PTSA-ZnCl2: An efficient catalyst for the synthesis of 1,2,4-oxadiazoles from amidoximes and organic nitriles

Article abstract of DOI:10.1021/jo900818h

(Chemical Equation Presented) PTSA-ZnCl₂ has been proved to be an efficient and mild catalyst for the synthesis of 3,5-disubstituted-1,2,4- oxadiazoles from amidoximes and organic nitriles.

Full text of DOI:10.1021/jo900818h

pubs.acs.org/joc
acyl-Gly dipeptidomimetics,6 signal transduction inhibi-
PTSA-ZnCl2: An Efficient Catalyst for the
Synthesis of 1,2,4-Oxadiazoles from Amidoximes and
Organic Nitriles
tors,7 or cell adhesion inhibitors.8
1,2,4-Oxadiazoles are most commonly synthesized from
amidoximes and carboxylic acid derivatives in two steps.
During the first step, the amidoxime prepared by the
addition of hydroxylamine to a nitrile compound is
O-acylated by an activated carboxylic acid derivative. The
heterocycle is subsequently formed by intramolecular cyclo-
dehydration.6-12 All of these approaches generally require
long reaction times. In an attempt to improve on these
procedures, microwave-assisted methods for this cyclization
have recently been reported.13 Yarovenko and co-workers
have reported a one-pot reaction of benzamidoxime with
organic nitriles such as acetonitrile and propionitrile to
produce the corresponding 5-alkyl-3-phenyl-1,2,4-oxadia-
zoles.14 Unfortunately, the reaction required drastic condi-
tions (heating to 180 °C in a sealed tube with excess of nitrile),
and the yields of cyclization products did not exceed
15-20%. This prompted us to study the feasibility of
synthesizing 1,2,4-oxadiazoles from amidoximes and org-
anic nitriles under mild conditions.
John Kallikat Augustine,* Vani Akabote, Shrivatsa
Ganapati Hegde, and Padma Alagarsamy
Syngene International Ltd., Biocon Park, Plot Nos. 2 & 3,
Bommasandra IV Phase, Jigani Link Road, Bangalore
560 099, India
*To whom correspondence should be addressed. Tel:
+91 80 2808 3131. Fax: +91 80 2808 3150.
john.kallikat@syngeneintl.com
Received April 21, 2009
PTSA-ZnCl2 has been proved to be an efficient and mild
catalyst for the synthesis of 3,5-disubstituted-1,2,4-oxa-
diazoles from amidoximes and organic nitriles.
The 1,2,4-oxadiazole heterocycle has been utilized as a
stable ester or amide bioisostere1 and is found in several
drugs and drug leads2 including the potent S1P1 agonist (1),3
the metabotropic glutamate subtype 5 (mGlu5) receptor (2),4
and muscarinic receptor (3)5 for the treatment of Alzheimer’s
disease. Several papers have reported the use of 1,2,4-ox-
adiazole in peptide mimetics, including the design of amino
After a series of trials with various acid catalysts, we were
delighted to find that PTSA could be used in combination
with ZnCl2 for the smooth preparation of 1,2,4-oxadiazoles
from amidoximes with organic nitriles under mild condi-
tions. Herein, we report our results on the highly effective
p-toluenesulfonic acid mediated zinc chloride catalyzed
synthesis of 1,2,4-oxadiazoles from amidoximes and organic
nitriles.
In initial studies, we used benzamidoxime 1a (1 equiv) and
benzonitrile (1 equiv) to test the feasibility of employing
PTSA/ZnCl2 as a catalyst for the preparation of 1,2,4-
oxadiazoles form amidoximes and organic nitriles. The
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5640 J. Org. Chem. 2009, 74, 5640–5643
Published on Web 06/04/2009
DOI: 10.1021/jo900818h
r
2009 American Chemical Society

JOCNote
TABLE 1. Screening Optimal Conditions
TABLE 2. PTSA/ZnCl2-Catalyzed Reaction of Benzamidoxime with
Various Organic Nitriles
entry catalyst Ia catalyst IIb solvent time (h)c yield of 2a (%)
1
2
3
4
5
6
7
8
9
10
11
12e
13f
14
15
PTSA
DMF
DMF
DMF
DMF
DMF
toluene
MeNO2
dioxane
DMF
DMF
DMF
12
12
5
12
12
12
12
12
5
12
12
5
4
2
12
NRd
NRd
71
13
52
16
59
62
81
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnBr2
SnCl4
FeCl3
ZnCl2
ZnCl2
ZnCl2
PTSA
AcOH
CF3COOH
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
8
NRd
93
DMF
DMF
CH3CN
DMF
PTSA
PTSA
CF3COOH
94
91g
NRd
a Catalyst I (0.2 equiv) was used. b Catalyst II (0.2 equiv) was used.
c All reactions were performed at 80 °C. d No reaction. e PTSA/ZnCl2
(0.3 equiv each) was used. f PTSA/ZnCl2 (0.5 equiv each) was used, and
the reaction was performed at 120 °C. g Isolated as 3a (see text for
details).
results are summarized in Table 1. Scarcely any reaction
occurred when PTSA (0.2 equiv) or ZnCl2 (0.2 equiv) was
used as a sole catalyst in DMF at 80 °C (Table 1, entries 1 and
2). When the reaction was conducted with PTSA/ZnCl2 (0.2
equiv each), the oxadiazole 2a was obtained in 71% yield
(Table 1, entry 3). Intrigued by this result, we examined the
reaction under various conditions to optimize the reaction.
The effects of various organic acids on oxadiazole formation
were also investigated. When using acetic acid or trifluoro-
acetic acid, the yield of 2a was only 13% and 52%, respec-
tively (Table 1, entries 4 and 5). Further, there was no
reaction when CF3COOH was used in the absence of ZnCl2
(Table 1, entry 15).
Next, we examined the effect of the solvent. Product
formation was moderate in nucleophilic solvents such as
nitromethane (Table 1, entry 7). The reaction did not pro-
ceed to completion in toluene, and in 1,4-dioxane, product
formation was moderate (Table 1, entries 6 and 8). However,
DMF had superior solvent effects for this catalytic system
(Table 1, entries 3, 9, and 12). Further, we examined the
effect of various Lewis acids on the formation of 1,2,4-
oxadiazole. While FeCl3 had no role in the reaction, SnCl4
was poorly active. Interestingly, both ZnCl2 and ZnBr2
showed the best cocatalytic effects (Table 1, entries 3 and
9-13). As ZnCl2 is much cheaper than ZnBr2 and has
satisfactory activity, it was selected as the cocatalyst for the
preparation of 1,2,4-oxadiazoles from amidoximes and or-
ganic nitriles. Further, the effect of the amount of ZnCl2 was
investigated. The results suggested that increasing the
amount of ZnCl2 had a positive effect on the catalytic activity
(Table 1, entries 3, 12, and 13). However, the enhancement of
ZnCl2 beyond 0.3 equiv did not give a significant increase in
the yield of 2a. Similarly, increasing the reaction temperature
from 80 to 120 °C gave only a slight decrease in the reaction
time, but with no significant increase in the yield of
a PTSA/ZnCl2 (0.3 equiv each) was used. b Reaction time was 5-8 h.
c Purified by crystallization or column chromatography.
oxadiazole (Table 1, entry 13). Interestingly, when acetoni-
trile was used as solvent (Table 1, entry 14), the product
formed was exclusively 3a (Table 3, entry 1) and benzonitrile
remained unreacted in the reaction mass. This indicates that
acetonitrile could be used as a solvent to prepare 5-methyl-3-
substituted-1,2,4-oxadiazoles.
To explore the generality and scope of oxadiazole synth-
esis catalyzed by PTSA/ZnCl2, various organic nitriles were
treated with 1a under standard reaction conditions in DMF
for 5-8 h (Table 2). The results showed that excellent yields
of 3-phenyl-5-substituted-1.2,4-oxadiazoles were obtained
(Table 2, entries 1-9) with the PTSA/ZnCl2 catalytic system.
When 1a (1 equiv) was treated with isophthalonitrile
(1 equiv) under the above reaction conditions, 2e was formed
exclusively in 91% yield (Table 2, entry 5).
Next, we examined the reaction of various amidoximes
(Table 3, entries 1-9) with acetonitrile. Interestingly, all
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JOCNote
TABLE 3. PTSA/ZnCl2-Catalyzed Reaction of Various Amidoximes
with Acetonitrile
TABLE 4. PTSA/ZnCl2-Catalyzed Reaction of Cyclopropane Car-
boxamidoxime with Various Organic Nitriles
a PTSA/ZnCl2 (0.3 equiv each) was used. b Reaction time was 4-6 h.
c Purified by crystallization or column chromatography.
SCHEME 1
nitro, halo, carboxylate, methoxy, N-Boc, nitrile, cyclopro-
pyl, and carboxylic acid. Further, aromatic and aliphatic
amidoximes reacted smoothly with organic nitriles under the
standard reaction conditions and provided the correspond-
ing 1,2,4-oxadiazoles in moderate to good yields. Substrates
possessing a ketoxime group (Table 3, entry 3) also provided
the corresponding 1,2,4-oxadiazole without affecting the
functional group.
A plausible mechanism for the formation of oxadiazole
can be explained through the formation of nitrile oxide 5
(Scheme 1).15 Initial activation of amidoxime by PTSA-
ZnCl2 might result in the formation of Lewis acid-ammonia
complex as the leaving group, resulting in the formation of
nitrile oxide. 1,3-Dipolar cycloaddition of nitrile oxides to
a PTSA/ZnCl2 (0.3 equiv each) was used. b Acetonitrile was used as
solvent. c Reaction time was 1-2 h.
of the reactions were complete in 1-2 h to provide an
excellent yield of 3-substituted 5-methyl-1.2,4-oxadiazoles.
Further, the reaction was examined with a strained cyclo-
alkyl amidoxime by treating it with various organic nitriles
(Table 4). Thus, the reaction of 1h, a fairly special amidox-
ime, with various aromatic and aliphatic nitriles in DMF in
the presence of a catalytic amount of PTSA-ZnCl2 gave good
yield of corresponding oxadiazoles (Table 4, entries 1-7).
This proves the versatility of the method in producing the
3,5-disubstituted 1,2,4-oxadiazoles from amidoximes and
organic nitriles. From Tables 2-4, we can discern that this
reaction tolerates a wide scope of functional groups, such as
(15) For various methods of nitrile oxide synthesis, see: (a) Mukaiyama,
T.; Hoshino, T J. Am. Chem. Soc. 1960, 82, 5339–5342. (b) Howe, R. K.; Liu,
K.; Shelton, B. R. J. Org. Chem. 1980, 45, 3916–3918. (c) Carreira, E. M.;
Bode, J. W.; Muri, D. Org. Lett. 2000, 2, 539–542.
5642 J. Org. Chem. Vol. 74, No. 15, 2009

JOCNote
organonitriles resulting in the formation of oxadiazoles is
well established.16 However, the Lewis acid might also be
involved in the formation of heterocycles via a Lewis acid
catalyzed [3 + 2] cycloaddition reaction.
In summary, PTSA-ZnCl2-catalyzed preparation of var-
ious 3,5-disubstituted 1,2,4-oxadiazoles from amidoximes
and aromatic nitriles under mild conditions is unveiled. This
method offers excellent yields of the corresponding 1,2,4-
oxadiazoles. The one-stage character of the process and the
availability of nitriles and amidoximes obtained from them
can be considered advantages of the method.
Representative Procedure for the Synthesis of 3,5-Disub-
stituted 1,2,4-Oxadiazoles from Amidoximes and Organic
Nitriles. To a mixture of 1a17 (2.5 g, 0.0183 mol) and
benzonitrile (1.87 g, 0.0183 mol) in DMF18 (15 mL)
were added p-toluenesulfonic acid monohydrate (1.04 g,
0.0054 mol) and anhydrous ZnCl2 (0.75 g, 0.0055 mol).
The mixture was heated to 80 °C under nitrogen atmosphere
for 5 h. The completion of the reaction was confirmed by
TLC. After the mixture was cooled room temperature, ethyl
acetate (50 mL) was added, and the resulting mixture was
washed with saturated sodium hydrogen carbonate solution
(3 Â 50 mL) and brine (3 Â 30 mL). The organic phase was
dried over anhydrous magnesium sulfate. The solvent was
removed under reduced pressure, and the resulting material
was passed through a small plug of silica using 5% ethyl
acetate in hexanes to afford 2a19 (3.8 g, 93%) as off-white
solid: mp = 104.9-106.1 °C; 1H NMR (400 MHz, DMSO-
d6) δ 8.17 (d, 2H, J = 7.6 Hz), 8.09-8.07 (m, 2H), 7.74-7.70
(m, 1H), 7.67-7.57 (m, 5H); 13C NMR (100 MHz, DMSO-
d6) δ 175.8, 168.7, 133.8, 132.1, 130.0, 129.7, 128.3, 127.5,
126.6, 123.8; IR (KBr) 1689, 1608, 1444, 1362, 722 cm-1; MS
(ESI-APCI) for C14H10N2O 223 (M + H)+. Anal. Calcd for
C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found: C, 75.71; H,
4.56; N, 12.52.
Acknowledgment. We thank Dr. Ashis Baran Mandal and
gratefully acknowledge Dr. Goutam Das, COO, Syngene
International Ltd. for his invaluable support.
(16) Nadezhda, A. B.; Anatolii, V. K.; Vadim, Y. K.; Matti, H.;
Armando, J. L. P. Inorg. Chem. 2003, 42, 896–903.
Supporting Information Available: Physical data of com-
pounds 1a-i, 2b-i, 3a-i, and 4a-h. Copies of 1H NMR, 13
NMR, and LCMS report of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Gangloff, A. R.; Litvak, J.; Shelton, E. J.; Sperandio, D.; Wang, V.
R.; Rice, K. D. Tetrahedron Lett. 2001, 42, 1441–1444.
(18) Acetonitrile was used as a solvent and reagent for the synthesis of 3-
substituted 5-methyl-1,2,4-oxadiazoles described in Table 3.
(19) Chiou, S.; Shine, H. J. J. Heterocycl. Chem. 1989, 26, 125–128.
C
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