Efficient synthesis of 1,2,4-oxadiazine-5-ones via [3+3] cycloaddition of in situ generated aza-oxyallylic cations with nitrile oxides

Article abstract of DOI:10.1016/j.tetlet.2018.04.025

1,2,4-Oxadiazin-5-ones were prepared via [3+3] cycloaddition of in situ generated aza-oxyallylic cations with nitrile oxides in good yields and excellent functional group compatibility. This efficient transformation is metal-free and is promoted by an inorganic base Cs₂CO₃. In addition, this reaction features simple-operation, mild conditions, and high regioselectivity.

Full text of DOI:10.1016/j.tetlet.2018.04.025

Accepted Manuscript
Efficient Synthesis of 1,2,4-Oxadiazine-5-ones via [3+3] Cycloaddition of In
Situ Generated Aza-oxyallylic Cations with Nitrile Oxides
Gangqiang Wang, Rongxing Chen, Sen Zhao, Liangfeng Yang, Haibing Guo,
Shaofa Sun, Jian Wang, Justin Domena, Yalan Xing(s)
PII:
S0040-4039(18)30483-0
https://doi.org/10.1016/j.tetlet.2018.04.025
TETL 49888
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
20 March 2018
10 April 2018
Please cite this article as: Wang, G., Chen, R., Zhao, S., Yang, L., Guo, H., Sun, S., Wang, J., Domena, J., Xing(s),
Y., Efficient Synthesis of 1,2,4-Oxadiazine-5-ones via [3+3] Cycloaddition of In Situ Generated Aza-oxyallylic
Cations with Nitrile Oxides, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.04.025
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Gangqiang Wanga, Rongxing Chena, Sen Zhaoa, Liangfeng Yanga, Haibing Guoa,
Shaofa Sun*,a, Jian Wanga, Justin Domenab and Yalan Xing(s)*,b
a.
Professor Shaofa Sun
Non-power Nuclear Technology Collaborative Innovation Center, School of Nuclear Technology
and Chemistry & Biology, Hubei University of Science and Technology, Xianning 437100, China
E-mail: sunshaofa@hbust.edu.cn
b. Professor Yalan Xing
Department of Chemistry, William Paterson University of New Jersey,
300 Pompton Road, Wayne, NJ 07470, US

1,2,4-oxadiazin-5-ones were prepared via [3+3] cycloaddition of in situ generated aza-oxyallylic cations with nitrile oxides in good yields and excellent
functional group compatibility. This efficient transformation is metal-free and is promoted by an inorganic base Cs2CO3. In addition, this reaction features
simple-operation,
mild
conditions,
and
high
regioselectivity.
In 2017, Zhao and Wang independently reported [3+3]
cycloaddition of azaoxyally cations and nitrones for a facile
Introduction
1, 2, 4-oxadiazin-5-ones are important class of heterocyclic
structure motifs which exhibit interesting biological activities.
For instance, 1, 2, 4-oxadiazin-5-one structure motifs are
present in many pesticide molecules1 and angiotensin receptor
antagonists2 (Scheme 1). The synthesis of these structure
motifs have attracted significant attentions from the synthetic
community due to their excellent biological properties.3
Scheme 1. 1,2,4-Oxadiazine-5-ones containng bioactive
molecules
access to 1,2,4-oxadiazinan-5-ones (Scheme 2).7 Very recently,
Cheng described a silver mediated [3+3] cycloaddition of C,N-
cyclic azomethine imines with aza-oxyallyl cations for the
synthesis of isoquinoline-fused triazines (Scheme 2).8 In our
work, we are interested in the utilization of nitrile oxides for
the [3+3] cycloaddition with aza-oxyallylic cations.
In the course of our research into the preparation of
biologically important heterocyclic structures, we thought to
utilize the [3+3] cycloaddition of aza-oxyallylic cations to
construct the heterocyclic ring. Aza-oxyallylic cations, which
-halohydroxamates in the
presence of organic or inorganic bases, represent a class of
useful and versatile synthons for organic synthesis. Recently,
Aza-oxyallylic cations have become widely utilized in the
synthesis of heterocyclic molecules via cycloaddition
reaction.4 Last year, we reported efficient [3+2] cycloaddition
reactions of aza-oxyallylic cations with alkynes5 and
isothiocyanates6 for the synthesis of 1,3-dihydro-2H-pyrrol-2-
ones and thiazolidin-4-ones respectively (Scheme 2). Herein,
we would like to present our study on the synthesis of 1,2,4-
oxadiazine-5-ones via [3+3] cycloaddition of aza-oxyallylic
cations and nitrile oxides.
Our investigation started from using -bromohydroxamate 1a
and hydroximoyl chloride 2a as the model substrates. Toluene
and hexafluoro-2-propanol (HFIP) were employed as solvents.
Different bases such as NaCO3, K2CO3, CsCO3, TEA, DMAP,
NaOH were screened to identify the optimal base for the
generation of both aza-oxyallylic cations and nitrile oxides. The
o
reaction was conducted at room temperature or 50 C for 2 to
24 hours. It was found that CsCO3 in HFIP at rt for 2 hours gave
the best yield (80%) of the [3+3] cycloaddition product 3a
(entry 11, table 1). Triethyl amine in toluene produced the
desired product in comparable yield (78%, entry 5, table 1) but
required higher reaction temperature (50 oC). The optimal
conditions we found are mild and operationally simple,
meanwhile allowing us to efficiently access the novel 1,2,4-
oxadiazine-5-one structure and construct both a C-O bond and
a C-N bond within one pot.
Entrya
Base
Na2CO3
K2CO3
Solvent
Tol
T/h
24
24
24
T/oC
50
Yieldb
25%
27%
36%
1
2
3
Scheme 2. Cycloaddition reaction with aza-oxyallylic cations
Tol
50
Cs2CO3
Tol
50

4
5
TEA
TEA
Tol
2
2
2
2
2
2
2
2
2
r.t.
50
50
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40%
78%
68%
51%
56%
68%
71%
80%
45%
Tol
6
DMAP
TEA
Tol
7
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
8
DMAP
Na2CO3
K2CO3
Cs2CO3
NaOH
9
10
11
12
a Reaction conditions: a mixture of 1a (1.0 mmol), 2a (1.0 mmol),
and base (2.1 mmol) in solvent (2 mL) was stirred at the set
temperature for a certain period of time. bYield of isolated product.
Table 1. Reaction optimization
With the optimal conditions in hand, we next proceeded the
study of both the substrate scope and limitation of this
transformation. First, we fixed a-bromohydroxamate 1a as the
precursor for aza-oxyallylic cation and varied the structure of
hydroximoyl chloride
oxides (Scheme 3). We found that this reaction has a very
general substrate scope and excellent functional group
2 for the formation of a variety of nitrile
Scheme 3. Substrate scope of hydroximoyl chlorides
compatibility. For the substituent on hydroximoyl chloride 2,
both aromatic rings including heteroaromatic rings and
aliphatic chains are tolerated under the optimal conditions.
Additionaly, both electron withdrawing groups and donating
groups on the phenyl ring did not affect the reaction yields.
For instance, halogens such as fluorine and chlorine at
different positions of the phenyl ring all gave good to excllent
yields. The usage of dichloro-substitued phenyl ring (3i) also
provided good yield of the desired product. Electron donating
groups such as methyl (3e) and methoxyl (3c) groups on the
phenyl ring gave slightly lower reaction yields of the
cycloaddition products.
Next, structures of
-halohydroxamate 1 were varied and N-
hydroxybenzimidoyl chloride 2a was used for the investigation
of the substrate scope of the aza-oxyallylic cations (Scheme 4).
Scheme 4. Substrate scope of a-halohydroxamate.
It was found that the substituents at the alpha position of
1
tolerate both mono-substituted alkyl and aromaic groups such
as ethyl (4b) and phenyl (4c) groups. More sterically hindered
substituents at the alpha position did not affect the
performance [3+3] cycloaddition reaction. For example, both
In terms of the reaction mechanism, we believe that the use of
base promotes the formation of the aza-oxyallylic cations from
-halohydroxamate and also nitrile oxides from hydroximoyl
chlorides (Scheme 5). The [3+3] cycloaddition between aza-
oxyallylic cations and nitrile oxides produces 1,2,4-oxadiazine-
5-ones efficiently. The excellent regioselectivity of this reaction
can be explained by both electronic nature and steric effect of
both substrates.
-dimethyl
bromohydroxamates provided good yield of the cycloaddition
products 4d and 4e It is worth to mention that -
and
-methyl,
-ethyl
substituted
.
chlorohydroxamate can also be used to generate aza-oxyallylic
cations as cycloaddition product 4a was smoothly prepared by
using
substituent on the nitrogen of
tolerate methoxy group ( ) and gave good yield.
-chlorohydroxamate as the precursor. In addition, the
-halohydroxamate can also
a
Scheme 5. Substrate scope of -halohydroxamate.

Conclusions
In summary, a highly efficient [3+3] cycloaddition reaction of in situ
generated aza-oxyallylic cations and nitrile oxides were developed.
Structurally fascinating and biologically important 1,2,4-oxadiazine-
5-ones were prepared in good yields, mild reaction conditions,
excllent functional group compatibility, and high regioselectivity.
Conflicts of interest
There are no conflicts to declare
Acknowledgements
This work was supported by University and Education
Department of Hubei Province Science and Technology
Research Project (Nos. Q20162803). Hubei Provincial Natural
Science Foundation of China (Nos. 2017CFC859). The authors
are also grateful to National Natural Science Foundation
(21602053). This research was supported by a grant from the
Center for Research, College of Science and Health, William
Paterson University of New Jersey. The authors are also
grateful to the ART program, College of Science and Health,
and Chemistry Department of William Paterson University.
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8



Efficient synthesis of 1,2,4-Oxadiazine-5-ones
derivatives
[3+3] cycloaddition of in situ generated Aza-
oxyallylic cations with nitrile oxides
Easy operation, metal-free, good yields
Broad functional group tolerance, excellent
regioselelctivity

