) and 3-(2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-1H-
pyrazole (5c) were further conformed by the single crystal X-ray diffraction. Moreover, the
antifungal activity of compounds 4 and 5 against phytopathogenic fungi (Cytospora sp.,
Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani and Fusarium solani) were
evaluated in vitro. The test showed that compounds 4c, 4d, 4e, 5d, and 5g exhibited fairly
effective antifungal activity against those five phytopathogenic fungi.
Acknowledgements
This research was supported by the National Natural Science Foundation of China (NO. 21672132)
and the Fundamental Research Funds for the Central Universities (NO. 2016CBY002).
Abbreviations
HRMS, high resolution mass spectrometry; TLC, thin-layer chromatography; Mp., melting point;
IC50, half-maximal inhibitory concentration.
Appendix A. Supplementary data
CCDC 886075 and 1528616 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif. HRMS and NMR spectra of compounds 4 and 5.
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