Novel cyclodextrin-modified h-BN@Pd(II) nanomaterial: An efficient and recoverable catalyst for ligand-free C-C cross-coupling reactions in water

Article abstract of DOI:10.1002/aoc.3854

An environmentally friendly palladium(II) catalyst supported on cyclodextrin-modified h-BN was successfully prepared. The catalyst was characterized by FT-IR, SEM, TG, XRD and XPS, and the loading level of Pd in h-BN@β-CD@Pd(II) was measured to be 0.088?mmol g^?1 by ICP. It exhibits excellent catalytic activity for the Suzuki and Heck reactions in water, and can be easily separated and consecutively reused for at least nine times. In addition, a series of pharmacologically interesting products were successfully synthesized using this catalyst to demonstrate its potential applications in pharmaceutical industries. Above all, this work opens up an interesting and attractive avenue for the use of cyclodextrin-functionalized h-BN as an efficient support for hydrophilic heterogeneous catalysts.

Full text of DOI:10.1002/aoc.3854

Received: 9 October 2016
DOI: 10.1002/aoc.3854
Revised: 9 December 2016
Accepted: 26 March 2017
F U L L PA P E R
Novel cyclodextrin‐modified h‐BN@Pd(II) nanomaterial: An
efficient and recoverable catalyst for ligand‐free C‐C
cross‐coupling reactions in water
Xiaojun Ma1 | Guanghui Lv2 | Xu Cheng1 | Weijian Li1 | Rui Sang1 | Yong Zhang1 |
Qiantao Wang1 | Li Hai1 | Yong Wu1
1 Key Laboratory of Drug Targeting and Drug
Delivery System of Education Ministry,
Department of Medicinal Chemistry, West
China School of Pharmacy, Sichuan
University, No. 17, 3rd Section, South
Renmin Road, Chengdu 610041, P. R. China
An environmentally friendly palladium(II) catalyst supported on cyclodextrin‐modi-
fied h‐BN was successfully prepared. The catalyst was characterized by FT‐IR, SEM,
TG, XRD and XPS, and the loading level of Pd in h‐BN@β‐CD@Pd(II) was
measured to be 0.088 mmol g−1 by ICP. It exhibits excellent catalytic activity for
2 Department of Pharmacy, Taihe Hospital,
Hubei University of Medicine, Hubei,
Shiyan, 442000, China
the Suzuki and Heck reactions in water, and can be easily separated and
consecutively reused for at least nine times. In addition, a series of pharmacologically
interesting products were successfully synthesized using this catalyst to demonstrate
its potential applications in pharmaceutical industries. Above all, this work opens up
an interesting and attractive avenue for the use of cyclodextrin‐functionalized
h‐BN as an efficient support for hydrophilic heterogeneous catalysts.
Correspondence
Yong Wu, Key Laboratory of Drug Targeting
and Drug Delivery System of Education
Ministry, Department of Medicinal
Chemistry, West China School of Pharmacy,
Sichuan University, No. 17, 3rd Section,
South Renmin Road, Chengdu
610041 (P. R. China).
KEYWORDS
boron nitride, cross‐coupling reaction, cyclodextrin, heterogeneous catalyst, water
Email: smile@scu.edu.cn;
wyong@scu.edu.cn
Funding information
National Natural Science Foundation of
China (NSFC), Grant/Award Number:
81373259 & 81573286
1 | INTRODUCTION
On the other hand, biphenyls and acrylates constitute a
class of key structural motifs present in numerous
With the rapid development of the modern industry,
environmental concerns are of increasing interests. Further
development of catalytic system has been planned based on
using advanced catalysts that can selectively catalyze the
specific chemical reactions with a high reactivity, and also
can be recycled through the simple separation and regenera-
tion process.[1] Not surprisingly, the use of heterogeneous
catalysts appears to be a promising methodology for the
development of environmentally friendly organic processes,
because of their separability, reusability, as well as their
unique activity that came from the interaction between the
catalytic species and supports.[2]
biologically important compounds, such as nifedipine,
biphenylindanone A, losartan HIV‐1 protease and taxol.[3]
They are also useful for the construction of structurally
important compounds, such as triphenylamino‐1,8‐
naphthalimides,
benzothiadiazole‐cyclopentadithiophene
poly(9,9‐dihexyl)‐fluorene
and
(BTZ‐CDT),[4]
which are widely used in solar cells and electroluminescent
materials.[5] To the best of our knowledge, Suzuki and Heck
cross‐coupling reactions are the most common and powerful
methods to form C‐C bonds in the synthesis of these com-
pounds.[6,7] However, these reactions generally proceeds in
the presence of homogeneous palladium catalyst, of which
Appl Organometal Chem. 2017;e3854.
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https://doi.org/10.1002/aoc.3854

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MA ET AL.
the recycling and separation are complicated and difficult and
may also cause unacceptable palladium contamination of
products. Furthermore, even though palladium‐phosphine
catalyzed Suzuki and Heck reactions have achieved great suc-
cess over the last decade,[8] the expensive, air‐sensitive, and
virulent phosphine ligands often limited their spreading in
large‐scale application. So, it is highly desirable to design a
more efficient, stable and recoverable ligand‐free heteroge-
neous palladium catalyst for C‐C cross coupling reactions.
Boron nitride (BN) is the isoelectric and isostructural
analog to graphite with alternating boron and nitrogen atoms
in the structure.[9–11] Within each layer, boron and nitrogen
are connected by strong covalent bonds, while weaker van
der Waals bonding stablizes the stacked neighbour layers.
Recently, h‐BN has attracted increasing attentions due to its
high intrinsic thermal conductivity, excellent electrical insu-
lation, and low dielectric constant.[12] By utilizing its intrinsic
thermal conductivity, h‐BN was studied as an effective heat
transferring medium between an electrical conductor made
of CNTs/CNFs and an epoxy resin in shape memory polymer
nanocomposites for Joule heating and infrared light induced
shape recovery behaviors.[13,14] Moreover, its strong mechan-
ical and corrosion resistance, high stability against thermal
shock, chemical attacks[15] and oxidation[16–18] make h‐BN
a promising catalyst support for all applications where stabil-
ity is a concern.
In addition, from the viewpoint of green chemistry, it is
preferable to use water to replace toxic organic solvents as
the reaction medium. However, many developed heteroge-
neous catalytic systems suffer from the drawbacks of low cat-
alytic activity and selectivity, and are not suitable for the
reactions in aqueous media as most organic substrates have
poor solubilities in water. These problems can be easily
solved by introducing a water‐soluble material onto the het-
erogeneous catalysts. For instance, β‐cyclodextrin (β‐CD), a
kind of excipients, is such a material. It is composed of seven
glucoside units and contains a hydrophobic internal cavity
capable of hosting a wide range of inorganic and organic
molecules to form the inclusion complexes.[19] This hosting
process has been shown enhanced fluorescence intensity
when β‐CD are bound with various substrates.[20,21] Further-
more, β‐CD is able to stabilize catalytically active nanoparti-
cles via hydrophobic–hydrophobic interactions between
metal nanoparticles and cyclodextrin.[22,23] Based on this
property, combinations of nanomaterials and cyclodextrins
have been successfully employed in the analysis of
environmental pollutants[24–26] and in biosensing
applications.[27,28]
phenomena. This is probably due to the lack of sufficient
binding sites on the surface of pristine h‐BN, where the metal
nanoparticles are bounded only by weak non‐covalent
interactions. On the other hand, despite several studies on
the morphology, properties and preparation of organic modi-
fied h‐BN,[30] no metal has been immobilized onto organic‐
functionalized boron nitride as a heterogeneous catalyst.
Herein, we report the first production of Pd catalyst based
on β‐CD modified h‐BN, as a separable and recyclable cata-
lyst for Suzuki and Heck coupling reactions. All these reac-
tions were performed in water and ligand‐free conditions
with high efficiency and excellent yields. To the best of our
knowledge, this is the first report on the immobilization of
palladium ion on BN for catalytic application purpose. And,
this also is the first time to synthesize a BN‐based heteroge-
neous catalyst for C‐C coupling reactions.
2 | RESULTS AND DISCUSSION
2.1 | Catalyst preparation
As shown in Scheme 1, to immobilize the Pd(II) onto β‐CD‐
functionalized hexagonal boron nitride, a four steps process
was introduced. Firstly, pristine h‐BN was treated with
hydroxide anions, resulting in the formation of free hydroxyl
group on the edge of BN sheets. Secondly, h‐BN@OH
reacted with amino propyl trimethoxy silane (APTMS) to
synthesize amino‐functionalized boron nitride. Thirdly,
β‐cyclodextrin was attached to h‐BN@APTMS via the
carbonyldimidazole (CDI) promoted condensation reaction.
Ultimately, the complexation of Pd(OAc)2 onto β‐CD gener-
ated the heterogeneous Pd(II) catalyst.
2.2 | Catalyst characterization
The synthesized nanocatalyst was characterized using several
different microscopic and spectroscopic techniques including
FT‐IR, SEM, TGA, ICP, XRD and XPS analysis.
Scanning electron microscopy (SEM) has been used in
order to shed light on the presence, distribution, and dimen-
sion of the prepared hybrid nanomaterials. As shown in
Figure 1a‐b, no obvious morphology difference has been
found between h‐BN and h‐BN@OH. They all exhibit schis-
tose structures with smooth edges and flat surfaces. And it
can be clearly seen that the size of palladium(II) loaded
nanocatalyst is in ranges of 50–500 nm. Notably, after
functionalization, the h‐BN nanosheets still arranged in
schistose structures but appeared to be broken and aggregated
(Figure 1c).
The introduction of metal nanoparticles into pristine h‐
BN has been widely reported during the past few years, and
their application in organic synthesis have also been investi-
gated.[29] However, these catalysts often show a broad size
distribution and, in many cases, suffer from severe leaching
Infra‐red spectroscopy was used to characterize the
organic components bound to the surface of h‐BN
(Figure 2). The characteristic absorption band of B‐N bonds
was observed at 1395 cm−1 and 799 cm−1 (Figure 2a), which

MA ET AL.
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SCHEME 1 The synthetic strategy for the synthesis of h‐BN@β‐CD@Pd(OAc)2
was slightly shifted to 1391 cm−1 and 806 cm−1 after conju-
h‐BN@APTMS particles. For the curve of h‐BN@β‐
CD@Pd(OAc)2, the first step in the curve is associated
with the loss of water molecules (below 200 °C). The second
weight loss, starting at 200 °C disintegrates the supported
organic parts with a calculated loss of 4.18%. The amount of
palladium (0.94%) of h‐BN@β‐CD@Pd(OAc)2 was deter-
mined by inductively coupled plasma (ICP) analysis. The
TGA curve and atomic absorption analysis also confirmed
the successful supporting of Pd(OAc)2 onto the functionalized
h‐BN. In all, these results further corroborated the FT‐IR data.
Figure 4 shows the wide angle XRD patterns of h‐
BN@APTMS and h‐BN@β‐CD@Pd(OAc)2 nanomaterials.
These two samples show the same diffraction peaks at
2θ = 26.7, 41.6, 43.9, 50.1 and 55.1, which correspond
to the (002), (100), (101), (102) and (004) lattice planes
of a typical hexagonal boron nitride structure (JCPDS no.
34–0421). It suggests that the crystal structure of the h‐
BN has not been compromised by the reaction. And in
the process of the coordination between the h‐BN@β‐CD
and palladium ions, the formation of Pd nanoparticles was
completely avoided. No characteristic peaks of palladium
particles were found in the XRD pattern of h‐BN@β‐
CD@Pd(OAc)2, which implies that all of the catalytic
activity is attributed to divalent palladium. Moreover, no
peaks corresponding to any other impurity were observed.
Detailed surface information of h‐BN@APTMS and h‐
BN@β‐CD@Pd(OAc)2 was collected by X‐ray photoelectron
spectroscopy (XPS) and the corresponding results are pre-
sented in Figure 5. The new peaks of O 1 s, C 1 s and Si
gating with APTMS (Figure 2a vs b). And all the functional-
ized h‐BN showed a strong band at around 3420 cm−1
,
which was attributed to the stretching vibrations of O‐H bonds
(Figure 2a‐b and d). Comparison studies on h‐BN@OH and h‐
BN@APTMS revealed that the additional strong bands at
1120 and 1033 cm−1 may correspond to the characteristic
absorption of Si‐O bonds formed through the silylation pro-
cess. Besides, another h‐BN@APTMS peak at 2928 cm−1
could be assigned to the stretching vibration of C‐H bonds of
propyl‐amine groups (Figure 2b). Moreover, the spectrum of
β‐CD (Figure 2c) displayed characteristic peaks at 1050 and
927 cm−1 were also observed in spectrum of h‐BN@β‐CD
with little shift (Figure 2d). These results provided direct
evidences of the conjugation of APTMS and β‐CD on h‐BN.
For the quantitative analysis, the as‐prepared h‐BN@OH,
h‐BN@APTMS, h‐BN@β‐CD, and h‐BN@β‐CD@Pd(OAc)2
were further observed via TGA, and these results are shown in
Figure 3. The experiments were performed at up to 800 °C in an
N2 atmosphere at a heating rate of 10 °C min−1. Under these.
conditions, a weight loss of about 1.72% was observed for
h‐BN@OH, it could be ascribed to the removal of physically
adsorbed solvents and surface hydroxyl groups. Likewise, a
weight loss of about 3.66% and 5.64% were observed for
h‐BN@APTMS and h‐BN@β‐CD, respectively. These
should be due to the thermal degradation of organic compo-
nents on the BN complex. Moreover, around 1.98% weight
loss was observed when comparing these two samples. It
suggests that β‐CD was successfully conjugated to

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MA ET AL.
FIGURE 1 SEM of (a) pristine h‐BN, (b) h‐BN@OH and (c)
h‐BN@β‐CD@Pd(OAc)2
2p seen in Figure 5a, indicated that (3‐Aminopropyl)
trimethoxysilane (APTMS) had been successfully attached
to the surface and edges of pristine BN particles. And the
FIGURE 2 FT‐IR spectra of (a) h‐BN@OH, (b) h‐BN@APTMS, (c)
β‐CD, (d) h‐BN@β‐CD

MA ET AL.
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FIGURE 3 TGA thermograms of h‐BN@OH, h‐BN@APTMS,
h‐BN@β‐CD, and h‐BN@β‐CD@ Pd(OAc)2
spectrum of the h‐BN@β‐CD@Pd(OAc)2 showed a large
increase in the signal intensity of the O 1 s and C 1 s peaks.
This could be attributed to covalently attachment of β‐CD to
the h‐BN@APTMS.
The B 1 s spectra of h‐BN@β‐CD@Pd(OAc)2 showed a
strong binding energy peak for the B‐N bond and a weak
binding energy peak for the B‐OH bond at 190.1 eV and
192.0 eV, respectively (Figure 5b).[31] The B‐OH peak
resulted from the introduction of a hydroxyl group by the
base treatment. In order to provide clearer evidence of chem-
ical bonding between the BN particles and the silane curing
agent, the Si 2p peak can be fitted by a curve with several
component peaks (Figure 5c). In the de‐convoluted Si 2p
spectra, the strong peak at 102.1 eV of the binding energy
represented the bond between silicon and oxygen originating
from the BN particles (B‐O‐Si), indicating that the surface
curing agent and BN particles were connected through the
hydroxyl groups. The peak at 103.3 eV is attributed to silox-
ane (Si‐O‐Si) resulting from the partial hydrolysis of the
silane curing agent molecules during the silanization reac-
tion. Moreover, the peak 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
FIGURE 5 Full range XPS spectrum of h‐BN@APTMS and
h‐BN@β‐CD@Pd(OAc)2 (a), and the B 1 s (b), Si 2p (c), Pd 3d (d)
core level region XPS spectra of the h‐BN@β‐CD@Pd(OAc)2
nanocomposite
FIGURE
CD@Pd(OAc)2
4
XRD patterns of h‐BN@APTMS and h‐BN@β‐

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MA ET AL.
silane, including the hydrolysis of ‐OCH3, condensation to
oligomers, hydrogen bonds between oligomer and hydroxyl
groups on the substrate, and the formation of the covalent
linkage between silane and the substrate. The peak at
102.5 eV then might be attributed to the Si‐OH bonding,
indicating that some hydroxyl groups were not hydrolyze
and a small amount of hydroxyl group remained.[32]
The XPS spectrum of the Pd 3d core level region for the
h‐BN@β‐CD@Pd(OAc)2 nanocomposite displayed 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 correspond to the Pd(II) binding
energies of Pd(OAc)2.
reaction 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. And the best yield was obtained in the
presence of K2CO3 (Table 1, entries 1–6). With respect to
the amount of K2CO3, 1.5 equivalents was found to be
adequate, as neither larger nor smaller amount showed better
yields (Table 1, entries 7–9). When the reaction was allowed
to proceed in different temperatures, an optimal yield of
99% was obtained at 70 °C (Table 1, entries 4, 10–12). For
the optimization of the amount of Pd used in the model reac-
tion, less than 0.05 equivalent led to the incompletion of the
reaction (Table 1, entry 13). And up to 0.1 or 0.2 equiv. of
Pd did not increase the yield of 3a significantly (Table 1,
entries 14–15). Above all, aryl halides (1, 1 mmol) in the
presence of a catalytic amount of h‐BN@β‐CD@Pd(OAc)2
(0.05 mmol) and K2CO3 (1.5 mmol) with phenylboronic acids
(2, 1.5 mmol) in water at 70 °C was considered to be the ideal
reaction conditions.
2.3 | Investigation of the catalytic activity of
h‐BN@β‐CD@Pd(OAc)2 in the Suzuki reaction
Cross‐coupling reactions such as Suzuki and Heck reactions
are powerful tools for the preparation of natural products,
advanced materials and biologically active compounds.
Therefore, h‐BN@β‐CD@Pd(OAc)2 was primarily used as
a novel heterogeneous and highly reusable nanocatalyst in
the Suzuki reaction. For this purpose, the coupling of
4‐bromoacetophenone (1a) with phenylboronic acid (2a)
was selected as a simple model reaction to optimize the
After the optimization of the reaction conditions, we
examined the catalytic activity of h‐BN@β‐CD@Pd(OAc)2
for various aryl halides and phenylboronic acids. As shown
in Scheme 2, all the substrates including electron‐donating
or electron‐withdrawing functional groups were successfully
converted to the corresponding biphenyls in good to excellent
TABLE 1 Optimization of the Suzuki reaction between 4‐bromoacetophenone and phenylboronic acid using h‐BN@β‐CD@Pd(OAc)2 as catalysta
Entry
Base
Pd (.Equiv)
Temp. (°C)
Yield b (%)
1
Cs2CO3
KOH
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.01
0.1
70
70
70
70
70
70
70
70
70
25
50
100
70
70
70
81
90
87
99
79
75
76
85
97
37
77
81
75
99
97
2
3
t‐BuOK
K2CO3
Et3N
4
5
6
NaHCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
7c
8d
9e
10
11
12
13
14
15
0.2
aReaction conditions: 1a (1 mmol), 2a (1.5 mmol), h‐BN@β‐CD@Pd(OAc)2 (0.05 mmol), base (1.5 mmol), H2O (1 mL), Ar, 0.5 h. b Isolated yield. c K2CO3 (0.5 mmol).
d K2CO3 (1.0 mmol). e K2CO3 (2.0 mmol)

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TABLE 2 Optimization of the Heck reaction between iodobenzene
and styrene using h‐BN@β‐CD@Pd(OAc)2 as catalysta
Entry
Base
Pd (.Equiv)
Temp. (°C)
Yield b (%)
1
Cs2CO3
KOH
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.01
0.02
0.1
90
90
90
90
90
90
90
90
90
50
70
100
90
90
90
67
83
80
93
72
77
11
70
81
20
67
83
60
75
93
2
3
t‐BuOK
K2CO3
Et3N
4
5
6
NaHCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
7c
8d
9e
10
11
12
13
14
15
SCHEME 2 Investigation of the substrate scope for Suzuki reaction
catalyzed by h‐BN@β‐CD@Pd(OAc)2. Reaction conditions: 1
(1 mmol), 2 (1.5 mmol), h‐BN@β‐CD@Pd(OAc)2 (0.05 mmol) and
K2CO3 (1.5 mmol) in water (1 mL) at 70 °C
aReaction conditions: 4a (1 mmol), 5a (1.5 mmol), h‐BN@β‐CD@Pd(OAc)2
(0.05 mmol), base (2 mmol), H2O (1 ml), 3.5 h. bIsolated yield. cK2CO3
e
(0.5 mmol). dK2CO3 (1.0 mmol). K2CO3 (3.0 mmol)
yields. Besides, synthetically useful naphthyl and pyridyl
were well tolerated in this transformation, giving 3 k and
3q in good yields. Furthermore, the experimental procedure
is very simple and convenient, and can tolerate a variety of
different functional groups such as OH, OCH3, CN, CHO,
NO2, NH2 and halogen.
100 °C, the yield of 6a dropped to 83% (Table 2, entry 12).
Only 20% and 67% yields of 6a were obtained when the reac-
tion were conducted at 50 and 70 °C (Table 2, entries 10–11).
Moreover, after extensive screening, 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 tend
to be: iodobenzene (1 mmol), styrene (1.5 mmol), h‐
BN@β‐CD@Pd(OAc)2 (0.05 mmol) and K2CO3 (2.0 mmol)
in water at 90 °C.
To further define the scope of this new catalyst for the
Heck reaction, a wide range of aryl halides, styrenes and
acrylates were reacted under the optimized conditions. And
the results were summarized in Scheme 3. A host of aryl
halides bearing either the electron‐donating groups or
electron‐withdrawing groups were well tolerated during the
course of the reaction, providing the desired compounds
6b–h in good to excellent yields. Besides, in addition to
stilbenes, the acrylate derivatives 6i–j and 6 l–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
functional groups such as carbonyl, ether, halogen, amino,
nitro and aldehyde groups were well‐suited for this reaction.
2.4 | Investigation of the catalytic activity of
h‐BN@β‐CD@Pd(OAc)2 in the Heck reactions
In order to extend the catalytic applications of h‐BN@β‐
CD@Pd(OAc)2, it was then applied to another C‐C cross
coupling reaction. At the beginning of our investigation,
experiments were carried out using iodobenzene (4a) and
styrene (5a) as the model substrates. Among various bases
examined, K2CO3 turned out to be the best choice, while
others such as Cs2CO3, KOH, t‐BuOK, Et3N and NaHCO3
were less effective (Table 2, entries 1–6). For the optimal
amount of K2CO3 used in the model reaction, two equivalent
was found to be adequate, as neither larger nor smaller
amount showed better yields (Table 2, entries 7–9). Further
investigation indicated that temperature was important for
this transformation. An excellent yield has been obtained
when the reaction was carried out at 90 °C (Table 2, entry
4). However, when the temperature was increased to

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MA ET AL.
and methyl acrylate. The Heck reaction in the 8th and 9th runs
gave the desired product in 90% and 92% yields (Figure 6b).
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.
2.6 | Synthesis of pharmacologically relevant
compounds via Suzuki and Heck reactions
The synthesis of pharmacologically interesting compounds is
one of the most important applications of C‐C coupling reac-
tions.[33] And the impressive ability of Pd catalysts to create
C‐C bonds provides many new avenues for designing medicinal
candidates. Inspired by its high efficiency, excellent recyclabil-
ity and wide scope of substrates, h‐BN@β‐CD@Pd(OAc)2 was
utilized in the synthesis of three pharmacologically important
products through Suzuki and Heck reactions (Figure 7).
Felbinac 3u, a non‐steroidal anti‐inflammatory drug
(NSAID), was first launched in 1993 by Takeda and Wyeth
Pharmaceuticals (now Pfizer) for the treatment of rheumatic
and mild arthritic pain, sprains, strains and other soft tissue
injuries.[34] Felbinac acts as a non‐selective inhibitor of the
enzyme cyclooxygenase (COX), and inhibits both cyclooxy-
genase‐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@β‐CD@Pd(OAc)2 as catalyst under the optimized
conditions, providing Felbinac in 93% yield. On the other
hand, diverse derivatives of cinnamic acid possess various
pharmacological activities. For example, Zhu et al. reported
that compound 6q showed strong antifungal activity by
altering the permeability of fungal cell membrane.[35] And
good antibacterial activity of compound 6r had been
exhibited by Davis and co‐works.[36] These two compounds
can be easily obtained in 97% and 95% yields via h‐BN@β‐
CD@Pd(OAc)2 catalyzed Heck reactions.
SCHEME 3 Investigation of the substrate scope for Heck reaction
catalyzed by h‐BN@β‐CD@Pd(OAc)2. aReaction conditions: 4
(1 mmol), 5 (1.5 mmol), h‐BN@β‐CD@ Pd(OAc)2 (0.05 mmol) and
c
K2CO3 (2 mmol) in water (1 ml) at 90 °C. bR3 = I. R3 = Br. d70 oC
2.5 | Recycling of the catalyst
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 filtration and successively washed with water,
dichlormethane and acetone. And in the recycling experiment,
the recovered dry catalyst was recharged with a fresh substrate
for the next run under the same reaction conditions. h‐BN@β‐
CD@Pd(OAc)2 has been reused thirteen times in the reaction
of 4‐bromoacetophenone and phenylboronic acid without sig-
nificant loss of its catalytic activity (Figure 6a). Similarly, the
catalyst also remained to be catalytically active after being
reused nine times in the reaction of 1‐iodo‐2‐nitrobenzene
2.7 | Large‐scale experiments
Finally, considering the general application of this catalyst,
we demonstrated the gram‐scale progress, and two examples
FIGURE 6 Reusability of h‐BN@β‐CD@Pd(OAc)2 for the synthesis
of 3a (a) and 6o (b)
FIGURE 7 Pharmacologically relevant compounds synthesized by
using h‐BN@β‐CD@Pd(OAc)2 as catalyst

MA ET AL.
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Fourier transform infrared (FT‐IR) spectra were performed
on a Nicolet 6700 FI‐IR spectrometer (Nicolet), using KBr
pellets. X‐ray photoelectron spectroscopy (XPS) measure-
DLD
ments were carried out on AXIS Ultra
spectrometer
(KRATOS). X‐ray diffractometer (XRD) spectra were
recorded with EMPYREAN spectrometer (Panalytical).
The morphologies of h‐BN catalyst were observed by using
scanning electron microscopy (SEM, JSM‐7500F). Thermal
gravitational analysis (TGA) was performed with a thermal
analyzer (TGA/DSC2, METTLER TOLEDO) at rate of
10 °C/min under N2 protection. The loading content of Pd
was determinded by inductively coupled plasma optical
emission spectroscopy (ICP‐OES, SPECTRO ARCOS).
SCHEME 4 Large‐scale reactions
of large‐scale reactions with excellent yields of the products
are shown in Scheme 4.
3 | CONCLUSIONS
4.2 | Preparation of the catalyst
4.2.1 | Preparation of hydroxy functionalised
h‐BN (h‐BN@OH)
In conclusion, we have introduced an efficient and simple
method for the chemical modification of h‐BN, as an excellent
supportfor thePdheterogeneouscatalyst. Ithasbeenusedasan
excellent heterogeneous catalyst in the Suzuki and Heck C‐C
cross coupling reactions. Wide scope of substrates, good to
excellent yields, low reaction time, water as solvent, ligand‐
free, non‐toxicity and recyclability of the catalyst are the main
merits of these protocols. In addition, this nanocatcalyst can
be separated easily by filtration, and can be recycled for at least
nine times without appreciable loss of its catalytic activity. Fur-
therstudies forotherapplications ofthisnovelnanomaterialare
ongoing in our laboratory. We anticipate that this work would
open upa newdirection for the development of novel andgreen
nanocatalysts using organic modified h‐BN as the support.
First, h‐BN (4 g) was dispersed in 5 M sodium hydroxide
solution (500 mL) at 120 °C for 24 h. Then the particles were
filtered and washed with D.I. water (3 x 150 ml) to adjust the
pH from basic to neutral. Finally, the obtained white solid
(3.50 g) was dried under reduced pressure at 80 °C for 6 h,
and stored in a desiccator at room temperature.
4.2.2 | Preparation of amino functionalised
h‐BN (h‐BN@APTMS)
The h‐BN@OH particles (3 g) were dispersed in dry tolu-
ene (120 ml) and stirred at 25 °C for 20 mins. Then, to the
resulting solution, 1.6 ml (3‐Aminopropyl)trimethoxysilane
(APTMS) was added drop wise. And the mixture was
stirred for 24 h at 120 °C under argon protection. The
resulting particles (h‐BN@APTMS) were filtered and
wished several times with toluene. Finally, the obtained
white solid (3.05 g) was dried under reduced pressure at
80 °C for 6 h.
4 | EXPERIMENTAL
4.1 | General
The h‐BN powder (99.9%) was obtained from Micxy Regent
Co. Ltd. (Chengdu, China). (3‐Aminopropyl)trimethoxysilane
(APTMS, 97%), 1,1‐carbonyldiimidazole (CDI, 97%) were
purchased from Aladdin Reagent Co.Ltd. (Shanghai, China).
β‐cyclodextrin (β‐CD, 99.0%), was provided by Chengdu
Kelong Chemicals Co. Ltd. (Chengdu, China). Sodium
hydroxide (NaOH, 96%) was collected from Tianjin Ruijinte
Chemicals Co. Ltd. (Tianjin, China). Palladous acetate
(Pd(OAc)2, 99.0%) was supplied by Xian Catalyst Chemicals
Co. Ltd. (Xian, China). All other materials were commercially
availableandusedwithoutfurtherpurification.Thinlayerchro-
matography (TLC) characterization was performed with
precoated silica gel GF254 (0.2 mm), while column chroma-
tography characterization was performed with silica gel
4.2.3 | Preparation of 1,1‐
carbonyldiimidazole‐β‐cyclodextrin complex
(β‐CD‐CDI)
β‐cyclodextrin (1 g, 0.88 mmol) and 1,1‐carbonyldiimidazole
(1.16 g, 7.14 mmol) were dissolved into 14 mL N,N‐
dimethyl‐formamide (DMF) and stirred with argon protection
at room temperature for 2 h. The solution was then precipi-
tated with cold diethylether and filtered. The resulted white
solid (1.04 g) was rined with acetone for 6 times and dried
with vacuum desiccator at room temperature for 2 h.
1
(100‐200mesh). H NMR spectra were recorded at 400 or
600 MHz and 13C NMR spectra were recorded at 100 MHz.

10 of 11
MA ET AL.
ACKNOWLEDGEMENTS
4.2.4 | Preparation of β‐cyclodextrin
conjugated h‐BN (h‐BN@β‐CD)
We are grateful for support from the National Natural Science
Foundation of China (NSFC) (grant number 81373259 &
81573286).
The prepared h‐BN@APTMS (1 g) was dispersed into dry
DMF (60 ml) and stirred at room temperature for 1.5 h. Next,
β‐CD‐CDI (0.45 g) was added into the above solution. And
the mixture was further stirred in a two‐neck flask with argon
protection at room temperature for 7 h. The resulting particles
(h‐BN@β‐CD) were filtered and successively washed with
DMF and DCM each for 5 times to remove unreacted
chemicals. Finally, the particles (0.99 g) were dried under
vacuum desiccator at room temperature for 6 h.
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SUPPORTING INFORMATION
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the supporting information tab for this article.
How to cite this article: Ma X, Lv G, Cheng X, et al.
Novel cyclodextrin‐modified h‐BN@Pd(II)
nanomaterial: An efficient and recoverable catalyst for
ligand‐free C‐C cross‐coupling reactions in water.
Appl Organometal Chem. 2017;e3854. https://doi.org/
10.1002/aoc.3854
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