Copper-Catalyzed Carbonyl Group Controlled Coupling of Isatin Oximes with Arylboronic Acids To Prepare N-Aryloxindole Nitrones

Article abstract of DOI:10.1002/ejoc.201701324

A variety of (E)-N-aryloxindole nitrones were prepared in good to excellent yields by using a copper-catalyzed coupling reaction of isatin oximes and arylboronic acids under mild conditions. Various arylboronic acids that contain sensitive functional groups were tolerated in the transformation, and detailed studies show that the carbonyl group of the isatin oximes serves as a ligand to control the formation of the (E)-oxindole nitrones. This method to prepare (E)-N-aryloxindole nitrones was easily performed on a gram scale and efficiently used to synthesize estrone-derived oxindole nitrone in high yield.

Full text of DOI:10.1002/ejoc.201701324

A Journal of
Accepted Article
Title: Copper-Catalyzed Carbonyl Group Controlled Coupling of Isatin
Oximes with Arylboronic Acids to Prepare N-Aryl Oxindole
Nitrones
Authors: Xue-Ling Mo, Chun-Hua Chen, Cui Liang, and Dong-Liang
Mo
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701324
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701324
Supported by

10.1002/ejoc.201701324
European Journal of Organic Chemistry
FULL PAPER
Copper-Catalyzed Carbonyl Group Controlled Coupling of Isatin
Oximes with Arylboronic Acids to Prepare N-Aryl Oxindole
Nitrones
Xue-Ling Mo,[†] Chun-Hua Chen,[†] Cui Liang, and Dong-Liang Mo*
Abstract: A variety of (E)-N-aryl oxindole nitrones were prepared in
good to excellent yields by copper-catalyzed coupling of N-
unprotected isatin oximes with aryl boronic acids under mild reaction
conditions. The reaction was tolerant various arylboronic acids with
diverse sensitive functional groups. Detailed studies showed that the
carbonyl group in isatin oximes might be served as a carbonyl ligand
or a controlled group playing important roles in the formation of (E)
oxindole nitrones. This method developed to prepare (E)-N-aryl
oxindole nitrones was easily performed at gram-scale and efficiently
used to synthesize estrone-derived oxindole nitrone in high yield.
or strong acid.
A) Strategies to prepare (Z)-isatin nitrones under metal-free conditions
Ar
X
O
N
OH
O
N
PhNHOH
Ar2IOTf
O
R1
O
R1
KOH/MeOH
25 exmaples
N
X = O, NPh
N
H
N
H
H
only one example
Mehrdad's work
Z- isatin nitrone
Mo's work
B) Strategies to prepare N-protected (E)-isatin nitrones under metal-free conditions
O
O
Ar
O
N2
N
ArNHOH
ArNO
R1
O
R1
O
R1
CF3COOH
silica gel
N
N
R
R ¹ H
N
24 exmaples
R
14 examples
R
Introduction
R ¹ H
E- isatin nitrone
Huang's work
Shi's work
Nitrones served as powerful intermediates in organic
synthesis have been extensively used in synthetic approaches
toward natural products and biologically active compounds.1
Many elegant examples have been developed to prepare the
nitrones from various starting materials.2 N-Aryl oxindole
nitrones have attracted much attention to access spirooxindole
derivatives via (3+2) or (3+3) cycloadditions with diverse
dipolarophiles.3−5 In 2011, Mehrdad and coworkers developed a
condensation of isatin or isatin imine with phenyl hydroxylamine
to selectively prepare (Z)-isatin ketonitrone but only affording
one example (Scheme 1-A, left).4 In 2017, Mo’s group reported a
metal-free selective N-arylation of isatin oximes with
diaryliodonium salts to synthesize (Z)-isatin ketonitrones in
excellent yields (Scheme 1-A, right).6 In 2012, Shi and
coworkers found that trifluoroacetic acid could promote the
condensation of isatin and aryl hydroxylamines to afford the (E)-
isatin ketonitrones in good yields (Scheme 1-B, left).5 Recently,
Huang’s group reported that a silica gel mediated reaction of
diazooxindoles and nitroarenes furnished (E)-isatin ketonitrones
under mild conditions (Scheme 1-B, right).7 Although these
metal-free conditions to prepare (E)-isatin ketonitrones have
been developed well, these strategies suffered from limited
substrate scope (such as oximes limited for N-protecting isatin
oximes), functional groups tolerance (such as aldehyde, ester
groups), and unreadily available materials (aryl hydroxylamines,
or diazooxindoles) due to the use of unstable starting materials,
C) Anderson's work, copper-mediated coupling of oximes with arylboronic acids to access nitrones
OH
Ar
O
N
Cu(OAc)2 (2.0 equiv)
N
ArB(OH)2
+
Ar1
Ar2
Ar1
Ar2
pyridine, DCE
rt, in air
25 examples
37-85% yields
D) This work, copper catalyzed carbonyl group controlled synthesis of (E)-N-aryl isatin nitrones
HO
O
Ar
O
N
N
Cu(OAc)2 (10%)
R1
O
R1
+
ArB(OH)2
pyridine, DCE
rt, in air
N
N
H
H
E- isatin nitrone
Scheme 1. An overview for preparation of N-aryl isatin ketonitrones.
Oxidative cross-coupling reaction has been identified as a
valuable strategy for the construction of carbon–carbon or
carbon–heteroatom bonds in modern synthetic chemistry.8 In
particular, the Chan–Evans–Lam coupling reaction provides an
elegant example of the construction of carbon–heteroatom
bonds with a variety of O-, and N-based nucleophiles under mild
conditions.9,10 The direct method to prepare N-arylnitrones is N-
arylation of oximes. However, oximes served as ambient
nucleophiles (N- or O-atoms), most of coupling examples by
transition-metal catalysis are O-arylation products.11 In 2013,
Anderson group pioneered a novel strategy to prepare N-aryl
nitrones by copper-promoted cross-coupling of oximes with
arylboronic acids under mild conditions (Scheme 1-C).12 This is
a superior method to synthesize N-aryl nitrones and further
continued to synthesize N-vinyl nitrones using this strategy by
the same group,2k-l but there are several questions to be figured
out: 1) requirement of 1.0 or 2.0 equivalents of copper salts; 2)
the scope of oxime substrates, especially for substrate
containing additional nucleophilic groups; 3) the relationship of
E/Z geometry between nitrones and oximes; 4) lack of gram-
scalable preparations. Recently, we are interested in the copper-
catalyzed selective cross-coupling reaction and developed a
selective coupling of isatin oximes with alkenyl boronic acids to
[a]
Xue-Ling Mo, Chun-Hua Chen, Cui Liang, and prof. Dong-Liang Mo
State Key Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources, Ministry of Science and Technology of China;
School of Chemistry and Pharmaceutical Sciences
Guangxi Normal University
15 Yu Cai Road, Guilin 541004, China
E-mail: moeastlight@mailbox.gxnu.edu.cn
[†]
X.-L. Mo and C.-H. Chen contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701324
European Journal of Organic Chemistry
FULL PAPER
prepare (E)-N-vinyl oxindole nitrones in good yields.13 To further
explore the selective coupling to prepare isatin N-aryl
ketonitrones, we surmised that the carbonyl group in isatin
oximes can be served as a carbonyl ligand to reduce the
equivalents of copper salt and control the definite configuration
of nitrones.14 The E/Z isomers of nitrones have often occupied a
central position in rationalizing the stereoselectivity of the
important 1,3-dipolar cycloaddition reactions.15 Exploring
efficient methods to selectively prepare E/Z isomers of nitrones
is desirable. Therefore, we continued to investigate the coupling
of isatin oximes with aryl boronic acids to figure out the
aforementioned questions. Herein, we reported a general and
scalable carbonyl group controlled N-arylation of N-unprotected
isatin oximes with arylboronic acids to prepare (E)-N-aryl
oxindole nitrones (Scheme 1-D).
O
HO
Ph
N
N
Cu salt (10 mol%)
+
PhB(OH)2
O
O
base, solvent
rt, in air
N
N
H
H
1a
2a
3aa
entry
1
Cu salt
solvent
base
pyr
3aa%b
70
79
91
87
43
95
60
35
10
86
trace
4
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl
MeOH
MeCN
DMF
2
pyr
3
pyr
4
DMSO
toluene
DCE
pyr
5
pyr
6
pyr
7
dioxane
THF
pyr
Results and Discussion
8
pyr
Initially, isatin oxime 1a and phenyl boronic acid 2a were
chosen as model substrates for the coupling reaction to prepare
N-aryl isatin ketonitrone 3aa using the conditions previously
described from our group.13 Treatment of 1a and 2a under 10
mol% of Cu(OAc)2 with 3.0 equiv of pyridine (pyr) in MeOH
without additive in air atmosphere afforded nitrone 3aa in 70%
yield (Table 1, entry 1). Nitrone 3aa was assigned as E-isomer
and matched the literature.7 Although oxime 1a was prepared in
previous works, the E or Z configuration of oxime 1a was not
definitely assigned. The observation of high selective E-nitrone
3aa attracted us to figure out the configuration of isatin oxime 1a.
Finally, the oxime 1a we used was assigned as an E-
configuration which was determined by its X-ray diffraction.16
Solvent screening revealed that the DCE gave the best result for
3aa in 95% yield (Table 1, entries 1−9). The type of copper salts
had a great influence on the yield of 3aa. 86% yield of 3aa was
obtained by using CuCl as a catalyst while the reaction did not
take place or afforded low yields of 3aa when CuCl2 and CuSO4
were used (Table 1, entries 10−12). The yield of 3aa was
dropped to 11% or 8% when pyridine was replaced by NEt3 or
Cs2CO3 (Table 1, entry 13−14). A slightly decreased yield of 3aa
was observed using 5% of Cu(OAc)2 but requiring a longer
9
acetone
DCE
pyr
10
11
12
13
14
15c
16d
17e
18f
19g
20h
21i
pyr
CuCl2
DCE
pyr
CuSO4
DCE
pyr
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DCE
NEt3
Cs2CO3
pyr
11
8
DCE
DCE
94
86
55
69
9
DCE
pyr
DCE
pyr
DCE
pyr
DCE
pyr
DCE
pyr
0
DCE
pyr
83
reaction time for 30
h (Table 1, entry 15). Reducing
[a] Reaction conditions: Cu salts (10 mol%), 1a (0.3 mmol), 2a (0.45 mmol, 1.5
equiv), base (0.90 mmol, 3.0 equiv), solvent (5 mL), 25 °C, 2−18 h; [b] Isolated
yield; [c] Cu(OAc)2 (5 mol%) for 30 h; [d] 2a (2.0 equiv); [e] air was replaced
with H2O2; [f] air was replaced with O2; [g] without air; [h] 2a was replaced with
PhB(pin) (1.5 equiv); [i] 2a was replaced with PhBF3K (1.5 equiv).
phenylboronic acid 2a to 2.0 equiv afforded 86% yield of 3aa
(Table 1, entry 16). When the air was replaced by H2O2 or O2,
the yield of 3aa was dropped to 55% and 69% yields,
respectively (Table 1, entries 17-18). However, the yield of 3aa
was only obtained in 9% without air (Table 1, entry 19). No 3aa
was observed by replacing 2a with PhB(Pin) while 83% yield of
3aa was obtained using PhBF3K (Table 1, entries 20-21). Hence,
the optimal conditions for the coupling reaction were 10% of
Cu(OAc)2 with 3.0 equiv of pyridine as base in DCE at room
temperature in air atmosphere..
With the optimized conditions in hand, we began to investigate
the scope of copper-catalyzed N-arylation of various arylboronic
acids 2 with isatin oxime 1a. As shown in Table 2, most of
arylboronic acids containing electron-donating groups or
electron-withdrawing groups with para, meta, ortho-substituents
afforded the desired product 3 in good to excellent yields at
room temperature open to air. When the 2-bromophenyl boronic
acid 2o was carried out in the optimized conditions, 47% yield of
3ao was obtained. When heteroarylboronic acids, such as 3-
Table 1. Optimization of the reaction conditions.a
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10.1002/ejoc.201701324
European Journal of Organic Chemistry
FULL PAPER
thienyl, 2-thienyl as well as 5-indolyl boronic acids 2q-s, were
conducted in the presence of 1.0 equiv of Cu(OAc)2, the desired
product 3aq-3as were obtained in 73%, 14%, and 60% yields,
respectively. It is worthy to note that ortho-substituted aryl and
heteroaryl nitrones were not reported in Anderson’s work.12
However, no desired product 3at was observed even though
Cu(OAc)2 was carried out with 1.0 equiv or 2.0 equiv. When
oxime 1a was performed with 1.6 g to react with arylboronic acid
2b or 2i, nitrones 3ab and 3ai were obtained in 74% and 68%
yields, respectively. In all cases, no Z-isomer of 3aa and N1-
arylation products were observed. It can be seen that the
coupling reaction for arylboronic acids were tolerated a variety of
sensitive functional groups, such as halides, vinyl, aldehyde, as
well as heteroaryl groups, which will make these compounds
more useful by further transformations.
reacted with 2a to afford the desired products 3aa-3ja in good to
excellent yields (Table 3, entries 1−10). However, when oxime
1g with a bromo group at 6-position, the yield of 3ga was
obtained in only 22% yield, which might be because of the
solubility of oxime 1g in DCE (Table 3, entry 7). When oxime 1k
and 1l with a methyl or phenyl protecting group on N-atom was
subjected into the optimal conditions, the desired nitrones 3ka
and 3la were afforded in 97% and 94% yields, respectively
(Table 3, entries 11−12).
Table 3. The scope of isatin oxime 1.a
O
OH
O
Ph
O
N
N
4
7
5
Cu(OAc)2 (10%)
pyr, DCE, rt, in air
+
R
PhB(OH)2
R
N
R1
6
N
Table2. The scope of arylboronic acid 2.a,b
R1
2a
1
3
HO
N
O
Ar
O
N
entry
1
1
R
R1
H
3
yield%b
95
Cu(OAc)2 (10%)
O
+
ArB(OH)2
pyr, DCE, rt, in air
N
N
H
1a
H
3aa
3ba
3ca
3da
3ea
3fa
H
1a
2
3
2
1b
1c
1d
1e
1f
5-OMe
5-OCF3
5-Me
5-F
H
95
OPh
OMe
O
O
O
SMe
O
N
N
N
3
H
81
N
O
O
O
O
4
H
87
N
N
N
N
H
H
H
H
3aa, 95%
3ab, 94%, 74%c
3ac, 97%
3ad, 96%
5
H
82
Me
NMe2
O
O
N
F
O
N
O
N
6
5-NO2
6-Br
7-F
H
66
N
O
O
O
O
7
1g
1h
1i
H
3ga
3ha
3ia
22
N
N
H
N
H
N
H
H
8
H
88
3ag, 73%
3ae, 77%
3af, 80%
3ah, 89%
CHO
Br
CF3
O
N
O
O
N
O
N
9
7-CF3
4-F
H
98
N
OMe
O
O
O
O
10
11
12
1j
H
3ja
60
N
H
N
H
N
N
H
H
c
3ai
, 91%, 68%
3aj, 72%
3ak
, 94%
3al
, 75%
1k
1l
H
Me
Ph
3ka
3la
97
Me
Br
H
94
O
N
O
N
O
N
O
N
Br
Me
[a] Reaction conditions: Cu(OAc)2 (10 mol%), 1 (0.3 mmol), 2a (0.45 mmol, 1.5
equiv), pyridine (0.9 mmol, 3.0 equiv), DCE (3 mL), 25 °C, 2−18 h; [b] Isolated
yield.
O
O
O
O
N
H
N
H
N
H
N
H
3am, 74%
3an, 68%
3ao, 47%
3ap, 79%
To investigate the type of oximes affecting the copper-
catalyzed coupling reaction, several oximes were performed
under the optimized conditions (Scheme 2). When oxime 1m
was carried out with 2a for 12−24 h, no O-arylation or N-
arylation products were observed obviously and only
decomposition of oximes (Scheme 2-1). To our delight, oxime
1n and 1o reacted with 2a provided the desired nitrone 3na in
77% yield with a 5:1 E/Z ratio (Scheme 2-2) and 3oa in 84%
yield (Scheme 2-3), respectively. To our surprise, when oxime
1p with Z-configuration ran with 2a under the optimal conditions,
no desired coupling products were observed and only oxime 1p
with an E-configuration was isolated in 30% yield (Scheme 2-4),
which revealed that the E or Z configuration of oxime might be
reversed under the copper conditions.
NH
O
N
O
N
O
N
O
S
N
N
S
O
O
O
O
N
H
N
H
N
H
N
H
3aq, 73%d
3ar, 14%d
d,e
3as, 60%
3at
, 0%
[a] Reaction conditions: Cu(OAc)2 (10 mol%), 1a (0.3 mmol), 2 (0.45 mmol,
1.5 equiv), pyridine (0.9 mmol, 3.0 equiv), DCE (3 mL), 25 °C, 2−18 h; [b]
Isolated yield; [c] 1a (1.6 g, 10 mmol) was used; [d] Cu(OAc)2 (1.0 equiv); [e]
Cu(OAc)2 (2.0 equiv).
Afterward, an array of substituted isatin oximes (1a-l) were
assessed under the copper-catalyzed reaction conditions (Table
3). Various isatin oximes containing electron-donating groups or
electron-withdrawing groups at 4, 5, 6, or 7-postions of aryl ring
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10.1002/ejoc.201701324
European Journal of Organic Chemistry
FULL PAPER
O
conditions, nitrone 3sa was obtained only in 46% yield with a 5:1
E/Z ratio (Scheme 4-1). This result of oxime 1s without carbonyl
group giving lower yields suggests that the carbonyl group might
promote the copper coupling reaction. To figure out the
relationship between the configuration of oxime 1s and nitrone
3sa, the two E and Z isomers of oxime 1s were purified by flash
column chromatography and E-configuration of 1s was
determined by X-ray diffraction.17 When E-1s was subjected into
the reaction conditions, a mixture of 7:1 E/Z ratio of nitrone 3sa
was observed with 38% yield (Scheme 4-2). While Z-1s reacting
with 2a under copper catalyst, nitrone 3sa was also obtained in
30% yield with a mixture of 2:1 E/Z ratio (Scheme 4-3). These
results suggested that the Z-isomer of oxime 1s might be
converted to E-isomer under copper conditions.
Cu(OAc)2 (10 %)
N
complex mixtures
+
OH
PhB(OH)2
Ph
O
1)
2)
pyr, DCE, rt, in air
Me
2a
1m
OH
Ph
N
O
N
Cu(OAc)2 (10 %)
pyr, DCE, rt, in air
77% yield
O
PhB(OH)
+
CO2Et
2
CO2Et
Ph
1n
Ph
3na
2a
E / Z= 5:1
OH
N
O
Ph
Cu(OAc)2 (10%)
N
+ PhB(OH)2
MeO2C
CO2Me
OH
3)
pyr, DCE, rt, in air
84% yield
MeO2C
CO2Me
2a
1o
3oa
HO
Ph
N
N
Cu(OAc)2 (10%)
pyr, DCE, rt, in air
30% yield
4)
+
PhB(OH)2
Ph
CN
CN
2a
OH
Ph
Ph
O
N
(Z)-1p
N
Cu(OAc)2 (10%)
(E)-1p
+
PhB(OH)2
Ph
1)
2)
pyr, DCE, rt, in air
46%
2a
Scheme 2. N-Arylation of different oximes.
Ph
Ph
1s
3sa
E/ Z = 5:1
Ph
E/ Z = 3:1
When nitrone 3aa was carried out with phenyl boronic acid 2a,
nitrone 3la could not be observed and only 3aa was recovered
(Scheme 3-1). However, methyl protected oxime 1q can furnish
N1-arylation product 3qa in 32% yield (Scheme 3-2). To test the
role of carbonyl group, oxime 1r was prepared and put in the
copper-catalyzed coupling reaction. O-Arylation product 3ra was
obtained in 16% yield with the starting material 1r recovered
(Scheme 3-3). These results revealed that the carbonyl group
might tune the nucleophilicity of N- or O-atoms to control on the
N-arylation of isatin oxime.
OH
N
O
N
Cu(OAc)2 (10%)
+
PhB(OH)2
Ph
Ph
pyr, DCE, rt, in air
38%
2a
Ph
Ph
3sa
E/ Z = 7:1
E-1s
X-ray structure
HO
N
Ph
O
N
Cu(OAc)2 (10%)
3)
+
Ph
PhB(OH)2
Ph
pyr, DCE, rt, in air
30%
2a
Ph
Ph
1s
Z-
3sa
E/ Z = 2:1
O
N
O
N
Ph
O
Ph
O
Cu(OAc)2 (10%)
Scheme 4. The effect of E/Z isomers of chalcone oxime on the formation of
+
PhB(OH)2
1)
nitrones.
pyr, DCE, rt, in air
0% yield
N
Ph
3la
2a
N
H
3aa
MeO
Based on the experimental results and previous mechanistic
studies of Chan-Evans-Lam reaction,18 a plausible mechanism
for the copper-catalyzed coupling reaction of isatin oxime and
arylboronic acids was proposed (Scheme 5). Intermediate A
might be formed through an initial coordination with pyridine and
attacked by nucleophilic N-atom of N-O bond in oxime 1a.19 The
intermediate A was stabilized by the carbonyl group in oxime 1a
which served a carbonyl ligand to coordinate with copper
species.14a Then Intermediate A underwent transmetallation with
arylboronic acid 2 to provide intermediate B, which went through
disproportionation or oxidation under O2 to form a Cu(III) specie
C. Finally, reductive elimination of intermediate C to give
intermediate D which released Cu(I) specie to afford N-aryl isatin
ketonitrone 3. The Cu(I) specie was oxidized to Cu(II) species
under O2 to finish the catalytic cycle.
MeO
N
N
Cu(OAc)2 (10%)
O
+
PhB(OH)2
O
2)
N
pyr, DCE, rt, in air
32% yield
N
H
2a
Ph
3qa
1q
Ph
N
HO
N
O
Cu(OAc)2 (10%)
pyr, DCE, rt, in air
16% yield
+
PhB(OH)2
3)
Ph
Ph
2a
N
N
3ra
1r
Scheme 3. The studies on the role of the carbonyl group in oximes.
Although Anderson’s work12 did not report the details about
E/Z ratio of N-aryl chalcone nitrone 3sa, we also performed
oxime 1s in our coupling conditions (Scheme 4). When oxime 1s
with a mixture of 3:1 E/Z ratio was carried out in the optimized
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10.1002/ejoc.201701324
European Journal of Organic Chemistry
FULL PAPER
in Scheme 7, estrone-derived arylboronic acid 2u was easily
prepared by Lee’s method in 3-steps.20 When arylboronic acid
2u and isatin oxime 1a were carried out in the copper-catalyzed
reaction conditions, the desired estrone-derived nitrone 3au was
afforded in 81% yield.
O
CuII(OAc)2
pyr
HO
N
N
Ph
O
O
N
H
N
CuII(OAc)2(pyr)
H
3
1a
oxidation
AcO
O2
N-nucleophilic
attack
Pyr·HOAc
O
Me
O
Me
H
O
II OAc
Cu
ref 20
H
N
O
N
H
H
OAc
CuI
pyr
Ph
O
pyr
H
H
O
(HO)2B
O
3-steps
HO
N
2u
H
Estrone
N
H
A
Me
O
D
H
PhB(OH)2
H
Reductive
elimination
transmetalation
2a
N
1a
H
Cu(OAc)2 (10%)
O
B(OH)2(OAc)
N
H
pyr, DCE, rt, in air
81% yield
AcO
III
O
O
II
3au
Ph
disproportionation
Ph
N
Cu
N
Cu
Scheme 7. Application of N-arylation to prepare estrone-derived nitrone 3au.
pyr
pyr
O
O
N
H
N
C
H
B
Conclusions
Scheme 5. Proposed mechanism.
In summary, we have developed an efficient method to
prepare E-N-aryl isatin ketonitrones from copper-catalyzed
coupling reaction of isatin oximes and arylboronic acids under
mild conditions. The carbonyl group in oximes might play
important roles of tuning the nucleophilicity of the N- and O-
atoms, as well as serving as a carbonyl ligand to afford the E-
nitrones. This method features broad substrate scope, good
functional group tolerance, readily available materials and gram-
scalable preparation of N-unprotected N-aryl isatin ketonitrones.
Encouraged by the efficiency of the copper catalyzed N-
arylation to prepare N-aryl isatin ketonitrones, gram-scalable
preparations of nitrones were performed with oxime 1a and 1k.
As shown in Scheme 6, when 3.2 gram of 1a and 3.5 gram of 1k
were carried out in the optimal conditions, the desired nitrone
3aa and 3ka was obtained in 75% (3.57 g) and 71% (3.58 g)
yields, respectively. Compared to Shi’s and Huang’s methods,5,7
the easy handling operation, readily available starting materials,
and gram-scalable preparation of these nitrones by our
procedure were meaningful and important for further studies of
cycloaddition reactions.
Experimental Section
All reactions were performed under an air atmosphere. Commercially
available reagents were used without further purification. The NMR
spectra were recorded in CDCl3 or DMSO-d6 on 400, or 500 MHz
instrument with TMS as the internal standard. NMR data are represented
as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet), coupling constants in hertz (Hz), and
integration. IR spectra were recorded on FT-IR spectrometer, and only
major peaks are reported in cm‒1. HRMS were measured in ESI mode
and the mass analyzer of the HRMS was TOF. Flash column
chromatography was performed on silica gel (300-400 mesh).
Arylboronic acid 2a-t was purchased from Sigma-Aldrich and 2u20 was
prepared according to literature method and its spectral data matched
literature values.
HO
O
Ph
O
N
N
Cu(OAc)2 (10%)
+
O
PhB(OH)2
1)
pyr, DCE, rt, in air
N
N
H
H
1a
2a
3aa
3.57 g, 75% yield
3.2 g, 20 mmol
HO
N
O
Ph
N
2)
Cu(OAc)2 (10%)
pyr, DCE, rt, in air
+
O
N
PhB(OH)2
O
N
Me
Me
General procedure for synthesis of compound 3: In a 25 mL flask
was charged with isatin oxime 1 (0.3 mmol), aryl boronic acid 2 (0.45
mmol, 1.5 equiv), and Cu(OAc)2 (0.03 mmol, 10%) under an air
atmosphere. Then, DCE (3.0 mL) and pyridine (0.9 mmol, 3.0 equiv) was
added via syringe. The reaction flask was then capped with a septum
pierced with a ventilation needle and stirred vigorously at 25 °C for 2−30
h until oxime 1 disappeared (monitored by TLC). At this time, the reaction
was quenched by H2O (10 mL) and extracted with DCM (3 × 10 mL).
Then, dried over with Na2SO4 and filtered. The solvent was removed
1k
2a
3ka
3.5 g, 20 mmol
3.58 g, 71% yield
Scheme 6. Gram-scalable preparations of N-aryl isatin ketonitrones.
Next, we tried to prepare more complex N-aryl isatin nitrones
by this efficient copper-catalyzed N-arylation strategy. As shown
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10.1002/ejoc.201701324
European Journal of Organic Chemistry
FULL PAPER
under reduced pressure and the crude product was purified by flash
chromatography (the crude residue was dry loaded on silica gel, 1/10 to
1/6, ethyl acetate/petroleum ether) to provide N-aryl isatin ketonitrone 3.
17.6 Hz, 1H), 5.41 (d, J = 10.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
δ 160.5, 146.1, 141.5, 139.5, 136.1, 135.0, 132.8, 126.8, 124.9, 124.6,
122.3, 119.0, 116.9, 110.3; IR (thin film) 3078, 2966, 1706, 1539, 1258,
771, 698 cm−1; HRMS (ESI) m/z calcd for C16H11N2O2 (M−H)− 263.0821,
found 263.0830.
(E)-N-(2-Oxoindolin-3-ylidene) aniline oxide (3aa)3e, an orange solid,
0.068 g, 95% yield. Mp: 205−206 °C; 1H NMR (400 MHz, DMSO–d6): δ
10.76 (s, 1H), 8.28 (d, J = 7.6 Hz, 1H), 7.57−7.49 (m, 5H), 7.41−7.38 (t, J
= 3.6 Hz, 1H), 7.08−7.04 (t, J = 3.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H); 13C
NMR (125 MHz, DMSO–d6): δ 160.5, 146.9, 141.5, 135.0, 132.8, 130.7,
129.3, 124.7, 124.5, 122.3, 118.9, 110.3; IR (thin film) 3080, 2922, 1707,
1541, 1257, 771, 657 cm−1; HRMS (ESI) m/z calcd for C14H11N2O2
(M+H)+ 239.0821, found 239.0842.
(E)-N-(4-Fluorophenyl)-2-oxoindolin-3-imine oxide (3ah), an orange
solid, 0.068 g, 89% yield. Mp: 213−214 °C; 1H NMR (400 MHz, DMSO-
d6): δ 10.77 (s, 1H), 8.26 (d, J =7.6 Hz, 1H), 7.69−7.65 (m, 2H),
7.42−7.32 (m, 3H), 7.08 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H); 13C
NMR (100 MHz, DMSO-d6): δ 164.2 (d, J = 245.0 Hz), 160.5, 143.2 (d, J
= 2.9 Hz), 141.5, 135.2, 132.9, 127.1 (d, J = 8.7 Hz), 124.7, 122.3, 118.9,
116.3 (d, J = 23.3 Hz), 110.3; IR (thin film) 3182, 2923, 1700, 1532, 1225,
745, 661 cm−1; HRMS (ESI) m/z calcd for C14H10FN2O2 (M+H)+ 257.0726,
found 257.0749.
(E)-N-(4-Methoxyphenyl)-2-oxoindolin-3-imine oxide (3ab), an orange
solid, 0.076 g, 94% yield. Mp: 184−185 °C; 1H NMR (500 MHz, DMSO-
d6): δ 10.72 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 9.0 Hz, 2H),
7.39 (t, J = 8.0 Hz, 1H), 7.06−7.01 (m, 3H), 6.89 (d, J = 8.0 Hz, 1H), 3.84
(s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 161.0, 160.6, 141.2, 140.1,
134.6, 132.5, 126.2, 124.5, 122.2, 119.2, 114.1, 110.2, 56.0; IR (thin film)
3178, 2925, 1702, 1503, 1261, 737, 661 cm−1; HRMS (ESI) m/z calcd for
C15H13N2O3 (M+H)+ 269.0926, found 269.0929.
(E)-N-(4-Bromophenyl)-2-oxoindolin-3-imine oxide (3ai), an orange
solid, 0.086 g, 91% yield. Mp: 211−212 °C; 1H NMR (400 MHz, DMSO-
d6): δ 10.78 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 7.73−7.71 (m, 2H),
7.57−7.55 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.90
(d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 160.5, 145.9, 141.6,
135.3, 133.0, 132.3, 126.7, 124.8, 123.8, 122.4, 118.8, 110.4; IR (thin
film) 3137, 2924, 1706, 1526, 1200, 773, 658 cm−1; HRMS (ESI) m/z
calcd for C14H10BrN2O2 (M+H)+ 316.9926, found 316.9910.
(E)-2-Oxo-N-(4-phenoxyphenyl) indolin-3-imine oxide (3ac), an
orange solid, 0.097 g, 97% yield. Mp: 204−205 °C; 1H NMR (500 MHz,
DMSO-d6): δ 10.75 (s, 1H), 8.27 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.5 Hz,
2H), 7.48−7.45 (m, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H),
7.14 (d, J = 7.5 Hz, 2H), 7.06 (d, J = 8.5 Hz, 3H), 6.90 (d, J = 8.0 Hz, 1H);
13C NMR (125 MHz, DMSO-d6): δ 160.5, 158.8, 156.1, 141.9, 141.4,
134.9, 132.7, 130.8, 126.6, 124.9, 124.6, 122.3, 120.0, 119.1, 118.1,
(E)-2-Oxo-N-(4-(trifluoromethyl)phenyl) indolin-3-imine oxide (3aj),
an orange solid, 0.066 g, 72% yield. Mp: 236−237 °C; 1H NMR (400 MHz,
DMSO-d6): δ 10.82 (s, 1H), 8.27 (d, J = 7.5 Hz, 1H), 7.92−7.90 (m, 2H),
7.84−7.83 (m, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.92
(d, J = 7.5 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 160.5, 149.5, 141.8,
135.6, 133.2, 130.8 (q, J = 25.5 Hz), 126.7 (q, J = 2.9 Hz), 125.7, 125.3
(q, J = 216.4 Hz), 124.9, 122.4, 118.6, 110.5; IR (thin film) 3187, 2923,
110.3; IR (thin film) 3148, 3073, 2922, 1707, 1491, 1253,751, 658 cm−1
;
HRMS (ESI) m/z calcd for C20H13N2O3 (M−H)− 329.0926, found 329.0938.
1710, 1543, 1328, 773, 661 cm−1
; HRMS (ESI) m/z calcd for
(E)-N-(4-(Methylthio)phenyl)-2-oxoindolin-3-imine oxide (3ad), an
orange solid, 0.082 g, 96% yield. Mp: 201−202 °C; 1H NMR (400 MHz,
DMSO-d6): δ 10.75 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.53−7.51 (m, 2H),
7.40−7.33 (m, 3H), 7.07 (t, J = 7.6 Hz, 2H), 6.89 (d, J = 7.6 Hz, 1H), 2.55
(s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 160.5, 143.6, 141.9, 141.4,
134.9, 132.7, 125.6, 125.1, 124.6, 122.3, 119.1, 110.3, 14.8; IR (thin film)
3177, 2919, 1714, 1543, 1293, 745, 657 cm−1; HRMS (ESI) m/z calcd for
C15H13N2O2S (M+H)+ 285.0698, found 285.0715.
C15H8F3N2O2 (M−H)− 305.0538, found 305.0548.
(E)-N-(4-Formylphenyl)-2-oxoindolin-3-imine oxide (3ak), an orange
solid, 0.075 g, 94% yield. Mp: 206−207 °C; 1H NMR (500 MHz, DMSO-
d6): δ 10.81 (s, 1H), 10.10 (s, 1H), 8.28 (d, J = 7.5 Hz, 1H), 8.06−8.04 (m,
2H), 7.82−7.80 (m, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H),
6.91 (d, J = 7.5 Hz, 1H); 13C NMR (125 MHz,DMSO-d6): δ 192.9, 160.5,
150.5, 141.8, 137.4, 135.6, 133.2, 130.6, 125.5, 124.9, 122.4, 118.6,
110.5; IR (thin film) 3700, 3043, 2923, 1696, 1459, 1199, 768, 659 cm−1
;
(E)-N-(4-(Dimethylamino) phenyl)-2-oxoindolin-3-imine oxide (3ae), a
brown solid, 0.065 g, 77% yield. Mp: 214−215 °C; 1H NMR (500 MHz,
DMSO-d6): δ 10.67 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.5 Hz,
2H), 7.35 (t, J = 7.5 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.87 (t, J = 7.5 Hz,
1H), 6.70 (t, J = 9.0 Hz, 2H), 3.01 (s, 6H); 13C NMR (125 MHz, DMSO-
d6): δ 160.7, 152.2, 140.7, 135.8, 133.2, 131.9 126.0, 124.1, 122.1, 119.9,
HRMS (ESI) m/z calcd for C15H11N2O3 (M+H)+ 267.0770, found 267.0754.
(E)-N-(3-Methoxyphenyl)-2-oxoindolin-3-imine oxide (3al), an orange
solid, 0.060 g, 75% yield. Mp: 207−208 °C; 1H NMR (400 MHz, DMSO-
d6): δ 10.73 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.43 (q, J = 13.2, 6.8 Hz,
2H), 7.18 (s, 1H), 7.12−7.04 (m, 3H), 6.90 (d, J = 6.4 Hz, 1H), 3.78 (s,
3H); 13C NMR (100 MHz, DMSO-d6): δ 160.4, 159.8, 147.8, 141.5, 134.9,
132.8, 130.2, 124.7, 122.3, 118.9, 116.5, 110.3, 56.0; IR (thin film) 3068,
2923, 1722, 1646, 1289, 751, 687 cm−1; HRMS (ESI) m/z calcd for
C15H13N2O3 (M+H)+ 269.0926, found 269.0937.
110.9, 110.0; IR (thin film) 3093, 2919, 1717, 1515, 1124, 814, 684 cm−1
;
HRMS (ESI) m/z calcd for C16H16N3O2 (M+H)+ 282.1243, found 282.1233.
(E)-2-Oxo-N-(p-tolyl) indolin-3-imine oxide (3af), an orange solid,
0.071 g, 61% yield. Mp: 195−196 °C; 1H NMR (400 MHz, CDCl3): δ 8.39
(d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.33−7.29 (m, 2H), 7.25−7.19 (m, 3H),
7.06 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 2.36 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 160.5, 144.1, 141.2, 139.1, 134.4, 132.1, 129.5,
125.2, 123.6, 123.0, 119.1, 109.6, 21.5; IR (thin film) 3139, 2916, 1697,
1533, 1346, 744, 662 cm−1; HRMS (ESI) m/z calcd for C15H13N2O2
(M+H)+ 253.0977, found 253.0980.
(E)-N-(3-Bromophenyl)-2-oxoindolin-3-imine oxide (3am), an orange
solid, 0.070 g, 74% yield. Mp: 190−191 °C; 1H NMR (400 MHz, DMSO-
d6): δ 10.78 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.88 (s, 1H), 7.76 (d, J = 8.0
Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.43 (t, J = 7.2
Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H); 13C NMR (100
MHz, DMSO-d6): δ 160.5, 147.7, 141.7, 135.4, 133.5, 133.1, 131.4,
127.4, 124.9, 123.8, 122.4, 121.4, 118.7, 110.4; IR (thin film) 3100, 2924,
(E)-2-Oxo-N-(4-vinylphenyl) indolin-3-imine oxide (3ag), an orange
solid, 0.057 g, 73% yield. Mp: 196−197 °C; 1H NMR (400 MHz, DMSO-
d6): δ 10.76 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.61−7.54 (m, 4H), 7.41 (t, J
= 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.90−6.79 (m, 2H), 5.99 (d, J =
1698, 1537, 1257, 771, 658 cm−1
C14H10BrN2O2 (M+H)+ 316.9926, found 316.9925.
; HRMS (ESI) m/z calcd for
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701324
European Journal of Organic Chemistry
FULL PAPER
(E)-N-(3,5-Dimethylphenyl)-2-oxoindolin-3-imine oxide (3an), an
orange solid, 0.069 g, 68% yield. Mp: 213−214 °C; 1H NMR (400 MHz,
DMSO-d6): δ 10.72 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.2 Hz,
1H), 7.16−7.14 (m, 3H), 7.07 (t, J = 7.2 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H),
2.32 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ 160.4, 146.9, 141.4,
138.7, 134.8, 132.7, 132.0, 124.6, 122.3, 121.8, 118.9, 110.3, 21.1; IR
(thin film) 3105, 2919, 1719, 1554, 1300, 772, 680 cm−1; HRMS (ESI) m/z
calcd for C16H15N2O2 (M+H)+ 267.1134, found 267.1158.
119.5, 118.7, 110.9, 110.1, 56.1; IR (thin film) 3299, 2924, 1713, 1543,
1256, 781, 611 cm−1; HRMS (ESI) m/z calcd for C15H11N2O3 (M−H)−
267.0770, found 267.0780.
(E)-N-(2-Oxo-5-(trifluoromethoxy) indolin-3-ylidene)aniline oxide
(3ca), an orange solid, 0.079 g, 81% yield. Mp: 225−226 °C; 1H NMR
(400 MHz, DMSO-d6): δ 10.96 (s, 1H), 8.18 (s, 1H), 7.61−7.50 (m, 5H),
7.43 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6): δ 160.4, 146.7, 143.2, 140.5, 134.8, 131.0, 129.3, 125.8,
124.5, 122.0 (q, J = 254.4 Hz), 119.8, 117.3, 111.2; IR(thin film) 3176,
2925, 1702, 1536, 1467, 764, 662 cm−1; HRMS (ESI) m/z calcd for
C15H8F3N2O3 (M−H)− 321.0487, found 321.0496.
(E)-N-(2-Bromophenyl)-2-oxoindolin-3-imine oxide (3ao), an orange
solid, 0.045 g, 47% yield. Mp: 196−197 °C; 1H NMR (400 MHz, DMSO-
d6): δ 10.83 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H),
7.63−7.61 (m, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.48−7.42 (m, J = 7.6 Hz, 2H),
7.12 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.0 Hz,, 1H); 13C NMR (100 MHz,
DMSO-d6): δ 160.2, 146.0, 141.9, 135.7, 133.6, 133.4, 131.8, 129.4,
126.4, 125.0, 122.6, 117.9, 116.2, 110.6; IR (thin film) 3032, 2923, 1728,
1553, 1247, 758, 649 cm−1; HRMS (ESI) m/z calcd for C14H10BrN2O2
(M+H)+ 316.9926, found 316.9925.
(E)-N-(5-Methyl-2-oxoindolin-3-ylidene) aniline oxide (3da), an orange
solid, 0.066 g, 87% yield. Mp: 215−216 °C; 1H NMR (400 MHz, DMSO-
d6): δ 10.64 (s, 1H), 8.12 (s, 1H), 7.54−7.50 (m, 5H), 7.21 (d, J = 7.6 Hz,
1H), 6.79 (d, J = 8.4 Hz, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, DMSO-
d6): δ 160.6, 146.9, 139.3, 135.1, 133.2, 131.2, 130.6, 129.3, 125.1,
124.5, 119.0, 110.1, 21.1; IR (thin film) 3212, 2919, 1716, 1548, 1483,
1251, 649 cm−1; HRMS (ESI) m/z calcd for C15H11N2O2 (M−H)− 251.0821,
found 251.0829.
(E)-N-(Naphthalen-1-yl)-2-oxoindolin-3-imine oxide (3ap), an orange
solid, 0.068 g, 79% yield. Mp: 205−206 °C; 1H NMR (400 MHz, DMSO-
d6): δ 10.79 (s, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 8.06−8.01(m,
3H), 7.67−7.61 (m, 3H), 7.44 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H),
6.92 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 160.6, 144.2,
141.5, 135.2, 133.8, 132.9, 132.7, 129.1, 129.1, 128.3, 128.1, 127.5,
124.7, 123.5, 122.4, 122.4, 119.0, 110.4; IR (thin film) 3701, 3150, 2923,
1704, 1537, 1255, 745, 697 cm−1; HRMS (ESI) m/z calcd for C18H13N2O2
(M+H)+ 289.0977, found 289.0979.
(E)-N-(5-Fluoro-2-oxoindolin-3-ylidene) aniline oxide (3ea), an orange
solid, 0.063 g, 82% yield. Mp: 214−215 °C; 1H NMR (400 MHz, DMSO-
d6): δ 10.79 (s, 1H), 8.02−7.99 (m, 1H), 7.59−7.49 (m, 5H), 7.29−7.23 (m,
1H), 6.90−6.86 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 160.5, 159.2
(d, J = 234.8 Hz), 146.7, 137.9, 135.1(d, J = 2.9 Hz), 131.0, 129.3, 124.5,
119.8 (d, J = 10.2 Hz), 119.2 (d, J = 24.1 Hz), 111.5 (d, J = 21.8 Hz),
111.2 (d, J = 2.1 Hz); IR (thin film) 3165, 2923, 1725, 1548, 1289, 762,
652 cm−1; HRMS (ESI) m/z calcd for C14H8FN2O2 (M−H)− 255.0570,
found 255.0579.
(E)-2-Oxo-N-(thiophen-3-yl)indolin-3-imine oxide (3aq), an orange
solid, 0.053 g, 73% yield. Mp: 181−182 °C; 1H NMR (500 MHz, DMSO-
d6): δ 10.76 (s, 1H), 8.26 (d, J = 7.5 Hz, 1H), 8.06−8.05 (m, 1H),
7.62−7.60 (m, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 4.5 Hz, 1H), 7.06
(t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H); 13C NMR (125 MHz, DMSO-
d6): δ 160.4, 144.3, 141.3, 135.3, 132.9, 126.2, 124.7, 124.3, 123.5,
122.3, 119.0, 110.3; IR (thin film) 3692, 3267, 3091, 1706, 1547, 1245,
771, 625 cm−1; HRMS (ESI) m/z calcd for C12H9N2O2S (M+H)+ 245.0385,
found 245.0379.
(E)-N-(5-Nitro-2-oxoindolin-3-ylidene) aniline oxide (3fa)21, an orange
solid, 0.056 g, 66% yield. Mp: 220−221 °C; 1H NMR (400 MHz, DMSO-
d6): δ 9.18 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.61−7.45 (m,
5H), 6.99−6.97 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 159.1, 147.1,
146.6, 143.2, 133.4, 131.5, 130.2, 129.4, 127.7, 124.5, 119.1, 109.7; IR
(thin film) 3112, 2924, 1709, 1591, 1339, 750, 687 cm−1; HRMS (ESI) m/z
calcd for C14H8N3O4 (M−H)− 282.0515, found 282.0527.
(E)-2-Oxo-N-(thiophen-2-yl)indolin-3-imine oxide (3ar), an orange
solid, 0.010 g, 14% yield. Mp: 176−177 °C; 1H NMR (400 MHz, DMSO-
d6): δ 10.84 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 3.2 Hz, 1H),
7.74 (d, J = 4.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.08−7.02 (m, 2H), 6.89
(d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): 160.1, 147.9, 141.3,
135.5, 133.3, 128.6, 126.0, 125.5, 125.1, 122.4, 119.4, 110.3; IR (thin
film) 3467, 3171, 3069, 2921, 1735, 1620, 1203, 974, 754 cm−1; HRMS
(ESI) m/z calcd for C12H9N2O2S (M+H)+ 245.0385, found 245.0379.
(E)-N-(6-Bromo-2-oxoindolin-3-ylidene) aniline oxide (3ga), an
orange solid, 0.021 g, 22% yield. Mp: 231−232 °C; 1H NMR (400 MHz,
DMSO-d6): δ 10.89 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.58−7.49 (m, 5H),
7.27 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ
160.2, 146.8, 142.7, 134.5, 130.9, 129.3, 125.9, 125.2, 125.0, 124.4,
118.2, 113.1; IR (thin film) 3171, 2923, 1698, 1534, 1334, 764, 673 cm−1
;
HRMS (ESI) m/z calcd for
C
14H8BrN2O2 (M−H)− 314.9769, found
314.9781.
(E)-N-(1H-Indol-7-yl)-2-oxoindolin-3-imine (3as), a brown solid, 0.050
g, 60% yield. Mp: 230−231 °C;1H NMR (400 MHz, DMSO-d6): δ 11.45 (s,
1H), 10.69 (s, 1H), 8.31(d, J = 7.6 Hz, 1H), 7.77 (s, 1H), 7.49−7.45 (m,
2H), 7.39 (t, J = 7.6 Hz, 1H), 7.27−7.25 (m, 1H), 7.07(t, J = 7.2 Hz, 1H),
6.89 (d, J = 7.6 Hz, 1H), 6.55 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ
160.6, 141.1, 139.7, 136.9, 134.4, 132.3, 127.8, 127.1, 124.4, 122.2,
119.5, 117.8, 116.6, 111.7, 110.1, 102.9; IR (thin film) 3072, 2958, 1699,
1530, 1344, 1201, 740, 651 cm−1; HRMS (ESI) m/z calcd for C16H12N3O2
(M+H)+ 278.0930, found 278.0949.
(E)-N-(7-Fluoro-2-oxoindolin-3-ylidene) aniline oxide (3ha), an orange
solid, 0.068 g, 88% yield. Mp: 218−219 °C; 1H NMR (400 MHz, DMSO-
d6): δ 11.27 (s, 1H), 8.12 (d, J = 7.5 Hz, 1H), 7.59−7.50 (m, 5H), 7.35 (t, J
= 9.0 Hz, 1H), 7.10−7.06 (m, 1H); 13C NMR (125 MHz, DMSO-d6): δ
160.3, 147.5 (d, J = 241.4 Hz), 146.8, 134.8 (d, J = 4.6 Hz), 130.9, 129.3,
128.3 (d, J = 13.6 Hz), 124.5, 123.3 (d, J = 6.4 Hz), 121.8 (d, J = 4.6 Hz),
120.8 (d, J = 2.8 Hz), 119.6 (d, J = 13.9 Hz); IR (thin film) 3159, 2927,
1704, 1527, 1216, 764, 680 cm−1; HRMS (ESI) m/z calcd for C14H8FN2O2
(M−H)− 255.0570, found 255.0581.
(E)-N-(5-Methoxy-2-oxoindolin-3-ylidene)aniline oxide (3ba), an
orange solid, 0.076 g, 95% yield. Mp: 224−225 °C; 1H NMR (500 MHz,
DMSO–d6): δ 10.56 (s, 1H), 7.90 (s, 1H), 7.54−7.51 (m, 5H), 7.01−6.99
(m, 1H), 6.82 (d, J = 7.5 Hz, 1H), 3.76 (s, 3H); 13C NMR (125 MHz,
DMSO–d6): δ 160.5, 155.0, 146.9, 135.4, 135.3, 130.7, 129.3, 124.5,
(E)-N-(2-Oxo-7-(trifluoromethyl)indolin-3-ylidene) aniline oxide (3ia),
an orange solid, 0.090 g, 98% yield. Mp: 216−217 °C; 1H NMR (400 MHz,
DMSO-d6): δ 11.22 (s, 1H), 8.56 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.0 Hz,
1H), 7.62−7.51 (m, 5H), 7.26 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701324
European Journal of Organic Chemistry
FULL PAPER
DMSO-d6): δ 160.8, 146.9, 138.4 (q, J = 2.2 Hz), 133.8, 131.0, 129.4,
128.4 (q, J = 4.3 Hz), 127.8, 125.2 (q, J = 257.6 Hz), 124.5, 122.4, 120.7,
111.4 (q, J = 32.8 Hz); IR (thin film) 3201, 2927, 1710, 1529, 1321, 1118,
685 cm−1; HRMS (ESI) m/z calcd for C15H8F3N2O2 (M−H)− 305.0538,
found 305.0550.
(E)-2-phenyl-3H-indol-3-one O-phenyl oxime (3ra), an orange solid,
0.011 g, 16% yield. Mp: 62−63 °C; 1H NMR (400 MHz, CDCl3): δ
8.37−8.35 (m, 2H), 8.27 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H),
7.52−7.48 (m, 4H), 7.46−7.42 (m, 4H), 7.33 (t, J = 7.6 Hz, 1H), 7.20−7.19
(m, 1H); 13C NMR (125 MHz, CDCl3): δ 166.1, 159.2, 155.9, 155.3, 133.0,
132.2, 131.1, 129.8, 129.6, 128.5, 128.1, 127.4, 124.1, 122.0, 121.2,
115.0; IR (thin film) 2945, 1658, 1591, 1488, 1335, 960, 751, 672 cm−1
;
(E)-N-(4-Fluoro-2-oxoindolin-3-ylidene) aniline oxide (3ja), a yellow
solid, 0.046 g, 60% yield. Mp: 168−169 °C; 1H NMR (400 MHz, DMSO-
d6): δ 10.99 (s, 1H), 7.56−7.48 (m, 5H), 7.42−7.36 (m, 1H), 6.84−6.79 (m,
1H), 6.71 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 160.1,
157.9 (d, J = 257.4 Hz), 147.7, 143.3 (d, J = 7.3 Hz), 134.6 (q, J = 14, 8.0
Hz), 130.9, 129.3, 127.9, 124.6, 110.6 (d, J = 23.3 Hz), 106.9 (d, J = 2.9
Hz), 106.1 (d, J = 18.2 Hz); IR (thin film) 3203, 1718, 1629.5, 1594, 1327,
1233, 770, 662 cm−1; HRMS (ESI) m/z calcd for C14H8FN2O2 (M−H)−
255.0570, found 255.0578.
HRMS (ESI) m/z calcd for C20H15N2O (M+H)+ 299.1184, found 299.1168.
(E)-N-((E)-1,3-Diphenylallylidene)aniline oxide (3sa)12, a yellow solid,
0.023 g, 38% yield. 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 16.4 Hz,
1H), 7.54 (d, J = 7.2 Hz, 2H), 7.36−7.26 (m, 8H), 7.22−7.17 (m, 5H), 6.73
(d, J = 16.4 Hz, 1H), 13C NMR (125 MHz, CDCl3): δ 149.9, 146.9, 140.8,
136.2, 132.7, 130.8, 129.3, 128.9, 128.7, 128.6, 128.5, 128.3, 127.9,
124.8, 121.9.
(E)-N-(1-Methyl-2-oxoindolin-3-ylidene)aniline oxide (3ka)7, an orange
solid, 0.073 g, 97% yield. Mp: 138−139 °C; 1H NMR (400 MHz, CDCl3): δ
8.48 (d, J = 7.6 Hz, 1H), 7.55−7.41 (m, 6H), 7.17 (t, J = 7.6 Hz, 1H), 6.86
(d, J = 8.0 Hz, 1H), 3.19 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.5,
146.4, 142.1, 134.6, 132.2 130.6, 129.0, 125.1, 123.6, 123.1, 118.0,
(8R,9S,13S,14S,E)-13-methyl-17-oxo-N-(2-oxoindolin-3-ylidene)-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-
cyclopenta[a]vphenanthren-3-amine oxide (3au), an orange solid,
0.100 g, 81% yield. Mp: 226−227 °C; 1H NMR (400 MHz, CDCl3): δ 8.38
(d, J = 7.6 Hz, 1H), 8.01(s, 1H), 7.32−7.25 (m, 2H), 7.21−7.19 (m, 1H),
7.05 (t, J = 7.6 Hz,1H), 6.73 (d, J = 7.6 Hz, 1H), 2.89−2.87 (m, 2H),
2.49−2.42 (m, 1H), 2.37−2.24 (m, 2H), 2.14−2.07 (m, 1H), 2.05−1.90 (m,
3H), 1.60−1.37 (m, 7H), 0.85 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
220.8, 160.5, 144.2, 142.8, 139.2, 137.7, 134.3, 132.1, 125.8, 125.2,
123.9, 123.0, 121.0, 119.1, 109.6, 50.4, 47.9, 44.4, 37.6, 35.8, 31.5, 29.2,
26.1, 25.5, 21.6, 13.8; IR (thin film) 3194, 2926, 2861, 1730, 1458, 1252,
772, 698 cm−1; HRMS (ESI) m/z calcd for C26H27N2O3 (M+H)+ 415.2022,
found 415.2016.
107.9, 26.0; IR (thin film) 3059, 2924, 1694, 1607, 1468, 766, 690 cm−1
;
HRMS (ESI) m/z calcd for C15H11N2O2(M−H)− 251.0826, found 251.0829.
(E)-N-(2-Oxo-1-phenylindolin-3-ylidene)aniline oxide (3la), a yellow
solid, 0.088 g, 94% yield. Mp: 154−155 °C; 1H NMR (400 MHz, CDCl3): δ
8.61 (d, J = 7.6 Hz, 1H), 7.52−7.47 (m, 8H), 7.40−7.36 (m, 4H), 7.22 (t, J
= 7.2 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
158.9, 146.4, 141.9, 134.3, 133.5, 132.1, 130.6, 129.5, 129.0, 128.2,
126.6, 125.2, 123.7, 123.5, 118.2, 109.3; IR (thin film) 3059, 2923, 1702,
1601, 1455, 753, 691 cm−1; HRMS (ESI) m/z calcd for C20H13N2O2
(M−H)− 313.0977, found 313.0988.
Preparation of oxime 1: A mixture of corresponding ketone (10 mmol)
and hydroxylamine hydrochloride (10.6 mmol) in water (25 ml) was
heated to reflux for 30 min. Then sodium acetate (10 mmol) was added in
one portion and the solution was continued to stir for 30 min. The mixture
was cooled down to room temperature. The solid was filtered out and
dried to afford a yellow or white solid oxime 1.
N-(1-Ethoxy-1,3-dioxo-3-phenylpropan-2-ylidene) aniline oxide (3na),
ratio: 5/1; a light yellow solid, 0.069 g, 77% yield. Mp: 48−49 °C; major
isomer: 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 7.2 Hz, 2H), 7.55−7.52
(m, 7H), 7.66 (t, J = 7.2 Hz, 1H), 4.14 (q, J = 14.0, 6.8 Hz, 2H), 1.08 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 187.1, 159.2, 147.2, 136.8,
134.4, 134.4, 131.0, 129.1, 128.7, 123.1, 62.3, 13.7; minor isomer: 1H
NMR (400 MHz, CDCl3): δ 7.80 (d, J = 7.2 Hz, 2H), 7.55−7.52 (m, 7H),
7.30−7.26 (m, 1H), 4.32 (q, J = 14.4, 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 186.5, 160.4, 147.4, 136.3, 134.6, 134.1,
131.2, 128.8, 128.8, 123.6, 62.3, 13.7; IR (thin film) 3062, 2970, 1726,
1673, 1237, 762, 691 cm−1; HRMS (ESI) m/z calcd for C17H14NO4 (M−H)−
296.0923, found 296.0934.
The oxime 1a-o13, 1p23, 1q5, 1r24, and 1s12 were prepared according to
literature methods and their spectral data matched literature values.
(E)-3-(Hydroxyimino)indolin-2-one (1a)5, a yellow solid. 1H NMR (400
MHz, CD3OD): δ 8.03 (d, J = 7.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.07 (t,
J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H). The structure of E-1a was
further confirmed by X-ray diffraction.16
(E)-2-phenyl-3H-indol-3-one oxime (1r)24, a light yellow solid, Mp:
148−149 °C; 1H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 6.8 Hz, 1H), 8.42
(s, 1H), 7.95 (d, J = 6.0 Hz, 2H), 7.67−7.59 (m, 3H), 7.54 (d, J = 6.0 Hz,
2H), 7.23 (d, J = 6.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 165.4, 140.6,
134.3, 133.7, 132.6, 132.2, 129.1, 127.2, 124.2, 121.1, 116.4, 102.2; IR
(thin film) 2966, 1650, 1502, 1486, 1310, 1262, 766, 710 cm−1; HRMS
(ESI) m/z calcd for C14H11N2O (M+H)+ 223.0871, found 223.0858.
N-(1,3-Dimethoxy-1,3-dioxopropan-2-ylidene) aniline oxide (3oa)22, a
light yellow solid, 0.060 g, 84% yield. Mp: 62−63 °C; 1H NMR (400 MHz,
CDCl3): δ 7.46−7.37 (m, 3H), 7.33−7.31 (m, 2H), 3.89 (s, 3H), 3.60 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 160.7, 158.9, 146.9, 132.6, 130.5,
129.0, 122.8, 53.2, 52.9; IR (thin film) 3016, 2958, 1740, 1529, 1434, 784,
691 cm−1; HRMS (ESI) m/z calcd for C11H10NO5 (M−H)− 236.0559, found
236.0567.
(1E,2E)-Chalcone oxime (1s)12, a white solid. 1H NMR (400 MHz,
CDCl3): δ 7.69 (d, J = 16.8 Hz, 1H), 7.54−7.44 (m, 7H), 7.37−7.26 (m,
3H), 6.83 (d, J = 16.4 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 157.6,
139.6, 136.1, 134.7, 129.2, 129.1, 128.7, 128.4, 127.5, 117.1. The
structure of E-1s was further confirmed by X-ray diffraction.17
(E)-3-(Methoxyimino)-1-phenylindolin-2-one (3qa),
a yellow liquid,
0.024 g, 32% yield. 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 7.2 Hz, 1H),
7.55−7.51 (m, 2H), 7.42−7.40 (m, 3H), 7.34−7.30 (t, J = 7.6 Hz, 1H), 7.12
(t, J = 7.6 Hz, 1H), 4.34 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.7,
144.4, 143.4, 133.6, 132.3, 129.7, 128.3, 128.0, 126.5, 123.4, 115.7,
109.7, 64.8; IR (thin film) 3069, 2931, 1733, 1500, 1003, 747, 639 cm−1
HRMS (ESI) m/z calcd for C15H13N2O2 (M+H)+ 253.0977, found 253.0967.
;
(1Z,2E)-Chalcone oxime (1s)12, a white solid. 1H NMR (400 MHz,
CDCl3): δ 7.52−7.46 (m, 3H), 7.40−7.28 (m, 7H), 7.09 (d, J = 16.4 Hz,
1H), 6.50 (d, J = 16.4 Hz, 1H).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701324
European Journal of Organic Chemistry
FULL PAPER
68, 7735; c) Handbook of “Synthetic methods in drug discovery” P. Y. S.
Lam, RSC 2016, 1, 242; d) X.-P. Ma, F.-P. Liu,; D.-L. Mo, Chin. J. Org.
Chem. 2017, 37, 1069.
Acknowledgements
Financial support from the “Overseas 100 Talents Program” of
Guangxi Higher Education, National Natural Science Foundation
of China (21562005, 21602037), State Key Laboratory for
Chemistry and Molecular Engineering of Medicinal Resources,
Ministry of Science and Technology of China (CMEMR2015-
A05), and Natural Science Foundation of Guangxi
(2015GXNSFCA139001, 2016GXNSFFA380005) are greatly
appreciated.
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Keywords: copper-catalyzed cross-coupling • isatin oxime •
nitrone • aryl broronic acid • N-arylation
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Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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Cambridge
Crystallographic
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10.1002/ejoc.201701324
European Journal of Organic Chemistry
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Coupling Reaction*
O
HO
Ar
N
O
N
H
Me
Ar B(OH)2
N
O
Xue-Ling Mo,[†] Chun-Hua Chen,[†] Cui
Liang, and Dong-Liang Mo*
H
Cu(OAc)2 (10%)
pyridine, DCE, rt, air
O
R
O
R
N
H
H
N
O
H
N
H
25 exmaples
14-98% yields
(E)-isomer
81% yield
Page No. – Page No.
Copper-Catalyzed Carbonyl Group
Controlled Coupling of Isatin Oximes
with Arylboronic Acids to Prepare N-
Aryl Oxindole Nitrones
An efficient carbonyl group controlled strategy was developed to prepare E-N-aryl
isatin ketonitrones in good to excellent yields from copper-catalyzed coupling
reaction of isatin oximes and arylboronic acids under mild conditions.
*Coupling reaction
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