Heteroannulation of Alkenes with Enynyl Benziodoxolones and Silver Nitrite Involving CC bond Oxidative Cleavage: Entry to 3-Aryl-?2-isoxazolines

Article abstract of DOI:10.1021/acs.orglett.0c01285

A copper-catalyzed [2 + 2 + 1] heteroannulation of alkenes with enynyl benziodoxolones and AgNO2 involving oxidative cleavage of the CC bond promoted by cooperative Zn(OTf)2, KOAc, and 4 ? MS for producing 3-aryl δ2-isoxazolines is reported. Mechanistic s

Full text of DOI:10.1021/acs.orglett.0c01285

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Letter
[2 + 2 + 1] Heteroannulation of Alkenes with Enynyl
Benziodoxolones and Silver Nitrite Involving CC bond Oxidative
Cleavage: Entry to 3‑Aryl‑Δ2‑isoxazolines
Cheng-Yong Wang, Fan Teng, Yang Li,* and Jin-Heng Li*
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ABSTRACT: A copper-catalyzed [2 + 2 + 1] heteroannulation of alkenes with enynyl benziodoxolones and AgNO2 involving
oxidative cleavage of the CC bond promoted by cooperative Zn(OTf)2, KOAc, and 4 Å MS for producing 3-aryl Δ2-isoxazolines is
reported. Mechanistic studies indicate that AgNO2 serves as the N/O two-atom unit source, enabling the formation of three bonds
through NO2 addition across the CC bond, NO-transfer, CC bond cleavage, and annulation cascades.
soxazolines are ubiquitous core structures that exist in many
natural products, pharmaceuticals, and organic materials
philic addition or transition-metal catalysis.3−6 However, most
of which are restrict to special unsaturated compounds under
harsh conditions. In particular, approaches for preparing Δ2-
isoxazolines are much less developed, and such versions that
are general to alkenes, especially unactivated alkenes, are
rare.3−6 In 2015, Xu and co-workers developed a multi-
component strategy to regioselectively access 3-carbonyl Δ2-
isoxazolines via tBuCN-promoted [2 + 2 + 1] heteroannulation
of terminal alkynes with alkenes and Cu(NO3)2 (Scheme 2a).5
By employing stoichiometric Cu(NO3)2 as both the catalyst
and the N/O two-atom unit source, this process enables the
I
and serve as ligands and versatile synthetic intermediates.1,2
Among them, Δ2-isoxazolines, especially 3-aryl-substituted
systems (Scheme 1), have discovered broad applications as
Scheme 1. Examples of Important 3-Aryl-Δ2-isoxazolines
Scheme 2. [2 + 2 + 1] Heteroannulation
agrochemicals, pharmaceuticals, and organic materials.2 For
example, both afoxolaner (I) and lotilaner (II) show highly
insecticidal activity and have been used commercially for
animal health.2a,b Oxathiapiprolin (III) is an antifungal agent
as discovered by DuPont that is used for control of plant
diseases caused by oomycetes.2c,d For these reasons, the
development of efficient synthetic processes to the assembly of
functionalized Δ2-isoxazolines in a modular and selectivity-
controlled manner remains a great significance.
Traditionally, typical methods to build such isoxazoline
skeletons focus on the use of nitrile oxides and their precursors
as reactants3−6 via intermolecular 1,3-dipolar [3 + 2]
cycloaddition of nitrile oxide intermediates with unsaturated
compounds (e.g., alkenes, enols and alkynes)4,5 or intra-
molecular cyclization of γ,δ-unsaturated oximes6 by electro-
Received: April 12, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01285
© XXXX American Chemical Society
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A

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formation of four new bonds in a single reaction involving an
alkyne hydration process. However, this method is limited to
the activated electron-poor alkenes and alkylalkenes leading to
the 3-carbonyl-substituted skeleton. Thus, unremitting discov-
ery of new general multicomponent strategies that accom-
modate to broad alkenes and readily introduce functional
groups for building functionalized Δ2-isoxazolines, especially
the important 3-aryl-susbtituted system, is highly desirable.
Herein, we report a new Cu(MeCN)4PF6-catalyzed three-
component [2 + 2 + 1] heteroannulation of alkenes and enynyl
benziodoxolones (EBXs) and AgNO2 promoted by the
Zn(OTf)2/KOAc/4 Å MS system for producing functionalized
Δ2-isoxazolines, especially including pharmacologically relevant
3-aryl-substituted variants (Scheme 2b). The reaction employs
AgNO2 as the N/O two-atom unit source7 to allow the
formation of three new bonds, a C−C bond, a C−O bond, and
a CN bond, through NO2 addition across the CC bond,
NO-transfer, CC bond cleavage, and annulation cascades
and features a broad scope of alkenes, including unactivated
alkenes.
and 4 Å MS afforded the desired product 4aaa in 70% yield
(entry 1). A very small amount of product was obtained
without Cu(MeCN)4PF6 (entry 2). Several other Cu salts,
namely CuI, CuBr, copper(I) thiophene-2-carboxylate
(CuTc), and Cu(OTf)2, showed high catalytic activity, but
they all were less efficient than Cu(MeCN)4PF6 (entries 3−6).
We found that Zn(OTf)2, 4 Å MS or KOAc acted as a
promoter since omission of each the reaction could occur
(entries 7−9). Using DBU or K2CO3 instead of KOAc was
proven to be disfavored (entries 10 and 11). Both DMF and
toluene both were inferior to MeCN (entries 12 and 13).
While a lower temperature (60 °C) had a negative effect (entry
14), a higher reaction temperature (100 °C) gave a yield
identical to that of 80 °C (entry 15). A series of other N/O
two-atom unit sources, including NaNO2 2b, NaNO2 2b/
t
AgOAc, AgNO3 2c, BuNO2 (TBN; 2d), and Cu(NO3)2 2e,
were evaluated (entries 16−19). Three sources, NaNO2,
NaNO2//AgOAc, and AgNO3, were less reactive than
AgNO2 attributed to a lower conversion of alkene 1a (entries
16 and 17). Similarly, both TBN and Cu(NO3)2, the reported
effective N/O two-atom unit source,5 had no reactivity for the
[2 + 2 + 1] heteroannulation reaction, but vinyl C−H nitration
formed 5aa (entries 18 and 19). Notably, no [2 + 2 + 1]
heteroannulation of 1a with 2a occurred under the Xu
conditions (entry 20).5 These results suggest a different
mechanism from the Xu reaction5 probably because the
current reaction utilized EBXs that are internal alkynes with
internal oxidation to replace common terminal alkynes used by
Xu group. Delightedly, the reaction with a scale up to 1 mmol
of 1a was successful to afford 4aaa in 65% yield (entry 21).
The scope of this [2 + 2 + 1] heteroannulation protocol with
respect to alkenes 1 and EBXs 2 was investigated (Schemes 3
and 4). A wide range of alkenes, including arylalkenes,
alkylalkenes and acrylates, were compatible with the optimal
conditions (4baa−taa). For arylalkenes, several substituents,
We initiated our efforts to explore a multicomponent [2 + 2
+ 1] heteroannulation strategy for the synthesis of Δ2-
isoxazoline using 4-methoxystyrene (1a), phenylenynyl
benziodoxolone (Ph-EBX; 2a), and AgNO2 (3a) as model
substrates (Table 1). Gratifyingly, treatment of alkene 1a with
Ph-EBX 2a, AgNO2 3a, Cu(MeCN)4PF6, Zn(OTf)2, KOAc,
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry
variation from the standard conditions
4aaa
5aa
1
2
3
4
5
6
7
8
none
70
10
55
59
57
55
30
42
50
31
47
54
50
53
66
15
6
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
without Cu(MeCN)4PF6
CuI instead of Cu(MeCN)4PF6
CuBr instead of Cu(MeCN)4PF6
CuTc instead of Cu(MeCN)4PF6
Cu(OTf)2 instead of Cu(MeCN)4PF6
without Zn(OTf)2
a
Scheme 3. Variation of the Alkenes (1) and EBXs (2)
without molecular sieve
without KOAc
9
10
11
12
13
14
15
16
17
18
19
20
DBU instead of KOAc
K2CO3 instead of KOAc
DMF instead of MeCN
toluene instead of MeCN
60 °C
100 °C
b
NaNO2 (2b) instead of AgNO2
AgNO3 (2c) instead of AgNO2
tBuNO2 (2d) instead of AgNO2
Cu(NO3)2 (2e) instead of AgNO2
Xu conditions5
c
trace
trace
0
82
80
30
0
d
e
21
none
65
a
Reaction conditions: 1a (0.3 mmol), 2a (2 equiv), AgNO2 (2 equiv),
Cu(MeCN)4PF6 (10 mol %), Zn(OTf)2 (50 mol %), KOAc (1
equiv), 4 Å MS (50 mg), MeCN (1 mL), argon, 80 °C, and 24 h.
b
>80% of 1a was recovered in the presence/absence of AgOAc (2
c
d
a
equiv). >90% of 1a was recovered. Cu(NO3)2·3H2O (2 equiv),
Reaction conditions: 1 (0.3 mmol), 2 (2 equiv), AgNO2 (2 equiv),
e
tBuCN (2 equiv), PhCN (1.5 mL), 60 °C and N2. 1a (1 mmol) and
Cu(MeCN)4PF6 (10 mol %), Zn(OTf)2 (50 mol %), KOAc (1
equiv), 4 Å MS (50 mg), MeCN (1 mL), argon, 80 °C, and 24 h.
36 h.
B
https://dx.doi.org/10.1021/acs.orglett.0c01285
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the oxygen atom in 4aaa was not from water (eq 2). Omission
of alkenes 1 led to the formation of benzonitrile 8a from the
reaction of Ph-EBX 2a with AgNO2 3a (eq 3). The reaction
still proceeded smoothly when a stoichiometric radical
inhibitor, TEMPO or 2,6-di-tert-butyl-4-methylphenol
(BHT), was used, thus ruling out a free-radical process (eq
4). Replacement of Ph-EBX 2 by benzaldehyde or
Scheme 4. Synthetic Utilizations, Control Experiments, and
Possible Mechanisms
benzaldehyde oxime (the previous reported effect reagent3−6
)
indicated that benzaldehyde was inert (eq 5), and
benzaldehyde oxime furnished benzonitrile 8a, not the
expected isoxazoline 4aaa (eq 6). The results suggest that
AgNO2 first reacts with EBXs, and either benzaldehyde or
benzaldehyde oxime was not the intermediates. Employing 2-
nitro-1-phenylethan-1-one 9 instead of EBXs 2 promoted by
AgNO2 3a afforded 3-carbonyl isooxazoline 10,5 not 4aaa,
implying that substrate 9 is not the intermediate (eq 7).
The possible mechanism of the [2 + 2 + 1] heteroannulation
protocol was proposed on the basis of the present results and
literature results (Scheme 4).3−7 Complexation of Ph-EBX 2a
with the active LnCu(I) species affords the intermediate A,
followed by addition across the CC bond to afford the
intermediate B. Reductive elimination and NO transfer of the
intermediate B forms the intermediates C or D and regenerate
the active LnCu(I) species.3−5,7 The C−C bond cleavage9 of
the intermediate D by a combined effect of 2a, AgNO2,
Cu(MeCN)4PF6, Zn(OTf)2, KOAc, and 4 Å MS delivers the
dipolar nitrile oxide intermediate E and releases CO (Figure
S1, Supporting Information). Finally, annulation of the
intermediate E with alkene 1 furnished product 4.
such as MeO, Br, Cl, and NO2, on the aryl ring at the terminal
alkene were perfectly tolerated, and their electronic and
position nature affected the reaction (4baa−kaa). While
styrene 1b was converted to 4baa in 63% yield, alkene 1f
with a strong electron-withdrawing NO2 group gave 4faa in
diminishing yield. Fascinatingly, the halogen (Br and Cl)
groups were retained in the resulting products 4daa−eaa,
which would be used as a vehicle for further manipulations. We
found that m-Me-substituted arylalkene 1g was more reactive
than o-Me-substituted 1h (4gaa,haa). Functionalized arylal-
kenes, 2-vinylnaphthalene (1i), 2-vinylpyridine (1j), and 4-
methyl-5-vinylthiazole (1k), were subjected to the reaction
(4iaa−kaa). Oct-1-ene (1l), a terminal aliphatic alkene, was a
suitable substrate (4laa). Using electron-poor alkenes 1m,n
efficiently furnished 4maa,naa in good yields. Bulky 1,1-
disubstituted alkenes 1o−q also worked well to give 4oaa−
qaa, respectively. The reaction accommodated internal alkenes
(norbornene and its derivatives) 1r−t, which makes this
reaction more attractive in synthetic applications (4raa−taa).
The generality of this [2 + 2 + 1] heteroannulation protocol
to the EBXs 2 was next exploited. The reaction was affected by
the substitution effect at the terminal alkyne. While electron-
donating Me-substituted aryl-EBX 2b furnished 4aba with 66%
yield, electron-withdrawing Br-, Cl-, and MeCO-substituted
aryl-EBXs 2c−e assembled 4aca−aea, respectively, in 55%−
58% yields. Aryl-EBXs 2f−h bearing a m-MeO, an o-Ph or a
naphthalen-1-yl group were also viable to assemble 4afa−aha.
Unfortunately, aliphatic EBX 2i was inert for the hetero-
annulation (4aia). Another alkynyl hypervalent iodine (2j)
exhibited lower reactivity, giving 4aaa in 10% yield. However,
(iodoethynyl)benzene (2k) and phenylacetylene (2l) had no
reactivity.
On the other hand, the intermediate E might undergo the
reduction reaction with the active LnCu(I) species to afford
benzonitrile 8.10 The role of 4 Å MS might play a drying effect
to avoid hydration of alkynes.
In conclusion, we have developed a novel copper-catalyzed
[2 + 2 + 1] heteroannulation of alkenes, EBXs, and AgNO2 for
the synthesis of 3-aryl Δ2-isoxazolines involving the CC
bond cleavage. The reaction is facilitated by the Zn(OTf)2/
KOAc/4 Å MS system and features a broad alkene scope with
exquisite selectivity control and excellent functional group
tolerance. Importantly, AgNO2 serves as the efficient N/O
two-atom unit source to access polysubstituted Δ2-isoxazo-
lines, which had been applied as versatile synthetic
intermediates in preparing highly valuable compounds.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01285.
Experimental details, NMR spectra, and details of the
experiments (PDF)
Accession Codes
CCDC 1040053 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Gratifyingly, isoxazoline 4aaa is a versatile intermediate and
could be readily converted into valuable isoxazole 6aaa8a or 3-
amino-propan-1-ol 7aaa8b in high yields (eq 1; Scheme 4).
The 18O-labeled experiment was conducted and indicated that
C
https://dx.doi.org/10.1021/acs.orglett.0c01285
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AUTHOR INFORMATION
Corresponding Authors
■
̈
Yang Li − Key Laboratory of Jiangxi Province for Persistent
Pollutants Control and Resources Recycle, Nanchang Hangkong
University, Nanchang 330063, China;
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Email: liyang8825490@126.com
Jin-Heng Li − Key Laboratory of Jiangxi Province for Persistent
Pollutants Control and Resources Recycle, Nanchang Hangkong
University, Nanchang 330063, China; State Key Laboratory of
Chemo/Biosensing and Chemometrics, Hunan University,
Changsha 410082, China; Key Laboratory of Functional
Metal−Organic Compounds of Hunan Province, Key
Laboratory of Functional Organometallic Materials, University
of Hunan Province, Hengyang Normal University, Hengyang
421008, China; orcid.org/0000-0001-7215-7152;
Email: jhli@hnu.edu.cn
Authors
Cheng-Yong Wang − Key Laboratory of Jiangxi Province for
Persistent Pollutants Control and Resources Recycle, Nanchang
Hangkong University, Nanchang 330063, China; Key
Laboratory of Functional Metal−Organic Compounds of
Hunan Province, Key Laboratory of Functional Organometallic
Materials, University of Hunan Province, Hengyang Normal
University, Hengyang 421008, China
Fan Teng − Key Laboratory of Jiangxi Province for Persistent
Pollutants Control and Resources Recycle, Nanchang Hangkong
University, Nanchang 330063, China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(Nos. 21625203 and 21871126) for financial support.
■
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