Mild and efficient one-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from nitriles mediated by K 3PO 4

Article abstract of DOI:10.1080/00397911.2013.797997

Potassium phosphate, K₃PO₄, has been proved to be a cheap, strong, and efficient reagent for the one-pot synthesis of 3,5-disubstituted-1,2,4-oxadiazoles from nitriles and acid chlorides under mild conditions. [Supplementary material

Full text of DOI:10.1080/00397911.2013.797997

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A Mild and Efficient One-Pot Synthesis of 3,5-
disubstituted 1,2,4-oxadiazoles From Nitriles Mediated
by K3PO4
Barahman Movassagh a & Farzaneh Talebsereshki a
a Department of Chemistry , K. N. Toosi University of Technology , Tehran , Iran
Accepted author version posted online: 27 Aug 2013.
To cite this article: Synthetic Communications (2013): A Mild and Efficient One-Pot Synthesis of 3,5-disubstituted 1,2,4-
oxadiazoles From Nitriles Mediated by K3PO4 , Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.797997
To link to this article: http://dx.doi.org/10.1080/00397911.2013.797997
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A Mild and Efficient One-pot Synthesis of 3,5-disubstituted 1,2,4-Oxadiazoles from
Nitriles Mediated by K3PO4
Barahman Movassagh1, Farzaneh Talebsereshki1
1Department of Chemistry, K. N. Toosi University of Technology, Tehran, Iran
Corresponding author. Tel: +98-21-22886575; Fax: +98-21-22853650; E-mail:
bmovass1178@yahoo.com
Abstract
Potassium phosphate, K3PO4, has been proved to be a cheap, strong, and efficient reagent
for the one-pot synthesis of 3,5-disubstituted-1,2,4-oxadiazoles from nitriles and acid
chlorides under mild conditions.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
KEYWORDS: 1,2,4-Oxadiazoles; potassium phosphate; nitriles; amidoximes; acid
chlorides
INTRODUCTION
Recently, the compounds containing the 1,2,4-oxadiazole scaffold have received
considerable attention because of their unique chemical structure and broad spectrum of
biological properties including histamine H3 antagonism,[1] muscarinic agonism,[2]
tyrosine kinase inhibition,[3] antitumor,[4] anti-inflammation,[5] and monoamine oxidase
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inhibition.[6] In addition, anticancer activity of some 3,5-disubstituted-1,2,4-oxadiazoles
has recently been reported.[7] The 1,2,4-oxadiazoles are also widely used as heterocyclic
amide or ester bioisosters[8] and in the design of dipeptidomimetics as peptide building
blocks,[9] and are found in several drugs and drug leads[4] including the metabotropic
glutamate subtype 5 (mGlu 5) receptor (Fig. 1, 1),[10] the muscarinic receptor for the
treatment of Alzheimer’s disease (Fig. 1, 2),[11] and the potent S1P1 agonist (Fig.1, 3).[12]
Generally, five synthetic methods are used for the preparation of 1,2,4-oxadiazole
scaffold: (i) cyclization of O-acylamidoxime formed from reaction of the amidoxime
with a carboxylic acid or its activated derivative,[13] (ii) condensation of N-
acylamidoximes,[14] (iii) 1,3-dipolar cycloaddition of nitriles to nitrile oxides,[15] (iv)
oxidation of 4,5-dihydro-1,2,4-oxadiazoles [16] and (v) electrocyclic ring closure of
nitrenoides.[17] More commonly, 1,2,4-oxadiazoles are prepared from amidoximes and
carboxylic acid derivatives in two steps. In the first step, the amidoxime, prepared by the
addition of hydroxylamine to a nitrile compound, is O-acylated by a carboxylic acid or its
activated derivative; the heterocycle is subsequently formed by intramolecular
cyclodehydration.[18–20] However, to react with amidoximes, carboxylic acid needs a
coupling reagent, such as diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDC), O-benzotriazol-1-yl-N,N,N´,N´-
tetramethyluronium hexafluorophosphate (HBTU), and dicyclohexylcarbodiimide
(DCC).[13] In these cases, the reaction time is relatively long. Moreover, many methods
are not one-pot procedures and instead of readily available nitriles, they require
amidoximes, as their starting materials;[13a,c,d,16b] also, some of the reported procedures
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suffer from long reaction times and harsh reaction conditions which exclude additional
functionality on the oxadiazole.[13a,c,d,18] Very recently, a one-pot synthesis of 1,2,4-
oxadiazoles directly from nitriles and hydroxylamine hydrochloride using potassium
fluoride has been introduced;[21] this method, however, has the following drawbacks: (a)
synthesizing oxadiazoles with only two identical substituents on the 3- and 5-positions,
(b) having a long reaction time (12 h), and (c) being inapplicable to aliphatic nitriles. In
fact, to improve these procedures several microwave-[18,22] and ultrasound-assisted[23]
methods have been introduced.
RESULTS AND DISCUSSION
Tripotassium phosphate, K3PO4, continues to attract the attention of organic chemists due
to its versatile applications in synthetic chemistry; it is a cheap, non-toxic, and strong
inorganic base (pKa 12.32 for the conjugate acid), used as an alternative non-nucleophilic
base in several reactions.[24] In the framework of our ongoing research on the synthetic
utility of potassium phosphate in different reactions,[25] we have examined its application
in the one-pot synthesis of 1,2,4-oxadiazoles from readily available starting materials.
Owing to the pharmacological importance of the compounds containing the 1,2,4-
oxadiazole scaffold, in this communication, we report a very simple, convenient, and
high yielding one-pot method mediated by K3PO4, as a strong base, for the synthesis of
these compounds from nitriles and hydroxylamine hydrochloride.
In initial studies, benzonitrile (1 equiv) and hydroxylamine hydrochloride (1.25 equiv)
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were first mixed and monitored, by TLC, with various amounts of K3PO4, solvents, and
temperatures to test the feasibility of the reagent to produce the corresponding amidoxime
(Scheme 1, Table 1). Different solvents such as toluene, 1,2-dichloroethane, and N,N-
dimethylformamide (DMF) were screened for this reaction; the best result was
obtained in
DMF with 2 equiv of K3PO4 at 90 °C (Table 1, entry 3). Then, various amounts of
K3PO4, and temperatures were studied in this solvent, DMF; complete conversion to the
corresponding benzamidoxime intermediate was observed after 45 min when 1.5 equiv of
K3PO4 in DMF at 90 °C was used (Table 1, entry 4). Utilizing this reaction conditions in
a one-pot manner, starting from benzonitrile and hydroxylamine hydrochloride (90 °C)
followed by reaction with acetyl chloride at 110 °C, without the separation of
benzamidoxime, gave 3-phenyl-5-methyl-1,2,4-oxadiazole in 85% overall yield (based
on benzonitrile).
In order to probe into the scope of the K3PO4-mediated synthesis of a wide range of 3,5-
disubstituted-1,2,4-oxadiazoles, a variety of nitriles reacted with hydroxylamine
hydrochloride followed by reaction with different acid chlorides (Scheme 2). The results
are shown in Table 2. All products were fully characterized by physical and spectroscopic
methods and compared with the authentic samples. The methodology appears to be quite
common with respect to substitution at the oxadiazole 3-and 5-positions, with a range of
aliphatic and aromatic substituents.
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In order to investigate the possibility of observing the N-acylated adduct alongside the O-
acylated derivative, an experiment was conducted with pure benzamidoxime (mp 70-71
°C) as starting material; treatment of benazamidoxime 5a (2 mmol) with acetyl chloride
(2 mmol) in the presence of K3PO4 (2 mmol) in DMF (4 mL) at 110 °C, after 7 min, gave
O-acylamidoxime 8a (28%; mp 89-91 °C; υ (cm-1): 1756 (C=O), 3404 and 3348 (NH2)),
along with the N-acylated adduct 9a (17%; υ (cm-1): 3430 (OH), 1648 (C=O)), and the
condensation product 7a (34%) as indicated from their IR spectra after separation
(Scheme 3).
In conclusion, K3PO4-mediated preparation of various 3,5-disubstituted-1,2,4-oxadiazoles
from nitriles and acid chlorides under mild conditions is unveiled. This protocol offers
high to excellent yields of the corresponding 1,2,4-oxadiazoles. The one-pot character
of the process, short reaction times, and ready availability of the reagent can be
considered as advantages of this method.
EXPERIMENTAL
General Procedure: Nitrile (2 mmol) was added to a suspension of hydroxylamine
hydrochloride (2.5 mmol) and K3PO4 (3 mmol) in DMF (4 mL). Then, the reaction
mixture was heated at 90 °C for 30-60 min. After nearly complete conversion to the
corresponding amidoxime, as indicated by TLC monitoring, acid chloride (2 mmol) was
added dropwise, and the mixture was heated at 110 °C for another 20-60 min. On
completion of the reaction (TLC), the hot mixture was poured into ice-water (50 mL). In
the case of the products 7a, 7b-7f and 7h-7m, the obtained crude solids were purified by
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recrystallization from 95% ethanol, and the oxadiazoles 7b and 7g were purified, after
extraction with CHCl3 (2 × 10 mL) and drying (Na2SO4), by preparative TLC ( silica gel,
cyclohexane-EtOAc, 1:3 as eluent).
ACKNOWLEDGEMENT
This work was supported by the Research Council of the K. N. Toosi University of
Technology. The authors express their gratitude to Dr. Sogand Noroozizadeh for editing
the English content of this manuscript.
Supporting Information: This material can be found via the “Supplementary Content”
section of this article’s webpage.
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Table 1. Optimization of the K3PO4-mediated preparation of benzamidoxime
Entry Solvent
K3PO4 (equiv) Temp (°C) Time (h) Yield (%)a
1
2
3
4
5
6
7
Toluene
1,2-Dichloroethane
DMF
2
90
83
90
90
90
70
110
7
43
21
87
89
77
78
65
2
6
2
0.75
0.75
1.7
1.7
0.75
DMF
1.5
1
DMF
DMF
1.5
1.5
DMF
aIsolated yields.
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Table 2. Synthesis of 3,5-disubstituted-1,2,4-oxadiazoles
Entry R1
R2
Producta Time(h) Yield (%)b
1
C6H5
CH3
7a[26]
7b[26]
7c[22a]
1
85
76
2
C6H5
(CH3)2CH
C6H5
1.75
1.5
3
C6H5
83
82
87
88
88
87
86
90
96
92
62
4
C6H5
p-CH3OC6H4 7d[18]
1.75
1.5
5
C6H5
p-ClC6H4
CH3
7e[22a]
7f[26]
6
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
0.83
1.25
1.5
7
(CH3)2CH
7g[25]
7h[18]
8
C6H5
9
p-CH3OC6H4 7i[18]
1.5
10
11
12
13
p-ClC6H4
7j[22b]
7k[18]
1.25
1.25
1.25
2
2,4-Cl2C6H3 C6H5
2,4-Cl2C6H3 p-CH3OC6H4 7l [18]
CH3 C6H5
7m[20d]
aReferences provided for known compounds.
bIsolated yields.
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Scheme 1.
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14

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Scheme 2.
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Scheme 3.
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Figure 1. Examples of some biologically active oxadiazoles.
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