An Easy Access to Oxime Ethers by Pd-Catalyzed C—O Cross-Coupling of Activated Aryl Bromides with Ketoximes and Chalcone Oximes

Article abstract of DOI:10.1002/cjoc.201900540

An efficient Pd-catalyzed method for C—O cross-coupling of ketoximes and chalcone oximes with activated aryl bromides and bromo-chalcones has been developed. All oxime ethers were obtained in good to excellent yields by [(π-allyl)PdCl]₂/tBuXPhos (L7) catalyst system. TrixiePhos (L11) was also found to be effective for the oxime coupling. This method offers an easy and smooth coupling of chalcone oximes with activated aryl bromides and bromo-chalcones, which has not been previously explored.

Full text of DOI:10.1002/cjoc.201900540

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: An Easy Access to Oxime ethers by Pd-Catalyzed C‒O Cross-Coupling of
Activated Aryl bromides with Ketoximes and Chalcone oximes
Authors: Reeta, T. M. Rangarajan,* Raj Pal Singh,* R. P. Singh, Manjula Singh
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.201900540.
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.201900540.
ISSN 1001-604X • CN 31-1547/O6
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An Easy Access to Oxime ethers by Pd-Catalyzed C‒O Cross-Coupling of Activated Aryl bromides with Ketoximes and
Chalcone oximes Reeta,a,b T. M. Rangarajan,*,c Raj Pal Singh,*,a R. P. Singh,c Manjula Singhd
a Centre for Fire, Explosive and Environment Safety, DRDO, Delhi, India.
b Department of Chemistry, University of Delhi, Delhi, India.
c Department of Chemistry, Sri Venkateswara College, University of Delhi, New Delhi, India.
d Department of Chemistry, Shivaji College, University of Delhi, New Delhi, India.
E-mail: rangarajan93150@gmail.com; rajcfees@gmail.com
Cite this paper: Chin. J. Chem. 2020, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion An efficient Pd-catalyzed method for C‒O cross-coupling of ketoximes and chalcone oximes with activated
aryl bromides and bromo-chalcones has been developed. All oxime ethers were obtained in good to excellent yields by [(π-allyl)PdCl]2/tBuXPhos (L7)
catalyst system. TrixiePhos (L11) was also found to be effective for the oxime coupling. This method offers an easy and smooth coupling of chalcone
oximes with activated aryl bromides and bromo-chalcones which has not been previously explored .
Background and Originality Content
Oxime ethers are one of the most important structural motifs
in organic chemistry which continue to beguile the chemists’
Moreover, O-aryl oxime ethers could also be used as a ligand
in Pd-catalyzed Suzuki-Miyaura coupling reaction to synthesize
interest thanks to their pharmaceutical and agricultural
biaryls.[4] Conventionally, the synthesis of O-aryl oxime ethers
were achieved by i) condensation of O-aryloxyamines with
carbonyl compounds,[1a,3e,f,5] and ii) O-arylation of oximes with
activated nitro- or fluoroarene derivatives in the presence of a
strong base via SNAr type process.[1a,3e,5a,6]
applications.[1] Examples concerning the biological importance of
oxime ethers (Figure 1) are as potent inhibitors of transthyretin
amyloid fibril formation,[1a] antibiotic (Cefmenoxime,[1b]
Aztreonam,[1c] Roxithromycin),[1d] anti-inflammatory (Ridogrel),[1e]
antifungal
(Oxiconazole),[1f]
neuroleptic
activity,[1g]
The O-aryloxyamines could be obtained from an amine
exchange reaction of 2,4-dinitrophenoxyamine with phenols[3f,7]
and O-arylation of ethyl acetohyroxamate,[1a,5d,8] or N-protected
hydroxylamine[9] by SNAr type process, and subsequent hydrolysis
with acid (Scheme 1).
immunosuppressive agents,[1h] antihistamine (1a),[1i] therapeutic
agent for insomnia (Eplivanserin) (1b),[1j,k] melanin-concentrating
hormone1 receptor antagonists (1c),[1l] antiplasmodial
property,[1m] monamine oxidase and Acethylcholinesterase
inhibitors (1d),[1n] insecticidal,[1o] fungicidal,[1p,q] herbicidal,[1r] etc.
Moreover, oxime ethers are served as important and versatile
intermediates in the synthesis of various structural motifs.[2] The
O-aryl oxime ethers have been paid much interest due to their
accessibility to myriad of medicinally and synthetically important
r
R/A
R
B OH
( )
2
r
O
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B
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C
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i
R
ii
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r
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ii NH NH
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compounds[2]
such
as
benzoxazole,[3a-c]
benzofurans,[3e-h,m] phenols,[3i]
ii
O
)
organic
2
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OH
dihydrobenzofuran,[3d,e]
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.
on
d
ase
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ase
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quinolines,[3j] 3-Aminobenzisoxazoles,[3k] pyrroles,[3l] etc.
r
R/A
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H
R
+
)
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r
r
IA X
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+
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N
r
R/A
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ase
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tihi
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t
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(
ormone rece or an a on s s
c
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h
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pt
t
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R
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e
OM
OH
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'
+
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R
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X
OH
B OH
(
)
2
EtO
N
N
OEt
O
F
O
or
(
)
e
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e
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e
M
'
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onoam ne ox ase an
ce
ors
c
o
nes erase
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asmo a ac
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i
id
d A tyl
h
li
t
A
tipl
di
l ti ity
n
i
hibit
1d
(
)
Scheme 1 Previous synthetic routes to oxime ethers
Figure 1 Examples of pharmaceutical molecules containing oxime
ethers structural motif
Other methods describing the synthesis of alkoxy and
aryloxyamines are the oxyaziridines as aminating agent for a wide
range of alcohols as nucleophile.[10]
This article has been accepted for publication and undergone full peer review but has not been
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.201900540
This article is protected by copyright. All rights reserved.

Chen et al.
Breaking Report
In the recent past, several other improved methods for the
synthesis of O-aryloxyamines developed are i) copper-catalyzed
coupling of phenylboronic acids with N-hydroxyphthalimide,[11] ii)
base promoted O-arylation of N-hydroxyphthalimide and
N-hydroxysuccinimide with diaryliodonium salts[12] and
Results and Discussion
Finding practicable supporting phosphine ligands for
Pd-catalyzed O-arylation of acetophenone oxime with
4-bromoacetophenone was starting point of our investigation.
The commercially available Buchwald and Beller type ligands
shown in Figure 2 were employed for this O-arylation process.
subsequent
cleavage with hydrazine, hydroxylamine or
ammonia, and iii) O-arylation of ethyl acetohydroxamate or
oximes either with aryl coupling partner under Pd-catalyzed C‒O
coupling methodology[1m,3m] or with diaryl iodonium salts under
basic condition (Scheme 1).[3f] However, the synthesis of O-aryl
oxime ethers by direct coupling of aryl halides with ketoxime was
not well explored and is highly inviting and only one method
available was reported by Maitra et al. .[13a] This method described
the copper-catalyzed coupling of aryl iodides with oximes in
moderate to good yields but the functional group tolerance of aryl
iodides, and aryl bromides has not been fully explored and also
required to carry out at reflux temperature of toluene. After the
pioneering work of Maitra et al., several other groups reported
the methods for the direct coupling of oximes with phenyl boronic
acids, under different conditions using copper catalyst,[13b-f] and
diaryliodonium salts under basic conditions (Scheme 1).[3f,g,14]
Therefore, the synthesis of O-aryl oxime ethers reported so far,
despite their generality, requires multistep synthesis that includes
the synthesis of starting materials such as arylboronic acids or
diaryliodonium salts, which are usually obtained from aryl halides
and commercially these starting materials are relatively expensive
when compared with corresponding aryl halides.
PCy2
r
iP
PCy2
P
P
C
y
2
e
OM
P
r
iP
e
O
O
M
O
r
r
iP
iP
r
iP
- -
r c c o ex
os ne
r s
u
os ne
os
SPh
t i
y
l
h
ylph phi
os
L4
u
os
R Ph
L5
T i t b tylph phi
XPh
L3
L1
L2
e
OM
(
)
e
e
OM
e
O
M
M
(
)
e
e
M
M
-
-
u
u
e
P t B
P t B
M
O
r
PCy2
(
)
2
(
)
2
e
u
M
P tB
(
iP
)
2
r
r
r
r
r
iP
iP
iP
iP
iP
iP
r
iP
r
O
PPh2
PPh2
r
iP
r
iP
r
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r
iP
e
M
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t
M B
)
os
e
u
os
4tB XPh
an
X
os
u
os
re
os
ttPh
XP
h
O
(
M
thPh
L6
tB XPh
L7
B
3
L8
L9
L10
e
OM
e
OM
e
OM
Cy
u
P tB
(
e
M
u
e
u
e
O
r
P
O
r
P tB
iP
M
P tB
r
M
iP
P C H F
)
2
(
)
N
(
iP
)
2
(
r 8
iP
)
6
2
3
2
r
r
iP
Cy
iP
r
iP
r
iP
r
iP
-
-
c o ex os no
ylph phi
)
c
di y
l h
-
2
(
r x e os
T i Ph
L11
oc
os
u re
tt
B
os
Ph
t
i
ac
e
os
ki Ph
R
kPh
L12
B
n
en o e
d
1 ph yli l
J
L13
L14
L15
u
tB
u
tB
Cy
P
Cy
u
tB
Cy
P
P
P
N
P
N
N
N
N
u
tB
u
tB
u
tB
Cy
e
e
M
O
M
O
ca a
t
um
n
t
CXi ® PI
B
ca a
um
CXi ® POM Cy
L17
e
ca a
t
um
L18
e
ca a
um
ca a
t
um
t
CXi ® POM tB
t
CXi ® PCy
CXi ® PtB
Although general and efficient Pd-catalyzed methods for the
direct coupling of aryl halides with ethyl acetohydroximate were
reported,[1m,3m] no Cu or Pd-catalyzed direct coupling of aryl
bromides with ketoximes is available to date. Moreover, the
reaction of chalcone oximes with i) arylboronic acids, under
copper catalyzed conditions,[15a,b] and ii) diaryliodonium salts
under basic conditions led to N-arylation products
predominantly over O-arylation products (Scheme 2). [15c]
L19
L20
L16
Figure 2 Structure of ligands used for Pd-catalyzed O-arylation of
acetophenoneoxime.
The ligand screening reaction was carried out under
conditions, [(π-allyl)PdCl]2 (1.0 mol %), ligands, L1–L20 (2.5 mol %),
in toluene (2.0 mL), at 60 C and is summarized in table 1. The
o
Scheme 2 Reactions of chalcone oximes with arylboronic acids
only ligand tBuXPhos (L7) gave the O-arylation product 1 in 72%
yields with complete conversion in short reaction time (Entry 7).
The ligand TrixiePhos (L11) gave the desired product in poor yield
(Entry 11, 53%) with 65% conversion even after 17 h. The ligands
cataCXium®PIntB (L16), and cataCXium®PtB (L20), produced
promising results in our previous report for the coupling of
bromo-chalcones with ethyl acetohydroxamate,[1m] were
unsuccessful in the present coupling reaction. It is important to
note that other promising ligands such as BrettPhos (L9),[16a,b]
RockPhos (L12),[16f] tBuBrettPhos (L13)[16g] in the C‒O
cross-coupling reactions were also unsuccessful to couple
4-bromoacetophenone with acetophenones oxime. This due to
the fact that the property of the ligands and their complexes
directs different mechanistic reductive elimination pathway
from nucleophile to nucleophile. Some ligands do not facilitate
the reductive-elimination step and hence no reaction.[16a,h]
and diaryliodonium salts
In the latter method, D. L. Mo et al. observed a mixture of O- (55%)
and N-arylation (34%) of chalcone oxime and decided to switch the
selectivity from O- to N-arylation process.[15c] Therefore, the
O-arylation of chalcone oxime is not fully explored at all and no
methods are available for this coupling to date.
Herein, in the light of the above, we report an efficient Pd-catalyzed
method for O-arylation of ketoximes and chalcone oximes with aryl
bromides and bromo-chalcones.[15d]
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www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
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This article is protected by copyright. All rights reserved.
ar a on ro uc s
O
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ti t
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Running title
Chin. J. Chem.
Other Pd catalysts with the ligand L7 were also checked towards
the coupling (Entries 5-8), showed that the only catalyst
[Pd2(dba)3] as effective as [(π-allyl)PdCl]2 catalyst in the coupling
reaction and afforded the desired product in excellent yield 92%
(Entry 7). Further feasibility studies with various bases (Entries
9-11), and solvents (Entries 12, and 13) were also unsuccessful. As
a result, the ligand (L11) and the catalyst [Pd2(dba)3] were also
found to be effective towards the O-arylation of acetophenone
oxime.
With those optimized reaction conditions in hand, we were
pleased to examine the generality of the coupling of aryl
bromides with structurally diversified ketoximes (Table 3). First,
we continued O-arylation of acetophenone oxime with different
electronic nature of aryl bormides. Aryl bromides with
electron-withdrawing group at 4-position gave the desired
products 1-5 in good to excellent yields under optimized
conditions with 1 mol % Pd catalyst. However, the catalyst system
was failed to give the coupled products, 6 – 8 by coupling of
acetophenone oxime with aryl bromides, such as 2′- and
3′-bromoacetophenones, and 4-bromoanisole even in higher
catalyst loading and at 90 oC, which reveals that the catalyst
system allows the C‒O reductive elimination step via electronic
pathway.[16a-e] We then continued the O-arylation of various
ketoximes with activated aryl bromides. The C‒O coupling of
4-bromobenzophenone with benzophenone oxime under
optimized conditions was incomplete (40% conv.) with 1 mol % Pd
catalyst while the same was successful at 2.0 mol % catalyst
loading reveals that the higher catalyst loading is required for
other ketoximes. All other structurally diversified ketoximes were
Table1. Ligand Evaluationa
e
M
e
M
r
B
-
O
,
HO
a
L1 L20
llyl PdCl
)
N
[(
]
2
N
+
,
e
e
M
M
s
o uene
l
C
2CO3
T
1
60 o
C
O
O
Reaction Conv.
Yield
(%)c
NR
NR
NR
NR
NR
NR
72
Reaction
Time (h)
17
Conv.
(%)b
65
66
ND
ND
ND
60
ND
64
ND
59
Yield
(%)c
53
12
NR
NR
NR
25
NR
26
NR
14
Entry Ligand
Entry
Ligand
Time (h)
(%)b
ND
ND
ND
ND
ND
ND
100
ND
ND
ND
1
2
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
17
17
17
17
11
12
13
14
15
16
17
18
19
20
L11
L12
L13
L14
L15
L16
L17
L18
L19
L20
17
17
17
17
17
17
17
17
17
3
4
5
6
17
17
3
17
7
8
NR
NR
NR
9
10
17
17
aReaction Conditions: 4′-Bromoacetophenone (0.5 mmol, 1.0 eq.), acetophenoneoxime (0.55 mmol, 1.1
eq.), Cs2CO3 (0.75 mmol, 1.5 eq.), [(π-allyl)PdCl]2 (1.0 mol %), Ligand, L1–L20 (2.5 mol %), toluene
(2.0 mL), 60 oC, Ar atm.. bBased on starting material recovered. cIsolated yield. ND = Not Determined.
NR = No Reaction.
With this practicable ligand L7, we further optimized the reaction
conditions such as temperature, Pd source, base, and solvent
(Table 2). Initially, the efficiency of the ligand, L7 was checked at a
bit higher temperature, 90 oC. Surprisingly, the ligands, L7,
afforded the desired product 1 in excellent yield, 96% (Table 2;
Entry 1). With this interesting result, we further engaged in
carrying out the coupling reaction using other two ligands L11,
and L16 with moderate results (Table 1) to check the effect of
temperature. To our surprise, the ligand TrixiePhos (L11) was also
successful towards the coupling with a significant improvement in
the yield of the product 1, 83% (Table 2; Entry 2), whereas the
ligand L16 did not afford a significant improvement in the yield of
the product 1 (Table 2; Entry 3). The reduction of catalyst
[(π-allyl)PdCl]2 loading from 1.0 to 0.5 mol % with L7 (Entry 4) was
unsuccessful.
then
R
,
a
llyl PdCl
]
2
[(
)
r
R
O
B
-
'
R
u
os
L7
(
o uene
t B XPh
N
)
'
+
O
R
,
H
N
s
C
2CO3 T l
Pd Source
Base
Reaction
Time (h)
2 h
23
Conv.
(%)b
100
100
66
62
ND
ND
100
ND
84
71
ND
73
Y
(
R
R
Entry
90 o
C
Ligand
(1.0 mol %)
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
(1.5 eq.)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1
2
L7
L11
8
e
M
e
M
e
O 3
M
L16
23 M
e
O
N
O
N
4
L7
L7
L7
O
2N3
2
N
N
N
2
Pd(PPh3)4
Pd(OAc)2
[Pd2(dba)3]
O2
N
5
Cs2CO3
22 h
1
4
NC
e
3
OOC
O
6
7
8
Cs2MCO3
23 h
(78%, 1.33 h)
(92%, 1 h)
d
(90%, 1 h)
(96%, 2 h)
L7
Cs2CO3
Cs2CO3
K3PO4
K2CO3
KOHO
Cs2CO3
Cs2CO3
4 h
(75%, 4h)
e
M
[(π-cinnamylPdCl)2]
L7
L7
L7
L7
22 h
N
e
M
e
M
e
O
O23Mh
O
O
N
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
9
O
N
Ph
N
N
5
10
23 h
Table 2 Optimization of reaction conditionsa
e
O
6
M
8
7
11
N
5
N
22 h
O
(NR, 24 h)c [(π-allyl)PdCl]2
(NR, 8 h)c
(91%, 1.40 h)
(85%, 3 h)d
c
12
13
L7
19 h
23 h
(NR, 8 h)
e
e
M
M
[(π-allyl)PdCl]2
L7
ND
F
aReaction Conditions: 4
′
-Bromoacetophenone (0.5 mmol, 1.0 eq.), Acetophenoneoxime (0.6
r
B
O
HO
,
e
1.2 eq.), Cs2CO3 (0.75 mmol, 1.5 eq.), Pd source (1.0 mol O%),MLigands (2.5 mol %), tolue
L
N
Pd
,
N
+
e
M
N
e
M
O
N
mL), temperature 90 C, Ar atm. OBased on starting material recoverd. cIsolated yields. dR
o
b
ase o uene
O
B
T
90 o
l
N
N
1
time not optimized. e[M(πO-aOlClyl)PdCl]2 (0.5 mol %),OL2igand, L7 (1.25 mol %). f1,4-Dioxane (2
Ph
N
12
F
C
e
9
NC
O
g
10
O
11
THF (2.0 mL). ND = Not Determined; NR = No Reaction.
O
F
(80%, 2 h)c
(85%, 2 h)c
(92%, 3 h)c
(71%, 23 h)c
e
M
e
M
e
e
M
M
Pd Source
(1.0 mol %)
Base
Reaction
Time (h)
2 h
23
23
23
22 h
23 h
4 h
22 h
23 h
23 h
22 h
19 h
23 h
Conv.
Yield
(%)c
96
O
O
Entry
Ligand
O
O
(1.5 eq.)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
K2CO3
KOH
Cs2CO3
Cs2CO3
(%)b
100
100
66
N
N
N
N
Ph
e
O
NC
M
1
2
3
4
5
6
7
8
9
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
Pd(PPh3)4
Pd(OAc)2
[Pd2(dba)3]
[(π-cinnamylPdCl)2]
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
[(π-allyl)PdCl]2
L7
L11
L16
L7
L7
L7
L7
L7
L7
L7
L7
e
M
e
OM
O2
N
14
13
(92%, 2 h)c
83d
41
O
O
16
15
(81%, 23 h)c
(81%, 6 h)c
(94%, 18 h)c
62
26e
NR
NR
92
e
M
ND
ND
100
ND
O
N
O
S
O
N
O
N
N
NC
20
e
COOM
18
e
M
OOC
19
17
(66%, 3 h)c
O
(93%, 3 h)c
(78%, 1 h)c
NR
42
47
(75%, 2 h)c
84
71
aReaction Conditions: Aryl halides (0.5 mmol, 1.0 eq.), ketoxime (0.525 mmol, 1.05 eq.), Cs2CO3 (1.5 mmol, 1.5
eq.), [(π-allyl)PdCl]2 (1.0 mol %), tBuXPhos (L7) (2.5 mol %), toluene (2.0 mL), temperature 90 oC, Ar atm.
bIsolated yield. c[(π-allyl)PdCl]2 (2.0 mol %), tBuXPhos (L7) (5.0 mol %); d[Pd2(dba)3] (1.0 mol %), tBuXPhos (L7)
(2.5 mol %).
10
11
12
ND
73
ND
NR
L7
L7
56f
13
NRg
aReaction Conditions: 4
′-Bromoacetophenone (0.5 mmol, 1.0 eq.), Acetophenoneoxime (0.6 mmol,
smoothly coupled with activated aryl bromides to afford the
1.2 eq.), Cs2CO3 (0.75 mmol, 1.5 eq.), Pd source (1.0 mol %), Ligands (2.5 mol %), toluene (2.0
mL), temperature 90 oC, Ar atm. bBased on starting material recoverd. cIsolated yields. dReaction
time not optimized. e[(π-allyl)PdCl]2 (0.5 mol %), Ligand, L7 (1.25 mol %). f1,4-Dioxane (2.0 mL);
gTHF (2.0 mL). ND = Not Determined; NR = No Reaction.
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chen et al.
Breaking Report
desired products (9-20) in good to excellent yields. The catalyst
system comprised of [Pd2(dba)3]/tBuXPhos (L7) was also checked
Owing to widespread applications of chalcones in
medicinal,[1j,k,m,17] synthetic,[18] and material chemistries,[19] we
extend the generality of the catalyst system to bromo-chalcones
as coupling partner in the C‒O cross-coupling reaction with
ketoximes. These novel chalcone products may open the door to
find several therapeutic properties (Scheme 1).[1m,n] The coupling
of various ketoximes with different bromo-chalcones by
[(π-allyl)PdCl]2/tBuXPhos (L7) system was required to carry out
with 3.0 mol % Pd-catalyst loading and a bit lower temperature,
for
the
coupling
of
1-bromo-4-nitrobenzene
and
4-bromobenzophenone with acetophenone oxime to afford the
desired products 2 and 5 in 75% and 85% respectively.
Table
3 Pd-catalyzed O-arylation of ketoximes with aryl
bromides.a,b
o
75 C (Table 4). The chalcones bearing the bromine substitution
on
the
3-phenyl
ring,
(E)-3-(4-bromophenyl)-1-(substitutedphenyl)prop-2-en-1-ones,
were coupled smoothly with different ketoximes to afford the
desired products 21-29 in moderate to excellent yields (60-90%).
Table 4 Pd-catalyzed C‒O cross-coupling of bromo-chalcones with
ketoximesa,b
Similarly, the chalcones bearing the bromine substitution
on
the
1-phenyl
ring,
(E)-1-(4-bromophenyl)-3-(substitutedphenyl)prop-2-en-1-ones,
were also coupled smoothly with different ketoximes to afford
the desired coupled products 30-35 in good to excellent yields
(73-98%).
(E)-1-(4-bromophenyl)-3-(substituted-phenyl)prop-2-en-1-ones,
tolerate well under reaction conditions than
The
yield
range
shows
that
(E)-3-(4-bromophenyl)-1-(substituted-phenyl)prop-2-en-1-ones.
Interestingly, many reactions were complete in short reaction
times.
Finally, we turned our attention, with eager, to explore the
coupling of chalcone oximes with activated aryl bromides and
bromo-chalcones as the chalcone oximes interestingly underwent
N-arylation rather than O-arylation product under the reported
conditions. [15] Moreover, no efficient methodology is available for
O-arylation of chalcone oximes except an example reported by
Mo and coworkers.[15c] Chalcone oximes were obtained by
reaction of corresponding chalcones with hydroxylamine
hydrochloride in the presence of pyridine as base in methanol to
afford the product with a mixture of isomers E:Z (about 3:0.3).
The coupling was carried out with 3.0 mol % catalyst loading at 75
oC (Table 5).
O
O
O
O
O
,
'
R
a
u
llyl PdCl
)
e
M
[(
]
HO
R
2
N
Table 5 Pd-catalyzed C‒O cross-coupling of chalcones oximesa,b
O
)
r
N
os
O
N
B
L7
tB XPh
R
(
R
O
+
e
O
O
O
N
N
O
e
M
PhR
e
O
23
M
M
O
,
O
22
'
s
o uene
l
R
C
2CO3
T
21
e
M
e
M
Ph
75 o
C
R
(90%, 3 h)
(75%, 3 h)
(80%, 3 h)
R
'
R
N
r
B
O
O
O
O
R
N
O
N
N
O
Ph
e
M
O
O
F
F
24
26
25
Ph
(60%, 23 h)
(70%, 40 min)
O
(82%, 1.5 h)
O
O
e
M
O
F
S
N
O
N
N
O
27
O
28
2
9
e
M
e
M
e
M
(69%, 7 h)
(89%, 2 h)
(71%, 3 h)
O
O
O
F
N
N
e
OM
3
1
N
O
O
e
OM
e
M
O
3
2
30
e
M
(98%, 3 h)
(90%, 23 h)
(86%, 1 h)
O
O
O
e
e
e
OM
OM
e
e
OM
Ph
N
O
N
N
OM
3
5
S
O
33
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© 2019
SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
O
O
M
34
e
M
e
OM
Ph
e
M
(73%, 24 h)
(95%, 2 h)
(97%, 1 h)
aReaction conditions: Bromo-chalcones (0.5 mmol, 1.0 eq.), ketoximes (0.5 mmol, 1..0 eq.), Cs2CO3 (1.5 mmol, 1.5 eq.),
This article is protected by copyright. All rights reserved.
[(π-allyl)PdCl]2 (3.0 mol %), tBuXPhos (L7) (7.5 mol %), toluene (3.0 mL), temperature 75 oC, Ar atm; bIsolated yield.

Running title
Chin. J. Chem.
First, (2E)-1-(4-methoxyphenyl)-3-phenyl prop-2-en-1-one oxime
was coupled with 4-bromoacetophenone; interestingly, the
reaction was complete in 1.5 h, and gave the expected O-coupled
product 36 in 86% yield. The O-arylation product was confirmed
EWG
O
EWG
,
HO
a
u
llyl PdCl
)
a cone
l
[(
]
2
L
N
Ch
O
r
B
os
7
tB XPh
(
)
or
or
+
(
)
(
)
'
''
,
s
o uene
l
R
R
T
N
C
2CO3
N
75 o
C
-
a cone
Ch
r
B
l
'
''
'
''
R
R
R
R
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Chen et al.
Breaking Report
by 13C NMR with characteristic =N‒O‒C(Ar) carbon signal which
appeared about 160 p.m., while it would not appear in the
N-arylation product.[15] The O-arylated product was also obtained
as a mixture of E:Z isomers (3.3:1) determined from 1H NMR
spectrum. 13C NMR signals of E- isomers were identified from
signals of Z-isomers in the mixture by their intensity and DEPT-90,
and only few 13C NMR signals were seen for Z- isomers due to
an adaptor. The flask was charged with Cs2CO3 and dried with hot
air gun under vacuum. The R.B. flask was allowed to cool under
argon atmosphere. Bromo coupling partner, ketoximes, Pd-source
and ligands were added in quick succession. The flask was then
evacuated and refilled with argon for three times. To this, 2.0
mL of anhydrous toluene was added via syringe and again the
flask evacuated and refilled with argon for three times. The flask
o
was placed in a pre-heated oil bath at a temperature 75 C or 90
oC. The reaction mixture was stirred vigorously until completion
of the reaction as indicated by TLC analysis. The reaction mixture
was allowed to cool to room temperature and the crude product
was purified by column chromatography on silica gel (60-120
mesh size) using ethyl acetate-hexane solvent mixture as eluent.
The solvent removal under reduced pressure afforded the desired
compounds as a solid.
their
low
concentration
in
the
mixture.
Next,
(2E)-1,3-bis(4-methoxyphenyl)prop-2-en-1-one oxime was also
smoothly coupled with with 4-bromoacetophenone and methyl
4-bromobenzoateto afford the desired O-coupled products 37
and 38 in 94 and 80% yields respectively with same E:Z isomers
ratio. The catalyst system was also successfully used for the
coupling of bromo-chalcones with chalcone oximes for the first
time.
The
chalcone
oxime,
(2E)-1,3bis-(4-methoxyphenyl)prop-2-en-1-one
oxime
was Supporting Information
coupled with (E)-3-(bromophenyl)-1-phenyl prop-2-en-1-one to
afford the desired product 39 in good yield, 82%. The other
chalcone oximes were also effectively coupled with various
bromo-chalcones to afford the products 40, 41, and 42 in 81, 77,
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement (optional)
and
76%
yields
respectively.
The
Authors are grateful to Defense R & D Organization (DRDO)
for financial assistance. Authors also acknowledge Director, CFEES,
DRDO and Principal, Sri Venkateswara College, University of Delhi,
for their encouraging support throughout this work. We thank
Head, Department of Chemistry and USIC, University of Delhi for
providing analytical and other technical supports.
(E)-1-(bromophenyl)-3-(substitutedphenyl)prop-2-en-1-ones were
also coupled to afford the desired products 43, and 44 in 89, and
86% respectively. All the reactions were complete in short
reaction times. The aldoximes could also be effectively coupled
with activated aryl bromides by this catalyst system has recently
been published.[21]
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chen et al.
Breaking Report
Entry for the Table of Contents
Page No.
An Easy Access to Oxime ethers by Pd-Catalyzed
C‒O Cross-Coupling of Activated Aryl bromides
with Ketoximes and Chalcone oximes
Reeta,a,b T. M. Rangarajan,*,c Raj Pal Singh,*,a
R. P. Singh,c Manjula Singhd
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.