Copper Nitrate Mediated Regioselective [2+2+1] Cyclization of Alkynes with Alkenes: A Cascade Approach to Δ2-Isoxazolines

Article abstract of DOI:10.1002/anie.201503393

An efficient method for the regioselective synthesis of pharmacologically relevant polysubstituted Δ²-isoxazolines is based on the copper-mediated direct transformation of simple terminal alkynes and alkenes. The overall process involves the formation of four chemical bonds with inexpensive and readily available copper nitrate trihydrate as a novel precursor of nitrile oxides. The reaction can be easily handled and proceeds under mild conditions.

Full text of DOI:10.1002/anie.201503393

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201503393
German Edition: DOI: 10.1002/ange.201503393
Cascade Reactions
Copper Nitrate Mediated Regioselective [2+2+1] Cyclization of
Alkynes with Alkenes: A Cascade Approach to D2-Isoxazolines**
Mingchun Gao, Yingying Li, Yuansheng Gan, and Bin Xu*
Abstract: An efficient method for the regioselective synthesis
of pharmacologically relevant polysubstituted D2-isoxazolines
is based on the copper-mediated direct transformation of
simple terminal alkynes and alkenes. The overall process
involves the formation of four chemical bonds with inexpen-
sive and readily available copper nitrate trihydrate as a novel
precursor of nitrile oxides. The reaction can be easily handled
and proceeds under mild conditions.
b-galactosidase-inhibiting properties.[6e] Furthermore, they
can also be employed as efficient chiral ligands[7] and eminent
building blocks in organic synthesis as the precursors of
diverse key synthetic intermediates, such as b-amino acids,[8]
b-hydroxy ketones,[9] b-hydroxy nitriles,[10] and g-amino
alcohols.[11] Therefore, the development of convenient meth-
ods for the synthesis of D2-isoxazoline scaffolds has invoked
ever-growing synthetic efforts over the last decades.[12] Gen-
erally, D2-isoxazolines are prepared by 1,3-dipolar cycloaddi-
tion reactions of olefins and nitrile oxides, which are
commonly generated in situ from substituted oximes[13] or
nitro compounds[4,14] in the presence of various additives.
Although these methods are often effective, some of them
suffer from a limited scope of starting materials, need harsh
reaction conditions, or require that the substrates are
employed as the solvent. Thus, the development of methods
for the efficient synthesis of D2-isoxazolines from readily
available starting materials continues to be an active and
rewarding research area.
Alkynes have been widely used in cross-coupling reac-
tions, such as the Sonogashira reaction, and for the con-
struction of various heterocycles.[15] Owing to their signifi-
cance and wide application in organic synthesis, the explora-
tion of new types of transformations with alkynes has
attracted considerable attention.[16] Recently, an elegant
procedure for the direct transformation of alkynes into
nitriles was developed by Jiao and co-workers and involved
C
opper nitrate and other nitrate salts are ubiquitous
reactants in nitration reactions owing to their many advan-
tages, such as inexpensiveness, stability, hypotoxicity, and ease
of handling, compared with nitric acid or nitrite salts.[1]
Among those nitration reactions, most of them proceed via
nitrogen dioxide radicals or via the nucleophilic attack of
alkenes or aryl rings at a cationic intermediate.[2] Although
copper nitrate has been disclosed as an effective direct
nitration reagent for arenes[3] and ketones,[4] the use of this
simple and inexpensive reagent as a new and versatile
nitrogen and oxygen source to replace the traditionally
required agents still remains both challenging and of great
value.
D2-Isoxazoline derivatives represent an important class of
five-membered heterocycles[5] and are frequently found in
numerous biologically active molecules with antibacterial,[6a]
antitubercular,[6b] siderophore,[6c] antidepressant,[6d] and
ꢀ
a Ag-catalyzed nitrogenation reaction by C C bond cleav-
[*] M. Gao, Y. Li, Y. Gan, Prof. Dr. B. Xu
School of Materials Science and Engineering
Department of Chemistry, Innovative Drug Research Center
Shanghai University
age.[17] Herein, we report a novel copper nitrate trihydrate
mediated cascade reaction from simple terminal alkynes and
alkenes that provides polysubstituted D2-isoxazolines in high
yields through a regioselective [2+2+1] cyclization under
mild conditions (Scheme 1). The significance of this trans-
Shanghai 200444 (China)
E-mail: xubin@shu.edu.cn
Homepage: http://www.xubin.shu.edu.cn
Prof. Dr. B. Xu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Shanghai 200032 (China)
and
Scheme 1. Copper nitrate mediated synthesis of D2-isoxazolines.
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry
East China Normal University
Shanghai 200062 (China)
formation is threefold: 1) It is the first example of a copper-
mediated direct transformation of simple terminal alkynes
and alkenes into pharmacologically relevant D2-isoxazolines.
2) Compared with the traditional activation of alkynes by
noble metals,[16a,c] a readily available copper nitrate trihydrate
reactant is employed for the transformation of simple alkynes,
and reported to act as a precursor of the crucial nitrile oxide
dipole for the first time. 3) The valuable mechanistic insights
that were obtained along the way may promote the discovery
[**] We thank the National Natural Science Foundation of China
(21272149) and the Innovation Program of Shanghai Municipal
Education Commission (14ZZ094) for financial support. We thank
Prof. Qitao Tan for helpful discussions and Prof. Hongmei Deng
(Laboratory for Microstructures, SHU) for NMR spectroscopic
measurements.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503393.
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of other new types of cascade reactions for the construction of
bioactive N-containing heterocycles.
We started our investigation by exploring the reaction of
phenylacetylene (1a) with n-butyl acrylate (2a) in the
presence of copper nitrate trihydrate in acetonitrile at 608C
under nitrogen atmosphere. Intriguingly, isoxazoline 3aa was
formed in 34% yield along with phenyl(5-phenylisoxazol-3-
yl)methanone (3aa’, 15% yield) as a side product (Table 1,
Table 1: Optimization of the reaction conditions.[a]
Entry Nitrogen
source
Solvent Additive
Atmosphere Yield
[%][b]
(x equiv)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Cu(NO3)2·3H2O MeCN
Cu(NO3)2·3H2O PhCN
–
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
34[c]
67
<5
–
–
–
–
–
–
–
-
Cu(NO3)2·3H2O toluene
Cu(NO3)2·3H2O MeOH
Cu(NO3)2·3H2O DMF
Cu(NO3)2·3H2O DMSO
Fe(NO3)3·9H2O PhCN
Co(NO3)2·6H2O PhCN
Scheme 2. Alkyne substrate scope. Reaction conditions: 1a–1p
(0.3 mmol), 2a (0.45 mmol), Cu(NO3)2·3H2O (2.0 equiv), tBuCN
(2.0 equiv), PhCN (1.5 mL), 1–4 h, N2 atmosphere, 608C. Yields of
isolated products are given. [a] 2a (4.0 equiv). [b] 26 h. [c] 2a
(3.0 equiv). [d] Cu(NO3)2·3H2O (4.0 equiv). [e] tBuCN (4.0 equiv).
<5
<5
<5
41
<5
<5
<5
<5
<5
<5
79
KNO3
Ce(NH4)2(NO3)6 PhCN
tBuONO PhCN
PhCN
–
–
substitution patterns and functional groups were tolerated.
Substrates bearing different functional groups on the aryl
ring, such as acetamide (3ba and 3ca), halide (3da, 3ha, and
3ia), alkyl (3ea), alkoxy (3 fa), or acetyl (3ga) moieties, were
compatible with this reaction and provided the corresponding
products in moderate to good yields, regardless of their
different electronic properties and substitution patterns. The
reaction was not limited to simple benzene-based aryl
alkynes, as naphthyl- or heterocycle-substituted alkynes also
gave the desired products in good yields (3ja and 3ka).
Notably, reactions of alkynes with cyclopropyl (3la) or
tertiary alcohol (3ma and 3na) substituents proceeded
smoothly and afforded the corresponding products in mod-
erate to good yields. However, a substrate with a secondary
alcohol moiety gave no product under the optimized con-
ditions (3oa), which may be due to the oxidation of the
hydroxy group during the reaction. To our delight, a dimeric
product (3pa) was successfully isolated from the reaction of
(E)-1,2-bis(3-ethynylphenyl)diazene; 3pa is a symmetric azo
compound with carbonyl linkers and a potential dye.
Cu(NO3)2·3H2O PhCN
Cu(NO3)2·3H2O PhCN
Cu(NO3)2·3H2O PhCN
Cu(NO3)2·3H2O PhCN
Cu(NO3)2·3H2O PhCN
Cu(NO3)2·3H2O PhCN
Cu(NO3)2·3H2O PhCN
Cu(NO3)2·3H2O PhCN
Cu(NO3)2·3H2O PhCN
Cu(NO3)2·3H2O PhCN
Cu(NO3)2·3H2O PhCN
Cu(NO3)2·3H2O PhCN
1,10-phen (2) N2
TMEDA (2)
1-AdCN (2)
tBuNC (2)
tBuCN (2)
tBuCN (2)
tBuCN (2)
tBuCN (2)
tBuCN (1)
tBuCN (3)
tBuCN (2)
tBuCN (2)
N2
N2
N2
N2
N2
N2
N2
N2
N2
O2
air
81
83
82[d]
77[e]
70[f]
77
77
<5
71
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), nitration
reagent (0.6 mmol), solvent (1.5 mL), nitrogen atmosphere. [b] Yield of
isolated product. [c] 3aa’ was also isolated in 15% yield. [d] 708C.
[e] 508C. [f] Cu(NO3)2·3H2O (1.0 equiv) was used. 1-AdCN=1-ada-
mantane carbonitrile, TMEDA=N,N,N’,N’-tetramethylethylenediamine.
entry 1). By switching the solvent from acetonitrile to
benzonitrile, the yield was increased to 67% (entry 2),
whereas other solvents provided only trace amounts of 3aa
with unexpected 1,4-diphenylbuta-1,3-diyne as the major
product by the homocoupling of 1a (entries 3–6). An
extensive screening of nitrogen sources (entries 7–11), ligands
(entries 12–16),[18] temperature (entries 17 and 18), copper
loading (entry 19), additives (entries 20 and 21), and the
atmosphere (entries 22 and 23) revealed that the use of two
equivalents of Cu(NO3)2·3H2O in benzonitrile at 608C under
nitrogen atmosphere using tert-butylnitrile (2.0 equiv) as an
additive provides the most suitable conditions and afforded
3aa in 83% yield.
To further explore the scope and generality of this
method, we next used various alkenes as the coupling partners
for this cascade reaction under the optimized conditions
(Scheme 3). Alkyl and aryl acrylates provided the corre-
sponding products in high yields with good regioselectivities
(3ab–3ag), regardless of the electron-donating or -withdraw-
ing properties of the aryl ring. A substrate bearing an amide
group also afforded the desired product in good yield (3ah),
À
and the free C(O)NH2 group remained untouched in the
reaction. The identity of product 3ah was determined by
NMR spectroscopy and further confirmed by X-ray crystal-
lography.[19] Moreover, N-substituted acrylamide, acryl
ketone, acrylonitrile, and phenyl vinyl sulfone substrates
could also be employed in this transformation and afforded
With the optimized conditions in hand, various alkynes
with different substituents were investigated for the synthesis
of isoxazolines. As illustrated in Scheme 2, a wide variety of
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Scheme 4. Synthetic applications. AIBN=azobis(isobutyronitrile),
NBS=N-bromosuccinimide.
To illustrate the synthetic utility of our method, we
studied further transformations of our products (Scheme 4).
Isoxazoline 3aa could be directly transformed into the
corresponding oxidized isoxazole
4 by treatment with
Scheme 3. Alkene substrate scope. Reaction conditions: 1a
AIBN/NBS in the presence of K2CO3. The scaffold of 4 has
been shown to be a privileged structure in medicinal
chemistry and can be found in many marketed drugs
[Eq. (1)]. Notably, spiro product 3ay could be synthesized
smoothly from tert-butyl 4-methylenepiperidine-1-carboxyl-
ate (2y),[19] and is a close analogue of the potent GPR119
agonist, a new antidiabetic target,[20] and a potential precursor
to an antimuscarinic agent, which was previously synthesized
(0.3 mmol), 2b–2x (1.5 equiv), Cu(NO3)2·3H2O (2.0 equiv), tBuCN
(2.0 equiv), PhCN (1.5 mL), 1–2 h, N2 atmosphere, 608C. Yields of
isolated products are given. [a] Alkene (1.0 equiv). [b] Cu(NO3)2·3H2O
(4.0 equiv). [c] Alkene (4.0 equiv). [d] Diastereomeric ratio determined
by 1H NMR spectroscopy. Bn=benzyl, Ts =para-toluenesulfonyl.
the corresponding products in good yields (3ai–3al). To
determine the effect of the electronic properties of the alkene
on the cascade process, a series of electron-rich alkenes, such
as vinyl acetate (2m), and substrates with various allylic
substituents (2n–2r), including protected (2n and 2o) and
unprotected allylic alcohols (2p), were investigated and
afforded the desired products in good yields (3am–3ar). For
disubstituted acrylates, the regioselectivity of the isoxazoline
formation arises from the contribution of the dominant next
lowest unoccupied molecular orbital (NLUMO) of the 1,3-
dipole generated in situ from phenylacetylene during the
reaction with the alkene dipolarophiles,[14a] so that the oxygen
atom is attached to the sterically most hindered carbon atom
of the alkene (3as and 3at). For example, excellent regiose-
lectivity could be achieved with 1,1-disubstituted ethyl
methacrylate (2s), and a good regioselectivity (3at-A/3at-B
2.2:1) was observed for 1,2-disubstituted (E)-ethyl but-2-
enoate (2t). Furthermore, bicyclic (3au) and spiro (3av–3ax)
compounds could be obtained smoothly, which further
illustrates the broad substrate scope and product diversity.
It should be noted that both six- and five-membered (hetero)-
cycles could be embedded in the final spiro products, and the
chiral center in the starting material was not affected during
the reaction (3aw). Compound 3aw was formed with
a diastereoselectivity of approximately 2:1 as determined by
1H NMR spectroscopy, which indicates that this transforma-
tion could be performed in a diastereoselective way upon
further optimization.
through
a longer process and in lower overall yield
[Eq. (2)].[21]
To gain insight into possible intermediates and the
pathway of this reaction, several control experiments were
carried out (Scheme 5). The desired product was not obtained
when acetophenone was used instead of phenylacetylene
under the optimized conditions, which suggests that aceto-
phenone is not a key intermediate of this reaction [Eq. (1)].
When the reaction time was reduced to 45 min under
conditions A, 2-nitro-1-phenylethanone 5 could be isolated
in 9% yield together with isoxazoline 3aa in 76% yield
[Eq. (2)]. The in situ generated intermediate 5 could be
consumed completely through a fast transformation into 3aa
by prolonging the reaction time. Isolated nitro compound 5
could further be transformed into 3aa in almost quantitative
yield under conditions A [Eq. (3)], which indicates that this
cyclization reaction may mainly proceed via intermediate 5 to
afford isoxazoline 3aa. However, a high yield of 3aa could
still be achieved in the presence of 30 mol% of copper nitrate
[Eq. (4)], whereas no reaction was observed in the absence of
the copper salt [Eq. (5)]. These results imply that the
presence of catalytic amounts of the copper salt is crucial
for this transformation. Furthermore, the addition of 2,6-di-
tert-butyl-4-methylphenol (BHT) as a radical scavenger had
no significant effect on this reaction so that a radical
mechanism could be ruled out.
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reaction with copper nitrate participation; four chemical
bonds are thus formed under mild conditions. This convenient
and practical method can be applied to the regioselective
construction of pharmacologically interesting D2-isoxazolines
in moderate to good yields and features a wide substrate
scope, good functional group tolerance, and high modularity.
Simple and commercially available copper nitrate trihydrate
was employed to mediate the transformation of alkynes and
as a novel precursor of nitrile oxides from alkynes. Further
applications of this reaction are currently studied in our
laboratory.
Experimental Section
1a (33.0 mL, 0.3 mmol), 2a (65.0 mL, 0.45 mmol), Cu(NO3)2·3H2O
(145.0 mg, 0.6 mmol), tBuCN (66.0 mL, 0.6 mmol), and PhCN
(1.5 mL) were added to a Schlenk tube. The mixture was stirred at
608C for one hour under N2 atmosphere, and the reaction was
monitored by TLC. Upon completion of the reaction, the solution was
cooled down to room temperature, quenched with water, and
extracted with ethyl acetate (3 ” 10 mL); the combined organic
extracts were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate = 30:1) to give
3aa (68.3 mg, 83%) as a pale-yellow oil.
Scheme 5. Preliminary mechanistic studies. Conditions A: Cu-
(NO3)2·3H2O (2.0 equiv), tBuCN (2.0 equiv), PhCN, 608C, N2.
Although the details of the reaction pathway remain to be
clarified, a plausible mechanism for this reaction was
proposed on the basis of the above results (Scheme 6).
Keywords: alkenes · alkynes · cascade reactions · copper ·
isoxazolines
How to cite: Angew. Chem. Int. Ed. 2015, 54, 8795–8799
Angew. Chem. 2015, 127, 8919–8923
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Scheme 6. Proposed mechanism for the synthesis of 3a from 1a
(ligands are omitted for clarity).
ꢀ
Initially, copper nitrate coordinates to the C C bond, which is
followed by an insertion reaction to cis adduct A. Sequential
transfer of the nitro group and hydrolysis via complex B lead
to key intermediate 5. Subsequently, a-nitroketone 5 is
presumably converted into intermediate C with the assistance
of catalytic amounts of copper nitrate, which then affords
copper salt D in a dehydration reaction. Cleavage of the
À
Cu O bond in compound D in the presence of free nitrate
ions leads to the formation of the crucial nitrile oxide E and
regenerates copper nitrate. Finally, isoxazoline product 3aa
was afforded by a 1,3-dipolar cycloaddition reaction of nitrile
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alkynes into polysubstituted D2-isoxazolines through a cascade
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Received: April 14, 2015
Published online: June 18, 2015
Angew. Chem. Int. Ed. 2015, 54, 8795 –8799
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8799