A highly diastereoselective [3+3] annulation reaction of aza-oxyallyl cations and nitrones

Article abstract of DOI:10.1016/j.tetlet.2018.03.085

An efficient synthesis of 1,2,4-oxadiazinan-5-ones via [3+3] cycloaddition of in situ generated aza-oxyallyl cations with nitrones has been developed. The protocol features easy operation, excellent yields, excellent diastereo-control, broad substrate sco

Full text of DOI:10.1016/j.tetlet.2018.03.085

Accepted Manuscript
A Highly Diastereoselective [3+3] Annulation Reaction of Aza-oxyallyl Cations
and Nitrones
Rongxing Chen, Shaofa Sun, Gangqiang Wang, Haibin Guo
PII:
S0040-4039(18)30412-X
https://doi.org/10.1016/j.tetlet.2018.03.085
TETL 49854
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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14 February 2018
26 March 2018
28 March 2018
Please cite this article as: Chen, R., Sun, S., Wang, G., Guo, H., A Highly Diastereoselective [3+3] Annulation
Reaction of Aza-oxyallyl Cations and Nitrones, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.03.085
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An efficient synthesis of 1,2,4-oxadiazinan-5-ones via [3+3]
A Highly Diastereoselective [3+3] Annulation
Reaction of Aza-oxyallyl Cations and
Nitrones
cycloaddition of in situ generated aza-oxyallyl cations with
nitrones has been developed, The protocol features easy
operation, excellent yields, excellent diastereoselectivities,
broad substrate scope and good functional group tolerance.

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A Highly Diastereoselective [3+3] Annulation Reaction of Aza-oxyallyl Cations and
Nitrones
Rongxing Chen, Shaofa Sun,* Gangqiang Wang,* Haibin Guo
College of Chemistry and Biological Sciences, Hubei University of Science and Technology, Hubei Province 437100, China; E-mail: sunshaofa@hbust.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient synthesis of 1,2,4-oxadiazinan-5-ones via [3+3] cycloaddition of in situ generated
aza-oxyallyl cations with nitrones has been developed, The protocol features easy operation,
excellent yields, excellent diastereo-control, broad substrate scope and good functional group
tolerance.
Available online
2014 Elsevier Ltd. All rights reserved.
Keywords:
[3+3] annulation
aza-oxyallyl cations
nitrones
metal-free
The aza-oxyallylic cation intermediates had long been
investigated since the Sheehan group reported it in 1960s1 and
following confirmed by Sakamoto et al.2 Owing to its unique
chemical properties, many efforts have been made to use these
intermediates to rapidly construct medicinally important
heterocycles3. In 2011, the Jeffrey group reported an elegant [4+3]
cycloaddition reaction of aza-oxyallylic cations with dienes4,
resulting in a bridged bicyclic compound (Scheme 1e). Later on, the
Jeffrey group and others discovered a novel [3+2] cycloaddition by
utilizing aza-oxyallylic cations as intermediates to react with various
substituted indoles, affording pyrrolindolines in good to excellent
yields5. Recently, Wang, Lin and Jeffrey successfully uncovered a
[3+2] cycloaddition of aza-oxyallyl cations to aldehydes respectively
(Scheme 1b-c)6. Additionally, Xing and co-workers conducted the
synthesis of 1,3-dihydro-2H-pyrrol-2-one derivatives by using a [3+2]
cycloaddition of aza-oxyallylic cations and alkynes (Scheme 1d)7.
Shortly after, Chen and co-workers reported [3+1] (Scheme 1a) and
[3+2] cycloaddition reactions of azaoxyallyl cations with sulfur
ylides to give - and -lactam derivatives8. In contrast to other
intensively studied cycloadditions of aza-oxyallylic cations, to date,
the [3+3] cycloadditions of aza-oxyallylic cations received much less
attention. There is an only example of [3+3] cycloaddition of
azaoxyallyl cations reported by Wu et al. very recently (Scheme 1f).9
On the other hand, nitrones are useful synthons and used as
versatile 3-units in [3+2]10 or [3+3]11 cycloaddition reactions12 for
the construction of densely functionalized five- or six-membered
N,O-containing heterocycles13. Meanwhile, most nitrones are stable
compounds that could be operated easily. As part of our interests on
seeking efficient methods for heterocyclic synthesis,14 we herein
wish to report a practical procedure for making 1,2,4-
oxadiazinan-5-ones through a formal [3+3] cycloaddition of
Scheme 1. Cycloaddition reactions of aza-oxyallyl cations.

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nitrones with aza-oxyallylic cations under mild conditions
afford the corresponding products in good to high yields (3n and 3o,
98% and 78%, respectively). In addition, when N-benzyl group
replaced N-methyl substituent on nitrones, excellent yields were still
generally achieved (3ru, 9096%).
(Scheme 1g) 15
.
Considering the easily preparation of azaoxyallyl
cations and excellent diastereo-control of this process, we believe
our method has developed a formal [3+3] cycloadditions.
The model reaction of N-(benzyloxy)-2-bromopropanamide 1a
and nitrone 2a in the presence of Na2CO3 was initially investigated.
As shown in Table 1, the solvent seems to play a critical role on
reaction efficiency. CH3CN allows the reaction proceeded smoothly
to afford the corresponding 4-(benzyloxy)-2,6-dimethyl-3-phenyl-
1,2,4 oxadiazinan-5-one 3a in good yield and excellent
diastereoselectivity (entry 7, 73%, >19: dr, 24 h). To our delight,
Table 2. Scope of nitrones.a
o
elevating temperature to 50 C yielded 3a almost quantitatively
in 3 h only (entry 8, 98%). Nevertheless, no product was
achieved when the reaction was carried out in other solvents
such as methanol, trifluoroethanol (CF3CH2OH), DCM, THF
and DCM (entries 1-2, 4-6). Hexafluoroisopropanol (HFIP)
could give the desired product 3a in a moderate yield (65%),
but only with a poor diastereoselectivity (entry 3, 1.6:1 dr).
Further study showed that the base is also another critical factor for
the reaction efficiency (entries 9-14). Organic bases (e.g. pyridine,
DBU) and inorganic base (e.g. NaOAc) almost did not promote the
reaction (entries 10, 12-14). Surprisingly, K2CO3, NaOH and TEA
provided fair to moderate yields of 3a (entries 9, 11, and 14, 75%,
32%, and 53%, respectively). Finally, the optimal conditions were
achieved when the reaction was performed in the presence of
Na2CO3 as base and CH3CN as medium.
Table 1. Optimization of the reaction conditions.a
Entry
Base
Solvent
Time (h) Yield
(%)b
d.r.c
1
2
3
4
5
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
NaOAc
NaOH
MeOH
CF3CH2OH
HFIP
24
24
24
24
24
24
24
3
24
24
24
24
24
24
<5
<5
65
<5
<5
<5
73
98
75
<5
32
<5
<5
53
-
-
1.6:1
-
-
-
>19:1
>19:1
>19:1
-
>19:1
-
DMF
THF
DCM
6
7
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
8d
9
10
11
12
13
14
pyridine
DBU
TEA
-
>19:1
a
Reaction conditions: a mixture of 1a (1.0 mmol), 2a (1.1 mmol),
and base (2.0 mmol) in solvent (2 mL) was stirred at roomg
temperature for a certain period of time. b Yield of isolated product. c
Diastereomeric ratio. d 50 oC.
With the optimized conditions in hand, we next evaluated the
generality of nitrones 2. As indicated in Table 2, the substituent
pattern and the electronic nature of nitrones 2 have limited effects on
reaction conversion. In general, the corresponding products were
obtained in good to high yields and with all excellent
diastereoselectivities (3ak, 7898%, >19:1 dr). When nitrones
beared 2-naphthyl, alkenyl, alkynyl or disubstituted pattern on
phenyl ring, the corresponding products were obtained in high yields
a
(3lm and 3pq, 8189%). Moreover, nitrones bearing
a
Reaction conditions: a mixture of 1a (1.0 mmol), 2a (1.1 mmol),
heterocyclic ring (e.g. 2-thiophenyl or 3-pyridinyl ring) could still

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3
and Na2CO3 (2.0 mmol) in CH3CN (2.0 mL) was stirred at 50 oC for
4-6 h. b Yield of isolated product.
We then turned our attention to examine the scope of α-
halohydroxamates 1. As shown in Table 3, all substrates displayed
good performance and provided the corresponding products in
moderate to high yields. When R1 = H and R2 = ethyl, phenyl or
chloro group, reaction yielded the corresponding products 4ac in
good to excellent yields (7696%). When R1 and R2 were identical
groups (e.g. chloro or methyl), the relative O-alkylhydroxamates
provided excellent reactivity (4d and 4e, 95% and 98%, respectively).
When N-OBn was replaced by N-OMe, 4f could still be achieved in
a high yield and an excellent dr (Table 3). The relative configuration
of products was assigned by X-ray single crystal analysis of 4g
(Figure 1).16
Scheme 2. Proposed mechanism.
Table 3. Scope of α-halohydroxamates.a
In summary, we have developed an efficient [3+3]
cycloaddition of nitrones to in situ generated aza-oxyallylic
cations. This protocol provides a straightforward access to
biologically important 1,2,4-oxadiazinan-5-ones derivatives in
good to excellent yields under mild conditions. The further
development of this cycloaddition process to other heterocycles
is ongoing in our laboratory.
Acknowledgments
Financial support from the Hubei Provincial Department of
Education (T201419) and Education Department of Hubei Province
Science and Technology Research Project (Nos. Q20162803), the
Hubei Provincial Natural Science Foundation of China
(2017CFC859) and the Non-power Nuclear Technology
Collaborative Innovation Center (Hubei Province) are greatly
appreciated.
Supplementary Material
Supplementary data associated with (experimental procedures and
compound characterization data) this article can be found, in the
online version.
a Reaction conditions: a mixture of 1 (1.0 mmol), 2a (1.1 mmol), and
o
Na2CO3 (2.0 mmol) in CH3CN (2.0 mL) was stirred at 50 C for 4-6
h. b Yield of isolated product.
References and notes
On the basis of above experimental results,
a plausible
mechanism was proposed (Scheme 2). Under standard conditions,
Na2CO3 promotes the formation of the intermediate azaoxyallyl
cation A. The followed nucleophilic attack of nitrones 2 delivers the
zwitterion intermediate B. Finally, the nitrogen anion undergoes
intramolecular nucleophilic attack to generate final product 3 or 4.
The diastereomeric ratios of all cycloadducts were >19:1, suggested
that the major trans-cycloadduct is favoured thermodynamically.
Further investigation of enantiomeric control of this reaction is under
way. Additionally, a concerted [3+3] cycloaddition mechanism
cannot be completely ruled out.
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Figure 1. X-ray single crystal analysis of 4g.

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15. In the preparation of this manuscript, the Wang group reported a
very similar work: Jia, D.; Li, D.; Lang, M.; Zhang, K.; Wang, J.
Adv. Synth. Catal. 2017, 359, 3837. Unfortunately, relatively
low disastereoselectivities were observed in their products (4aj,
Table 4). In sharp contrast, our reaction system provided
excellent diastereo-control for all products (Table 3).
16. CCDC 1541516
(
4g
)
contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.

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Highlights



excellent diastereo-control
broad substrate scope
high chemical yield