Design, Synthesis, and Antifungal Evaluation of Novel Benzoxazole Derivatives Containing a 1,2,3-Triazole Moiety

Article abstract of DOI:10.1002/jccs.201700129

For finding novel bioactive compounds with significant antifungal activities, 17 novel benzoxazole derivatives containing a 1,2,3-triazole moiety were synthesized by the copper(II) acetylacetonate-catalyzed cyclization reaction between 2-aminophenol deriv

Full text of DOI:10.1002/jccs.201700129

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Design, Synthesis, and Antifungal Evaluation of Novel Benzoxazole Derivatives
Containing a 1,2,3-Triazole Moiety
a
Yu-Qin Jiang,a Shu-Hong Jia,a Xi-Yong Li,b Ya-Min Sun,b Wei Li,a Wei-Wei Zhang
*
a
*
and Gui-Qing Xu
aHenan Engineering Laboratory of Chemical Pharmaceuticals and Biomedical Materials, Collaborative Innovation
Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media
and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University,
Xinxiang, Henan, 453007, China
bDepartment of Marine Fisheries, Weihai Ocean Vocational College, Weihai, Shandong 264300, China
(Received: April 10, 2017; Accepted: July 6, 2017; DOI: 10.1002/jccs.201700129)
For finding novel bioactive compounds with significant antifungal activities, 17 novel benzoxazole
derivatives containing a 1,2,3-triazole moiety were synthesized by the copper(II) acetylacetonate-
catalyzed cyclization reaction between 2-aminophenol derivatives and 1H-1,2,3-triazole-4-
carbaldehyde derivatives (4a), which were prepared through three steps using aromatic amine as
the starting material. Antifungal activities of the prepared compounds were evaluated against
Botrytis cinerea (BC) and Fusarium Verticillium (FV). The test results indicated that compounds
5b, 5c, 5h, and 5n show good inhibitory effects on fungi. The preliminary structure–activity rela-
tionship is also discussed.
Keywords: Benzoxazole derivatives; Antifungal activity; 1,2,3-Triazole.
INTRODUCTION
Gray mold is a major pathogenic factor during
aminopeptidase 2 inhibitors,13 and anti-HIV-1 agents.14
The benzoxazole and triazole frameworks have been
widely identified as privileged structures or pharmaco-
phores. It has been reported that maleimide, indole, or
paeonol connected to 1,2,3-triazole moieties shows
potent antitumor activity15 or antifungal activity.16–18
Here, in continuation of our previous research on
the synthesis of novel heterocycles, we report the design
and synthesis of a series of novel benzoxazole deriva-
tives containing the 1,2,3-triazole framework, to be
used as antifungal agents. The antifungal activities of
these novel benzoxazole derivatives were evaluated
in vitro against two plant pathogenic fungi, namely
Botrytis cinerea (BC) and Fusarium Verticillium (FV),
using hymexazol as the standard drug.
vegetable growth in the world, and is especially harmful
for the growth of tomato,1 strawberry,2 and onion.3
Verticillium is a class of fungi distributed all over the
world, which can endanger a variety of woody plant
roots, causing xylem discoloration, wilting, and falling
of leaves.4 Plant diseases caused by gray mold and ver-
ticillium have become a serious problem. To effectively
prevent and control plant diseases, fungicides, especially
chemical fungicides, are indispensable and crucial.
N-Heterocyclic compounds are extraordinarily
important compounds that are ubiquitous in vital bioac-
tive molecules and macromolecules. Novel lead com-
pounds in medicinal chemistry are found as hybrids of
different heterocyclic scaffolds.5 Among the various het-
erocycles, benzoxazoles, and triazoles play an important
role in the pharmaceutical and pesticides industries
because of their remarkable biological activities, such as
antibacterial and antifungal agents,6,7 cholesteryl ester
transfer protein (CETP) inhibitors,8 antitumor agents,9,10
anti-inflammatory agents,11,12 reversible methionine
RESULTS AND DISCUSSION
The general strategy for the synthesis of the target
compounds 5a–5q is illustrated in Scheme 1. Aromatic
azides 2a–2f were prepared from aromatic amines by the
diazo reaction.19 The reaction of 2 with propargyl
alcohol gave (1-phenyl-1H-1,2,3-triazol-4-yl)methanol
*Corresponding authors. Email: zhangweiwei@htu.edu.cn; guiqingxu@163.com
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1

Article
Jiang et al.
the two tested fungi at 40 μg/mL. Besides, the com-
pounds showed better activity toward BC than
FV. Among all the tested compounds, 5b, 5c, 5 h, and
5n exhibited the best antifungal activity toward BC,
which exceeded 80%. In these mentioned structures,
when the benzoxazole moiety and benzotriazole were
without substituents at aromatic ring, we obtained the
best antifungal activity against BC (Table 1, 5b). How-
ever, the benzotriazole moiety containing a 2-CH3,
compounds 5c and 5n, showed good inhibitory activity
with 81.9% and 81.5% inhibition of BC, respectively
(Table 1, 5c, 5n). It is worth mentioning that when the
benzotriazole moiety had a 3-Cl and the benzoxazole
ring had a 5-CH3, the inhibition ratio was 81.9% as for
BC (Table 1, 5h). Besides, compound 5a, 5e–5g, and 5j,
with a 2-F or 4-CH3 group connected to the benzotria-
zole moiety, showed moderate inhibitory activity
toward BC. However, as for FV, only compound 5c
reached 70% inhibition (Table 1, 5c), probably because
of the rapid growth of FV in the beginning. Taking
every aspect into consideration, compounds 5b, 5c, 5h,
and 5n are worthy of further investigations, being the
most effective compounds in this study.
Scheme 1. Synthesis of compounds 5a–5q.
derivatives (3),20 which were oxidized by Dess–Martin
periodinane to produce 1-phenyl-1H-1,2,3-triazole-4-
carbaldehyde derivatives (4).21 Then the oxidative
cyclization reaction of 4 with 2-aminophenol derivatives
catalyzed by 20 mol% copper(II) acetylacetonate (Cu
(acac)2) in xylene (3 mL) at 120ꢀC gave the desired com-
pounds 5a–5q with excellent yields (Table 1), which was
the key step for the synthesis of the target molecules.
The structures of 5a–5q were confirmed by NMR, IR,
and high-resolution mass spectroscopy (HRMS).
These novel benzoxazole-linked 1,2,3-triazole
derivatives 5a–5q were evaluated in vitro for their anti-
fungal activities against two plant pathogenic fungi
BC and FV, with hymexazol as the positive control.
The inhibition ratios are summarized in Table 1.
As can be seen from Table 1, most of the tested
compounds exhibited moderate to high activity against
In conclusion, a series of novel benzoxazole deri-
vatives linked to a 1,2,3-triazole ring system were
Table 1. Target compounds 5a–5q and their antifungal activity at 40 μg/mL.
Inhibition ratioa (%)
BC
Compound
R1
R2
Yield (%)
FV
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
4-CH3
H
2-CH3
3-Cl
2-F
4-CH3
4-CH3
3-Cl
H
H
H
H
91
95
91
92
93
93
94
94
93
90
89
89
92
93
94
91
88
53.3
81.9
81.9
34.3
53.3
53.8
53.8
81.9
62.9
53.3
34.3
34.3
43.8
81.5
43.8
34.3
35.4
31.4
47.3
70.0
38.2
26.8
24.5
24.5
42.7
33.6
29.1
29.1
29.1
31.4
56.4
38.2
31.4
29.1
H
5-CH3
4-Cl
5-CH3
5-CH3
4-Cl
4-Cl
5-CH3
5-CH3
4-Cl
5-CH3
4-Cl
H
2-F
2-F
3-Cl
4-(COOCH3)benzyl
2-CH3
2-CH3
H
H
5q
4-(COOCH3)benzyl
Hymexazol
a Data were collected at 48 h.
100
100
2
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CHEMICAL SOCIETY
Antifungal Evaluation of Benzoxazoles
designed and synthesized. Most of the target products
exhibited good antifungal activity toward BC and
FV. Among them, 5b, 5c, 5h, and 5n were the most
promising compounds. These results provide a reference
for further study of chemical fungicides.
the mixture was extracted with CH2Cl2 (3 × 25 mL).
The organic phase was dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue obtained
was purified by column chromatography on silica gel
using ethyl acetate/petroleum ether (1:2, v:v) as eluent.
Procedure for the synthesis of compounds 5a–5q
Aldehydes (4, 1.0 mmol), 2-aminophenol deriva-
tives (1.0 mmol), and Cu(acac)2 (0.2 mmol, 52 mg,
20 mol%) were put into a three-necked flask (25 mL)
containing xylene (3.0 mL) and equipped with a mag-
netic stirrer. The reaction mixture was heated to 120ꢀC
with stirring. When the starting materials were com-
pletely consumed, as determined by TLC analysis, the
reaction mixture was concentrated under vacuum and
the product was purified by silica gel column chroma-
tography using ethyl acetate/petroleum ether (1:10, v:v)
as eluent.
EXPERIMENTAL
General
All reagents were purchased from commercial
sources and used without further purification, unless
otherwise indicated. The unknown products were char-
1
acterized using H NMR, 13C NMR, melting points,
IR spectra, and HRMS. The H NMR and 13C NMR
1
spectra were recorded on a Bruker Avance (400 MHz)
or Bruker AVANCE III HD (600 MHz) spectrometer,
with CDCl3 as solvent. Data is represented as follows:
chemical shift, integration, multiplicity (s = singlet, d =
doublet, dd = double of doublets, t = triplet, q = quar-
tet, m = multiplet), and coupling constants (J) are in
hertz (Hz). Melting points were determined on a
YUHUA X-5 melting point apparatus and are reported
uncorrected. IR spectra were recorded on a NEXUS
FTIR-Raman spectrometer. HRMS was performed on
a MicrOTOF-QII mass spectrometer with an electro-
spray ionization (ESI) source (Waters, Manchester).
2-(1-(4-Methylphenyl)-1H-1,2,3-triazol-4-yl)benzo
[d]oxazole (5a). Gray solid. mp 227–228ꢀC. IR (KBr)
(νmax, cm−1): 3142 (C─H, Ar), 1646 (C N), 1589,
1
1520, 1452 (C─C), 1402 (C─N), 1241 (C─O). H NMR
(600 MHz, CDCl3) δ: 8.67 (s, 1H, triazole), 7.79–7.77
(m, 1H, H6), 7.69 (d, J = 6.0 Hz, 2H, H4, H7),
0
0
0
7.66–7.64 (m, 1H, H5), 7.41–7.36 (m, 4H, H2 , H3 , H5 ,
H6 ), 2.45 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3)
0
δ: 155.8, 150.4, 141.4, 139.8, 137.7, 134.0, 130.5, 125.6,
124.9, 122.6, 120.6, 120.1, 111.0, 21.2. HRMS ((+)ESI):
m/z Calcd for C16H12N4O + Na: 299.0903, found
299.0886.
Procedure for the synthesis of compounds 3a–3f
Aryl azide (2, 10.0 mmol), propargyl alcohol
(10.0 mmol, 560 mg), CuSO4ꢁ5H2O (0.1 mmol, 25 mg),
and sodium ascorbate (1.0 mmol, 198 mg) were added
to a 100-mL three-necked flask with the solvent
(40 mL, methanol/water = 1:1). The reaction was car-
ried out at 55ꢀC for ~1 h. When the reaction was com-
pleted, as monitored by TLC, the reaction mixture was
concentrated in vacuo and the product was purified by
silica gel column chromatography using ethyl acetate/
petroleum ether (1:4, v:v) as eluent.
2-(1-Phenyl-1H-1,2,3-triazol-4-yl)benzo[d]oxazole
(5b). White solid. mp 181–183ꢀC. IR (KBr) (νmax
,
cm−1): 3095 (C─H, Ar), 1644 (C N), 1589, 1473, 1450
(C C), 1401 (C─N), 1233 (C─O). 1H NMR
(400 MHz, CDCl3) δ: 8.72 (s, 1H, triazole), 7.84–7.81
0
(m, 2H, H5, H6), 7.81–7.78 (m, 1H, H2 )7.68–7.63 (m,
0
0
0
1H, H6 ), 7.59 (t, J = 8.0 Hz, 2H, H3 , H5 ), 7.52 (t,
J = 6.0 Hz, 1H, H4 ), 7.44–7.37 (m, 2H, H4, H7). 13C
0
Procedure for the synthesis of compounds 4a–4 f
NMR (100 MHz, CDCl3) δ: 155.7, 150.4, 141.4, 137.9,
136.4, 130.0, 129.5, 125.7, 125.0, 122.6, 120.7, 120.2,
111.0. HRMS ((+)ESI): m/z Calcd for C15H10N4O +
Na: 285.0747, found 285.0732.
1-Phenyl-1H-1,2,3-triazole-4-methanol derivatives
(3, 5.0 mmol) and the Dess–Martin reagent (6.0 mmol,
1.2 equiv., 2.54 g) were added to a round-bottomed
flask. The reaction mixture was stirred at room temper-
ature and monitored by TLC until the raw material
was completed consumed. To the above system, 1 M
sodium thiosulfate-saturated sodium bicarbonate solu-
tion was added until no bubbles were produced. Then
2-(1-(2-Methylphenyl)-1H-1,2,3-triazol-4-yl)benzo
[d]oxazole (5c). Light yellow solid. mp 179–181ꢀC. IR
(KBr) (νmax, cm−1): 3090 (C─H, Ar), 1638 (C N),
1
1510, 1495, 1454 (C C), 1400 (C─N), 1240 (C─O). H
NMR (400 MHz, CDCl3) δ: 8.48 (s, 1H, triazole),
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1
7.82–7.76 (m, 1H, H5), 7.68–7.63 (m, 1H, H6),
1507, 1449 (C C), 1400 (C─N), 1255 (C─O). H NMR
(400 MHz, CDCl3) δ: 8.67 (s, 1H, triazole), 7.76 (d,
0
0
0
0
7.50–7.37 (m, 6H, H4, H7, H2 , H3 , H4 , H5 ), 2.29 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3) δ: 155.8,
150.4, 141.4, 137.2, 135.7, 133.6, 131.7, 130.5, 127.1,
126.1, 125.9, 125.7, 124.9, 120.1, 111.0, 17.9. HRMS
((+)ESI): m/z Calcd for C16H12N4O + Na: 299.0903,
found 299.0875.
0
0
J = 1.9 Hz, 1H, H4), 7.69 (d, J = 8.4 Hz, 2H, H2 , H6 ),
7.57 (d, J = 8.7 Hz, 1H, H7), 7.39–7.36 (m, 3H, H6, H3 ,
H5 ), 2.46 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ:
157.1, 149.0, 142.6, 139.9, 137.3, 134.0, 130.5, 125.9,
122.9, 120.6, 120.1, 111.7, 21.2. HRMS ((+)ESI): m/z
Calcd for C16H11ClN4O + Na: 333.0514, found 333.0530.
2-(1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)-6-
0
0
2-(1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)benzo
[d]oxazole (5d). White solid. mp 167–168ꢀC. IR (KBr)
(νmax, cm−1): 3107 (C─H, Ar), 1645 (C N), 1590,
1495, 1451 (C C), 1395 (C─N), 1245 (C─O). 1H NMR
(400 MHz, CDCl3) δ: 8.71 (s, 1H, triazole), 7.89 (t,
methylbenzo[d]oxazole
(5h).
White
solid.
mp
172–173ꢀC. IR (KBr) (νmax, cm−1): 3116 (C─H, Ar),
1639 (C N), 1510, 1486, 1464 (C C), 1402 (C─N),
1
0
J = 1.9 Hz, 1H, H6 ), 7.81–7.77 (m, 1H, H5), 7.73 (dt,
1252 (C─O). H NMR (400 MHz, CDCl3) δ: 8.68 (s,
0
0
J = 7.7, 1.8 Hz, 1H, H6), 7.67–7.62 (m, 1H, H2 ),
1H, triazole), 7.89 (t, J = 1.9 Hz, 1H, H6 ), 7.72 (dt,
0
0
0
7.55–7.47 (m, 2H, H4, H7), 7.44–7.37 (m, 2H, H3 , H4 ).
13C NMR (100 MHz, CDCl3) δ: 155.3, 150.3, 141.3,
138.1, 137.1, 135.8, 131.1, 129.6, 125.8, 125.0, 122.5,
121.0, 120.2, 118.6, 111.0. HRMS ((+)ESI): m/z Calcd
for C15H9ClN4O + Na: 319.0357, found 319.0328.
2-(1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl)benzo
[d]oxazole (5e). White solid. mp 176–177ꢀC. IR (KBr)
(νmax, cm−1): 3123 (C─H, Ar), 1635 (C N), 1506,
1475, 1451 (C C), 1400 (C─N), 1240 (C─O). 1H NMR
(400 MHz, CDCl3) δ: 8.84 (s, 1H, triazole), 8.08 (t,
J = 7.7, 1.8 Hz, 1H, H2 ), 7.65 (d, J = 8.1 Hz, 1H, H5),
0
0
7.55–7.47 (m, 2H, H7, H4 ), 7.44 (s, 1H, H3 ), 7.21 (d,
J = 7.3 Hz, 1H, H4), 2.52 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3) δ: 154.9, 150.7, 139.2, 138.3, 137.2,
136.4, 135.9, 131.1, 129.5, 126.3, 122.2, 121.0, 119.5,
118.6, 111.1, 21.8. HRMS ((+)ESI): m/z Calcd for
C16H11ClN4O + Na: 333.0514, found 333.0524.
2-(1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl)-6-
methylbenzo[d]oxazole (5i). Light pink solid. mp
190–191ꢀC. IR (KBr) (νmax, cm−1): 3176 (C─H, Ar),
1634 (C N), 1519, 1508, 1475 (C C), 1400 (C─N),
0
J = 7.0 Hz, 1H, H2 ), 7.84–7.78 (m, 1H, H5), 7.68–7.63
1
(m, 1H, H6), 7.54–7.48 (m, 1H, H7), 7.43–7.34 (m, 4H,
1254 (C─O). H NMR (400 MHz, CDCl3) δ: 8.80 (d,
H4, H3 , H4 , H5 ). 13C NMR (100 MHz, CDCl3) δ:
155.5, 154.5, 152.0, 150.4, 141.4, 137.7, 131.0 (d,
J = 8.0 Hz, CH), 125.7, 125.6, 125.5 (d, J = 4.0 Hz,
CH), 125.0, 124.8, 120.2, 117.2 (d, J = 20.0 Hz, CH),
111.0. HRMS ((+)ESI): m/z Calcd for C15H9FN4O +
Na: 303.0653, found 303.0632.
J = 2.6 Hz, 1H, triazole), 8.07 (t, J = 8.0 Hz, 1H, H2 ),
0
0
0
0
7.66 (d, J = 8.1 Hz, 1H, H5), 7.53–7.48 (m, 1H, H7),
0
0
0
7.45 (s, 1H, H3 ), 7.40–7.33 (m, 2H, H4 , H5 ), 7.21 (d,
J = 8.1 Hz, 1H, H4), 2.52 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3) δ: 155.0, 154.5, 152.1, 150.7, 139.2,
137.9, 136.3, 130.9 (d, J = 8 Hz, CH), 126.2, 125.4 (d,
J = 4 Hz, CH), 125.4, 124.9, 119.5, 117.2 (d, J = 19 Hz,
CH), 111.1, 21.8. HRMS ((+)ESI): m/z Calcd for
C16H11FN4O + Na: 317.0809, found 317.0818.
6-Methyl-2-(1-(4-methylphenyl)-1H-1,2,3-triazol-4-
yl)benzo[d]oxazole (5f ). Brick red solid. mp 214–215ꢀC.
IR (KBr) (νmax, cm−1): 3121 (C─H, Ar), 1637 (C N),
1522, 1510 (C C), 1401 (C─N), 1244 (C─O). H NMR
(400 MHz, CDCl3) δ: 8.63 (s, 1H, triazole), 7.69 (d,
1
5-Chloro-2-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-
yl)benzo[d]oxazole (5j). Light red solid. mp 205–206ꢀC.
J = 4.0 Hz, 2H, H2 , H6 ), 7.64 (d, J = 8.0 Hz, 1H, H5),
IR (KBr) (νmax, cm−1): 3097 (C─H, Ar), 1634 (C N),
0
0
1
0
0
7.44 (s, 1H, H7), 7.36 (d, J = 8.1 Hz, 2H, H3 , H5 ), 7.20
(d, J = 8.9 Hz, 1H, H4), 2.51 (s, 3H, 6-CH3), 2.44 (s, 3H,
H5, 40-CH3). 13C NMR (100 MHz, CDCl3) δ: 155.3,
150.7, 139.7, 139.24, 137.9, 136.2, 134.1, 130.4, 126.2,
122.3, 120.6, 119.4, 111.1, 21.8, 21.1. HRMS ((+)ESI).: m/
z Calcd for C17H14N4O + Na: 313.1060, found 313.1030.
5-Chloro-2-(1-(4-methylphenyl)-1H-1,2,3-triazol-4-yl)
benzo[d]oxazole (5g). White solid. mp 184–185ꢀC. IR
(KBr) (νmax, cm−1): 3120 (C─H, Ar), 1636 (C N), 1519,
1506, 1474, 1448 (C C), 1400 (C─N), 1259 (C─O). H
NMR (400 MHz, CDCl3) δ: 8.83 (d, J = 2.5 Hz, 1H,
triazole), 8.08 (t, J = 7.9 Hz, 1H, H4), 7.77 (d,
0
J = 1.9 Hz, 1H, H7), 7.57 (d, J = 8.6 Hz, 1H, H2 ),
0
0
7.55–7.49 (m, 1H, H6), 7.41–7.34 (m, 3H, H3 , H4 ,
H5 ). 13C NMR (100 MHz, CDCl3) δ: 156.9, 154.5,
152.0, 149.0, 142.6, 137.3, 131.1 (d, J = 8 Hz, CH),
130.5, 126.0, 125.9, 125.5 (d, J = 4 Hz, CH), 124.8,
120.2, 117.3(d, J = 20 Hz, CH), 111.7. HRMS ((+)
0
4
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Antifungal Evaluation of Benzoxazoles
ESI): m/z Calcd for C15H8FClN4O + Na: 337.0263,
found 337.0257.
CH3). 13C NMR (100 MHz, CDCl3) δ: 157.1, 149.0, 142.6,
136.8, 135.7, 133.6, 131.7, 130.5, 130.5, 127.1, 126.4, 126.0,
125.9, 120.1, 111.7, 17.9. HRMS ((+)ESI): m/z Calcd for
C16H11ClN4O + Na: 333.0514, found 333.0513.
6-Methyl-2-(1-phenyl-1H-1,2,3-triazol-4-yl)benzo[d]
oxazole (5o). Brick red solid. mp 199–200ꢀC. IR (KBr)
(νmax, cm−1): 3051 (C─H, Ar), 1635 (C N), 1515,
1502, 1482 (C C), 1400 (C─N), 1343 (C─O). 1H NMR
(400 MHz, CDCl3) δ: 8.68 (s, 1H, triazole), 7.82 (d,
5-Chloro-2-(1-(3-chlorophenyl)-1H-1,2,3-triazol-4-
yl)benzo[d]oxazole (5k). Off-white solid. mp 205–206ꢀC.
IR (KBr) (νmax, cm−1): 3099 (C─H, Ar), 1592 (C N),
1
1584, 1490, 1448 (C C), 1403 (C─N), 1257 (C─O). H
NMR (400 MHz, CDCl3) δ: 8.72 (s, 1H, triazole), 7.90
0
(t, J = 1.8 Hz, 1H, H6 ), 7.77 (d, J = 2.0 Hz, 1H, H4),
7.72 (dt, J = 7.6, 1.9 Hz, 1H, H7), 7.59–7.51 (m, 3H,
H2 , H3 , H4 ), 7.38 (dd, J = 8.7, 2.1 Hz, 1H, H6). 13C
NMR (100 MHz, CDCl3) δ: 156.7, 149.0, 142.5, 137.7,
137.1, 136.0, 131.1, 130.8, 129.7, 126.1, 122.8, 121.1,
120.2, 118.6, 111.7. HRMS ((+)ESI): m/z Calcd for
C15H8Cl2N4O + Na: 352.9967, found 352.9950.
J = 8.1 Hz, 2H, H2 , H6 ), 7.65 (d, J = 8.1 Hz, 1H,
0
0
0
0
0
0
0
0
H3 ), 7.58 (t, J = 7.6 Hz, 2H, H4 , H5 ), 7.51 (m,
J = 8.0 Hz, 1H, H5), 7.44 (s, 1H, H7), 7.20 (d,
J = 8.8 Hz, 1H, H4), 2.52 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3) δ: 155.2, 150.7, 139.2, 138.0, 136.4,
136.3, 130.0, 129.5, 126.2, 122.4, 120.7, 119.5, 111.1,
21.8. HRMS ((+)ESI): m/z Calcd for C16H12N4O + Na:
299.0903, found 299.0917.
5-Chloro-2-(1-phenyl-1H-1,2,3-triazol-4-yl)benzo[d]
oxazole (5p). Orange solid. mp 203–205ꢀC. IR (KBr)
(νmax, cm−1): 3135 (C─H, Ar), 1634 (C N), 1505, 1450,
1428 (C C), 1400 (C─N), 1261 (C─O). 1H NMR
(400 MHz, CDCl3) δ: 8.71 (s, 1H, triazole), 7.83–7.80
Methyl 4-(4-((6-methylbenzo[d]oxazol-2-yl)methyl)-
1H-1,2,3-triazol-1-yl)benzoate (5l). Light yellow solid.
mp 197–198ꢀC. IR (KBr) (νmax, cm−1): 3093 (C─H, Ar),
1723 (C O), 1644 (C N), 1615, 1485, 1437 (C C),
1378 (C─N), 1249 (C─O). 1H NMR (400 MHz,
DMSO-d6) δ: 9.14 (s, 1H, triazole), 7.98 (d, J = 8.2 Hz,
2H, Ar─H), 7.67 (d, J = 8.1 Hz, 1H, Ar─H), 7.62 (s,
1H, Ar─H), 7.50 (d, J = 8.2 Hz, 2H, H5, H7), 7.24 (d,
J = 8.1 Hz, 1H, H4), 5.85 (s, 2H, CH2), 3.85 (s, 3H, 6-
CH3), 2.47 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-
d6) δ: 165.8, 155.3, 149.9, 140.6, 138.8, 136.1, 135.7,
129.6, 129.4, 128.2, 127.0, 126.1, 119.12, 110.9, 52.7,
52.2, 21.2. HRMS ((+)ESI): m/z Calcd for
C19H16N4O3 + Na: 371.1115, found 371.1105.
0
(m, 2H, H4, H7), 7.76 (d, J = 2.0 Hz, 1H, H2 ),
0
0
0
0
7.61–7.50 (m, 4H, H3 , H4 , H5 , H6 ), 7.37 (dd, J = 8.7,
2.1 Hz, 1H, H6). 13C NMR (100 MHz, CDCl3) δ: 157.0,
149.0, 142.6, 137.5, 136.3, 130.5, 130.0, 129.6, 126.0,
122.9, 120.7, 120.1, 111.7. HRMS ((+)ESI): m/z Calcd
for C15H9ClN4O + Na: 319.0357, found 319.0358.
Methyl 4-((4-(benzo[d]oxazol-2-yl)-1H-1,2,3-tria-
zol-1-yl)methyl)benzoate (5q). Light yellow solid. mp
192–194ꢀC. IR (KBr) (νmax, cm−1): 3098 (C─H, Ar),
1712 (C O), 1645 (C N), 1615, 1445, 1433 (C C),
1282 (C─N), 1240 (C─O). 1H NMR (400 MHz,
DMSO-d6) δ: 9.19 (s, 1H, triazole), 7.98 (d, J = 8.2 Hz,
2H, Ar─H), 7.83–7.80 (m, 2H, H5, H6), 7.51 (d,
J = 8.2 Hz, 2H, H4, H7), 7.47–7.41 (m, 2H, Ar─H),
5.86 (s, 2H, CH2), 3.84 (s, 3H, CH3). 13C NMR
(100 MHz, DMSO-d6) δ: 165.8, 155.8, 149.6, 141.0,
140.6, 136.0, 129.6, 129.4, 128.2, 127.3, 125.6, 125.0,
119.8, 111.0, 152.7, 152.2. HRMS ((+)ESI): m/z Calcd
for C18H14N4O3 + Na: 357.0958, found 357.0955.
6-Methyl-2-(1-(4-methylphenyl)-1H-1,2,3-triazol-4-
yl)benzo[d]oxazole (5m). Off-white solid. mp 184–186ꢀC.
IR (KBr) (νmax, cm−1): 3088 (C─H, Ar), 1635 (C N),
1510, 1497, 1467 (C C), 1400 (C─N), 1240 (C─O). H
NMR (400 MHz, CDCl3) δ: 8.45 (s, 1H, triazole), 7.65
1
0
0
0
(d, J = 8.1 Hz, 1H, H4 ), 7.50–0.37 (m, 5H, H2 , H3 ,
0
H5 , H5, H7), 7.21 (d, J = 8.1 Hz, 1H, H4), 2.53 (s, 3H,
6-CH3), 2.29 (s, 3H, 60-CH3). 13C NMR (100 MHz,
CDCl3) δ: 155.3, 150.7, 139.3, 137.4, 136.2, 135.8, 133.6,
131.7, 130.4, 127.1, 126.2, 126.0, 125.9, 119.4, 111.1,
21.8, 17.9. HRMS ((+)ESI): m/z Calcd for
C17H14Cl2N4O + Na: 313.1060, found 313.1066.
7-Chloro-2-(1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl)
benzo[d]oxazole (5n). White solid. mp 138–140ꢀC. IR
(KBr) (νmax, cm−1): 3072 (C─H, Ar), 1651 (C N), 1503,
1466, 1446 (C C), 1380 (C─N), 1256 (C─O). H NMR
(400 MHz, CDCl3) δ: 8.47 (s, 1H, triazole), 7.76 (d,
J = 2.0 Hz, 1H, H4), 7.57 (d, J = 8.7 Hz, 1H, H7),
7.50–7.36 (m, 5H, H2 , H3 , H4 , H5 , H6), 2.29 (s, 3H,
Antifungal activity
1
The antifungal activity of the target compounds
against BC and FV was evaluated at the College of Life
Science, Henan Normal University, using hymexazol as
positive control. The procedures were as follows22:
0
0
0
0
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5

Article
Jiang et al.
5. A. Shafiee, Eur. J. Med. Chem. 2015, 97, 334.
A stock solution of each compound was prepared
6. T. Kusumi, T. Ooi, M. R. Wälchli, H. Kakisawa, J. Am.
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D. R. Bell, M. F. G. Stevens, C. S. Matthews,
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at 1.0 mg/mL using DMSO as solvent. A working solu-
tion (0.04 mg/mL) was then prepared by diluting the
stock solution (0.04 mL) into a 10-cm-diameter Petri
dish containing potato dextrose agar (PDA, 10 mL).
Before the plate solidification, the PDA was completely
mixed by turning around the Petri dish in the sterilized
operation disk six times to decentralize the compounds
in PDA evenly. Then 0.8 mm of diameter of the fungi
cake was vaccinated on the plate and cultured in an
incubator at 28ꢀC. At the same time, blank control and
positive control were prepared using the same proce-
dures. After 48 h, the diameter of fungi spread was
measured. The antifungal activity was evaluated using
the antifungal inhibition ratio, which was calculated by
comparing the average diameter of fungi spread with
that of the corresponding control, according to Eq. (1).
12. S. Shafi, M. M. Alam, N. Mulakayala, C. Mulakayala,
G. Vanaja, A. M. Kalle, R. Pallu, M. S. Alam, Eur.
J. Med. Chem. 2012, 49, 324.
A−B
A
W =
× 100
ð1Þ
13. L. S. Kallander, Q. Lu, W. Chen, T. Tomaszek, G. Yang,
D. Tew, T. D. Meek, G. A. Hofmann, C. K. Schulz-
Pritchard, W. W. Smith, C. A. Janson, M. D. Ryan,
G. F. Zhang, K. O. Johanson, R. B. Kirkpatrick,
T. F. Ho, P. W. Fisher, M. R. Mattern, R. K. Johnson,
M. J. Hansbury, J. D. Winkler, K. W. Ward, D. F. Veber,
S. K. Thompson, J. Med. Chem. 2005, 48, 5644.
14. R. Alvarez, S. Velázquez, A. San-Félix, S. Aquaro, E. De
Clercq, C. F. Perno, A. Karlsson, J. Balzarini,
M. J. Camarasa, J. Med. Chem. 1994, 37, 4185.
15. G. Q. Xu, D. Y. Kong, W. Li, W. J. Xu, Y. Q. Jiang,
J. Chem. Pharm. Res. 2014, 6, 947.
where W is the antifungal inhibition ratio (in vivo) (%),
A is the average diameter of the blank fungi spread
in vivo, and B is the average diameter of drug-
containing fungi spread in vivo.
ACKNOWLEDGMENTS
This work was supported by the Innovative Talents
Program of Henan Province (No. 164100510015 and
174100510025), the Foundation of Henan Educational
Committee (Nos. 15A150054 and 16A350015), and the
Scientific
Research
Foundation
for
Doctors
16. Y. Q. Jiang, B. Q. Ren, X. M. Lv, W. W. Zhang, W. Li,
G. Q. Xu, J. Chem. Res. 2015, 39, 243.
(No. qd16106) of Henan Normal University.
17. G. Q. Xu, J. L. Zhao, Y. Q. Jiang, P. Zhang, W. Li,
J. Chem. Res. 2016, 40, 269.
18. G. Q. Xu, S. Mao, L. Mao, Y. Q. Jiang, P. Zhang,
W. Li, Z. Naturforsch. 2016, 71, 953.
Supporting information
Additional supporting information is available in
the online version of this article.
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20. D. B. Ramachary, A. B. Shashank, S. Karthik, Angew.
Chem. Int. Ed. 2014, 53, 10420.
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6
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© 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2017