Polymer-supported copper complex for the direct synthesis of O-aryloxime ethers via cross-coupling of oximes and arylboronic acids

Article abstract of DOI:10.1016/j.catcom.2009.12.012

L-proline functionalized chloroacetylated polystyrene supported copper (II) complex was prepared and found to be effective for the cross-coupling reaction between aromatic oximes and arylboronic acids under mild conditions. Only catalytic amount of cataly

Full text of DOI:10.1016/j.catcom.2009.12.012

Catalysis Communications 11 (2010) 532–536
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Polymer-supported copper complex for the direct synthesis of O-aryloxime
ethers via cross-coupling of oximes and arylboronic acids
*
Liang Wang, Chengyan Huang, Chun Cai
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2009
Received in revised form 7 December 2009
Accepted 10 December 2009
Available online 13 December 2009
L-proline functionalized chloroacetylated polystyrene supported copper (II) complex was prepared and
found to be effective for the cross-coupling reaction between aromatic oximes and arylboronic acids
under mild conditions. Only catalytic amount of catalyst was required and no deoximation occurred.
The catalyst could be recovered by simple filtration and reused several times without significant loss
of activity.
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Polymer-supported copper catalyst
O-aryloxime ether
Arylboronic acid
Cross-coupling
1. Introduction
This novel methodology is characterized by the mild conditions
(room temperature, weak base, in air) and also a series of new sub-
O-aryloxime ethers derivatives are attractive synthetic targets
due to their considerable potential application in medicinal and
bioorganic chemistry [1,2]. For example, some have been reported
as inhibitors of protein chaperone Hsp90 [1]; some others show
good neuroleptic activities [2]. Also, they are very important pre-
cursors of benzofuran derivatives, which possess a broad range of
biological activities [3–5] (Fig. 1).
Known synthetic methods for preparation of O-aryloxime
ethers involved the reaction of oximes with fluorobenzene deriva-
tives [3], aryl nitrates [4] and diazonium salts [5], while these pro-
cedures lacked generality. Recently, Kelly and co-workers reported
that O-aryloxime ethers could be prepared from aryloxyamines
and aldehydes/ketones [6]. Although the yields were satisfactory,
long synthetic steps were required. An alternative method re-
ported by Maitra and co-workers was via cross-coupling between
oximes and haloarenes, however, it was subjected to deoximation
and loss of the metal catalyst at the end of the reaction [7].
Copper-promoted C–N and C–O coupling reactions of NH/OH-
containing substrates with arylboronic acids have emerged as a
powerful synthetic methodology since their initial reports [8–13].
strates have been well documented [14–20]. Recently, Meyer and
co-workers found oximes could undergo such transformation med-
iated by Cu(OAc)2 [21], however, stoichiometric quantity of
Cu(OAc)2 was required and the metal catalyst could not be recov-
ered after reaction.
Great efforts in catalysis research have been devoted in recent
years to the introduction and application of effective and safe het-
erogeneous catalysts [22]. The utilization of polymer-supported
catalyst offers several advantages in preparative procedures. Such
catalysts are as active as their homogeneous counterparts while
having the distinguishing characteristics of being easily separable
from the reaction media, recyclability, enhanced stability, easier
handling, non-toxicity and lower cost [23].
Amino acids functionalized Merrifield resin was demonstrated
to be good support for immobilization of copper (II) complex
[24,25]. However, the preparation of Merrifield resin was problem-
atic with respect to the utilization of carcinogenic chloromethyl
methyl ether, polysubstitution and secondary crosslinking.
Advancement was achieved by Elman and Moberg [26], who pre-
pared chloroacetylated polystyrene resin, with the same function
as Merrifield resin, whereas the preparation process was more
green and the structure was more simple. Also, the chloroacetyl
group was stable and unhydrolyzable. Liu and co-workers opti-
mized the reaction conditions for the preparation of chloroacety-
lated polystyrene and controlled the loading capacity of the
chloroacetyl group, making it applicable for industry processes
[27]. However, such a new polymer has not received enough atten-
Abbreviations: ICP, inductively coupled plasma; TGA, thermogravimetry analy-
sis; TLC, thin layer chromatography; Cu(OAc)2, copper (II) acetate; TEBA, benzyl-
triethylammonium bromide; DCE, 1,2-dichloroethane; DBU, 1,8-diazabicyclo
[5.4.0]undec-7-ene; DMSO, N,N-dimethyl sulfoxide; THF, tetrahydrofuran.
* Corresponding author. Tel.: +86 25 84315514; fax: +86 25 84315030.
E-mail address: c.cai@mail.njust.edu.cn (C. Cai).
1566-7367/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2009.12.012

L. Wang et al. / Catalysis Communications 11 (2010) 532–536
533
water and methanol, dried at 80 °C under vacuum overnight. Ele-
mental analysis for nitrogen after ligand attachment gave values
of 3.5%, which corresponds to 2.5 mmol of L-proline anchored
per gram of resin.
2.3. Preparation of polymer-supported copper catalyst
The functionalized beads (1.0 g) were kept in contact with eth-
anol (10 mL) for 1 h. To this was added an ethanolic solution
(15 mL) of Cu(OAc)2 (0.455 g, 2.5 mmol) containing 0.4 mL acetic
acid and the mixture was stirred at room temperature for 8 days.
Then the dark brown beads were filtered, washed thoroughly with
water, acetone and methanol, dried at 90 °C under vacuum for 6 h.
Fig. 1. O-aryloxime ethers derivatives and as precursors for benzofuran derivatives.
tion, and most polymer modification processes still rest on the
Merrifield resin.
So, as a part of our program aiming at the development of novel
functionalized polymer-supported catalysts, we sought to develop
a supported copper complex, as a heterogeneous catalytic system,
that can be benefit from lower costs, lower metal contamination
and the improved workup procedures. Here we reported the prep-
aration of amino acid functionalized chloroacetylated polystyrene
and the supported copper catalyst, and also illustrated its applica-
tion in the cross-coupling reactions between aromatic oximes and
arylboronic acid under mild conditions (Scheme 1).
2.4. Typical procedure cross-coupling reaction and recycling of catalyst
A 25 mL round-bottomed flask was charged with an oxime
(0.5 mmol), supported copper catalyst (47 mg, 1.08 mmol/g,
0.05 mmol), arylboronic acid (1 mmol), base (1.5 mmol) and DCE
(3 mL). The reaction mixture was agitated vigorously under air or
oxygen and monitored by TLC. After 48 h, the reaction mixture
was diluted with DCE (10 mL) and catalyst was filtrated, which
was washed with MeOH and dried for next cycle. The combined or-
ganic filtrates were concentrated and loaded onto a samplet for
flash chromatography on silica gel. All the products were charac-
terized and compared with authentic compounds previously
reported.
2. Experimental
2.1. General remarks
All of the reagents and solvents were commercially available
and were used without further purification. Melting points were
determined with a WRS-1B apparatus and were uncorrected. IR
spectra were recorded in KBr disks with a Bomem MB154S FT-IR
spectrometer. Elemental analysis was performed on a Yanagimoto
MT3CHN recorder. 1H NMR and 13C NMR were recorded on a Bru-
ker AdvanceRX300 analyzer. Copper content was measured by
inductively coupled plasma (ICP) on a Varian AA240 analyzer.
Thermogravimetric analysis was carried out on a Shimadzu DT-
30 instrument at a heating rate of 20 °C minÀ1 under an atmo-
sphere of nitrogen. All the products were known compounds and
were identified by comparing of their physical and spectra data
with those reported in the literature.
3. Results and discussion
The supported catalyst was readily accessible in two steps from
chloroacetylated polystyrene. Treatment of the polymer with L-
proline provided the corresponding amino acid functionalized
polystyrene, which was then treated with Cu (OAc)2 in ethanol to
yield the catalyst as brown beads (Scheme 2). Characterization of
the catalyst was performed by IR, elemental analysis, TGA and
ICP analysis (see Supplementary material). The representative IR
peaks at 3440, 1668, 1647, 1450 and 1082 cmÀ1 indicated the suc-
cessful attachment of L-proline on to the resin. The thermal studies
(TGA) showed that the support was stable up to 130 °C, while the
catalyst was even more stable, with a decomposition temperature
being higher than 150 °C. The copper content of the catalyst was
1.08 mmol/g determined by ICP analysis.
2.2. Preparation of L-proline grafted chloroacetylated polystyrenes
The investigation was initiated by exploring the cross-coupling
of acetophenone oxime 1 and phenylboronic acid 2 under standard
conditions according to the literature [9]. We were pleased to find
Pre-washed chloroacetylated polystyrene beads (1.0 g)
(4.1 mmol Cl) were swollen in 30 mL 1,2-dichloroethane for 12 h,
then 10 mmol L-proline, 0.2 g TEBA, 10 mL 25% sodium hydroxide
solution were added subsequently, and the mixture was stirred for
8 h at 90 °C. After cooling to room temperature, the pH was ad-
justed to 5.0 with 5% HCl solution and the color of the beads chan-
ged to yellow. The beads were filtered and washed thoroughly with
Scheme 1. Polymer-supported copper complex catalyze the synthesis of O-
aryloxime ethers from oximes and arylboronic acids.
Scheme 2. Preparation of polymer-supported copper complex.

534
L. Wang et al. / Catalysis Communications 11 (2010) 532–536
that the reaction furnished the desired O-phenylacetophenone
oxime 3 in 35% yield under the following conditions: catalyst
(0.1 equiv), 2 (2 equiv), Et3N (3.0 equiv), air, in 1,2-dichloroethane
(DCE), room temperature and 48 h (Table 1, entry 1). Encouraged
by the good result, we started to screen the reaction conditions
by varying the reaction atmosphere, bases, solvents and catalyst
loadings. The results were summarized in Table 1.
DCE was optimal compared with toluene, DMSO, MeOH and THF
(Table 1, entries 10–13). Temperature was also important for the
reaction. Upon heating the mixture to 50 °C, the yield increased
to 70%, however, it did not give better yield when the reaction
was conducted under reflux conditions (Table 1, entries 14 and
15). We also tried other reaction systems such as DMSO/KOH
and toluene/Na2CO3. Although better result (69% yield) was ob-
tained in DMSO/KOH system, only 25% yield was obtained in the
second run (Table 1, entry 17). This is maybe due to the loss of
the copper in such harsh conditions. Finally, different catalyst load-
ings were evaluated and it was found that 10 mol% of catalyst was
sufficient to promote the conversion (Table 1, entries 18–20).
Next, the reusability of our supported catalyst was investigated
(Table 1, entry 14). The catalyst was recycled five times to give
yields of 70%, 68%, 65%, 63% and 60%. This showed that the catalyst
retained activity through recycling. Control experiments were car-
ried out to confirm whether the reaction was promoted by sup-
ported catalyst or the copper leached to the solution. After
suspending the supported copper catalyst in DCE overnight fol-
lowed by filtration off the catalyst, the cross-coupling reaction of
acetophenone oxime and phenylboronic acid was performed in
the same solvent. No conversion was detected after 48 h indicated
by TLC (Table 1, entry 21), showing that the reaction was indeed
promoted by the supported copper catalyst. Also comparison
experiment using homogeneous Cu(OAc)2/L-proline system was
performed (Table 1, entry 22). It was obvious that our system
It was reported that stoichiometric quantities of Cu(OAc)2 were
required in the copper-mediated coupling reactions of NH/OH-con-
taining substrates with arylboronic acids. Recently, important dis-
coveries by Collman [28], Lam [29] and Buchwald [30]
demonstrated that such transformations could be catalyzed by cat-
alytic amount of Cu(OAc)2 when a variety of oxidants were em-
ployed. In this reaction, we also compared the influence of
different reaction atmosphere on the reaction. It was found that
better yield (49%) was obtained when the reaction was conducted
under oxygen, which improved the efficient oxidation of reduced
copper intermediate [10]. The choice of base was important for
the reaction. Thus, several organic and inorganic bases were inves-
tigated. The results indicated that pyridine was found to be the
best base, maybe due to its dual role in the reaction [13]. Using
either 1 equiv or 5 equiv of pyridine resulted in the diminished
yields (Table 1, entries 4 and 5). Et3N and DBU were less effective
than pyridine. Inorganic bases, such as Na2CO3, KOH and NaH,
however, gave quite low yields of the corresponding products. Dif-
ferent solvents were evaluated next. The results suggested that
Table 1
Optimize the reaction conditionsa.
OH
B(OH)2
N
O
N
+
3
1
2
Entry
Catalyst (equiv)
Solvent
Base
Temperature (°C)
Yield (%)b
1
2
3
4
5
6
7
8
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
–
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Et3N
Et3N
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
35c
49
Pyridine
Pyridine
Pyridine
DBU
Na2CO3
KOH
52
31d
28e
35
Trace
Trace
18
Trace
27
9
DCE
NaH
10
11
12
13
14
15
16
17
18
19
20
21
22
Toluene
DMSO
MeOH
THF
DCE
DCE
Toluene
DMSO
DCE
DCE
DCE
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Na2CO3
KOH
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
21
12
rt
50
Reflux
Reflux
100
50
50
50
50
50
70,68,65,63, 60f
68
39
69, 25f
0
0.05
0.2
0.1
0.1
21
67
DCE
DCE
0g
71h
a
b
C
d
e
f
Reaction conditions: acetophenone oxime (0.5 mmol), phenylboronic acid (1 mmol), base (1.5 mmol), solvent (3 mL), oxygen ball and 48 h.
Isolated yield.
Under air.
1 equiv base was used.
5 equiv base was used.
Recycle experiment.
Comparison experiment.
Homogeneous Cu(OAc)2/L-proline system.
g
h

L. Wang et al. / Catalysis Communications 11 (2010) 532–536
535
Table 2
Table 3
Cross-coupling of acetophenone oxime derivatives and with phenylboronic acids
Cross-coupling of acetophenone oxime with arylboronic acids catalyzed by supported
catalyzed by supported copper complexa.
copper complexa.
OH
OH
O
O
N
B(OH)2
B(OH)2
N
N
N
R2
+
+
R1
R1
R
Entry Oxime
1
Product
Yield
(%)b
Entry
1
Arylboronic acid
Product
Yield (%)b
73
B(OH)2
70
65
60
OH
O
Cl
N
O
N
N
Cl
B(OH)2
2
3
OH
OH
2
75
O
N
N
N
O
NO2
N
O
NO2
N
3
4
54
19
B(OH)2
O
OMe
N
Cl
Cl
4
59
64
OH
N
O
N
B(OH)2
O
MeO
N
MeO
5
OH
N
O
N
5
6
7
10
54
57
Cl
B(OH)2
Cl
O2N
O2N
O
N
a
Reaction conditions: oxime (0.5 mmol), phenylboronic acid (1 mmol), pyridine
(1.5 mmol), DCE (3 mL), catalyst (0.05 mmol), oxygen ball, 50 °C and 48 h.
b
Isolated yield.
B(OH)2
was comparable with the homogeneous system and was more
advantageous in terms of easy purification, reusability of the cata-
lyst as well as environmentally friendly process.
O
N
With the optimal conditions in hand, we subjected a series of
acetophenone oxime derivatives bearing both electron-withdraw-
ing and electron-donating substituents to the copper-catalyzed
cross-coupling with phenylboronic acid to explore the generality
and scope of the process. As shown in Table 2, we were pleased
to find that this methodology was applicable to a broad substrate
scope. No significant electronic effects were observed for both elec-
tron-rich and electron-poor oximes, and all the acetophenone
oxime derivatives gave the corresponding products in satisfactory
yields (Table 2, entries 1–5).
B(OH)2
Cl
O
N
Cl
a
Reaction conditions: acetophenone oxime (0.5 mmol), arylboronic acid
The scope of the reaction with respect to arylboronic acids was
then investigated (Table 3). In contrast to the acetophenone oxime
derivatives, thearylboronicacidsbearingdifferentsubstituentsgave
different situation. Arylboronic acids bearing electron-withdrawing
groups such as nitro group and halogen were more active than phen-
ylboronic acid and better yields, 73% and 75% respectively, were
obtained (Table 3, entries 1 and 2). 4-Methylphenylboronic acid,
however, was less efficient and 54% yield was obtained. Steric effects
were also observed. The meta-substituted and para-substituted
(1 mmol), pyridine (1.5 mmol), DCE (3 mL), catalyst (0.05 mmol), oxygen ball, 50 °C
and 48 h.
b
Isolated yield.
arylboronic acids afforded the corresponding products in moderate
yields, while more steric ortho-substituted arylboronic acids, such
as 2-methylphenylboronic acid and 2-chlorophenylboronic acid

536
L. Wang et al. / Catalysis Communications 11 (2010) 532–536
Table 4
4. Conclusion
Cross-coupling of aldoximes and other ketoximes with phenylboronic acids catalyzed
by supported copper complexa.
In summary, a polymer-supported copper-catalyzed cross-cou-
pling of ketoximes and aldoximes with arylboronic acids under
mild reaction conditions have been developed. This methodology
offered a direct way to construct O-aryloxime ether motifs in mod-
erate to good yields using catalytic amount of catalyst. The scope of
the both oximes and arylboronic acids were investigated and a
variety of substrates could participate in the process. The poly-
mer-supported catalysis system not only could avoid deoximation
effectively, but also was expected to contribute to the development
of benign chemical process.
Entry Oxime
1
Product
Yield (%)b
40
OH
H
N
O
H
N
2
46
38
OH
H
N
O
H
N
Acknowledgment
MeO
MeO
We gratefully thank Nature and Science Foundation of Jiangsu
Province (BK2007592) for financial support.
3
OH
N
O
N
H
Appendix A. Supplementary material
H
Cl
Cl
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.catcom.2009.12.012.
4
65
55
OH
N
O
N
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were less active and gave the products in poor yields (19 and 10%,
respectively) (Table 3, entries 4 and 5).
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oxylbenzaldoxime, 4-chlorobenzaldoxime were also investigated
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were less efficient than ketoximes. Other ketoximes such as benzo-
phenone oxime and cyclohexanone oxime were also proceeded
smoothly to afford the corresponding oxime ethers in moderate
to good yields.
It should be noted that there was no by-product in our system.
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[7,31]. Hence, additive such as Na, K-tartrate was necessary and
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