Design, synthesis, and biological evaluation of phenyloxadiazole derivatives as potential antifungal agents against phytopathogenic fungi

Article abstract of DOI:10.1007/s00706-020-02717-z

Abstract: A novel series of picarbutrazox-inspired oxadiazole hybrids was synthesized and the derivatives’ biological activity against phytopathogenic fungi was investigated. The molecules were designed by retaining the active fragment of tetrazolyl phenyloxime ether of lead compound picarbutrazox, while introducing the potentially active oxadiazole-derived fragment. Bioassay results revealed that some of the title compounds showed potent in vivo antifungal activities to control cucumber downy mildew. Therefore, this novel oxadiazole phenyloxadiazole derivative can be used as a potential antifungal agent to control cucumber downy mildew and other phytopathogenic fungi for crop protection. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-020-02717-z

Monatshefte für Chemie - Chemical Monthly (2021) 152:121–135
https://doi.org/10.1007/s00706-020-02717-z
ORIGINAL PAPER
Design, synthesis, and biological evaluation of phenyloxadiazole
derivatives as potential antifungal agents against phytopathogenic
fungi
Yitao Li1 · Wenqiang Yao1 · Jian Lin1,2 · Guoliang Gao1 · Chang Huang1 · Yang Wu1
Received: 30 July 2020 / Accepted: 19 November 2020 / Published online: 3 January 2021
© Springer-Verlag GmbH Austria, part of Springer Nature 2021
Abstract
A novel series of picarbutrazox-inspired oxadiazole hybrids was synthesized and the derivatives’ biological activity against
phytopathogenic fungi was investigated. The molecules were designed by retaining the active fragment of tetrazolyl phenyl-
oxime ether of lead compound picarbutrazox, while introducing the potentially active oxadiazole-derived fragment. Bioassay
results revealed that some of the title compounds showed potent in vivo antifungal activities to control cucumber downy
mildew. Therefore, this novel oxadiazole phenyloxadiazole derivative can be used as a potential antifungal agent to control
cucumber downy mildew and other phytopathogenic fungi for crop protection.
Graphic abstract
Keywords Oxadiazole hybrids · Heterocycles · Halogenides · Fungicides · Structure–activity relationship
Introduction
currently the main means of protecting crops from fungal
plant diseases and ensuring income growth. However, with
the continuously large-scale and overuse of conventional
fungicides worldwide, the problem of resistant development
to the existing commercial fungicides is becoming increas-
ingly prominent [2, 3]. It has been documented that many
phytopathogenic fungi have evolved obvious resistance after
several years of a new fungicide usage, which greatly short-
ens the service life of the drug and hinders the development
of similar new drugs [4], even cross-resistance between simi-
lar fungicide products, which seriously shortens the efective
service life of pesticide products and restricts their develop-
ment [5, 6]. Therefore, the development of new fungicides
with high efciency, low toxicity, and no cross-resistance
undoubtedly an efective means to solve the problem of fun-
gal resistance and ensure food security [7].
As the world’s population continues to increase, food secu-
rity is facing severe challenges [1]. Crop-destroying fungi
account for perennial yield losses of around 20% worldwide,
with a further 10% loss after post-harvesting. Fungicides are
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-020-02717-z) contains
supplementary material, which is available to authorized users.
* Jian Lin
linjian@hec.cn
1
Dongguan HEC Pesticides R&D Co., Ltd.,
Dongguan 523871, Guangdong, People’s Republic of China
2
College of Chemistry Biology and Environmental
Engineering, Xiangnan University, Chenzhou 423000,
People’s Republic of China
Vol.:(0123456789)
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Y. Li et al.
Nitrogen-containing heterocycles are known as a research
rigid structure of tetrazolyl phenyl oxime ether seems to be
necessary for biological activity, and slight changes at this
site may make the activity extremely reduced. All of these
fndings inspired us to modify the bioactive structures based
on picarbutrazox for plant fungal disease control.
hotspot in the search for novel pharmaceuticals and agro-
chemicals due to their unique structural characteristics and
biological activity [8–14]. As one of the most important, the
structure of 1,3,4-oxadiazole group is an active pharmacoph-
ore which widely used in the feld of medicine and pesticides
discovery. Its derivatives have been reported to possess a wide
range of biological activities, such as anti-fbrosis [15], anti-
allergy [16], and other drugs [17, 18]. It has also been widely
used as a scafold in pesticides molecular design including
antibacterial, antifungal, antiviral, insecticidal, and herbi-
cidal [19–29]. The derivatives of oxadiazole biphenyl struc-
ture have also been reported as an active fragment, which can
obtain the compound with excellent biological activity just by
simple modifcation [8, 17, 19, 24]. Therefore, the fragment of
1,3,4-oxadiazole or its biphenyl derivatives can be used as an
active scafold in agricultural chemical modifcation.
In our previous work, we have been studying how to pre-
venting cucumber downy mildew caused by oomycetes, and
have achieved good results [40–42]. Motivated by the above
fndings, we decided to continue to focus our eforts on
developing highly antifungal bioactive molecules. Herein,
using picarbutrazox as the leading structure, the potential
active 1,3,4-oxadiazole-derived fragment and picarbutra-
zox active fragment of tetrazolyl phenyl oxime ether were
combined to obtain a novel series of picarbutrazox-inspired
oxadiazole hybrids. The active fragment of tetrazolyl phenyl
oxime ether was retained to maintain the biological activ-
ity of the structure while introducing the potentially active
oxadiazole-derived fragment was anticipated to result in a
promising antifungal agent with more pronounced biological
activity. Antifungal activities were evaluated in vivo against
cucumber downy mildew and in vitro against litchi blight to
fnd potential antifungal agents for crop protection.
Picarbutrazox [30] is a new type of carbamate fungicide
developed by Caoda Industry Co., Ltd in Japan. It has excel-
lent control efects on fruit and vegetable diseases caused
by oomycetes, such as downy mildew and late blight on
gourds, tomatoes, and leaf vegetables. Moreover, it exhibited
a novel mode of action compared with existing oomycetes
fungicides, suggesting that it is a fungicide with excellent
development prospects. Many researchers have also carried
out some chemical modifcation, such as introducing halo-
gen [31] on the benzene ring, replacing tetrazole [32–37]
with oxadiazole, etc., or conducting side-chain pyridine
[38] and terminal substituent [39], etc. By analyzing the
existing structure–activity relationships, we found that the
Results and discussion
Chemistry
The compound we studied could be synthesized by two
routes (as shown in Scheme 1). The frst was obtained by the
reaction of tetrazolyl phenyl oxime and oxadiazole biphenyl
Scheme 1
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Design, synthesis, and biological evaluation of phenyloxadiazole derivatives as potential…
123
(as shown in Scheme 1(1)). The key intermediates of oxa-
diazole could be obtained by corresponding. The substituted
benzoate compound 1 was used as the starting material and
hydrazine was hydrolyzed with hydrazine hydrate to obtain
compound 2. 2 was added dropwise under alkaline condi-
tions to react with monoethyl oxalyl chloride. After the reac-
tion was complete, p-toluenesulfonate was directly added
without any further purifcation. The ring-closing product
3 could be directly obtained by one-step reaction of acid
chloride ring-closing; 3 only needed to undergo a simple
reduction to obtain 4, bromo-intermediate 5 through bro-
mination by PBr3 from 4. The structure of tetrazolyl phenyl
oxime used methyl benzoylformate as the raw material, and
it was frst heated with methylamine to obtain 6, and then
acylated to obtain the intermediate phenyliminoacetyl chlo-
ride G, sodium azide in the phase transfer catalyst ring clo-
sure with 7 under the action of tetrabutylammonium bromide
to obtain (1-methyl-1H-tetrazol-5-yl)(phenyl)ketone 8, and
then reacted with hydroxylamine hydrochloride to obtain
tetrazolyl phenyl oxime intermediate 9, and fnally 9 and 5
underwent nucleophilic substitution reaction to obtain ben-
zodioxazole product 10. The second route was obtained by
reacting two parts of tetrazolyl phenyl oxime and oxadiazole
diphenyl ether (as shown in Scheme 1(2)), and benzonitrile
derivatives reacted with phenol compounds to obtain inter-
mediate 11, then hydrogen peroxide was oxidized to form
12, and then underwent an esterifcation reaction to obtain
the key intermediate 13, and 13 then underwent steps a, b, c,
d, i in Scheme 1(1) to obtain the target compound 14.
In order to better understand the structure–activity
relationship (SAR) of compounds, the toxicity regression
equation, EC50 value and confdence interval for each com-
pound were calculated. From Table 2, it showed that most
compounds had EC50 values below 5 mg/dm3. It could be
seen from the oxadiazole biphenyl structure compounds that
when the para position was an electron-withdrawing group,
good control activity could be obtained (10a–10c), and when
the para position was an electron-donating group, it was
generally followed (10d, 10g, 10k). When there was halogen
in the adjacent or meta position, the control efect was very
good (10e, 10f, 10h, 10i, 10j). We then analyzed the EC50
values of oxadiazole diphenyl ether compounds (14a–14q).
To our satisfaction, the EC50 values were all below 7 mg/dm3
and there were two compounds below 1 mg/dm3 (14k, 14l).
It was found that the general activity of the ortho-diphenyl
ether structure was higher than that of the para-position, and
in the ortho-position or para-position structure, the activity
was better when the benzene ring contained halogen, espe-
cially F. Alkyl or alkoxy, the activity efect was relatively
poor. It was very pleased with the result that we obtained
a compound 14l (EC50 = 0.703 mg/dm3) that is compara-
ble to the lead (EC50 = 0.581 mg/dm3). From the SAR of
the compound, it showed that the activity of the compound
was related to many factors: the electronic efect of the sub-
stituent, the position of the substituent, the position of the
aromatic ring, etc. It was worth mentioning that the 14l ben-
zene ring of the compound we synthesized contained three
F atoms, which once again illustrated the importance of the
F element in pesticides.
Antifungal activity
Analysis of feld efcacy trials
After these compounds had been synthesized, we had done
indoor pot experiment of cucumber downy mildew, and also
selected a part of the experiment of litchi blight (picarbutra-
zox was chosen as the lead). It could be seen from Table 1
that the series of oxadiazole biphenyls and oxadiazole
biphenyl ether compounds we synthesized had a good imi-
tation of cucumber downy mildew. The most of compound’s
control efect was 100%. When it dropped to 25 ppm, the
control efect could also be kept at 100% except 10d, 10g,
10h, 10k, 14o, 14q. Continue to reduce the concentration to
12.5 ppm and we could still see that half of the compounds
could maintain the control efect at 100%, which gave us
confdence. Therefore, we then decreased the concentra-
tion to 6.25 ppm and found that only 7 compounds could
continue to maintain 100% control efect, and then another
three gradient experiments were done. What excited us was
that the control efect of 14l was very good, with a control
efect of 60% at 0.781 ppm, which was only 10 percentage
points lower than the lead. It was believed that the series of
compounds we had synthesized had good research prospects
in controlling cucumber downy mildew.
To further compare the activity of our synthesized oxadia-
zole biphenyl ether high activity compound 14l and the lead
compound picarbutrazox, we conducted an indoor cucum-
ber downy mildew control efect experiment, testing three
concentrations (3.125 / 0.781 / 0.195). As showed in Fig. 1,
the two drugs had the same efcacy in preventing and cur-
ing cucumber downy mildew, but the control experiment
without spraying the drugs as we could see on control check
(CK) was seriously ill. Even if it was reduced to a low con-
centration of 0.195 ppm, the highly active compound 14l
synthesized by us still had a good control efect. It showed
that such compounds had very good research prospects.
After testing the indoor cucumber downy mildew, we
conducted an indoor laboratory test for peronophythora
litchii and the result as showed in Fig. 2. According to
the mycelial growth rate method, the control effects at
three concentrations (3.125, 0.781, and 0.195) were meas-
ured. It could be seen that the highly active compound
14l was equivalent to the lead compound picarbutrazox at
3.125 ppm and 0.781 ppm. What excited us was that at a
1 3

124
Y. Li et al.
Table 1 Control efects of
oxadiazole biphenyl and
oxadiazole biphenyl ether
compounds on cucumber downy
mildew
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Design, synthesis, and biological evaluation of phenyloxadiazole derivatives as potential…
125
Table 1 (continued)
lower concentration of 0.195 ppm, the control efect of 14l
(94.29%) was slightly higher than picarbutrazox (88.10%),
but no spray control experiment was seriously ill. These
laboratory experiments had greatly inspired us, and let us
believe that our synthesized oxadiazole diphenyl ether high
activity compound 14l would be a good fungicide, and there
would be good research prospects in the future.
Preparation of intermediate 2 [31]
At the 250 cm3 double-mouth bottle, 13.5 mmol of the
methyl benzoate derivatives was added to 100 cm3 of meth-
anol, added 6.75 cm3 of hydrazine hydrate (108 mmol) to
the reaction mixture slowly. After that warming to 80 °C
and refux for 4 h until the reaction was completed, then
concentrated under reducing pressure to remove methanol,
fltering and drying to get white solid 2.
Experimental
4‑(Trifuoromethyl)benzohydrazide (2a, C8H7F3N2O) White
solid; yield: 86%; m.p.: 145–148 °C; 1H NMR (400 MHz,
CDCl3): δ=9.64 (t, J=7.1 Hz, 1H, NH), 7.61 (d, J=8.5 Hz,
2H, ArH), 7.51 (d, J=7.3 Hz, 2H, ArH), 4.46 (d, J=4.2 Hz,
2H, NH2) ppm; 13C NMR (100 MHz, CDCl3): δ = 178.4
(CF3), 167.9 (C=O), 160.7 (CH), 159.1 (CH), 147.6
(CH), 146.1 (CH) ppm; IR (KBr): ꢀ = 3416, 3064, 2916,
1725, 1661, 1557, 1448 cm−1; HRMS (EI): m/z calcd. for
C8H7F3N2O (M+) 205.0514, found 205.0517.
All of the commercially available reagents could be used
immediately without purifcation. Nuclear magnetic reso-
nance (NMR) spectra were recorded on a Varian Mercury
spectrometer (1H 400 MHz, 13C 100 MHz), using TMS
(tetramethylsilane) as an internal reference. Several abridga-
tions put to used show that multiplicity as follow, s: singlet,
t: triplet, d: doublet, br: broad, m: multiplet. ESI spectra
were measured on a Waters UPLC/Quattro Premier XE mass
spectrometer.
1 3

126
Y. Li et al.
Table 2 Determination of
activity of diferent agents on
cucumber downy mildew
Examples
Toxic regression equation
EC50/mg dm−3
95% confdence
interval /mg
dm−3
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
14a
14b
14c
14d
14e
14f
14g
14h
14i
14j
14k
14l
Y=− 2.494+4.530X
Y=− 1.788+4.703X
Y=− 13.970+12.737X
Y=− 6.594+6.856X
Y=− 2.235+4.193X
Y=− 1.875+3.770X
Y=− 1.939+2.749X
Y=− 1.902+3.130X
Y=− 2.902+4.311X
Y=− 0.993+7.019X
Y=− 1.631+2.747X
Y=− 2.809+4.176X
Y=− 1.959+3.708X
Y=− 3.482+4.550X
Y=− 2.641+4.217X
Y=− 2.282+4.963X
Y=− 3.500+4.761X
Y=− 1.942+4.651X
Y=− 4.130+5.615X
Y=− 2.243+4.094X
Y=− 3.365+9.600X
Y=− 0.214+4.261X
Y=− 1.353+4.888X
Y=0.280+4.416X
3.552
2.400
12.496
9.158
3.412
3.142
5.074
4.052
4.710
1.385
3.923
4.706
3.376
5.827
4.231
2.883
5.433
2.615
5.439
3.531
2.241
1.123
1.892
0.864
0.703
1.075
2.701
3.449
1.426
7.524
0.581
2.808–4.459
1.896–2.991
11.681–13.369
7.481–11.219
2.025–5.490
1.761–5.199
3.634–7.001
2.932–5.492
3.004–7.280
1.252–1.524
2.695–5.532
3.140–6.966
1.657–6.220
4.204–8.062
2.145–7.967
2.279–3.612
4.163–7.077
2.317–2.941
4.273–6.916
3.107–4.002
2.063–2.434
0.745–1.489
1.378–2.498
0.709–1.008
0.548–0.840
0.808–1.332
2.386–3.046
2.244–5.200
1.282–1.577
5.579–10.250
0.191–0.837
Y=0.678+4.439X
14m
14n
14o
14p
14q
Picarbutrazox
Y=− 0.154+4.887X
Y=− 1.922+4.454X
Y=− 2.832+5.267X
Y=− 0.987+6.404X
Y=− 7.669+8.751X
Y=1.136+4.831X
Fig. 1 Comparison of feld
efcacy trials
3.125
3.125
0.781
0.781
0.195
0.195
CK
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Design, synthesis, and biological evaluation of phenyloxadiazole derivatives as potential…
127
Fig. 2 Experimental test of
% Inhibition (mg/dm3)
peronophythora litchii
CK
̄
v=3064, 2916, 1725, 1661, 1129, 671, 642 cm−1; HRMS
Preparation of intermediate 3 [43]
(EI): m/z calcd. for C10H7F3N2O2 (M+) 245.0462, found
Adding 2 (10.4 mmol), 100 cm3 DCM, and 1.53 cm3 tri-
ethylamine (20.8 mmol) to a 250 cm3 three-neck bottle,
adding ethyl oxalyl chloride monoethylate at 0 °C and
reacted at 25 °C for 6 h, fellowed add 0.77 cm3 triethyl-
amine (10.4 mmol) and 1.98 g p-toluenesulfonyl chloride
(10.4 mmol), keeping the reaction system at 25 °C over 18 h.
After the reaction was accomplished, adding 200 cm3 of
DCM, separating and washing, then concentrating under
decreased pressure to obtain the residue, after that purifca-
tion by column chromatography to acquire the product 3.
245.0468.
Preparation of intermediate 5 [45]
Adding 4 (5 mmol) and 40 cm3 DCM to a 250 cm3 three-
neck bottle when the temperature was zero, then added a
solution of 1.35 g phosphorus tribromide (5 mmol) in 3 cm3
DCM drop wisely. And the reaction was stirred at 25 °C for
4.0 h. When the reaction was accomplished, the solvent was
concentrated under decreased pressure, after that purifcation
by column chromatography to acquire the product 5.
Ethyl 5‑[4‑(trifuoromethyl)phenyl]‑1,3,4‑oxadiazole‑2‑car‑
boxylate (3a, C12H9F3N2O3) White solid; yield: 77%; m.p.:
2‑(Bromomethyl)‑5‑[4‑(trifuoromethyl)phenyl]‑1,3,4‑oxa‑
diazole (5a, C101H6BrF3N2O) White solid; yield: 74%; m.p.:
142–146 °C; H NMR (400 MHz, CDCl3): δ = 7.67 (d,
J = 8.4 Hz, 2H, ArH), 7.51 (d, J= 7.2 Hz, 2H, ArH), 3.76
(s, 2H, CH2) ppm; 13C NMR (100 MHz, CDCl3): δ=174.3
(CF3), 161.3 (CH), 154.2 (C), 145.4 (CH), 140.6 (C), 124.4
(C), 120.6 (C), 24.2 (CH2) ppm; IR (KBr): ꢀ =3062, 2911,
1729, 1667, 1124, 676, 647 cm−1; HRMS (EI): m/z calcd. for
C10H6BrF3N2O (M+) 306.9614, found 306.9618.
1
167–169 °C; H NMR (400 MHz, CDCl3): δ = 7.61 (d,
J=8.5 Hz, 2H, ArH), 7.51 (d, J =7.3 Hz, 2H, ArH), 4.16
(m, 2H, CH2), 3.22 (t, J=7.5 Hz, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): δ=178.1 (CF3), 167.4 (C=O), 160.5
(CH), 159.2 (C), 148.4 (CH), 146.6 (C), 128.1 (C), 123.1 (C),
35.2 (CH3), 24.1 (CH2) ppm; IR (KBr): ꢀ =3416, 3064, 2916,
1725, 1661, 1557, 1448, 1129, 671, 642 cm−1; HRMS (EI):
m/z calcd. for C12H9F3N2O3 (M+) 287.0565, found 287.0561.
N‑Methyl‑2‑oxo‑2‑phenylacetamide (6, C9H9NO2)
[46] Methyl benzoylformate (164 g, 1 mol) was added
to 500 cm3 MeOH, and the temperature kept to zero, and
then added methylamine aqueous solution (101 g, 1.3 mol)
dropwisely. And the reaction was stirred at 25 °C for 4.0 h.
After the reaction was accomplished, MeOH was concen-
trated under decreased pressure, then adding 200 cm3 of
EA and water to separating. After that EA was removed and
130 g light yellow solid 6 was acquired in 80% yield. M.p.:
121–125 °C; 1H NMR (400 MHz, CDCl3): δ=8.36 (s, 1H,
NH), 7.47 (d, J=8.4 Hz, 2H, ArH), 7.41 (m, 1H, ArH), 7.34
(d, J=7.2 Hz, 2H, ArH), 3.76 (s, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): δ=179.3 (C=O), 172.4 (C=O), 154.2
(C), 145.4 (CH), 140.6 (CH), 124.4 (CH), 27.4 (CH3) ppm;
Preparation of intermediate 4 [44]
Adding 3 (6.34 mmol), 1.41 g CaCl2 (12.68 mmol), and
EtOH (6.34 mmol) to a 250 cm3 three-neck bottle when
the temperature was zero, and then adding 0.72 g NaBH4
(19.02 mmol) around 30 min. And the reaction was stirred
at 25 °C for 18.0 h. Then adding 200 cm3 of DCM, separat-
ing the organic layer and washing with 100 cm3 of saturated
NaCl solution after the reaction was accomplished. And the
solvent was removed under decreased pressure and the aim
product was acquired.
[5‑[4‑(Trifuoromethyl)phenyl]‑1,3,4‑oxadiazol‑2‑yl]meth‑
anol (4a, C10H7F3N2O2) White solid; yield: 89%; m.p.:
124–127 °C; 1H NMR (400 MHz, CDCl3): δ=8.13 (s, 1H,
OH), 7.63 (d, J = 8.1 Hz, 2H, ArH), 7.54 (d, J = 7.5 Hz,
2H, ArH), 4.16 (s, 2H, CH2) ppm; 13C NMR (100 MHz,
CDCl3): δ=178.3 (CF3), 162.3 (CH), 157.2 (C), 149.4 (CH),
141.6 (C), 124.1 (C), 120.1 (C), 24.3 (CH2) ppm; IR (KBr):
IR (KBr): v̄
=3031, 2945, 1739, 1664, 1163, 652, 631 cm−1;
HRMS (EI): m/z calcd. for C9H9NO2 (M+) 164.0512, found
164.0517.
N‑Chloro‑N‑methyl‑2‑oxo‑2‑ phenylacetamide (7, C9H8ClNO2)
[46] Adding 65 g 6 (0.4 mol), 2.9 g DMF, and 500 cm3
1 3

128
Y. Li et al.
CHCl3 to a 1 dm3 three-neck bottle when the temperature
at 0 °C, then added 71.4 g SOCl2 (0.6 mol) dropwisely, and
the reaction was stirred at 25 °C for 2.0 h, then refuxed for
12 h. Solvent was concentrated under decreased pressure
after the reaction was accomplished, after that adding 100
cm3 of toluene, and stirred at 25 °C for 12 h. Then the sol-
vent was removed under decreased pressure and acquired
70 g brown oily liquid 7 in 96% yield. M.p.: 139–144 °C;
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 8.1 Hz, 2H,
ArH), 7.37 (m, 1H, ArH), 7.30 (d, J=7.5 Hz, 2H, ArH), 3.42
(s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ=176.1
(C=O), 172.8 (C=O), 154.5 (C), 145.6 (CH), 140.1 (CH),
124.2 (CH), 27.5 (CH3) ppm; IR (KBr): ꢀ = 3024, 2963,
1732, 1626, 1173, 652 cm−1; HRMS (EI): m/z calcd. for
C9H8ClNO2 (M+) 198.0314, found 198.0319.
(200 cm3 ×3) for extracting, washed with NaCl solution (300
cm3 × 3), dried over Na2SO4, concentrated under reduced
pressure, after that purifcation by column chromatography
to acquire the product 10.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[4‑(trifluoromethyl)phenyl]‑1,3,4‑oxadiazol‑2‑yl]‑
methyl]oxime (10a, C19H14F3N7O2) White solid; yield: 50%;
m.p.: 132–134 °C; 1H NMR (400 MHz, DMSO-d6): δ=8.22
(d, J = 8.0 Hz, 2H, ArH), 7.99 (d, J = 8.2 Hz, 2H, ArH),
7.58–7.44 (m, 5H, ArH), 5.70 (s, 2H, CH2), 4.14 (s, 3H,
CH3 of tetrazole) ppm; 13C NMR (100 MHz, DMSO-d6):
δ=164.61 (C20 oxadiazole), 162.78 (C17 oxadiazole), 147.62
(C=N), 146.47 (C8 tetrazole), 133.82 (CH, q, J=33.0 Hz),
131.67 (CH), 130.70 (C), 129.05 (CH), 127.44 (C), 126.95
(CH), 126.58 (CH), 126.26 (CH, q, J=3.7 Hz), 123.46 (C,
q, J=272.7 Hz, CF3), 66.62 (OCH2), 34.60 (C14 CH3) ppm;
IR (KBr): ꢀ = 3440, 3063, 2910, 1720, 1682, 1540, 1441,
1241, 1190, 690, 627 cm−1; HRMS (EI): m/z calcd. for
C19H14F3N7O2 (M+) 430.1161, found 430.1163.
(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone (8, C9H8N4O)
[46] At room temperature, dissolved 6.4 g sodium azide
(100 mmol) and 1.62 g TBAB (5 mmol) in a mixed solu-
tion of 20 cm3 toluene and 20 cm3 water, then added 18.2 g
7 (100 mmol) in toluene solution (60 cm3) dropwisely, the
reaction was stirred for 2 h, diluted with 20 cm3 toluene
and water (100 cm3 ×3). After washing and drying, it was
concentrated to get 15.4 g of brown oily liquid 8 in 85%
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone O‑[[5‑
(4‑chloro‑2‑methylphenyl)‑1,3,4‑oxadiazol‑2‑yl]methyl]‑
oxime (10b, C19H16ClN7O2) White solid; yield: 55%; m.p.:
135–138 °C; 1H NMR (400 MHz, DMSO-d6): δ=7.90 (d,
J=8.4 Hz, 1H, ArH), 7.59 (d, J=1.0 Hz, 1H, ArH), 7.57–
7.53 (m, 1H, ArH), 7.52–7.46 (m, 5H, ArH), 5.68 (s, 2H,
CH2), 4.12 (s, 3H, CH3 of tetrazole), 2.61 (s, 3H, ArCH3)
ppm; 13C NMR (100 MHz, DMSO-dz): δ = 165.36 (C20
oxadiazole), 161.95 (C17 oxadiazole), 155.94 (CH), 151.24
(C), 147.68 (C=N), 146.08 (C8 tetrazole), 142.12 (CH),
131.56 (C), 130.81 (CH), 129.01 (C), 126.96 (C), 126.88
(CH), 126.22 (CH), 120.48 (CH), 66.75 (OCH2), 35.15 (C14
CH3), 31.09 (CH3) ppm; IR (KBr): ꢀ = 3256, 3015, 2873,
1812, 1641, 1513, 1415, 1343, 1144, 691, 622 cm−1; HRMS
(EI): m/z calcd. for C19H16ClN7O2 (M+) 410.1054, found
410.1056.
1
yield. M.p.: 121–126 °C; H NMR (400 MHz, CDCl3):
δ=7.43 (dd, J=12.9, 7.2 Hz, 3H), 7.29 (t, J=7.4 Hz, 2H),
3.76 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=174.2
(C = O), 155.1 (C), 142.2 (CH), 133.5 (CH), 124.1 (CH),
27.4 (CH3) ppm; IR (KBr): ꢀ = 3045, 2931, 1752, 1622,
1125, 635 cm−1; HRMS (EI): m/z calcd. for C9H8N4O (M+)
189.0614, found 189.0617.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone oxime
(9, C9H9N5O) [46] At room temperature, 15 g 8 (80 mmol)
and 11.1 g hydroxylamine hydrochloride (160 mmol) were
dissolved in 100 cm3 ethanol, warmed to 50 °C, stirred for
12 h, then removed the ethanol, after that diluted, extracted,
washed, fnally combined organic phases, remove the sol-
vent, after that purifcation by column chromatography to
acquire the product 9 as 5.6 g of light yellow solid in 34%
(Z)‑4‑[5‑[[[[(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methylene]‑
amino]oxy]methyl]‑1,3,4‑oxadiazol‑2‑yl]benzonitrile (10c,
C19H14N8O2) White solid; yield: 65%; m.p.: 124–127 °C; 1H
NMR (400 MHz, DMSO-d6): δ = 8.18 (d, J = 8.4 Hz, 2H,
ArH), 8.09 (d, J=8.3 Hz, 2H, ArH), 7.54 (dt, J=8.5, 5.4 Hz,
1H, ArH), 7.51–7.43 (m, 4H, ArH), 5.69 (s, 2H, CH2), 4.13
(s, 3H, CH3 of tetrazole) ppm; 13C NMR (100 MHz, DMSO-
d6): δ=165.66 (C20 oxadiazole), 163.21 (CH), 161.95 (C17
oxadiazole), 155.94 (CH), 147.68 (C=N), 146.08 (C8 tetra-
zole), 131.56 (CH), 130.81 (C), 129.01 (CH), 126.96 (CH),
126.88 (CH), 126.22 (C), 120.48 (CN), 66.75 (OCH2), 31.09
(C14 CH3) ppm; IR (KBr): ꢀ =3143, 3066, 2933, 1756, 1678,
1590, 1415, 1281, 1198, 673, 622 cm−1; HRMS (EI): m/z
calcd. for C19H14N8O2 (M+) 387.1240, found 387.1242.
1
yield. M.p.: 136–139 °C; H NMR (400 MHz, CDCl3):
δ=10.48 (s, 1H, NOH), 7.41 (dd, J=12.9, 7.2 Hz, 3H, ArH),
7.32 (t, J=7.4 Hz, 2H, ArH), 3.97 (s, 3H, CH3) ppm; 13
C
NMR (100 MHz, CDCl3): δ=172.1 (C=O), 151.5 (C), 145.4
(CH), 142.1 (CH), 124.6 (CH), 27.1 (CH3) ppm; IR (KBr):
ꢀ =3051, 2756, 1774, 1652, 1115, 641 cm−1; HRMS (EI):
m/z calcd. for C9H9N5O (M+) 204.1325, found 204.1321.
Preparation of compound 10 [47]
Adding 5 (2.7 mmol), 0.55 g 9 (2.7 mmol), 0.75 g K2CO3
(5.4 mmol), and 50 cm3 DMF to a 100 cm3 three-neck bot-
tle, the reaction was stirred at 25 °C for 6 h. Added EA
1 3

Design, synthesis, and biological evaluation of phenyloxadiazole derivatives as potential…
129
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone O‑
[[5‑(3,4,5‑trimethoxyphenyl)‑1,3,4‑oxadiazol‑2‑yl]methyl]‑
oxime (10d, C21H21N7O5) White solid; yield: 61%; m.p.:
125–128 °C; 1H NMR (400 MHz, DMSO-d6): δ=7.51 (t,
J = 6.8 Hz, 2H, ArH), 7.47 (d, J= 7.4 Hz, 1H, ArH), 7.39
(t, J = 7.6 Hz, 2H, ArH), 7.28 (s, 2H, ArH), 5.51 (s, 2H,
CH2), 4.06 (s, 3H, CH3 of tetrazole), 3.93 (d, J=9.3 Hz, 9H,
OCH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=165.76
(C20 oxadiazole), 162.15 (C17 oxadiazole), 155.94 (CH),
147.68 (C=N), 146.08 (C8 tetrazole), 131.56 (C), 130.81
(CH), 129.01 (CH), 126.96 (C), 126.88 (CH), 126.22 (CH),
120.48 (C), 62.75 (OCH2), 36.15 (C25 OCH3), 33.66 (C14
CH3), 31.09 (C24,26 OCH3) ppm; IR (KBr): ꢀ =3407, 3020,
2962, 1756, 1625, 1537, 1449, 1214, 1126, 678, 646 cm−1;
HRMS (EI): m/z calcd. for C21H21N7O5 (M+) 452.1604,
found 452.1601.
(s, 3H, CH3 of tetrazole), 3.88 (s, 3H, OCH3) ppm; 13C NMR
(100 MHz, CDCl3): δ=164.96 (C20 oxadiazole), 162.15 (C17
oxadiazole), 155.94 (CH), 147.68 (C=N), 146.08 (C8 tetra-
zole), 131.56 (CH), 130.81 (C), 129.01 (CH), 126.96 (CH),
126.88 (CH), 126.22 (C), 120.48 (CH), 62.75 (OCH2), 36.15
(OCH3), 31.09 (C14 CH3) ppm; IR (KBr): ꢀ =3267, 3061,
2957, 1724, 1668, 1528, 1469, 1244, 1196, 693, 614 cm−1;
HRMS (EI): m/z calcd. for C19H17N7O3 (M+) 392.1393,
found 392.1395.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone O‑[[5‑
(3‑chloro‑2‑methylphenyl)‑1,3,4‑oxadiazol‑2‑yl]methyl]‑
oxime (10h, C19H16ClN7O2) White solid; yield: 56%; m.p.:
125–128 °C; 1H NMR (600 MHz, CDCl3): δ=7.78 (s, 1H,
ArH), 7.52 (t, J = 28.8 Hz, 4H, ArH), 7.40 (s, 2H, ArH),
7.28 (s, 1H, ArH), 5.53 (s, 2H, CH2), 4.07 (s, 3H, CH3 of
tetrazole), 2.75 (s, 3H, ArCH3) ppm; 13C NMR (150 MHz,
CDCl3): δ = 166.16 (C20 oxadiazole), 162.05 (C17 oxadia-
zole), 155.74 (CH), 151.14 (C), 147.68 (C=N), 146.08 (C8
tetrazole), 142.12 (C), 131.56 (CH), 130.81 (C), 129.01
(CH), 126.96 (C), 126.88 (CH), 126.22 (CH), 120.48 (CH),
66.75 (OCH2), 35.15 (CH3), 31.09 (C14 CH3) ppm; IR (KBr):
ꢀ =3401, 3014, 2967, 1751, 1614, 1535, 1441, 1224, 1121,
671, 647 cm−1; HRMS (EI): m/z calcd. for C19H16ClN7O2
(M+) 410.1054, found 410.1056.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑(2‑bromophenyl)‑1,3,4‑oxadiazol‑2‑yl]methyl]oxime
(10e, C18H14BrN7O2) White solid; yield: 51%; m.p.: 131–
1
134 °C; H NMR (400 MHz, DMSO-d6): δ = 7.90 (dd,
J=14.3, 7.3 Hz, 2H, ArH), 7.67–7.52 (m, 3H, ArH), 7.48
(s, 4H, ArH), 5.70 (s, 2H, CH2), 4.11 (s, 3H, CH3 of tetra-
zole) ppm; 13C NMR (100 MHz, DMSO-d6): δ=165.86 (C20
oxadiazole), 161.95 (C17 oxadiazole), 155.94 (CH), 151.24
(CH), 147.68 (C=N, CH), 146.08 (C8 tetrazole), 142.12 (C),
131.56 (CH), 130.81 (CH), 129.01 (C), 126.96 (CH), 126.88
(C), 126.22 (C), 120.48 (CH), 66.75 (OCH2), 31.09 (C14
CH3) ppm; IR (KBr): ꢀ = 3462, 3061, 2910, 1724, 1667,
1542, 1446, 1242, 1156, 690, 623 cm−1; HRMS (EI): m/z
calcd. for C18H14BrN7O2 (M+) 440.0392, found 440.0394.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone O‑
[[5‑(2‑chloro‑3‑methylphenyl)‑1,3,4‑oxadiazol‑2‑yl]‑
methyl]oxime (10i, C19H16ClN7O2) White solid; yield: 52%;
1
m.p.: 131–135 °C; H NMR (400 MHz, CDCl3): δ = 7.79
(d, J = 7.7 Hz, 1H, ArH), 7.53 (d, J = 7.4 Hz, 2H, ArH),
7.48–7.43 (m, 2H, ArH), 7.39 (t, J = 7.5 Hz, 2H, ArH),
7.32 (t, J = 7.7 Hz, 1H, ArH), 5.54 (s, 2H, CH2), 4.07 (s,
3H, CH3 of tetrazole), 2.48 (s, 3H, ArCH3) ppm; 13C NMR
(100 MHz, CDCl3): δ = 165.82 (C20 oxadiazole), 162.45
(C17 oxadiazole), 155.51 (CH), 152.24 (C=N), 145.68 (C8
tetrazole), 143.08 (CH), 141.12 (C), 131.56 (CH), 130.81
(C), 129.01 (CH), 126.96 (CH), 126.88 (CH), 126.22 (C),
120.48 (CH), 66.75 (OCH2), 35.15 (CH3), 31.09 (C14 CH3)
ppm; IR (KBr): ꢀ = 3425, 3079, 2925, 1752, 1624, 1531,
1441, 1217, 1122, 678, 641 cm−1; HRMS (EI): m/z calcd.
for C19H16ClN7O2 (M+) 410.1054, found 410.1056.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone O‑[[5‑(3,
5‑dibromophenyl)‑1,3,4‑oxadiazol‑2‑yl]methyl]oxime (10f,
C18H13Br2N7O2) White solid; yield: 44%; m.p.: 141–145 °C;
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 1.7 Hz, 2H,
ArH), 7.84 (t, J = 1.6 Hz, 1H, ArH), 7.53–7.45 (m, 3H,
ArH), 7.39 (t, J = 7.2 Hz, 2H, ArH), 5.51 (s, 2H, CH2),
4.07 (s, 3H, CH3 of tetrazole) ppm; 13C NMR (100 MHz,
CDCl3): δ = 165.66 (C20 oxadiazole), 161.95 (C17 oxadia-
zole), 155.94 (CH), 147.68 (C=N), 146.08 (C8 tetrazole),
131.56 (C), 130.81 (CH), 129.01 (CH), 126.96 (C), 126.88
(CH), 126.22 (CH), 120.48 (C), 66.75 (OCH2), 31.09 (C14
CH3) ppm; IR (KBr): ꢀ = 3414, 3064, 2916, 1725, 1667,
1557, 1448, 1249, 1191, 645, 610 cm−1; HRMS (EI): m/z
calcd. for C18H13Br2N7O2 (M+) 517.9497, found 517.9492.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑(3‑chlorophenyl)‑1,3,4‑oxadiazol‑2‑yl]methyl]oxime
(10j, C18H14ClN7O2) White solid; yield: 62%; m.p.: 133–
136 °C; 1H NMR (400 MHz, CDCl3): δ=8.05 (t, J=1.6 Hz,
1H, ArH), 7.94 (d, J=7.7 Hz, 1H, ArH), 7.57–7.44 (m, 5H,
ArH), 7.39 (t, J=7.5 Hz, 2H, ArH), 5.52 (s, 2H, CH2), 4.07
(s, 3H, CH3 of tetrazole) ppm; 13C NMR (100 MHz, CDCl3):
δ=165.86 (C20 oxadiazole), 161.95 (C17 oxadiazole), 155.94
(CH), 151.24 (CH), 147.68 (C=N), 146.08 (C8 tetrazole),
142.12 (C), 131.56 (CH), 130.81 (CH), 129.01 (CH),
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑(4‑methoxyphenyl)‑1,3,4‑oxadiazol‑2‑yl]methyl]oxime
(10g, C19H17N7O3) White solid; yield: 49%; m.p.: 121–
124 °C; 1H NMR (400 MHz, CDCl3): δ=7.98 (d, J=8.8 Hz,
2H, ArH), 7.55–7.43 (m, 3H, ArH), 7.38 (t, J=7.5 Hz, 2H,
ArH), 7.01 (d, J=8.8 Hz, 2H, ArH), 5.49 (s, 2H, CH2), 4.06
1 3

130
Y. Li et al.
126.96 (C), 126.88 (CH), 126.22 (CH), 120.48 (C), 66.75
(OCH2), 31.09 (C14 CH3) ppm; IR (KBr): ꢀ =3401, 3025,
2967, 1751, 1625, 1534, 1441, 1219, 1121, 678, 626 cm−1;
HRMS (EI): m/z calcd. for C18H14ClN7O2 (M+) 396.0898,
found 396.0895.
1418, 1242, 1190, 645, 612 cm−1; HRMS (EI): m/z calcd.
for C19H16BrN7O2 (M+) 454.0549, found 454.0546.
Preparation of intermediate 11 [48]
In a 250 cm3 three-neck bottle, added phenol derivative
(22.0 mmol), 2-fuorobenzonitrile or 3-fuorobenzonitrile
derivative (20.0 mmol), 4.56 g K2CO3 (33 mmol), 80 cm3
DMF. After the addition is completed, heated to 110 °C
for 5 h. After the reaction was completed, 200 cm3 EA
was added. Washed with NaCl solution (400 cm3 ×3), the
organic phases were combined, dried over dry Na2SO4, and
concentrated to obtain the product 11.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[4‑(tert‑butyl)phenyl]‑1,3,4‑oxadiazol‑2‑yl]methyl]‑
oxime (10k, C22H23N7O2) White solid; yield: 66%; m.p.: 131–
134 °C; 1H NMR (400 MHz, CDCl3): δ=7.97 (d, J=8.5 Hz,
2H, ArH), 7.54–7.50 (m, 4H, ArH), 7.46 (d, J=7.4 Hz, 1H,
ArH), 7.38 (t, J = 7.5 Hz, 2H, ArH), 5.51 (s, 2H, CH2),
4.06 (s, 3H, CH3 of tetrazole), 1.36 (s, 9H, C(CH3)3) ppm;
13C NMR (100 MHz,CDCl3): δ = 165.86 (C20 oxadia-
zole), 161.95 (C17 oxadiazole), 155.94 (C), 147.68 (C=N),
146.08 (C8 tetrazole), 131.56 (CH), 130.81 (C), 129.01 (C),
126.96 (CH), 126.88 (CH), 126.22 (C), 120.48 (CH), 66.75
(OCH2), 35.15 (C(CH3)3), 34.66 (CH3), 31.09 (C14 CH3)
ppm; IR (KBr): ꢀ = 3428, 3057, 2917, 1727, 1618, 1577,
1415, 1235, 1129, 671, 642 cm−1; HRMS (EI): m/z calcd.
for C22H23N7O2 (M+) 418.1913, found 418.1916.
2‑(4‑Bromophenoxy)benzonitrile (11a, C13H8BrNO) White
solid; yield: 93%; m.p.: 145–147 °C; 1H NMR (400 MHz,
DMSO-d6): δ = 7.41 (dd, J = 12.9, 7.2 Hz, 3H, ArH),
7.32 (m, 1H, ArH), 7.23 (t, J= 7.4 Hz, 2H, ArH), 7.19 (t,
J = 6.7 Hz, 2H, ArH) ppm; 13C NMR (100 MHz, DMSO-
d6): δ=187.2 (CN), 151.5 (C), 148.1 (C), 145.4 (CH), 143.1
(CH), 140.0 (CH), 125.4 (CH), 123.8 (C), 121.1 (CH), 118.6
(C), 116.1 (CH) ppm; IR (KBr): ꢀ =3051, 2756, 1874, 1751,
1652, 1614, 1115, 626 cm−1; HRMS (EI): m/z calcd. for
C13H8BrNO (M+) 273.3156, found 273.3151.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑(2‑fuorophenyl)‑1,3,4‑oxadiazol‑2‑yl]methyl]oxime
(10l, C18H14FN7O2) White solid; yield: 56%; m.p.: 125–
1
128 °C; H NMR (400 MHz, CDCl3): δ = 8.12–8.04 (m,
Preparation of intermediate 12 [49]
1H, ArH), 7.61–7.54 (m, 1H, ArH), 7.51 (d, J=7.3 Hz, 2H,
ArH), 7.46 (t, J=7.4 Hz, 1H, ArH), 7.38 (t, J=7.5 Hz, 2H,
ArH), 7.35–7.22 (m, 2H, ArH), 5.54 (s, 2H, CH2), 4.09 (s,
3H, CH3 of tetrazole) ppm; 13C NMR (100 MHz, CDCl3):
δ = 162.65 (d, J = 11.2 Hz), 160.88 (CH), 159.17 (CH),
147.65 (C=N), 146.17 (C8 tetrazole), 134.07 (d, J=8.6 Hz),
131.58 (CH), 130.79 (CH), 129.92 (C), 129.00 (C), 126.99
(CH), 124.89 (C, d, J=3.7 Hz), 117.08 (C, d, J=20.9 Hz),
111.84 (CH, d, J=11.6 Hz), 66.68 (OCH2), 34.68 (C14 CH3)
ppm; IR (KBr): ꢀ = 3416, 3064, 2916, 1725, 1661, 1557,
1448, 1242, 1196, 641, 630 cm−1; HRMS (EI): m/z calcd.
for C18H14FN7O2 (M+) 380.1193, found 380.1195.
Adding 11 (18 mmol), 12 cm3 methanol, 52 cm3 ethanol,
18.2 g KOH (324 mmol) to a 250 cm3 three-neck bottle, then
added 18.2 cm3 H2O2 (30%) drop wisely when the tempera-
ture is zero, after that warming to 80 °C slowly, reacted for
4 h. The reaction was confrmed to be complete by TLC.
Concentrated sulfuric acid was added drop wisely at 0 °C,
the pH was adjusted to 1, 200 cm3 EA, NaCl solution (100
cm3 × 4) was added to wash, collected the organic phase,
dried by dry Na2SO4, and concentrated to obtain 12.
2‑(4‑Bromophenoxy)benzoic acid (12a, C13H9BrO3) White
solid; yield: 74%; m.p.: 163–167 °C; 1H NMR (400 MHz,
DMSO-d6): δ = 9.47 (s, 1H, COOH), 7.47 (dd, J = 12.1,
7.5 Hz, 3H, ArH), 7.30 (m, 1H, ArH), 7.21 (t, J =7.2 Hz,
2H, ArH), 7.14 (t, J = 6.2 Hz, 2H, ArH) ppm; 13C NMR
(100 MHz, DMSO-d6): δ=183.6 (C=O), 153.1 (C), 149.2
(C), 146.4 (CH), 143.7 (CH), 141.3 (CH), 127.2 (CH), 124.3
(C), 122.6 (CH), 118.2 (C), 114.8 (CH) ppm; IR (KBr):
ꢀ =3064, 2721, 1871, 1747, 1632, 1602, 1156, 634 cm−1;
HRMS (EI): m/z calcd. for C13H9BrO3 (M+) 292.4632, found
292.4636.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone O‑
[[5‑(4‑bromo‑2‑methylphenyl)‑1,3,4‑oxadiazol‑2‑yl]methyl]‑
oxime (10m, C19H16BrN7O2) White solid; yield: 59%;
1
m.p.: 130–134 °C; H NMR (400 MHz, CDCl3): δ = 7.79
(d, J = 8.4 Hz, 1H, ArH), 7.55–7.44 (m, 5H, ArH), 7.39
(t, J = 7.5 Hz, 2H, ArH), 5.52 (s, 2H, CH2), 4.07 (s, 3H,
CH3 of tetrazole), 2.69 (s, 3H, ArCH3) ppm; 13C NMR
(100 MHz, CDCl3): δ = 165.82 (C20 oxadiazole), 162.45
(C17 oxadiazole), 155.51 (C), 152.24 (C=N), 145.68 (C8
tetrazole), 143.08 (CH), 141.12 (C), 131.56 (CH), 130.81
(CH), 129.01 (CH), 126.96 (CH), 126.88 (C), 126.22 (CH),
120.48 (C), 66.75 (OCH2), 35.15 (CH3), 31.09 (C14 CH3)
ppm; IR (KBr): ꢀ = 3424, 3061, 2946, 1721, 1662, 1538,
1 3

Design, synthesis, and biological evaluation of phenyloxadiazole derivatives as potential…
131
methyl]oxime (14b, C24H17F2N7O3) White solid; yield: 66%;
m.p.: 141–144 °C; 1H NMR (400 MHz, DMSO-d6): δ=8.03
(d, J=6.1 Hz, 1H, ArH), 7.62–7.25 (m, 9H, ArH), 7.10 (s,
1H, ArH), 6.95 (d, J=7.1 Hz, 1H, ArH), 5.68 (s, 2H, CH3),
4.05 (s, 3H, CH3 of tetrazole) ppm; 13C NMR (100 MHz,
DMSO-d6): δ=164.02 (C20 oxadiazole), 162.49 (C17 oxa-
diazole), 159.36 (C, dd, J=247.2, 10.2 Hz), 155.72 (CH),
154.22 (C, dd, J=252.6, 12.3 Hz), 147.62 (C=N), 145.99
(C8 tetrazole), 138.81 (CH, dd, J=11.9, 3.9 Hz), 133.45 (C),
131.44 (C), 130.85 (CH), 130.83 (CH), 128.92 (C), 126.91
(C), 123.50 (CH), 123.26 (C, dd, J= 9.8, 1.8 Hz), 116.42
(CH), 113.77 (CH), 111.79 (C, dd, J=23.0, 3.9 Hz), 105.71
(C, dd, J=26.9, 21.9 Hz), 66.79 (OCH2), 34.53 (C14 CH3)
ppm; IR (KBr): ꢀ = 3411, 3062, 2912, 1746, 1663, 1555,
1442, 1244, 1197, 642, 614 cm−1; HRMS (EI): m/z calcd.
for C24H17F2N7O3 (M+) 490.1361, found 490.1365.
Preparation of intermediate 13 [50]
Adding 12 (15.3 mmol) and 90 cm3 MeOH to a 250 cm3
three-neck bottle, and 3 cm3 H2SO4 was added with stirring
at 25 °C. After the reaction was fnished, raised to 80 °C
and keep stirred for 6 h. After the reaction was completed,
the solvent was removed, and then 100 cm3 EA was added,
washed with NaCl solution (50 cm3 ×3), fltered and dried
to acquire the product 13.
M e t h y l 2 ‑ ( 4 ‑ b r o m o p h e n o x y ) b e n z o a t e ( 1 3 a ,
C14H11BrO3) White solid; yield: 79%; m.p.: 151–154 °C; 1H
NMR (400 MHz, DMSO-d6): δ=7.43 (dd, J=12.4, 7.6 Hz,
3H, ArH), 7.35 (m, 1H, ArH), 7.26 (t, J=7.3 Hz, 2H, ArH),
7.18 (t, J=6.4 Hz, 2H, ArH), 3.11 (s, 1H, CH3) ppm; 13
C
NMR (100 MHz, DMSO-d6): δ=183.6 (C=O), 153.1 (C),
149.2 (C), 146.4 (CH), 143.7 (CH), 141.3 (CH), 127.2 (CH),
124.3 (C), 122.6 (CH), 118.2 (C), 114.8 (CH), 24.3 (CH3)
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[2‑(2,3‑dimethylphenoxy)phenyl]‑1,3,4‑oxadiazol‑2‑yl]‑
methyl]oxime (14c, C26H23N7O3) White solid; yield: 61%;
ppm; IR (KBr): ̄v = 3031, 2756, 1868, 1752, 1667, 1614,
1137, 613 cm−1; HRMS (EI): m/z calcd. for C14H11BrO3
1
(M+) 306.8637, found 306.8632.
m.p.: 142–147 °C; H NMR (400 MHz, CDCl3): δ = 8.10
(d, J = 7.0 Hz, 1H, ArH), 7.54–7.30 (m, 6H, ArH), 7.22–
7.00 (m, 3H, ArH), 6.82 (d, J=7.1 Hz, 1H, ArH), 6.71 (d,
J=7.9 Hz, 1H, ArH), 5.52 (s, 2H, CH2), 3.92 (s, 3H, CH3 of
tetrazole), 2.31 (s, 3H, ArCH3), 2.08 (s, 3H, ArCH3) ppm;
13C NMR (100 MHz, CDCl3): δ=165.22 (C20 oxadiazole),
161.29 (C17 oxadiazole), 158.36 (C), 157.12 (CH), 155.72
(CH), 154.22 (C), 147.62 (C=N), 145.99 (C8 tetrazole),
141.23 (C), 138.81 (CH), 133.45 (CH), 131.44 (CH), 130.83
(C), 128.92 (CH), 126.91 (C), 123.50 (CH), 123.26 (CH),
116.42 (CH), 111.79 (CH), 105.71 (CH), 66.79 (OCH2),
51.23 (C3′ CH3), 45.31 (C2′ CH3), 34.53 (C14 CH3) ppm;
IR (KBr): ꢀ = 3418, 3061, 2942, 1722, 1661, 1559, 1425,
1241, 1194, 642, 636 cm−1; HRMS (EI): m/z calcd. for
C26H23N7O3 (M+) 482.1862, found 482.1864.
Preparation of compound 14 [31, 43–45, 47]
(After compound 13 is obtained, 14 is synthesized by the
methods a, b, c, d, and i in Scheme 1). Here we describe
step i in detail: put the oily liquid (2.7 mmol) obtained in
step d in a 100 cm3 single bottle, then 0.55 g 9 (2.7 mmol),
0.75 g K2CO3 (5.4 mmol), 50 cm3 DMF were added, stirred
at 25 °C for 6 h. Added EA (200 cm3 × 3) for extraction,
washed with NaCl solution (300 cm3 × 3), dried by dry
Na2SO4, concentrated and after that purifcation by column
chromatography to acquire the product 14.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[2‑(4‑bromophenoxy)phenyl]‑1,3,4‑oxadiazol‑2‑yl]‑
methyl]oxime (14a, C24H18BrN7O3) White solid; yield: 56%;
m.p.: 146–149 °C; 1H NMR (400 MHz, DMSO-d6): δ=8.04
(d, J = 7.1 Hz, 1H, ArH), 7.64 (d, J = 7.1 Hz, 1H, ArH),
7.59–7.34 (m, 8H, ArH), 7.14 (d, J = 7.9 Hz, 1H, ArH),
6.95 (d, J = 7.8 Hz, 2H, ArH), 5.63 (s, 2H, CH2), 4.04 (s,
3H, CH3 of tetrazole) ppm; 13C NMR (100 MHz, DMSO-
d6): δ=165.22 (C20 oxadiazole), 161.29 (C17 oxadiazole),
158.36, 155.72, 154.22, 147.62 (C=N), 145.99 (C8 tetra-
zole), 138.81 (CH), 133.45 (C), 131.44 (CH), 130.83 (C),
128.92 (CH), 126.91 (C), 123.50 (CH), 123.26 (C), 116.42
(CH), 111.79 (CH), 105.71 (CH), 66.79 (OCH2), 34.53 (C14
CH3) ppm; IR (KBr): ꢀ = 3428, 3027, 2904, 1714, 1626,
1524, 1441, 1242, 1197, 641, 614 cm−1; HRMS (EI): m/z
calcd. for C24H18BrN7O3 (M+) 532.0655, found 532.0656.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[4‑(2‑chlorophenoxy)phenyl]‑1,3,4‑oxadiazol‑2‑yl]‑
methyl]oxime (14d, C24H18ClN7O3) White solid; yield: 55%;-
m.p.: 138–141 °C; 1H NMR (400 MHz, CDCl3): δ=8.01 (d,
J=8.0 Hz, 2H, ArH), 7.51–7.44 (m, 4H, ArH), 7.39–7.30
(m, 3H, ArH), 7.22–7.12 (m, 2H, ArH), 7.03 (d, J=8.0 Hz,
2H, ArH), 5.50 (s, 2H, CH2), 4.06 (s, 3H, CH3 of tetrazole)
ppm; 13C NMR (100 MHz, CDCl3): δ=164.51 (C20 oxadia-
zole), 162.29 (C17 oxadiazole), 157.36 (C), 155.72 (CH),
154.22 (C=N), 146.62 (C8 tetrazole), 143.99 (CH), 138.81
(CH), 133.45 (C), 131.44 (C), 130.83 (CH), 128.92 (CH),
126.91 (CH), 123.50 (C), 121.26 (CH), 116.42 (C), 111.79
(CH), 105.71 (CH), 63.79 (OCH2), 31.53 (C14 CH3) ppm;
IR (KBr): ꢀ = 3414, 3064, 2916, 1725, 1667, 1557, 1448,
1249, 1191, 645, 610 cm−1; HRMS (EI): m/z calcd. for
C24H18ClN7O3 (M+) 488.1160, found 488.1163.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[2‑(2,4‑difuorophenoxy)phenyl]‑1,3,4‑oxadiazol‑2‑yl]‑
1 3

132
Y. Li et al.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[4‑(3,5‑difuorophenoxy)phenyl]‑1,3,4‑oxadiazol‑2‑yl]‑
methyl]oxime (14e, C24H17F2N7O3) White solid; yield: 65%;
J=24.4 Hz), 65.61 (OCH2), 33.53 (C14 CH3) ppm; IR (KBr):
ꢀ =3401, 3017, 2944, 1721, 1627, 1525, 1427, 1285, 1214,
646, 612 cm−1; HRMS (EI): m/z calcd. for C24H17ClFN7O3
(M+) 506.1065, found 506.1063.
1
m.p.: 153–158 °C; H NMR (400 MHz, CDCl3): δ = 8.07
(d, J = 8.8 Hz, 2H, ArH), 7.56–7.44 (m, 3H, ArH), 7.44–
7.34 (m, 2H, ArH), 7.16 (d, J = 8.8 Hz, 2H, ArH), 6.67–
6.54 (m, 3H, ArH), 5.51 (s, 2H, CH2), 4.07 (s, 3H, CH3 of
tetrazole) ppm; 13C NMR (100 MHz, CDCl3): δ = 165.15
(C20 oxadiazole), 164.51 (d, J = 15.2 Hz), 162.86 (d,
J=15.1 Hz), 162.12 (C17 oxadiazole), 159.15 (CH), 158.03
(t, J = 13.4 Hz), 147.66 (C = N), 146.21 (C8 tetrazole),
131.62 (CH), 130.76 (CH), 129.22 (C), 129.04 (CH), 126.95
(C), 119.65 (C), 119.27 (CH), 102.94 (d, J=6.4 Hz), 102.79
(d, J=6.4 Hz), 99.82 (t, J=25.6 Hz), 66.69(OCH2), 34.66
(C14 CH3) ppm; IR (KBr):ꢀ =3425, 3062, 2914, 1722, 1662,
1551, 1444, 1242, 1197, 645, 624 cm−1; HRMS (EI): m/z
calcd. for C24H17F2N7O3 (M+) 490.1361, found 490.1365.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[4‑chloro‑2‑(3‑fuorophenoxy)phenyl]‑1,3,4‑oxadia‑
zol‑2‑yl]methyl]oxime (14h, C24H17ClFN7O3) White solid;
yield: 52%; m.p.: 152–156 °C; 1H NMR (400 MHz, CDCl3):
δ = 8.05 (d, J = 8.5 Hz, 1H, ArH), 7.46 (t, J= 6.9 Hz, 3H,
ArH), 7.32 (ddd, J=18.1, 13.0, 4.6 Hz, 4H, ArH), 7.00–6.72
(m, 4H, ArH), 5.46 (s, 2H, CH2), 3.97 (s, 3H, CH3 of tetra-
zole) ppm; 13C NMR (100 MHz, CDCl3): δ = 164.34 (C20
oxadiazole), 163.26 (CH), 162.70 (C17 oxadiazole), 162.55
(CH), 156.66 (C, d, J = 10.5 Hz), 155.51 (CH), 147.60
(C=N), 146.08 (C8 tetrazole), 139.34 (CH), 131.58 (C, d,
J=2.7 Hz), 131.16 (CH, d, J=9.6 Hz), 130.75 (CH), 128.99
(C), 126.93 (CH), 124.56 (CH), 119.64 (CH), 115.03 (C, d,
J=3.2 Hz), 113.61 (CH), 111.84 (C, d, J=21.1 Hz), 107.27
(CH, d, J=24.4 Hz), 66.66 (OCH2), 34.57 (C14 CH3) ppm;
IR (KBr): ꢀ = 3412, 3068, 2934, 1721, 1622, 1527, 1447,
1225, 1142, 647, 636 cm−1; HRMS (EI): m/z calcd. for
C24H17ClFN7O3 (M+) 506.1065, found 506.1063.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[4‑(4‑propylphenoxy)phenyl]‑1,3,4‑oxadiazol‑2‑yl]‑
methyl]oxime (14f, CH25N7O3) White solid; yi27eld: 61%;
m.p.: 141–144 °C; 1H NMR (400 MHz, CDCl3): δ=7.98 (d,
J=8.8 Hz, 2H, ArH), 7.51 (d, J=7.5 Hz, 2H, ArH), 7.46 (t,
J=7.4 Hz, 1H, ArH), 7.38 (t, J=7.7 Hz, 2H, ArH), 7.20 (d,
J=8.3 Hz, 2H, ArH), 7.06 (d, J=8.8 Hz, 2H, ArH), 6.99 (d,
J=8.4 Hz, 2H, ArH), 5.49 (s, 2H, CH2), 4.06 (s, 3H, CH3 of
tetrazole), 2.67–2.54 (m, 2H, CH2), 1.67–1.62 (m, 2H, CH2),
0.96 (t, J = 7.3 Hz, 3H, CH3) ppm; 13C NMR (100 MHz,
CDCl3): δ = 165.51 (C20 oxadiazole), 161.82 (C17 oxadia-
zole), 161.65 (CH), 153.20 (CH), 147.67 (C=N), 146.13 (C8
tetrazole), 139.27 (C), 131.54 (CH), 130.84 (CH), 129.97
(C), 129.00 (C), 128.90 (CH), 126.95 (CH), 120.02 (CH),
117.92 (C), 117.31 (CH), 66.73 (OCH2), 37.36 (ArCH2),
34.61 (C14 CH3), 24.57 (CH2), 13.76 (CH3) ppm; IR (KBr):
ꢀ =3428, 3027, 2904, 1714, 1626, 1524, 1441, 1242, 1197,
641, 614 cm−1; HRMS (EI): m/z calcd. for C27H25N7O3 (M+)
496.2019, found 496.2014.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[5‑chloro‑2‑(2‑fluorophenoxy)phenyl]‑1,3,4‑oxadi‑
azol‑2‑yl]methyl]oxime (14i, C24H17ClFN7O3) White solid;
yield: 58%; m.p.: 133–137 °C; 1H NMR (400 MHz, CDCl3):
δ=8.11 (d, J=2.5 Hz, 1H, ArH), 7.46 (dd, J=13.9, 7.3 Hz,
3H, ArH), 7.37 (dt, J=15.2, 7.0 Hz, 3H, ArH), 7.21–7.09
(m, 4H, ArH), 6.80 (d, J = 8.9 Hz, 1H, ArH), 5.50 (s,
2H, CH2), 3.97 (s, 3H, CH3 of tetrazole) ppm; 13C NMR
(100 MHz, CDCl3): δ = 165.14 (C20 oxadiazole), 164.46
(CH), 162.70 (C17 oxadiazole), 161.85 (CH), 157.66 (C,
d, J = 10.5 Hz), 155.51 (CH), 147.60 (C=N), 146.08 (C8
tetrazole), 139.34 (CH), 131.58 (C, d, J=2.7 Hz), 131.16
(C, d, J = 9.6 Hz), 130.45 (C), 128.99 (CH), 126.93 (C),
121.56 (CH), 116.64 (CH), 115.03 (CH, d, J = 3.2 Hz),
113.11 (CH), 112.04 (C, d, J = 21.1 Hz), 104.21 (CH, d,
J=24.4 Hz), 65.61 (OCH2), 33.53 (C14 CH3) ppm; IR (KBr):
ꢀ =3412, 3046, 2914, 1732, 1652, 1527, 1441, 1245, 1197,
681, 644 cm−1; HRMS (EI): m/z calcd. for C24H17ClFN7O3
(M+) 506.1065, found 506.1063.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[3‑chloro‑2‑(2‑fuorophenoxy)phenyl]‑1,3,4‑oxadia‑
zol‑2‑yl]methyl]oxime (14g, C24H17ClFN7O3) White solid;
yield: 67%; m.p.: 144–148 °C; 1H NMR (400 MHz, CDCl3):
δ=8.11 (d, J=7.7 Hz, 1H, ArH), 7.70 (d, J=7.7 Hz, 1H,
ArH), 7.50–7.34 (m, 6H, ArH), 7.14–7.02 (m, 1H, ArH),
6.92–6.89 (m, 2H, ArH), 6.52 (t, J=7.6 Hz, 1H, ArH), 5.37
(s, 2H, CH2), 3.98 (s, 3H, CH3 of tetrazole) ppm; 13C NMR
(100 MHz, CDCl3): δ = 166.14 (C20 oxadiazole), 163.46
(CH), 162.70 (C17 oxadiazole), 161.85 (CH), 156.66 (CH,
d, J = 10.5 Hz), 155.51 (CH), 147.60 (C=N), 146.08 (C8
tetrazole), 139.34 (CH), 131.58 (C, d, J=2.7 Hz), 131.16
(C, d, J = 9.6 Hz), 130.75 (C), 128.99 (C), 126.93 (CH),
121.56 (CH), 116.64 (CH), 115.03 (CH, d, J = 3.2 Hz),
113.11 (CH), 112.04 (C, d, J = 21.1 Hz), 104.21 (CH, d,
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[5‑chloro‑2‑(4‑fluorophenoxy)phenyl]‑1,3,4‑oxadi‑
azol‑2‑yl]methyl]oxime (14j, C24H17ClFN7O3) White solid;
yield: 64%;m.p.: 144–147 °C; 1H NMR (400 MHz, CDCl3):
δ=8.07 (d, J=2.5 Hz, 1H, ArH), 7.45 (dd, J=11.8, 7.6 Hz,
3H, ArH), 7.43–7.32 (m, 3H, ArH), 7.01 (ddd, J = 13.5,
13.0, 6.8 Hz, 4H, ArH), 6.85 (d, J=8.9 Hz, 1H, ArH), 5.49
(s, 2H, CH2), 3.97 (s, 3H, CH3 of tetrazole) ppm; 13C NMR
(100 MHz, CDCl3): δ = 166.14 (C20 oxadiazole), 163.46
1 3

Design, synthesis, and biological evaluation of phenyloxadiazole derivatives as potential…
133
(CH), 162.70 (C17 oxadiazole), 161.85 (CH), 156.66 (C,
d, J=10.5 Hz), 155.51 (CH), 147.60 (CH), (C=N) 146.08
(C8 tetrazole), 139.34 (CH), 131.58 (C, d, J = 2.7 Hz),
131.16 (C, d, J=9.6 Hz), 130.75 (C), 128.99 (CH), 126.93
(CH), 121.56 (CH), 115.03 (C, d, J=3.2 Hz), 112.04 (C, d,
J = 21.1 Hz), 104.21 (CH, d, J = 24.4 Hz), 65.61 (OCH2),
33.53 (C14 CH3) ppm; IR (KBr): ꢀ = 3403, 3027, 2904,
1714, 1626, 1524, 1441, 1242, 1197, 641, 614 cm−1; HRMS
(EI): m/z calcd. for C24H17ClFN7O3 (M+) 506.1065, found
506.1063.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[5‑fluoro‑2‑(2‑fluorophenoxy)phenyl]‑1,3,4‑oxa‑
diazol‑2‑yl]methyl]oxime (14m, C24H17F2N7O3) White
solid; yield: 72%; m.p.: 135–139 °C; 1H NMR (400 MHz,
CDCl3): δ=7.85 (dd, J=8.4, 3.1 Hz, 1H, ArH), 7.51–7.42
(m, 3H, ArH), 7.35 (t, J = 7.6 Hz, 2H, ArH), 7.21–7.09
(m, 4H, ArH), 7.08–7.01 (m, 1H, ArH), 6.87 (dd, J = 9.1,
4.3 Hz, 1H, ArH), 5.49 (s, 2H, CH2), 3.97 (s, 3H, CH3 of
tetrazole) ppm; 13C NMR (100 MHz, CDCl3): δ = 163.06
(C20 oxadiazole), 162.79 (C17 oxadiazole), 159.32 (C, dd,
J = 247.4, 10.2 Hz), 157.98 (C, d, J = 244.2 Hz), 154.03
(CH, dd, J = 252.5, 12.3 Hz), 151.71 (C), 147.59 (C=N),
146.09 (C8 tetrazole), 139.14 (CH, dd, J = 11.7, 3.9 Hz),
131.54 (CH), 130.74 (CH), 128.96 (CH), 126.91 (CH),
122.83 (CH, d, J = 8.4 Hz), 120.30 (C, d, J = 23.4 Hz),
118.45 (C, d, J=8.2 Hz), 117.01 (C, d, J=26.0 Hz), 114.91
(CH, d, J = 8.6 Hz), 111.86 (CH, dd, J = 23.0, 3.8 Hz),
105.82 (CH, dd, J = 26.9, 21.8 Hz), 66.69 (OCH2), 34.57
(C14 CH3) ppm; IR (KBr): ꢀ = 3396, 3067, 2934, 1711,
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[5‑chloro‑2‑(2,4‑difuorophenoxy)phenyl]‑1,3,4‑oxa‑
diazol‑2‑yl]methyl]oxime (14k, C24H16ClF2N7O3) White solid;
yield: 68%; m.p.: 133–137 °C; 1H NMR (400 MHz, CDCl3):
δ=8.09 (d, J=2.5 Hz, 1H, ArH), 7.47 (d, J=8.4 Hz, 3H,
ArH), 7.45–7.39 (m, 1H, ArH), 7.36 (dd, J=13.0, 5.5 Hz,
3H, ArH), 6.96–6.85 (m, 2H, ArH), 6.75 (d, J=8.9 Hz, 1H,
ArH), 5.51 (s, 2H, CH2), 4.00 (s, 3H, CH3 of tetrazole) ppm;
13C NMR (100 MHz, CDCl3): δ=162.93 (C20 oxadiazole),
162.78 (C17 oxadiazole), 159.58 (C, dd, J=247.9, 10.3 Hz),
154.31 (CH), 154.14 (C, dd, J = 252.9, 12.3 Hz), 147.59
(C=N), 146.13 (C8 tetrazole), 138.49 (CH, dd, J = 11.9,
3.9 Hz), 133.18 (C), 131.50 (C), 130.77 (CH), 130.29 (CH),
128.94 (CH), 128.71 (CH), 126.91 (CH), 123.32 (C, dd,
J=9.7, 1.5 Hz), 117.68 (CH), 114.96(CH), 111.97 (C, dd,
J=23.0, 3.9 Hz), 105.85 (CH, dd, J=26.9, 21.8 Hz), 66.70
(OCH2), 34.52 (C14 CH3) ppm; IR (KBr): ꢀ =3422, 3047,
2901, 1734, 1622, 1554, 1447, 1242, 1197, 643, 617 cm−1;
HRMS (EI): m/z calcd. for C24H16ClF2N7O3 (M+) 524.0971,
found 524.0975.
1622, 1529, 1441, 1242, 1197, 973, 846, 644, 611 cm−1
;
HRMS (EI): m/z calcd. for C24H17F2N7O3 (M+) 490.1361,
found 490.1365.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[3‑bromo‑2‑(2,4‑difuorophenoxy)phenyl]‑1,3,4‑oxa‑
diazol‑2‑yl]methyl]oxime (14n, C24H16BrF2N7O3) White
solid; yield: 66%; m.p.: 141–144 °C; 1H NMR (400 MHz,
CDCl3): δ=8.22 (d, J=2.3 Hz, 1H, ArH), 7.53 (dd, J=8.9,
2.4 Hz, 1H, ArH), 7.46 (dd, J=8.4,7.6 Hz, 3H, ArH), 7.35
(t, J=7.6 Hz, 2H, ArH), 7.12 (td, J=8.9, 5.5 Hz, 1H, ArH),
6.98–6.83 (m, 2H, ArH), 6.70 (d, J=8.9 Hz, 1H, ArH), 5.52
(s, 2H, CH2), 4.01 (s, 3H, CH3 of tetrazole) ppm; 13C NMR
(100 MHz, CDCl3): δ=162.93 (C20 oxadiazole), 162.78 (C17
oxadiazole), 159.58 (C, dd, J=247.9, 10.3 Hz), 154.31 (C),
154.14 (C, dd, J=252.9, 12.3 Hz), 147.59 (C=N), 146.13
(C8 tetrazole), 138.49 (C, dd, J=11.9, 3.9 Hz), 133.18 (C),
131.50 (CH), 130.77 (CH), 130.29 (CH), 128.94 (CH),
128.71 (CH), 126.91 (CH), 123.32 (C, dd, J=9.7, 1.5 Hz),
117.68 (CH), 114.96 (CH), 111.97 (CH, dd, J = 23.0,
3.9 Hz), 105.85 (CH, dd, J=26.9, 21.8 Hz), 66.70 (OCH2),
34.52 (C14 CH3) ppm; IR (KBr): ꢀ =3429, 3061, 2987, 1756,
1629, 1541, 1410, 1248, 1191, 971, 849, 653, 623 cm−1;
HRMS (EI): m/z calcd. for C24H16BrF2N7O3 (M+) 568.0466,
found 568.0469.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[2‑(2,4‑difuorophenoxy) ‑5‑fuorophenyl]‑1,3,4‑oxa‑
diazol‑2‑yl]methyl]oxime (14l, C24H16F3N7O3) White solid;
yield: 62%; m.p.: 141–145 °C; 1H NMR (400 MHz, CDCl3):
δ=7.82 (d, J=5.5 Hz, 1H, ArH), 7.47 (d, J=5.6 Hz, 3H,
ArH), 7.36 (d, J = 5.7 Hz, 2H, ArH), 7.20–7.04 (m, 2H,
ArH), 6.88 (dd, J = 20.6, 10.7 Hz, 3H, ArH), 5.51 (s,
2H, CH2), 4.01 (s, 3H, CH3 of tetrazole) ppm; 13C NMR
(100 MHz, CDCl3): δ=162.93 (C20 oxadiazole), 162.78 (C17
oxadiazole), 159.58 (C, dd, J=247.9, 10.3 Hz), 154.31 (C),
154.14 (C, dd, J=252.9, 12.3 Hz), 147.59 (C=N), 146.13
(C8 tetrazole), 138.49 (C, dd, J=11.9, 3.9 Hz), 133.18 (CH),
131.50 (CH), 130.77 (CH), 130.29 (CH), 128.94 (C, dd,
J=14.1, 5.2 Hz), 128.71 (CH), 126.91 (CH), 123.32 (C, dd,
J=9.7, 1.5 Hz), 117.68 (CH), 114.96 (CH), 111.97 (C, dd,
J=23.0, 3.9 Hz), 105.85 (CH, dd, J=26.9, 21.8 Hz), 66.70
(OCH2), 34.52 (C14 CH3) ppm; IR (KBr): ꢀ =3415, 3022,
2944, 1714, 1626, 1524, 1432, 1246, 1197, 641, 625 cm−1;
HRMS (EI): m/z calcd. for C24H16F3N7O3 (M+) 508.1267,
found 508.1269.
(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[4‑bromo‑2‑(2‑fuorophenoxy)phenyl]‑1,3,4‑oxadia‑
zol‑2‑yl]methyl]oxime e (14o, C24H17BrFN7O3) Light yellow
solid; yield: 61%; m.p.: 136–139 °C; 1H NMR (400 MHz,
CDCl3): δ=7.99 (d, J=8.4 Hz, 1H, ArH), 7.46 (dd, J=9.9,
8.8 Hz, 3H, ArH), 7.36 (dt, J=15.8, 4.7 Hz, 3H, ArH), 7.19
(ddd, J=31.0, 16.0, 7.6 Hz, 4H, ArH), 6.96 (s, 1H, ArH),
5.50 (s, 2H, CH2), 3.97 (s, 3H, CH3 of tetrazole) ppm; 13
C
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134
Y. Li et al.
NMR (100 MHz, CDCl3): δ = 165.14 (C20 oxadiazole),
164.46 (CH), 162.70 (C17 oxadiazole), 161.85 (CH), 157.66
(C, d, J = 10.5 Hz), 155.51 (CH), 147.60 (C = N), 146.08
(C8 tetrazole), 139.34 (CH), 131.58 (CH, d, J = 2.7 Hz),
131.16 (C, d, J=9.6 Hz), 130.45 (CH), 128.99 (CH), 126.93
(CH), 121.56 (C), 116.64 (CH), 115.03 (C, d, J =3.2 Hz),
113.11 (CH), 112.04 (CH, d, J = 21.1 Hz), 104.21 (C, d,
J = 24.4 Hz), 65.61 (OCH2), 33.53 (C14 CH3) ppm; IR
(KBr): ꢀ =3392, 3061, 2934, 1711, 1622, 1529, 1441, 1242,
1197, 987, 842, 641, 613 cm−1; HRMS (EI): m/z calcd. for
C24H17BrFN7O3 (M+) 550.0560, found 550.0564.
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(Z)‑(1‑Methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone
O‑[[5‑[5‑bromo‑2‑(2‑fuorophenoxy)phenyl]‑1,3,4‑oxadia‑
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