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Published on the web July 5, 2013
A Simple and Straightforward Protocol to 3,5-Disubstituted 1,2,4-Oxadiazoles
from Carboxylic Acids
Tadikonda Ramu, Sarakula Prasanthi, Nakka Mangarao, Gajula Mahaboob Basha,
Rayavarapu Srinuvasarao, and Vidavalur Siddaiah*
Department of Organic Chemistry, Foods, Drugs and Water, Andhra University,
Visakhapatnam-530 003, India
(Received March 4, 2013; CL-130187; E-mail: drsiddu@andhrauniversity.info)
A convenient one-pot synthesis of 1,2,4-oxadiazoles is
yields. Therefore, developing a mild and more general procedure
to access 1,2,4-oxadiazoles is still highly desirable.
described. The condensation of carboxylic acids and amidox-
imes in the presence of 2-chloro-4,6-dimethoxy-1,3,5-triazine
(CDMT) and N-methylmorpholine (NMM) has been employed
to synthesize a variety of 3,5-disubstituted 1,2,4-oxadiazoles in
good to excellent yields. The methodology has been applied for
the synthesis of a metabotropic glutamate subtype 5 (mGlu5)
receptor antagonist.
Over the last few years, there has been considerable
application of cyanuric chloride or its derivatives in organic
synthesis.14 2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) was
recently found to have applications as a condensing reagent in
peptide chemistry15 and used for the in situ activation of the
carboxylic group in many transformations, such as the synthesis
of N-methoxy-N-methyl amides,16 aldehydes, ketones or ¡-
amino ketones,17 2-oxazolines,18 and monoacylated pipera-
zines.19 It is commercially available, stable and can also be
prepared from commercially available and inexpensive cyanuric
chloride. Thus, in continuation of our work20 on the develop-
ment of efficient new synthetic methodologies for heterocyclic
compounds, herein, we describe an efficient one flask method
for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from
carboxylic acids and amidoximes using CDMT and NMM in
1,4-dioxane at reflux conditions (Scheme 1).
In the standard procedures, first the CDMT reacts with
N-methylmorpholine (NMM) to form 4-(4,6-dimethoxy-1,3,5-
triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), and
then the carboxylic acid is added to generate an active ester. This
activated ester is further treated with an amidoxime to afford the
3,5-disubstituted 1,2,4-oxadiazoles. In a model study, benzoic
acid (1a) was treated with CDMT and NMM in dichloromethane
at room temperature. The corresponding activated ester was
quantitatively formed after 30 min (monitored by TLC). This
white suspension containing the activated ester was subsequent-
ly treated with N-hydroxybenzamidine (2a) at reflux conditions
to get desired 3,5-diphenyl-1,2,4-oxadiazole. It was found that
the reaction led to 10% yield after 8 h (Table 1, Entry 1). Then
we optimized the reaction conditions to increase the yield of the
product and to reduce the reaction time. Thus, we investigated
the effect of various solvents such as CHCl3, THF, CH3CN, 1,4-
dioxane, and toluene on the model reaction (Table 1, Entries
2-6). Among the tested solvents 1,4-dioxane and toluene gave
the best result. However, 1,4-dioxane was preferred over toluene
because it provided better solubility for polar reactants. But,
other solvents were not as sufficient for this purpose. Further-
more, the by-products formed were removed by a simple
aqueous workup, and the desired 1,2,4-oxadiazole product was
purified by silica gel column chromatography.
Heterocycles containing 1,2,4-oxadiazole moiety exhibit a
wide range of biological activities such as anti-inflammatory,1,2
antiviral,3 antirhinoviral,4 and antitumor agents.5 1,2,4-Oxadia-
zoles have often been used as bioisosteres of esters and amides,4
and as dipeptide mimetics6 in a number of pharmacologically
important molecules. They can also be found in a number of
biologically important molecules, such as muscarinic agonists,7
serotoninergic (5-HT3) antagonists,8 benzodiazepine receptor
antagonists,9 and dopamine ligands.10 Moreover, 1,2,4-oxadi-
azole scaffolds are found in several drugs and drug leads10
including the potent S1P1 agonist A11a (Figure 1) and the
metabotropic glutamate subtype 5 (mGlu5) receptor antagonist
B,11b and muscarinic receptor11c for the treatment of Alzheimer’s
disease. Owing to their important applications various method-
ologies have been developed for the synthesis of 1,2,4-
oxadiazoles.12a Generally, 1,2,4-oxadiazoles are synthesized by
cyclodehydration of O-acylamidoximes, promoted by either heat
or by bases, such as NaH, NaOEt, or pyridine.12b A recent report
has described the use of tetrabutylammonium fluoride (TBAF)
as an activator to promote the cyclization of O-acylamidox-
imes.13 Usually, O-acylamidoximes are prepared by the reaction
of amidoximes with activated carboxylic acid derivatives or with
carboxylic acids. The majority of the reported methods use
expensive coupling reagents such as 1-ethyl-3-(3-dimethylami-
nopropyl)carbodiimide (EDC), N,N¤-diisopropylcarbodiimide
(DIC), or 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU) for the formation of O-acylamidox-
imes. Moreover, cyclization of the O-acylamidoximes is also a
most difficult and time-consuming step, and often requires sealed
tube conditions and long reaction times, and gives unsatisfactory
CN
O
N
O
N
N
N
OH
N
HOOC
OMe
N
OMe
N
N
N
O
R1
NH2
N
O
(2)
R
N
NMM, 1,4-dioxane
rt, 30 min
O
N
R
R1
A
B
1,4-dioxane
reflux, 3 h
N
OH
Cl
N
OMe
R
O
N
OMe
3a-o
1
Figure 1. Biologically active 3,5-disubstituted 1,2,4-oxadi-
azoles.
Scheme 1. Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles.
Chem. Lett. 2013, 42, 722-724
Ramu, Tadikonda
