Microwave-assisted efficient, one-pot, three-component synthesis of 3,5-disubstituted 1,2,4-oxadiazoles under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2006.02.102

A novel synthesis of 1,2,4-oxadiazoles is described from a one-pot, three-component reaction between nitriles, hydroxylamine, and aldehydes under microwave irradiation and solvent-free conditions in excellent yields.

Full text of DOI:10.1016/j.tetlet.2006.02.102

Tetrahedron Letters 47 (2006) 2965–2967
Microwave-assisted efficient, one-pot, three-component synthesis
of 3,5-disubstituted 1,2,4-oxadiazoles under solvent-free conditions
Mehdi Adib,a,* Amin Haghighat Jahromi,a Narjes Tavoosi,b Mohammad Mahdavia and
Hamid Reza Bijanzadehc
aSchool of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
bDepartment of Biotechnology, University College of Science, University of Tehran, Tehran, Iran
cDepartment of Chemistry, Tarbiat Modarres University, Tehran, Iran
Received 21 November 2005; revised 7 February 2006; accepted 16 February 2006
Available online 10 March 2006
Abstract—A novel synthesis of 1,2,4-oxadiazoles is described from a one-pot, three-component reaction between nitriles, hydroxyl-
amine, and aldehydes under microwave irradiation and solvent-free conditions in excellent yields.
Ó 2006 Elsevier Ltd. All rights reserved.
H
Nitrogen–oxygen heterocycles are of synthetic interest
because they constitute an important class of natural
N
NH2
and non-natural products, many of which exhibit useful
N
biological activities.1 The interest in five-membered sys-
N
N
O
tems containing one oxygen and two nitrogen atoms
N
N
(positions 1, 2, and 4) stems from the occurrence of sat-
urated and partially saturated 1,2,4-oxadiazoles in bio-
logically active compounds and natural products.2
1,2,4-Oxadiazoles have recently received considerable
attention as heterocyclic amide and ester bioisosteres.
Bioisosteric replacement of the amide moiety represents
an area that is currently a center of focus because of its
implications in peptide chemistry and the development
of peptidomimetics.3 Furthermore, derivatives contain-
ing 1,2,4-oxadiazole ring systems have been employed
as antirhinovirals, tyrosin kinase inhibitors, serotoniner-
gic (5-HT3) antagonists (Fig. 1, 1), dopamine receptor
(D4) ligands, anti-inflammatory agents, antitumor
agents, monoamine oxidase inhibitors, coronary artery
dilators, anesthetic agents, muscle relaxants, antischist-
osomal agents, and aldose reductase inhibitors.2,4 More-
over the oxadiazole nucleus, a well studied traditional
pharmacophoric scaffold, is the core structural unit of
various muscarinic agonists (Fig. 1, 2), benzodiazepine
O
H
exo-diastereoisomer
N
2, highly efficacious muscarinic agonist
1, potent 5-HT3 antagonist
Figure 1. Examples of biologically active 1,2,4-oxadiazoles.
receptor partial agonists and growth hormone
secretagogues.4,5
So far, five general synthetic methods have been reported
for the preparation of 1,2,4-oxadiazole ring systems: (i)
condensation of amidoximes with derivatives of carbox-
ylic acids to give O-acylamidoximes, which are cyclized
to 1,2,4-oxadiazoles; (ii) cyclization of N-acylamidoxi-
mes; (iii) 1,3-dipolar cycloaddition of nitrile oxides to
nitriles; (iv) electrocyclic ring closure of nitrenoids; and
(v) oxidation of 4,5-dihydro-1,2,4-oxadiazoles.2
The most common methods recently reported for the
synthesis of 1,2,4-oxadiazoles are cyclization of O-acyl-
amidoximes obtained from acylation of amidoximes
by carboxylic acids or acid chlorides.6 However, these
methods have several drawbacks. Acid chlorides are
very toxic and reactive chemicals and thus are hard
to store and handle, and only a few acid chlorides are
Keywords: Aldehydes; 1,2,4-Oxadiazoles; One-pot, three-component
reaction; Microwave irradiation; Solvent-free synthesis.
*
Corresponding author. Tel./fax: +98 21 6649 5291; e-mail: madib@
khayam.ut.ac.ir
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.102

2966
M. Adib et al. / Tetrahedron Letters 47 (2006) 2965–2967
readily available. On the other hand, carboxylic acids
need a coupling reagent such as DCC, EDC, CDI,
TBTU, HOBt, or HBTU7 to react with amidoximes6,8
and also the reaction time is relatively long.
The reactions were carried out by first mixing the nitrile
and hydroxylamine. Reaction proceeded in the presence
of a catalytic amount of acetic acid under microwave
irradiation. After a minute and nearly complete conver-
sion to the corresponding amidoxime intermediate, as
indicated by TLC monitoring, the aldehyde was added
to the reaction mixture, which was irradiated for a fur-
The application of microwave irradiation in organic
synthesis for conducting reactions at highly accelerated
rates is an emerging technique.9 In fact, in recent years,
the use of microwaves have become popular among syn-
thetic organic chemists both to improve classical organic
reactions (shortening reaction times and/or improving
yields) as well as to promote new reactions.
1
ther three minutes. TLC and H NMR analysis of the
reaction mixtures clearly indicated formation of 1,2,4-
oxadiazoles 7 in excellent yields.11 Mechanistically, it
is reasonable to assume that first, the in situ prepared
amidoxime is condensed with the aldehyde to form the
imine derivative 8. Then, this intermediate is cyclized
to the 4,5-dihydro-1,2,4-oxadiazole derivative 9, which
is finally oxidized under the reaction conditions to pro-
duce 1,2,4-oxadiazole 7 (Scheme 2).
Knowing the pharmacological importance of the 1,2,4-
oxadiazole ring systems, we have recently focused on
improving the synthesis of this nucleus bearing in mind
new synthetic methodologies. To date, we know of no
published report concerning the synthesis of 3,5-disub-
stituted 1,2,4-oxadiazoles using aldehydes as the third
reactant coupled with nitriles and hydroxylamine (or
as the second coupled with amidoximes). In this letter
we report a facile synthesis of 3,5-disubstituted 1,2,4-
oxadiazoles via a one-pot, three-component reaction
between nitriles, hydroxylamine, and aldehydes. Thus,
arylnitriles 3 and hydroxylamine 4 are converted
in situ to amidoximes 5. Next, the amidoximes are con-
densed with aldehydes 6 under microwave irradiation10
and solvent-free conditions to produce 1,2,4-oxadiazoles
7 in 92–97% yields (Scheme 1).
In conclusion, we have developed a novel microwave-as-
sisted one-pot, three-component reaction for the prepa-
ration of 1,2,4-oxadiazoles of potential synthetic and
pharmacological interest. Excellent yields, a simplified
purification process, short reaction times, one-pot, and
solvent-free conditions and finally using aldehydes in-
stead of carboxylic acid derivatives are the main advan-
tages of this method. This method appears to have
broad scope with respect to variation in the oxadiazole
3- and 5-positions and presents a straightforward proce-
dure for the efficient synthesis of 3,5-disubstituted 1,2,4-
oxadiazoles.
Ar
NH2
N
AcOH (Cat.)
Ar'CHO (6)
Ar
Ar
C
N
+
NH2OH
N
MW 3 min
MW 1 min
Ar'
NOH
O
7
3
5
4
7
Ar
Ar
C6H5
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
% Yielda
95
a
b
c
d
e
f
g
h
i
C6H5
C6H5
C6H5
C6H5
92
94
97
94
92
93
96
93
94
92
96
4-CH3C6H4 C6H5
4-CH3C6H4 4-CH3C6H4
4-CH3C6H4 4-CH3OC6H4
3-ClC6H4 C6H5
3-ClC6H4 3-ClC6H4
3-ClC6H4 4-CH3C6H4
3-ClC6H4 4-CH3OC6H4
3-ClC6H4 4-ClC6H4
j
k
l
aIsolated yields
Scheme 1.
Ar
Ar
Ar'
N
H
NH2
NOH
N
N
Ar'CHO
Ar
Ar
N
N
Ar'
Ar'
(6)
NO
H
O
O
5
8
9
7
Scheme 2.

M. Adib et al. / Tetrahedron Letters 47 (2006) 2965–2967
2967
9. Microwaves in Organic Synthesis, 2nd reprint; Loupy, A.,
Ed.; Wiley-VCH: Weinheim, 2004.
Acknowledgement
10. The experiments were performed using a microwave oven
(ETHOS 1600, Milestone) with a power of 600 W specially
designed for organic synthesis.
This research was supported by the Research Council of
the University of Tehran as research project (6102036/1/
02).
11. The procedure for the preparation of 3,5-diphenyl-1,2,4-
oxadiazole 7a is described as an example: A mixture of
benzonitrile (0.21 g, 2 mmol), hydroxylamine 50%
(0.13 g, 2 mmol), and a catalytic amount of AcOH was
irradiated with microwaves at 100 °C for 1 min. After
nearly complete conversion to the corresponding ami-
doxime as was indicated by TLC, benzaldehyde (0.21 g,
2 mmol) was added to the reaction mixture and it was
irradiated at 150 °C for a further three minutes. After
cooling to room temperature, the solid residue was
recrystallized from 95% ethanol. The product 7a was
obtained as colorless crystals, mp 106–108 °C (lit.: 109–
110 °C);12 1H NMR (500.1 MHz, CDCl3): d 7.49–7.55
(5H, m, 5CH), 7.59 (1H, t, J = 7.1 Hz, CH), 8.17 (2H,
dd, J = 7.5 and J = 1.5 Hz, 2CH), 8.21 (2H, d, J =
7.8 Hz, 2CH). 13C NMR (125.8 MHz, CDCl3): d 124.29
and 126.95 (2C), 127.50, 128.13, 128.82, 129.06, 131.15,
and 132.69 (6CH), 168.94 (NCN), 175.68 (NCO). Com-
pound 7b: Colorless crystals, mp 113–115 °C (lit.: 117–
118 °C);13 1H NMR (500.1 MHz, CDCl3): d 2.38 (3H, s,
CH3), 7.28 (2H, d, J = 8.0 Hz, 2CH), 7.47–7.49 (3H, m,
3CH), 8.06 (2H, d, J = 8.0 Hz, 2CH), 8.17 (2H, dd,
J = 7.3 and J = 1.9 Hz, 2CH). 13C NMR (125.8 MHz,
CDCl3): d 21.65 (CH3), 121.55 and 127.10 (2C), 127.44,
128.05, 128.76, 129.72, and 131.03 (5CH), 143.35 (C),
168.80 (NCN), 175.76 (NCO). Compound 7c: Colorless
crystals, mp 94–96 °C (lit.: 98 °C);13 1H NMR
(500.1 MHz, CDCl3): d 3.83 (3H, s, OCH3), 6.99 (2H,
d, J = 8.7 Hz, 2CH), 7.45–7.55 (3H, m, 3CH), 8.12 (2H,
d, J = 8.8 Hz, 2CH), 8.15 (2H, dd, J = 8.4 and
J = 1.7 Hz, 2CH). 13C NMR (125.8 MHz, CDCl3): d
55.41 (OCH3), 114.43 (CH), 116.82 and 127.14 (2C),
127.45, 128.74, 129.98, and 130.99 (4CH), 163.10 (O–C),
168.74 (NCN), 175.52 (NCO). Compound 7d: Colorless
crystals, mp 118–119 °C (lit.: 121–122 °C);13 1H NMR
(500.1 MHz, CDCl3): d 7.45–7.55 [3H: m; and 2H: d
(J = 8.7 Hz), 5CH], 8.12 (2H, d, J = 8.7 Hz, 2CH), 8.14
(2H, dd, J = 7.4 and J = 1.4 Hz, 2CH). 13C NMR
(125.8 MHz, CDCl3): d 122.72 and 126.74 (2C), 127.47,
128.81, 129.38, 129.44, and 131.22 (5CH), 139.11 (C),
168.98 (NCN), 174.72 (NCO). Compound 7f: Colorless
crystals, mp 135–136 °C (lit.: 134–135 °C);14 1H NMR
(500.1 MHz, CDCl3): d 2.39 and 2.40 (6H, 2s, 2CH3),
7.27 (2H, d, J = 7.6 Hz, 2CH), 7.28 (2H, d, J = 7.8 Hz,
2CH), 8.05 (2H, d, J = 7.8 Hz, 2CH), 8.06 (2H, d,
J = 7.6 Hz, 2CH). 13C NMR (125.8 MHz, CDCl3): d
21.51 and 21.64 (2CH3), 124.28 (C), 127.39 and 128.03
(2CH), 128.87 (C), 129.46 and 129.68 (2CH), 141.28 and
143.25 (2C), 168.79 (NCN), 175.57 (NCO).
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