Ligand-Free C–C Coupling Reactions Promoted by Hexagonal Boron Nitride-Supported Palladium(II) Catalyst in Water

Article abstract of DOI:10.1002/adsc.201600815

A micron-scale palladium(II) material has been successfully prepared using Schiff base-modified hexagonal boron nitride as a support and used for the first time as an efficient and recyclable catalyst in organic synthesis. The morphology, composition, metal loading and thermal stability of the catalyst were studied using scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), infrared spectroscopy (FT-IR), inductively coupled plasma (ICP) and thermogravimetric (TG) analyses. Then, the micron material was tested in various C–C cross-coupling reactions and exhibited excellent catalytic activities in the Suzuki and Heck reactions. Moreover, the catalyst could be easily recovered by simple filtration and reused at least ten times without significant loss of its catalytic activity. In general, this work demonstrates the possibility of using Schiff-base@hexagonal boron nitride as an efficient support for heterogeneous catalysts. (Figure presented.).

Full text of DOI:10.1002/adsc.201600815

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DOI: 10.1002/adsc.201600815
Ligand-Free C–C Coupling Reactions Promoted by Hexagonal
Boron Nitride-Supported Palladium(II) Catalyst in Water
Xu Cheng,+a Weijian Li,+a Ruifang Nie,a Xiaojun Ma,a Rui Sang,a Li Guo,a,*
and Yong Wua,*
a
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of
Pharmacy, Sichuan University, Chengdu 610041, Peopleꢀs Republic of China
Fax : +(86)-28-8550-3666; e-mail: guoli@scu.edu.cn or wyong@scu.edu.cn
+
These authors contributed equally to this work.
Received: August 7, 2016; Revised: November 18, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600815.
Abstract: A micron-scale palladium(II) material has and exhibited excellent catalytic activities in the
been successfully prepared using Schiff base-modi- Suzuki and Heck reactions. Moreover, the catalyst
fied hexagonal boron nitride as a support and used could be easily recovered by simple filtration and
for the first time as an efficient and recyclable cata- reused at least ten times without significant loss of
lyst in organic synthesis. The morphology, composi- its catalytic activity. In general, this work demon-
tion, metal loading and thermal stability of the cata- strates the possibility of using Schiff-base@hexagonal
lyst were studied using scanning electron microscopy boron nitride as an efficient support for heterogene-
(SEM), X-ray photoelectron spectroscopy (XPS), X- ous catalysts.
ray diffraction (XRD), infrared spectroscopy (FT-
IR), inductively coupled plasma (ICP) and thermo- Keywords: C–C cross-coupling; heterogeneous catal-
ACHTUNGTRENNUNG
Introduction
and sensitive to oxygen and water.[4] Moreover, the
preparations of most reported ligands seem rather la-
Transition metals and their complexes play a dominant borious and time consuming. Therefore, designing
role in catalyzing various common transformations, a more efficient, stable and recoverable ligand-free
namely, C–C cross-coupling and carbon-heteroatom heterogeneous palladium catalyst for C–C cross-cou-
bond formation, oxidation, reduction and reductive pling reactions is of great interest.
amination reactions, thus enabling the synthesis of or-
Hexagonal boron nitride (h-BN) has recently re-
ganic building blocks, natural products,[1] pharmaceut- ceived increasing attention due to its excellent me-
icals, and agrochemicals.[2] Palladium-catalyzed cross- chanical strength, chemical inertness, and thermal
coupling reactions are some of the most powerful conductivity.[5] In many ways, it resembles graphite,
methods for the creation of new carbon-carbon bonds featuring stacked sheets with the component atoms
due to their high selectivities, functional group toler- arranged in a honeycomb pattern; the boron/nitrogen
ances and regio-stereoselectivities.[3] Due to the high pair is isoelectric to the carbon pair in graphite. In ad-
cost of Pd, as well as the environmental and safety dition, both materials are good thermal conductors.
issues, the development of reusable, highly active het- Unlike graphite, however, h-BN forms wide band gap
erogeneous Pd catalysts is crucial for industrial appli- semiconductors that do not absorb visible light and
cations of these coupling reactions since homogene- are, therefore, sometimes referred as “white graph-
ous Pd-based catalysts are often difficult to recover ite”.[6] Another distinctive property of BN sheets in
and reuse. In addition, although C–C cross-coupling comparison to graphite is the high thermal stability
reactions catalyzed by palladium-phosphine systems and chemical inertness:[7] graphite undergoes combus-
have achieved great success over the last decade, tion upon heating in the presence of oxygen. More-
phosphine ligands are expensive, toxic, unrecoverable over, experiments have suggested that h-BN may out-
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perform graphite in applications such as field emitters, with aminopropyl(trimethoxy)silane (APTMS) to syn-
far ultraviolet light-emitting diodes, and polymer thesize amino-functionalized boron nitride. Third, sal-
matrix nanocomposites operated in extreme environ- icylaldehyde was attached to h-BN@APTMS via the
ments.[8–10] Therefore, it is of great interest to further acetic acid-promoted condensation reaction. Ulti-
explore the potential of h-BN in more complex struc- mately, the complexation of Pd(OAc)2 onto the Schiff
tures.
On the other hand, the development of green
base generated the heterogeneous Pd(II) catalyst.
The synthesized micron catalyst was characterized
chemistry through organic reactions conducted in using several different microscopic and spectroscopic
water has become one of the most exciting research techniques, including FT-IR, SEM, TGA, ICP, XRD
endeavors in organic synthesis.[11] Water is the most and XPS analyses.
ubiquitous solvent in biological systems. It is abun-
Scanning electron microscopy (SEM) has been used
dant, non-toxic, non-flammable, and environmentally to shed light on the presence, distribution, and dimen-
benign and is sometimes regarded as the solvent of sions of the prepared hybrid micron materials. As
nature.[12] It also has unique physical and chemical shown in Figure 1a and b, no obvious morphology dif-
properties, such as amphiphilicity and hydrogen bond- ference has been found between h-BN and h-
ing capability, and can influence the reactivity of BN@OH. They all exhibit schistose structures with
chemicals and the selectivity of reactions.[13] Despite smooth edges and flat surfaces. In addition, the size
the limited aqueous solubility of organic reactants, of the palladium(II)-loaded micron catalyst is in the
water has been widely used as a solvent in organic re- range of 50–500 nm. Notably, after functionalization,
actions, such as pericyclic reactions, multicomponent the h-BN micron sheets are still arranged in schistose
reactions, the Wittig reaction, and olefin metathesis.[12] structures but appear to be broken and aggregated
The study of aqueous heterogeneous reactions has (Figure 1c–e). The broken BN sheets could be attrib-
become active again since the report of a number of uted to the strong base, high temperature and vigo-
“on water” reactions by Sharpless and co-workers.[14]
The introduction of metal nanoparticles onto pris-
rous stirring during the preparation process.
Infrared spectroscopy was used to characterize the
tine h-BN has been widely reported during the past organic components bound to the h-BN surface
À
few years, and their applications in organic synthesis (Figure 2). The characteristic absorption bands of B
have also been investigated.[15] However, these cata- N bonds were observed at 1395 cmÀ1 and 799 cmÀ1
lysts often show broad size distributions and, in many (Figure 2a and b), which were slightly shifted to
cases, suffer from severe leaching phenomena. This is 1391 cmÀ1 and 806 cmÀ1 after conjugation with
probably due to the lack of sufficient binding sites on APTMS (Figure 2a vs. c). In addition, all the function-
the pristine h-BN surface, where only weak non-cova- alized h-BN showed a strong band at approximately
lent interactions exist between the pristine BN and 3420 cmÀ1, which was attributed to the stretching vi-
À
the metal nanoparticles. Moreover, despite several brations of O H bonds (Figure 2b–e). Comparison
studies on the morphology, properties and prepara- studies on h-BN@OH and h-BN@APTMS revealed
tion of organic-modified h-BN,[16] no metal has been that the additional strong bands at 1120 and
immobilized onto functionalized boron nitride as 1033 cmÀ1 may correspond to the characteristic ab-
À
a heterogeneous catalyst. In this paper, we report the sorption of Si O bonds formed through the silylation
production of Pd catalysts based on Schiff base-modi- process. In addition, another h-BN@APTMS peak at
fied h-BN, as a separable and recyclable catalyst for 2928 cmÀ1 could be assigned to the stretching vibra-
À
Suzuki and Heck coupling reactions. All these reac- tion of C H bonds of propylamine groups (Figure 2c).
tions showed high efficiencies and excellent yields Unfortunately, the stretching vibrations of C=N
when performed in ligand-free conditions in water. To bands, near 1625 cmÀ1,[17] were concealed under the
À
the best of our knowledge, this is the first report on broad absorption peak of the B N bonds. However,
immobilizing palladium(II) on BN for catalytic pur- the condensation of h-BN@APTMS with salicylalde-
poses, and the first use of a BN-based heterogeneous hyde can be confirmed by TGA and XPS (Figure 3
catalyst for C–C coupling reactions.
and Figure 5a).
For the quantitative analysis, the pristine h-BN, h-
BN@OH, h-BN@APTMS, h-BN@Sal and h-
BN@Sal@Pd(OAc)2 were further observed via TGA,
and these results are shown in Figure 3. The experi-
Results and Discussion
As shown in Scheme 1, to immobilize the Pd(II) onto ments were performed at up to 6508C in an N2 atmos-
the Schiff base-functionalized hexagonal boron ni- phere at a heating rate of 108CminÀ1. Under these
tride, a four-step process was introduced. First, pris- conditions, a weight loss of approximately 1.58% was
tine h-BN was treated with hydroxide anions, result- observed for h-BN@OH, which could be ascribed to
ing in the formation of free hydroxy groups on the the removal of physically adsorbed solvents and sur-
edges of the BN sheets. Second, h-BN@OH reacted face hydroxy groups. Likewise, weight losses of ap-
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Scheme 1. The synthetic strategy for the synthesis of h-BN@Sal@Pd(OAc)2.
proximately 3.28% and 5.24% were observed for h- five samples show the same diffraction peaks at 2q=
BN@APTMS and h-BN@Sal, respectively. These 26.7, 41.6, 43.9, 50.1 and 55.1, which correspond to the
should be due to the thermal degradation of organic (002), (100), (101), (102) and (004) lattice planes of
components on the BN complex. Moreover, a weight a typical hexagonal boron nitride structure (JCPDS
loss of approximately 1.96% was observed when com- no. 34-0421), which suggests that the crystal structure
paring these two samples, which suggests that salicyl- of the h-BN has not been compromised by the reac-
ACHTUNGTRENNUNGaldehyde was successfully conjugated to the h- tion. In addition, in the process of the coordination
BN@APTMS particles. For the curve of h- between the h-BN@Sal and palladium ions, the for-
BN@Sal@Pd(OAc)2, the first step in the curve is asso- mation of Pd nanoparticles was completely avoided.
ciated with the loss of water molecules (below No characteristic peaks of palladium particles were
2008C). The second weight loss starting at 2008C dis- found in the XRD pattern of h-BN@Sal@Pd(OAc)2,
integrates the supported organic parts with a calculat- which implies that all of the catalytic activity is attrib-
ed loss of 5.8%. The amount of palladium (1.8%) on uted to divalent palladium. Moreover, no peaks corre-
h-BN@Sal@Pd(OAc)2 was determined by inductively sponding to any other impurity were observed.
coupled plasma (ICP) analysis. The TGA curve and
Detailed surface information about the pristine h-
atomic absorption analysis also confirmed the success- BN, h-BN@OH, h-BN@APTMS, h-BN@Sal and h-
ful supporting of Pd(OAc)2 onto the functionalized h- BN@Sal@Pd(OAc)2 was collected using X-ray photo-
BN. In all, these results further corroborate the FT-IR electron spectroscopy (XPS), and the corresponding
data.
results are presented in Figure 5. The new peaks of O
Figure 4 shows the wide angle XRD patterns of 1s, C 1s and Si 2p seen in Figure 5a indicated that (3-
pristine h-BN, h-BN@OH, h-BN@APTMS, h-BN@Sal aminopropyl)trimethoxysilane (APTMS) had been
and h-BN@Sal@Pd(OAc)2 micron materials. These successfully attached to the edges of the pristine BN
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Figure 1. SEM of (a) pristine h-BN, (b) h-BN@OH, (c) h-BN@APTMS, (d) h-BN@Sal and (e) h-BN@Sal@Pd(OAc)2.
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Figure 2. FT-IR spectra of (a) pristine h-BN, (b) h-BN@OH, (c) h-BN@APTMS, (d) h-BN@Sal and (e) h-BN@Sal@P-
d(OAc)2.
particles. In addition, the spectrum of the h-BN@Sal B–OH peak resulted from the introduction of a hy-
showed a large increase in the signal intensity of the droxy group by the base treatment. To provide clearer
O 1s and C 1s peaks. This could be attributed to the evidence of chemical bonding between the BN parti-
covalent attachment of salicylaldehyde to the h- cles and the silane curing agent, the Si 2p peak can be
BN@APTMS (Figure 5a).
fitted by a curve with several component peaks (Fig-
The B 1s spectra of h-BN@Sal@Pd(OAc)2 showed ure 5c). In the deconvoluted Si 2p spectra, the strong
À
a strong binding energy peak for the B N bond and peak at 102.1 eV binding energy represented the
a weak binding energy peak for the B–OH bond at bond between silicon and oxygen originating from the
190.1 eV and 192.0 eV, respectively (Figure 5b).[18] The BN particles (B–O–Si), indicating that the surface
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Figure 3. TGA thermograms of pristine h-BN, h-BN@OH,
h-BN@APTMS, h-BN@Sal and h-BN@Sal@Pd(OAc)2.
Figure 4. XRD patterns of pristine h-BN, h-BN@OH, h-
BN@APTMS, h-BN@Sal and h-BN@Sal@Pd(OAc)2.
Figure 5. Full range XPS spectra of pristine h-BN, h-BN@OH, h-BN@APTMS, h-BN@Sal and h-BN@Sal@Pd(OAc)2 (a),
and the B 1s (b), Si 2p (c), and Pd 3d (d) core level region XPS spectra of the h-BN@Sal@Pd(OAc)2 micron composite.
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Table 1. Optimization of the Suzuki reaction between 4-bro-
moacetophenone and phenylboronic acid using h-
BN@Sal@Pd(OAc)2 as a catalyst.[a]
curing agent and BN particles were connected
through the hydroxy groups. The peak at 103.3 eV is
attributed to siloxane (Si–O–Si) resulting from the
partial hydrolysis of the silane curing agent molecules
during the silanization reaction. Moreover, the peak
À
at 100.8 eV could be attributed to Si C bonding in
the silane curing agent molecules. These results are in
agreement with the reaction mechanism of silane, in-
cluding the hydrolysis of OCH3, condensation to olig-
omers, hydrogen bonds between oligomer and hy-
droxy groups on the substrate and the formation of
the covalent linkage between the silane and the sub-
strate. The peak at 102.5 eV thus might be attributed
to Si–OH bonding, indicating that some hydroxy
groups were not hydrolyzed and a small number of
hydroxy groups remained.[19]
The XPS spectrum of the Pd 3d core level region
for the h-BN@Sal@Pd(OAc)2 micron composite dis-
played main peaks at 338.2 and 343.4 eV, which could
be attributed to the binding energy of Pd 3d5/2 and Pd
3d3/2, respectively (Figure 5d). These values corre-
spond to the Pd(II) binding energies of Pd(OAc)2.
Entry Base
Pd (equiv.) Temp. [oC] Yield[b] [%]
1
Cs2CO3
0.05
0.05
0.05
0.05
0.05
70
70
70
70
70
70
70
70
70
25
50
100
70
70
70
89
85
90
99
70
75
70
90
97
21
73
67
81
98
96
2
KOH
3
4
5
t-BuOK
K2CO3
Et3N
6
NaHCO3 0.05
7[c]
8[d]
9[e]
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0.05
0.05
0.05
0.05
0.05
0.05
0.01
0.1
Cross-coupling reactions, such as the Suzuki and 10
11
12
13
14
15
Heck reactions, are powerful tools for the preparation
of natural products, advanced materials and biologi-
cally active compounds. Therefore, h-BN@Sal@P-
d(OAc)2 was primarily used as a novel heterogeneous
and highly reusable micron catalyst in the Suzuki re-
action. For this purpose, the coupling of 4-bromoace-
tophenone (1a) with phenylboronic acid (2a) was se-
lected as a simple model reaction to optimize the re-
action conditions, and the results are summarized in
Table 1. First, a range of bases, such as Cs2CO3, KOH,
t-BuOK, K2CO3, Et3N and NaHCO3, were used in
this transformation. However, all of them were unsat-
isfactory except for K2CO3 (Table 1, entries 1–6).
0.2
[a]
Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), h-
BN@Sal@Pd(OAc)2 (0.05 mmol), base (1.5 mmol), H2O
(1 mL), argon, 0.5 h.
Isolated yield.
K2CO3 (0.5 mmol).
[b]
[c]
[d]
[e]
K2CO3 (1.0 mmol).
K2CO3 (2.0 mmol).
With respect to the amount of K2CO3, 1.5 equivalents electron-withdrawing functional groups were success-
were found to be adequate, as neither larger nor fully converted to the corresponding biphenyls in
smaller amounts showed better yields (Table 1, en- good to excellent yields. In addition, synthetically
tries 7–9). When the reaction was allowed to proceed useful naphthyl and pyridyl groups were well tolerat-
at different temperatures, an optimal yield of 99% ed in this transformation, giving 3k and 3q in good
was obtained at 708C (Table 1, entries 4, 10–12). For yields. Furthermore, the experimental procedure is
the optimization of the amount of Pd used in the very simple and convenient and has the ability to tol-
model reaction, less than 0.05 equivalents led to the erate a variety of different functional groups, such as
incomplete reaction (Table 1, entry 13). In addition, OH, OCH3, CN, CHO, NO2, NH2 and halogens.
up to 0.1 or 0.2 equiv. of Pd did not increase the yield
To extend the catalytic applications of h-
of 6a significantly (Table 1, entries 14 and 15). Above BN@Sal@Pd(OAc)2, it was then applied for another
all, for reactions with aryl halides (1, 1 mmol) and C-C cross coupling reaction, namely, the Heck reac-
phenylboronic acids (2, 1.5 mmol), a catalytic amount tion. At the beginning of our investigation, experi-
of h-BN@Sal@Pd(OAc)2 (0.05 mmol) and K2CO3 ments were carried out using iodobenzene (4a) and
(1.5 mmol) in water at 708C were considered to be styrene (5a) as the model substrates. Among the vari-
the ideal reaction conditions.
After optimization of the reaction conditions, choice, while others, such as Cs2CO3, KOH, t-BuOK,
we examined the catalytic activity of Et3N and NaHCO3, were less effective (Table 2, en-
ous bases examined, K2CO3 turned out to be the best
h-BN@Sal@Pd(OAc)2 for various aryl halides and tries 1–6). For the optimization of the amount of
phenylboronic acids. As shown in Figure 6, all the K2CO3 used in the model reaction, two equivalents
substrates including those with electron-donating or were found to be adequate, as neither larger nor
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Figure 6. Investigation of the substrate scope for the Suzuki reaction catalyzed by h-BN@Sal@Pd(OAc)2. Reaction condi-
tions: 1 (1 mmol), 2 (1.5 mmol), h-BN@Sal@ Pd(OAc)2 (0.05 mmol) and K2CO3 (1.5 mmol) in water (1 mL) at 708C.
Figure 7. Investigation of the substrate scope for the Heck reaction catalyzed by h-BN@Sal@Pd(OAc)2. Reaction conditions:
4 (1 mmol), 5 (1.5 mmol), h-BN@Sal@ Pd(OAc)2 (0.05 mmol) and K2CO3 (2 mmol) in water (1 mL) at 908C.
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Table 2. Optimization of the Heck reaction between iodo-
benzene and styrene using h-BN@Sal@Pd(OAc)2 as a cata-
lyst.[a]
ing groups or electron-withdrawing groups was well
tolerated during the course of the reaction, providing
the desired compounds 6b–h in good to excellent
yields. In addition to stilbenes, the acrylate derivatives
6i, j and 6l–p could also be obtained in excellent
yields. Notably, synthetically useful heterocyclic
groups, such as thienyl (6p), were well tolerated in
this transformation. Furthermore, a variety of func-
tional groups, such as carbonyl, ether, halogen, amino,
nitro and aldehyde groups, was well suited for this re-
action.
Entry Base
Pd (equiv.) Temp. [oC] Yield[b] [%]
For practical applications of catalytic systems, the
lifetime of the catalyst and its level of reusability are
significant factors. To clarify this issue, the feasibility
of recycling the Pd catalyst was then examined. After
the reaction, the catalyst was simply separated by fil-
tration and successively washed with water, dichloro-
methane and acetone. In addition, in the recycling ex-
periments, the recovered dry catalyst was recharged
with fresh substrate for the next run under the same
reaction conditions. h-BN@Sal@Pd(OAc)2 has been
reused ten times in the reaction of 4-bromoacetophe-
none and phenylboronic acid without significant loss
of its catalytic activity (Figure 8a). In addition, the
amount of palladium in h-BN@Sal@Pd(OAc)2 was
measured to be 1.71% after recycling ten times. Simi-
larly, the catalyst also remained catalytically active
after being reused eleven times in the reaction of 1-
iodo-2-nitrobenzene and methyl acrylate. The Heck
reaction on the 10th and 11th runs gave the desired
product in 90% and 89% yields (Figure 8b). Thus, it is
reasonable to believe that the immobilized catalyst
can be repeatedly used for large-scale production
without a significant loss of its catalytic activity.
1
2
3
4
5
6
Cs2CO3
KOH
t-BuOK
K2CO3
Et3N
0.05
0.05
0.05
0.05
0.05
90
90
90
90
90
90
90
90
90
50
70
100
90
90
90
63
85
84
92
73
87
21
74
91
26
73
82
37
51
91
NaHCO3 0.05
7[c]
8[d]
9[e]
10
11
12
13
14
15
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0.05
0.05
0.05
0.05
0.05
0.05
0.01
0.02
0.1
[a]
Reaction conditions: 4a (1 mmol), 5a (1.5 mmol), h-
BN@Sal@Pd(OAc)2 (0.05 mmol), base (2 mmol), H2O
(1 mL), 3.5 h.
Isolated yield.
K2CO3 (0.5 mmol).
K2CO3 (1.0 mmol).
K2CO3 (3.0 mmol).
[b]
[c]
[d]
[e]
In addition, after h-BN@Sal@Pd(OAc)2 had been
smaller amounts showed better yields (Table 2, en- reused ten times in the Suzuki reaction, it was charac-
tries 7–9). Further investigation indicated that temper- terized by SEM, FT-IR, TGA, XRD and XPS analysis
ature was important for this transformation. An excel- (Figure 9). The reused catalyst has similar morpholo-
lent yield was obtained when the reaction was carried
out at 908C (Table 2, entry 4). However, with the
temperature increasing to 1008C, the yield of 6a drop-
ped to 82% (Table 2, entry 12). Only 26% and 73%
yields of 6a were obtained when the reactions were
conducted at 50 and 708C (Table 2, entries 10 and
11). Moreover, after extensive screenings, we were
pleased to find that 0.05 mmol of Pd was enough to
catalyze this reaction (Table 2, entries 4, 13–15).
Therefore, as observed in this study, the optimized
conditions for the synthesis of 6a proved to be
iodobenzene
(1 mmol),
styrene
(1.5 mmol),
h-BN@Sal@Pd(OAc)2 (0.05 mmol) and K2CO3
(2.0 mmol) in water at 908C.
To further define the scope of this new catalyst for
the Heck reaction, wide ranges of aryl halides, styr-
enes and acrylates were reacted under the optimized
conditions. The results are summarized in Figure 7. A
Figure 8. Reusability of h-BN@Sal@Pd(OAc)2 for the syn-
host of aryl halides bearing either the electron-donat- thesis of 3a (a) and 6o (b).
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Figure 9. SEM image (a), FT-IR spectrum (b) and TGA thermogram (c) of the recycled h-BN@Sal@Pd(OAc)2; XRD pat-
terns of h-BN@Sal@Pd(OAc)2 and the recycled h-BN@Sal@Pd(OAc)2 (d); Full range XPS spectra (e) and the Pd 3d core
level region XPS spectrum of the recycled h-BN@Sal@Pd(OAc)2 (f).
gy and infrared data as the fresh one, indicating that BN@Sal@Pd(OAc)2 (Figure 9d). In addition, XPS
there is relatively no change in structure after the cat- analysis of the recycled catalyst shows the existence
alyst has been recycled ten times (Figure 9a and b). of the 3d3/2 and 3d5/2 peaks for Pd(0) species next to
Notably, the characteristic peaks of Pd(0) can be the peaks of Pd(II) at lower binding energies (see Fig-
found in the XRD patterns of the recycled h- ure 9f), indicating the reduction of some Pd(II) spe-
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cies to Pd(0) during the coupling reactions. As far as For example, Zhu et al. reported that compound 6q
we know, organic amines, such as ethidenediamine, showed strong antifungal activity by altering the per-
could be used as a reducing agent for the preparation meability of fungal cell membranes.[21] In addition, the
of metal nanoparticles. Therefore, the reducing agent good antibacterial activity of compound 6r had been
of Pd(II) might be the exposed APTMS on h-BN.
reported by Davis and co-workers.[22] These two com-
The synthesis of pharmacologically interesting com- pounds can be easily obtained in 93% and 91% yields
pounds is one of the most important applications of via h-BN@Sal@Pd(OAc)2-catalyzed Heck reactions.
C–C coupling reactions. In addition, the impressive
À
ability of Pd catalysts to create C C bonds provides
many new avenues for designing medicinal candi- Conclusions
dates. Inspired by its high efficiency, excellent
recyclability and wide scope of substrates, In summary, a novel, efficient and recoverable cata-
h-BN@Sal@Pd(OAc)2 was utilized in the synthesis of lyst was synthesized by immobilizing the Pd(II) com-
pharmacologically important products through Suzuki plex on h-BN using a Schiff base. This material
and Heck reactions (Scheme 2).
showed excellent catalytic activity for the Suzuki and
Heck C–C cross-coupling reactions. With the aid of
the new catalyst, the reactions can now occur in
ligand-free conditions in water with good to excellent
yields. Using this catalyst, the synthesis of a series of
pharmacologically relevant products was also dis-
cussed. This demonstrates the potential applications
of organic-modified-h-BN supported catalysts in
“green chemistry” in the future.
Experimental Section
General
The h-BN powder (99.9%) was obtained from Micxy
Regent Co. Ltd. (Chengdu, China). (3-Aminopropyl)trime-
thoxysilane (APTMS, 97%) was purchased from Aladdin
Reagent Co. Ltd. (Shanghai, China). Sodium hydroxide
(NaOH, 96%) was collected from Tianjin Ruijinte Chemi-
cals Co. Ltd. (Tianjin, China). Salicylaldehyde (99.0%) was
provided by Chengdu Kelong Chemicals Co. Ltd. (Chengdu,
China). Palladium(II) acetate [Pd(OAc)2, 99.0%] was sup-
plied by Xian Catalyst Chemicals Co. Ltd. (Xian, China).
All other materials were commercially available and used
without further purification. Thin layer chromatography
(TLC) characterization was performed with precoated silica
gel GF254 plates (0.2 mm), while column chromatography
characterization was performed with silica gel (100–200
Scheme 2. Pharmacologically relevant compounds synthe-
sized using h-BN@Sal@Pd(OAc)2 as the catalyst.
1
Felbinac 3u, a non-steroidal anti-inflammatory drug
(NSAID), was first launched in 1993 by Takeda and
Wyeth Pharmaceuticals (now Pfizer) for the treat-
mesh). H NMR spectra were recorded at 400 or 600 MHz
and 13C NMR spectra were recorded at 100 MHz. Fourier
transform infrared (FT-IR) spectra were performed on
ment of rheumatic and mild arthritic pain, sprains, a Nicolet 6700 FI-IR spectrometer (Nicolet) using KBr pel-
strains and other soft-tissue injuries.[20] Felbinac acts
lets. X-ray photoelectron spectroscopy (XPS) measurements
DLD
were carried out on an AXIS Ultra
spectrometer
as a non-selective inhibitor of the enzyme cyclooxyge-
nase (COX) and inhibits both cyclooxygenase-
1 (COX-1) and cyclooxygenase-2 (COX-2) isoen-
zymes. The Suzuki reaction of 4-bromophenylacetic
acid with phenylboronic acid was smoothly conducted
using h-BN@Sal@Pd(OAc)2 as a catalyst under the
optimized conditions, providing Felbinac in 96%
yield. On the other hand, diverse derivatives of cin-
(KRATOS). X-ray diffractometer (XRD) spectra were re-
corded with an EMPYREAN spectrometer (Panalytical).
The morphologies of the h-BN catalysts were observed
using scanning electron microscopy (SEM, JSM-7500F).
Thermal gravitational analysis (TGA) was performed with
a thermal analyzer (TGA/DSC2, METTLER TOLEDO) at
rate of 108CminÀ1 under N2 protection. The loading content
of Pd was determined by inductively coupled plasma optical
namic acid possess various pharmacological activities. emission spectroscopy (ICP-OES, SPECTRO ARCOS).
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Preparation of the Catalyst
Acknowledgements
Preparation of hydroxyl-functionalized h-BN (h-BN@OH):
First, h-BN (4 g) was dispersed in 5M sodium hydroxide so-
lution (500 mL) at 1208C for 24 h. Then, the particles were
filtered and washed with deionized water (3ꢂ150 mL) to
adjust the pH from basic to neutral. Finally, the obtained
white solid (3.50 g) was dried under reduced pressure at
808C for 6 h and stored in a desiccator at room tempera-
ture.
We are grateful for support from the National Natural Sci-
ence Foundation of China (NSFC) (grant numbers 81373259
& 81573286).
References
Preparation
of
amino-functionalized
h-BN
(h-
BN@APTMS): The h-BN@OH particles (3 g) were dis-
persed in dry toluene (120 mL) and stirred at 258C for 20
[1] K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem.
2005, 117, 4516; Angew. Chem. Int. Ed. 2005, 44, 4442.
[2] a) J. A. Baur, D. A. Sinclair, Nat. Rev. Drug Discovery
2006, 5, 493; b) C. Torborg, M. Beller, Adv. Synth.
Catal. 2009, 351, 3027.
[3] a) R. F. Heck, Palladium reagents in organic synthesis,
Academic Press, 1990; b) X. F. Wu, P. Anbarasan, H.
Neumann, M. Beller, Angew. Chem. 2010, 122, 9231;
Angew. Chem. Int. Ed. 2010, 49, 9047.
min.
Then,
1.6 mL
(3-aminopropyl)trimethoxysilane
(APTMS) was added dropwise to the resulting solution. In
addition, the mixture was stirred for 24 h at 1208C under
argon protection. The resulting particles (h-BN@APTMS)
were filtered and washed several times with toluene. Finally,
the obtained white solid (3.05 g) was dried under reduced
pressure at 808C for 6 h.
Preparation of h-BN@Sal@Pd(OAc)2: First, the prepared
h-BN@APTMS particles (400 mg) were dispersed in 40 mL
absolute ethanol. Then, salicylaldehyde (240.6 mg,
1.97 mmol) and three drops of acetic acid were added to the
suspension. After refluxing for 5 h, a pale yellow solid was
obtained by filtering the mixture and washing with methanol
3 times. Next, the particles were mixed with Pd(OAc)2
(292 mg, 1.3 mmol) in DCM (50 mL) and stirred for 24 h
under argon protection at room temperature. The resulting
mixture was filtered and washed with DCM 5 times to
remove unreacted Pd(OAc)2. A gray-green solid (348 mg)
was obtained by drying in a vacuum desiccator at room tem-
perature for 5 h.
[4] M. B. Gawande, R. V. Jayaram, Catal. Commun. 2006,
7, 931.
[5] a) D. Golberg, Y. Bando, Y. Huang, T. Terao, M.
Mitome, C. Tang, C. Zhi, ACS Nano 2010, 4, 2979;
b) M. Corso, W. Auwrter, M. Muntwiler, A. Tamai, T.
Greber, J. Osterwalder, Science 2004, 303, 217; c) L. Ci,
L. Song, C. Jin, D. Jariwala, D. Wu, Y. Li, A. Srivasta-
va, Z. F. Wang, K. Storr, L. Balicas, F. Liu, P. M.
Ajayan, Nat. Mater. 2010, 9, 430; d) Y. Lin, T. V. Wil-
liams, J. W. Connell, J. Phys. Chem. Lett. 2010, 1, 277.
[6] A. Pakdel, X. Wang, Y. Bando, D. Golberg, Acta
Mater. 2013, 61, 1266.
[7] a) Y. Lin, J. W. Connell, Nanoscale 2012, 4, 6908; b) C.
Zhi, Y. Bando, C. Tang, H. Kuwahara, D. Golberg,
Adv. Mater. 2009, 21, 2889.
[8] a) C. Zhi, Y. Bando, C. Tang, H. Kuwahara, D. Gol-
berg, Adv. Mater. 2009, 21, 2889; b) Y. Wang, Z. Shi, J.
Yin, J. Mater. Chem. 2011, 21, 11371.
[9] a) D. Pacile, J. C. Meyer, C. O. Girit, A. Zettl, Appl.
Phys. Lett. 2008, 92, 133107; b) A. Nag, K. Raidongia,
K. P. S. S. Hembram, R. Datta, U. V. Waghmare,
C. N. R. Rao, ACS Nano 2010, 4, 1539.
[10] a) L. Song, L. Ci, H. Lu, P. B. Sorokin, C. Jin, J. Ni,
A. G. Kvashnin, D. G. Kvashnin, J. Lou, B. I. Yakobson,
P. M. Ajayan, Nano Lett. 2010, 10, 3209; b) J. Yu, X.
Huang, C. Wu, X. Wu, G. Wang, P. Jiang, Polymer
2012, 53, 471; c) X. Xu, B. Sun, P. R. Berman, D. G.
Steel, A. S. Bracker, D. Gammon, L. J. Sham, Science
2007, 317, 929.
General Procedure for the Suzuki Reaction
In a typical run, h-BN@Sal@Pd(OAc)2 (0.05 mmol) was
added to a mixture of arylboronic acid 1 (1.0 mmol), aryl
bromide 2 (1.5 mmol) and K2CO3 (1.5 mmol) in water
(1 mL). The resulting mixture was stirred at 708C, and the
progress of the reaction was monitored by TLC. After com-
pletion of the reaction, ethyl acetate was added to the reac-
tion mixture and the catalyst was separated. The organic
phase was washed with water and dried over anhydrous
Na2SO4, and the solvent was evaporated under reduced
pressure. Finally, the residue was isolated by chromatogra-
phy on a column of silica gel to afford the corresponding
product 3.
[11] a) L. Bai, J. X. Wang, Y. Zhang, Green Chem. 2003, 5,
615; b) M. Nuchter, B. Ondruschka, W. Bonrath, A.
Gum, Green Chem. 2004, 6, 128; c) V. Pironti, S. Colon-
na, Green Chem. 2005, 7, 43; d) N. E. Leadbeater,
Chem. Commun. 2005, 41, 2881.
[12] a) C. J. Cramer, D. G. Truhlar, Structure and Reactivity
in Aqueous Solution, American Chemical Society,
Washington, 1994; b) M. B. Gawande, V. D. B. Bonifa-
cio, R. Luque, P. S. Branco, R. S. Varma, Chem. Soc.
Rev. 2013, 42, 5522; c) M. O. Simon, C. J. Li, Chem.
Soc. Rev. 2012, 41, 1415; d) R. N. Butler, A. G. Coyne,
Chem. Rev. 2010, 110, 6302; e) U. M. Lindstrom, Chem.
Rev. 2002, 102, 2751; f) C. J. Li, Chem. Rev. 1993, 93,
2023.
General Procedure for the Heck Reaction
A mixture of aryl halide 4 (1.0 mmol), substituted alkene 5
(1.5 mmol), K2CO3 (2.0 mmol) and h-BN@Sal@Pd(OAc)2
(0.05 mmol) was stirred in water at 908C (progress of the re-
action was monitored using TLC). After completion of the
reaction, the mixture was cooled to room temperature, and
then, the catalyst was separated and washed with ethyl ace-
tate three times. Then, the filtrate was diluted with water
and extracted with ethyl acetate. The organic layer was
dried over anhydrous sodium sulfate, and the solvent was re-
moved under vacuum. Finally, the crude residue was puri-
fied by flash chromatography on silica gel to give the final
product 6.
Adv. Synth. Catal. 0000, 000, 0 – 0
12
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ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
[13] a) Y. Hayashi, Angew. Chem. 2006, 118, 8281; Angew.
Chem. Int. Ed. 2006, 45, 8103; b) U. M. Lindstrom,
Chem. Rev. 2002, 102, 2751; c) T. Head-Gordon, G.
Hura, Chem. Rev. 2002, 102, 2651; d) M. C. Bellissent-
Funnel, J. C. Dore, Hydrogen Bond Networks, Kluwer
Academic Publishers, Boston, 1994; e) F. H. Stillinger,
Science 1980, 209, 451.
[14] a) S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin,
H. C. Kolb, K. B. Sharpless, Angew. Chem. 2005, 117,
3339; Angew. Chem. Int. Ed. 2005, 44, 3275; b) J. E.
Klijn, J. B. F. N. Engberts, Nature 2005, 435, 746; c) R.
Breslow, Acc. Chem. Res. 2004, 37, 471; d) S. Mellouli,
L. Bousekkine, A. B. Theberge, W. T. S. Huck, Angew.
Chem. 2012, 124, 8105; Angew. Chem. Int. Ed. 2012, 51,
7981; e) M. Sengoden, T. Punniyamurthy, Angew.
Chem. 2013, 125, 600; Angew. Chem. Int. Ed. 2013, 52,
572; f) J.-S. Yu, Y.-L. Liu, J. Tang, X. Wang, J. Zhou,
Angew. Chem. 2014, 126, 9666; Angew. Chem. Int. Ed.
2014, 53, 9512; g) A. Chanda, V. V. Fokin, Chem. Rev.
2009, 109, 725.
[16] a) R. Kumar, K. Gopalakrishnan, I. Ahmad, C. N. R.
Rao, Adv. Funct. Mater. 2015, 25, 5910; b) H. C. Wu,
M. R. Kessler, ACS Appl. Mater. Interfaces 2015, 7,
5915; c) T. Sainsbury, A. Satti, P. May, A. OꢀNeill, V.
Nicolosi, Y. K. Gun’ko, J. N. Coleman, Chem. Eur. J.
2012, 18, 10808; d) Z. H. Cui, A. J. Oyer, A. J. Glover,
H. C. Schniepp, D. H. Adamson, Small 2014, 10, 2352;
e) K. H. Oh, D. Lee, M. J. Choo, K. H. Park, S. Jeon,
S. H. Hong, J. K. Park, J. W. Choi, ACS Appl. Mater. In-
terfaces 2014, 6, 7751; f) Z. H. Cui, A. P. Martinezb,
D. H. Adamson, Nanoscale 2015, 7, 10193; g) N. Yang,
C. Xu, J. Hou, Y. M. Yao, Q. X. Zhang, M. E. Grami,
L. Q. He, N. Y. Wang, X. W. Qu, RSC Adv. 2016, 6,
18279; h) W. W. Lei, V. N. Mochalin, D. Liu, S. Qin, Y.
Gogotsi, Y. Chen, Nat. Commun. 2015, 6, 8849.
[17] Q. S. Zhao, C. Bai, W. F. Zhang, Y. Li, G. L. Zhang,
F. B. Zhang, X. B. Fan, Ind. Eng. Chem. Res. 2014, 53,
4232.
[18] K. Kim, M. Kim, Y. Hwang, J. Kim, Ceram. Int. 2014,
40, 2047.
[15] a) Y. Yabe, T. Yamada, S. Nagata, Y. Sawama, Y. Mon-
guchi, H. Sajiki, Adv. Synth. Catal. 2012, 354, 1264;
b) Y. Yabe, Y. Sawama, Y. Monguchi, H. Sajiki, Chem.
Eur. J. 2013, 19, 484; c) K. Uosaki, G. Elumalai, H. No-
guchi, T. Masuda, A. Lyalin, A. Nakayama, T. Taketsu-
gu, J. Am. Chem. Soc. 2014, 136, 6542; d) Y. Yabe, Y.
Sawama, T. Yamada, S. Nagata, Y. Monguchi, H. Sajiki,
ChemCatChem 2013, 5, 2360; e) L. Meyer, M. Devil-
lers, S. Hermans, Catal. Today 2015, 241, 200; f) N.
Meyer, K. Bekaert, D. Pirson, M. Devillers, S. Her-
mans, Catal. Commun. 2012, 29, 170.
[19] a) S. Contarini, S. P. Howlett, C. Rizzo, B. A. DeAnge-
lis, Appl. Surf. Sci. 1991, 51, 177; b) K. Fujita, A. Oya,
J. Mater. Sci. Technol. 1996, 31, 4609.
[20] J. Prous, J. Castaner, Drugs Future 1987, 12, 120.
[21] J. Zhu, H. Zhu, N. Kobamoto, M. Yasuda, S. Tawata, J.
Pesticide Sci. 2000, 25, 263.
[22] D. C. Davis, H. Mohammad, K. Kyei-Baffour, W.
Younis, C. N. Creemer, M. N. Seleem, M. J. Dai, Eur. J.
Med. Chem. 2015, 101, 384.
Adv. Synth. Catal. 0000, 000, 0 – 0
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14 Ligand-Free C–C Coupling Reactions Promoted by
Hexagonal Boron Nitride-Supported Palladium(II) Catalyst
in Water
Adv. Synth. Catal. 2017, 359, 1 – 14
Xu Cheng, Weijian Li, Ruifang Nie, Xiaojun Ma, Rui Sang,
Li Guo,* Yong Wu*
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