Base-mediated one-pot synthesis of 1,2,4-oxadiazoles from nitriles, aldehydes and hydroxylamine hydrochloride without addition of extra oxidant

Article abstract of DOI:10.1039/c6ob01794k

A simple base-mediated one-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from nitriles, aldehydes and hydroxylamine hydrochloride has been developed, in which the aldehydes act as both substrates and oxidants. The reactions include three sequential

Full text of DOI:10.1039/c6ob01794k

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: W. Wang, H. Xu, Y.
Xu, T. Ding, W. Zhang, Y. Ren and H. Chang, Org. Biomol. Chem., 2016, DOI: 10.1039/C6OB01794K.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 9
View Article Online
DOI: 10.1039/C6OB01794K
Journal Name
ARTICLE
Base-Mediated One-Pot Synthesis of 1,2,4-Oxadiazoles from
Nitriles, Aldehydes and Hydroxylamine Hydrochloride without
Addition of Extra Oxidant
Received 00th January 20xx,
Accepted 00th January 20xx
Wei Wang, Hao Xu,* Yuanqing Xu,* Tao Ding, Wenkai Zhang, Yanrong Ren and Haibo Chang
DOI: 10.1039/x0xx00000x
A
simple base-mediated one-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from nitriles, aldehydes and
www.rsc.org/obc
hydroxylamine hydrochloride has been developed, in which the aldehydes act as both substrates and oxidants. The
reactions undergo sequential three procedures: base-promoted intermolecular addition of hydroxylamine to nitrile to lead
to amidoxime, treatment of the amidoxime with aldehyde to form 4,5-dihydro-1,2,4-oxadiazole, and oxidization of the 4,5-
dihydro-1,2,4-oxadiazole by aldehyde to afford 1,2,4-oxadiazole. This method presents a direct and simple protocol for the
synthesis of 3,5-disubstituted 1,2,4-oxadiazoles.
employing air as oxidant under MW and acidic condition;5o
This method uses simpler substrates compared to other
methods. However, under acidic condition, even the formation
Introduction
Substituted 1,2,4-oxadiazoles are
a kind of important
of amidoximes have to resort to MW means using unstable
HONH2 (without protection of hydrochloride) as a substrate.
All the methods above are efficient, but most of them suffer
from the use of unavailable starting materials or harsh
condition (microwave radiation, addition of strong acid or
strong dehydrant, high reaction temperature).
heterocycles that often occur in natural products,1 and have
been widely used as pharmacophores, bioactive molecules and
functional materials.2 The 1,2,4-oxadiazole derivatives have
been proved to possess a broad range of biological activities
such as antitumour, antiviral, antibacterial, antischistosomal
activities.3 Furthermore, these five-membered heterocyclic
compounds can serve as bioisosteres for esters and amides in
peptide mimetics.4 Therefore, their synthesis have attracted
much attention, and various synthetic methods have been
developed.5 Among the known synthetic strategies of 1,2,4-
oxadiazoles, it is the most common approach to utilize
amidoximes as starting materials or intermediates; and the
previous synthetic methods through this approach are mainly
divided into the following three categories (Scheme 1): (A) 1,3-
dipolar cycloaddition of nitrile oxides to nitriles.5a,5b (B) O-
acylation of amidoximes using carboxylic acids or activated
carboxylic acid derivatives such as esters, anhydrides and acid
chlorides, followed by intramolecular cyclodehydration;5c-5h
When using carboxylic acids as the O-acetylating reagent of
amidaximes, strong dehydrants are needed. (C) Intermolecular
cyclodehydration of amidoximes with aldehydes to form 4,5-
dihydro-1,2,4-oxadiazoles,
followed
by
oxidative
dehydrogenation.5i-5n (D) Used as intermediates, amidoximes
react with Aldehydes and Hydroxylamine to form 4,5- dihydro-
1,2,4-oxadiazoles, followed by oxidative dehydrogenation
Institute of Fine Chemistry and Engineering, Henan Engineering Laboratory of
Flame-retardant and Functional Materials, College of Chemistry and Chemical
Engineering, Henan University, Kaifeng 475004, P. R. China.
Scheme 1 Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles from
E-mail : xuhao@henu.edu.cn; 18937822307@163.com
Electronic Supplementary Information (ESI) available: NMR spectra for all target
compounds. See DOI: 10.1039/x0xx00000x
Amidoximes.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 9
ARTICLE
When aldehydes and amidoximes are used as the substrates
Journal Name
View Article Online
DOI: 10.1039/C6OB01794K
to prepare 1,2,4-oxadiazoles, oxidants such as KMnO4, MnO2
or NaOCl are usually needed (Scheme 1C).5l-5n Moreover,
amidoximes are prepared from nitriles generally; the previous
attempt to synthesize 1,2,4-oxadiazoles from simpler nitriles
and aldehydes have to use unstable HONH2 (without
protection of hydrochloride) as the substrate employing air as
the oxidant under MW condition (Scheme 1D).5o In fact,
aldehydes are weak oxidants. For instance, aldehydes can take
place self-redox reactions in the presence of concentrated
strong alkaline (i.e. Cannizzaro reaction). However, aldehydes
are seldom used as oxidants in the synthesis of N-heterocycles.
In continuation of our endeavors to develop the synthetic
methods of N-heterocycles from readily available substrates,6
herein, we report a simple and efficient base-mediated one-
pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from
nitriles, aldehydes and hydroxylamine under mild conditions,
using aldehydes as both the substrates and oxidants.
Entry
1
Base
Cs2CO3
NaOH
Solvent-1/Solvent-2 T (oC) Yield of 3a (%)b
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/CH3CN
t-BuOH/DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
50
93
70
72
58
64
61
43
26
80
68
64
45
74
89
trace
60
87
84
91
79
80
2
3
K2CO3
K3PO4
4
5
AcONa
DBU
6
7
t-BuONa
-
Results and discussion
8
Firstly, sequential reactions of benzonitrile
(1a) with
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
hydroxylamine hydrochloride and benzaldehyde (2a) were
chosen as the model to optimize conditions including the
bases and solvents. As shown in Table 1, the one-pot synthesis
of 3,5-diphenyl-1,2,4-oxadiazole (3a) underwent sequential
three procedures: (a) Nucleophilic addition of hydroxylamine
to 1a to provide benzamidoxime (I-1) was performed in the
presence of triethylamine (TEA) at 80 oC for 18 h without
exclusion of air; (b) Base-mediated cascade reactions including
coupling and cyclization of I-1 with 2a to form intermediate I-2
(c) Oxidative dehydrogenation of I-2 by 2a to afford the target
compound (3a) in the presence of base. Seven bases (2 equiv.)
were tested using t-BuOH as the solvent in the first step and
DMSO as the solvent in the second step (Table1, entries 1-7),
and Cs2CO3 provided the highest yield. Only 26 % yield was
afforded in the absence of base (entry 8). We also attempted
to use various solvents (entries 1, 9-14), and DMSO as the
10
11
12
13
14
15
16
17
18c
19d
20e
21f
t-BuOH/Xylene
t-BuOH/THF
t-BuOH/DCM
t-BuOH/ME
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
80
;
120
100
100
100
100
a
Reaction conditions: For the first step, without exclusion of air,
1a (1a) (0.45 mmol, 46 μL), hydroxylamine
solvent in the second step was the best choice. Considering benzonitrile
(
)
the possible weak oxidizability of DMSO, we used 2- hydrochloride (0.5 mmol, 34.7 mg), triethylamine (TEA) (0.9 mmol,
methoxyethanol (ME) replacing DMSO to carry out the model 126 μL), solvent-1 (1.5 mL), temperature (80 oC), time (18 h). For the
reaction, and a 89 % yield was provided (entry 14). We tried second step, benzaldehyde (2a) (1.0 mmol, 102 μL), base (0.9 mmol),
o
different reaction temperatures (entries 1, 15-17), and 100 C solvent-2 (1.0 mL), temperature (100 oC), time (24 h) in a Schlenk
was suitable. When the second step was performed under O2 tube under N2 balloon (1 bar). b Isolated yield. c Reaction time (12 h)
d
or air, a relatively low yield was obtained (compare entries 1, for the second step. Reaction time (48 h) for the second step. e
20-21), and the result was probably due to the oxidation of Under O2 for the second steps. f Under air for the second steps.
benzaldehyde 2a to form the stable benzoic acid under O2 or
air.
Under the optimized reaction conditions, we examined the
substrate scope for the base-mediated one-pot synthesis of
Table 1. Base-Mediated One-Pot Synthesis of 3,5-Diphenyl- 1,2,4-oxadiazoles, and various kinds of nitriles
(1) and
1,2,4-Oxadiazole (3a) via Sequential Reactions of Benzonitrile aldehydes (2) including aromatic nitriles, heterocyclic nitriles,
(1a) with Hydroxylamine Hydrochloride and Benzaldehyde (2a): aromatic aldehydes and heterocyclic aldehydes could be
Optimization of conditions.a
converted into the corresponding 3,5-disubstituted
oxadiazoles in moderate to good yields (Table 2). Diverse
electron-donating groups (Me, OMe; entries 2-4, 6, 11-16, 20)
and electron-withdrawing groups (Cl, Br, CF3; entries 5, 17-22)
in the substituents were also tolerated in the transformation.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 9
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
Generally, the substrates with the larger steric hindrance gave benzonitrile (1a) and butaldehyde (aliphatic aldehyde) as
View Article Online
DOI: 10.1039/C6OB01794K
the lower yields (entries 2-4, 11, 14-15). Interestingly, no extra substrates under the optimized conditions; Unfortunately,
oxidant or additive was needed in the reactions. We also Only the corresponding 4,5-dihydro-1,2,4-oxadiazole could be
carried out the one-pot synthesis of 1,2,4-oxadiazoles using obtained under N2 atmosphere.
Table 2. Base-Mediated One-Pot Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles.a
Entry
1
1
2
3
Yield (%)b
93
CHO
2
3
4
5
6
7
89
83
73
70
72
65
1a
1a
1a
1a
1a
1a
2b
H3C
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 9
ARTICLE
Journal Name
Table 2. Continued
View Article Online
DOI: 10.1039/C6OB01794K
Yield (%)b
Entry
1
2
3
8
9
80
73
79
1a
1a
1a
10
11
12
13
14
83
67
75
64
2a
2e
2h
2a
1b
1b
15
16
56
85
2a
2a
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 9
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
Table 2. Continued
View Article Online
DOI: 10.1039/C6OB01794K
Yield (%)b
Entry
1
2
3
17
18
19
80
73
57
2a
2a
2e
1g
1g
1g
20
50
2f
21
22
2h
2a
2a
66
75
23
70
a
Reaction conditions: For the first step, without exclusion of air, R1-CN (
1) (0.45 mmol), hydroxylamine hydrochloride (0.5 mmol, 34.7 mg),
o
triethylamine (TEA) (0.9 mmol, 126 μL), t-BuOH (1.5 mL), temperature (80 C), time (18 h). For the second step, R2-CHO (
2) (1.0 mmol),
Cs2CO3 (0.9 mmol, 293 mg), DMSO (1.0 mL), temperature (100 oC), time (24 h) in a Schlenk tube under N2 balloon (1 bar). b Isolated yield.
In order to investigate the reaction mechanism for the were suitable solvents. (C) Considering the Cannizzaro reaction
synthesis of 1,2,4-oxadiazoles, we performed the following of naphthaldehyde under basic condition, we conducted the
control experiments as follows (Scheme 2): (A) Reaction of 1a reaction of benzamidoxime with naphthoic acid under
with 2g provided 3g and 4g in 65% and 55% yields respectively. standard condition. However, no reaction occurred in the
(B) 3,5-Disubstituted-4,5-dihydro-1,2,4-oxadiazole (I-3) was absence of dehydrant. Furthermore, we also prepared 3,5-
first prepared according the previous procedure,6 and the diphenyl-4,5-dihydro-1,2,4-oxadiazole according to the
corresponding 1,2,4-oxadiazole 3g from I-3 was obtained in literature.6 and 3,5-diphenyl-1,2,4-oxadiazole (3a) was also
good yields in the presence of base and aldehyde under N2 obtained in good yield in the presence of base and aldehyde
balloon (1 bar), in which DMSO and 2-methoxyethanol (ME) all (Figure S1 in supporting information).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 9
ARTICLE
Journal Name
View Article Online
DOI: 10.1039/C6OB01794K
Scheme 2. (A) Base-Mediated Coupling of 1a with 2g under Standard Condition. (B) Aldehyde-Oxidized Synthesis of 3g from I-3 and
2g. (C) Reaction of Amidoxime with Benzoic Acid or Naphthoic Acid.
We have developed a simple and efficient base-mediated
OH
one-pot method for synthesis of 3,5-disubstituted 1,2,4-
N
HONH2 HCl, TEA
R1
C
N
oxadiazole derivatives. The protocol uses simple and readily
available nitriles, aldehydes and hydroxylamine hydrochloride
as the starting materiels, and the aldehydes were used as both
substrates and oxidants under basic conditions. Furthermore,
no extra oxidants or additives are needed in this
transformation. The one-pot reactions include sequential
intermolecular addition of hydroxylamine to nitrile to afford an
amidoxime; base-mediated treatment of the amidoxime with
aldehyde to form the corresponding 4,5-dihydro-1,2,4-
oxadiazole, oxidization of the 4,5-dihydro-1,2,4-oxadiazole by
another aldehyde to afford the target 1,2,4-oxadiazole in
moderate to good yields. This method can tolerate various
functional groups, and presents a direct and simple protocol
for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles.
R1
NH2
1
I
R2 CHO
2
base
N
O
OH
H
N
N
Cs2CO3
CsHCO3
R1
R2
R1
R2
N
R1
NH2
N
O
H2O
I
III
II
N
O
-
OCs+ CsCO3
N
H
R1
R2
H2O
+
+
R2
OH
R1
R2
N
N
O
R2
H
4
2
III
3
Scheme
3
Possible Mechanism for Synthesis of 1,2,4-
Oxadiazoles
These results above exhibited that benzaldehyde acted as
an oxidant besides as a substrate in this reaction; And a
possible mechanism for synthesis of 1,2,4-oxadiazoles was
proposed in Scheme 3. Firstly, intermolecular nucleophilic
addition of amino group of hydroxylamine to the cyano group
Experimental Section
General experimental procedures: The first step reaction is
carried out in air and the second step under nitrogen
atmosphere. Proton and carbon magnetic resonance spectra
(1H NMR and 13C NMR) were recorded using tetramethylsilane
(TMS) in the solvent of DMSO-d6 as the internal standard (1H
NMR: TMS at 0.00 ppm, DMSO at 2.50 ppm; 13C NMR: DMSO
at 39.52 ppm).
of R1-CN (
then treatment of
II). Deprotonation of II by base affords III, and base-mediated
reduction of the aldehyde ( ) by III gives the target compound
) leaving corresponding alcohol ( ).
1
) provides amidoxime
with forms 4,5-dihydro-1,2,4-oxadiazole
I
in the presence of TEA,8 and
I
2
(
2
General procedure for synthesis of 1,2,4-triazoles (3a-w):
(3
4
Nitrile (1) (0.45 mmol), hydroxylamine hydrochloride (0.5
mmol, 34.7 mg), triethylamine (0.9 mmol, 126 μL) and t-BuOH
(1.5 mL) were added to a 25 mL Schlenk tube charged with a
magnetic stirrer. The mixture was stirred at 80 oC for 18 h
Conclusions
without exclusion of air for the first step. Aldehyde (2) (1.0
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 9
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
mmol), Cs2CO3 (0.9 mmol, 293 mg) and DMSO (1.0 mL) were 5-(Furan-2-yl)-3-phenyl-1,2,4-oxadiazole
ARTICLE
(3h).12
Eluent:
View Article Online
added to the Schlenk tube, and the mixture was stirred at 100 petroleum ether/ethyl acetate (100:1).DYOieI:l1d0.170639m/Cg6O(B800179%4)K.
oC for another 24 h under N2 balloon (1 bar) for the second Yellow solid, m.p. 99.1-101.2 °C (lit.12 m.p. 101-103 °C). 1H
o
step. The resulting solution was concentrated by a rotary NMR (d6-DMSO, 400 MHz, 25 C) δ 8.21-8.18 (m, 1H), 8.14-
evaporator, and the residue was purified by column 8.04 (m, 2H), 7.71-7.55 (m, 4H), 6.94-6.86 (m, 1H). 13C NMR
chromatography on silica gel using petroleum ether/ethyl (d6-DMSO, 100 MHz, 25 oC) δ 168.4, 167.8, 148.9, 139.4, 132.2,
acetate as the eluent to give the desired target product (3a-w). 129.7, 127.6, 126.3, 118.2, 113.6. APCI-MS [M+H]+ m/z 213.1.
3,5-Diphenyl-1,2,4-oxadiazole (3a).5a Eluent: petroleum 3-Phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole (3i).13 Eluent:
ether/ethyl acetate (100:1). Yield 93 mg (93 %). White solid, petroleum ether/ethyl acetate (100:1). Yield 75 mg (73 %).
1
m.p. 108.5-110.1 °C (lit.5a m.p. 104.9-106.1 °C). H NMR (d6- white solid, m.p. 106-108 °C (lit.13 m.p. 108-109 °C). 1H NMR
o
DMSO, 400 MHz, 25 oC) δ 8.25-8.20 (m, 2H), 8.17-8.11 (m, 2H), (d6-DMSO, 400 MHz, 25 C) δ 8.20-8.01 (m, 4H), 7.71-7.54 (m,
o
7.81-7.75 (m, 1H), 7.74-7.61 (m, 5H). 13C NMR (d6-DMSO, 100 3H), 7.43-7.34 (m, 1H). 13C NMR (d6-DMSO, 100 MHz, 25 C) δ
o
MHz, 25 C) δ 175.9, 168.7, 133.8, 132.1, 130.0, 129.7, 128.3, 171.5, 168.5, 134.6, 133.3, 132.2, 129.7, 127.6, 126.3, 124.9.
127.5, 126.6, 123.8. APCI-MS [M+H]+ m/z 223.1.
APCI-MS [M+H]+ m/z 229.05.
3-Phenyl-5-(p-tolyl)-1,2,4-oxadiazole (3b).5f Eluent: petroleum 3-Phenyl-5-(pyridin-2-yl)-1,2,4-oxadiazole
(3j).14
Eluent:
ether/ethyl acetate (100:1). Yield 95 mg (89 %). White solid, petroleum ether/ethyl acetate (5:1). Yield 79 mg (79 %). White
m.p. 115.0-117.1 °C (lit.5f m.p. 114-116 °C). 1H NMR (d6-DMSO, solid, m.p. 114.0-116.2 °C (lit.14 m.p. 116 °C). 1H NMR (d6-
o
400 MHz, 25 C) δ 8.18-8.06 (m, 4H), 7.62 (t, J = 6.3 Hz, 3H), DMSO, 400 MHz, 25 oC) δ 8.97-8.84 (m, 1H), 8.36 (d, J = 7.8 Hz,
7.24-7.14 (m, 2H), 3.89 (s, 3H). 13C NMR (d6-DMSO, 100 MHz, 1H), 8.19-8.10 (m, 3H), 7.80-7.72 (m, 1H), 7.70-7.59 (m, 3H).
o
25 C) δ 175.7, 168.5, 163.5, 132.0, 130.3, 129.6, 127.5, 126.7, 13C NMR (d6-DMSO, 100 MHz, 25 oC) δ 174.9, 168.8, 151.0,
116.1, 115.4, 56.0. APCI-MS [M+H]+ m/z 237.1.
143.2, 138.6, 132.2, 129.8, 127.9, 127.6, 126.4, 124.9. APCI-MS
3-Phenyl-5-(m-tolyl)-1,2,4-oxadiazole (3c).9 Eluent: petroleum [M+H]- m/z 224.1.
ether/ethyl acetate (100:1). Yield 88 mg (83 %). White solid, 5-Phenyl-3-(p-tolyl)-1,2,4-oxadiazole (3k).15 Eluent: petroleum
1
m.p. 71.2-72.0 °C (lit.9 m.p. 74-75 °C). H NMR (d6-DMSO, 400 ether/ethyl acetate (100:1). Yield 88 mg (83 %) .White solid,
o
1
MHz, 25 C) δ 8.16-8.06 (m, 2H), 8.04-7.93 (m, 2H), 7.70-7.49 m.p. 101.0-102.1°C (lit.15 m.p. 98-100 °C). H NMR (d6-DMSO,
(m, 5H), 2.44 (s, 3H). 13C NMR (d6-DMSO, 100 MHz, 25 C) δ 400 MHz, 25 C) δ 8.30-8.23 (m, 2H), 8.07 (d, J = 8.1 Hz, 2H),
o
o
175.9, 168.6, 139.5, 134.4, 132.0, 129.8, 129.7, 128.6, 127.5, 7.86-7.70 (m, 3H), 7.49 (d, J = 7.9 Hz, 2H), 2.48 (s, 3H). 13C NMR
126.6, 125.5, 123.7, 21.2. APCI-MS [M+H]+ m/z 237.1.
(d6-DMSO, 100 MHz, 25 oC) δ 174.5 , 167.5, 140.9, 132.6, 129.1,
3-Phenyl-5-(o-tolyl)-1,2,4-oxadiazole (3d).9 Eluent: petroleum 128.8, 127.2, 126.3, 122.7, 122.6, 20.4. APCI-MS [M+H]+ m/z
ether/ethyl acetate (100:1). Yield 78 mg (73 %). White solid, 237.1.
1
m.p. 55.2-55.5 °C (lit.9 m.p. 53-54 °C). H NMR (d6-DMSO, 400 5-(4-Chlorophenyl)-3-(p-tolyl)-1,2,4-oxadiazole (3l).16 Eluent:
o
MHz, 25 C) δ 8.16-8.08 (m, 3H), 7.68-7.56 (m, 4H), 7.54-7.43 petroleum ether/ethyl acetate (100:1). Yield 82 mg (67 %).
o
(m, 2H), 2.73 (s, 3H). 13C NMR (d6-DMSO, 100 MHz, 25 C) δ White solid, m.p. 142.2-143.0 °C(lit.16 m.p. 138-140 °C). 1H
176.3, 168.3, 139.0, 133.1, 132.4, 132.0, 130.3, 129.7, 127.5, NMR (d6-DMSO, 400 MHz, 25 oC) δ 8.22 (d, J = 8.5 Hz, 2H), 8.01
127.1, 126.7, 123.0, 21.8. APCI-MS [M+H]+ m/z 237.1.
(d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.0 Hz,
o
5-(4-Chlorophenyl)-3-phenyl-1,2,4-Oxadiazole (3e).10 Eluent: 2H), 2.44 (s, 3H). 13C NMR (CDCl3, 100 MHz, 25 C) δ 173.5,
petroleum ether/ethyl acetate (100:1). Yield 81 mg (70 %). 167.9, 140.5, 138.0, 128.5, 128.4, 128.3, 126.3, 122.8, 121.7.
White solid, m.p. 121.1-122.0 °C(lit.10 m.p 121-122 °C). 1H NMR APCI-MS [M+H]+ m/z 271.1.
o
(d6-DMSO, 400 MHz, 25 C) δ 8.27-8.18 (m, 2H), 8.15-8.07 (m, 5-(Furan-2-yl)-3-(p-tolyl)-1,2,4-oxadiazole
(3m).
Eluent:
2H), 7.80-7.73 (m, 2H), 7.69-7.57 (m, 3H). 13C NMR (CDCl3, 100 petroleum ether/ethyl acetate (100:1). Yield 76 mg (75 %).
o
MHz, 25 C) δ 173.7, 167.9, 138.1, 130.2, 128.4, 128.3, 127.8, Yellow solid, m.p. 95.1-96.2 °C. H NMR (d6-DMSO, 400 MHz,
1
126.4, 125.6, 121.6, APCI-MS [M+H]+ m/z 257.1.
25 oC) δ 8.22-8.17(m, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.68-7.62 (m,
5-(4-Methoxyphenyl)-3-phenyl-1,2,4-Oxadiazole (3f).5o Eluent: 1H), 7.41 (d, J = 7.9 Hz, 2H), 6.92-6.86 (m, 1H), 2.40 (s, 3H). 13
C
o
petroleum ether/ethyl acetate (6:1). Yield 82 mg (72 %). White NMR (d6-DMSO, 100 MHz, 25 C) δ 168.4, 167.6, 148.8, 142.2,
solid, m.p. 97.1-99.0 °C(lit.5o m.p. 102-104 °C). 1H NMR (d6- 139.5, 130.3, 127.5, 123.5, 118.0, 113.6, 21.5. APCI-MS [M+H]+
DMSO, 400 MHz, 25 oC) δ 8.20-8.07 (m, 4H), 7.64 (t, J = 6.2 Hz, m/z 226.2. Anal. Calcd. for C13H10N2O2: C, 69.02; H, 4.46; N,
3H), 7.26-7.17 (m, 2H), 3.91 (s, 3H). 13C NMR (d6-DMSO, 100 12.38. Found C, 68.89; H, 4.48; N, 12.32.
o
MHz, 25 C) δ 175.7, 168.5, 163.5, 132.0, 130.4, 129.6, 127.5, 5-Phenyl-3-(m-tolyl)-1,2,4-oxadiazole
(3n).5j
Eluent:
126.7, 116.1, 115.4, 56.1. APCI-MS [M+H]+ m/z 253.1.
petroleum ether/ethyl acetate (100:1). Yield 68 mg (64 %).
1
5-(Naphthalen-1-yl)-3-phenyl-1,2,4-oxadiazole (3g).11 Eluent: White solid, m.p. 85.1-85.5 °C (lit.5j mp 87-88 °C). H NMR (d6-
o
petroleum ether/ethyl acetate (200:1). Yield 80 mg (65 %). DMSO, 400 MHz, 25 C) δ 8.24-8.15(m, 2H), 7.96-7.86 (m, 2H),
White solid, m.p. 101.5-102 °C (lit.11 m.p. 101-102 °C). 1H NMR 7.79-7.63 (m, 3H), 7.54-7.40 (m, 2H), 2.43 (s, 3H). 13C NMR (d6-
o
o
(d6-DMSO, 400 MHz, 25 C) δ 9.17 (d, J = 8.4 Hz, 1H), 8.45 (d, J DMSO, 100 MHz, 25 C) δ 175.7, 168.7, 139.1, 133.7, 132.7,
= 7.0 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.26-8.09 (m, 3H), 7.88- 130.0, 129.6, 128.3, 127.9, 126.5, 124.7, 123.8, 21.3. APCI-MS
7.57 (m, 6H). 13C NMR (d6-DMSO, 100 MHz, 25 oC) δ 175.8, [M+H]+ m/z 237.1.
168.6, 134.5, 133.9, 132.2, 130.6, 129.8, 129.5, 129.1, 127.6, 5-Phenyl-3-(o-tolyl)-1,2,4-oxadiazole (3o).17 Eluent: petroleum
127.4, 126.7, 125.8, 125.5, 120.1. APCI-MS [M+H]+ m/z 273.1.
ether/ethyl acetate (100:1). Yield 60 mg (56 %). White solid,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 9
ARTICLE
Journal Name
1
m.p. 78.5-79.0 °C (lit.17 mp 79-81 °C). H NMR (d6-DMSO, 400 3-(4-Chlorophenyl)-5-phenyl-1,2,4-Oxadiazole(3vV).ie5wf ArticEleluOennlinte:
o
MHz, 25 C) δ 8.25-8.17 (m, 2H), 8.07-7.99 (m, 1H), 7.79-7.64 petroleum ether/ethyl acetate (100:1).DYOieI:l1d0.180739m/Cg6O(B705179%4)K.
(m, 3H), 7.55-7.39 (m, 3H), 2.62 (s, 3H). 13C NMR (d6-DMSO, White solid, m.p. 109.0-110.1 °C (lit.5f m.p. 107-109 °C). 1H
o
100 MHz, 25 C) δ 174.86, 169.3, 138.0, 133.8, 131.9, 131.4, NMR (d6-DMSO, 400 MHz, 25 C) δ 8.25-8.20 (m, 2H), 8.17-
o
130.2, 130.0, 128.4, 126.7, 125.9, 123.8, 22.1. APCI-MS [M+H]+ 8.12 (m, 2H), 7.82-7.76 (m, 1H), 7.75-7.68 (m, 4H). 13C NMR
m/z 237.1.
(d6-DMSO, 100 MHz, 25 oC) δ 176.0, 167.9, 136.8, 133.9,
3-(4-Methoxyphenyl)-5-phenyl-1,2,4-oxadiazole (3p).18 Eluent: 130.0,129.9, 129.3, 128.4, 125.4, 123.7. APCI-MS [M+H]+ m/z
petroleum ether/ethyl acetate (100:1). Yield 97 mg (85 %). 257.1.
1
White solid, m.p. 101.0-102.1 °C (lit.18 m.p. 98-99 °C). H NMR 5-Phenyl-3-(pyridin-4-yl)-1,2,4-oxadiazole (3w).20 Eluent:
(d6-DMSO, 400 MHz, 25 oC) δ 8.23-8.15 (m, 2H), 8.04 (d, J = 8.8 petroleum ether/ethyl acetate (5:1). Yield 70 mg (70 %). White
Hz, 2H), 7.80-7.63 (m, 3H), 7.15 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H). solid, mp 145.1-147.0 °C (lit.20 mp 148 °C). 1H NMR (CDCl3, 400
13C NMR (d6-DMSO, 100 MHz, 25 oC) δ 175.5, 168.4, 162.2, MHz, 25 oC) δ 8.81-8.65(m, 2H), 8.22-8.07 (m, 2H), 8.01-7.91(m,
133.7, 130.0, 129.2, 128.3, 123.9, 118.8, 115.1, 55.8. APCI-MS 2H), 7.67-7.39 (m, 3H). 13C NMR (CDCl3, 100 MHz, 25 oC) δ
[M+H]+ m/z 253.1.
175.4, 166.3, 149.6, 133.3, 132.1, 128.1, 127.1, 122.7, 120.2.
APCI-MS [M+H]+ m/z 224.1.
5-Phenyl-3-[4-(trifluoromethyl)phenyl]-1,2,4-
Oxadiazole(3q) 17
.
Eluent: petroleum ether/ethyl acetate Synthesis of 3g from I-3: The I-3 (0.45 mmol, 123 mg),
(100:1). Yield 104 mg (80 %), White solid, m.p. 125-127 °C naphthaldehyde ( ) (0.5 mmol, 68 μL), Cs2CO3 (1 mmol, 326
2
o
(lit.17 mp 93-95 °C). 1H NMR (d6-DMSO, 400 MHz, 25 C) δ 8.28 mg), DMSO (1 mL) were added to the Schlenk tube, and the
(d, J = 8.1 Hz, 2H), 8.23-8.16 (m, 2H), 7.96 (d, J = 8.3 Hz, 2H), mixture was stirred at 100 oC for another 24 h under N2
7.81-7.73 (m, 1H), 7.68 (t, J = 7.5 Hz, 2H). 13C NMR (d6-DMSO, balloon (1 bar). The resulting solution was concentrated by a
o
100 MHz, 25 C) δ 176.3, 167.7, 134.0, 131.9 (q), 130.1, 128.4, rotary evaporator, and the residue was purified by column
128.4, 126.6 (q). APCI-MS [M+H]+ m/z 291.2.
chromatography on silica gel using petroleum ether/ethyl
3-(4-Bromophenyl)-5-phenyl-1,2,4-Oxadiazole (3r).5f Eluent: acetate as the eluent to give the desired target product 3g
petroleum ether/ethyl acetate (100:1). Yield 99 mg (73 %). (100 mg, 82 %) and by-product 1-Naphthalenemethanol 4b (42
White solid, m.p. 110.1-111.2 °C (lit.5f m.p. 110-112 °C). 1H mg, 59 %).21 Eluent: petroleum ether/ethyl acetate (1:1).
1
NMR (d6-DMSO, 400 MHz, 25 oC) δ 8.12 (d, J = 7.3 Hz, 2H), 7.96 White solid, m.p. 62.1-64.0 °C (lit.21 m.p. 62-63 °C). H NMR
(d, J = 8.4 Hz, 2H), 7.80-7.68 (m, 3H), 7.68-7.60 (m, 2H). 13C (CDCl3, 400 MHz, 25 oC) δ 7.95 (d, J = 8.4 Hz, 1H), 7.79-7.64 (m,
o
NMR (d6-DMSO, 100 MHz, 25 C) δ 175.9, 167.9, 133.8, 132.7, 2H), 7.46-7.26 (m, 4H), 4.95 (s, 2H), 2.21 (s, 1H). 13C NMR
o
129.9, 129.3, 128.3, 125.7, 125.6, 123.6. APCI-MS [M+H]+ m/z (CDCl3, 100 MHz, 25 C) δ 135.1, 132.6, 130.1, 127.5, 127.4,
301.1.
125.2, 124.7, 124.3, 124.2, 122.5, 62.4. APCI-MS [M-H]- m/z
157.0.
3-(4-Bromophenyl)-5-(4-chlorophenyl)-1,2,4-Oxadiazole(3s).
Eluent: petroleum ether/ethyl acetate (100:1). Yield 86 mg
1
(57 %). White solid, m.p. 131.1-132.0 °C. H NMR (CDCl3, 400
o
MHz, 25 C) δ 8.13-8.04 (m, 2H), 8.01-7.93 (m, 2H), 7.62-7.55
Acknowledgements
(m, 2H), 7.50-7.43 (m, 2H). 13C NMR (CDCl3, 100 MHz, 25 C) δ
o
This work was supported by National Natural Science
Foundation of China (Grant No. 21502042, 21204018),
Scientific Research Key Project Fund of Henan Provincial
Education Department (Grant No. 15A150041), Developing
Program of Natural Science of Henan Province (No.
142300410122), Scientific Research Fund of Henan University
(No. 2013YBZR008).
174.0, 167.3, 138.3, 131.2, 128.6, 128.4, 128.0, 124.9, 124.7,
121.5. APCIMS [M+H]+ m/z 335.1. Anal. Calcd. for
C14H8BrClN2O: C, 50.11; H, 2.40; N, 8.35. Found C, 49.86; H,
2.46; N, 8.43.
3-(4-Bromophenyl)-5-(4-methoxyphenyl)-1,2,4-
Oxadiazole(3t) 19
Eluent: petroleum ether/ethyl acetate
.
(100:1). Yield 75 mg (50 %). White solid, m.p. 88.5-92.0 °C
(lit.19 mp 88-91 °C). 1H NMR (CDCl3, 400 MHz, 25 oC) δ 8.07 (d, J
= 8.8 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H),
6.96 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H). 13C NMR (CDCl3, 100 MHz,
References
1
M. Carbone, Y. Li, C. Irace, E. Mollo, F. Castelluccio, A. Di
Pascale, G. Cimino, R. Santamaria, Y. W. Guo and M.
Gavagnin, Org. Lett., 2011, 13, 2516.
o
25 C) δ 175.8, 168.1, 163.2, 132.1, 130.1, 129.0, 126.0, 125.6,
116.6, 114.5, 55.6. APCI-MS [M+H]+ m/z 331.1.
2
(a) A. Pace, S. Buscemi, A. P. Piccionello and I. Pibiri, Adv.
Heterocycl. Chem., 2015, 116, 85; (b) A. V. Gulevich, A. S.
Dudnik, N. Chemyak and V. Gevorgyan, Chem. Rev., 2013,
3-(4-Bromophenyl)-5-(2-furanyl)-1,2,4-Oxadiazole (3u). Eluent:
petroleum ether/ethyl acetate (100:1). Yield 86 mg (66 %).
1
White solid, m.p. 109-111°C. H NMR (d6-DMSO, 400 MHz, 25
113, 3084; (c) J. Bostrӧm, A. Hogner, A. Llinàs, E. Wellner and
oC) δ 8.25 (d, J = 1.1 Hz, 1H), 8.09-8.01 (m, 2H), 7.92-7.81 (m,
2H), 7.72 (d, J = 3.6 Hz, 1H), 7.00-6.90(m, 1H). 13C NMR (d6-
A. T. Plowright, J. Med. Chem., 2012, 55, 1817; (d) N. P. Rai, V.
K. Narayanaswamy, T. Govender, B. K. Manuprasad, S.
Shashikanth and P. N. Arunachalam, Eur. J. Med. Chem.,
2010, 45, 2677; (e) Y. -J. Chen, S. -C. Yang, C. -C. Tsai, K.-C.
Chang, W. -H. Chuang, W. -L. Chu, V. Kovalev and W. -S.
Chung, Chem. Asian J., 2015, 10, 1025; (f) O. Francescangeli,
V. Stanic, S. I. Torgova, A. Strigazzi, N. Scaramuzza, C. Ferrero,
o
DMSO, 100 MHz, 25 C) δ 167.9, 167.7, 149. 5, 139.3, 132.8,
129.5, 125.8, 125.5, 118.4, 113.6. APCI-MS [M+H]+ m/z 291.0.
Anal. Calcd. for C12H7BrN2O2: C, 49.51; H, 2.42; N, 9.62. Found
C, 49.59; H, 2.38; N, 9.67.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 9
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
I. P. Dolbnya, T. M. Weiss, R. Berardi, L. Muccioli, S. Orlandi
and C. Zannoni, Adv. Funct. Mater., 2009, 19, 2592.
View Article Online
DOI: 10.1039/C6OB01794K
3
(a) R. Sarges, H. R. Howord, R. G. Browne, L. A. Label, P. A.
Seymourand and B. K. Koe, J. Med. Chem., 1990, 33, 2240; (b)
E. De Clercq, J. Clin. Virol., 2004, 30, 115; (c) A. R. Bhat, G. V.
Bhat and G. G. Shenoy, J. Pharm. Pharmacol., 2001, 53, 267;
(d) B. S. Holla, K. N. Poorjary, B. S. Rao and M. K. Shivananda,
Eur. J. Med. Chem., 2002, 3, 511; (e) Y. Naito, F. Akahoshi, S.
Takeda, T. Okada, M. Kajii, H. Nishimura, M. Sugiura, C.
Fukaya and Y. Kagitani, J. Med. Chem., 1996, 39, 3019.
(a) L. M. Lima and E. J. Barreiro, Curr. Med. Chem., 2005, 12,
4
5
23; (b) S. Borg, R. C. Vollinga, M. Labarre, K. Payza, L.
Terenius and K. Luthman, J. Med. Chem., 1999, 42, 4331.
(a) J. K. Augustine, V. Akabote, S. G. Hegde and P.
Alagarsamy, J. Org. Chem., 2009, 74, 5640; (b) D. S. Bolotin, K.
I. Kulish, N. A. Bokach, G. L. Starova, V. V. Gurzhiy and V. Y.
Kukushkin, Inorg. Chem., 2014, 53, 10312; (c) Y. Wang, R. L.
Miller, D. R. Sauer and S. W. Djuric, Org. Lett., 2005, 7, 925;
(d) M. D. Evans, J. Ring, A. Schoen, A. Bell, P. Edwards, D.
Berthelot, R. Nicewonger and C. M. Baldino, Tetrahedron
Lett., 2003, 44, 9337; (e) S. Kandre, P. R. Bhagat, R. Sharma
and A. Gupte, Tetrahedron Lett., 2013, 54, 3526; (f) B.
Kaboudin and L. Malekzadeh, Tetrahedron Lett., 2011, 52
,
6424; (g) K. K. D. Amarasinghe, M. B. Maier, A. Srivastava and
J. L. Gray, Tetrahedron Lett., 2006, 47, 3629; (h) B. Kaboudin
and F. Saadati, Tetrahedron Lett., 2007, 48, 2829; (i) J. Lessel,
Arch. Pharm., 1993, 326, 383; (j) R. M. Srivastava, M. V. S.
Freire, A. S. S. C. Chaves and T. M. Beltrao, J. Heterocyclic
Chem., 1987, 24, 101; (k) M. Okimoto and Y. Takahashi, Bull.
Chem. Soc. Jpn., 2003, 76, 427; (l) R. M. Srivastava, A. A. Lima,
O. S. Viana, M. J. C. Silva, M. T. J. A. Catanho and J. O. F.
Morais, Bioorgan. Med. Chem., 2003, 11, 1821; (m) B. I.
Buzykin and O. A. Kharitonova, Russ. J. Gen. Chem. (Engl.
Transl.), 1993, 63, 1829; (n) D. B. Repke, H. P. Albrecht and J.
G. Moffat, J. Org. Chem., 1975, 40, 2481; (o) M. Adib, A. H.
Jahromi, N. Tavoosi, M. Mahdavi and H. R. Bijanzadeh,
Tetrahedron Lett., 2006, 47, 2965;
6
(a) H. Xu, S. -F. Li, H. -X. Liu, H. Fu and Y. -Y. Jiang, Chem.
Commun., 2010, 46, 7617; (b) H. Xu and H. Fu, Chem. Eur. J.,
2012, 18, 1180; (c) H. Xu, Y. -Y. Jiang and H. Fu, Synlett, 2013,
24, 125; (d) H. Xu, S. Ma, Y. -Q. Xu, L. -X. Bian, T. Ding, X. -X.
Fang, W. -K. Zhang and Y. -R. Ren, J. Org. Chem., 2015, 80
1789.
,
7
8
Y. -F. Wang, F. -L. Zhang and S. Chiba, Org. Lett., 2013, 15
2842.
,
(a) A. R. Burns, J. H. Kerr, W. J. Kerr, J. Passmore, L. C.
Paterson and A. J. B. Watson, Org. Biomol. Chem., 2010,
8
,
2777; (b) R. M. Srivastava, M. C. Pereira, W. W. M. Foustino,
K. Coutinho, J. V. dos Anjos and S. J. de Melo, Monatsh.
Chem., 2009, 140, 1319.
9 G. Leandri, Ann. Chim. (Rome, Italy), 1957, 47, 376.
10 P. Molina, Synthesis, 1986, 843.
11 S. Chiou, J. Heterocyclic Chem., 1989, 26, 125.
12 S. Baykov, T. Sharonova, A. Osipyan, S. Rozhkov, A. Shetnev
and A. Smirnov, Tetrahedron Lett., 2016, 57, 2898.
13 P. D. Parker and J. G. Pierce, Synthesis, 2016, 48, 1902.
14 S. Robev, Dokl. Bulg. Akad. Nauk., 1977, 30, 1031.
15 V. Santagada, Bioorg. Med. Chem. Lett., 2004, 14, 4491.
16 S. Rostamizadeh, Tetrahedron, 2010, 66, 494.
17 W. Guo, K. -B. Huang, F. -H. Ji, W. -Q. Wu and H. -F. Jiang,
Chem. Commun., 2015, 51, 8857.
18 D. Grant, J. Org. Chem., 2008, 73, 7219.
19 J. V. Dos Anjos, Lett. Org. Chem., 2007,
20 C. S. Naveena, Org. Chem. Indian J. 2008,
4
, 393.
, 333.
4
21 B. Z. Zeynizadeh, Naturforsch. B, 2004, 59, 704.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins