Palladium-Catalyzed Sequential Cyclization/Functionalization of Oxime Ethers with Unactivated Vinyl Ethers for Tunable Assembly of Structurally Diverse Isoxazoles

Article abstract of DOI:10.1002/cjoc.202100482

A novel and viable palladium-catalyzed sequential cyclization/functionalization of alkynone O-methyloximes with unactivated vinyl ethers under aerobic conditions was described. The structure of the products could be successfully controlled by varying the nature of the substituents of the vinyl ethers. This new approach provides a convenient and straightforward synthetic protocol for the preparation of structurally diverse 4-(1-alkoxyvinyl)-isoxazoles and 4-vinylisoxazoles in moderate to good yields with highly regioselectivity. Remarkably, this protocol can be performed on a gram scale, showing the promising application in synthetic and pharmaceutical chemistry.

Full text of DOI:10.1002/cjoc.202100482

Chinese Journal
of Chemistry
CJC 中 国 化 学 - An International Journal
Accepted Article
Title: Palladium-catalyzed sequential cyclization/functionalization of oxime ethers
with unactivated vinyl ethers for tunable assembly of structurally diverse isoxazoles
Authors: Jianxiao Li,* Zidong Lin, Dan He, Wanqing Wu and Huanfeng Jiang
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2021, 39, 10.1002/cjoc.202100482.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.202100482.
ISSN 1001-604X • CN 31-1547/O6
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Jiang Huanfeng (Orcid ID: 0000-0002-4355-0294)
Cite this paper: Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
Palladium-catalyzed sequential cyclization/functionalization of
oxime ethers with unactivated vinyl ethers for tunable assembly
of structurally diverse isoxazoles
Jianxiao Li,*a,b Zidong Lin, Dan He, Wanqing Wu and Huanfeng Jiang
a
a
a
a
a
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China
University of Technology, Guangzhou 510640, P. R. China.Fax: (+86) 20-87112906.
b
Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, South China University of Technology, Guangzhou
5
10640, P. R. China.
Keywords
Palladium-catalyzed | Vinyl ether | Alkynes | Annulation reaction | Isoxazoles
Main observation and conclusion
A novel and viable palladium-catalyzed sequential cyclization/functionalization of alkynone O-methyloximes and unactivated vinyl
ethers under aerobic conditions was described. The structure of the products could be successfully controlled by varying the nature
of the substituents of the vinyl ethers. This new approach provides the convenient and straightforward synthetic protocol for the
preparation of structurally diverse 4-(1-alkoxyvinyl)-isoxazoles and 4-vinylisoxazoles in moderate to good yields with highly regioselec-
tivity. Remarkably, this protocol can be performd on a gram scale, showing the promising application in synthetic and pharmaceutical
chemistry.
Comprehensive Graphic Content
O
N
R2
Pd(OAc)
O
2
∗
∗
∗
Excellent selectivity
Gram scale synthesis
Highly atom economic
R1
R3
3
R O
OMe
N
Controllable
Synthesis
Diverse Building
Blocks
R1
R2
∗
O
R2
Functional group tolerance
Ar
N
∗
∗
O
Available starting materials
Mild reaction conditions
R1
Pd(OAc)
Novel protocol
2
Tunable regioselectivity
Broad substrate scope
*E-mail: cejxli@scut.edu.cn
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Supporting Information
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
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through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202100482
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First author et al.
Given the importance of these privileged heterocyclic scaffolds, a
good many representative achievements have been obtained in
the past few years. One of the most straightforward and efficient
approaches of constructing 4-functionalized isoxazole derivatives
Background and Originality Content
Transition-metal-catalyzed cascade functionalization of al-
kynes have been recognized as one of the most straightforward
and practical synthetic methodologies for assembling a vast array
is
the
transition
metal-catalyzed
sequential
cycliza-
[
1]
tion/functionalization reaction of alkynone O-methyloximes with
of organic small molecules and functional molecules. Among
them, the nucleometallation of alkynes have gained considerable
attention in the recent years because its easy access to diverse
vinylmetallic active species for further precise transformation to
construct various polyfunctionalized organic small molecules in a
[
16]
various coupling reagents (Scheme 1a). Using this strategy, Ryu
and co-workers discovered an elegant gold-catalyzed cycliza-
tion/fluorination cascade approach using Selectfluor as the suita-
[16a]
ble fluorination reagent.
Moreover, in the presence of CO (1
[
2]
atm), our group also developed a palladium-catalyzed domino
oxidative aminocarbonylation of alkynes for producing the diversi-
fied 4-carboxamide isoxazoles in good to excellent yields with
atom- and step-economical ways. In this regard, the nucleopal-
[
3]
[4]
ladation of alkynes such as halopalladation, oxypalladation,
[
5]
and aminopalladation have been identified as the most flexible
and versatile synthetic methodologies for constructing diverse
unconventional and more elaborated polyfunctionalized scaffolds
in contemporary organometallic chemistry. Generally, the vinyl-Pd
species derived from alkynes can be effectively captured by ole-
[
17]
perfective atom-economical. Aside from the above cyclization/
functionalization reactions, the cascade alkenylation reactions
[18]
have been less studied in the recent years (Scheme 1b). . For
instance, Chen also demonstrated an elegant palladium-catalyzed
sequential cyclization/alkenylation of alkynes for the rapid synthe-
sis of polyfunctionalized 4-alkenyl-3,4,5-trisubstituted isoxa-
[
6]
[7]
[8]
[9]
fins, alkynes, CO, and others . Undoubtedly, olefins as the
good participants in the chemical reaction displayed the remarka-
ble reactivity. Mostly, the olefins were restricted to several elec-
tron-biased activated olefins, such as styrene, acrylic ester, and
allyl halides. Additionally, the electron-rich vinyl ethers have been
[
18a]
zoles.
However, in most cases, this method needed activated
olefins as the alkenylation reagents. Recently, our group also de-
scribed a palladium-catalyzed “one-pot” cyclization/alkylation of
O-methyl oximes with unactivated enols to access fully substitut-
[
10]
[11]
widely used in organic synthesis
and polymer chemistry
.
[19]
ed β/ɷ-isoxazole aldehydes/ketones. Although great progress
has been achieved in this field, the diverse assembly of function-
alized isoxazole heteroaromatic building blocks with tunable vinyl
motifs via transition-metal-catalyzed coupling reaction using the
unactivated vinyl ethers as the alkenyl sources is highly desirable.
With our continuing interests in palladium-catalyzed tandem reac-
Various transition metal catalysts such as Pd, Rh, and Ru have
[
12]
been successfully applied for these vinylation reaction. As ex-
pected, the corresponding internal olefins were obtained as the
dominant products. Compared with the regular activated olefins,
the electron-nonbiased olefins and some unactivated olefins such
as vinyl ethers have less investigated owing to their sluggish reac-
tivity and the tendency of β-H elimination. Therefore, the de-
velopment of an efficient and novel synthetic protocol to capture
the vinyl-Pd species using the unactivated vinyl ethers for the
rapidly construction of diversified functionalized molecules would
be highly desirable to the synthetic community.
[
20]
[
13]
tions of alkynes with alkenes,
we herein described a palladi-
um-catalyzed sequential cyclization/functionalization of O-methyl
oximes with unactivated vinyl ethers for tunable assembly of
structurally diverse isoxazoles (Scheme 1c).
Results and Discussion
(
a) Transition metal-catalyzed cascade cyclization/functionalization reaction
OR3
O
R2
N
M
[
]
N
Table 1 Optimization of the reaction conditions a
R1
Yield b
[
M
] = [Pd]/[Au]/[Ag]/[Fe]/[Al]
R1
Entry
Catalyst
Oxidant
air
Solvent
DMF
FG
R2
R3 = allyl, Me
PdBr
PdBr
PdBr
PdBr
PdBr
PdBr
PdBr
PdBr
16
1
2
3
4
5
6
7
8c
9
2
2
2
2
2
2
2
2
FG tolerated: F, RSe, RS, allyl, alkynyl, alkyl, amide
1,4-NQ
Anthraquinone
1,4-BQ
DMF
DMF
20
(b) Palladium(II)-catalyzed cascade cyclization/alkenylation
R3
21
O
R2
OMe
[Pd]
N
or
N
DMF
18
R1
R4
Ref. 15
R1
2,6-dimethoxy-1,4-BQ
P-Chloranil
1,2-NQ
DMF
13
R2
R
activated olefins
internal olefins
DMF
trace
52
This work: Palladium-catalyzed cyclization/alkynylation
c)
(
DMF
O
R2
∗
∗
∗
Pd(OAc)
2
N
Excellent selectivity
Gram scale synthesis
Highly atom economic
1,2-NQ
DMF
52
R3
R1
PdBr2
PdBr
PdBr2
-
DMF
trace
38
O
OMe
3
R O
N
2
1,2-NQ
THF
10
Diverse Building
Blocks
Controllable
Synthesis
R1
1,2-NQ
DMSO
PEG-400
12
11
12
13
14
O
R2
∗
∗
∗
R2
Functional group tolerance
Available starting materials
Mild reaction conditions
Ar
N
PdBr
PdBr
PdBr
PdBr
1,2-NQ
N.D.
N.D.
trace
2
2
2
O
R1
1,2-NQ
3
CH CN
Pd(OAc)
Novel protocol
2
Tunable regioselectivity
Broad substrate scope
1,2-NQ
o-Xylene
1
1
1
5
6
7
2
1,2-NQ
1,2-NQ
1,2-NQ
1,2-NQ
1,2-NQ
1,2-NQ
Ethylene glycol
DMF
trace
68
Scheme 1 Strategies for the synthesis of structurally diverse isoxazoles
Pd(OAc)
Pd(TFA)
PdI
Pd(dppe)Cl
20 Pd(PPh Cl
2
Isoxazoles is one of the most important five-membered het-
erocycles containing oxygen atom, and nitrogen atom at the ad-
jacent position, which is an indispensable structural motif in
pharmaceutical molecules, materials science as well as in organic
2
DMF
60
18
2
DMF
62
19
2
DMF
52
[
14]
synthesis.
For example, Sulfisoxazole is approved for the
[
15]
)
3 2
2
DMF
24
treatment of long-lasting urinary tract infections, and severe.
www.cjc.wiley-vch.de
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Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
alkyl group of the O-methyl oximes proceeded smoothly to the
desired products 3w and 3x under the standard conditions.
2
1
2
Pd(MeCN)
2
Cl
2
1,2-NQ
1,2-NQ
1,2-NQ
1,2-NQ
1,2-NQ
1,2-NQ
1,2-NQ
1,2-NQ
1,2-NQ
1,2-NQ
DMF
DME
DME
DME
DME
DME
DME
DME
DME
DME
62
70 (69)
38
2
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
-
2
2
2
3d
4e
2
2
2
2
2
2
2
Scheme 2 Substrate scope of O-methyl oximes 1 [a]
(10 mol%)
O
3
54
R
2
OCH3
Pd(OAc)
2
N
N
1
nBu
1,2-naphthaquinone (1 equiv)
2
5f
64
O
TBAB (2 equiv)
n
R1
DME (1 mL)
0
C, 8 h
R1
O Bu
2
a
o
8
2
2
6g
trace
46
R2
R1
O
Ph
7h
O
O
N
Ph
Ph
O
R = 2-Me, 3b, 58%;
R = 4-Me, 3c, 69%;
R = 4-Et, 3d, 62%;
R = 4-F, 3e, 69%;
R = 4-Cl, 3f, 62%;
N
N
n
8i
O Bu
2
46
n
nBu
O Bu
Ph
66%;
29j
50
R = 4-Br, 3g,
3h, 60%
3
a, 69%
R
F
3
C
30
N.D.
O
Ph
O
Ph
OnBu
N
O
Ph
O
N
Ph
N
N
n
a
O Bu
Reaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), palladium catalyst
10 mol %), TBAB (2 equiv), solvent (1mL), oxidant (1 equiv), at 80 C for 8
h. Isolated yield was shown in brackets. BQ: 1,4-Benzoquinone. P-chloranil:
n
n
O Bu
O Bu
o
(
Ph
68%
n
3i, 64%
3j, 56%
3k
n = 1, 3l, 56%;
n = 2, 3m, 60%;
F3CS
b
1
2
,3,5,6-Tetrachlorobenzo-1,4-quinone. Yield (%) was determined by
H
R2
Cl
Br
c
balloon. d at 65 C. at 75 C. at 85 C. 1 equiv Cs
o
e
o
f
o
g
NMR. O
2
2
CO
CO
3
was used.
was used.
R
R = 3-Me, 3n, 70%;
R = 4- Bu, 3o, 66%;
O
O
O
t
h
i
j
N
N
1
equiv K
2
CO
3
was used. 1 equiv KF was used. 1 equiv Na
2
3
N
R = 4-OMe, 3p, 68%;
R = 4-OEt, 3q, 62%;
R = 4-F, 3r, 64%;
n
O Bu
n
n
O Bu
Ph
O Bu
Ph
Ph
For the preliminary studies, we chose the O-methyloxime(1a)
3t, 54%
3s, 62%
and n-butyl vinyl ether(2a) as the model substrates to optimize
the suitable conditions. As outlined in Table 1, various oxidants
were firstly screened for this chemical transformation, such as air,
S
n
O
N
O
n
Bu
O
C H
6
13
N
O
N
N
n
O
nBu
n
O Bu
O Bu
Ph
Ph
n
1
(
,4-naphthaquinone (1,4-NQ), Anthraquinone, 1,4-Benzoquinone
1,4-BQ), 2,6-dimethoxy-1,4-BQ, 2,3,5,6-Tetrachlorobenzo-1,4-
quinone (P-chloranil), 1,2-naphthaquinone (1,2-NQ), and
,2-naphthaquinone/O , and 1,2-naphthaquinone gave the best
Ph
O Bu
3v, 71%
3w, 69%
3
u, 62%
3x, 68%
1
2
a
Reactions conditions: 1 (0.20 mmol), 2a (0.30 mmol), Pd(OAc)
TBAB (2 equiv), DME (1mL), 1, 2-naphthaquinone(1 equiv), at 80 C for 8 h.
Yields referred to isolated yield.
In addition, the generality and limitations of vinyl ethers were
then evaluated under the established conditions. As expected in
Scheme 3, a variety of alkyl substituted vinyl ethers were eligible
substrates, generating the alkenylation products 4a-4g in moder-
ate yields (41%-84%). Notably, the chlorinated vinyl ether (2e) was
also applicable to the present catalytic system, leading to the
product 4e in 84% yield. Moreover, the structure of the product 4e
2
(10 mol %),
result, which furnishing the corresponding product 3a in 52% GC
yield (entries, 1-7). Inspired by the above results, we next investi-
gated different solvents such as THF, DMF, DMSO, CH CN,
3
o-Xylene, PEG-400 and DME, and we found that DME was a suita-
ble solvent (entries, 10-15, 22). Other potential palladium salts
o
2
were then evaluated, and Pd(OAc) displayed eminent catalytic
performance in this chemical transformation (entries, 16-22). In
contrast, the yield was slightly decreased when increasement or
reduction of the reaction temperature (entries, 23-25). Subse-
2 3 2 3 2 3
quently, different bases such as Cs CO , K CO , KF, and Na CO
[
18]
was unequivocally confirmed by X-ray diffraction. To our delight,
the substrates bearing the hydroxyl group proved to be an amena-
ble substrate and gave the products 4f and 4g in 46% and 48%
yields, respectively. Unfortunately, other unactivated vinyl ethers
such as allyl ether (2h), vinyl silyl ether (2i), 1,4-dioxene (2k),
arabino-hex-1-enitol (2l), and vinyl acetate (2m), were not toler-
ated with the current transformation, and the corresponding
starting materials were almost completely recovered after the
reaction. The instability of the substrates 2i, 2l and 2m under the
palladium catalytic condition might be a reasonable explanation
for these results. Additionally, the unsatisfied transformation of 2j
likely because of the steric hindrance of the methyl group hin-
were tried, revealing that the base was not necessary for this
transformation (entries, 26-29). Finally, control experiments sug-
gested that the Pd(OAc) and 1,2-naphthaquinone both played a
2
crucial role in the current reaction (entries, 9, 30).
With the optimal conditions in hand, we next explored the
substrate scope of O-methyl oximes, and the representative re-
sults are presented in Scheme 2. The suitability of a large library of
1
O-methyl oximes (R ) was firstly examined. Satisfactorily, various
t
oximes bearing electron-donating groups such as Me, Bu, and
OMe group or electron-withdrawing groups such as F, Cl, Br, CF
and SCF substituents on the aryl ring were nicely tolerated, deliv-
ering the expected products 3a-3i with yields ranging from 58% to
9%. Additionally, the styrenyl group of the O-methyl oximes was
3
,
3
[22]
dered the alkene insertion step.
6
Interestingly, the 4-vinylisoxazole derivatives (5) were obtained
when the phenyl vinyl ether (2n) was used as the coupling part-
ners. Subsequently, we further investigated the coupling of
O-methyloximes (1) with 2n under the standard conditions
applicable substrate to afford the corresponding product 3j in 56%
yield. To our delight, the alkyl and cycloalkyl substituted O-methyl
oximes bearing five, or six-membered ring groups also participated
well under the optimized condition, furnishing the expected
products 3k-3m in moderate yields. Inspired by the obtained ex-
perimental results, the applicability of R substituted O-methyl
oximes were further surveyed. Similarly, a wide array of R substi-
(
Scheme 4). Satisfactorily, diverse O-methyloximes bearing various
functional groups on the aryl ring were successfully transformed in
moderate yields. It is remarkable that the alkyl substituted oximes
were all compatible with this approach, providing the
2
2
tuted O-methyl oximes with different groups such as -Me,
4
-vinylisoxazole products 5h, 5i, and 5j in 55%, 51%, and 52%
-
tBu,-OMe, -OEt, -F, -Cl and -Br were all eligible substrates in this
yields, respectively. In addition, the absolute configuration of the
catalytic system, generating the target products in moderate yields.
Gratifyingly, alkyl-substituted substrates, such as the propyl and
5
sis.
c was unequivocally confirmed by X-ray crystallographic analy-
[
23]
1
-hexyl O-methyl oximes were also investigated, producing the
desired products 3u and 3v in 62% and 71% yields, respectively. It
is noteworthy that the substrates with 3-thienyl group and double
Chin. J. Chem. 2021, 39, XXX－XXX
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Report
First author et al.
Scheme 3 Substrate scope of vinyl ethers 2 [a]
Scheme 5 Gram-scale transformation of 1a
(
10 mol%)
O
4
OCH
3
Pd(OAc)
2
Ph
O
Ph
N
OCH3
(10 mol%)
N
1
R3
N
1,2-naphthaquinone (1 equiv)
Pd(OAc)
2
N
O
2
nBu
TBAB (2 equiv) DME (1 mL)
o
OR3
1,2-naphthaquinone (1 equiv)
Ph
Ph
O
n
O Bu
80
C, 8 h
Ph
TBAB (2 equiv) DME (3 mL)
Ph 3a
a
Ph
2a
7.5 mmol
o
1a
80 C, 8 h
Ph
O
5 mmol
53%,0.8479g
O
O
O
Ph
Ph
Ph
Ph
O
N
N
N
N
OEt
O
t
Bu
Ph
O
Additionally, the substituent effect of oximes of this strategy
was then evaluated under the standard condition (Scheme 6). The
result revealed that the O-benzyl oximes is well accommodated
and produced the product 3a in 66% yield along with BnBr in 70%
GC yield (Scheme 6a). However, in the presence of 2 equiv of
Ph
Ph
Ph
4
a, 41%
4b, 54%
4c, 62%
4d, 64%
O
O
N
Ph
Ph
O
O
N
Ph
N
O
Ph
Ph
4f, 46%
O
OH Ph
2 3
Cs CO , the 1,3-diphenyl oxime (7) was not compatible with the
Cl
4e
2
3
OH
current protocol, and no the desired product was detected by
GC-MS, instead the protonolysis product 8 was isolated in 49%
yield (Scheme 6b).
4
e, 84%
4g
O
,
48%
failed examples
O
N
O
Ph
Ph
Ph
N
N
4
h, 0%
4i, 0%
4j, 0%
O
O
Scheme 6 The substituent effect of oximes
Ph
Ph
Ph
n
O Bu
Si
Allyl n-butyl ether
OBn
O
Ph
Vinyl trimethyl silyl ether
Ethyl propenyl ether
N
N
nBu
Standard Condition
O
BnBr (a)
n
Ph
Ph
OH
Ph
Ph
O Bu
O
Ph
O
1a
2a
Ph
3a, 66%
6
O
Ph
4k, 0%
4m, 0%
70% GC yield
N
O
O
O
OH
N
O
N
4l
, 0%
OH
Ph
(10 mol%)
OH
Ph
O
N
7
O
N
Ph
nBu
Pd(OAc)
2
Ph
2
,3-Dihydro-1,4-dioxine
Arabino-hex-1-enitol
Vinyl acetate
O
1,2-naphthaquinone (1 equiv)
(b)
2a
TBAB (2 equiv) DME (1 mL)
(2 equiv), 80
o
Ph
H
, 49%
Ph
Cs
2
CO
3
C, 8 h
8
a
Reactions conditions: 1a (0.20 mmol), 2 (0.30 mmol), Pd(OAc)
2
(10
Furthermore, we next evaluated the two types of common ac-
mol %), TBAB (2 equiv), DME (1mL), 1, 2-naphthaquinone(1 equiv), at 80 oC
tivated olefins under our optimized conditions (Scheme 7). Inter-
estingly, the substrate styrene was nicely compatible with this
approach, and the corresponding product 9 was isolated in 80%
yield. Similarly, the methyl acrylate can also be directly converted
to the corresponding 10 in 76% yield using this method. It is
noteworthy that the structure of the two compounds were identi-
for 8 h. Yields referred to isolated yield.
Scheme 4 Reaction of O-methyloximes with phenyl vinyl ether 2n [a]
OCH
3
Pd(OAc)
1,2-naphthaquinone (1 equiv)
2
O
R2
N
Ph
N
[18a]
O
cal with those previously reported.
R1
TBAB (2 equiv) DME (1 mL)
o
2n
R1
80
C, 8 h
1
R2
5
Scheme 7 Investigation of the common activated olefins
O
Ph
O
Ph
N
N
O
Ph
N
(10 mol%)
Ph
OCH
3
Pd(OAc)
,2-naphthaquinone (1 equiv)
2
N
O
1
Ph
Ph
N
Ph
5
b, 62%
5c, 66%
TBAB (2 equiv) DME (1 mL)
Ph
o
b
80
5
a, 60%, (51%)
1a
C, 8 h
9
, 80%
(
63%)
c
F
3
C
Ph
Ph
Ph
(71%)d
Me
,
F
Cl
(10 mol%)
OCH
3
O
Ph
N
Pd(OAc)
2
S
O
N
O
O
O
OMe 1,2-naphthaquinone (1 equiv)
N
N
CO
10, 76%
2
Me
N
N
Ph
TBAB (2 equiv) DME (1 mL)
o
1
a
O
8
0
C, 8 h
Ph
Ph
Ph
5
d, 66%
Ph
Ph
5g, 52%
5
e, 60%
5f, 58%
Based on the above experimental results and the previous lit-
erature reports, a plausible mechanism for this sequential cycliza-
tion/functionalization is proposed (Scheme 8). Firstly, coordination
O
O
O
N
N
N
Ph
2
of the Pd(OAc) to the alkyne motifs of alkynone O-methyloximes
Ph
5
h, 55%
5
i, 51%
5j, 52%
(1) forms a π-coordinated alkyne adduct I. Then, the oxygen atom
attacks the adduct I via 5-endo cyclization to give the heteroaryl
palladium intermediate II. And then, subsequent nucleophilic at-
a
Reactions conditions: O-methyloximes 1 (0.20 mmol), phenyl vinyl ether
n (0.30 mmol), Pd(OAc)
-naphthaquinone(1 equiv), at 80 C for 8h. Yields referred to isolated
2
2
2
(10 mol %), TBAB (2 equiv), DME (1mL), 1,
-
tacks by Br in the presence of TBAB releasing bromomethane, and
o
alkenes insertion to afford palladium intermediate III. Subse-
quently, the alkyl palladium species undergoes β-hydrogen elimi-
nation to form the diverse isoxazoles and generates the Pd(0) cat-
alytic species. After that, the further oxidation of Pd(0) to Pd(II)
by 1,2-naphthaquinone completes the catalytic cycle. As for the
path b, on the basis of the strong p-π conjugation of the oxygen
atom with aryl of the aryl vinyl ether, the intensity of the C(β)-O
bond is weakening. Consequently, the alkyl palladium intermedi-
ate III undergoes β-heteroatom elimination to afford the
b
c
yield. without 1, 2-naphthaquinone. 4-Methoxyphenyl vinyl ether was
used. d 4-Cyanophenyl vinyl ether was used.
To demonstrate the synthetic practicability of this new ap-
proach, a gram-scale experiment for the synthesis of 3a was car-
ried out under the similar reaction conditions. As illustrated in
Scheme 5, when 5 mmol of 1a and 7.5 mmol of 2a was used, 0.85
g of the 3a was obtained in 53% yield.
[
24]
4
-vinylisoxazoles.
www.cjc.wiley-vch.de
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
Scheme 8 Plausible reaction mechanism
WWW under https://doi.org/10.1002/cjoc.2021xxxxx.
Pd(OAc)
2
1
Me
Acknowledgement
O
-
I
[
O]
OAc
N
We thank the National Natural Science Foundation of China
(21971072), the Ministry of Science and Technology of the Peo-
ple’s Republic of China (2016YFA0602900), the Guangdong Natu-
ral Science Foundation (2018B030308007), the Open Fund of
Guangdong Provincial Key Laboratory of Luminescence from Mo-
lecular Aggregates (2019B030301003) for financial support.
R2
R1
path b
Pd(OAc)2
5
β
-
OAr
elimination
Pd0
Me
O
path a
O
R2
References
N
or
R = Ar
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3
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II
fin-Assisted Pd -Catalyzed Oxidative Alkynylation of Enallenes.
The supporting information for this article is available on the
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

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Entry for the Table of Contents
Palladium-catalyzed sequential cyclization/functionalization of oxime ethers with unactivated vinyl ethers for tunable assembly of structurally
diverse isoxazoles
Jianxiao Li,* Zidong Lin, Dan He, Wanqing Wu and Huanfeng Jiang
Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
O
R2
OMe
R3
N
O
R2
Ar
N
N
O
O
R1
R1
Pd(OAc)
2
Pd(OAc)
2
1
R
1
3
R2
R O
2 examples
up to 71% yields
Novel protocol
31 examples
up to 84% yields
Tunable regioselectivity
Broad substrate scope
A palladium-catalyzed sequential cyclization/functionalization of O-methyloximes and unactivated vinyl ethers under aerobic conditions was de-
scribed. The structure of the products could be successfully regulated by varying the electrical property of the substituents of the vinyl ethers. This
new approach provides the convenient and effective protocol for the preparation of a great variety of 4-(1-alkoxyvinyl)-isoxazoles and 4-vinylisoxazoles
in moderate to good yields with high regioselectivity.
a
c
Department, Institution, Address 1
Department, Institution, Address 3
E-mail:
E-mail:
b
Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template
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