From Alkenes to Isoxazolines via Copper-Mediated Alkene Cleavage and Dipolar Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.9b02748

An unprecedented copper-mediated anion transformation is reported, along with selective C= C double bond cleavage and dipolar cycloaddition reaction from simple alkenes and inexpensive copper nitrate. Various transformations demonstrate the generality of this method. Further mechanistic investigation indicates a novel ionic pathway for alkene cleavage and highlights the coeffect of iodide and boric acid as additives on the inhibition of well-documented competitive nitration byproducts.

Full text of DOI:10.1021/acs.orglett.9b02748

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
From Alkenes to Isoxazolines via Copper-Mediated Alkene Cleavage
and Dipolar Cycloaddition
Mingchun Gao,†,§ Yuansheng Gan,†,§ and Bin Xu*,†,‡
†Department of Chemistry, Innovative Drug Research Center, School of Materials Science and Engineering, Shanghai University,
Shanghai 200444, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
S
* Supporting Information
ABSTRACT: An unprecedented copper-mediated anion
transformation is reported, along with selective CC double
bond cleavage and dipolar cycloaddition reaction from simple
alkenes and inexpensive copper nitrate. Various trans-
formations demonstrate the generality of this method. Further
mechanistic investigation indicates a novel ionic pathway for alkene cleavage and highlights the coeffect of iodide and boric acid
as additives on the inhibition of well-documented competitive nitration byproducts.
Scheme 1. Copper-Mediated Anion Transformations and
Alkene Cleavage
opper-promoted coupling reaction is one of the most
Cpowerful tools in organic synthesis. In the past decades,
this strategy has been widely applied in the formation and
cleavage of inert chemical bonds, leading to complicated
molecules or heterocyclic compounds.1 For example, the
Chan−Evans−Lam coupling reaction is a frequently used
method for C−N bond formation,2 while the Ullmann reaction
provides an efficient pathway to biaryls through C−C bond
formation.3 The characteristics of low cost and abundant
reserves make copper salts favorable over other noble
transition metals and acceptable to use in stoichiometric
amounts in reactions. Thus, more and more attention has been
given to copper-mediated anion transformations. In these
reactions, copper salt acts not only as a reagent, but also as a
crucial promoter or catalyst (Scheme 1a). The classic
Sandmeyer reaction is representative, involving C−X (X =
Cl, Br, CN) bond formation through C−N bond cleavage.4
Alternatively, C−Si5 and C−B6 bond functionalization were
further explored with stoichiometric copper salts. In recent
decades, copper-mediated anion transformations involving C−
H functionalization turn out to be a superior choice. An
elegant example was reported by Yu group, where Cu(OAc)2
was employed for acetylation and hydroxylation.7 Almost at
the same time, Shi and co-workers developed a ortho C−H
chlorination in the presence of CuCl2.8 Isocyanide induced
activation of copper sulfate is recently disclosed by our group,
affording sulfonic esters through C−H sulfonation.9 Besides,
copper nitrate has been proven to be a common and versatile
reagent10 for the synthesis of nitro compounds,11 nitrates,12
and heterocycles.13
Transition-metal-promoted alkene cleavage is a fundamental
functional group interconversion in olefin chemistry, and takes
a privileged position in the synthesis of a wide variety of
natural products, pharmaceuticals, and functional materials.14
Oxidative cleavage using Lemieux−Johnson protocol15 and
Received: August 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02748
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ring-closing metathesis (RCM) process16 are two of the most
common methods, although noble metals and toxic reagents
are often required. Recently, great progresses have been made
on copper-promoted aerobic alkene cleavage (Scheme 1b).17
However, in most cases, only carbonyl products are generally
obtained via radical pathway with the assistance of copper salts
and oxygen. Herein, we report an unprecedented copper
nitrate-mediated anion transformation from simple alkenes to
isoxazolines, involving sequential one CC double bond
cleavage and three new chemical bond formations (Scheme
1c). The significance of this given chemistry is 3-fold: (1) it is
the first example for the synthesis of N-heterocycles through
the combination of copper-mediated anion transformation and
selective alkene cleavage; (2) easily accessible nitroalkenes18
and nitroethanols,19 by well-documented olefinic competitive
nitration reaction, are greatly inhibited through the coeffect of
iodide and boric acid as additives; and (3) different from the
previous works, copper-mediated selective alkene cleavage is
realized in this work through a novel ionic pathway.
transformation, since ferric, cobalt, or potassium nitrate failed
to initiate the reaction (Table 1, entry 7). Surprisingly, the
yield of 2a increased dramatically to 53% when 1 equiv of NaI
was employed as an additive (Table 1, entry 8). This result
encouraged us to examine a series of additives, and KI was the
best choice since the undesired byproduct 2a′ was almost
inhibited under the conditions (Table 1, entries 9−12). To our
delight, desired product could be isolated in 80% yield when
mixed solvent was used (Table 1, entry 13), and the yield of 2a
increased to 87% in the presence of 1 equiv of boric acid
(Table 1, entry 14).20 After further optimization of solvent
ratio, temperature, and atmosphere, we confirmed that the
reaction performed best at 80 °C under an air atmosphere
(Table 1, entry 14 vs entries 15−21).
With the optimized reaction conditions in hand, we next
examined the substrate scope of alkenes (Scheme 2). Various
a
Scheme 2. Substrate Scope of Alkenes
We commenced the study by examining the reaction of n-
butyl acrylate (1a) with copper nitrate trihydrate in
acetonitrile. Intriguingly, the desired isoxazoline product 2a
was afforded in 33% yield, along with the unexpected
formation of 2a′ in 27% yield (Table 1, entry 1). Other
solvents including toluene, dioxane, DMSO, EtOH, and PhCN
were proven to be less efficient in this reaction (Table 1,
entries 2−6). A further screening of various nitrate salts
indicated that copper nitrate was crucial to the success of this
a
Table 1. Optimization of Reaction Conditions
b
entry
solvent
CH3CN
toluene
dioxane
DMSO
EtOH
PhCN
CH3CN
additive
yield (%)
1
2
3
4
5
/
/
/
/
/
/
/
33 (27)
<5
20
<5
<5
16
6
7
a
Reaction conditions: 1 (0.4 mmol), Cu(NO3)2·3H2O (1.0 equiv),
c
<5
KI (1.0 equiv), B(OH)3 (1.0 equiv), CH3CN/PhCN (2:1, v/v, 2.0
mL), air, 80 °C. Yields shown are of the isolated products. The
reaction was performed in CH3CN.
8
9
CH3CN
CH3CN
CH3CN
CH3CN
NaI
KI
TBAI
LiI·H2O
KBr
KI
KI + B(OH)3
KI + B(OH)3
KI + B(OH)3
KI + B(OH)3
KI + B(OH)3
KI + B(OH)3
KI + B(OH)3
KI + B(OH)3
53
66
29
58
<5
80
87
74
75
72
b
10
11
12
13
14
15
16
17
18
19
20
21
acrylates performed smoothly (2a−2f), albeit a slightly
decreased yield was obtained for the sterically hindered
substrate (2f). Success of this transformation could also be
applied to vinyl ketones, regardless of aryl or aliphatic
substituents (2g−2k). Furthermore, the reaction conditions
were also suitable for acrylamides (2l and 2m). However, no
corresponding product could be generated from acrylonitrile
substrate (2n), which might be due to the strong coordination
of the cyano group to the Cu center.
CH3CN
CH3CN/PhCN (2:1)
CH3CN/PhCN (2:1)
CH3CN/PhCN (1:1)
CH3CN/PhCN (5:1)
CH3CN/PhCN (1:2)
CH3CN/PhCN (2:1)
CH3CN/PhCN (2:1)
CH3CN/PhCN (2:1)
CH3CN/PhCN (2:1)
d
77
82
73
e
f
Generally, it is relatively more difficult to realize the
intermolecular reactions for alkene substrates in a chemo-
selective manner, compared with intramolecular ones. The
difficulty lies in promoting the desired reaction selectively
while avoiding the unexpected homocoupling reactions.21 We
contemplated the problem might be overcome through
increasing the amount of copper nitrate, so that the alkene
substrate with slightly higher reactivity will be quickly turned
g
78
a
Reaction conditions: 1a (0.4 mmol), Cu(NO3)2·3H2O (0.4 mmol),
additive (0.4−0.8 mmol), solvent (2.0 mL), air, 80 °C, 18−20 h.
b
Isolated yield of product 2a. Yield of byproduct 2a′ is given in the
c
parentheses. Fe(NO3)3·9H2O, Co(NO3)2·6H2O or KNO3 was used
d
e
as nitrogen source instead of Cu(NO3)2·3H2O. At 70 °C. At 90 °C.
f
g
Under O2. Under N2.
B
DOI: 10.1021/acs.orglett.9b02748
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Organic Letters
Letter
into the intermediate, and then captured by another alkene.
Acrylates and vinyl ketones were then chosen as the substrates
for the modular synthesis, which afforded isoxazolines
selectively with various substituents at 3- and 5-positions, as
shown in Scheme 3. The reaction features good functional
benzoyl isoxazoline and isoxazole were afforded by initiating
the reaction from alkyne instead of acrylate.13a
To further demonstrate the generality of this reaction, a
variety of cyclic alkenes were explored as the dipolarophiles.
Pleasingly, the fused bicyclic products were afforded for both
acrylates (4a−4c) and vinyl ketone (4d) with free N−H
untouched. Alternatively, N-substituted maleimides could also
act as good dipolarophiles in the cycloaddition, regardless of
aliphatic or aryl substituents on the nitrogen atom (4e−4l).
Notably high regioselectivity was obtained during the cyclo-
addition, affording products (4m−4o) without regio-isomers.
After oxidative aromatization, the obtained “saccharin-like”
compounds could be further converted into structural
analogues of commercial nonsteroidal anti-inflammatory
drugs (NSAID) Tenoxicam and Piroxicam.22
Scheme 3. Substrate Scope of Alkenes for Intermolecular
a
Reactions
To illustrate the utility of this approach, further trans-
formations of generated products were performed (Scheme 4).
Scheme 4. Transformations of Products
Because of the inductive effect of oxygen atom in isoxazoline
ring, the carbonyl group at its β-position could be reduced
selectively at low temperature in the presence of NaBH4,23
affording the lactam product 5a in excellent yield. Alternatively,
under the reductive conditions of Pd/C and tetrahydronaph-
thalene (THN), product 5b was obtained in 76% yield with
the isoxazoline ring broken, the structure of which was further
determined by X-ray diffraction.24 Note that no approach has
been documented to prepare the amino acid-derived
polysubstituted captodative alkenes so far. As expected, the
alkoxy carbonyl group on the 3-position could smoothly be
hydrolyzed into the carboxylic group almost quantitatively
under mild basic conditions (5c). When ammonium hydroxide
was used as the base, fully substituted isoxazoline 5d was
achieved in 60% yield, which was hard to synthesize through
other approaches. However, under the same conditions,
aromatized isoxazole 5e was obtained from 4o, where the
sulfonyl group was eliminated during the reaction.24
To define the possible intermediate and clarify the pathway
of the reaction, a series of control experiments were conducted
(Scheme 5). The reaction occurred smoothly in the presence
of radical inhibitors such as 1,4-dinitrobenzene or 2,2,6,6-
tetramethylpiperidine-1-oxy (TEMPO), which suggested that
the radical mechanism might be ruled out (eq 1 in Scheme 5).
Based on the fact that ethyl-2-nitroacetate 6 could be
transformed to the final product in almost quantitative yield,
a
Reaction conditions: 1 (0.3 mmol), 1 or 3 (4.0 equiv), Cu(NO3)2·
3H2O (4.0 equiv), KI (1.0 equiv), B(OH)3 (1.0−2.0 equiv),
CH3CN/PhCN (2:1, v/v, 3.0 mL), air, 80 °C. Yields shown are of
the isolated products. In CH3CN. At 70 °C. dThe reaction was
b
c
conducted in 1 g scale.
group tolerance, for example, amide (2o), sulfonyl (2p),
perfluoroalkyl (2q), and phosphate (2r and 2s) substituents
could be successfully assembled on the isoxazoline skeleton
using this method without exception. Surprisingly, cleavage of
the CC double bond occurred selectively on styrene
substrates (1t and 1u) rather than acrylate 1a, leading to 3-
aryl substituted isoxazolines 2t and 2u, respectively. The
reason could be ascribed to the stronger electron-withdrawing
property of styrene containing nitro or cyano group, compared
with acrylate. When vinyl acetate 1v was treated with acrylate
1a, 3-formyl isoxazoline 2v was isolated as a major product. In
this reaction, we speculated that copper nitrate might be
inclined to coordinate with the electron-rich CC double
bond of 1v, generating β-nitro hemiacetal as key intermediate.
For the reaction of ethyl acrylate and phenylacetylene, 3-
C
DOI: 10.1021/acs.orglett.9b02748
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Scheme 5. Preliminary Mechanistic Studies
Scheme 6. Plausible Mechanism
which may also be achieved directly via the insertion reaction
in complex A (Path B). After an intramolecular rearrangement
and successive hydrolysis, the key intermediate 6 would be
formed with the exclusion of formaldehyde. In this step, boric
acid might be coordinated with the O atoms in ester and
nitrate groups,20 which will further assist the C−C bond
cleavage. Subsequently, nitro compound 6 would be activated
by copper nitrate.13 After the isomerization and dehydrating
process, the free nitrate anion assisted the cleavage of the O−
Cu bond in complex F, which could be further transformed to
the nitrile oxide G.26 The final products 2b and 4b would be
obtained from G, respectively, through the well-documented
[3 + 2] cycloaddition of nitrile oxide and alkene. On the other
hand, under the circumstance without KI, the bulky Cu atom
was assembled on the less-hindered carbon of alkene and
generated complex H. The byproduct 2b′ was then formed
through successive rearrangement and hydrolysis process19
(Path C). Presumably, the coeffect of KI and boric acid will
make Paths A and B more dominant than Path C.
In conclusion, we have disclosed a novel copper nitrate-
mediated anion transformation from simple alkenes via
selective alkene cleavage and successive dipolar cycloaddition
reaction, affording pharmacologically interesting isoxazoline
skeletons in excellent regioselectivity and chemoselectivity.
The overall conversion involves a sequence of one CC
double bond cleavage and the formation of three new chemical
bonds. The good selectivity and various transformations of
given products could be highlighted on the promising prospect
of the present method, leading to newly built skeletons in
diversity. Further mechanistic investigation provides a
distinguishing ionic pathway and indicates the coeffect of
iodide and boric acid as additives on the inhibition of well-
documented competitive nitration reaction.
we speculated that the nitro compound 6 might be the key
intermediate during the reaction (eq 2 in Scheme 5). No
product could be isolated in the absence of copper salt, while a
reasonable yield was obtained in the presence of 30 mol % of
copper salt (eq 3 in Scheme 5), which indicated that copper
nitrate was crucial and acted as a catalyst for the cycloaddition
process. When the reaction was conducted in the absence of
KI, the desired product 2b and byproduct 2b′ was isolated in
35% and 31% yield, respectively. Considering 2b′ was not
observed under standard conditions and failed to convert into
2b (eq 4 in Scheme 5), KI was proposed to play a significant
role in the selective synthesis of products. To our delight, 4-
nitrobenzaldehyde 8 was isolated in 78% yield when (E)-ethyl
3-(4-nitrophenyl)acrylate 7 was used as the substrate, which
suggested that the formed aldehyde was the leaving fragment
after cleavage of the CC double bond (eq 5 in Scheme 5).
Based on the documented result that copper nitrate would be
transformed to CuI and iodine in the presence of iodide,25 to
illustrate the reaction intermediate, we next conducted the
reaction with CuI, I2, and KNO3, instead of Cu(NO3)2·3H2O
and KI. However, a trace amount of product 2b was observed,
which will exclude CuI or I2 as the intermediate during the
reaction (eq 6 in Scheme 5).
ASSOCIATED CONTENT
* Supporting Information
■
Although a detailed reaction pathway remains to be clarified,
a plausible mechanism for this reaction was proposed on the
basis of the above results (Scheme 6). Initially, copper nitrate
was coordinated with the CC double bond to give complex
A, then complex B was generated from A with the assistance of
KI (Path A). The nucleophilic substitution of nitrate anion
occurred to afford complex C in the presence of boric acid,
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02748.
Experimental procedures and characterization data for
all compounds (PDF)
D
DOI: 10.1021/acs.orglett.9b02748
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
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CCDC 1895015−1895016 contain the supplementary crys-
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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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xubin@shu.edu.cn.
ORCID
Mingchun Gao: 0000-0002-8564-4387
Bin Xu: 0000-0002-9251-6930
Author Contributions
(15) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J.
Org. Chem. 1956, 21, 478.
§These authors contributed equally.
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Murahashi, S., Ed.; Wiley−VCH: Weinheim, Germany, 2005; pp
153−178.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21871174 and 21672136) and Innovation Program of
Shanghai Municipal Education Commission (No. 2019-01-07-
00-09-E00008) for financial support. The authors thank Prof.
Qitao Tan (SHU), Prof. Changhua Ding (SHU), and Prof.
Ming-Hua Xu (SUSTech) for helpful discussion; Prof. Bingxin
Liu (SHU) for analysis of single-crystal X-ray diffraction; and
Prof. Hongmei Deng (SHU) for NMR spectroscopic measure-
ments.
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