Tandem synthesis of 3-halo-5-substituted isoxazoles from 1-copper(I) alkynes and dihaloformaldoximes

Article abstract of DOI:10.1021/ol503008t

A tandem synthesis of 3-halo-5-substituted isoxazoles has been developed from 1-copper(I) alkynes and dihaloformaldoximes under base-free conditions. Thus, 1,3-dipolar cycloaddition and all its drawbacks can now be avoided completely.

Full text of DOI:10.1021/ol503008t

Letter
pubs.acs.org/OrgLett
Tandem Synthesis of 3‑Halo-5-Substituted Isoxazoles from
1‑Copper(I) Alkynes and Dihaloformaldoximes
Wenwen Chen, Bo Wang, Nan Liu, Dayun Huang, Xinyan Wang,* and Yuefei Hu*
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
S
* Supporting Information
ABSTRACT: A tandem synthesis of 3-halo-5-substituted isoxazoles has been developed from 1-copper(I) alkynes and
dihaloformaldoximes under base-free conditions. Thus, 1,3-dipolar cycloaddition and all its drawbacks can now be avoided
completely.
Scheme 1. 1,3-DPCA and This Work
he isoxazoles are a large family of heterocycles that are
Tfound in numerous natural products and synthetic
compounds.1 As shown in Figure 1, 3-halo-5-substituted
isoxazoles (1 and 2) are very important members due to the
substitution of halogen atoms on the ring. Many of them not
only have novel medicinal properties2 but also are versatile
intermediates in organic synthesis.3−5
the nitrile oxide by using weak bases, low temperatures, and
slow addition of a reactant (α-halo-oxime or base). Yet, these
approaches have no significant impact on the 1,3-DPCA when
3 or 4 is used as a substrate2f,3d,4d,6i,8 because these geminal
dihalides generate the corresponding halonitrile oxides at a rate
too fast for the reactants to be controlled. Recently, several
Cu(I)-catalyzed procedures have been reported to optimize the
1,3-DPCA of terminal alkynes.9 As shown in Scheme 2,
terminal alkyne 8 was initially converted into a 1-Cu(I)
acetylide intermediate 7, whereafter the reactivity and
regioselectivity of the triple bond were enhanced. Unfortu-
nately, when we treated the mixture of 3 and phenylethyne
(8a) with the same catalytic system, 3-bromo-5-phenylisoxazole
(1a) was obtained as a single regioisomer in only 51% yield
accompanied by some dimer 5. This may be caused by fast
formation of the bromonitrile oxide in an aqueous KHCO3
solution.
Figure 1. Applications of 3-haloisoxazoles.
Investigation showed that 1,3-dipolar cycloaddition (1,3-
DPCA) of an alkyne with nitrile oxide is the most popular
method for the synthesis of substituted isoxazoles.1,6 Although
nitrile oxides are carefully generated in situ by dehydrohaloga-
nation of α-halo-oximes or by dehydrogenation of oximes, their
extremely high reactivity often leads to two drawbacks: poor
regiocontrol in the products and dimerization of the nitrile
oxide.1,6,7 As shown in Scheme 1, when dihaloformaldoxime (3
or 4) is used as a substrate, the isoxazole 1 or 2 is synthesized
with the same drawbacks. But, this is the only practical method
for the synthesis of such products to date.
Herein, we would like to report a novel tandem synthesis of
1 or 2 from 1-Cu(I) alkynes (7) and 3 or 4. Since the method
does not involve a 1,3-DPCA and the intermediacy of a
halonitrile oxide, all drawbacks of a 1,3-DPCA are avoided
completely.
To further reduce the rate of bromonitrile oxide formation,
we tried to use powdered KHCO3 in an organic solvent. Thus,
In the literature, early improvements to this type of 1,3-
DPCA were focused on ways to reduce the formation rate of
Received: October 13, 2014
© XXXX American Chemical Society
A
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Letter
a
Scheme 2. Cu(I)-Catalyzed 1,3-DPCA
Scheme 3. Two Competitive Experiments
a
The conditions in ref 9f were used: CuSO4·5H2O (2 mol %), NaAsc
(10 mol %), KHCO3 (4.3 equiv), H2O/t-BuOH (1:1), rt, 4 h.
the premade 7a was employed as a substrate because it could
not be generated from 8a and CuSO4·5H2O/NaAsc (sodium
ascorbate)9f in an organic solvent. As shown in Table 1, the
Figure 2. Structure of intermediate (E)-11.
a
Table 1. Reactions by Using 7a as a Substrate
Scheme 4. Cu(I)-Catalyzed Cyclization of (E)-11
b
entry
base
3:7a (by mole) temp (°C) time (h) 1a (%)
1
KHCO3
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1:1
25
25
25
25
25
25
25
35
45
50
45
45
45
45
12
12
12
12
12
12
12
76
76
73
70
68
20
93
93
94
85
75
80
94
94
2
CsF
3
K2CO3
4
K3PO4
converted into 1a smoothly in the presence of CuBr in DCE,
but in only 45% yield. Realizing that the commercial CuBr is a
polymer with much lower catalytic activity than that of in situ
generated CuBr, the coordinating solvent DMF was used to
give 1a in 95% yield within 20 min. Further experiments
indicated that this conversion was a Cu(I)-catalyzed cyclization,
and use of 0.1 equiv of CuBr was sufficient to produce excellent
results.
5
NaOAc
6
Bu4NOAc
7
−
−
−
−
−
−
−
−
8
7.5
9
1.0
0.5
1.0
1.0
1.0
1.0
10
11
12
13
14
1.1:1
1.5:1
2:1
Recently, several gold(III)-catalyzed intramolecular cycliza-
tions of propynal or propynone oximes (12) have been
reported for the synthesis of isoxazoles (Scheme 5).10 They
a
The mixture of 3 and 7a (0.5 mmol) in ClCH2CH2Cl (1 mL) was
b
stirred in a stoppered glass tube. The isolated yields.
Scheme 5. Chemoselective Cyclization of E/Z-Oximes
yield of 1a was increased to 76% after a mixture of 3, 7a, and
KHCO3 in DCE was stirred for 12 h (entry 1). Similar results
were observed by using different insoluble bases (entries 1−5).
To our great surprise, 1a was obtained in 93% yield under base-
free conditions (entry 7). The reaction time was reduced
significantly by increasing the temperature, but the yield of 1a
was not influenced (entries 7−9). No dimer 5 was detected
even when a large excess of 3 was employed (entries 13−14).
These results strongly suggested that the base-free reactions did
not proceed by way of 1,3-DPCA and a bromonitrile oxide.
To prove our hypothesis, two competitive experiments were
run as shown in Scheme 3. In the presence of KHCO3, the
reaction of 3, 7a, and 9 gave two products 1a and 10. However,
the same reaction gave 1a as a single product in the absence of
KHCO3. These results clearly indicated that the first experi-
ment was a 1,3-DPCA, with bromonitrile oxide as an
intermediate, while the latter experiment went through an
unknown mechanism.
showed high regioselectivity in the products formed, but their
precusor substrates (12) were associated with some drawbacks:
they needed to be preprepared as an E/Z-mixture; but, only
one isomer (cis-position between hydroxyl and alkynyl)
underwent the cyclization with the other isomer having to be
separated off before or after the cyclization. When the E/Z-
mixture (1:1) of 3-phenyl-propynal oxime (12a) was used as
the substrate under our conditions, only the Z-isomer
underwent the cyclization, with almost quantitative recovery
of the E-isomer.
Based on the above results, a possible tandem pathway was
proposed as shown in Scheme 6. Under the base-free
conditions, the formation of bromonitrile oxide by dehydro-
chlorination of 3 was inhibited. Therefore, 3 underwent a
Luckily, a small amount of an intermediate was separated
when the reaction of 3 and 7a was performed at 20 °C. Its
structure was assigned as (E)-1-bromo-3-phenylpropynal oxime
[(E)-11] by NMR spectra and single crystal X-ray diffraction
analysis (Figure 2). As shown in Scheme 4, (E)-11 was
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Letter
1o) compared to arylethynes. But, (4-methoxyphenyl)ethyne
(7q) and (4-nitrophenyl)ethyne (7r) gave unsatisfactory
results. It seems that 7q has very low nucleophilicity because
it gave a complicated mixture with 1,4-diarylbutadiyne (an
oxidative coupling product) as a major product. The substrate
7r gave a very low yield of the expected product even with a
prolonged reaction time (24 h). This problem may be caused
by the fact that both the substrate and product have very poor
solubility in DCE. Therefore, it was difficult to convert one
solid into another solid. On a 1.5-g scale, 1a was prepared in
85% yield without optimization.
Scheme 6. A Possible Tandem Pathway
Unfortunately, the product 2a was obtained in only 30%
yield from dichloroformaldoxime (4) and 7a under similar
conditions, which may be caused by the lower reactivity of 4.
Since the 1-copper(I) alkyne usually has a polymeric structure
and its reactivity can be enhanced by using coordinating
solvents to dissociate its polymeric structure,12 this problem
was resolved easily by using DMF as a solvent. As shown in
Scheme 8, 2a was obtained in 92% yield within 1 h and all other
nucleophilic addition−elimination with 7a to selectively give
(E)-11 as an intermediate. Then, (E)-11 carried out a Cu(I)-
catalyzed intramolecular cyclization to give 1a. In this pathway,
the Cu(I) ion may play three important roles: (a) the triple
bond in 7a is polarized by the Cu(I) to increase its reactivity
and regioselectivity;11 (b) the (E)-configuration of 11 is well
controlled by coordination of the Cu(I) with oxime; (c) the
cyclization of (E)-11 is catalyzed by the Cu(I). Thus, this new
pathway has the convenience of intermolecular substitution and
the good regioselectivity of intramolecular cyclization.
As shown in Table 2 (see: SI), many solvents can be used for
the reaction of 3 and 7a. Noncoordinating solvents usually give
better yields of 1a (entries 1−4) than coordinating solvents
(entries 5−9). The yield of 1a is reduced significantly in the
presence of a ligand, which may also function as a base (entries
10−13). Finally, entry 1 was assigned as our standard
conditions.
Scheme 8. Scope of 4-Cl-5-Substituted Isoxazoles
The scope of this method was tested with dibromo-
formaldoxime (3) as shown in Scheme 7. All tested products
Scheme 7. Scope of 4-Br-5-Substituted Isoxazoles
a
Separated yields were obtained.
desired products (2a−2p) were obtained in good-to-excellent
yields. It is noteworthy that 7q and 7r gave the expected
products 2k and 2l in excellent yields. It seems that the use of 4
as a substrate achieved higher efficiency (shorter time and
higher yield) than that of 3. On a 1.5-g scale, 2k was prepared
in 90% yield without optimization.
In summary, a highly regioselective tandem synthesis of 3-
halo-5-substituted isoxazoles has been developed. To the best
of our knowledge, our method offers a second practical pathway
for the synthesis of such products besides 1,3-DPCA. A possible
mechanism and functions of Cu(I) were proposed. The
method may find wide use because it proceeds under extremely
convenient conditions.
a
Separated yields were obtained.
(1a−1p) were obtained in good-to-excellent yields by simply
stirring the mixture of 3 and 7 in DCE. The reactions of
arylethynes bearing electron-donating groups were mainly
influenced by steric effects (see: 1b−1d), while those bearing
electron-withdrawing groups were mainly influenced by
electronic effects (see: 1e−1g). Alkylethynes usually gave the
products in higher yields with shorter reaction times (see: 1k−
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experiments, characterization, H and 13C NMR spectra for all
products and CIF file for (E)-11. This material is available free
of charge via the Internet at http://pubs.acs.org.
C
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wangxinyan@mail.tsinghua.edu.cn.
*E-mail: yfh@mail.tsinghua.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by NNSFC (Nos. 21472107,
21372142, and 21221062).
■
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