Synthesis and fungicidal activity of novel 2,5-disubstituted-1,3,4- oxadiazole derivatives

Article abstract of DOI:10.1021/jf303807a

A novel series of 1,3,4-oxadiazole derivatives containing a 5-phenyl-2-furan moiety were synthesized from the intermediates diacylhydrazine 3 and acylhydrazone 5 via an efficient approach under microwave irradiation in good yields. Their structures were characterized by IR, ¹H NMR, and elemental analysis. The antifungal tests indicated that the title compounds showed in vivo fungicidal activity against Botrytis cinerea and Rhizoctonia solanii at 500 μg/mL obviously. Some tested compounds even had a superiority effect over the commercial fungicides 40% Pyrimethanil SC and 3% Validamycin AS. The activity between the title compound and their precursors diacylhydrazine 3 and acylhydrazone 5 was also compared and discussed.

Full text of DOI:10.1021/jf303807a

Article
pubs.acs.org/JAFC
Synthesis and Fungicidal Activity of Novel 2,5-Disubstituted-1,3,4-
oxadiazole Derivatives
Zi-Ning Cui,†,§ Yan-Xia Shi,‡ Li Zhang,† Yun Ling,† Bao-Ju Li,‡ Yoshihiro Nishida,§ and Xin-Ling Yang*,†
†Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, 100193, People's Republic of China
‡Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, People's Republic of China
§Department of Nanobiology, Graduate School of Advanced Integration Science, Chiba University, Matsudo, Chiba 271-8510, Japan
ABSTRACT: A novel series of 1,3,4-oxadiazole derivatives containing a 5-phenyl-2-furan moiety were synthesized from the
intermediates diacylhydrazine 3 and acylhydrazone 5 via an efficient approach under microwave irradiation in good yields. Their
1
structures were characterized by IR, H NMR, and elemental analysis. The antifungal tests indicated that the title compounds
showed in vivo fungicidal activity against Botrytis cinerea and Rhizoctonia solanii at 500 μg/mL obviously. Some tested compounds
even had a superiority effect over the commercial fungicides 40% Pyrimethanil SC and 3% Validamycin AS. The activity between
the title compound and their precursors diacylhydrazine 3 and acylhydrazone 5 was also compared and discussed.
KEYWORDS: 2,5-disubstituted-1,3,4-oxadiazole, 5-phenyl-2-furan, fungicidal activity, microwave irradiation, synthesis
diacylhydrazine 3 and acylhydrazone 5 via an efficient approach
under microwave irradiation in good yields (Scheme 2). Their
antifungal activities were evaluated, and the activity between the
title compound and their precursors was also compared and
discussed in this paper.
1. INTRODUCTION
1,3,4-Oxadiazoles and their derivatives have a wide range of
biological activities including antimicrobial,1 antifungal,2
insecticidal,3 antitumor,4 anti-inflammatory,5 and antihyperten-
sive6 activities. The widespread use of 1,3,4-oxadiazoles as a
scaffold in pesticidal and medicinal chemistry establishes this
moiety as an important structural class.
The common synthetic method for these compounds is
cyclodehydration of diacylhydrazines and their derivatives with
dehydrants, such as phosphorus oxychloride,7 trifluoroacetic
anhydride,8 thionyl chloride,9 polyphosphoric acid,10 and so on.
However, the conventional route to cyclodehydration in
dehydrants solution showed certain disadvantages; for example,
(a) the reaction conditions for the synthesis of oxadiazoles involve
longer durations of time, and (b) the yields of oxadiazoles are
low. Recently, there has been growing interest in the application
of microwave irradiation in chemical reaction enhancement, the
salient features being improved reaction rates and increased
yields.11
The furan ring is an electron-rich system that is amenable to
various chemical reactions and easily forms hydrogen bonds
with different kinds of biological enzymes. It was reported that
the derivatives of 5-phenyl-2-furan showed broad-spectrum
antibacterial,12 plant growth regulator,13 and herbicidal14 activity,
which also exhibited pharmacological properties, including
serving as anti-inflammatory agents15 and methionine amino-
peptidase inhibitors.16 Thus, 5-phenyl-2-furan was regarded as an
active scaffold in drug design.
2. MATERIALS AND METHODS
2.1. Instruments. All of the melting points were determined with a
Cole-Parmer melting point apparatus, while the thermometer was
uncorrected. IR spectra were recorded on a NEXUS-470 FTIR (Nicolet)
1
spectrometer with KBr pellets. H NMR spectra were recorded with a
Bruker DPX300 instrument, while tetramethylsilane was used as the
internal standard. Analytical thin-layer chromatography (TLC) was
carried out on precoated plates (silica gel 60 F254), and spots were
visualized with ultraviolet (UV) light. Elemental analysis, which was
performed at the laboratory of the Institute of Chemistry, Chinese
Academy of Sciences, was carried out with a Flash EA 1112 elemantal
analyzer. Mass spectra were measured on a Bruker ESQUIRE-LC
spectrometer. The microwave-assisted reaction was carried out with a
CEM Microwave synthesizer (CEM Discover S-Class).
2.2. Synthetic Procedures. 2.2.1. General Synthetic Procedure
for the Key Intermediates. Intermediate 2 was synthesized from
substituted aniline by Meerwein arylation reaction using the reported
procedure.17,22 Intermediates 3 and 5 were synthesized according to
our previous literatures.18,19
N-(4-Bromobenzoyl)-N′-[5-(2′-chlorophenyl)-2-furoyl]hydrazine
3a (R1 = 4-Br; R2 = 2-Cl): white powdery crystals; yield, 67.3%; mp
1
219−220 °C. H NMR (300 MHz, DMSO-d6): δ 7.34 (d, J = 3.69 Hz,
1H, FuH), 7.39 (d, J = 3.69 Hz, 1H, FuH), 7.42−7.54 (m, 2H, ArH-Fu),
7.62 (dd, J = 7.83, 1.29 Hz, 1H, ArH-Fu), 7.75−7.79 (m, 2H, ArH),
7.86−7.89 (m, 2H, ArH), 8.23 (dd, J = 7.80, 1.73 Hz, 1H, ArH-Fu), 10.64
(s, 1H, NH), 10.66 (s, 1H, NH). Anal. calcd (%) for C18H12BrClN2O3: C,
51.52; H, 2.88; N, 6.68. Found: C, 51.52; H, 2.95; N, 6.67.
In our previous work, some benzoylureas,17 acylhydrazones,18
diacylhydrazines,19 semicarbazide,20 pyrazole, and 1,2,4-tri-
azole21 derivatives containing 5-phenyl-2-furan moiety were
designed and synthesized. All of the compounds showed diverse
and promising bioactivities such as insecticidal, fungicidal, and
antitumor activities. In continuation of our research on the
design and synthesis of bioactive compounds, a series of novel
1,3,4-oxadiazole derivatives containing 5-phenyl-2-furan moiety
were designed (Scheme 1) and synthesized from the precursors
N-(4-methylbenzoyl)-N′-[5-(4′-chlorophenyl)-2-furoyl]hydrazine
3b (R1 = 4-CH3; R2 = 4-Cl): light yellow powdery crystals; yield,
1
56.3%; mp 242−244 °C. H NMR (300 MHz, DMSO-d6): δ 7.23
Received: May 6, 2012
Accepted: November 7, 2012
Published: November 7, 2012
© 2012 American Chemical Society
11649
dx.doi.org/10.1021/jf303807a | J. Agric. Food Chem. 2012, 60, 11649−11656

Journal of Agricultural and Food Chemistry
Article
Scheme 1. Design Strategy for the Title Compounds
(d, J = 3.60 Hz, 1H, FuH), 7.34 (d, J = 3.63 Hz, 1H, FuH), 7.56−7.61
(m, 3H, 2ArH + ArH-Fu), 7.68−7.72 (m, 1H, ArH-Fu), 7.88−7.91
(m, 1H, ArH-Fu), 7.95 (t, J = 1.71 Hz, 1H, ArH-Fu), 7.99−8.02 (m,
2H, ArH), 10.66 (s, 2H, NHNH). Anal. calcd (%) for C19H15ClN2O3:
C, 64.32; H, 4.26; N, 7.90. Found: C, 64.39; H, 4.39; N, 7.82.
N-(4-chlorobenzoyl)-N′-[5-(2′-nitrophenyl)-2-furoyl]hydrazine 3c
(R1 = 4-Cl; R2 = 2-NO2): light yellow powdery crystals; yield,
10.48 (s, 1H, NH). Anal. calcd (%) for C19H15N3O6: C, 59.84; H,
3.96; N, 11.02. Found: C, 59.85; H, 4.00; N, 11.02.
N-(4-ethoxybenzoyl)-N′-[5-(2′-nitrophenyl)-2-furoyl]hydrazine 3e
(R1 = 4-OEt; R2 = 2-NO2): yellow powdery crystals; yield, 74.3%; mp
172−173 °C. 1H NMR (300 MHz, DMSO-d6): δ 1.35 (t, J = 6.98 Hz,
3H, CH3−C-O), 4.11 (q, J = 6.96 Hz, 2H, O−CH2-C), 6.96 (d, J =
3.63 Hz, 1H, FuH), 7.04 (d, J = 8.88 Hz, 2H, ArH), 7.39 (d, J = 3.66
Hz, 1H, FuH), 7.69 (td, J = 7.76, 1.36 Hz, 1H, ArH-Fu), 7.83 (td, J =
7.68, 1.27 Hz, 1H, ArH-Fu), 7.89 (dd, J = 6.99, 1.88 Hz, 2H, ArH),
8.00−8.04 (m, 2H, ArH-Fu), 10.36 (s, 1H, NH), 10.49 (s, 1H, NH).
Anal. calcd (%) for C20H17N3O6: C, 60.76; H, 4.33; N, 10.63. Found:
C, 60.50; H, 4.38; N, 10.66.
1
79.8%; mp 193−194 °C. H NMR (300 MHz, DMSO-d6): δ 6.96 (d,
J = 3.66 Hz, 1H, FuH), 7.40 (d, J = 3.66 Hz, 1H, FuH), 7.60−7.64 (m,
2H, ArH), 7.70 (td, J = 7.77, 1.34 Hz, 1H, ArH-Fu), 7.84 (td, J = 7.65,
1.23 Hz, 1H, ArH-Fu), 7.91−7.95 (m, 2H, ArH), 8.00−8.04 (m, 2H,
ArH-Fu), 10.59 (s, 1H, NH), 10.62 (s, 1H, NH). Anal. calcd (%) for
C18H12ClN3O5: C, 56.04; H, 3.14; N, 10.89. Found: C, 55.92; H, 3.11;
N, 10.87.
N-(4-methoxybenzoyl)-N′-[5-(4′-nitrophenyl)-2-furoyl]hydrazine
3f (R1 = 4-OCH3; R2 = 4-NO2): yellow powdery crystals; yield, 75.1%;
N-(4-methoxybenzoyl)-N′-[5-(2′-nitrophenyl)-2-furoyl]hydrazine
1
3d (R1 = 4-OCH3; R2 = 2-NO2): yellow powdery crystals; yield,
mp 237−238 °C. H NMR (300 MHz, DMSO-d6): δ 3.84 (s, 3H,
1
OCH3), 7.07 (d, J = 8.85 Hz, 2H, ArH), 7.40 (d, J = 3.69 Hz, 1H,
FuH), 7.50 (d, J = 3.66 Hz, 1H, FuH), 7.92 (d, J = 8.88 Hz, 2H, ArH),
8.24 (d, J = 9.03 Hz, 2H, ArH-Fu), 8.36 (d, J = 9.03 Hz, 2H, ArH-Fu),
10.56 (brs, 2H, NHNH). Anal. calcd (%) for C19H15N3O6: C, 59.84;
H, 3.96; N, 11.02. Found: C, 59.61; H, 3.98; N, 11.33.
69.7%; mp 197−198 °C. H NMR (300 MHz, DMSO-d6): δ 3.84 (s,
3H, OCH3), 6.95 (d, J = 3.63 Hz, 1H, FuH), 7.06 (d, J = 8.85 Hz, 2H,
ArH), 7.38 (d, J = 3.66 Hz, 1H, FuH), 7.70 (td, J = 7.77, 1.17 Hz, 1H,
ArH-Fu), 7.83 (td, J = 7.65, 1.04 Hz, 1H, ArH-Fu), 7.90 (d, J =
8.82 Hz, 2H, ArH), 8.00−8.04 (m, 2H, ArH-Fu), 10.37 (s, 1H, NH),
11650
dx.doi.org/10.1021/jf303807a | J. Agric. Food Chem. 2012, 60, 11649−11656

Journal of Agricultural and Food Chemistry
Article
Scheme 2. General Synthetic Procedure for Title Compounds
N-(4-ethoxybenzoyl)-N′-[5-(4′-nitrophenyl)-2-furoyl]hydrazine 3g
(R1 = 4-OEt; R2 = 4-NO2): yellow powdery crystals; yield, 85.2%; mp
252−253 °C. 1H NMR (300 MHz, DMSO-d6): δ 1.36 (t, J = 6.96 Hz,
3H, CH3−C-O), 4.12 (q, J = 6.96 Hz, 2H, O−CH2-C), 7.05 (d, J =
8.88 Hz, 2H, ArH), 7.40 (d, J = 3.69 Hz, 1H, FuH), 7.50 (d, J = 3.66
Hz, 1H, FuH), 7.91 (d, J = 8.85 Hz, 2H, ArH), 8.24 (d, J = 9.00 Hz,
2H, ArH-Fu), 8.35 (d, J = 9.03 Hz, 2H, ArH-Fu), 10.40 (brs, 1H,
NH), 10.67 (brs, 1H, NH). Anal. calcd (%) for C20H17N3O6: C, 60.76;
H, 4.33; N, 10.63. Found: C, 60.75; H, 4.43; N, 10.89.
was refluxed for 6−8 h. After it was cooled to room temperature, the
reaction was quenched by addition of ice water. The precipitate was
filtered, washed with water and dried, finally recrystallized from
ethanol to afford the pure 2,5-disubstituted-1,3,4-oxadiazoles 4.
2.2.3. General Procedure for the Synthesis of the Target
Compounds 4 by Microwave Radiation. All reactions were carried
out in a pressure tube, sealed with a Teflon septum. The mixture of the
diacylhydrazines 3 (2 mmol) and phosphorus oxychloride (20 mL)
was taken in the pressure tube. The pressure tube was introduced to
the center of a CEM Discover microwave oven and irradiated for
10 min at 150 W (the reaction temperature was set to 105 °C). After
completion of the reaction, the reaction mixture was allowed to cool,
and then, it was poured slowly with stirring into ice water. The
resulting precipitate was filtered, washed with water and dried, and
finally recrystallized from ethanol to afford the corresponding 2,5-
disubstituted-1,3,4-oxadiazoles 4.
2.2.4. General Procedure for the Synthesis of the Target
Compounds 6 and 7 by Conventional Method. The mixture of
the acylhydrazones 5 (2 mmol) and the corresponding anhydrides
(20 mL) was refluxed for 3−4 h. After it was cooled to room tem-
perature, it was poured slowly with stirring into ice water. The
precipitate was filtered, washed with water and dried, and finally
recrystallized from ethanol to produce the pure 1,3,4-oxadiazolines 6
and 7.
N-(2-chlorobenzoyl)-N′-[5-(4′-fluorophenyl)-2-furoyl]hydrazine
3h (R1 = 2-Cl; R2 = 4-F): light yellow powdery crystals; yield,
65.1%; mp 191−192 °C. 1H NMR(300 MHz, DMSO-d6): δ 7.16
(d, J = 3.57 Hz, 1H, FuH), 7.33−7.39 (m, 3H, FuH + 2ArH-Fu),
7.48−7.58 (m, 4H, ArH), 8.05 (dd, J = 8.79, 5.42 Hz, 2H, ArH-Fu),
10.43 (s, 1H, NH), 10.69 (s, 1H, NH). Anal. calcd (%) for
C18H12FClN2O3: C, 60.26; H, 3.37; N, 7.81. Found: C, 60.06; H,
3.43; N, 7.96.
Benzaldehyde 5-(4-chlorophenyl)-2-furoyl hydrazone 5a (R1 = H;
1
R2 = 4-Cl): light yellow needle crystals; mp 188−189 °C. H NMR
(300 MHz, DMSO-d6): δ 7.26 (d, J = 3.63 Hz, 1H, FuH), 7.41−7.61
(m, 6H, FuH + 2ArH-Fu + 3ArH), 7.74−7.77 (m, 2H, ArH), 7.99−
8.01 (m, 2H, ArH-Fu), 8.53 (s, 1H, CHN), 11.86 (s, 1H, NH).
Anal. calcd (%) for C18H13ClN2O2: C, 66.57; H, 4.03; N, 8.63. Found:
C, 66.44; H, 4.00; N, 8.61.
4-Bromobenzaldehyde-5-(2-chlorophenyl)-2-furoyl hydrazone 5b
(R1 = 4-Br; R2 = 2-Cl): light yellow powdery crystals; mp 189−190 °C.
1H NMR (300 MHz, DMSO-d6): δ 7.33 (d, J = 3.69 Hz, 1H, FuH),
7.42−7.56 (m, 3H, FuH + 2ArH-Fu), 7.61−7.74 (m, 5H, 4ArH +
ArH-Fu), 8.15−8.17 (m, 1H, ArH-Fu), 8.50 (s, 1H, CHN), 11.94
(s, 1H, NH). Anal. calcd (%) for C18H12BrClN2O2: C, 53.56; H, 3.00;
N, 6.94. Found: C, 53.34; H, 3.19; N, 7.02.
2.2.5. General Procedure for the Synthesis of the Target
Compounds 6 and 7 by Microwave Radiation. All reactions were
carried out in a pressure tube, sealed with a Teflon septum. The mixture
of the acylhydrazones 5 (2 mmol) and acetic anhydride or propionic
anhydride (20 mL) was taken in the pressure tube. The pressure tube
was introduced to the center of a CEM Discover microwave oven
and irradiated for 10 min at 150 W (for the solution of acetic anhydride,
the reaction temperature was set to 155 °C; for the solution of acetic
anhydride, the reaction temperature was set to 165 °C). After the
reaction was completed, the reaction mixture was allowed to cool, and
then, it was poured slowly with stirring into ice water. The resulting
precipitate was filtered, washed with water and dried, and finally
recrystallized from ethanol to produce the corresponding 1,3,4-oxadi-
azolines 6 and 7.
4-Chlorobenzaldehyde-5-(2-fluorophenyl)-2-furoyl hydrazone 5c
1
(R1 = 4-Cl; R2 = 2-F): white powdery crystals; mp 209−210 °C. H
NMR (300 MHz, DMSO-d6): δ 7.05 (t, J = 3.48 Hz, 1H, ArH-Fu),
7.36−7.56 (m, 6H, 2FuH + 2ArH-Fu + 2ArH), 7.77−7.80 (m, 2H,
ArH), 8.15−8.20 (m, 1H, ArH-Fu), 8.52 (s, 1H, CHN), 11.96 (s,
1H, NH). Anal. calcd (%) for C18H12ClFN2O2: C, 63.08; H, 3.53; N,
8.17. Found: C, 63.22; H, 3.53; N, 8.51.
All of the title compounds were solid. Their structures were
2-Chlorobenzaldehyde-5-(4-fluorophenyl)-2-furoyl hydrazone 5d
(R1 = 2-Cl; R2 = 4-F): yellow powdery crystals; mp 182−183 °C.
1H NMR (300 MHz, DMSO-d6): δ 7.19 (d, J = 3.63 Hz, 1H, FuH),
7.35−7.57 (m, 6H, FuH + 2ArH-Fu + ArH), 8.04−8.07 (m, 3H, ArH +
2ArH-Fu), 8.92 (s, 1H, CHN), 12.08 (s, 1H, NH). Anal. calcd (%)
for C18H12ClFN2O2: C, 63.08; H, 3.53; N, 8.17. Found: C, 63.39; H,
3.65; N, 7.93.
2.2.2. General Procedure for the Synthesis of the Target
Compounds 4 by Conventional Method. The mixture of the
diacylhydrazines 3 (5 mmol) and phosphorus oxychloride (20 mL)
1
confirmed by H NMR, IR, MS, and elemental analysis. The data are
listed in Tables 1 and 2.
2.3. Bioassays. Using pot culture test according to the references,21,23
the in vivo fungicidal activities of the title compounds against B. cinerea,
Corynespora cassiicola, Cladosporium cucumerinum, and R. solanii were
evaluated in a greenhouse with four commercial fungicides, 40%
Pyrimethanil SC, 75% Chlorothalonil WP, 40% Flusilazole EC, and 3%
Validamycin AS, as controls. All of the strains were conserved in the
Institute of Vegetable and Flowers, Chinese Academy of Agricultural
11651
dx.doi.org/10.1021/jf303807a | J. Agric. Food Chem. 2012, 60, 11649−11656

Journal of Agricultural and Food Chemistry
Article
Table 1. Physical, MS, and Elemental Analysis Data of Title Compounds 4, 6, and 7
elemental analysis (found %)
compd
R1
R2
appearance
brown solid
mp (°C)
175−176
yield (%)
79.5
MS/ESI m/e (%)
C
H
N
4a
4-Br
2-Cl
424.1[M+Na]+ (53)
402.3[M+H]+ (36)
359.0[M+Na]+ (40)
337.0[M+H]+ (57)
389.8[M+Na]+ (100)
367.9[M+H]+ (43)
385.9[M+Na]+ (100)
364.0[M+H]+ (47)
399.9[M+Na]+ (100)
377.9[M+H]+ (66)
364.1[M+H]+ (57)
53.83
(53.48)
67.76
2.51
(2.55)
3.89
6.97
(7.17)
8.32
4b
4c
4d
4e
4f
4-Me
4-Cl
4-Cl
light yellow solid
yellow solid
yellow solid
brown solid
yellow solid
yellow solid
gray solid
198−199
192−193
150−151
155−156
236−237
214−215
166−167
169−170
154−155
166−167
162−163
165−166
175−176
78.0
76.0
72.0
74.0
79.0
80.2
80.4
84.6
86.8
79.5
76.9
84.3
82.8
(67.65)
58.79
(3.91)
2.74
(8.06)
11.43
(11.14)
11.57
(11.48)
11.14
(11.10)
11.57
(11.45)
11.14
(11.04)
8.22
2-NO2
2-NO2
2-NO2
4-NO2
4-NO2
4-F
(58.59)
62.81
(2.80)
3.61
4-OMe
4-OEt
4-OMe
4-OEt
2-Cl
(62.53)
63.66
(3.70)
4.01
(63.42)
62.81
(4.10)
3.61
(62.54)
63.66
(3.65)
4.01
4g
4h
6a
6b
6c
6d
7a
7b
378.2[M+H]+ (56)
341.3[M+H]+ (69)
389.4[M+Na]+(88)
468.2[M+Na]+(93)
407.2[M+Na]+(100)
407.2[M+Na]+(100)
(63.59)
63.45
(4.11)
2.96
(63.50)
65.49
(3.13)
4.12
(8.01)
7.64
H
4-Cl
yellow solid
light yellow solid
light yellow solid
white solid
(65.55)
53.90
(4.14)
3.17
(7.70)
6.29
4-Br
2-Cl
(53.94)
62.43
(3.14)
3.67
(6.17)
7.28
4-Cl
2-F
(62.43)
62.43
(3.62)
3.67
(7.56)
7.28
2-Cl
4-F
(62.28)
54.86
(3.60)
3.51
(7.44)
6.09
4-Br
2-Cl
white solid
498.9[M+K]+ (6.0)
483.0[M+Na]+ (100)
437.0[M+K]+ (9.7)
421.2[M+Na]+ (100)
(54.60)
63.24
(3.62)
4.04
(6.14)
7.02
2-Cl
4-F
white solid
(63.05)
(4.09)
(7.03)
Science (Beijing, China). B. cinerea, C. cassiicola, C. cucumerinum, and
R. solanii were maintained on potato dextrose agar (PDA) medium at
4 °C. The culture plates were cultivated at 24 1 °C. Germination
was conducted by soaking cucumber seeds in water for 2 h at 50 °C
and then keeping the seeds moist for 24 h at 28 °C in an incubator.
When the radicles were 0.5 cm, the seeds were grown in plastic pots
containing a 1:1 (v/v) mixture of vermiculite and peat. Cucumber
plants used for inoculations were at the stage of two seed leaves.
Tested compounds and commercial fungicides were sprayed with a
hand spray on the surface of the seed leaves, which will be inoculated with
B. cinerea, C. cassiicola, C. cucumerinum, and R. solanii at the standard
concentration of 500 μg/mL. Three replicates were used per treatment.
After the leaves were dried, inoculations of C. cassiicola and
C. cucumerinum were carried out by spraying a conidial suspension, and
inoculations of B. cinerea and R. solanii were carried out by spraying
a mycelial suspension. The experiment was repeated three times. After
inoculation, the plants were maintained at 24 1 °C and above 80%
relative humidity.
from the diacylhydrazines 3 or acylhydrazones 5 by cyclo-
dehydration reaction in the dehydrants phosphorus oxychloride
or anhydride. To establish the general validity of the newly
developed method, several selected one-pot microwave-assisted
syntheses were carried out. This method appeared to be ex-
peditious and economical, with a wide range of applications.
The reaction was found to proceed smoothly under microwave
irradiation within 10 min, whereas 3−8 h was required under
conventional reflux condition in POCl3 or the corresponding
anhydride (Table 3). The products were isolated by simple cold
aqueous workup followed by precipitation and were finally
purified by recrystallization wherever necessary, to afford pure
2,5-disubstituted-1,3,4-oxadiazole (oxadiazolines). The yield was
raised from 8 to 18.6% as compared to the conventional method.
The present method, which was more rapid and simple than the
conventional method, is a good contribution to microwave-
assisted synthetic methodologies.
3.2. Fungicidal Activity. The in vivo fungicidal results of
the compounds against R. solanii, B. cinerea, C. cassiicola, and
C. cucumerinum are listed in Table 4. Not only the title com-
pounds but also the intermediates diacylhydrazine and
acylhydrazone showed promising results in inhibiting the
mycelial growth of the test fungi especially against B. cinerea
and R. solanii at 500 μg/mL. Meanwhile, all of these tested
compounds were found safe for the plants. The comparison of
the fungicidal activity of compounds for four test fungi to those
of commercial fungicides leads to the following conclusions: (a)
Compounds 3c and 4c exhibited a significant inhibition effect
against R. Solanii, and the fungicidal activities (control efficacy
of 95.56 4.05 and 94.38 3.60%) were equal to the active
The fungicidal activity was evaluated when the nontreated cucumber
plant (blank) fully developed symptoms. The area of inoculated treated
leaves covered by disease symptoms was assessed and compared to
that of nontreated ones to determine the average disease index. The
relative control efficacy of compounds compared to the blank assay was
calculated via the following equation:
I (%) = [(CK − PT)/CK] × 100%
where I is the relative control efficacy, CK is the average disease index
during the blank assay, and PT is the average disease index after treat-
ment during testing.
3. RESULTS AND DISCUSSION
3.1. Synthesis. The synthetic route of title compounds 4, 6,
and 7 is shown in Scheme 2. Title compounds were obtained
11652
dx.doi.org/10.1021/jf303807a | J. Agric. Food Chem. 2012, 60, 11649−11656

Journal of Agricultural and Food Chemistry
Article
11653
dx.doi.org/10.1021/jf303807a | J. Agric. Food Chem. 2012, 60, 11649−11656

Journal of Agricultural and Food Chemistry
Article
activities of cyclic 1,3,4-oxadiazolines were higher than the cor-
responding ring-opening ones. For example, the activity of
Table 3. Comparison between Conventional Heating
Method and Microwave-Assisted Method for the Synthesis
of Title Compounds 4, 6, and 7 in Terms of Time and Yield
compound 5a was 10.20
0.20%, and after cyclizatio, the
3.00 and
activities of 6a and 7a were increased to 69.09
conventional
microwave
63.87 2.02%. The difference between R1 and R2 also affected
the fungicidal activity against R. solanii. When R2 was 2-NO2,
such as 3c, 3e, 4c, and 4e displayed higher fungicidal activity.
(b) Some compounds exhibited good control efficacy against
B. cinerea (exceeding 70% efficacy rate), which had a higher
compd
time (min)
yield (%)
time (min)
yield (%)
4a
4b
4c
4d
4e
4f
480
360
420
480
480
420
480
480
210
180
210
210
240
210
68.4
65.6
62.7
58.3
61.4
65.6
68.5
66.9
73.6
74.3
69.4
65.4
76.3
64.2
10
10
10
10
10
10
10
10
10
10
10
10
10
10
79.5
78.0
76.0
72.0
74.0
79.0
80.2
80.4
84.6
86.8
79.5
76.9
84.3
82.8
activity than 40% Pyrimethanil SC (69.57
worthy to note that compounds 3h, 5b, and 4d, whose efficacy
rates were 89.57 3.39, 91.76 3.30, and 92.68 3.46%,
3.35%). It was
4g
4h
6a
6b
6c
6d
7a
7b
respectively, were found to be much more effective as compared
to the fungicide 40% Pyrimethanil SC (69.57 3.35%) against
B. cinerea. The variances between pre- and postcyclization
had no obvious relationship with the fungicidal activity against
B. cinerea. (c) For C. cassiicola, compounds 3c, 4a, and 4e
exhibited favorable fungicidal activities of 66.09 3.02, 90.59
3.09, and 74.71
4.05%, respectively. Compound 4a had
almost the same activity as that of 75% Chlorothalonil WP
against C. cassiicola (93.53 3.20%). (d) All of the compounds
showed lower effects against C. cucumerinum than the fungicide
40% Flusilazole EC (95.56 3.20%).
The change of the Y moiety in Scheme 1 could bring a
variant of bioactivity. The designed urea derivatives from that of
benzoylphenyl urea (BPU) showed good larvicidal activity.17
When it was changed to the hydrazide and hydrazone moieties,
the bioactive spectra were broadened and not only showed
promising insecticidal activity but also exhibited obvious fungicidal
fungicide 3% Validamycin AS (93.68 3.21%). The variances
between pre- and postcyclization had a great effect on the
fungicidal activity against R. solanii. For compound 4, the
activity of most compounds before cyclization was higher than
cyclic 1,3,4-oxadiazoles. For example, the activities of com-
pounds 3a and 3h were 49.42 2.25 and 69.35 3.02%, and
after cyclization, the activities of 4a and 4h were decreased to
−1.16 0.09 and 25.54 1.14%. For compounds 6 and 7, the
Table 4. Fungicidal Activities of Compounds 3−7 against Four Fungus Species at 500 μg/mL in Vivo
control efficacy (%)
compd
3a
R1
4-Br
R2
C. cucumerinum
C. cassiicola
B. cinerea
R. solanii
2-Cl
14.20 1.02
29.80 2.25
14.44 1.71
2.61 0.42
8.24 0.75
50.87 2.62
66.09 3.02
28.35 2.24
18.82 1.15
36.36 2.26
38.24 2.38
34.26 3.12
90.59 3.09
28.24 2.00
15.17 2.05
48.61 3.02
74.71 4.05
10.59 1.15
25.49 2.02
27.94 2.11
50.78 2.25
28.79 2.10
−3.05 0.95
13.87 2.07
35.29 2.12
32.03 1.15
28.85 2.20
28.72 2.26
41.18 3.01
46.75 2.62
5.23 0.88
24.64 2.26
4.35 1.10
49.42 2.25
19.80 1.75
95.56 4.05
56.45 3.20
78.93 2.25
24.45 1.52
71.90 1.05
69.35 3.02
−1.16 0.09
24.13 1.11
94.38 3.60
48.48 4.05
65.58 4.05
−3.97 0.75
63.47 2.03
25.54 1.14
10.20 0.20
57.85 2.02
−5.20 0.15
8.00 0.20
3b
4-Me
4-Cl
4-Cl
3c
2-NO2
2-NO2
2-NO2
4-NO2
4-NO2
4-F
79.58 4.00
35.50 2.37
−43.27 1.02
29.90 2.03
79.13 3.61
89.57 3.39
−2.61 0.22
42.38 3.02
−30.02 1.02
92.68 3.46
33.75 1.62
47.83 3.02
77.78 4.03
76.52 4.11
11.00 0.00
91.76 3.30
27.00 1.60
72.00 2.00
70.71 3.35
23.23 2.11
18.89 2.25
76.28 4.06
13.91 1.19
−24.90 1.12
1.53 0.21
3d
4-OMe
4-OEt
4-OMe
4-OEt
2-Cl
3e
10.00 2.00
57.89 3.35
28.35 2.25
30.32 3.05
17.90 1.75
5.85 0.55
3f
3g
3h
4a
4-Br
2-Cl
4b
4-Me
4-Cl
4-Cl
4c
2-NO2
2-NO2
2-NO2
4-NO2
4-NO2
4-F
17.20 2.13
15.00 2.23
8.89 1.10
4d
4-OMe
4-OEt
4-OMe
4-OEt
2-Cl
4e
4f
12.35 1.15
16.48 2.03
7.78 1.14
4g
4h
5a
H
4-Cl
−8.10 0.75
19.75 1.74
37.30 3.02
−22.00 1.15
45.61 3.05
16.67 2.01
31.11 2.01
40.00 3.20
23.98 2.11
31.48 2.65
3.18 0.75
5b
4-Br
2-Cl
5c
4-Cl
2-F
5d
2-Cl
4-F
6a
4-Br
2-Cl
69.09 3.00
14.30 1.14
66.28 2.65
31.03 2.11
63.87 2.02
52.33 1.25
2.22 0.79
6b
4-Br
2-Cl
6c
4-Cl
2-F
6d
2-Cl
4-F
7a
4-Br
2-Cl
7b
2-Cl
4-F
acetone
fungicides
(control)
a
95.56 3.20 a
93.53 3.20 b
69.57 3.35 c
93.68 3.21 d
a
Control fungicides: a, 40% Flusilazole EC; b, 75% Chlorothalonil WP; c, 40% Pyrimethanil SC; and d, 3% Validamycin AS.
11654
dx.doi.org/10.1021/jf303807a | J. Agric. Food Chem. 2012, 60, 11649−11656

Journal of Agricultural and Food Chemistry
Article
and antitumor activities.18,19 In the present work, while the
hydrazide and hydrazone were cyclodehydrated to the corre-
sponding 1,3,4-oxadiazole and oxadiazoline derivatives, the in vivo
fungicidal activity was maintained. Especially, when Y was 1,3,4-
oxadiazoline, its activity was improved to a certain extent. The
evaluation of the further fungicidal bioassay and other tests about
the bioactive spectra is under going.
In summary, a novel series of 1,3,4-oxadiazole derivatives
containing a 5-phenyl-2-furan moiety were synthesized by an
efficient approach with microwave irradiation in good yields.
Their antifungal tests indicated that most of the title compounds
and the intermediates diacylhydrazine and acylhydrazone
showed fungicidal activity obviously against B. cinerea and
R. solanii at 500 μg/mL in vivo. Meanwhile, all of the tested
compounds were found safe for the plants. Among the tested
compounds, some showed superiority over the commercial
fungicides during the present studies. These compounds could
be lead compounds for further discovery of fungicides.
M.; Mahfouz, N. M.; EL-Gendy, M. A. Novel 5-(2- hydroxyphenyl)-3-
substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: Promising
anticancer agents. Bioorg. Med. Chem. 2006, 14 (4), 1236−1246.
(5) (a) Chavan, R. S.; Nirmal, D. A.; Bhosale, A. V. Synthesis and
biological evaluation of 1,3,4-oxadiazole derivatives as novel analgesic
and antiinflammatory agents. Asian J. Chem. 2011, 23 (9), 3919−3922.
(b) Jayashankar, B.; Lokanath Rai, K. M.; Baskaran, N.; Sathish, H. S.
Synthesis and pharmacological evaluation of 1,3,4-oxadiazole bearing
bis(heterocycle) derivatives as anti-inflammatory and analgesic agents.
Eur. J. Med. Chem. 2009, 44 (10), 3898−3902.
(6) Bankar, G. R.; Nampurath, G. K.; Nayak, P. G.; Bhattacharya, S. A
possible correlation between the correction of endothelial dysfunction
and normalization of high blood pressure levels by 1,3,4-oxadiazole
derivative, an L-type Ca2+ channel blocker in deoxycorticosterone
acetate and NG-nitro-L-arginine hypertensive rats. Chem.-Biol. Interact.
2010, 183 (2), 327−331.
(7) Vansdadia, R. N.; Roda, K. P.; Parekh, H. Studies on 1,3,4-
oxadiazoles. Part X. Preparation and antimicrobial activity of 2-aryl-5-
p-phenylsulfophenyl-1,3,4- oxadiazoles. J. Indian Chem. Soc. 1988, 65
(11), 809−811.
(8) Liras, S.; Allen, M. P.; Segelstein, B. E. A mild method for the
preparation of 1,3,4-oxadiazoles: Triflic anhydride promoted cycliza-
tion of diacylhydrazines. Synth. Commun. 2000, 30 (3), 437−443.
(9) Al-Talib, M.; Tashtoush, H.; Odeh, N. A convenient synthesis of
alkyl and aryl substituted bis-1,3,4-oxadiazoles. Synth. Commun. 1990,
20 (12), 1811−1817.
(10) Wang, S.; Li, Z. T.; Hua, W. T. Synthesis and characterization of
fully conjugated schiff base macrocycles containing 1,3,4-oxadiazole
moiety. Synth. Commun. 2002, 32 (21), 3339−3345.
(11) (a) Polshettiwar, V.; Varma, R. S. Greener and expeditious
synthesis of bioactive heterocycles using microwave irradiation. Pure Appl.
Chem. 2008, 80 (4), 777−790. (b) Chauveau, E.; Marestin, C.; Schiets,
F.; Mercier, R. Synthesis of 2,4,5-triarylimidazoles in aqueous solution, under
microwave irradiation. Green Chem. 2010, 12 (6), 1018−1022. (c) Insuasty,
B.; Garcia, A.; Quiroga, J.; Abonia, R.; Nogueras, M.; Cobo, J. Synthesis of
novel 6,6a,7,8-tetrahydro-5H-naphtho [1,2-e]pyrimido[4,5-b][1,4]
diazepines under microwave irradiation as potential anti-tumor agents.
Eur. J. Med. Chem. 2010, 45 (7), 2841−2846.
(12) (a) Owens, R. G. Plant disease control by 5-nitrofuran
derivatives in relation to chemical structure. Contrib. Boyce Thompson
Inst. 1959, 20, 141−149. (b) Kupchik, E. J.; Pisano, M. A.; Whalen, S.
M.; Lynch, J. Synthesis and antimicrobial activity of triorganotin 5-
nitro-2-furoates. J. Pharm. Sci. 1982, 71 (3), 311−314.
(13) (a) Wei, T.; Chen, J.; Wang, X.; Yang, S. Studies on the
synthesis and biological activity of N-aryl-N′-(5-aryl-2-furoyl)thiourea
derivatives. Chem. J. Chin. Univ. 1992, 13 (9), 1217−1221. (b) Chen,
J.; Wei, T.; Wang, X.; Yang, S. Studies on the synthesis and biological
activity of N-aryl-N′-(5-aryl-2-furoyl)thiourea derivatives. Chin. Chem.
Lett. 1991, 2 (6), 433−436.
(14) (a) Ke, S.; Wei, T.; Xue, S.; Duan, L.; Li, J. Phase transfer
catalyzed synthesis under ultrasonic irradiation and bioactivity of N′-
(4,6-disubstituted-pyrimidin-2- yl)-N-(5-aryl-2- furoyl) thiourea de-
rivatives. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2005,
44B (9), 1957−1960. (b) Xue, S.; Ke, S.; Duan, L.; Li, J. Ultrasonically
irradiated synthesis and bioactivity of 5,7-disubstituted-2-(5-aryl-2-
furoylimino)-[1,2,4]-thiadiazolo[2,3-a]pyrimidine derivatives. Chin. J.
Org.Chem. 2004, 24 (12), 1610−1613. (c) Xue, S.; Bian, W. Method
for preparation and application of 2-(5-o-chlorophenyl-2-furoylamino)-
acetamidopyrimidine derivatives. CN 101220022 A, 2008.
(15) (a) Kort, M. E.; Drizin, I.; Gregg, R. J.; Scanio, M. J. C.; Shi, L.;
Gross, M. F.; Atkinson, R. N.; Johnson, M. S.; Pacofsky, G. J.; Thomas,
J. B.; Carroll, W. A.; Krambis, M. J.; Liu, D.; Shieh, C. C.; Zhang, X. F.;
Hernandez, G.; Mikusa, J. P.; Zhong, C. M.; Joshi, S.; Honore, P.;
Roeloffs, R.; Marsh, K. C.; Murray, B. P.; Liu, J. R.; Werness, S.;
Faltynek, C. R.; Krafte, D. S.; Jarvis, M. F.; Chapman, M. L.; Marron,
B. E. Discovery and Biological Evaluation of 5-Aryl-2-furfuramides,
Potent and Selective Blockers of the Nav1.8 Sodium Channel with
Efficacy in Models of Neuropathic and Inflammatory Pain. J. Med.
Chem. 2008, 51 (3), 407−416. (b) Burch, H. A.; White, R. E.; Wright,
AUTHOR INFORMATION
Corresponding Author
*Tel/Fax: +86-10-62732223. E-mail: yangxl@cau.edu.cn.
Funding
Financial support was provided by the National Natural Science
Foundation of China (21102173), the National Key Project for
Basic Research (2010CB126104), the Japan Society for the
Promotion of Science (JSPS, ID No. P10100), and Advanced
Multi-Career Training Program for Postdoctoral Scholars from
JST.
■
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) Suresh Kumar, G. V.; Rajendraprasad, Y.; Mallikarjuna, B. P.;
Chandrashekar, S. M.; Kistayya, C. Synthesis of some novel 2-
substituted-5-[isopropylthiazole] clubbed 1,2,4-triazole and 1,3,4-
oxadiazoles as potential antimicrobial and antitubercular agents. Eur.
J. Med. Chem. 2010, 45 (5), 2063−2074. (b) Farshori, N. N.; Banday,
M. R.; Ahmad, A.; Khan, A. U.; Rauf, A. Synthesis, characterization,
and in vitro antimicrobial activities of 5-alkenyl/hydroxyl-alkenyl-2-
phenylamine-1,3,4-oxadiazoles and thiadiazoles. Bioorg. Med. Chem.
Lett. 2010, 20 (6), 1933−1938.
(2) (a) Khanum, S. A.; Shashikanth, S.; Sathyanarayana, S. G.;
Lokesh, S.; Deepak, S. A. Synthesis and antifungal activity of 2-
azetidinonyl-5-(2-benzoylphenoxy) methyl-1,3,4-oxadiazoles against
seed-borne pathogens of Eleusine coracana (L.) Gaertn. Pest Manage.
Sci. 2009, 65 (7), 776−780. (b) Ishii, M.; Jorge, S. D.; de Oliveira, A.
A.; Palace-Berl, F.; Sonehara, I. Y.; Pasqualoto, K. F. M.; Tavares, L. C.
Synthesis, molecular modeling and preliminary biological evaluation of
a set of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole as
potential antibacterial, anti-Trypanosoma cruzi and antifungal agents.
Bioorg. Med. Chem. 2011, 19 (21), 6292−6301. (c) Xu, W. M.; Han, F.
F.; He, M.; Hu, D. Y.; He, J.; Yang, S.; Song, B. A. Inhibition of
Tobacco Bacterial Wilt with Sulfone Derivatives Containing an 1,3,4-
Oxadiazole Moiety. J. Agric. Food Chem. 2012, 60 (4), 1036−1041.
(3) Cui, Z. N.; Yang, L.; Li, X. C.; Wang, Z.; Yang, X. L. Progress in
the study on the synthesis and the activities as insect growth regulators
of 2,5-disubstituted 1,3,4-oxadiazoles. Chin. J. Org. Chem. 2006, 26
(12), 1647−1656.
(4) (a) Bondock, S.; Adel, S.; Etman, H. A.; Badria, F. A. Synthesis
and antitumor evaluation of some new 1,3,4-oxadiazole-based
heterocycles. Eur. J. Med. Chem. 2012, 48, 192−199. (b) Somani, R.
R.; Shirodkar, P. Y.; Kadam, V. J. Synthesis and anticancer evaluation of
some newer 2,5-disubstituted-1,3,4-oxadiazole analogues. Lett. Drug Des.
Discovery 2008, 5 (6), 364−368. (c) Aboraia, A. S.; Abdel-Rahman, H.
11655
dx.doi.org/10.1021/jf303807a | J. Agric. Food Chem. 2012, 60, 11649−11656

Journal of Agricultural and Food Chemistry
Article
G. C.; Goldenberg, M. M. Phenylfurans. IV: Spasmolytic 3-
diethylamino-2,2-(dimethyl) propyl esters of 5-substituted phenyl-2-
furancarboxylic acids. J. Pharm. Sci. 1980, 69 (1), 107−110.
(16) (a) Ye, Q. Z.; Xie, S. X.; Huang, M.; Huang, W. J.; Lu, J. P.; Ma,
Z. Q. Metalloform-Selective Inhibitors of Escherichia coli Methionine
Aminopeptidase and X-ray Structure of a Mn(II)-Form Enzyme
Complexed with an Inhibitor. J. Am. Chem. Soc. 2004, 126 (43),
13940−13941. (b) Vedantham, P.; Zhang, M.; Gor, P. J.; Huang, M.;
Georg, G. I; Lushington, G. H.; Mitscher, L. A.; Ye, Q. Z.; Hanson, P.
R. Studies Towards the Synthesis of Methionine Aminopeptidase
Inhibitors: Diversification Utilizing a ROMP-Derived Coupling
Reagent. J. Comb. Chem. 2008, 10 (2), 195−203.
(17) (a) Yang, X. L.; Wang, D. Q.; Chen, F. H.; Ling, Y.; Zhang, Z.
N. The synthesis and larvicidal activity of N-aroyl-N′-(5-aryl-2-furoyl)
ureas. Pestic. Sci. 1998, 52, 282−286. (b) Yang, X. L.; Ling, Y.; Wang,
D. Q.; Chen, F. H. The synthesis and biological activity of N-phenyl-
N′-(5-phenyl-2-furoyl) ureas. Chin. J. Synth. Chem. 2002, 10, 510−512.
(c) Cui, Z. N.; Zhang, L.; Huang, J.; Li, Y.; Ling, Y.; Yang, X. L. 3D-
QSAR studies on diacyl urea derivatives containing furan moiety. Acta
Chim. Sin. 2008, 66 (12), 1417−1423.
(18) (a) Cui, Z. N.; Li, Y.; Huang, J.; Ling, Y.; Cui, J. R.; Wang, R. Q.;
Yang, X. L. New Class of Potent Antitumor Acylhydrazone Derivatives
Containing Furan. Eur. J. Med. Chem. 2010, 45 (12), 5576−5584.
(b) Cui, Z. N.; Yang, X. L.; Shi, Y. X.; Uzawa, H.; Cui, J. R.; Dohi, H.;
Nishida, Y. Molecular design, synthesis and bioactivity of glycosyl
hydrazine and hydrazone derivatives: Notable effects of the sugar
moiety. Bioorg. Med. Chem. Lett. 2011, 21 (23), 7193−7196.
(19) (a) Cui, Z. N.; Wang, Z.; Li, Y.; Zhou, X. Y.; Ling, Y.; Yang, X.
L. Synthesis of 5-(chlorophenyl)-2-furancarboxylic acid 2-(benzoyl)-
hydrazide derivatives and determination of their insecticidal activity.
Chin. J. Org. Chem. 2007, 27 (10), 1300−1304. (b) Cui, Z. N.; Huang,
J.; Li, Y.; Ling, Y.; Yang, X. L.; Chen, F. H. Synthesis and bioactivity of
novel N,N′-diacylhydrazine derivatives containing furan(I). Chin. J.
Chem. 2008, 26 (5), 916−922. (c) Li, X. C.; Yang, X. L.; Cui, Z. N.; Li,
Y.; He, H. W.; Ling, Y. Synthesis and Bioactivity of Novel N,N′-
Diacylhydrazine Derivatives Containing Furan(II). Chin. J. Chem.
2010, 28 (7), 1233−1239. (d) Cui, Z. N.; Zhang, L.; Huang, J.; Yang,
X. L.; Ling, Y. Synthesis and Bioactivity of Novel N,N′-
Diacylhydrazine Derivatives Containing Furan(III). Chin. J. Chem.
2010, 28 (7), 1257−1266. (e) Zhang, L.; Cui, Z. N.; Yin, B.; Yang, G.
F.; Ling, Y.; Yang, X. L. QSAR and 3D-QSAR studies of the diacyl-
hydrazine derivatives containing furan rings based on the density
functional theory. Sci. China Chem. 2010, 53 (6), 1322−1331.
(20) Cui, Z. N.; Ling, Y.; Li, B. J.; Li, Y. Q.; Rui, C. H.; Cui, J. R.; Shi,
Y. X.; Yang, X. L. Synthesis and Bioactivity of N-benzoyl-N′-[5-(2′-
substituted phenyl)-2- furoyl] semicarbazide Derivatives. Molecules
2010, 15 (6), 4267−4282.
(21) Cui, Z. N.; Shi, Y. X.; Cui, J. R.; Ling, Y.; Li, B. J.; Yang, X. L.
Synthesis and Bioactivities of Novel Pyrazole and Triazole Derivatives
Containing 5-Phenyl-2-Furan. Chem. Biol. Drug Des. 2012, 79 (1),
121−127.
(22) Krutosikova, A.; Kovac, J.; Sykora, V. Furan derivatives. LIII.
Synthesis of 5-aryl-2-furancarboxylic acids. Collect. Czech. Chem. Commun.
1974, 39 (7), 1892−1897.
(23) (a) Shi, Y. X.; Yuan, L. P.; Zhang, Y. B.; Li, B. J. Fungicidal
activity of novel fungicide chlorphenomizole and efficacy in controlling
main diseases on vegetable in field. Chin. J. Pestic. Sci. 2007, 9 (2),
126−130. (b) Wang, B. L.; Shi, Y. X.; Ma, Y.; Liu, X. H.; Li, Y. H.;
Song, H. B.; Li, B. J.; Li, Z. M. Synthesis and Biological Activity of
Some Novel Trifluoromethyl-Substituted 1,2,4- Triazole and Bis(1,2,4-
Triazole) Mannich Bases Containing Piperazine Rings. J. Agric. Food
Chem. 2010, 58 (9), 5515−5522. (c) Liu, X. H.; Shi, Y. X.; Ma, Y.;
Zhang, C. Y.; Dong, W. L.; Pan, L.; Wang, B. L.; Li, B. J.; Li, Z. M.
Synthesis, antifungal activities and 3D QSAR study of N-(5-
substituted-1,3,4- thiadiazol-2-yl) cyclopropanecarbox-amides. Eur. J.
Med. Chem. 2009, 44 (7), 2782−2786. (d) Zhang, C. Y.; Liu, X. H.;
Wang, B. L.; Wang, S. H.; Li, Z. M. Synthesis and antifungal activities
of new pyrazole derivatives via 1,3-dipolar cycloaddition reaction.
Chem. Biol. Drug Des. 2010, 75 (5), 489−493.
11656
dx.doi.org/10.1021/jf303807a | J. Agric. Food Chem. 2012, 60, 11649−11656