Palladium-Catalyzed Cascade Annulation/Allylation of Alkynyl Oxime Ethers with Allyl Halides: Rapid Access to Fully Substituted Isoxazoles

Article abstract of DOI:10.1021/acs.joc.9b01593

A novel and efficient approach for the synthesis of functionalized isoxazoles via palladium-catalyzed cascade annulation/allylation of alkynyl oxime ethers with allyl halides has been established. The present protocol exhibits mild reaction conditions, good functional group compatibility, and convenient operation. Moreover, scalability was performed and further decoration of the isoxazole product was achieved.

Full text of DOI:10.1021/acs.joc.9b01593

Subscriber access provided by Nottingham Trent University
Article
Palladium-Catalyzed Cascade Annulation/Allylation of Alkynyl Oxime
Ethers with Allyl Halides: Rapid Access to Fully Substituted Isoxazoles
Can Li, Jianxiao Li, Fei Zhou, Chaosheng Li, and Wanqing Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01593 • Publication Date (Web): 29 Aug 2019
Downloaded from pubs.acs.org on August 29, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Palladium-Catalyzed Cascade Annulation/Allylation of
Alkynyl Oxime Ethers with Allyl Halides: Rapid Access to
Fully Substituted Isoxazoles
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
b
b
b
,a,b
Can Li , Jianxiao Li , Fei Zhou , Chaosheng Li , and Wanqing Wu*
a.
State Key Laboratory of Luminescent Materials and Devices, South China University of
Technology, Guangzhou 510640, China
b.
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of
Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640,
China
Fax: (+86) 20-87112906; E-mail: cewuwq@scut.edu.cn
R2
O
R3
N
PdII
O
R3
N
X
+
R1
R1
R2
X = Cl, Br, I
3
9 Examples up to 99% yield
0 Gram-scale Synthesis
5-45 min
1
Base and Oxidant Free
Mild Reaction Conditions
C-O and C-C Bond Formations
Abstract: A novel and efficient approach for the synthesis of functionalized
isoxazoles via palladium-catalyzed cascade annulation/allylation of alkynyl oxime
ethers with allyl halides has been established. The present protocol exhibits mild
reaction conditions, good functional group compatibility, and convenient operation.
Moreover, the scalability was performed and further decoration of the isoxazole
product was achieved.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
INTRODUCTION
Palladium-catalyzed coupling reaction has attracted substantial attention mainly due
to its ability for efficient and straightforward construction of carbon-carbon or/and
carbon-heteroatom bonds.1 As an important chemical transformation type,
nucleopalladation of unsaturated hydrocarbons such as halopalladation,2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
4
aminopalladation, and oxypalladation, has been established in recent years, which
can undergo different quenching manners to break the carbon-palladium bond and
generate diverse useful frameworks. In particular, the nucleopalladation of alkynes5
affords a highly reactive and crucial alkenylpalladium intermediate, which can be
6
7
8
9
captured by the activated alkenes, carbon monoxide, allenes, enols and other
1
0
participants, providing the corresponding alkyl-Pd intermediates. Classically, there
are three main approaches applied to quench the alkyl-Pd species: (i) β-H elimination
to give an alkene; (ii) β-heteroatom elimination also to afford an alkene; (iii) reductive
elimination to generate a saturated C-X bond. Among them, β-heteroatom elimination
has been typically investigated in the past few years. For example, Ma and co-workers
developed an elegant protocol for the palladium-catalyzed cyclization reaction of
2
,3-allenoic acids with -1-alkenyl halides for the construction of β-alkyl-substituted
butenolides.11 In 2011, Zhu’s group reported the first palladium-catalyzed
haloallylation reaction of alkynyl halides to generate various
1E/Z)-1,2-dihalo-1,4-dienes. Despite many significant advances in this field, most
1
2
(
approaches suffer from some limitations, such as limited substrate scope, low
efficiency and regioselectivity issues. Therefore, the development of convenient and
ACS Paragon Plus Environment

Page 3 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
practical synthetic methods under mild reaction conditions for the rapid and
straightforward assembly of highly functionalized frameworks is still highly desirable.
Isoxazole architectures represent a privileged scaffold extensively found in many
pharmaceutical agents and naturally occurring molecules.13 Specially, highly
substituted isoxazoles exhibit remarkable biological and therapeutic activities, such as
antinociceptive, antimicrobial, antibiotic, anti-inflammatory, and anticancer
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
4
activities. Many representative synthetic methods have been developed for building
15
this heterocyclic moiety in recent years. Among them, cyclization of alkynyl oxime
1
6
17
ether has aroused much attention which is summarized in Scheme 1. Ryu , Larock
1
8
and Ruchirawat et al. utilized electrophilic cyclization of alkynyl-O-methyl oximes
for the synthesis of 4-haloisoxazoles, respectively (Scheme 1, a). Chen19 and our
group20 developed the palladium-catalyzed coupling between alkynyl-O-methyl
oximes with activated alkenes/alkynes for the construction of 4-alkeny/alkyny
2
1
isoxazoles (Scheme 1, b and c). Recently, Yang and co-workers have reported the
synthesis of 4-sulfenyl isoxazoles via AlCl -mediated electrophilic
3
cyclization/sulfenylation of 2-alkyn-1-one O-methyloximes (Scheme 1, d). It is
noteworthy that the allyl moiety can improve their biological activities compared to
22
the non-allyl heterocyclic compounds. In 2010, Miyata and co-workers introduced
C4 allyl groups into the preformed isoxazoles via the gold-catalyzed intramolecular
domino cyclization and Claisen-type rearrangement reaction.23 Based on our
continuous interest in nucleopalladation of alkynes,24 herein, we disclose a
palladium-catalyzed cascade cyclization/alkylation of alkynes with alkenes for the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
synthesis of 4-allylisoxazole derivatives (Scheme 1, e). This protocol provides quick
access to diverse polyfunctionalized isoxazoles from readily available starting
materials, which should have potential applications in synthetic and pharmaceutical
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chemistry.
R2
R2
O
X source
S source
O
N
(
a) ref. 16-18
(d) ref. 21
N
X
[Au]/IX/NBX
[Al]
R1
SR
R1
X = F, Cl, Br, I
-Halogenation
4
R
4-Sulfenylation
O
R2
N
O
O
R3
R1
R2
O
(
b) ref. 19 N
R
[Pd]/[O]/[Base]
R3
R2
X
R1
N
O
(e) This Work
4-Alkenylation
[Pd]
R1
4
R2
-Allylation
Base and Oxidant Free
-Heteroatom Elimination
High Efficiency
O
R
(
c) ref. 20
N
[Pd]/[O]

R1
R
4-Alkynylation
Scheme 1. Representative Methods for the Synthesis of 4-Functionalized Isoxazoles
from Alkynyl Oxime Ethers
RESULTS AND DISCUSSION
Functionalized alkyne (1aa) and allyl bromide (2a) were selected as the model
substrates to screen the optimal conditions for this cascade protocol. As summarized
in Table 1, we initially used PdCl as the catalyst, and n-Bu NI as the additive in
2
4
o
DMF at 80 C, while a trace amount of allylated product 3aa was detected by GC-MS
after 3 h (entry 1). Additive screening revealed that n-Bu NBr was a suitable choice,
4
affording the desired product 3aa in 40% yield. However, other additives including
n-Bu NCl, NaBr and KBr were less effective (entries 2, 4 and 5). Pd(OAc) was
4
2
found to be better than other Pd catalysts such as PdCl or Pd(TFA) (entries 6 and 7).
2
2
ACS Paragon Plus Environment

Page 5 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Investigation of different solvents showed that DMF was the optimal solvent for this
reaction (entries 8-14), and product 3aa could be isolated in 95% yield when using
Pd(OAc) as the catalyst and DMF as the solvent (entry 6). Satisfyingly, reaction time
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
optimization revealed that this transformation could be finished in 20 min (entry 15).
It is noted that when the reaction was performed with only 3 mol % of Pd catalyst, the
desired product 3aa was still detected in 98% yield (entries 16-18). Further reaction
condition optimizations revealed that either decreasing or increasing the temperature
led to a negative effect on the product yield (entries 19-21). Control experiments
indicated that Pd catalyst and additive (n-Bu NBr) were necessary for this tandem
4
reaction (entries 22 and 23). Notably, under N atmosphere the reaction could be
2
performed successfully using Pd(OAc) as catalyst (entry 24). No reaction occurred
2
0
when Pd catalyst such as Pd(PPh ) , Pd(PCy ) and Pd (dba) was used (entries
3
4
3 2
2
3
2
5-27). Thus, the optimal conditions for this transformation was defined as follows:
Pd(OAc) (3 mol %) as catalyst, n-Bu NBr (1.0 equiv) as additive, DMF (1.0 mL) as
2
4
o
solvent at 80 C for 20 min.
Table 1. Optimization of Reaction Conditionsa.
Ph
OMe
O
N
N
H
[Pd], additive
solvent, T
+
Br
Ph
H
Ph
Ph
1
aa
2a
3aa
o
Yield (%)b
trace
Entry
Catalyst
Additive
Solvent
DMF
T ( C)
80
1
2
3
PdCl (10)
n-Bu NI
2
4
PdCl (10)
n-Bu NCl
DMF
80
20
2
4
PdCl (10)
n-Bu NBr
DMF
80
40 (37)
2
4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
5
6
7
8
9
PdCl (10)
NaBr
KBr
DMF
DMF
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
100
70
50
80
80
80
80
trace
trace
2
PdCl (10)
2
Pd(OAc) (10)
n-Bu NBr
DMF
98 (95)
80 (78)
trace
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Pd(TFA) (10)
n-Bu NBr
DMF
2
4
Pd(OAc) (10)
n-Bu NBr
Toluene
NMP
2
4
Pd(OAc) (10)
n-Bu NBr
trace
2
4
1
0
1
2
3
Pd(OAc) (10)
n-Bu NBr
DMSO
DCE
trace
2
4
1
1
1
Pd(OAc) (10)
n-Bu NBr
trace
2
4
Pd(OAc) (10)
n-Bu NBr
CH Cl
2
trace
2
4
2
Pd(OAc) (10)
n-Bu NBr
CH CN
47
2
4
3
14
Pd(OAc) (10)
n-Bu NBr
CH NO
trace
2
4
3
2
1
5c
6c
7c
8c
Pd(OAc) (10)
n-Bu NBr
DMF
98 (95)
98 (95)
98 (95)
80 (78)
90 (88)
72 (70)
50
2
4
1
1
1
Pd(OAc) (5)
n-Bu NBr
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
2
4
Pd(OAc) (3)
n-Bu NBr
2
4
Pd(OAc) (2)
n-Bu NBr
2
4
19c
Pd(OAc) (3)
n-Bu NBr
2
4
2
2
2
2
0c
1c
2c
3c
Pd(OAc) (3)
n-Bu NBr
2
4
Pd(OAc) (3)
n-Bu NBr
2
4
-
n-Bu NBr
n.r.
4
Pd(OAc) (3)
-
n.r.
2
24c, d
5d
Pd(OAc) (3)
n-Bu NBr
98 (95)
n.r.
2
4
2
Pd(PPh ) (3)
n-Bu NBr
3
4
4
ACS Paragon Plus Environment

Page 7 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
26d
7d
Pd(PCy ) (3)
n-Bu NBr
DMF
DMF
80
80
n.r.
n.r.
3
2
4
2
Pd (dba) (3)
n-Bu NBr
2
3
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
aReaction conditions: 1aa (0.5 mmol), 2a (0.6 mmol), [Pd] catalyst, additive (1.0 equiv), solvent
b
(
1.0 mL) were stirred for 3 h. Detected by GC-MS using n-dodecane as internal standard. Data in
c
the parentheses were referred to isolated yield. n.r. = no reaction. The reaction time was 20 min.
d
Under N atmosphere.
2
With the optimized conditions in hand, we first explored the substrate scope of
1
alkynyl oxime ethers with different R groups (Table 2). Generally, the substrates
bearing different groups at the ortho-, meta- or para-position of the phenyl ring
worked well and transformed to the isoxazole products in 95-98% yields in 10-30 min
(3aa-3aj). For instance, functional groups such as -OCF and -SCF could be
3
3
compatible under the standard reaction conditions, and the corresponding products
ac and 3ad were assembled in excellent yields. It should be noted that the good
3
tolerance with Cl and Br groups, which are known to undergo diverse Pd-mediated
transformations, offered easy handles for further modification (3af, 3ag and 3aj).
Moreover, the electron-donating groups could be also tolerated in this catalytic system,
and the desired product 3ah was formed in 95% yield in only 5 min. Multiple
substituted aromatic substrates were found to be suitable for this catalytic system,
converting to the corresponding products 3ak and 3al in excellent yields. In addition,
the substrates with aliphatic substituents also proved to be effective in this allylation
process and the target products could be obtained in 94-96% yields (3am-3ao).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Additionally, the reactions of styryl- and 2-thienyl- substituted alkynyl oxime ethers
proceeded smoothly, leading to the allylation products 3ap and 3aq in 94% and 95%
yields, respectively.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
a
Table 2. Scope of Oxime Ethers with Different R Groups
Ph
O
Pd(OAc) (3 mol %)
O
N
2
N
H
+
n-Bu NBr (1 equiv)
4
Br
R1
o
H
DMF, 80 C
R1
1
a
Ph
Ph
2a
3a
Ph
Ph
Ph
O
O
O
O
N
N
N
N
F3CO
F3CS
3aa, 20 min, 95%
3ab, 10 min, 98% 3ac, 20 min, 97% 3ad, 30 min, 97%
Ph
Ph Ph Ph
O
O
O
O
N
N
N
N
Et
Cl
3af, 20 min, 95% 3ag, 20 min, 96% 3ah, 5 min, 95%
Ph Ph Ph
Br
NC
3ae, 15 min, 95%
Ph
O
O
O
O
N
N
N
N
Br
O
O
F
3
ai, 30 min, 94%
3aj, 20 min, 96% 3ak, 20 min, 95% 3al
,
25 min, 97%
Ph
Ph
O
N
Ph
Ph
O
O
O
N
N
N
(
)n
S
Ph
3am, n = 1, 20 min, 94% 3ao, 20 min, 96% 3ap, 20 min, 94%
an, n = 2, 20 min, 95%
3
aq, 25 min, 95%
3
a
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol, 1.2 equiv), Pd(OAc) (3 mol %), n-Bu NBr
2
4
o
(
1.0 equiv), DMF (1.0 mL) were stirred at 80 C for the indicated time. Yields referred to isolated
yields.
ACS Paragon Plus Environment

Page 9 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
The substrate scope of alkynyl oxime ethers bearing different R groups and
different terminal alkenes was then investigated. As shown in Table 3, substrates
containing functional groups, such as Me, OEt, Ph, pentyloxy, F, Br at the ortho-,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
meta- or para-position exhibited good to excellent tolerance to this transformation
2
(
3ba-3bm). When R = Ar, different length of aliphatic substituents at the phenyl ring
were allowed to react with allyl bromide (2a), giving the corresponding products in
good to excellent yields (3bg-3bj). Notably, the thienyl alkynyl oxime ether was also
a suitable substrate, converting to the desired product 3bn in 95% yield. In addition,
the transformations of substrates with cyclopentyl and cyclohexyl moiety could also
occur to afford the allylated products in 95% (3bo) and 93% yields (3bp),
respectively. Gratifyingly, the linear chain aliphatic substrates were good candidates
to deliver the target products in good yields (3bq-3bt). When the branched chain
olefins were used, the corresponding products 3bu and 3bv could be generated in
97% and 95% yields, respectively. However, when disubstituted allyl bromide or
trisubstituted allyl bromide were used as the allyl sources, the desired products could
not be detected (3bw and 3bx).
2
a
Table 3. Scope of Oxime Ethers with Different R Groups and Alkenes
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R2
O
R3
O
Pd(OAc) (3 mol %)
N
2
N
R4
+
n-Bu NBr (1 equiv)
4
Br
Ph
Ph
o
R4
R5
DMF, 80 C
R3
R2
3b
1
b
2
R5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OEt
Ph
Br
O
O
O
O
N
N
N
N
Ph
Ph
Ph
Ph
3
ba, 10 min, 98%
3bb, 25 min, 98%
3bc, 40 min, 95%
( )n
3bd, 40 min, 95%
F
R
O
O
O
O
N
N
N
N
Ph
Ph
Ph
Ph
3bk, 15 min, 95%
3be, 15 min, 97%
3bf, R = pentyloxy, 15 min, 98% 3bg, n = 1, 15 min, 97%
3
3
3
bh, n = 2, 15 min, 97%
bi, n = 3, 20 min, 96%
bj, n = 4, 20 min, 94%
S
O
N
O
O
N
O
N
N
Br
Ph
Ph
Ph
Ph
3bm, 35 min, 94%
3
bl, 30 min, 94%
3bn, 35 min, 95%
3bo, 20 min, 95%
Ph
(
)n
O
Ph
O
O
O
N
N
N
N
Ph
Ph
Ph
Ph
bp, 20 min, 93%
R
3
3bq, n = 2, 25 min, 93%
br, n = 3, 20 min, 97%
bs, n = 4, 20 min, 95%
3bu, R = Me, 30 min, 97%;
3bv, R = Br, 30 min, 95%;
3bw, n.d.
3
3
O
Ph
N
3bt, n = 5, 30 min, 94%
Ph
3
bx, n.d.
a
Reaction conditions: 1b (0.5 mmol), 2 (0.6 mmol, 1.2 equiv), Pd(OAc) (3 mol %), n-Bu NBr
2
4
o
(1.0 equiv), DMF (1.0 mL) were stirred at 80 C for the indicated time. Yields referred to isolated
yields. n.d. = not detected.
ACS Paragon Plus Environment

Page 11 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Additionally, other allyl halide compounds such as allyl chloride and allyl iodide
could also be applied to this chemical process, and the desired product 3aa was given
respectively in 70% and 60% yields (Table 4), thus broadening the substrate scope of
this synthetic method. However, no desired product was detected when propenol or
allyl acetate was used as the substrate.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 4. Evaluation of Different Substituent of Alkenes
Ph
OMe
O
N
H
X
Standand conditions
N
+
Ph
H
Ph
1aa
Ph
2
3aa
entry
X
reaction time/min
yield of 3aa (%)
1
2
3
4
5
Cl
Br
I
40
20
30
60
60
70
95
60
OH
n.d.
n.d.
OAc
A 10-gram scale synthesis was then performed (Scheme 2, Eqn. 1), which further
demonstrated the utility of this method. When 50 mmol of alkynyl oxime ether (1aa)
was reacted with 75 mmol of allyl bromide (2a) under the standard reaction
conditions, 11.36 g of 3aa was isolated in 60 min. To demonstrate the synthetic utility
of this protocol, the newly formed allylated products were employed for further
elaborations. For example, the fused seven-membered ring compound 4 could be
obtained in 50% yield over 2 steps from the starting material 1aj (Scheme 2, Eqn.
2
).23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Ph
O
O
N
H
Br
standard conditions
N
(
Eqn. 1)
+
Ph
60 min
H
Ph
Ph
1
aa (50 mmol)
2a (75 mmol)
3aa (87%, 11.36 g)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
O
N
O
N
Br
P(o-tolyl)3, Et N
3
(Eqn. 2)
standard condition
Ph
Br
1aj (0.5 mmol)
4, 60 mg, 50% yield over 2 steps
Scheme 2. Scale-up Experiment and Late-stage Transformations of the Newly
Formed Products
Several control experiments were performed to unravel this reaction mechanism
(Scheme 3). Firstly, treatment of 5 and 2a with 3 mol % of Pd(OAc) and 1.0 equiv of
2
n-Bu NBr could not give 3aa, indicating that C-H activation was not involved in this
4
transformation (Scheme 3, Eqn. 1). When using 4-bromoisoxazole (6) as the substrate,
no desired product was detected under the standard conditions, which revealed that 6
should not be a possible intermediate in this process (Scheme 3, Eqn. 2). Moreover,
no desired product 3aa was detected when 7 was tested (Scheme 3, Eqn. 3). While
3
aa could be isolated in 68% yield under the standard conditions with 8 as the
substrate, and benzyl bromide was detected by GC analysis in 65% yield (Scheme 3,
Eqn. 4). Additionally, when using alkynyl oxime allyl ether 9 as the substrate without
allyl bromide, the desired product 3aa could be observed in 50% GC yield under the
standard conditions, and 4-bromo-3,5-diphenylisoxazole 6 was detected in 20% GC
yield (Scheme 3, Eqn. 5).
ACS Paragon Plus Environment

Page 13 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
O
Ph
Standard Conditions
N
+
2a
3aa
(Eqn. 1)
(Eqn. 2)
60 min
H
n.d.
Ph
5
Ph
Br
O
Standard Conditions
0 min
N
3aa
+
2a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
n.d.
Ph
6
OH
N
2a Standard Conditions
+
+
3aa
(Eqn. 3)
Ph
Ph
60 min
n.d.
7
Ph
O
Ph
N
Standard Conditions
2a
3aa
(Eqn. 4)
+
PhCH Br
2
60 min
Ph
68%
8
65% GC-MS yield
Ph
O
O
N
Standard Conditions
N
3aa
+
(Eqn. 5)
60 min
Br
Ph
Ph
Ph
9
50%
20% GC-MS yield
Scheme 3. Control Experiments
On the basis of the above results and previous reports, a plausible mechanism is
described in Scheme 4. Firstly, heteroaryl palladium intermediate I was formed by
-
-
-
-
Pd(II)-catalyzed 5-endo-dig cyclization. Attacked by Nu (Br , Cl or I ), intermediate
1
7
II would be afforded after the loss of a methyl group. Then, the intermediate II
could undergo alkene insertion to afford intermediate V. Finally, the β-X (X = Cl, Br,
I) elimination occurred to give the desired product 3. It should be noted that product
3’ formed by β-H elimination of intermediate V could not be detected, indicating that
β-heteroatom elimination was preferred in this process.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R1
O
N
N
O
PdII
R1
R2
R2
3
1
β -X elimination
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R1
R1
N
PdII
N
N
O
O
O
R1
H
X
H
X
R2
R2
R2
3'
N.D.
H
V
PdII
H
I
β -H elimination
Br-
H
MeBr
X
H
N
O
R1
2
R2
(X = Cl, Br, I)
PdII
II
Scheme 4. Proposed Mechanism
CONCLUSION
In summary, we have developed an efficient palladium-catalyzed rapid cyclization
reaction of alkynyl oxime ethers and 1-alkenyl halides. In this transformation, new
2
2
2
C(sp )-O and C(sp )-C(sp ) bonds are formed simultaneously with the high yield of a
series of structurally diverse fullysubstituted isoxazoles in 5-45 min. Easy operation,
good substrate scope, mild conditions, and convenient late-stage transformations of
the products are other features of this reaction, thus providing a concise and practical
strategy for 4-allylisoxazole derivatives and showing potential applications in the
fields of biochemistry and medicinal chemistry.
EXPERIMENTAL SECTION
All purchased reagents and solvents were used without further purification unless
otherwise noted. Analytical thin layer chromatography was performed by using
ACS Paragon Plus Environment

Page 15 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
commercially prepared 100-400 mesh silica gel plates (GF ) and visualization was
2
54
effected at 254 nm. All the haloalkynes were prepared according to known procedures.
1
13
H and C NMR spectra were recorded using a Bruker DRX-400 spectrometer using
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl as solvent. The chemical shifts are referenced to signals at 7.26 and 77.0 ppm,
3
respectively. Mass spectra were recorded on a Thermo Scientific ISQ gas
chromatograph-mass spectrometer. The data of HRMS was carried out on a
high-resolution mass spectrometer (LCMS-IT-TOF). IR spectra were obtained either
as potassium bromide pellets or as liquid films between two potassium bromide
pellets with a Bruker TENSOR 27 spectrometer. Melting points were determined with
a Büchi Melting Point B-545 instrument.
General Procedure for the Preparation of Ynone O-Methyl Oximes
Typical Procedure I:
Step 1: PdCl (PPh ) (0.02 mmol, 0.4 mol %, 14 mg), CuI (0.1 mmol, 2 mol %, 19
2
3 2
mg), and triethylamine (10 mL) were added to a 50 mL round-bottom flask. The flask
was flushed with nitrogen for 3 min, and the terminal acetylene (5.0 mmol) was added
to the stirred suspension, followed by immediate dropwise addition of acyl chloride
(6.5 mmol). The mixture was stirred at room temperature overnight. After the fully
consumption of starting material by TCL detection. The resulting solution was
extracted with diethyl ether (3 × 20 mL). The organic layers were combined and dried
over anhydrous MgSO . The solvent was removed under a vacuum, and the residue
4
was purified by flash column chromatography on silica gel using PE/EA as the eluent
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
to afford alkynone.
Step 2: Alkynone (3.5 mmol), methoxylamine hydrochloride (7.0 mmol, 2.0 equiv,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
581 mg), anhydrous Na SO (7.0 mmol, 2.0 equiv, 994 mg), pyridine (1 mL),
2
4
methanol (10 mL) were added to a 50 mL round-bottom flask. The reaction mixture
was stirred at room temperature overnight. The mixture was diluted with saturated
NH Cl solution (25 mL) and extracted with EtOAc (3 × 25 mL). The organic layers
4
were combined, washed with brine, and dried over anhydrous MgSO . The solvent
4
was removed under a vacuum, and the residue was purified by flash column
chromatography on silica gel using PE/EA as the eluent.
1ab, 1ac, 1af-1aj, 1al, 1an, 1ao, 1ba, 1be, 1bj, 1bn, 1br, 1bt are known compounds
and the NMR data are in good agreement with the literature[17-20]. 1aa, 1ad, 1ae, 1ak,
1
am, 1ap, 1aq, 1bb-1bd, 1bf-1bi, 1bk-1bm, 1bo-1bq and 1bs are unknown
compounds and the corresponding NMR spectra data are shown as bellow:
Z)-1,3-Diphenylprop-2-yn-1-one O-Methyl Oxime (1aa): R = 0.60 (PE/EA = 150:
(
f
o
1
1); 200 mg, 85% yield, white solid, mp: 98 - 99 C; H NMR (400 MHz, CDCl ): δ
3
8
.19-7.74 (m, 2H), 7.59 (d, J = 3.0 Hz, 2H), 7.35 (d, J = 11.4 Hz, 6H), 4.12 (s, 3H);
13
1
C{ H} NMR (100 MHz, CDCl ): δ 140.0, 133.7, 132.3, 129.8, 129.7, 128.6, 126.6,
3
-1
121.9, 101.3, 79.6, 63.2; IR (KBr)νmax/cm : 3065, 2933, 2206, 1453, 1332, 1046, 912,
+
7
61, 672, 530; HRMS (ESI, m/z): [M+H] Calcd. for C H NO, 236.1070, found:
1
6
14
236.1069.
(Z)-3-Phenyl-1-(4-((trifluoromethyl)thio)phenyl)prop-2-yn-1-one
O-Methyl
ACS Paragon Plus Environment

Page 17 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
Oxime (1ad): R = 0.50 (PE/EA = 150: 1); 275 mg, 82% yield, yellow oil; H NMR
f
(
400 MHz, CDCl ): δ 7.96 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 7.8 Hz, 2H), 7.60 (d, J =
3
13
1
7
.6 Hz, 2H), 7.42-7.31 (m, 3H), 4.14 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
138.8, 136.1 (d, JC-F = 4.1 Hz), 132.2, 129.8, 128.0 (q, JC-F = 257.9 Hz), 127.2, 125.7
-
1
(
q, JC-F = 1.7 Hz), 121.5, 101.9, 78.9, 63.4 (d, JC-F = 2.8 Hz); IR (KBr)νmax/cm : 2940,
2821, 2207, 1581, 1333, 1134, 1056, 916, 837, 758, 688, 512; HRMS (ESI, m/z):
+
[
M+H] Calcd. for C H F NOS, 336.0670, found, 336.0671.
1
7
13 3
(
Z)-1-(4-Ethylphenyl)-3-phenylprop-2-yn-1-one O-methyl Oxime (1ae): R = 0.45
f
o
1
(PE/EA = 150: 1); 200 mg, 76% yield, yellow solid, mp: 104 - 105 C; H NMR (400
MHz, CDCl ): δ 7.74 (d, J = 8.0 Hz, 2H), 7.55- 7.48 (m, 2H), 7.28 (d, J = 5.6 Hz, 3H),
3
7.13 (d, J = 8.0 Hz, 2H), 4.03 (s, 3H), 2.58 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.6 Hz,
1
3
1
3
H); C{ H} NMR (100 MHz, CDCl ): δ 146.2, 140.0, 132.2, 131.2, 130.0, 128.5,
3
-1
1
28.0, 126.6, 121.9, 100.9, 79.7, 63.1, 28.8, 15.5; IR (KBr)νmax/cm : 2972, 2207,
+
1760, 1247, 1044, 525; HRMS (ESI, m/z): [M+H] Calcd. for C H NO, 264.1383,
1
8
18
found: 264.1379.
(Z)-1-(3,4-Dimethoxyphenyl)-3-phenylprop-2-yn-1-one O-Methyl Oxime (1ak): Rf
o
1
=
0.50 (PE/EA = 200: 1); 266 mg, 90% yield, white solid, mp: 111 - 112 C; H NMR
(
400 MHz, CDCl ): δ 7.60 (d, J = 7.4 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.37 (d, J =
3
1
3
1
6.0 Hz, 3H), 6.88 (d, J = 8.4 Hz, 1H), 4.12 (s, 3H), 3.94 (s, 3H), 3.90 (s, 3H); C{ H}
NMR (100 MHz, CDCl ): δ 150.6, 148.9, 139.6, 132.1, 129.5, 128.5, 126.5, 121.9,
3
-1
120.4, 110.7, 108.5, 100.8, 63.0, 62.9, 55.9; IR (KBr)νmax/cm : 2949, 2206, 1762,
+
1
248, 1043, 761, 515; HRMS (ESI, m/z): [M+H] Calcd. for C H NO , 296.1281,
1
8
18
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
found: 296.1286.
(Z)-1-Cyclopentyl-3-phenylprop-2-yn-1-one O-Methyl Oxime (1am): R = 0.50
f
1
(PE/EA = 200: 1); 197 mg, 87% yield, black oil; H NMR (400 MHz, CDCl ): δ 7.51
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
(t, J = 6.7 Hz, 2H), 7.34 (d, J = 6.0 Hz, 3H), 3.96 (s, 3H), 2.05-1.50 (m, 10H); C{ H}
NMR (100 MHz, CDCl ): δ 145.8, 132.1, 131.9, 129.3, 128.4, 99.8, 79.4, 43.9, 31.1,
3
-
1
30.6, 25.8; IR (KBr)νmax/cm : 3067, 2209, 1760, 1475, 1340, 1242, 1047, 526;
+
HRMS (ESI, m/z): [M+H] Calcd. for C H NO, 228.1383, found: 228.1381.
1
5
18
(1E,3Z)-1,5-Diphenylpent-1-en-4-yn-3-one O-Methyl Oxime (1ap): R = 0.60
f
o
1
(PE/EA = 150: 1); 224 mg, 86% yield, black solid, mp: 98 - 99 C; H NMR (400
MHz, CDCl ): δ 7.52 (s, 2H), 7.42 (d, J = 21.7 Hz, 2H), 7.32- 7.11 (m, 7H), 6.83 (d, J
3
1
3
1
= 15.9 Hz, 1H), 3.98 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 141.5, 139.4, 136.3,
3
1
1
36.1, 132.2, 132.1, 129.6, 129.5, 129.2, 128.8, 128.7, 128.5, 127.9, 127.2, 123.4,
-1
21.7, 116.3, 101.0, 77.9, 63.1; IR (KBr)νmax/cm : 3065, 2928, 2208, 1763, 1452,
+
1048, 909, 754, 440; HRMS (ESI, m/z): [M+H] Calcd. for C H NO, 262.1226,
1
8
16
found: 262.1227.
(E)-3-Phenyl-1-(thiophen-2-yl)prop-2-yn-1-one O-Methyl Oxime (1aq): R = 0.45
f
1
(PE/EA = 200: 1); 193 mg, 80% yield, yellow oil; H NMR (400 MHz, CDCl ): δ
3
7
.89 (dd, J = 6.2, 2.6 Hz, 2H), 7.64 (d, J = 2.8 Hz, 1H), 7.39-7.34 (m, 3H), 7.31-7.21
1
3
1
(m, 2H), 4.11 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 139.9, 133.8, 130.9, 129.9,
3
-1
1
29.7, 128.4, 126.6, 125.7, 121.0, 96.4, 79.4, 63.1; IR (KBr)νmax/cm : 3052, 2816,
+
2209, 1750, 1334, 1049, 911, 758, 524; HRMS (ESI, m/z): [M+H] Calcd. for
C H NOS, 242.0634, found: 242.0631.
1
4
12
ACS Paragon Plus Environment

Page 19 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(Z)-3-(4-Ethoxyphenyl)-1-phenylprop-2-yn-1-one O-Methyl Oxime (1bb): R =
f
1
0
.50 (PE/EA = 150: 1); 237 mg, 85% yield, yellow oil; H NMR (400 MHz, CDCl ):
3
δ 7.91 (d, J = 5.0 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 4.8 Hz, 3H), 6.86 (d,
J = 7.8 Hz, 2H), 4.12 (s, 3H), 4.02 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 6.8 Hz, 3H);
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
C{ H} NMR (100 MHz, CDCl ): δ 160.1, 140.2, 133.9, 133.8, 129.6, 128.4, 126.6,
3
-1
114.6, 113.6, 101.8, 78.6, 63.6, 63.1, 14.7; IR (KBr)νmax/cm : 3057, 2662, 2207, 1703,
+
1
455, 1046, 970, 523; HRMS (ESI, m/z): [M+H] Calcd. for C H NO , 280.1332,
1
8
18
2
found: 280.1335.
(Z)-3-([1,1'-Biphenyl]-4-yl)-1-phenylprop-2-yn-1-one O-Methyl Oxime (1bc): R =
f
o
1
0
.45 (PE/EA = 150: 1); 266 mg, 85% yield, white solid, mp: 98 - 99 C; H NMR
(400 MHz, CDCl ): δ 7.88-7.77 (m, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 8.8 Hz,
3
1
3
1
4
1
H), 7.35- 7.20 (m, 6H), 4.02 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 142.4,
3
40.1, 140.0, 133.7, 132.7, 129.8, 129.0, 128.6, 128.0, 127.2, 127.1, 126.6, 120.7,
-1
101.3, 80.3, 63.2; IR (KBr)νmax/cm : 3066, 2208, 1579, 1453, 1321, 1159, 1047, 908,
+
7
54, 521; HRMS (ESI, m/z): [M+H] Calcd. for C H NO, 312.1383, found:
2
2
18
312.1389.
(
Z)-3-(4-Bromophenyl)-1-phenylprop-2-yn-1-one O-methyl oxime (1bd): R = 0.50
f
1
(
PE/EA = 100: 1); 231 mg, 88% yield, yellow oil; H NMR (400 MHz, CDCl ): δ
3
7.88 (d, J = 4.4 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.39 (s,
1
3
1
3
H), 4.13 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 139.7, 133.6, 133.4, 131.8,
3
-1
129.8, 128.5, 126.5, 124.1, 120.8, 99.9, 80.5, 63.2; IR (KBr)νmax/cm : 3054, 2944,
+
2
203, 1527, 1334, 1047, 915, 825, 667, 541; HRMS (ESI, m/z): [M+H] Calcd. for
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
C H BrNO, 314.0175, found：314.0182.
1
6
13
(Z)-3-(4-(Pentyloxy)phenyl)-1-phenylprop-2-yn-1-one O-Methyl Oxime (1bf): Rf
1
=
0.30 (PE/EA = 150: 1); 236 mg, 85% yield, yellow oil; H NMR (400 MHz, CDCl ):
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
δ 8.04-7.92 (m, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 5.0 Hz, 3H), 6.93 (d, J =
.6 Hz, 2H), 4.19 (s, 3H), 4.00 (t, J = 6.6 Hz, 2H), 1.92- 1.75 (m, 2H), 1.58-1.36 (m,
8
1
3
1
4H), 0.99 (t, J = 7.0 Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ 160.3, 140.2,
3
1
33.9, 129.6, 128.4, 126.6, 114.7, 113.6, 101.9, 78.7, 68.2, 63.1, 28.9, 28.2, 22.5, 14.1;
-1
IR (KBr)νmax/cm : 3047, 2935, 2462, 2204, 1334, 1046, 912, 817, 662, 516; HRMS
+
(ESI, m/z): [M+H] Calcd. for C H NO , 322.1797, found: 322.1802.
2
1
24
2
(Z)-3-(4-Ethylphenyl)-1-phenylprop-2-yn-1-one O-Methyl Oxime (1bg): R = 0.30
f
o
1
(PE/EA = 150: 1); 221 mg, 76% yield, yellow solid, mp: 99 - 100 C; H NMR (400
MHz, CDCl ): δ 8.01 (dd, J = 6.6, 3.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.46 (dd, J =
3
5
.0, 1.8 Hz, 3H), 7.27 (d, J = 8.0 Hz, 2H), 4.21 (s, 3H), 2.73 (q, J = 7.6 Hz, 2H), 1.31
1
3
1
(t, J = 7.6 Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ 146.2, 140.1, 133.8, 132.3,
3
-1
1
29.7, 128.5, 128.1, 126.6, 119.1, 101.7, 79.1, 63.1, 28.9, 15.3; IR (KBr)νmax/cm :
+
3055, 2207, 1760, 1242, 1048, 913, 678; HRMS (ESI, m/z): [M+H] Calcd. for
C H NO, 264.1383, found：264.1381.
1
8
18
(Z)-1-Phenyl-3-(4-propylphenyl)prop-2-yn-1-one O-Methyl Oxime (1bh): R =
f
1
0.50 (PE/EA = 150: 1); 211 mg, 85% yield, yellow oil; H NMR (400 MHz, CDCl ):
3
δ 8.02-7.81 (m, 2H), 7.51 (d, J = 7.4 Hz, 2H), 7.36 (d, J = 5.2 Hz, 3H), 7.14 (d, J =
7.6 Hz, 2H), 4.11 (s, 3H), 2.56 (t, J = 7.6 Hz, 2H), 1.94- 1.39 (m, 2H), 0.90 (t, J = 7.4
1
3
1
Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ 144.7, 140.1, 133.8, 132.2, 129.7,
3
ACS Paragon Plus Environment

Page 21 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
-
1
128.7, 128.5, 126.6, 119.1, 101.7, 79.2, 63.1, 38.1, 24.4, 13.8; IR (KBr)νmax/cm :
+
3
047, 2937, 2203, 1447, 1334, 1046, 915, 666; HRMS (ESI, m/z): [M+H] Calcd. for
C H NO, 278.1539, found: 278.1540.
1
9
20
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Z)-3-(4-Butylphenyl)-1-phenylprop-2-yn-1-one O-Methyl Oxime (1bi): R = 0.50
f
1
(
PE/EA = 100: 1); 222 mg, 89% yield, yellow oil; H NMR (400 MHz, CDCl ): δ
3
8.00 (dd, J = 6.6, 3.0 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.50-7.37 (m, 3H), 7.25 (d, J
8.0 Hz, 2H), 4.21 (s, 3H), 2.76-2.62 (m, 2H), 1.75-1.56 (m, 2H), 1.51-1.35 (m, 2H),
=
13
1
1
.00 (t, J = 7.3 Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ 144.9, 140.1, 133.8,
3
132.2, 129.7, 128.6, 128.4, 126.6, 119.0, 101.7, 79.1, 63.1, 35.7, 33.4, 22.4, 13.9; IR
-1
(
KBr)νmax/cm : 3066, 2946, 2204, 1960, 1335, 1046, 915, 544; HRMS (ESI, m/z):
+
[M+H] Calcd. for C H NO, 292.1691, found：292.1696.
2
0
22
(
Z)-1-Phenyl-3-(m-tolyl)prop-2-yn-1-one O-Methyl Oxime (1bk): R = 0.45
f
1
(
PE/EA = 150: 1); 272 mg, 87% yield, yellow oil; H NMR (400 MHz, CDCl ): δ
3
7.91 (d, J = 4.2 Hz, 2H), 7.49 (d, J = 7.4 Hz, 2H), 7.37 (s, 3H), 7.15 (d, J = 7.4 Hz,
1
3
1
2
H), 4.12 (s, 3H), 2.34 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 140.1, 133.8,
3
-1
132.1, 129.7, 129.3, 128.5, 126.6, 118.8, 101.7, 79.1, 63.2, 21.7; IR (KBr)νmax/cm :
+
3
070, 2211, 1761, 1477, 1242, 1047, 912; HRMS (ESI, m/z): [M+H] Calcd. for
C H NO, 250.1226, found: 250.1223.
1
7
16
(Z)-1-Phenyl-3-(o-tolyl)prop-2-yn-1-one O-Methyl Oxime (1bl): R = 0.60 (PE/EA
f
1
=
150: 1); 200 mg, 88% yield, yellow oil; H NMR (400 MHz, CDCl ): δ 7.90 (d, J =
3
4.2 Hz, 2H), 7.49 (d, J = 7.4 Hz, 2H), 7.37 (s, 3H), 7.15 (d, J = 7.4 Hz, 2H), 4.12 (s,
1
3
1
3
H), 2.34 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 140.7, 133.8, 132.1, 129.7,
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1
129.4, 128.5, 126.6, 118.8, 101.6, 79.1, 63.2, 21.7; IR (KBr)νmax/cm : 2940, 2217,
+
1
2
763, 1326, 1050, 886, 767; HRMS (ESI, m/z): [M+H] Calcd. for C H NO,
1
7
16
50.1226, found：250.1232.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Z)-3-(2-Bromophenyl)-1-phenylprop-2-yn-1-one O-Methyl Oxime (1bm): R =
f
1
0
.50 (PE/EA = 100: 1); 178 mg, 74% yield, yellow oil; H NMR (400 MHz, CDCl ):
3
δ 7.88 (d, J = 4.4 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.39 (s,
1
3
1
3
H), 4.13 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 139.7, 133.6, 133.4, 131.8,
3
-1
1
29.8, 128.5, 126.5, 124.1, 120.8, 99.9, 80.5, 63.2; IR (KBr)νmax/cm : 2940, 2207,
+
1758, 1242, 1049; HRMS (ESI, m/z): [M+H] Calcd. for C H BrNO, 314.0175,
1
6
13
found: 314.0171.
(Z)-3-Cyclopentyl-1-phenylprop-2-yn-1-one O-Methyl Oxime (1bo): R = 0.50
f
1
(
PE/EA = 100: 1); 159 mg, 79% yield, yellow oil; H NMR (400 MHz, CDCl ): δ
3
7
.51 (t, J = 6.7 Hz, 2H), 7.34 (d, J = 6.0 Hz, 3H), 3.96 (s, 3H), 2.17-1.48 (m, 10H);
1
3
1
C{ H} NMR (100 MHz, CDCl ): δ 145.8, 132.1, 131.9, 129.3, 128.4, 99.8, 79.4,
3
-1
6
2.3, 43.9, 31.1, 30.6, 25.8; IR (KBr)νmax/cm : 3066, 2946, 2204, 1967, 1335, 1046,
+
915, 523; HRMS (ESI, m/z): [M+H] Calcd. for C H NO, 228.1383, found:
1
5
18
2
28.1384.
(
Z)-3-Cyclohexyl-1-phenylprop-2-yn-1-one O-Methyl Oxime (1bp): R = 0.50
f
1
(PE/EA = 200: 1); 167 mg, 78% yield, yellow oil; H NMR (400 MHz, CDCl ): δ
3
7
.52 (s, 2H), 7.35 (d, J = 6.0 Hz, 3H), 3.96 (s, 3H), 2.41 (t, J = 11.7 Hz, 1H), 1.84 (dd,
J = 30.2, 11.3 Hz, 4H), 1.70 (d, J = 12.1 Hz, 1H), 1.51 (dd, J = 25.5, 12.9 Hz, 2H),
1
3
1
1
.41-1.14 (m, 3H); C{ H} NMR (100 MHz, CDCl ): δ 146.4, 132.1, 131.9, 129.3,
3
ACS Paragon Plus Environment

Page 23 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
128.4, 121.9, 100.2, 79.5, 62.2, 43.0, 36.9, 30.8, 29.5, 25.9, 25.8, 25.8; IR
-1
+
(
KBr)νmax/cm : 2999, 2210, 1761, 1242, 1049, 522; HRMS (ESI, m/z): [M+H] Calcd.
for C H NO, 242.1539, found: 242.1545.
1
6
20
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Z)-1-Phenylhex-2-yn-1-one O-Methyl Oxime (1bq): R = 0.50 (PE/EA = 150:1);
f
1
1
77 mg, 90% yield, yellow oil; H NMR (400 MHz, CDCl ): δ 8.10-7.72 (m, 2H),
3
7.52-7.22 (m, 3H), 4.07 (s, 3H), 2.50 (t, J = 7.0 Hz, 2H), 1.67 (h, J = 7.2 Hz, 2H),
1
3
1
1
1
.06 (t, J = 7.4 Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ 140.2, 133.9, 129.5,
3
-1
28.3, 126.5, 103.8, 71.7, 62.9, 21.8, 13.6; IR (KBr)νmax/cm : 3052, 1859, 1643, 1242,
1048, 688; HRMS (ESI, m/z): [M+H]+ Calcd. for C H NO, 202.1226,
1
3
16
found:202.1226.
(Z)-1-Phenyloct-2-yn-1-one O-Methyl Oxime (1bs): R = 0.60 (PE/EA = 80: 1); 200
f
1
mg, 86% yield, yellow oil; H NMR (400 MHz, CDCl ): δ 7.84 (ddd, J = 5.8, 3.0, 1.4
3
Hz, 2H), 7.47-7.28 (m, 3H), 4.08 (s, 3H), 2.53 (t, J = 7.2 Hz, 2H), 1.73-1.60 (m, 2H),
1.45 (ddd, J = 11.6, 8.2, 4.8 Hz, 2H), 1.36 (dd, J = 14.8, 7.2 Hz, 2H), 0.92 (t, J = 7.2
1
3
1
Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ 140.3, 134.0, 129.5, 128.3, 126.5,
3
-1
103.9, 71.6, 62.9, 31.1, 28.0, 22.2, 19.8, 13.9; IR (KBr)νmax/cm : 3062, 2941, 2217,
+
1
2
451, 1326, 1052, 767, 686, 552; HRMS (ESI, m/z): [M+H] Calcd. for C H NO,
1
5
20
30.1539, found: 230.1540.
General Procedure for the Synthesis of Isoxazole Derivatives
Typical Procedure Ⅱ: Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0 equiv, 161
2
4
mg), DMF (1.0 mL), alkynes 1 (0.5 mmol), and alkenes 2 (0.6 mmol) were added into
o
a test tube successively, and stirred at 80 C (oil bath) under open air. Upon full
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
consumption of the starting materials detected by TLC, the reaction was quenched by
saturated NH Cl (aq.) after cooling to room temperature and extracted with EtOAc (3
4
x 10 mL). The combined organic layers were dried over MgSO and concentrated in
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
vacuo. The crude product was purified by flash chromatography using PE/EA
(100:1~50:1) as eluent to afford the desired products 3.
2
3
4-Allyl-3,5-diphenylisoxazole (3aa) : Following Typical Procedure II, the reaction
of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0 equiv, 161 mg), DMF (1.0 mL),
2
4
1
aa (117.5 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol) afforded 3aa. R = 0.30 (PE/EA
f
o
1
= 60: 1); 124 mg, 95% yield, white solid, mp: 100 - 101 C; H NMR (400 MHz,
CDCl ): δ 7.78 (d, J = 6.8 Hz, 2H), 7.70 (dd, J = 6.4, 3.0 Hz, 2H), 7.47 (dd, J = 6.4
3
Hz, 6H), 6.15 - 6.04 (m, 1H), 5.25 (d, J = 10.4 Hz, 1H), 5.09 (d, J = 17.2 Hz, 1H),
1
3
1
3
1
.46 - 3.39 (m, 2H); C{ H} NMR (100 MHz, CDCl ): δ 166.8, 164.0, 135.4, 129.8,
3
29.6, 129.4, 128.9, 128.7, 128.4, 128.2, 126.9, 117.1, 110.1, 27.1; IR (KBr)νmax/cm-1:
3066, 2916, 2845, 1963, 1891, 1815, 1624, 1422, 1261, 1167, 1071, 922, 838, 757,
+
6
94, 583, 484; MS (EI) m/z 77, 105, 129, 156, 261; HRMS (ESI, m/z): [M+H] Calcd.
for C H NO, 262.1226, found 262.1229.
1
8
16
4
-Allyl-5-phenyl-3-(p-tolyl)isoxazole (3ab): Following Typical Procedure II, the
reaction of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0 equiv, 161 mg), DMF (1.0
2
4
mL), 1ab (125.4 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol) afforded 3ab. R = 0.45
f
o
1
(
PE/EA = 60: 1); 135 mg, 98% yield, white solid, mp: 102 -103 C; H NMR (400
MHz, CDCl ): δ 7.79 - 7.72 (m, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.44 (tdd, J = 6.8, 4.6,
3
2
.4 Hz, 3H), 7.25 (d, J = 8.0 Hz, 2H), 6.15 - 6.01 (m, 1H), 5.22 (dd, J = 10.2, 1.4 Hz,
ACS Paragon Plus Environment

Page 25 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1H), 5.07 (dd, J = 17.4, 1.2 Hz, 1H), 3.40 (dd, J = 4.4, 2.1 Hz, 2H), 2.38 (s, 3H);
1
3
1
C{ H} NMR (100 MHz, CDCl ):δ 166.7, 164.0, 139.6, 135.5, 129.8, 129.5, 128.9,
3
-1
1
28.3, 126.9, 126.6, 117.1, 110.2, 27.2, 21.4; IR (KBr)νmax/cm : 3068, 2918, 1623,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1497, 1430, 1335, 1117, 1073, 1031, 919, 824, 759, 694, 578, 497; MS (EI) m/z 77,
+
1
05, 155, 170, 275; HRMS (ESI, m/z): [M+H] Calcd. for C H NO, 276.1383,
1
9
18
found 276.1381.
4
-Allyl-5-phenyl-3-(4-(trifluoromethoxy)phenyl)isoxazole
(3ac):
Following
Typical Procedure II, the reaction of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0
2
4
equiv, 161 mg), DMF (1.0 mL), 1ac (159.6 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol)
afforded 3ac. R = 0.30 (PE/EA = 100: 1); 130 mg, 97% yield, white solid, mp:
f
o
1
103-104 C; H NMR (400 MHz, CDCl ): δ 7.75 (dd, J = 9.0, 2.0 Hz, 4H), 7.47 (dt, J
3
=
15.0, 5.0 Hz, 3H), 7.31 (d, J = 8.3 Hz, 2H), 6.15 - 6.03 (m, 1H), 5.26 (dd, J = 10.2,
13
1
1
.0 Hz, 1H), 5.07 (dd, J = 17.4, 1.0 Hz, 1H), 3.44 - 3.35 (m, 2H); C{ H} NMR (100
MHz, CDCl ): δ 167.3, 162.9, 150.2 (q, J = 1.7 Hz), 135.2, 130.0, 128.9, 128.1,
3
C-F
-1
1
27.9, 126.9, 121.1, 120.5 (q, JC-F = 257.9 Hz), 117.3, 109.9, 27.0; IR (KBr)νmax/cm :
3074, 2982, 2913, 1907, 1622, 1519, 1438, 1162, 1069, 1015, 922, 851, 761, 696, 585,
+
5
13, 440; MS (EI) m/z 77, 105, 155, 240, 345; HRMS (ESI, m/z): [M+H] Calcd. for
C H F NO , 346.1049, found 346.1046.
1
9
15
3
2
4-Allyl-5-phenyl-3-(4-((trifluoromethyl)thio)phenyl)isoxazole (3ad): Following
Typical Procedure II, the reaction of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0
2
4
equiv, 161 mg), DMF (1.0 mL), 1ad (167.5 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol)
afforded 3ad. R = 0.50 (PE/EA = 60: 1); 175 mg, 97% yield, white solid, mp:
f
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
105-106 C; H NMR (400 MHz, CDCl ): δ 7.89 - 7.74 (m, 6H), 7.51 (d, J = 7.0 Hz,
3
3
H), 6.23 - 6.08 (m, 1H), 5.31 (d, J = 10.2 Hz, 1H), 5.12 (d, J = 17.3 Hz, 1H), 3.46 (d,
13
1
J = 1.4 Hz, 2H); C{ H} NMR (100 MHz, CDCl ): δ 167.5, 162.8, 136.4, 135.2,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
132.1, 130.1, 129.3, 129.0, 128.0 (q, JC-F = 255.3 Hz), 126.9, 126.0 (q, JC-F = 1.9 Hz),
-1
1
25.9, 117.4, 110.0, 27.0; IR (KBr)νmax/cm : 3072, 2914, 1634, 1430, 1296, 1122,
1014, 956, 920, 840, 758, 694, 584, 509; MS (EI) m/z 77, 105, 155, 256, 361; HRMS
+
(
ESI, m/z): [M+H] Calcd. for C H F NOS, 362.0821, found 362.0826.
1
9
15 3
4
-Allyl-3-(4-ethylphenyl)-5-phenylisoxazole (3ae): Following Typical Procedure
II, the reaction of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0 equiv, 161 mg),
2
4
DMF (1.0 mL), 1ae (131.6 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol) afforded 3ae. Rf
1
= 0.30 (PE/EA = 80: 1); 137 mg, 95% yield, yellow oil; H NMR (400 MHz, CDCl ):
3
δ 7.82 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 7.4 Hz, 2H), 7.55 - 7.46 (m, 3H), 7.34 (d, J =
7
.5 Hz, 2H), 6.22 - 6.07 (m, 1H), 5.29 (d, J = 10.2 Hz, 1H), 5.13 (d, J = 17.3 Hz, 1H),
1
3
1
3.47 (s, 2H), 2.75 (q, J = 7.4 Hz, 1H), 1.39 - 1.18 (m, 2H); C{ H} NMR (100 MHz,
CDCl ): δ 166.7, 164.0, 145.9, 135.5, 129.7, 128.9, 128.3, 128.3, 126.9, 126.7, 117.1,
3
-1
110.1, 28.8, 27.2, 15.4; IR (KBr)νmax/cm : 3066, 2966, 2925, 2855, 1621, 1567, 1497,
1
432, 1394, 1268, 1177, 1068, 996, 958, 919, 838, 758, 695, 581, 518; MS (EI) m/z
+
7
7, 105, 155, 184, 289; HRMS (ESI, m/z): [M+H] Calcd. for C H NO, 290.1539,
2
0
20
found 290.1538.
4
-Allyl-3-(4-chlorophenyl)-5-phenylisoxazole (3af): Following Typical Procedure
II, the reaction of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0 equiv, 161 mg),
2
4
DMF (1.0 mL), 1af (134.6 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol) afforded 3af. Rf
ACS Paragon Plus Environment

Page 27 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
= 0.60 (PE/EA = 100: 1); 140 mg, 95% yield, yellow oil; H NMR (400 MHz, CDCl ):
3
δ 7.75 (dd, J = 134, 6.8 Hz, 3H), 7.59 (d, J = 7.3 Hz, 1H), 7.54 - 7.33 (m, 5H), 6.19 -
6
.00 (m, 1H), 5.27 (d, J = 10.3 Hz, 1H), 5.08 (d, J = 17.3 Hz, 1H), 3.50 - 3.32 (m, 2H);
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
C{ H} NMR (100 MHz, CDCl ): δ 167.2, 162.8, 135.1, 134.7, 131.1, 130.0, 128.9,
3
-1
1
28.4, 127.9, 126.9, 126.4, 117.3, 110.0, 27.0; IR (KBr)νmax/cm : 3073, 2915, 2817,
1566, 1496, 1442, 1387, 1267, 1171, 1080, 964, 918, 756, 692; MS (EI) m/z 77, 105,
+
1
2
55, 190, 295; HRMS (ESI, m/z): [M+H] Calcd. for C H ClNO, 296.0837, found
1
8
15
96.0832.
4-Allyl-3-(4-bromophenyl)-5-phenylisoxazole (3ag): Following Typical Procedure
II, the reaction of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0 equiv, 161 mg),
2
4
DMF (1.0 mL), 1ag (156.6 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol) afforded 3ag. Rf
o
1
=
0.30 (PE/EA = 30: 1). 163 mg, 96% yield, white solid, mp: 107-108 C; H NMR
(
400 MHz, CDCl ): δ 7.84 - 7.68 (m, 2H), 7.64 - 7.54 (m, 4H), 7.53 - 7.42 (m, 3H),
3
6.14 - 6.03 (m, 1H), 5.26 (dd, J = 10.2, 0.9 Hz, 1H), 5.07 (dd, J = 17.4, 0.9 Hz, 1H),
1
3
1
3
.44 - 3.34 (m, 2H); C{ H} NMR (100 MHz, CDCl ): δ 167.2, 163.1, 135.2, 132.0,
3
-1
130.0, 129.9, 128.9, 128.3, 127.9, 126.9, 124.1, 117.3, 109.9, 27.0; IR (KBr)νmax/cm :
3
5
066, 2918, 1598, 1496, 1427, 1384, 1267, 1171, 1073, 1009, 955, 920, 831, 757, 693,
+
83, 495; MS (EI) m/z 77, 105, 155, 234, 339; HRMS (ESI, m/z): [M+H] Calcd. for
C H BrNO, 340.0332, found 340.0330.
1
8
15
4
-(4-Allyl-5-phenylisoxazol-3-yl)benzonitrile (3ah): Following Typical Procedure
II, the reaction of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0 equiv, 161 mg),
2
4
DMF (1.0 mL), 1ah (130.1 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol) afforded 3ah. Rf
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 54
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
= 0.45 (PE/EA = 80: 1); 136 mg, 95% yield, white solid, mp: 100-101 C; H NMR
(
400 MHz, CDCl ): δ 7.87 - 7.82 (m, 2H), 7.81 - 7.72 (m, 4H), 7.55 - 7.45 (m, 3H),
3
6
.16 - 6.05 (m, 1H), 5.29 (dd, J = 10.4, 1.2 Hz, 1H), 5.08 (dd, J = 17.2, 1.1 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
3.43 (dt, J = 4.2, 2.0 Hz, 2H); C{ H} NMR (100 MHz, CDCl ): δ 167.8, 162.4,
3
1
35.0, 134.0, 132.5, 130.2, 129.0, 128.9, 127.7, 127.0, 118.4, 117.6, 113.4, 109.9,
+
26.9; MS (EI) m/z 77, 105, 271, 286; HRMS (ESI, m/z): [M+H] Calcd. for
C H N O, 287.1179, found, 287.1177.
1
9
15
2
4
-Allyl-5-phenyl-3-(o-tolyl)isoxazole (3ai): Following Typical Procedure II, the
reaction of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0 equiv, 161 mg), DMF (1.0
2
4
mL), 1ai (124.6 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol) afforded 3ai. R = 0.30
f
1
(PE/EA = 100: 1). 130 mg, 94% yield, yellow oil; H NMR (400 MHz, CDCl ): δ
3
7
5
.80 (d, J = 7.6 Hz, 2H), 7.48 (dd, J = 16.6, 9.0 Hz, 3H), 7.37 - 7.24 (m, 4H), 5.87 -
.74 (m, 1H), 5.04 (d, J = 10.2 Hz, 1H), 4.92 (d, J = 17.2 Hz, 1H), 3.30 - 3.18 (m, 2H),
1
3
1
2.29 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 165.8, 164.6, 137.5, 134.6, 130.4,
3
1
29.8, 129.7, 129.4, 128.9, 128.7, 128.3, 126.8, 125.6, 116.4, 111.5, 26.9, 20.0; IR
-1
(KBr)νmax/cm : 3064, 2921, 1634, 1496, 1409, 1268, 1169, 1034, 994, 956, 915, 757,
+
6
94, 586; MS (EI) m/z 77, 105, 155, 184, 275; HRMS (ESI, m/z): [M+H] Calcd. for
C H NO, 276.1383, found 276.1381.
1
9
18
4-Allyl-3-(2-bromophenyl)-5-phenylisoxazole (3aj): Following Typical Procedure
II, the reaction of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0 equiv, 161 mg),
2
4
DMF (1.0 mL), 1aj (156.5 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol) afforded 3aj. Rf
o
1
=
0.50 (PE/EA = 100: 1). 163 mg, 96% yield, white solid; mp: 100 - 101 C; H NMR
ACS Paragon Plus Environment

Page 29 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(400 MHz, CDCl ): δ 7.82 - 7.76 (m, 2H), 7.68 (d, J = 7.7 Hz, 1H), 7.51 - 7.42 (m,
3
3
5
H), 7.41 - 7.35 (m, 2H), 7.32 (ddd, J = 8.0, 5.9, 3.3 Hz, 1H), 5.82 - 5.68 (m, 1H),
13
1
.03 - 4.84 (m, 2H), 3.30 (dt, J = 5.5, 1.8 Hz, 2H); C{ H} NMR (100 MHz, CDCl ):
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
δ 166.0, 164.3, 134.4, 133.0, 131.7, 131.0, 130.8, 130.0, 129.0, 128.1, 127.3, 127.0,
-1
1
23.5, 116.4, 114.2, 27.2; IR (KBr)νmax/cm : 3068, 2917, 1627, 1501, 1421, 1332,
1254, 1165, 1024, 917, 757, 690, 582; MS (EI) m/z 77, 105, 155, 236, 260, 339;
+
HRMS (ESI, m/z): [M+H] Calcd. for C H BrNO, 340.0332, found, 340.0333.
1
8
15
4
-Allyl-3-(3,4-dimethoxyphenyl)-5-phenylisoxazole (3ak): Following Typical
Procedure II, the reaction of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0 equiv,
2
4
1
61 mg), DMF (1.0 mL), 1ak (147.5 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol)
afforded 3ak. R = 0.30 (PE/EA = 80: 1); 152 mg, 95% yield, white solid, mp:
f
o
1
1
3
10-111 C; H NMR (400 MHz, CDCl ): δ 7.76 (d, J = 7.1 Hz, 2H), 7.55 - 7.38 (m,
3
H), 7.29 (d, J = 7.3 Hz, 2H), 6.95 (d, J = 8.5 Hz, 1H), 6.15 (ddd, J = 14.8, 9.7, 4.5
Hz, 1H), 5.29 (d, J = 10.3 Hz, 1H), 5.13 (d, J = 17.3 Hz, 1H), 3.91 (d, J = 1.4 Hz, 6H),
1
3
1
3
.49 - 3.37 (m, 2H); C{ H} NMR (100 MHz, CDCl ): δ 166.9, 163.7, 150.2, 149.1,
3
135.6, 129.8, 128.9, 128.2, 126.9, 122.0, 121.0, 117.2, 111.4, 111.2, 109.8, 56.0, 55.9,
-1
2
7.2; IR (KBr)νmax/cm : 3074, 2937, 2836, 2584, 1599, 1521, 1439, 1329, 1528, 1147,
1
025, 922, 863, 757, 696, 628, 518, 482; MS (EI) m/z 77, 105, 185, 216, 321; HRMS
+
(ESI, m/z): [M+H] Calcd. for C H NO , 322.1438, found 322.1439.
2
0
20
3
4
-Allyl-3-(4-fluoro-3-methylphenyl)-5-phenylisoxazole (3al): Following Typical
Procedure II, the reaction of Pd(OAc) (3 mol %, 3.375 mg), n-Bu NBr (1.0 equiv,
2
4
1
61 mg), DMF (1.0 mL), 1al (133.5 mg, 0.5 mmol) and 2a (72 mg, 0.6 mmol)
ACS Paragon Plus Environment