Direct synthesis of 3,5-diaryl-1,2,4-oxadiazoles using 1-(2-oxo-2-arylethyl)pyridin-1-iums with benzamidines

Article abstract of DOI:10.1002/jhet.4354

An efficient domino protocol for the synthesis of 1,2,4-oxadiazole derivatives from readily available 1-(2-oxo-2-arylethyl)pyridin-1-iums and amidine hydrochlorides was developed. In this practical approach, N-acyl amidine precursors were formed firstly via a simple nucleophilic substitution, without the purification of N-acylamidine intermediates, and the following intramolecularly dehydrative cyclization gave 1,2,4-oxadiazole derivatives in the presence of I₂/K₂CO₃/DMSO, which exhibited excellent functional group tolerance and proceeded under simple experimental conditions.

Full text of DOI:10.1002/jhet.4354

Received: 30 June 2021
DOI: 10.1002/jhet.4354
Accepted: 18 August 2021
A R T I C L E
Direct synthesis of 3,5-diaryl-1,2,4-oxadiazoles using
1-(2-oxo-2-arylethyl)pyridin-1-iums with benzamidines
Yue Zhang | Chengjun Wu | Xinyi Wan | Cunde Wang
School of Chemistry and Chemical
Abstract
Engineering, Yangzhou University,
Yangzhou, China
An efficient domino protocol for the synthesis of 1,2,4-oxadiazole derivatives
from readily available 1-(2-oxo-2-arylethyl)pyridin-1-iums and amidine hydro-
chlorides was developed. In this practical approach, N-acyl amidine precursors
were formed firstly via a simple nucleophilic substitution, without the purifica-
tion of N-acylamidine intermediates, and the following intramolecularly
dehydrative cyclization gave 1,2,4-oxadiazole derivatives in the presence of I2/
K2CO3/DMSO, which exhibited excellent functional group tolerance and
proceeded under simple experimental conditions.
Correspondence
Cunde Wang, School of Chemistry and
Chemical Engineering, Yangzhou
University, 180 Siwangting Street,
Yangzhou, 225002, China.
Email: wangcd@yzu.edu.cn
K E Y W O R D S
1,2,4-oxadiazole, 1-(2-oxo-2-arylethyl)pyridin-1-ium, N-acyl amidine, intramolecularly
dehydrative cyclization, benzamidine
1 | INTRODUCTION
In addition, 3,5-disubstituted 1,2,4-oxadiazoles exhibited
exceptional applications in material sciences [16]. Owing
1,2,4-Oxadiazole is an important motif of natural
products such as potent antiproliferative marine
phidianidines A and B (Figure 1) [1]. This motif is pre-
sent in synthesized compounds with anti-prostate cancer
agents [2], tumor-selective and apoptosis-inducing activ-
ity [3], anticonvulsant activity [4], antibiotics [5], ant-
iviral activity [6], antiinflammatory activity [7], diuretic
activity [8], GABA modulators [9], 5HT3 receptor antago-
nists [10], central nervous system depressant activity [11],
and the potent sphingosine-1-phosphate receptor
1 (S1P1) agonist (Figure 1) [12]. Furthermore, many
3,5-disubstituted 1,2,4-oxadiazoles were investigated
widely as potential drugs, for example, Ataluren,
(3-(5-[2-fluorophenyl]1,2,4-oxadiazol-3-yl) benzoic acid,
an oral investigational drug, used in the treatment of cys-
tic fibrosis under phase-3 clinical trial (Figure 1) [13].
The mGlu5, (2-(3 [pyridin-2-yl]-1,2,4-oxadiazol-5-yl) ben-
zonitrile, was used as a promising metabotropic gluta-
mate subtype-5 receptor antagonist (Figure 1) [14]. And
pleconaril also was used for the treatment of potentially
life-threatening enterovirus infections [15].
to the inherent biological activity of these 1,2,4-oxadiazole
derivatives, the construction of these motifs has drawn
much attention throughout the years [17]. A number
of methods for the synthesis of substituted
1,2,4-oxadiazoles have been explored, mainly including
the cyclocondensation of amidoximes with acid chlo-
rides/carboxylic acids and esters [18]. And yet, Zhou and
Chen reported a tandem reaction for the synthesis of
substituted 1,2,4-oxadiazoles via the palladium-catalyzed
carbonylation of diaryliodonium salts with carbon mon-
oxide and amidoximes, followed by the intramolecular
dehydrative cyclization [19]. Recently, Vinaya and
coworkers used gem-dibromomethylarenes as benzoic
acid equivalents to afford the cyclocondensation with
amidoximes for the synthesis of 1,2,4-oxadiazoles [20].
Another important method for the preparation of
1,2,4-oxadiazoles involved the 1,3-dipolar cycloaddition
of nitrile oxides to nitriles or azetine derivatives [21]. For
example, Hong and coworkers reported a Cu-catalyzed
tandem method for the synthesis of 1,2,4-oxadiazoles
from amides and nitriles by a rare oxidative N–O bond
J Heterocyclic Chem. 2021;1–11.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

2
ZHANG ET AL.
FIGURE 1 Selected natural
products and bioactive
compounds containing
1,2,4-oxadiazole moiety
SCHEME 1 Selected previous works and this work based on 1-(2-oxo-2-arylethyl)-pyridin-1-ium unit substrates

ZHANG ET AL.
3
formation using O2 as a sole oxidant (Scheme 1) [22]. In
recent years, the metal-free direct condensation of
amidines and carboxylic acids and intramolecular
dehydrative cyclization drew a lot of attention. Hajela
and coworkers used HATU (2-[7-azabenzotriazol-1-yl]-
N,N,N0,N0-tetramethyluronium hexafluorophosphate) as
2 | RESULTS AND DISCUSSION
Firstly, our initial investigation commenced with the
model reaction of 1-(2-oxo-2-arylethyl)pyridin-1-iums
iodide 1a with benzamidine hydrochloride (2a) in a basic
medium. To our delight, the desired product N-(imino[p-
tolyl]methyl)-4-methoxybenzamide (3a) was obtained in
70% isolated yield (Table 1, entry 1). To further improve
the yield, various bases were evaluated (Table 1, entries
2–7). Substantially inorganic bases such as t-BuOK, K2CO3
as well as NaHCO3 gave good yields of benzamide 3a. Nota-
bly, the highest yield of 85% was produced in the presence
of NaHCO3 in N,N-dimethylformamide (DMF) (Table 1,
entry 7). However, these common organic amines DBU,
DABCO, and Et3N were not beneficial to the reaction.
Thus, screening of solvents was carried out (Table 1, entries
8–12); the reaction in DMSO, toluene, and CH3CN offered
benzamide 3a in 66%, 62%, and 56% yield, respectively.
However, the reaction did not take place in the presence of
1,4-dioxane and EtOH. Next, we studied the effect of tem-
perature on this reaction and found that the reaction tem-
perature (120ꢀC) gave the best yield of the target product
(Table 1, entry 13). Further decreasing the temperature to
110ꢀC, a detrimentally lower yield of product 3a was
obtained (80%) (Table 1, entry 14).
Increasing the NaHCO3 loading to 2.5 equiv. did not
have a significant improvement under otherwise identical
conditions (Table 1, entry 15). Lowering the NaHCO3
loading to 1.0 equiv. still resulted in 64% yield, albeit
requiring a reaction time of 10 h (Table 1, entry 16). Fur-
thermore, we further attempted to change the ratio of
pyridin-1-ium 1a and benzamidine hydrochloride (2a);
two relatively lower yields of the corresponding product
3a were obtained (Table 1, entries 17–18). Finally, a series
of experiments revealed that the optimal conditions were
obtained as 1a (1.0 mmol), 1.0 equiv. of 2a, and 2.0 equiv.
of NaHCO3 in 6 ml of DMF at 120ꢀC (Table 1, entry 13).
Recently, the efficiently oxidative cyclization of N-
acylamidine was developed to synthesize diversely
3,5-disubstituted-1,2,4-oxadiazoles, mainly including the
I2/K2CO3 [28] and NBS/DBU [29] oxidative system. Reac-
tions involving molecular iodine received enormous
attention in past years because iodine is a nontoxic, com-
mercially available, and inexpensive oxidant, which is
extensively being employed in various annulation reac-
tions [30]. Thus, the subsequent construction of
oxadiazole scaffold through oxidative iodination and
cyclization of N-(imino[aryl]methyl)benzamide 3a was
carried out in the presence of I2/K2CO3/DMSO according
to Hajela's method (Scheme 2) [28], which resulted in
87% yield of 1,2,4-oxadiazole 4a.
a
coupling reagent and N,N-diisopropylethylamine
as base to promote direct condensation between benzoic
acid and benzamidine hydrochloride; subsequently, the
resultant N-acylamidine was reacted with hydroxylamine
hydrochloride to give 1,2,4-oxadiazoles (Scheme 1) [13].
In addition, as an exceptional motif, 1,2,4-oxadiazole also
was formed via rearrangements of other heterocy-
cles [23].
1-(2-Oxo-2-arylethyl)pyridin-1-iums are very interest-
ing and important starting materials in the field of syn-
thetic organic chemistry. By using 1-(2-oxo-2-arylethyl)
pyridin-1-iums as synthetic acyl methyl halide [24] or acyl
halide equivalents [25], various applications have been
explored in synthetic organic chemistry [26]. We also used
1-(2-oxo-2-arylethyl)pyridin-1-iums as building blocks and
successfully applied the multicomponent reactions as a
versatile and highly efficient synthetic strategy for the
preparation of diversely cyclic compounds [27]. The nucle-
ophilic substitution reaction of benzamidine hydrochloride
as easily available substrates containing 1,3-dinitrogen
with benzoic acid or acyl halide equivalents and the subse-
quent intramolecular dehydrative cyclization to synthesis
efficiently 1,2,4-oxadiazoles are worth mentioning, and we
attempted to use 1-(2-oxo-2-arylethyl)pyridin-1-iums as
acyl halide equivalents to react with benzamidine
hydrochloride in the presence of basic conditions for the
construction of N-acylamidines. Soon afterwards, the N-
acylamidines undergo intramolecular dehydrative cycli-
zation to form a 1,2,4-oxadiazole scaffold using the I2/
K2CO3 [28] or N-bromosuccinimide/1,8-diazabicyclo
[5.4.0]undec-7-ene (NBS/DBU) [29] oxidative system.
To the best of our knowledge, there are no investigations
available on the synthesis of 1,2,4-oxadiazoles starting
from 1-(2-oxo-2-arylethyl)pyridin-1-iums. Although the
synthesis of 1,2,4-oxadiazoles has been extensively
researched, there were still many shortcomings such as
harsh conditions, harmful substrate, excessive coupling
reagents, and the difficult purification process. Therefore,
the development of a simple and stable method for the
synthesis of 1,2,4-oxadiazoles by using inexpensive and
readily available reagents would be highly desirable.
Herein, in continuation of our focus on the development
of new methodologies for the synthesis of heterocycles
using simple starting materials, detailed efforts to use the
reaction of 1-(2-oxo-2-arylethyl)pyridin-1-iums with
benzamidines for the synthesis of 1,2,4-oxadiazoles are
described.
Moreover, the I2/K2CO3/DMSO oxidative cyclization
proved to be the most appropriate (Scheme 2). Delighted

4
ZHANG ET AL.
TABLE 1 Optimization of the
reaction conditions for 3aa,b
Entry
1
1a/2a (mmol)
Base (eq.)
Solvent
DMF
T (ꢀC)
130
t (h)
6
Yield (%)
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:2
2:1
Cs2CO3(2.0)
t-BuOK(2.0)
K2CO3(2.0)
70
64
79
0
2
DMF
130
6
3
DMF
130
6
4
DBU(2.0)
DMF
130
24
24
24
7
5
DABCO(2.0)
Et3N(2.0)
DMF
130
0
6
DMF
130
trace
85
62
0
7
NaHCO3(2.0)
NaHCO3(2.0)
NaHCO3(2.0)
NaHCO3(2.0)
NaHCO3(2.0)
NaHCO3(2.0)
NaHCO3(2.0)
NaHCO3(2.0)
NaHCO3(2.5)
NaHCO3(1.0)
NaHCO3(2.0)
NaHCO3(2.0)
DMF
130
8
toluene
1,4-Dioxane
CH3CN
EtOH
DMSO
DMF
Reflux
Reflux
Reflux
Reflux
130
8
9
24
8
10
11
12
13
14
15
16
17
18
56
trace
66
88
80
85
64
81
88
24
8
120
8
DMF
110
8
DMF
120
8
DMF
120
10
10
10
DMF
120
DMF
120
aUnless otherwise noted, all reactions were carried out with 1-(2-oxo-2-arylethyl)pyridin-1-iums iodide 1a
(355.2 mg, 1.0 mmol), benzimidamide hydrochloride 2a (170.6 mg, 1.0 mmol), and base in 6.0 mL of
solvent.
bIsolated yield.
a 4-methylphenyl and a 4-methoxyphenyl substituent at
C (3) and C (5) of 1,2,4-oxadiazole core.
The scope and limitations of this method were
explored by performing the reaction of various pyridin-
1-iums 1 and different benzamidines hydrochloride
2 under the optimized reaction conditions. 1-(2-Aryl-
SCHEME 2 Synthesis of 1,2,4-oxadiazole 4a from N-(imino
[aryl]methyl)benzamide 3a using I2/K2CO3/DMSO
2-oxoethyl)pyridin-1-iums iodide
1
with electron-
donating substituents (p-CH3O, p-Me, m-Me, and o-Me)
formed respective 3,5-diaryl-1,2,4-oxadiazoles 4a–4f in
good yields (67–81%), which also showed an apparent ste-
ric effect on the reaction. Similarly, 1-(2-aryl-2-oxoethyl)
pyridin-1-iums iodide 1 bearing halogen substituents (m-
Cl, p-Cl, 2,4-dichloro, m-Br and p-Br) gave corresponding
products (Table 2, 4h-4k, 4q) in moderate yields (60%–
76%), while 1-(2-aryl-2-oxoethyl)pyridin-1-ium iodide
1 bearing a strong electron-withdrawing substituent p-
NO2 furnished the 1,2,4-oxadiazoles 4a in 62% yield.
These results implied in the benzene ring of 1-(2-aryl-
2-oxoethyl)pyridin-1-ium moiety that there was an
with the result, we further attempted to get rid of the
purification of 3a and directly used the unpurified 3a for
the next oxidative cyclization reaction. The result shown
in Scheme
3 confirmed that the target product
1,2,4-oxadiazole 4a was obtained efficiently in 81% yield
via two steps without the purification of N-(imino[aryl]
methyl)benzamide 3a (Scheme 3).
The structure of 3,5-diaryl-1,2,4-oxadiazole 4a was
unambiguously solved by X-ray crystallography
(Figure 2) [31]. X-Ray crystallographic analysis deter-
mined that product 3,5-diaryl-1,2,4-oxadiazole 4a possess

ZHANG ET AL.
5
SCHEME 3 Synthesis of
1,2,4-oxadiazole 4a from pyridin-
1-ium 1a and benzamidine
hydrochloride 2a
the intermediate [A]. Intermediate [A] underwent a
removal of pyridin-1-ium-1-ylmethanide to form N-
(imino[aryl]methyl)benzamide [B]. Next, an oxidative
iodination of the imino unit of intermediate [B] in the
presence of K2CO3 gave a N-iodo intermediate [C], which
then underwent the tautomerism to form easily the inter-
mediate [D]. Finally, an intramolecular nucleophilic sub-
stitution occurred in the presence of K2CO3 to offer
desired 3,5-diaryl-1,2,4-oxadiazoles 4a-s.
FIGURE 2 Molecular structure of 3,5-diaryl-1,2,4-oxadiazole
4a, non-hydrogen atoms are shown at the 30% probability level
3 | CONCLUSIONS
electronic effect. The substrates with electron-donating
groups usually gave the corresponding 1,2,4-oxadiazoles
with slightly higher yields compared to the electron-
withdrawing groups on the 1-(2-aryl-2-oxoethyl)pyridin-
1-iums 1 substrate.
In summary, we have developed an efficient domino pro-
tocol for the synthesis of 1,2,4-oxadiazole derivatives from
readily available 1-(2-oxo-2-arylethyl)-pyridin-1-iums and
amidine hydrochlorides. In this practical approach, N-acyl
amidine precursors were formed firstly via a simple
nucleophilic substitution, without the purification of N-
acylamidine intermediates; the following intramolecularly
oxidative cyclization gave 1,2,4-oxadiazole derivatives in
the presence of I2/K2CO3/DMSO. Moreover, the sequential
synthesis of 1,2,4-oxadiazole derivatives from 1-(2-oxo-
2-arylethyl)pyridin-1-iums and amidine hydrochlorides
exhibited excellent functional group tolerance and
proceeded under simple experimental conditions, thus
underscoring the unique reactivity of amidines and expan-
ding the repertoire of the useful transformations of these
reactive intermediates.
Furthermore, a series of substituted benzamidines
hydrochloride 2 were examined and the results are sum-
marized in Table 2. Electron-donating (MeO, EtO, Me)
groups attached to the aromatic ring of benzamidines
were well tolerated, with the corresponding
1,2,4-oxadiazoles obtained in moderate to good yields
(Table 2). Similarly, the benzamidines substituted by Cl
and Br could be efficiently transformed into the
corresponding products in moderate yields, which pro-
vided the possibility for further functionalization. These
results demonstrated that substituted positions at the
benzamidines have positive effects on the annulation.
The scope of this reaction was extended by employing
heteroaryl amidine hydrochloride with 1-(2-oxo-2-[p-
methoxyphenyl]ethyl)pyridin-1-iums iodide or 1-(2-oxo-
2-phenylethyl)pyridin-1-iums iodide, which afforded
1,2,4-oxadiazole 4l and 4n in 63% or 65%, respectively.
The structures of 3,5-diaryl-1,2,4-oxadiazoles 4b and
4p also were further confirmed by X-ray crystallography
(Figure 3) [31].
4 | EXPERIMENTAL SECTION
4.1 | General
All melting points were recorded using a Yanaco melting
point apparatus and are uncorrected. The 1H NMR
(400 MHz) and 13C NMR (150 MHz) spectra were
recorded in a Bruker AV-400 and AV-600 spectrometer
with TMS as internal reference in CDCl3 solution. The
J values are given in Hertz. IR spectra were recorded in a
Nicolet FT-IR 5DX spectrometer, and samples were
loaded neatly. High-resolution ESI mass spectra
On the basis of the above results and literature prece-
dent, a plausible mechanism is depicted in Scheme 4.
Firstly, in the presence of NaHCO3, benzamidine hydro-
chloride (2a-h) was transferred to natural benzamidine,
and the following nucleophilic addition to carbonyl of
1-(2-oxo-2-arylethyl)pyridin-1-iums iodide 1a-j afforded

6
ZHANG ET AL.
TABLE 2 Scopes of 1-(2-oxo-
2-arylethyl)pyridin-1-iums iodide and
benzimidamide hydrochloridea,b
t (h)
Entry
1
R
Ar
1st step
2nd step
Product
4a
Yield (%)b
p-MeO
p-MeO
p-MeO
p-Me
m-Me
o-Me
p-Br
p-MeC6H4
p-BrC6H4
m-BrC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
m-BrC6H4
p-ClC6H4
m-MeOC6H4
C6H5
8
7
7
7
7
8
7
8
7
8
6
8
7
6
6
8
8
8
8
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
81
75
67
77
74
69
74
64
69
68
76
63
73
65
69
64
60
69
62
2
4b
4c
3
4
4d
4e
5
6
4f
7
4g
8
p-Cl
4h
4i
9
m-Br
3,4-Cl
3,4-Cl
p-MeO
p-MeO
H
10
11
12
13
14
15
16
17
18
19
4j
4k
4l
Pyridin-3-yl
m-MeOC6H4
Pyridin-3-yl
m-BrC6H4
o-EtOC6H4
o-EtOC6H4
o-EtOC6H4
m-BrC6H4
4m
4n
4o
H
m-Me
m-Cl
p-MeO
p-O2N
4p
4q
4r
4s
aReaction conditions: First step, substituted 1-(2-oxo-2-arylethyl)pyridin-1-iums iodide 1a-j (1.0 mmol),
substituted benzimidamide hydrochloride 2a-h (1.0 mmol), sodium bicarbonate (168 mg, 2 mmol), N,N-
Dimethylformamide (DMF) (6 ml), 120ꢀC in oil bath, 6–8 h; second step, iodine (380.7 mg, 1.5 mmol),
DMSO (6 ml), potassium carbonate (414.6 mg, 3.0 mmol), 100ꢀC in oil bath, 3 h.
bIsolated yield.
FIGURE 3 Molecular structure of 3,5-diaryl-1,2,4-oxadiazoles 4b and 4p, non-hydrogen atoms are shown at the 30% probability level
were obtained on a UHR-TOF maXis (ESI) mass spec-
trometer. X-Ray crystallographic analysis was performed
monochromatic Mo KR radiation (λ) 0.71073 Å) and inte-
grated with the SAINT-Plus program. All calculations
were performed with programs from the SHELXTL
with
a
SMART APEX-II diffractometer using

ZHANG ET AL.
7
SCHEME 4 Mechanistic
rationalization for the synthesis
of 1,2,4-oxadiazole derivatives
crystallographic software package. Flash chromatography
was performed on silica gel (230–400 mesh) eluting with
an ethyl acetate–hexane mixture. All reactions were mon-
itored by thin-layer chromatography (TLC).
cooled reaction mixture was added water (10 ml) and
extracted with dichloromethane (10 ml ꢁ 2). The organic
phase was washed with brine (15 ml) and dried over
anhydrate sodium sulfate. After the removal of dic-
hloromethane, the crude product was not further purified
to use directly for the next step reaction. Subsequently, the
crude product was dissolved in DMSO (6 ml), and iodine
(380.7 mg, 1.5 mmol) and potassium carbonate (414.6 mg,
3.0 mmol) were added to the solution. The resultant mix-
ture was stirred at 100ꢀC in oil bath for 3 h. After the com-
pletion of the reaction monitored by TLC (EtOAc/hexanes,
1/10, silica gel) and the removal of solvent via reduced pres-
sure distillation, water was added to the cooled reaction
mixture (10 ml) and the mixture was extracted with dic-
hloromethane (10 ml ꢁ 2). The organic phase was washed
with brine (15 ml) and dried over anhydrate sodium sulfate.
After the removal of dichloromethane, the yellowish crude
product was purified by flash chromatography (EtOAc/hex-
anes, 1/20, silica gel) to give the desired products 4a-s.
4.1.1 | Preparation of N-(imino[p-tolyl]
methyl)-4-methoxybenzamide (3a)
The mixture of 1-(2-oxo-2-[4-methoxyphenyl]ethyl)
pyridin-1-iums iodide (1a, 355.2 mg, 1.0 mmol),
4-methylbenzimidamide hydrochloride (2a, 170.6 mg,
1.0 mmol) and sodium bicarbonate (168 mg, 2 mmol) in
DMF (6 ml) was stirred at 120ꢀC in oil bath for 8 h. After
the completion of the reaction monitored by TLC
(EtOAc/hexanes, 1/8, silica gel) and the removal of solvent
via reduced pressure distillation, the cooled reaction mix-
ture was added water (10 ml) and extracted with dic-
hloromethane (10 ml ꢁ 2). The organic phase was washed
with brine (15 ml) and dried over anhydrate sodium sulfate.
After the removal of dichloromethane, the crude product
was purified by flash chromatography (EtOAc/hexanes,
1/10, silica gel) to give a white solid product 3a (236.1 mg,
88%); 1H NMR (400 MHz, CDCl3) δ (ppm): 10.71 (brs, 1H),
8.32 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.29 (d,
J = 8.0 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 2.42
(s, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm): 179.8, 166.2,
162.7, 142.8, 132.2, 131.6, 130.6, 129.4, 127.4, 113.2, 55.3,
21.5; HR-MS (ESI) calcd. For C16H17N2O2 [(M + H)+]:
269.1290; found: 269.1281.
4.1.3 | 5-(4-methoxyphenyl)-3-(p-tolyl)-
1,2,4-oxadiazole (4a)
White solid, yield: 81%; m.p. 107.3–107.5ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3450, 1619, 1502, 1361, 1256, 1180, 1027,
1
835, 757; H NMR (400 MHz, CDCl3) δ (ppm): 8.15 (dd,
J1 = 8.0, J2 = 4.0 Hz, 2H), 8.05 (dd, J1 = 8.0, J2 = 4.0 Hz,
2H), 7.30 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H),
3.90 (s, 3H), 2.42 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
(ppm): 175.3, 168.7, 163.0, 141.3, 130.0, 129.4, 127.3,
124.2, 116.9, 114.4, 55.4, 21.5; HR-MS (ESI) calcd. For
C16H14N2NaO2 [(M + Na)+]: 289.0953; found: 289.0948.
4.1.2 | General procedure for the synthesis
of 3,5-diaryl-1,2,4-oxadiazoles 4a-s
The mixture of substituted 1-(2-oxo-2-arylethyl)pyridin-
1-iums iodide 1a-j (1.0 mmol), substituted benzimidamide
hydrochloride 2a-h (1.0 mmol), and sodium bicarbonate
(168 mg, 2 mmol) in DMF (6 ml) was stirred at 120ꢀC in oil
bath for 6–8 h. After the completion of the reaction moni-
tored by TLC (EtOAc/hexanes, 1/2, silica gel) and then the
removal of solvent via reduced pressure distillation, the
4.1.4 | 3-(4-Bromophenyl)-
5-(4-methoxyphenyl)-1,2,4-oxadiazole (4b)
White solid, yield: 75%; m.p. 162.3–162.6ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3450, 1623, 1500, 1358, 1257, 1177,
1
837, 758; H NMR (400 MHz, CDCl3) δ (ppm): 8.15 (dd,
J1 = 8.0, J2 = 4.0 Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H), 7.64

8
ZHANG ET AL.
(dd, J1 = 8.0, J2 = 4.0 Hz, 2H), 7.04 (dd, J1 = 8.0,
J2 = 4.0 Hz, 2H), 3.90 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ (ppm): 175.7, 168.0, 163.2, 132.0, 130.0, 128.9, 126.0,
125.5, 116.6, 114.5, 55.5; HR-MS (ESI) calcd. For
C15H11BrN2NaO2 [(M + Na)+]: 352.9902; found: 352.9896.
(d, J = 8.0 Hz, 2H), 7.51–7.46 (m, 3H), 7.37 (d, J = 8.0 Hz,
2H), 2.77 (s, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm):
176.5, 167.7, 139.1, 137.2, 132.3, 131.9, 130.1, 129.1, 128.8,
126.2, 125.5, 123.2, 21.9; HR-MS (ESI) calcd. For
C15H11ClN2NaO [(M + Na)+]: 293.0458; found: 293.0450.
4.1.5 | 3-(3-Bromophenyl)-
5-(4-methoxyphenyl)-1,2,4-oxadiazole (4c)
4.1.9 | 5-(4-Bromophenyl)-
3-(4-chlorophenyl)-1,2,4-oxadiazole (4 g)
White solid, yield: 67%; m.p.133.2–133.4ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3452, 1612, 1498, 1427, 1346, 1258, 1174,
1020, 846, 751; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.32 (s,
1H), 8.14 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.0 Hz, 1H), 7.63
(d, J = 8.0 Hz, 1H), 7.36 (dd, J1 = J2 = 8.0 Hz, 1H), 7.03 (d,
J = 8.0 Hz, 2H), 3.89 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
(ppm): 175.8, 167.6, 163.2, 133.9, 130.4, 130.3, 130.0, 129.0,
125.9, 122.8, 116.5, 114.5, 55.5; HR-MS (ESI) calcd. For
C15H11BrN2NaO2 [(M + Na)+]: 352.9902; found: 352.9895.
White solid, yield: 74%; m.p.180.2–180.5ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3448, 1639, 1407, 1355, 1091, 752; 1H NMR
(400 MHz, CDCl3) δ (ppm): 8.09 (d, J = 8.0 Hz, 2H), 8.07
(d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.58 (d,
J = 8.0 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ (ppm):
175.0, 168.2, 137.4, 132.5, 129.5, 129.1, 128.8, 127.8, 125.2,
122.9; HR-MS (ESI) calcd. For C14H8BrClN2NaO [(M
+ Na)+]: 356.9406; found: 356.9391.
4.1.10 | 3-(3-Bromophenyl)-
5-(4-chlorophenyl)-1,2,4-oxadiazole (4 h)
4.1.6 | 3-(4-Chlorophenyl)-5-(p-tolyl)-
1,2,4-oxadiazole (4d)
White solid, yield: 64%; m.p. 159.4–159.7ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3438, 1610, 1520, 1434, 1345, 1270, 1093,
928, 893, 796, 751, 674; 1H NMR (400 MHz, CDCl3) δ (ppm):
8.32 (s, 1H), 8.15 (d, J = 8.0 Hz, 2H), 8.09 (d, J = 8.0 Hz, 1H),
7.65 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.38 (dd,
J1 = J2 = 8.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ (ppm):
175.0, 167.9, 139.4, 134.2, 130.5, 130.4, 129.5, 129.4, 128.6,
125.9, 122.9, 122.5; HR-MS (ESI) calcd. For C14H8BrClN2NaO
[(M + Na)+]: 356.9406; found: 356.9375.
White solid, yield: 77%; m.p. 93.6–93.8ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3434, 2925, 1620, 1401, 1271, 1087,
836, 752; H NMR (400 MHz, CDCl3) δ (ppm): 8.13–8.07
(m, 4H), 7.48 (dd, J1 = 8.0, J2 = 4.0 Hz, 2H), 7.35 (d,
J = 8.0 Hz, 2H), 2.45 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ (ppm): 176.0, 168.0, 143.6, 137.2, 129.8, 129.1, 128.7,
128.1, 125.5, 121.3, 21.7; HR-MS (ESI) calcd. For
C15H11ClN2NaO [(M + Na)+]: 293.0458; found: 293.0449.
1
4.1.7 | 3-(4-Chlorophenyl)-5-(m-tolyl)-
1,2,4-oxadiazole (4e)
4.1.11 | 5-(3-Bromophenyl)-
3-(4-chlorophenyl)-1,2,4-oxadiazole (4i)
White solid, yield: 74%; m.p. 90.3–90.7ꢀC (EA/PE); IR (KBr,
White solid, yield: 69%; m.p. 157.5–157.7ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3451, 1637, 1355, 667; 1H NMR (400 MHz,
CDCl3) δ (ppm): 8.36 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H),
8.10 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.49 (d,
J = 8.0 Hz, 2H), 7.44 (dd, J1 = J2 = 8.0 Hz, 1H); 13C
NMR (150 MHz, CDCl3) δ (ppm): 174.4, 168.2, 137.5,
135.7, 131.0, 130.6, 129.2, 128.8, 126.6, 125.9, 125.1, 123.1;
HR-MS (ESI) calcd. For C14H8BrClN2NaO [(M + Na)+]:
356.9406; Found: 356.9394.
1
cmꢂ1): ν 3446, 1636, 1356, 1102, 618; H NMR (400 MHz,
CDCl3) δ (ppm): 8.11 (d, J = 8.0 Hz, 2H), 8.02 (s, 1H), 7.99
(d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.43 (d,
J = 4.0 Hz, 2H), 2.46 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
(ppm): 176.0, 168.0, 139.0, 137.2, 133.6, 129.1, 129.0, 128.7,
128.6, 125.4, 125.2, 123.9, 21.3; HR-MS (ESI) calcd. For
C15H11ClN2NaO [(M + Na)+]: 293.0458; found: 293.0449.
4.1.8 | 3-(4-Chlorophenyl)-5-(o-tolyl)-
1,2,4-oxadiazole (4f)
4.1.12 | 5-(3,4-Dichlorophenyl)-
3-(3-methoxyphenyl)-1,2,4-oxadiazole (4j)
White solid, yield: 69%; m.p. 81.2–81.6ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3448, 1637, 1411, 1359, 1093, 740; 1H NMR
(400 MHz, CDCl3) δ (ppm): 8.15 (d, J = 8.0 Hz, 1H), 8.11
White solid, yield: 68%; m.p.129.5–129.7ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3449, 2965, 1614, 1550, 1464, 1384, 1345,

ZHANG ET AL.
9
1
1241, 1121, 1043, 890, 753; H NMR (400 MHz, CDCl3) δ
(ppm): 8.32 (s, 1H), 8.04 (d, J = 8.0.0 Hz, 1H), 7.75 (d,
4.1.16 | 5-Phenyl-3-(pyridin-3-yl)-
1,2,4-oxadiazole (4n)
J
=
8.0 Hz, 1H), 7.68–7.61 (m, 2H), 7.42 (dd,
J1 = J2 = 8.0 Hz, 1H), 7.08 (dd, J1 = 8.0, J2 = 4.0 Hz, 1H),
3.90 (s, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm): 173.6,
169.0, 159.9, 137.4, 133.7, 131.3, 130.0, 129.9, 127.6, 127.0,
123.9, 119.9, 117.9, 112.0, 55.4; HR-MS (ESI) calcd. For
C15H10Cl2N2NaO2 [(M + Na)+]: 343.0017; found:
343.0009.
White solid, yield: 65%; m.p. 138.1–138.3ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 2980, 2314, 1768, 1554, 1451, 1406, 1364,
1
1066, 909, 828, 737, 689; H NMR (400 MHz, CDCl3) δ
(ppm): 9.42 (s, 1H), 8.78 (d, J = 4.0 Hz, 1H), 8.50 (d,
J = 8.0 Hz, 1H), 8.23 (d, J = 8.0 Hz, 2H), 7.67–7.61 (m,
1H), 7.61–7.54 (m, 2H), 7.54–7.48 (m, 1H); 13C NMR
(150 MHz, CDCl3) δ (ppm): 176.2, 166.8, 151.4, 148.2,
135.2, 133.0, 129.1, 128.2, 123.88, 123.84, 123.5; HR-MS
(ESI) calcd. For C13H10N3O [(M + H)+]: 224.0824; found:
224.0819.
4.1.13 | 5-(3,4-Dichlorophenyl)-3-phenyl-
1,2,4-oxadiazole (4 k)
White solid, yield: 76%; m.p.131.9–132.2ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3423, 2977, 1526, 1453, 1402, 1362, 1248,
1049, 882, 741, 686; H NMR (400 MHz, CDCl3) δ (ppm):
4.1.17 | 3-(3-Bromophenyl)-5-phenyl-
1,2,4-oxadiazole (4o)
1
8.32 (s, 1H), 8.15 (d, J = 8.0 Hz, 2H), 8.04 (d, J = 8.4 Hz,
1H), 7.64 (d, J = 8.0 Hz, 1H), 7.55–7.50 (m, 3H); 13C
NMR (150 MHz, CDCl3) δ (ppm): 173.7, 169.1, 137.3,
133.7, 131.4, 131.3, 129.9, 128.9, 127.5, 127.0, 126.4, 123.9;
HR-MS (ESI) calcd. For C14H8Cl2N2NaO [(M + Na)+]:
312.9911; found: 312.9899.
White solid, yield: 69%; m.p. 91.1–91.3ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 2987, 2313, 1769, 1554, 1456, 1405, 1359,
1262, 1068, 893, 737, 680; H NMR (400 MHz, CDCl3) δ
(ppm): 8.34 (s, 1H), 8.21 (d, J = 8.0 Hz, 2H), 8.11 (d,
J = 8.0 Hz, 1H), 7.63 (dd, J1 = 8.0, J2 = 4.0 Hz, 2H), 7.56
(dd, J1 = 8.0, J2 = 4.0 Hz, 2H), 7.38 (dd, J1 = J2 = 8.0 Hz,
1H); 13C NMR (150 MHz, CDCl3) δ (ppm): 175.9, 167.8,
134.1, 132.9, 130.5, 130.3, 129.1, 128.8, 128.1, 125.9, 124.0,
122.9; HR-MS (ESI) calcd. For C14H9BrN2NaO [(M
+ Na)+]: 322.9796; Found: 322.9797.
1
4.1.14 | 5-(4-Methoxyphenyl)-3-(pyridin-
3-yl)-1,2,4-oxadiazole (4 l)
White solid, yield: 63%; m.p. 148.6–148.9ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3452, 1629, 1503, 1435, 1359, 1266, 1016,
1
758, 700; H NMR (400 MHz, CDCl3) δ (ppm): 9.39 (d,
4.1.18 | 3-(2-Ethoxyphenyl)-5-(m-tolyl)-
J = 4.0 Hz, 1H), 8.75 (d, J = 4.0 Hz, 1H), 8.44 (d,
J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 2H), 7.46 (dd,
J1 = 8.0, J2 = 4.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 2H), 3.90
(s, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm): 176.0,
166.7, 163.3, 151.6, 148.4, 134.9, 130.1, 123.69, 123.55,
116.4, 114.5, 55.5; HR-MS (ESI) calcd. For C14H12N3O2
[(M + H)+]: 254.0930; Found: 254.0925.
1,2,4-oxadiazole (4p)
White solid, yield: 64%; m.p.79.3–79.5ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3427, 3060, 2974, 2312, 1562, 1473, 1390,
1274, 1160, 1041, 885, 752; H NMR (400 MHz, CDCl3) δ
(ppm): 8.08–8.04 (m, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.48–
7.38 (m, 3H), 7.07 (dd, J1 = 8.0, J2 = 4.0 Hz, 2H), 4.22 (q,
J = 8.0 Hz, 2H), 2.46 (s, 3H), 1.50 (t, J = 7.0 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ (ppm): 174.6, 167.4, 157.5,
138.9, 133.3, 132.1, 131.3, 128.9, 128.6, 125.2, 124.2, 120.5,
116.4, 112.9, 64.6, 21.3, 14.7; HR-MS (ESI) calcd. For
C17H16N2NaO2 [(M + Na)+]: 303.1109; found: 303.1110.
1
4.1.15 | 3-(3-Methoxyphenyl)-
5-(4-methoxyphenyl)-1,2,4-oxadiazole (4 m)
White solid, yield: 73%; m.p. 91.3–91.6ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3425, 2981, 1609, 1502, 1458, 1350, 1251,
1
1167, 1040, 896, 834, 758; H NMR (400 MHz, CDCl3) δ
4.1.19 | 5-(3-Chlorophenyl)-
(ppm): 8.15 (d, J = 8.0 Hz, 2H), 7.76 (dd, J1 = 8.0,
J2 = 4.0 Hz, 1H), 7.68 (s, 1H), 7.40 (dd, J1 = J2 = 8.0 Hz,
1H), 7.07–7.00 (m, 3H), 3.89 (s, 3H), 3.88 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ (ppm): 175.5, 168.7, 163.1,
159.8, 130.0, 129.8, 128.3, 119.9, 117.5, 116.8, 114.4, 112.0,
55.48, 55.42; HR-MS (ESI) calcd. For C16H14N2NaO3 [(M
+ Na)+]: 305.0902; found: 305.0898.
3-(2-ethoxyphenyl)-1,2,4-oxadiazole (4q)
White solid, yield: 60%; m.p.124.2–124.4ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 2978, 2903, 1560, 1458, 1347, 1251, 1055,
1
887, 747, 670; H NMR (400 MHz, CDCl3) δ (ppm): 8.22
(s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H),
7.56 (dd, J1 = 8.0, J2 = 4.0 Hz, 1H), 7.52–7.44 (m, 2H),

10
ZHANG ET AL.
Reddy, T. S. Reddy, S. P. Shaik, C. Bagul, A. Kamal, Bioorg.
Chem. 2016, 69, 7.
7.11–7.03 (m, 2H), 4.22 (q, J = 8.0 Hz, 2H), 1.50
(t, J = 8.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm):
173.2, 167.6, 157.5, 135.1, 132.5, 132.3, 131.3, 130.3, 128.1,
126.1, 126.0, 120.5, 116.1, 112.9, 64.6, 14.7; HR-MS (ESI)
calcd. For C16H13ClN2NaO2 [(M + Na)+]: 323.0563;
found: 323.0562.
[4] (a) A. Almasirad, S. A. Tabatabai, M. Faizi, A. Kebriaeezadeh,
N. Mehrabi, A. Dalvandi, A. Shafifiee, Bioorg. Med. Chem. Lett.
2004, 14, 6057. (b) M. Mohammadi-Khanaposhtani, M.
Shabani, M. Faizi, I. Aghaei, R. Jahani, Z. Sharafifi, N. S.
Zafarghandi, M. Mahdavi, T. Akbarzadeh, S. Emami, A.
Shafifiee, A. Foroumadi, Eur. J. Med. Chem. 2016, 112, 91.
[5] P. I. O'Daniel, Z. Peng, H. Pi, S. A. Testero, D. Ding, E. Spink,
E. Leemans, M. A. Boudreau, T. Yamaguchi, V. A. Schroeder,
W. R. Wolter, L. I. Llarrull, W. Song, E. Lastochkin, M.
Kumarasiri, N. T. Autunes, M. Espahbodi, K. Lichtenwalter,
M. A. Suckow, S. Vakulenko, S. Mobashery, M. Chang, J. Am.
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19, 845. (b) P. Y. Wang, L. Chen, J. Zhou, H. Fang, Z. B. Wu,
B. A. Song, S. Yang, J. Saudi. Chem. Soc. 2017, 21, 315.
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44, 794. (b) M. Krasavin, A. Shetnev, T. Sharonova, S. Baykov,
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Chem. 2018, 76, 88.
4.1.20 | 3-(2-Ethoxyphenyl)-
5-(4-methoxyphenyl)-1,2,4-oxadiazole (4r)
White solid, yield: 69%; m.p. 69.8–70.2ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 2979, 1740, 1508, 1355, 1253, 1174, 1047,
1
755, 679; H NMR (400 MHz, CDCl3) δ (ppm): 8.16 (d,
J = 8.0 Hz, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.45 (dd,
J1 = J2 = 8.0 Hz, 1H), 7.10–7.00 (m, 4H), 4.21 (q,
J = 8.0 Hz, 2H), 3.89 (s, 3H), 1.50 (t, J = 8.0 Hz, 3H); 13
C
NMR (150 MHz, CDCl3) δ (ppm): 174.3, 167.3, 162.9,
157.5, 132.0, 131.3, 130.0, 120.5, 117.0, 116.5, 114.4, 112.9,
64.6, 55.4, 14.7; HR-MS (ESI) calcd. For C17H16N2NaO3
[(M + Na)+]: 319.1059; Found: 319.1059.
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4.1.21 | 3-(3-Bromophenyl)-
5-(4-nitrophenyl)-1,2,4-oxadiazole (4 s)
[11] B. Cavalleri, G. Volpe, B. R. Del Turco, A. Diena, Farmaco
Ed. Sci. 1976, 31, 393.
White solid, yield: 62%; m.p. 170.6–170.8ꢀC (EA/PE); IR
(KBr, cmꢂ1): ν 3451, 1636, 1522, 1349, 674; 1H NMR
(400 MHz, CDCl3) δ (ppm): 8.44–8.39 (m, 4H), 8.33 (s,
1H), 8.11 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H),
7.40 (dd, J1 = J2 = 8.0 Hz, 1H); 13C NMR (150 MHz,
CDCl3) δ (ppm): 173.8, 168.2, 150.2, 134.5, 130.53, 130.51,
129.26, 129.22, 128.2, 126.0, 124.3, 123.0; HR-MS (ESI)
calcd. For C14H9BrN3O3 [(M + H)+]: 345.9827; found:
346.3308.
[12] (a) M. H. Bolli, C. Müller, B. Mathys, S. Abele, M. Birker, R.
Bravo, D. Bur, P. Hess, C. Kohl, D. Lehmann, O. Nayler, M.
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Keohane, M. J. Rosenbach, J. A. Milligan, G.-J. Shei, G.
Chrebet, S. A. Parent, J. Bergstrom, D. Card, M. Forrest, E. J.
Quackenbush, L. A. Wickham, H. Vargas, R. M. Evans, H.
Rosen, S. Mandala, J. Med. Chem. 2005, 48, 6169.
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M. A. Varney, P. Prasit, N. D. P. Cosford, J. Med. Chem. 2004,
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DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new
data were created or analyzed in this study.
ORCID
Cunde Wang https://orcid.org/0000-0001-5561-979X
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ZHANG ET AL.
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How to cite this article: Y. Zhang, C. Wu,
X. Wan, C. Wang, J. Heterocycl. Chem. 2021, 1.
https://doi.org/10.1002/jhet.4354