Acid-promoted reaction of N-(cyanomethyl) amide with nitrosation reagent: Facile synthesis of 1,2,4-oxadiazole-3-carboxamide

Article abstract of DOI:10.1016/j.tetlet.2021.153209

1,2,4-Oxadiazole-3-carboxamide has been extensively used in the pharmaceutical chemistry. In this study, 1,2,4-oxadiazole-3-carboxamide is accomplished through an acid-promoted reaction of N-(cyanomethyl)amide with nitrosation reagent. This novel preparat

Full text of DOI:10.1016/j.tetlet.2021.153209

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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Acid-promoted reaction of N-(cyanomethyl) amide with nitrosation
reagent: Facile synthesis of 1,2,4-oxadiazole-3-carboxamide
a,b,
Shaoqing Du a, Jin Li a, Wen Fu a, Xiaoyong Xu a, Xusheng Shao a, , Xuhong Qian
⇑
⇑
a Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
b School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
a r t i c l e i n f o
a b s t r a c t
Article history:
1,2,4-Oxadiazole-3-carboxamide has been extensively used in the pharmaceutical chemistry. In this
study, 1,2,4-oxadiazole-3-carboxamide is accomplished through an acid-promoted reaction of
N-(cyanomethyl)amide with nitrosation reagent. This novel preparation of 1,2,4-oxadiazole-3-carboxam-
ide was carried out at 25 °C, and the yield of target compounds was as high as 92%. At the same time, the
amount of acid used is reduced. A mechanism speculation for the formation of 1,2,4-oxadiazole-3-car-
boxamide has been provided. The new synthetic method provides great convenience for the synthesis
of compounds containing 1,2,4-oxadiazole-3-carboxamide.
Received 21 March 2021
Revised 17 May 2021
Accepted 24 May 2021
Available online xxxx
Keywords:
N-(Cyanomethyl)amide
1,2,4-Oxadiazole-3-carboxamide
Methyl 1,2,4-oxadiazole-3-carboxylate
N0-Hydroxycarbamimidoyl cyanide
Ó 2021 Published by Elsevier Ltd.
Introduction
can be nitrosated and dehydrated into a 1,2,4-oxadiazole-3-amide
[23]. However, the research on the reaction mechanism is not thor-
1,2,4-Oxadiazole was first synthesized by Tiemann and Kruger,
and it was originally named furan[ab1]diazole [1]. The oxadiazole
derivatives have a wide range of biological activities, such as insec-
ticidal [2], antimicrobial [3,4], genotoxic activity [5], immunosup-
pressive [6], anticancer [7–9], antitrypanosomal [3], Alzheimer’s
disease [10], and antitumor activity [11,12]. When 1,2,4-oxadia-
zole is substituted with alkyl, aryl or carboxamide groups at the
3,5 positions, it can also be used as an antagonist [13–17] and
antibacterial [18]. Due to its wide application in medicinal chem-
istry, agriculture and new materials, 1,2,4-oxadiazole-3-amide
has attracted more attention [19,20].
One of synthesis method of 1,2,4-oxadiazole-3-amide is using
acetic acid as a solvent, and the substituted formaldehyde and
diaminoglyoxime are reacted at 100 °C for 120 min [21,22]. How-
ever, the reaction environment is not very friendly due to the use
of acetic acid. And the reaction requires heating conditions, which
the reaction conditions are not mild enough. Thus, more environ-
mentally friendly synthesis methods need to be found.
ough enough, and further exploration is needed.
In this study, we provided a new convenient synthetic method
for 1,2,4-oxadiazole derivatives. N-(cyanomethyl)amide, nitrite
reagent and acid were used as substrates to synthesize 1,2,4-oxa-
diazole-3-amide at 25 °C (Scheme 1). Initially, it was expected that
the nitrososubstitution would occur on the amino group, leading to
iminosydnones product. However, no desired product was
observed for 1a when the reaction was performed in tetrahydrofu-
ran (THF) at 25 °C. The presence of a carbonyl group is thought to
cause the change in charge distribution on aminoacetonitrile, and
then, the intermediate 2a was obtained instead of 2a–D. Finally,
1,2,4-oxadiazole was obtained by completing the ring closure.
Results and discussion
N-(Cyanomethyl)benzamide (1a) was prepared according to the
literature [24]. It was assumed that 5-phenyl-1,2,4-oxadiazole-
3-carboxamide 3a was produced from the reaction of
N-(cyanomethyl)benzamide (1a), isoamyl nitrite and hydrogen
chloride, which can perform nucleophilic substituted (intermedi-
ates 2a) and then intramolecular cyclocondensation reactions to
get 3a. To perform such multi-component reactions (MCRs), the
reaction will only take about 1 h at 25 °C. Upon completing the
reaction, the final products were isolated and identified. The struc-
tural determination was performed by analyzing the 1H NMR and
13C NMR of the products. The 1H NMR spectrum presented the
Another synthesis method of 1,2,4-oxadiazole-3-amide is using
acetic acid and ether as a solvent, and N-(cyanomethyl)benzamide
⇑
Corresponding authors at: Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, 130 Meilong Road,
Shanghai 200237, China.
E-mail addresses: shaoxusheng@ecust.edu.cn (X. Shao), xhqian@ecust.edu.cn
(X. Qian).
https://doi.org/10.1016/j.tetlet.2021.153209
0040-4039/Ó 2021 Published by Elsevier Ltd.
Please cite this article as: S. Du, J. Li, W. Fu et al., Acid-promoted reaction of N-(cyanomethyl) amide with nitrosation reagent: Facile synthesis of 1,2,4-
oxadiazole-3-carboxamide, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153209

S. Du, J. Li, W. Fu et al.
Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. An unexpected reaction of N-(cyanomethyl)benzamide (1a).
expected resonance signatures including one NH amide group
signal at 8.41 ppm, another NH amide group signal at 8.20 ppm
and five signals for benzene ring. In the 13C NMR spectrum, the
observed signals were all consistent with the structure of
product 3a.
At the beginning, the compound 3a was obtained from entry 13,
and the yield is only 67%. Because the reaction requires anhydrous
reagents and hydrogen chloride in methanol, so the reaction condi-
tions are strict. In order to optimize the reaction, the reaction con-
ditions have been screened, which were shown in Table 1, at last,
the yield of the reaction can reach 92%. After entry 13, ordinary
THF was used instead of anhydrous THF, different acids were used
for reaction. The yield of hydrochloric acid (92%) was higher than
that of sulfuric acid (42%), nitric acid (63%) and trifluoroacetic acid
(none). And the yield of THF (92%) as solvent is better than that of
water (51%), acetonitrile (80%), acetic acid (75%) and dioxane
(78%). Then the temperature and reaction time were screened,
and the best reaction condition was one hour at 25 °C, namely
entry 2.
To explore the scope and limitations of this reaction, the same
procedure was applied to the various N-(cyanomethyl)amide 1.
As it can be found from Scheme 2, the reaction proceeded very effi-
ciently and led to the formation of the 1,2,4-oxadiazole-3-carbox-
amide 3a–g in good yields. However, if R1 is not a benzene ring,
such as pyridine, furan, cyclohexane, or cyclopropane, this reaction
will not happen.
Scheme 2. Reaction of Various Primary N-(cyanomethyl)amide.
sis of 1,2,4-oxadiazole is a substitution reaction on the methylene
of aminoacetonitrile to produce a nitrososubstitution, which is
helpful for us to understand the mechanism of reactions.
Various N-(cyanoethyl)amides (R1 = pH, cinnamyl, 4-Cl-pH,
furan-2-) were used as raw materials to study the range and limi-
tation of the reaction. It was found that this reaction can be applied
in a wider range and provides a new method to obtain N-(cyano
(nitroso)methyl)amide (Scheme 3).
In order to determine whether a compound with a planar struc-
ture is conducive to this reaction, single crystal culture was carried
out in 2d (CCDC 2067456). From the crystal structure of 2d (Fig. 1),
it is true that the cinnamyl group is partly coplanar with the N-(-
cyanomethyl)amide, which also proves the previous speculation.
In addition, by calculating the 3D structure of other R1 substitu-
tions (pyridine, furan, cyclohexane, or cyclopropane), it is found
that the reaction cannot occur when the molecules are not
coplanar.
In order to confirm the reaction process, dry HCl in ethyl acetate
(EA) without the presence of water was selected as an acid reagent.
Through similar conditions, the intermediate state structure (2a)
was obtained. This step demonstrates that a key step in the synthe-
Table 1
Optimization of reaction conditions 3a.
a
Entry
Solvent
Temp. (℃)
Time (h)
Nitrosation reagent
Acid
Yield (%)b
1
2
3
4
5
6
7
8
THF
THF
THF
Dioxane
MeCN
H2O
THF
THF
THF
THF
THF
THF
25
25
25
25
25
25
60
60
25
25
25
25
25
25
25
0.5
1
3
1
1
22
0.5
1
1
1
Isoamyl nitrite
Isoamyl nitrite
Isoamyl nitrite
Isoamyl nitrite
Isoamyl nitrite
Isoamyl nitrite
Isoamyl nitrite
Isoamyl nitrite
Isoamyl nitrite
Isoamyl nitrite
Tert-butyl nitrite
NaNO₂
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HNO3
H2SO4
HCl
HCl
HCl in MeOH
HCl
65
92
92
78
80
51
70
92
63
42
86
–
9
10
11
12
13
14
15
1
1
1
1
THF (redistilled)
Acetic acid
THF
Isoamyl nitrite
Isoamyl nitrite
Isoamyl nitrite
67
75
–
1
CF3COOH
Reaction conditions: N-(cyanomethyl)amide (1 mmol),nitrosation reagent (1.2 eq.), acid (2 eq.).
a
Acid concentration: HCl 36%; HNO3 98%; H2SO4 98%; CF3COOH 99%; HCl in MeOH 1 mol Lꢀ1
Isolated yields.
.
b
2

S. Du, J. Li, W. Fu et al.
Tetrahedron Letters xxx (xxxx) xxx
Scheme 3. Reaction of Various Primary N-(cyanomethyl)amide.
Scheme 5. Reaction of Various Primary N-(cyanomethyl)amide.
In experiments, it was found that when the solvent contained
alcohol, the product is no longer an amide, but the corresponding
ester (Scheme 5). Similar to Scheme 2, the applicability of this reac-
tion is limited. This reaction can only occur if the N-(cyanomethyl)
amide and R1 are planar. This reaction produces a by-product of
compound 3 (yield 15%), so the target compound 4 is obtained at
a medium yield.
Fig. 1. General view of 2d in a crystal.
In summary, we described an acid promoted reaction of N-(-
cyanomethyl)amide with nitrosation reagent and water, by adjust-
ing the type of acid to obtain products with different structures,
such as 1,2,4-oxadiazole-3-carboxamide, methyl 1,2,4-oxadia-
zole-3-carboxylate and N0-hydroxycarbamimidoyl cyanide.
Compared with the traditional synthetic method, the
advantages of current reaction include high yield, simple reaction
conditions, short reaction time, and easy post-processing. And an
acid-promoted reaction pathway is proposed. This provides great
convenience for the synthesis of compounds containing such struc-
tures. Apart from this, the limitations of the reaction were
explored, and the reaction mechanism proposed by the predeces-
sors was revised to deepen the research on this reaction.
In addition, when designing active compounds containing ben-
zamide, 1,2,4-oxadiazole-3-amide can be used to replace the rela-
tive benzamide, which can increase the diversity of the compound
structure. At the same time, it can reduce the risk of resistance.
This also provides an easy structure construction method for drug
design.
Scheme 4a. Reported mechanism for the formation of 3a.
In Bracrmtz’s article [23], the reaction mechanism is that the
compound 1a first undergoes a nitrosation reaction, then a ring-
closure reaction, and finally completes the hydrolysis of the cyano
group to obtain the target compound 3a (Scheme 4a).
After experimental verification, a new reaction mechanism is
proposed in Scheme 4b. Compound 2a completes the cyano group
hydrolysis and ring closure reaction at the same time under the
action of acid, without producing other intermediate products
(such as 5a). Finally, the target product was obtained by dehydro-
genation (Scheme 4b). The cyano group is important in this reac-
tion. When the cyano group of the compound 2a becomes a
carboxyl group, the reaction cannot take place.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
This work was financially supported by Key Project of the
Shanghai
Science
and
Technology
Committee
(No.
18DZ1112703), the National Natural Science Foundation of China
(No. 31830076) and the Shenzhen Science and Technology Pro-
gram (No. KQTD20180411143628272).
Scheme 4b. Proposed mechanism for the formation of 3a.
3

S. Du, J. Li, W. Fu et al.
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