Design, Synthesis, and Biological Evaluation of Novel 1,3,4-Thiadiazolylpyrazolines Compounds Containing Ferrocene

Article abstract of DOI:10.1002/jhet.3238

The synthesis of 1,3,4-thiadiazole skeleton compounds exhibiting high fungicidal activities has been demonstrated. Thirteen novel 1,3,4-thiadiazolyl-pyrazolines compounds containing ferrocene were designed and synthesized from the ferrocenylchalcones intermediates 3a–3m and the 2-hydrazino-5-phenyl-1,3,4-thiadiazole intermediate 8. All compounds were characterized by ¹H NMR, ¹³C NMR, FT-IR spectra, and HR-MS, and the structure of one of the new compounds N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-5-phenyl-pyrazoline 9a was further determined by X-ray diffraction analysis. The preliminary results of a biological activity assay indicated that all the title compounds exhibited significant fungicidal activities against Pythium solani, Gibberella saubinetii, and Gibberella nicotiancola. Furthermore, compounds 9e and 9h displayed even higher fungicidal activities against the three fungal species compared with the control drug pyraclostrobin.

Full text of DOI:10.1002/jhet.3238

Month 2018
Design, Synthesis, and Biological Evaluation of Novel 1,3,4-
Thiadiazolylpyrazolines Compounds Containing Ferrocene
Liqin Chen, Huihui Duan, Xinyu Zhang, Qiong Zhang, Hailian Huang, Junlong Zhao, Bang Chen, Chengwen Hua, and
*
Xiaofeng Gou
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry
& Materials Science, Northwest University, Xi’an 710127, China
*
E-mail: xdny917@163.com
Received November 21, 2017
DOI 10.1002/jhet.3238
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
The synthesis of 1,3,4-thiadiazole skeleton compounds exhibiting high fungicidal activities has been dem-
onstrated. Thirteen novel 1,3,4-thiadiazolyl-pyrazolines compounds containing ferrocene were designed and
synthesized from the ferrocenylchalcones intermediates 3a–3m and the 2-hydrazino-5-phenyl-1,3,4-
1
thiadiazole intermediate 8. All compounds were characterized by H NMR, 13C NMR, FT-IR spectra, and
HR-MS, and the structure of one of the new compounds N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
5-phenyl-pyrazoline 9a was further determined by X-ray diffraction analysis. The preliminary results of a
biological activity assay indicated that all the title compounds exhibited significant fungicidal activities
against Pythium solani, Gibberella saubinetii, and Gibberella nicotiancola. Furthermore, compounds 9e
and 9h displayed even higher fungicidal activities against the three fungal species compared with the control
drug pyraclostrobin.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
natural products, pharmaceutical agents, and like pyrazoline
derivatives. 1,3,4-Thiadiazoles have also been reported
to exhibit a variety of biological activities including
antitumor,[10] anti-inflammatory,[11] anticonvulsant,[12]
anticancer,[13] antibacterial,[14] antioxidant,[15] antifungal,
[16] herbicidal,[17] pesticidal,[18] and antitubercular[19]
activities. In addition, 1,3,4-thiadiazoles can be found as
precursors in a wide range of organic reactions.
In theory, ferrocene compounds exhibit aromaticity,
redox reversibility, high stability, electron affinity, and
low toxicity. Ferrocene derivatives have found
widespread applications in materials science,[20]
electrochemistry,[21] biology,[22,23] and medicine.
[24,25] Furthermore, it has already been reported that the
introduction of ferrocenyl functionalities provides
compounds with enhanced biological activity.[26–28]
Prompted by the aforementioned biological activities of
pyrazolines, 1,3,4-thiadiazoles and ferrocenes, we sought
to combine these structural scaffolds to design and
synthesize new derivatives of 1,3,4-thiadiazolyl-
pyrazolines containing ferrocene. We further determined
if more active substances could be obtained through the
superposition of the three active groups. In doing so, a
novel series of 1,3,4-thiadiazolyl-pyrazolines containing
ferrocene was synthesized from ferrocenylchalcones and
2-hydrazino-5-phenyl-1,3,4-thiadiazole. In addition, the
antifungal activities results of the newly synthesized
In the past few decades, heterocyclic compounds have
played an increasingly critical role in agricultural and
medical research. Various compounds containing nitrogen
atoms are known for their therapeutic activity. Some
pyrimidine and indole ring incorporated molecules are
reported to exhibit antitumor activity. Dihydroindolizino
indole and 1,2,3-triazole derivatives feature certain effect
in the treatment in human cancer cells.[1,2] Pyrazoline
represents a classical nitrogen-containing heterocycle that
is highly prevalent in a variety of natural and nonnatural
products. The five-membered nitrogen-containing
heterocyclic compound species has demonstrated a wide
range of biological activities including antitumor,[3]
antibacterial,[4] anti-inflammatory,[5] antioxidant,[6]
antimicrobial,[7] antifungal,[8] and insecticidal[9]
activities. In fact, pyrazoline derivatives have attracted
significant interest in the scientific community in recent
years, particularly in the development of pesticides and
pharmaceuticals. Furthermore, pyrazolines represent an
important compound species for theoretical heterocyclic
chemistry and can often be found as precursors used in
organic synthesis.
In terms of biological activities, 1,3,4-thiadiazoles have
also attracted wide interest because of their presence in a
large number of biologically active compounds, including
© 2018 Wiley Periodicals, Inc.

L. Chen, H. Duan, X. Zhang, Q. Zhang, H. Huang, J. Zhao, B. Chen, C. Hua, and X. Gou
Vol 000
1,3,4-thiadiazolyl-pyrazolines compounds have been
studied as discussed in this paper.
structures. The FT-IR spectrum of the title compounds
showed the presence of strong characteristic band at
1525–1545 cmꢀ1 corresponding to a C¼C stretching
band. Other prominent absorption bands observed in the
IR spectrum were 3000–3100 cmꢀ1 (Ar–H) and 1270–
RESULTS AND DISCUSSION
1
1340 (C–N) cmꢀ1, respectively. The recorded H NMR
Chemistry.
The synthesis of N-(4-phenyl-1,3,4-
spectra recorded for these compounds clearly supported
the proposed structures. The methylene protons of
pyrazoline ring appeared as two doublets at δ = 3.1–
3.9 ppm. The methine protons of pyrazoline ring
appeared as a doublet at δ = 3.1–3.9 ppm. All the other
additional peaks observed were in agreement with the
protons on the corresponding aromatic substituents and
the ferrocene ring. 13C NMR spectra of the compounds
confirmed the presence of a ferrocene ring due to the
presence of four carbon signals at δ = 64–75 ppm. The
HR-MS spectrometric data values and elemental analysis
data were also in good agreement with the proposed
structures.
Among these compounds, the crystal structure of
compound 9a was resolved by X-ray diffraction analysis.
The structural refinement parameters are provided in
Table 1, and the corresponding crystal structure is shown
in Figure 1. Red crystals of 9a were obtained through
slow evaporation of a mixed solvent solution (petroleum
ether : ethyl acetate : dichloromethane = 10:1:1). The
crystal structure of compound 9a was found to be
monoclinic with the space group P21/n. The structure
consisted of a pyrazoline ring with the carbon atom C17
thiadiazol-2-yl)-3-ferrocenyl-5-aryl-pyrazolines was
carried out as outlined in Scheme 1. The starting
compounds of ferrocenylchalcones were synthesized
according to known procedures from acetyl ferrocene
and aromatic aldehyde in the presence of sodium
hydroxide solution.[29] The compound 2-amino-5-aryl-
1,3,4-thiadiazole was obtained via direct cyclization of
a
carboxylic
acid
and
thiosemicarbazide
in
polyphosphoric acid.[30] Diazotization of 2-amino-5-
aryl-1,3,4-thiadiazole in concentrated hydrochloric acid
in the presence of metallic copper and sodium nitrite
provided 2-chloro-5-aryl-1,3,4-thiadiazole.[31] The latter
species was then reacted with hydrazine hydrate to
yield 2-hydrazino-5-phenyl-1,3,4-thiadiazole. The N-(4-
phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocen-yl-5-aryl-
pyrazolines were synthesized by reaction of 2-hydrazino-
5-phenyl-1,3,4-thiadiazole with ferrocenylchalcones in
ethanol.
The newly synthesized compounds (9a–m) were
characterized by FT-IR, H NMR, 13C NMR, and HR-
1
MS. The spectral data of all synthesized compounds
were obtained in good agreement with the proposed
Scheme 1. Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-5-aryl-pyrazoline.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Biological Evaluation of Novel 1,3,4-
Thiadiazolylpyrazolines Compounds Containing Ferrocene
Table 1
nicotiancola are shown in Table 2. The EC50 values for
all tested compounds were higher than the value reported
for pyraclostrobin against Pythium solani. The EC95
values for the compounds 9d, 9i, 9j, and 9k were found
to be lower than the EC95 value for the control drug
against Pythium solani. The results obtained show that
the antifungal activity at a high concentration was
superior to that at a low concentration. The EC50 values
for the compounds 9e and 9h were comparable with the
EC50 value for the control drug against Gibberella
sanbinetti. The EC95 values for the compounds 9e, 9h,
9h, 9j, and 9k were lower than the EC95 value for the
control drug against Gibberella sanbinetti. The data
indicated that compound 9h exhibited better fungicidal
activity against Gibberella sanbinetti and may therefore
be further studied as a lead compound for improved
fungicidal activity. Furthermore, the EC50 values for all
tested compounds were slightly higher compared with the
control drug against Gibberella nicotiancola. The EC95
values of compounds 9i and 9k were lower than the
control drug against Gibberella nicotiancola. The EC95
values of compounds 9e and 9l were comparable with the
EC95 value for the control drug against Gibberella
nicotiancola. Compounds 9i, 9k, 9e, and 9l also
exhibited significant fungicidal activities against
Gibberella nicotiancola.
Structural refinement parameters of 9a.
9a
Empirical formula
Formula weight
Crystal class
Space group
a (Å)
b (Å)
c (Å)
α (°)
β (°)
C
27H22FeN4S
490.40
Monoclinic
P21/n
10.927 (3)
20.749 (4)
11.189 (3)
69.802 (19)
115.509 (4)
90
γ (°)
V (Å3)
2289.7 (9)
4
1.423
Z
ρ
calc (g cmꢀ3
)
F(000)
Crystal size (mm)
Limiting indices
1016
0.36 × 0.28 × 0.14
ꢀ12 ≤ h ≤ 13, ꢀ24 ≤ k ≤ 24,
ꢀ13 ≤ l ≤ 8
11472
Reflections
collected
S on F2
1.082
0.1168, 0.3114
0.1764, 0.3517
R1, wRa2 [I > 2σ(I)]
R1, wRa2 (all data)
CONCLUSIONS
In summary, 13 novel N-(4-phenyl-1,3,4-thiadiazol-
2-yl)-3-ferrocenyl-5-arylpyrazoline derivatives containing
ferrocenyl, pyrazoline, and 1,3,4-thiadiazol functionalities
were designed and synthesized. The corresponding
structures were characterized by FT-IR, 1H NMR, 13C
NMR, and HR-MS. Furthermore, the fungicidal activities
of all title compounds were evaluated. The results
showed that all the tested compounds exhibited
significant antifungal activities. The antifungal activities
of the compounds against Gibberella sanbinetti
were found to be better than Pythium solani and
Gibberella nicotiancola. Compounds 9e and 9h in
particular exhibited efficient antifungal activities against
three fungal species, Pythium solani, Gibberella
sanbinetti, and Gibberella nicotiancola. The results
obtained demonstrate that our compounds should be
further studied and developed as promising antifungal
agents.
Figure 1. Molecular and crystal structures of compound 9a. [Color figure
can be viewed at wileyonlinelibrary.com]
substituted by ferrocene and a 5-phenyl-1,3,4-thiadiazole
group attached to the nitrogen atom N1. The pyrazoline
ring (C9/C16/C17/N1/N2) adopted an envelope
conformation with puckering parameter φ = 339.5°. The
two cyclopentadienyl rings (C18–C22) and (C23–C27)
on the ferrocenyl moiety were found to be nearly parallel,
with the dihedral angle of 3.16°. Furthermore, the
thiadiazole ring (C7/N1/N2/C8/S) was determined to be
planar. The intermolecular hydrogen bonds N⋯H–C
(N4⋯H14–C14, 2.646 Å; N1⋯H5–C5, 2.744 Å) were
found.
BIOLOGICAL ACTIVITIES
EXPERIMENTAL
The EC50 and EC95 values for the target compounds
9a–9m and the control drug pyraclostrobin against
Pythium solani, Gibberella sanbinetti, and Gibberella
General procedure. All reagents were obtained from
commercial sources and used without further purification.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. Chen, H. Duan, X. Zhang, Q. Zhang, H. Huang, J. Zhao, B. Chen, C. Hua, and X. Gou
Vol 000
Table 2
Antifungal activities of title compounds.
Compound
Fungus
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
Gibberella saubinetii
Gibberella nicotiancola
Pythium solani
y = ax + b
R2
EC50 (g/mL)
EC95 (g/mL)
9a
y = 1.591x + 0.9953
y = 1.6775x + 0.9979
y = 2.1622x ꢀ 0.1485
y = 1.5908x + 1.0252
y = 1.8283x + 0.7258
y = 1.5985x + 1.4188
y = 1.5711x + 1.3194
y = 1.7918x + 0.7728
y = 2.1474x ꢀ 0.0527
y = 2.0759x ꢀ 0.1025
y = 2.0074x + 0.2204
y = 1.9929x + 0.3538
y = 1.6256x + 1.2495
y = 1.709x + 1.2703
y = 2.7847x ꢀ 1.4219
y = 2.0536x + 0.0327
y = 2.147x ꢀ 0.0098
y = 1.947x + 0.6125
y = 1.7719x + 0.9809
y = 1.8416x + 0.697
y = 2.2328x + 0.0717
y = 1.6812x + 1.026
y = 1.7227x + 1.2568
y = 2.089x + 0.5257
y = 2.2318x + 0.1268
y = 1.7165x + 1.1251
y = 2.1495x + 0.5981
y = 1.8293x + 0.9483
y = 2.1056x + 0.0586
y = 2.0723x + 0.5621
y = 2.0971x + 0.2057
y = 2.0739x + 0.2034
y = 2.9758x ꢀ 1.4774
y = 1.554x + 1.4747
y = 1.6517x + 0.9207
y = 2.4593x ꢀ 0.4823
y = 1.274x + 2.0535
y = 1.7541x + 1.0185
y = 1.2883x + 2.2371
y = 1.3817x + 2.2809
y = 1.4692x + 1.9562
y = 1.557x + 2.1514
0.9953
0.9973
0.9942
0.9942
0.9964
0.9951
0.9971
0.9971
0.9967
0.9983
0.9972
0.9995
0.9991
0.9964
0.9915
0.9957
0.9965
0.9906
0.999
0.9977
0.9951
0.9996
0.993
0.9949
0.9932
0.9981
0.9915
0.9992
0.9942
0.993
0.329
0.243
0.241
0.315
0.218
0.174
0.22
0.229
0.225
0.229
0.24
0.214
0.203
0.146
0.202
0.262
0.215
0.179
0.185
0.217
0.161
0.231
0.149
0.139
0.153
0.181
0.112
0.164
0.222
0.139
0.193
0.203
0.15
3.556
2.324
1.386
3.409
1.8
9b
9c
1.859
2.453
1.893
1.315
1.418
1.586
1.435
2.085
2.252
0.788
1.659
1.258
1.254
1.572
1.697
0.93
9d
9e
9f
9g
9h
9i
2.199
1.342
0.85
0.833
1.643
0.65
9j
1.3
1.343
0.861
1.176
1.394
0.536
2.123
2.922
0.791
4.017
2.054
2.639
1.44
9k
9l
0.9923
0.999
0.9905
0.9983
0.9979
0.9906
0.9995
0.9928
0.9943
0.9959
0.9943
0.9961
0.186
0.295
0.17
0.205
0.193
0.14
0.093
0.118
0.068
9m
Control
Gibberella saubinetii
Gibberella nicotiancola
1.554
0.769
NMR spectral data were recorded at room temperature on a
400 MHz spectrometer (1H at 400 MHz and 13C at
Synthesis of ferrocenylchalcone (3a–3m).
Ferrocene
(10 g, 54 mmol) and acetic anhydride (60 mL,
635 mmol) were placed in a 200-mL dried round bottom
flask. Phosphoric acid (85%, 10 mL) was added dropwise
upon stirring of the mixture in an ice-water bath, and the
contents were heated to reflux for 30 min afterwards. The
progress of the reaction was monitored by TLC. Upon
reaction completion after approximately 30 min, the
reaction mixture was poured into a 500-mL beaker
containing crushed ice, stirred, and cooled. To reach a
solution pH of 7–8, 30% sodium hydroxide solution was
slowly added. After cooling for 30 min in an ice bath,
negative pressure was performed, and the obtained solid
was washed with deionized water twice. The solid was
100 MHz), using CDCl3 as
a
solvent with
tetramethylsilane as the internal standard. The chemical
shifts were reported relative to tetramethylsilane. High-
resolution mass spectra were recorded on a BRUKER
micrOTOF-QII mass spectrometer. Melting points were
recorded using an electrothermal melting point apparatus,
and the values were uncorrected and reported as obtained.
FT-IR spectra were recorded on a Tensor 27 Bruker
spectrometer. The crystallographic data of 9a were
collected using a Bruker SMART APEX II CCD
diffractometer. The corresponding structure refinement
parameters are listed in Table 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Biological Evaluation of Novel 1,3,4-
Thiadiazolylpyrazolines Compounds Containing Ferrocene
dried to obtain the crude product. Recrystallization in
petroleum ether afforded acetyl ferrocene 1 as fine
crystalline orange needles.
and ethanol were removed under reduced pressure to
obtain the crude product. Recrystallization in ethanol
afforded yellow crystals of compound 8.
Acetyl ferrocene (1, 1.2 g, 5 mmol), sodium hydroxide
solution (1 mL, 30%), and ethanol (20 mL) were
combined in a round-bottom flask at room temperature,
and the mixture was stirred until all solids dissolved
entirely. Then, to this mixture, aromatic aldehyde (2,
0.63 g, 6 mmol) was added dropwise over a period of
1 h, and the solution was stirred at room temperature for
15 h. Upon reaction completion (TLC, developing
solvent mixture = petroleum ether : ethyl acetate = 3:1),
the mixture was poured into ice water (100 mL). Next,
the solution was cooled down to room temperature and
allowed to precipitate for 1 h. The solids were filtered
off, washed with deionized water four times, and dried to
yield a red solid (compounds 3a–3m).
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl
-5-aryl-pyrazolines (9a–9m). A solution of 1-ferrocenyl-3-
aryl-2-propen-1-ones (0.32 g, 1.15 mmol), 2-hydrazino-5-
phenyl-1,3,4-thiadiazole (0.2 g, 1.04 mmol), sodium
hydroxide solution (2 mL, 10%), and ethanol was refluxed.
TLC analysis confirmed reaction completion. The solvent
was removed in vacuo, and the mixture was extracted with
dichloromethane (3 × 10 mL). The combined organic layers
were washed with brine (2 × 5 mL) and then dried
over anhydrous sodium sulfate. The solvent was removed,
and the crude product was purified by column
chromatography on silica gel using petroleum ether : ethyl
acetate : dichloromethane = 10:1:1 as the eluent mixture to
afford a red solid after solvent evaporation.
Synthesis of 2-amino-5-phenylthiadiazole (6).
Benzoic
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
acid (6.1 g, 50 mmol) and thiosemicarbazone (4.5 g,
50 mmol) were added to 10 mL of POCl3 under a dry air
atmosphere, and the mixture was heated to 70°C. The
progress of the reaction was monitored by TLC. After
reaction completion (approximately 3 h), the pink viscous
liquid was cooled to room temperature. Fifty milliliter of
water was slowly added to the reaction solution in an ice-
water bath, and the mixture was heated to reflux for 4 h
to obtain a lightly yellow solution. Upon cooling of the
reaction mixture to room temperature, 30% sodium
hydroxide solution was added to adjust the pH of the
solution to 9. Upon precipitation, filtration, and drying,
the crude product was obtained. Recrystallization from a
solvent mixture of ethanol and deionized water (1:1)
afforded white crystals of compound 6 in 81.4% yield.
Synthesis of 2-hydrazino-5-phenyl-1,3,4-thiadiazole (8).
Into a 100-mL round-bottom flask was slowly and
successively added a mixture of copper powders (1 g,
15 mmol), concentrated HCl (30 mL), and deionized
water (14 mL). The mixture was stirred in an ice-water
bath, and a mixture of 2-amino-5-phenyl-1,3,4-thiadiazole
(1.8 g, 10 mmol) and sodium nitrite (2 g, 20 mmol) was
slowly added to this mixture solution. The mixture was
stirred at room temperature for 2 h until no further gas
evolved. The reaction mixture was then extracted with
dichloromethane (2 × 10 mL), and the combined organic
layers were washed with an aqueous solution of saturated
sodium bicarbonate, dried with anhydrous sodium sulfate,
and evaporated under reduced pressure to obtain a khaki
colored of 2-chloro-5-phenyl-1,3,4-thiadiazole 7. The
latter was used directly in the next step without further
purification.
5-phenyl-pyrazoline (9a).
Red solid, yield: 52.3%, mp:
1
216–218°C; H NMR (CDCl3, 400 Hz): δppm 7.83 (dd,
J = 7.6 Hz, 1.6 Hz, 2H, Ar–H), 7.41–7.35 (m, 8H,
Ar–H), 5.64 (dd, J = 11.8 Hz, 5.8 Hz, 1H, CH), 4.72 (s,
1H, C5H4), 4.58 (s, 1H, C5H4), 4.43 (s, 2H, C5H4), 4.16
(s, 5H, C5H5), 3.84 (dd, J = 17.6 Hz, 11.2 Hz, 1H, CH2),
3.20 (dd, J = 17.4 Hz, 5.8 Hz, 1H, CH2); 13C NMR
(CDCl3, 100 Hz): δppm 165.8, 159.4, 155.6, 141.0,
131.2, 129.7, 129.0, 128.9, 128.0, 126.8, 126.1, 74.9,
70.6, 70.5, 69.5, 67.7, 67.2, 63.7, 45.5; IR (KBr, cmꢀ1):
ν (Fc–H) 3087, ν (N¼C) 1539, ν (N–C) 1301, ν (C–H)
2920; HRMS (ESI): m/z Calcd for C27H22FeN4S, [M
+H]+: 491.0993. Found: 491.0980.
Crystal structure of 9a. Selected bond distances (Å):
Centroid Cp (C1–C5)–Centroid Cp (C1–C5) 3.287, C(6)–
C(7) 1.463 (12), N(1)–N(2) 1.373 (9), N(1)–C(7) 1.289
(10), N(2)–C(8) 1.305 (10), S(1)–C(7) 1.763 (8), S(1)–
C(8) 1.739 (8), N(3)–C(8) 1.339 (11), N(3)–N(4) 1.406
(10), N(3)–C(9) 1.460 (11), N(4)–C(17) 1.279 (11),
C(9)–C(10) 1.536 (13). Selected bond angles (°): N1–
C7–C6 124.7 (7), C(6)–C(7)–S(1) 122.0 (6), N2–C8–N3
123.3 (7), N3–C8–S1 122.7 (6), N2–C11–N1 115.6 (2),
C16–C17–C18 122.0 (8), N4–C17–C18 125.0 (8) (Fig. 1).
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
5-(2-methylphenyl)-pyrazoline (9b).
Red solid, yield:
60.8%, mp: 242–245°C; 1H NMR (CDCl3, 400 Hz):
δppm 7.82 (d, J = 8.0 Hz, 2H, Ar–H), 7.42–7.37 (m, 3H,
Ar–H), 7.28 (d, J = 8.4 Hz, 2H, Ar–H), 7.16 (d,
J = 7.6 Hz, 2H, Ar–H), 5.60 (dd, J = 11.6 Hz, 6.0 Hz,
1H, CH), 4.72 (s, 1H, C5H4), 4.58 (s, 1H, C5H4), 4.43 (s,
2H, C5H4), 4.18 (s, 5H, C5H5), 3.83 (dd, J = 17.4 Hz,
11.8 Hz, 1H, CH2), 3.20 (dd, J = 17.4 Hz, 5.8 Hz, 1H,
CH2), 2.31 (s, 3H, CH3); 13C NMR (CDCl3, 100 Hz):
δppm 165.8, 159.3, 155.5, 138.0, 137.7, 131.2, 129.6,
128.8, 126.8, 126.1, 75.0, 70.5, 70.4, 69.5, 67.6, 67.2,
63.5, 45.4, 21.1; IR (KBr, cmꢀ1): ν (Fc–H) 3076, ν
A solution of 2-chloro-5-phenyl-1,3,4-thiadiazole (1 g,
5 mmol) and hydrazine hydrate (1 g, 20 mmol) in ethanol
(50 mL) was heated to reflux. TLC analysis confirmed
reaction completion after 2–5 h. Excess hydrazine hydrate
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. Chen, H. Duan, X. Zhang, Q. Zhang, H. Huang, J. Zhao, B. Chen, C. Hua, and X. Gou
Vol 000
(N¼C) 1527, ν (N–C) 1338, ν (C–H) 2933; HRMS (ESI):
m/z Calcd for C28H24FeN4S, [M+H]+: 505.1149. Found:
505.1142.
2H, C5H4), 4.15 (s, 5H, C5H5), 3.87 (dd, J = 17.2 Hz,
11.6 Hz, 1H, CH2), 3.21 (dd, J = 17.4 Hz, 6.2 Hz, 1H,
CH2); 13C NMR (CDCl3, 100 Hz): δppm 165.9, 159.7,
156.0, 131.1, 129.8, 129.6, 128.9, 127.9, 127.5, 126.8,
124.5, 116.1, 115.9, 74.7, 70.6, 70.5, 69.5, 67.8, 67.1,
58.7, 44.3; IR (KBr, cmꢀ1): ν (Fc–H) 3089, ν (N¼C)
1527, ν (N–C) 1305, ν (C–H) 2923; HRMS (ESI): m/z
Calcd for C27H21FFeN4S, [M+H]+: 509.0899. Found:
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
5-(4-methoxyphenyl)-pyrazoline (9c).
Red solid, yield:
52.6%, mp: 200–203°C; 1H NMR (CDCl3, 400 Hz):
δppm 7.82 (d, J = 8.0 Hz, 2H, Ar–H), 7.42–7.37 (m, 3H,
Ar–H), 7.32 (d, J = 8.8 Hz, 2H, Ar–H), 6.89 (d, 2H,
Ar–H), 5.59 (dd, J = 11.6 Hz, 6.0 Hz, 1H, CH), 4.71 (s,
1H, C5H4), 4.59 (s, 1H, C5H4), 4.43 (s, 2H, C5H4), 4.18
(s, 5H, C5H5), 3.82 (dd, J = 17.4 Hz, 11.8 Hz, 1H, CH2),
3.77 (s, 3H, OCH3), 3.20 (dd, J = 17.4 Hz, 5.8 Hz, 1H,
CH2); 13C NMR (CDCl3, 100 Hz): δppm 165.8, 159.3,
159.3, 155.5, 133.1, 131.2, 129.7, 128.9, 127.5, 126.8,
114.3, 75.0, 70.6, 70.5, 69.5, 67.7, 67.2, 63.3, 55.3, 45.4;
IR (KBr, cmꢀ1): ν (Fc–H) 3068, ν (N¼C) 1541, ν (N–C)
1303, ν (C–H) 2927; HRMS (ESI): m/z Calcd for
C28H24FeN4S, [M+H]+: 521.1098. Found: 521.1118.
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
509.0974.
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
5-(3-bromophenyl)-pyrazoline (9g).
Red solid, yield:
61.3%, mp: 210–211°C; 1H NMR (CDCl3, 400 Hz):
δppm 7.83 (dd, J = 7.4 Hz, 1.8 Hz, 2H, Ar–H), 7.52 (s,
1H, Ar–H), 7.43–7.39 (m, 4H, Ar–H), 7.33 (d,
J = 7.6 Hz, 1H, Ar–H), 7.23 (d, J = 8.0 Hz, 1H, Ar–H),
5.59 (dd, J = 11.8 Hz, 5.8 Hz, 1H, CH), 4.72 (s, 1H,
C5H4), 4.57 (s, 1H, C5H4), 4.44 (d, 2H, C5H4), 4.18 (s,
5H, C5H5), 3.85 (dd, J = 17.4 Hz, 11.8 Hz, 1H, CH2),
3.17 (dd, J = 17.4 Hz, 5.8 Hz, 1H, CH2); 13C NMR
(CDCl3, 100 Hz): δppm 165.7, 159.8, 155.5, 143.4,
131.2, 131.1, 130.7, 129.8, 129.1, 128.9, 126.9, 124.9,
123.1, 74.6, 70.7, 70.6, 69.6, 67.7, 67.2, 63.1, 45.4; IR
(KBr, cmꢀ1): ν (Fc–H) 3085, ν (N¼C) 1535, ν (N–C)
1305, ν (C–H) 2923; HRMS (ESI): m/z Calcd for
C27H21BrFeN4S, [M+H]+: 569.0098. Found: 569.0164.
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
5-(4-chlorophenyl)-pyrazoline (9d).
Red solid, yield:
58.7%, mp: 260–262°C; 1H NMR (CDCl3, 400 Hz):
δppm 7.82 (d, J = 8.0 Hz, 2H, Ar–H), 7.40–7.43 (m, 3H,
Ar–H), 7.33 (s, 4H, Ar–H), 5.60 (dd, J = 12.0 Hz, 6.0 Hz,
1H, CH), 4.70 (s, 1H, C5H4), 4.60 (s, 1H, C5H4), 4.45 (s,
2H, C5H4), 4.17 (s, 5H, C5H5), 3.86 (dd, J = 17.4 Hz,
11.8 Hz, 1H, CH2), 3.18 (dd, J = 17.2 Hz, 6.0 Hz, 1H,
CH2); 13C NMR (CDCl3, 100 Hz): δppm 165.7, 159.7,
155.5, 139.5, 133.8, 131.1, 129.8, 129.2, 128.9, 127.6,
126.9, 74.7, 70.7, 70.6, 69.5, 67.6, 67.3, 63.1, 45.3; IR
(KBr, cmꢀ1): ν (Fc–H) 3058, ν (N¼C) 1537, ν (N–C)
1303, ν (C–H) 2923; HRMS (ESI): m/z Calcd for
C27H21ClFeN4S, [M+H]+: 525.0603. Found: 525.0695.
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
5-(2-furanyl)-pyrazoline (9h).
Red solid, yield: 57.6%,
1
mp: 199–200°C; H NMR (CDCl3, 400 Hz): δppm 7.84
(dd, J = 7.2 Hz, 1.8 Hz, 2H, Ar–H), 7.44–7.38 (m, 4H,
Ar–H), 6.60 (d, J = 3.2 Hz, 1H, Ar–H), 6.36 (dd,
J = 3.2 Hz, 1.6 Hz, 1H, Ar–H), 5.73 (dd, J = 11.6 Hz,
5.6 Hz, 1H, CH), 4.80–4.79 (m, 1H, C5H4), 4.56–4.55
(m, 1H, C5H4), 4.43–4.46 (m, 2H, C5H4), 4.18 (s, 5H,
C5H5), 3.67 (dd, J = 17.2 Hz, 12.0 Hz, 1H, CH2), 3.55
(dd, J = 17.2 Hz, 5.6 Hz, 1H, CH2); 13C NMR (CDCl3,
100 Hz): δppm 165.8, 159.6, 155.8, 151.0, 142.3, 131.2,
129.8, 128.9, 126.9, 110.8, 109.5, 74.8, 70.7, 70.4, 69.7,
67.9, 66.9, 56.7, 40.8; IR (KBr, cmꢀ1): ν (Fc–H) 3112, ν
(N¼C) 1533, ν (N–C) 1309, ν (C–H) 2927; HRMS
(ESI): m/z Calcd for C25H20FeN4OS, [M+H]+: 481.0875.
Found: 481.0764.
5-(2,4-dichlorophenyl)-pyrazoline (9e).
Red solid, yield:
45.5%, mp: 230–232°C; 1H NMR (CDCl3, 400 Hz):
δppm 7.84 (dd, J = 7.4 Hz, 2.6 Hz, 2H, Ar–H), 7.47 (s,
1H, Ar–H), 7.44–7.39 (m, 3H, Ar–H), 7.21 (s, 2H,
Ar–H), 5.90 (dd, J = 11.8 Hz, 6.2 Hz, 1H, CH), 4.69 (s,
1H, C5H4), 4.59 (s, 1H, C5H4), 4.44 (s, 2H, C5H4), 4.13
(s, 5H, C5H5), 3.95 (dd, J = 17.4 Hz, 11.8 Hz, 1H, CH2),
3.06 (dd, J = 17.2 Hz, 6.4 Hz, 1H, CH2); 13C NMR
(CDCl3, 100 Hz): δppm 165.6, 160.0, 156.1, 136.6,
134.2, 132.8, 131.0, 130.0, 129.9, 129.0, 127.8, 127.6,
126.9, 74.4, 70.8, 69.9, 69.6, 67.7, 67.3, 61.1, 44.1; IR
(KBr, cmꢀ1): ν (Fc–H) 3087, ν (N¼C) 1525, ν (N–C)
1278, ν (C–H) 2923; HRMS (ESI): m/z Calcd for
C27H20Cl2FeN4S, [M+H]+: 559.0213. Found: 559.0222.
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
5-(5-methyl-2-furanyl)-pyrazoline (9i).
Red solid, yield:
53.9%, mp: 215–216°C; 1H NMR (CDCl3, 400 Hz):
δppm 7.84 (d, J = 7.2 Hz, 2H, Ar–H), 7.43–7.38 (m,
3H, Ar–H), 6.48 (d, J = 3.2 Hz, 1H, Ar–H), 5.93 (d,
J = 3.2 Hz, 1H, Ar–H), 5.65 (dd, J = 11.6 Hz, 6.0 Hz,
1H, CH), 4.82 (s, 1H, C5H4), 4.53 (s, 1H, C5H4), 4.45
(s, 1H, C5H4), 4.42 (s, 1H, C5H4), 4.28 (s, 5H, C5H5),
3.63 (dd, J = 17.2 Hz, 11.6 Hz, 1H, CH2), 3.57 (dd,
J = 17.2 Hz, 6.0 Hz, 1H, CH2), 2.26 (s, 3H, CH3); 13C
NMR (CDCl3, 100 Hz): δppm 165.7, 159.4, 155.7,
152.2, 149.0, 131.2, 129.7, 128.9, 126.8, 110.6, 106.8,
74.8, 70.7, 70.3, 68.1, 66.8, 56.8, 40.8, 13.8; IR (KBr,
5-(2-fluorophenyl)-pyrazoline (9f).
Red solid, yield:
48.1%, mp: 208–210°C; 1H NMR (CDCl3, 400 Hz):
δppm 7.83 (dd, J = 7.6 Hz, 2.0 Hz, 2H, Ar–H), 7.45–
7.38 (m, 3H, Ar–H), 7.34–7.25 (m, 2H, Ar–H), 7.11 (t,
J = 8.4 Hz, 2H, Ar–H), 5.84 (dd, J = 11.8 Hz, 6.2 Hz,
1H, CH), 4.72 (s, 1H, C5H4), 4.56 (s, 1H, C5H4), 4.42 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Biological Evaluation of Novel 1,3,4-
Thiadiazolylpyrazolines Compounds Containing Ferrocene
cmꢀ1): ν (Fc–H) 3076, ν (N¼C) 1541, ν (N–C) 1311, ν
(C–H) 2920; HRMS (ESI): m/z Calcd for
Ar–H), 7.05 (t, J = 8.6 Hz, 2H, Ar–H), 5.61 (dd,
J = 11.6 Hz, 6.0 Hz, 1H, CH), 4.70 (s, 1H, C5H4), 4.60
(s, 1H, C5H4), 4.44 (s, 2H, C5H4), 4.17 (s, 5H, C5H5),
3.85 (dd, J = 17.4 Hz, 11.8 Hz, 1H, CH2), 3.18 (dd,
J = 17.2 Hz, 6.0 Hz, 1H, CH2); 13C NMR (CDCl3,
100 Hz): δppm 165.8, 163.6, 161.1, 159.7, 155.5, 136.8,
131.1, 129.8, 128.9, 127.9, 126.8, 116.0, 115.8, 74.8,
70.7, 70.6, 69.5, 67.6, 67.3, 63.1, 45.4; IR (KBr, cmꢀ1):
ν (Fc–H) 3070, ν (N¼C) 1537, ν (N–C) 1303, ν (C–H)
2922; HRMS (ESI): m/z Calcd for C27H21FFeN4S, [M
+H]+: 509.0899. Found: 509.0957.
Bioactivity test. The freshly prepared compounds were
screened for their antifungal activities in vitro against
Pythium solani, Gibberella saubinetii, and Gibberella
nicotiancola. The culture medium was prepared by
dissolving agar (0.9 g) and sucrose (1.2 g) in potato juice
(60 mL) in a 100-mL conical flask. The flask was sealed,
sterilized, and stored at room temperature. The synthesized
target compounds and the control drug pyraclostrobin
C26H22FeN4OS, [M+H]+: 495.0942. Found: 495.0909.
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
5-(2-thienyl)-pyrazoline (9j). Red solid, yield: 48.8%, mp:
1
204–205°C; H NMR (CDCl3, 400 Hz): δppm 7.84 (dd,
J = 7.8 Hz, 1.8 Hz, 2H, Ar–H), 7.44–7.38 (m, 3H,
Ar–H), 7.24–7.23 (m, 2H, Ar–H), 6.96 (dd, J = 5.0 Hz,
3.8 Hz, 1H, Ar–H), 5.94 (dd, J = 11.4 Hz, 5.4 Hz, 1H,
CH), 4.76 (s, 1H, C5H4), 4.56 (s, 1H, C5H4), 4.45 (s, 1H,
C5H4), 4.43 (s, 1H, C5H4), 4.21 (s, 5H, C5H5), 3.83 (dd,
J = 17.2 Hz, 11.6 Hz, 1H, CH2), 3.38 (dd, J = 17.2 Hz,
5.6 Hz, 1H, CH2); 13C NMR (CDCl3, 100 Hz): δppm
166.0, 159.9, 155.6, 143.6, 131.1, 129.8, 128.9, 127.1,
126.9, 126.3, 125.1, 74.7, 70.7, 70.5, 69.6, 67.8, 67.1,
59.3, 45.4; IR (KBr, cmꢀ1): ν (Fc–H) 3093, ν (N¼C)
1531, ν (N–C) 1305, ν (C–H) 2923; HRMS (ESI): m/z
Calcd for C26H20FeN4S2, [M+H]+: 497.0557. Found:
497.0526.
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
(0.2 g) were dissolved in
a
small amount of
5-(2-pyridyl)-pyrazoline (9k).
Red solid, yield: 57.6%,
dimethylformamide. A drop of emulsifier T-80 was added,
and the solutions were diluted to a final concentration of
50 mg/L using sterile distilled water. Then, the solutions
were rapidly mixed with sterilized potato glucose agar
culture medium (60 mL) and diluted to four different
concentrations (125, 250, 500, and 1000 μg/L) in conical
flasks. Each mixture was poured into three Petri dishes
and labeled, respectively. After the dishes were cooled, the
solidified plates were incubated with 4-mm fungal strains
and incubated at 28°C for 72 h. The sterilized potato
glucose agar without treatment was used as the blank
control. The mycelial elongation radius (mm) of fungi
settlements was measured after 48 h of culture. Their
relative inhibitory ratio (%) was determined by using a
mycelium growth rate method. After the mycelia grew
completely, the diameters of the mycelia were measured,
and the inhibition rate was calculated according to the
formula as follows: I = (D1 ꢀ D2)/(D1 ꢀ D4) × 100%.
I represents the inhibition rate, D1 is the average
diameter of the mycelia in the blank test, and D2
represents the average diameter of mycelia in the
presence of the study compounds. The inhibition rate was
obtained by the percentage-probability transformation
table as the ordinate and the logarithm of the
concentration of the test solution as the abscissa to obtain
the virulence regression equation y = ax + b and the
linear regression coefficient R. EC50 and EC95 values
were calculated using this equation. The corresponding
results can be found summarized in Table 2.
1
mp: 199–201°C; H NMR (CDCl3, 400 Hz): δppm 8.63
(d, J = 4.4 Hz, 1H, Ar–H), 7.83 (d, J = 7.6 Hz, 2H,
Ar–H), 7.69 (t, J = 7.6 Hz, 1H, Ar–H), 7.59 (d,
J = 7.6 Hz, 1H, Ar–H), 7.43–7.37 (m, 3H, Ar–H), 7.23–
7.20 (dd, J = 6.8 Hz, 5.2 Hz, 1H, Ar–H), 5.73 (dd,
J = 11.6 Hz, 6.0 Hz, 1H, CH), 4.78 (s, 1H, C5H4), 4.57
(s, 1H, C5H4), 4.43 (s, 2H, C5H4), 4.24 (s, 5H, C5H5),
3.82 (dd, J = 17.2 Hz, 11.6 Hz, 1H, CH2), 3.67 (dd,
J = 17.2 Hz, 6.0 Hz, 1H, CH2); 13C NMR (CDCl3,
100 Hz): δppm 166.1, 159.6, 158.5, 156.6, 149.9, 136.9,
131.2, 129.8, 128.9, 126.8, 123.0, 122.7, 74.7, 70.7,
70.4, 69.7, 68.0, 67.0, 64.4, 43.0; IR (KBr, cmꢀ1): ν (Fc–
H) 3082, ν (N¼C) 1541, ν (N–C) 1309, ν (C–H) 2927;
HRMS (ESI): m/z Calcd for C26H21FeN5S, [M+H]+:
492.0945. Found: 492.0915.
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
5-(4-bromophenyl)-pyrazoline (9l).
Red solid, yield:
60.4%, mp: 261–263°C; 1H NMR (CDCl3, 400 Hz):
δppm 7.82 (dd, J = 7.6 Hz, 2.0 Hz, 2H, Ar–H), 7.49 (d,
J = 7.6 Hz, 2H, Ar–H), 7.43–7.39 (m, 3H, Ar–H), 7.28
(s, 2H, Ar–H), 5.58 (dd, J = 11.6 Hz, 6.0 Hz, 1H, CH),
4.69 (s, 1H, C5H4), 4.59 (s, 1H, C5H4), 4.44 (s, 2H,
C5H4), 4.17 (s, 5H, C5H5), 3.85 (dd, J = 17.4 Hz,
11.8 Hz, 1H, CH2), 3.17 (dd, J = 17.4 Hz, 6.2 Hz, 1H,
CH2); 13C NMR (CDCl3, 100 Hz): δ 164.7, 159.8, 155.5,
140.1, 132.2, 131.1, 129.8, 128.9, 127.9, 126.9, 121.9,
74.6, 70.7, 70.6, 69.5, 67.6, 67.3, 63.2, 45.3; IR (KBr,
cmꢀ1): ν (Fc–H) 3082, ν (N¼C) 1535, ν (N–C) 1303, ν
(C–H) 2922; HRMS (ESI): m/z Calcd for
C27H21BrFeN4S, [M+H]+: 569.0098. Found: 569.0093.
Synthesis of N-(4-phenyl-1,3,4-thiadiazol-2-yl)-3-ferrocenyl-
5-(2-fluoro4-phenyl)-pyrazoline (9m).
Red solid, yield:
50.7%, mp: 221–223°C; 1H NMR (CDCl3, 400 Hz):
δppm 7.81–7.84 (m, 2H, Ar–H), 7.41–7.35 (m, 5H,
Acknowledgment. This work was supported financially by the
National Natural Science Foundation of China (21703171).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. Chen, H. Duan, X. Zhang, Q. Zhang, H. Huang, J. Zhao, B. Chen, C. Hua, and X. Gou
Vol 000
[18] Foroumadi, A.; Pournourmohammadi, S.; Soltani, F.;
Asgharian-Rezaee, M.; Dabiri, S.; Kharazmi, A.; Shafiee, A. Bioorg
Med Chem Lett 2005, 15, 1983.
[19] Ramprasad, J.; Nayak, N.; Dalimba, U. Eur J Med Chem 2015,
106, 75.
[20] Togni, A.; Hayashi, T. Ferrocenes: Homogeneous Catalysis,
Organic Synthesis, Materials Science [M]. 2007.
[21] Wang, X. Y.; Deng, Z. X.; Jin, B. K.; Tian, Y. P.; Lin, X. Q.
Spectrochim Acta A 2002, 58, 3113.
[22] Kowalski, K.; Skiba, J.; Oehninger, L.; Ott, I.; Solecka, J.;
Rajnisz, A.; Therrien, B. Organometallics 2013, 32, 5766.
[23] Hussain, R. A.; Badshah, A.; Tahir, M. N.; Tamoor-ul-Hassan;
Bano, A. J Biochem Mol Toxicol 2014, 28, 60.
REFERENCES AND NOTES
[1] Raju, G.; Srinivas, R.; Damoder Reddy, M.; Raji Rdddy, C.;
Nagesh, N. Nucleosides Nucleotides Nucleic Acids 2014, 33, 489.
[2] Nagesh, N.; Raju, G.; Srinivas, R.; Ramesh, P.; Damoder
Reddy, M.; Raji Rdddy, C. Biochim Biophys Acta 2015, 1850, 129.
[3] Havrylyuk, D.; Zimenkovsky, B.; Vasylenko, O.; Day, C. W.;
Smee, D. F.; Grellier, P.; Lesyk, R. Eur J Med Chem 2013, 66, 228.
[4] Berghot, M. A.; Moawad, E. B. Eur J Pharm Sci 2003, 20,
173.
[5] He, J. Q.; Ma, L.; Wei, Z.; Zhu, J.; Peng, F.; Shao, M. F.; Lei,
L.; He, L.; Tang, M. H.; He, L. H.; Wu, Y. Z.; Chen, L. J. Bioorg Med
Chem Lett 2015, 25, 2429.
[24] Zhang, Q.; Zhao, B. H.; Song, Y. Y.; Hua, C. W.; Gou, X. F.;
Chen, B.; Zhao, J. L. Heteroat Chem 2015, 26, 348.
[25] Li, B. J.; Liu, W. Y.; Xie, T.; Huang, G. S.; Yong Xiang, M. A.
Chin Chem Lett 2000, 11, 583.
[26] Edwards, E. I.; Epton, R.; Marr, G. J. Org Chem 1976, 107,
351.
[27] Ratkovic, Z.; Juranic, Z. D. Bioorg Chem 2010, 38, 26.
[28] Liu, J. B.; Li, L. C.; Dai, H.; Liu, Z.; Fang, J. X. J Organomet
Chem 2006, 691, 2686.
[29] Wang, Q. L.; Li, Y.; Gao, K. Organic Chemistry Experiment;
Higher Education Press: Beijing, 2011, pp. 287–290.
[30] Nayak, A. S.; Madhav, N. V. Acta Chimica & Pharmaceutica
Indica 2014, 4(1), 63.
[6] Bandgar, B. P.; Adsul, L. K.; Chavan, H. V.; Jalde, S. S.;
Shringare, S. N.; Shaikh, R.; Meshram, R. J.; Gacche, R. N.; Masand,
V. Bioorg Med Chem Lett 2012, 22, 5839.
[7] Bano, S.; Alam, M. S.; Javed, K.; Dudeja, M.; Das, A. K.;
Dhulap, A. Eur J Med Chem 2015, 95, 96.
[8] Altıntop, M. D.; Özdemir, A.; Turan-Zitouni, G.; Ilgın, S.;
Atlı, Ö.; Demirel, R.; Kaplancıklı, Z. A. Eur J Med Chem 2015, 92, 342.
[9] Insuasty, B.; Ramírez, J.; Becerra, D.; Echeverry, C.; Quiroga,
J.; Abonia, R.; Robledo, S. M.; Vélez, L. D.; Upegui, Y.; Muñoz, J. A.;
Ospina, V. Eur J Med Chem 2015, 93, 401.
[10] Zhao, J.; Xuan, L. N.; Zhao, H. C.; Cheng, J.; Fu, X. Y.; Li, S.;
Jing, F.; Liu, Y. M.; Chen, B. Q. Chem Res Chin Univ 2014, 30(5), 764.
[11] Akhter, M. W.; Hassan, M. Z.; Amir, M. Z.; Amir, M. Arab J
Chem 2014, 7, 955.
[31] Carvalho, S. A.; da Silva, E. F.; Santa-Rita, R. M.; de Castro,
S. L.; Fraga, C. A. M. Bioorg Med Chem Lett 2004, 14, 5967.
[12] Jatav, V.; Mishra, P.; Kashaw, S.; Stables, J. P. Eur J Med
Chem 2008, 43, 1945.
[13] Dawood, K. M.; Eldebss, T. M. A.; ElZahabi, H. S. A.;
Yousef, M. H.; Metz, P. Eur J Med Chem 2013, 70, 740.
[14] El-Hashash, M. A.; Rizk, S. A.; Atta-Allah, S. R. Molecules
2015, 20, 22069.
SUPPORTING INFORMATION
[15] Khan, I.; Ali, S.; Hameed, S.; Rama, N. H.; Hussain, M. T.;
Wadood, A.; Uddin, R.; Ul-Haq, Z.; Khan, A.; Ali, S.; Choudhary, M.
L. Eur J Med Chem 2010, 45, 5200.
[16] Tang, Z. L.; Xia, Z. W.; Chang, S. H.; Wang, Z. X Bioorg Med
Chem Lett 2015, 25, 3378.
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
[17] Li, Y. J.; Sun, Y. Z.; Jin, H. Org Chem 2008, 28, 1074.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet