An efficient method for the one-pot tandem synthesis of 3,5-disubstituted-1,2,4-oxadiazoles from benzyl halides

Article abstract of DOI:10.3184/174751915X14353363823928

The first example of a one-pot tandem approach for the synthesis of 3,5-disubstituted-1,2,4-oxadiazole derivatives from benzyl halides and amidoxime is reported. Derivatives of 3,5-disubstituted 1,2,4-oxadiazole were obtained in excellent yields under mil

Full text of DOI:10.3184/174751915X14353363823928

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 JULY, 373–375
RESEARCH PAPER 373
An efficient method for the one-pot tandem synthesis of 3,5-disubstituted-
1,2,4-oxadiazoles from benzyl halides
Behrooz Mirza
Department of Applied Chemistry, Faculty of Science, Islamic Azad University, South Tehran Branch, Tehran, Iran
The first example of a one-pot tandem approach for the synthesis of 3,5-disubstituted-1,2,4-oxadiazole derivatives from benzyl halides
and amidoxime is reported. Derivatives of 3,5-disubstituted 1,2,4-oxadiazole were obtained in excellent yields under mild conditions using
DMSO in the absence of an additional oxidant. Benzyl bromides bearing a range of substituents proved to be suitable substrates for this
method which provides a very efficient and convenient application of the Kornblum oxidation.
Keywords: 3,5-disubstituted-1,2,4-oxadiazoles, benzyl halides, Kornblum oxidation, one-pot tandem reaction
The unique biological activity and remarkable chemical
structure of heterocyclic compounds containing the
1,2,4-oxadiazole scaffold, has received considerable attention
(Fig. 1).1 1,2,4-Oxadiazole derivatives possess different
pharmacological activities including antitumor, antibacterial,
analgesic, anti-inflammatory, anticancer, monoamine oxidase
inhibition, tyrosine kinase inhibition, muscarinic agonism, and
histamine H3 antagonism.2-10 The 1,2,4-oxadiazole ring system
is also widely reported as a β amyloid-imaging probe that plays
an important role in Alzheimer’s drug discovery,11 and peptide
building blocks.12 This scaffold appears in several drugs and
drug leads such as the metabotropic glutamate subtype 5 (mGlu
5) receptor,13 and S1P1 agonist.14 Consequently a new synthetic
route to 3,5 di-substituted 1,2,4-oxadiazoles, involving a rapid,
mild, efficient, and one-pot method is desirable.
O-Acylation of an amidoxime by an activated carbonyl
compounds in the first step followed by a second step of
cyclodehydration, is a standard method for the synthesis of
1,2,4-oxadiazole.15 There are many reports an improving the
chemical yields, conditions, and reaction time of this method.16
However, these methods suffer from the disadvantages such
as extended reaction times, low yields, and harsh conditions.
To overcome the drawbacks, different activated carbonyl
compounds have been used for the O-acylation step including
esters, acid chlorides, anhydrides and aldehydes.17-20
novel and straightforward approach for the preparation of
3,5-disubstituted 1,2,4-oxadiazoles which involves an in situ
oxidation–cyclocondensation sequence starting from benzyl
bromides (Scheme 1).
The selective oxidation of the benzylic positions of arenes to
the carbonyl compounds is an important step in the synthesis of
bioactive compounds.23 Several methods have been developed
to carry out the conversion of halides to the corresponding
aldehydes, such as the Kornblum reaction (DMSO/NaHCO3).24
The mechanism of the conventional Kornblum oxidation
involves an alkoxy sulfonium ion, which in the presence of a
base such as K2CO3, undergoes elimination to form the desired
aldehyde.
In the first step a series of benzyl bromides, under mild
Kornblum oxidation conditions, were reacted with DMSO in
the presence of K2CO3 as basic catalyst both under microwave
irradiation and conventional heating. The striking observation
was that the reaction under heating at 110 °C was considerably
accelerated as compared to that under classical conditions using
microwaves irradiation.
Thus, under modified Kornblum oxidation conditions, benzyl
bromide substrates 1 in DMSO in the presence of K2CO3 at 110
°C were converted into the corresponding aldehydes in excellent
yields. Subsequently the aldehydes were prepared in situ without
further purification, and condensed with different amidoximes
at 110 °C to form the corresponding 3,5-disubstituted
1,2,4-oxadiazole derivatives 3a–h in acceptable yields of 73–
82%.Treatment of the benzylic substrate 1 with DMSO leads
to an alkoxy sulfonium ion 4 which in the presence of K2CO3
undergo elimination of dimethyl sulfide (DMS) to form the
corresponding aldehyde 5.25,26 Next, the resulting aldehyde
condenses with the amine and a further molecule of DMSO
may add to this to form a sulfoxonium salt. In the third step
this loses the former aldehyde proton and dimethylsulfide to
form an amide. Next the hydroxyl group of the oxime adds to
the carbonyl group of the amide. Finally loss of water gives the
However, to our knowledge there are no reports on the
use of aryl halides as starting materials in the synthesis of
1,2,4-oxadiazole synthesis in a one-pot manner. Therefore, we
have evaluated the feasibility of synthesising 1,2,4-oxadiazoles
from amidoximes and commercially available benzyl halides
under mild conditions.
Results and discussion
As a part of our efforts to develop new route for the
synthesis of biologically active heterocyclic compounds
from readily available building blocks,21,22 we describe a
H
N
O
H
N
O
NOH
N
O
N
Ar2
Ar2
N
N
N
O
2
NH2
O
Ar1
Ar1
Br
N
H2N
Tryptase inhibitor
O
N
DMSO, K2CO3,110 oC
1
3a-h
5-HT-antagonist
Fig. 1 Two examples of biologically active 1,2,4-oxadiazoles.
* Correspondent. E-mail: b_mirza@azad.ac.ir
Scheme 1 Synthesis of 3,5-disubstituted-1,2,4-oxadiazole derivatives.

374 JOURNAL OF CHEMICAL RESEARCH 2015
S
K2CO3
-DMS
S
CHO
O
Ar1
Br
Ar1
O
Ar1
OH
5
4
1
N
2
Ar2
NH2
CH3
OH
HO
S+
H
O
N
O
N
O
CH3
N
OH
Ar1
-DMS
Ar2
N
H
Ar1
N
H
Ar2
N
H
Ar1
Ar2
8
7
6
-H2O
O
N
N
Ar1
Ar2
3
Scheme 2 The proposed mechanism.
Table 1 Synthesis of 3,5-disubstituted-1,2,4-oxadiazole derivatives 3a–h
500, using TMS as an internal standard. The elemental analysis was
performed with an Elementar Analysen system GmbH VarioEL CHNS
mode. All reagents and solvents were purchased from Aldrich and
Merck, and used without any purification.
Entry
Ar1
Ph
Ar2
Ph
4-CH3–C6H4
Ph
3-NO2–C6H4
4-Cl–C6H4
4-Cl–C6H4
4-CH3–C6H4
4-F–C6H4
Yield/%a Melting point/°C (lit.)
1
2
3
4
5
6
7
8
80
77
75
73
82
78
80
76
106–108(109–110) 27
134–135(135–136) 28
120–121(118–119) 29
153–154(156–157) 30
135–137(138–140) 31
180–182(183–185) 32
143–144(145–146) 33
175–176(177–179) 34
4-CH3–C6H4
4-Cl–C6H4
2-Cl–C6H4
4-CH3–C6H4
4-Cl–C6H4
2,4-Cl2C6H3
4-Br–C6H4
Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles derivatives 3a–h;
general procedure
A mixture of benzyl bromide 1 (1 mmol) and K2CO3 (1.5 mmol) in
dimethyl sulfoxide (DMSO) (1 mL) was stirred for 4 h at 110 °C. Then,
benzamidoxime 2 (1 mmol) were added to the reaction mixture and
stirring was continued at 110 °C for 4 h. The reaction mixture was cooled
to room temperature and H2O (3 mL) was added. The precipitate was
filtered, washed with H2O (2 mL) and dried. The crude products were
purified by column chromatography using diethyl ether/ethyl acetate
(5:1) as an eluent to give pure 3,5-diphenyl-1,2,4-oxadiazole 3a–h.
3,5-Diphenyl-1,2,4-oxadiazole (3a): Colourless crystals; m.p
106–108 °C; 1H NMR (500 MHz, CDCl3): δ (ppm): 7.48–7.57 (m, 5H),
7.60 (t, J = 7.1 Hz, 1H), 8.20 (d, J = 7.5 Hz, 2H), 8.28 (d, J = 7.8 Hz,
2H); 13C NMR (125 MHz, CDCl3): δ (ppm): 125.1, 126.4, 127.4, 128.2,
128.6, 129.7, 131.3, 132.8, 168.9, 175.5.
3,5-Di-p-tolyl-1,2,4-oxadiazole (3b): Colourless crystals; m.p
134–135 °C; 1H NMR (500 MHz, CDCl3): δ (ppm): 2.35 (s, 3H), 2.40
(s, 3H), 7.24 (d, J = 7.5 Hz, 2H), 7.28 (d, J = 7.7 Hz, 2H), 8.05 (d, J = 7.7
Hz, 2H), 8.16 (d, J = 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 21.5,
21.6, 122.2, 126.3, 127.1, 128.4, 129.4, 129.6, 141.2, 143.2, 168.7, 175.5.
5-(4-Chlorophenyl)-3-phenyl-1,2,4-oxadiazole (3c): Colourless
crystals; m.p 120–121 °C; 1H NMR (500 MHz, CDCl3): δ (ppm):
7.33–7.51 (m, 5H), 8.22 (d, J = 7.7 Hz, 2H), 8.38 (d, J = 7.4, 2H);
13C NMR (125 MHz, CDCl3): δ (ppm): 121.3, 125.7, 126.4, 129.8, 129.9,
130.4, 131.1, 138.1, 165.5, 171.3.
aIsolated yield after recrystallisation.
N=C of the 3,5-disubstituted 1,2,4-oxadiazoles 3a–h in good
yields (Scheme 2).
In this method, the starting materials were completely
converted to the corresponding products within 6–8 h. All the
products were characterised by melting point determination and
confirmed by 1H and 13C NMR spectral data (Table 1).
In conclusion, we have shown that 3,5-disubstituted-1,2,4-
oxadiazole derivatives can be simply synthesised thorough
an in situ oxidation–cyclodehydration sequence starting from
benzyl halides and different amidoximes. The reaction was
accomplished in the presence of DMSO and K2CO3 at 110
°C, without using additional reagents or catalysts. Some of
the principal synthetic benefits of this method are the mild
conditions, easy experimental installation, easy isolation of the
products, and the high yields. The simplicity of this procedure
makes it an interesting alternative to other approaches.
5-(2-Chlorophenyl)-3-(3-nitrophenyl)-1,2,4-oxadiazole (3d): Yellow
solid; m.p 153–154 °C; 1H NMR (500 MHz, CDCl3): δ (ppm): 7.59 (d,
J = 8.0 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.82
(t, J = 7.6 Hz, 1H), 8.18 (d, J = 7.4 Hz, 1H), 8.32–8.80 (m, 2H), 8.86 (s,
1H); 13C NMR (125 MHz, CDCl3): δ (ppm): 121.5, 123.5, 124.1, 126.3,
127.9, 129.8, 130.4, 131.8, 132.3, 132.5, 133.7, 150.2, 167.3, 175.2.
Experimental
Melting points were taken on a Kofler hot stage apparatus and are
1
uncorrected. H and 13C NMR spectrum was recorded on Bruker FT-

JOURNAL OF CHEMICAL RESEARCH 2015 375
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Received 15 March 2015; accepted 2 June 2015
Paper 1503249 doi: 10.3184/174751915X14353363823928
Published online: 9 July 2015
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