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D. Su et al. / Tetrahedron Letters 54 (2013) 6959–6963
Scheme 2. Mechanism for the formation of 3.
reaction temperature, and stoichiometry. The results are summa-
rized in Table 1. As shown, the solvent exerts an important effect
on the yield of product 3a. When using 4 equiv of Et3N as a base
and 1:2 mol ratio of benamidoxime to 2a, the reaction was com-
pleted within 4 h at an ambient temperature in dichloromethane
(DCM), furnishing product 3a in 81% yield (Table 1, entry 4). In
comparison, using acetonitrile, tetrahydrofuran, or acetone as a
solvent, the reaction provided product 1c in lower yields (Table 1,
entries 1–3). Decreasing the mole ratio of benamidoxime to 2a
(from 1:2 to 1:1) led to a decrease in the yield of product 3a (from
81% to 46%, Table 1, entries 4–6). However, increasing the mole ra-
tio up to 1:2.5 has no apparent effect on the reaction outcome (Ta-
ble 1, entry 8). While the reaction ratios of 1a:2a from 1:1 to 1:2.5
afforded the product 3a in 46–81%, the ratio 1:2 gave the best yield
(Table 1, entry 4). Additional increasing of temperature led to no
improvement in the yield (Table 1, entry 7). After the optimization
study, in terms of the reaction yields the best reaction conditions
were obtained as the following: 4 equiv of Et3N as a base,
1:2 mol ratio of benamidoxime to 2a, DCM as a solvent, and at
room temperature.
With optimized reaction conditions in hand, we turned our
attention to the scope of the reaction with respect to the ami-
doximes. As shown in Table 2, a variety of amidoximes, derived
from aromatic, and heteroaromatic and aliphatic nitriles4i, are
competent in the reaction. Especially, aryl amidoximes bearing
either electron-withdrawing or electron-donating substituents
on the phenyl ring all exhibited high reactivity to give the cor-
responding products in good to high yields. Electron-deficient
aryl amidoximes such as 4-fuloro-(Table 2, entry 4), 4-chloro-
(Table 2, entry 5), 4-bromo-(Table 2, entry 6), and 4-nitro-(Table 2,
entry 9) benzamidoxime were giving the corresponding prod-
ucts 3-substituted aromatic N,N-dimethy-1,2,4-oxadiazole-5-
amines in 72–76% yields. Similarly electron-rich aryl amidox-
imes, such as 4-methyl- and 4-methoxylbenzamidoxime pro-
vided the desired products in excellent yields (78%, 82%,
Table 2, entries 2–3). Substitution at the para- or meta-position
of the phenyl ring of aryl amidoximes did not interfere with
their reactivity (Table 2, entries 6 and 7). It is noteworthy that
ortho-position substituted aryl amidoximes, 2-bromo- and 2,6-
dichlorobenamidoxime, also gave the desired products in satis-
fied yields (57% and 64%, Table 2, entries 8 and 10). Gratify-
ingly, the reaction displayed high yields for heteroaromatic
amidoximes 1k, 1l, and 1m (72%, 62%, and 75%, Table 2, entries
11–13). In addition, the fused-ring aryl amidoxime 1n could
also apply into this reaction with yielding product 3n in mod-
erate yield (32%, Table 2, entry 13). However, in the case of ali-
phatic amidoximes, due to the poor solubility of 1o in DCM,
acetone was used as the solvent instead of DCM. To our delight,
products 3o and 3p were afforded in isolated yields of 40% and
56%, respectively (Table 2, entries 15, 16).
examined a range of other symmetrical and unsymmetrical Vils-
meier salts in the reactions of them with benzamidoxime 1a under
the identical conditions. Experimental results are summarized in
Table 3. Of interest is the result shown in entry 1, the ring-opening
of cyclic Vilsmeier salt 2b (2-chloro-1,3-dimethylimidazolium
chloride or DMC) proceeded smoothly and gave 78% yield of prod-
uct 3q with a hexaalkylguanidinium cation. And an increase in the
length of alkyl chains on dialkylamino groups, as we anticipated,
apparently affected the reactivity of Vilsmeier salts 2, such as com-
pound 2c, ultimately leading to give 40% yield (Table 3, entry 2). A
same trend was also observed when unsymmetrical Vilsmeier salts
2d and 2e reacted with benzamidoxime 1a; products 3q and 3r,
isolated from their mixtures with product 3a, were obtained in
42% and 45% yields respectively; however, product 3a was only gi-
ven in 12% and 14% yields respectively (Table 3,entries 3 and 4). For
the substrate 2f, however, the reaction did not give the expected
product under the experimental conditions.
In our previous studies8b, we found that 2-chloro-1,3-dimethy-
limidazolium chloride (DMC) could convert
a-amino alcohols to
guanidines instead of oxazolines; And, in this work, we success-
fully tapped the leaving dialkylamino group on DMC using DMC it-
self in the reaction of DMC and benzamidoxime, and synthesized
product 3q containing a guanidinium cation (Scheme 1). Based
on the above results, a possible mechanism, as shown in Scheme 2,
for this transformation is proposed: initially, the nucleophilic sub-
stitution between amidoxime g and Vilsmeier salt h leads to gua-
nidine intermediate A; subsequently, intermediate A undergoes an
intramolecular nucleophilic substitution and forms product 3 in
which process the dialkylamino group as a leaving group forms a
guanidine with remained DMC.
In summary, a novel approach, condensation of Vilsmeier salts
and amidoximes, to access N,N-dialkyl-1,2,4-oxadiazol-5-amines,
has been developed. By this approach, a broad range of N,N-dial-
kyl-1,2,4-oxadiazol-5-amines, including aromatic, and heteroaro-
matic and aliphatic substituents, can be synthesized in good to
high yields (up to 82%) under mild reaction conditions. Future ef-
forts will be devoted to extending the substrate scope and explor-
ing the application of this method in the synthesis of structurally
related bioactive molecules.
Acknowledgments
We thank the Facility Center of the College of Chemistry in Jilin
University for assistance with the NMR and HPLC-HRMS
measurements.
Supplementary data
Supplementary data associated with this article can be found, in
10.061. These data include MOL files and InChiKeys of the most
important compounds described in this article.
In order to explore the effect of structure of Vilsmeier salts on
their reactivity and selectivity of corresponding products, we also
Su, Dongshan
