Functionalized β-cyclodextrin as supramolecular ligand and their Pd(OAc)2 complex: Highly efficient and reusable catalyst for Mizoroki-Heck cross-coupling reactions in aqueous medium

Article abstract of DOI:10.1016/j.carres.2016.04.024

A novel class of water soluble palladium complexes with recognition abilities based on functionalized β-cyclodextrin has been synthesized. The complex demonstrated high catalytic activity and a supramolecular platform for phosphine-free Mizoroki-Heck cross-coupling reactions in water. The efficient arylation of alkenes was carried out using different iodo- and bromo-arenes with good to excellent yields (up to 96%). The advantages, like recyclability of catalysts, operational simplicity and accessibility in aqueous medium, make this protocol eco-friendly.

Full text of DOI:10.1016/j.carres.2016.04.024

Carbohydrate Research 430 (2016) 85–94
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Functionalized β-cyclodextrin as supramolecular ligand and their
Pd(OAc)
2
complex: highly efficient and reusable catalyst for Mizoroki–
Heck cross-coupling reactions in aqueous medium
Someshwar D. Dindulkar , Daham Jeong , Hwanhee Kim , Seunho Jung a,b,*
a
b
b
a
Institute for Ubiquitous Information Technology and Applications (UBITA) & Center for Biotechnology Research in UBITA (CBRU), Konkuk University, Seoul
1
43-701, South Korea
b
Department of Bioscience and Biotechnology, Microbial Carbohydrate Resource Bank (MCRB), Konkuk University, Seoul 143-701, South Korea
A R T I C L E
I N F O
A B S T R A C T
Article history:
A novel class of water soluble palladium complexes with recognition abilities based on functionalized
β-cyclodextrin has been synthesized. The complex demonstrated high catalytic activity and a supramo-
lecular platform for phosphine-free Mizoroki–Heck cross-coupling reactions in water. The efficient arylation
of alkenes was carried out using different iodo- and bromo-arenes with good to excellent yields (up to
Received 5 November 2015
Received in revised form 8 April 2016
Accepted 25 April 2016
Available online 29 April 2016
96%). The advantages, like recyclability of catalysts, operational simplicity and accessibility in aqueous
medium, make this protocol eco-friendly.
Keywords:
©
2016 Elsevier Ltd. All rights reserved.
β-cyclodextrin
Supramolecular catalyst
Mizoroki–Heck coupling
Reusable catalyst
Aqueous medium
1
. Introduction
anti-ecological organic solvents with no ecological prospects in the
context of green chemistry. Most of the reported methods having
a downside such as the use of costly ligands, supporting additives,
costly reagents, harmful organic media, high sensitivity of ligands
to air/moisture and tedious reaction work-up procedures. On the
contrary, the recovery and reusability of expensive used catalysts
are major challenges. Thus, the development of efficient, environ-
ment friendly catalysts and solvent systems for this palladium-
catalyzed coupling reaction is a priority for researchers.14 During
the past few years, many attempts have been made to overcome
these disadvantages. In this concern, some phosphine-free systems
involving naturally occurring or semi-synthetic novel ligands/
catalysts with a combination of environmentally green solvent
The palladium-catalyzed Heck cross-coupling reaction is one of
the most conducive single operational methods for the construc-
tion of biaryl compounds via C–C bond-forming processes in the
synthesis of multifunctional derivatives,1 natural products,
–4
5,6
7
bioactive compounds and active pharmaceutical intermediates. In
recent decades, chemists are paying more attention to this cross-
coupling reaction due to its reliability in the formation of C–C bonds
with excellent yields and the ability to obtain diverse products with
8
a single practical method. However, a large number of catalytic
systems have been proposed to minimize the drawbacks associ-
ated with the Heck reaction such as: use of costly palladium catalysts,
toxic organic solvents and the generation of a high amount of toxic
metal residue in large-scale reaction experiments, mostly in the phar-
maceutical industry and chemical plants.9
systems such as aqueous media, ionic liquid, and PEG (polyethyl-
ene glycol) have been explored for this transformation.1
5–18
However,
–11
solvents play a critical role in most organic transformations to ho-
mogenize the reaction system and increase the proximity of reactant
in the solution. Consequently, chemists have been more inter-
ested in exploring catalytic reactions in aqueous media due to
advantages such as green, cost effective solvents and easy purifi-
The use of palladium–phosphine complexes as a catalytic system
for Heck reactions is well documented.2
reactions were carried out with expensive metal catalysts and
,12,13
However, most of these
1
9,20
cation without the formation of toxic waste.
In recent years, supramolecular chemistry has gained more in-
terest in many scientific fields and notably contributes to the
*
Corresponding author. Department of Bioscience and Biotechnology,
Microbial Carbohydrate Resource Bank (MCRB), Konkuk University,
20 Neungdong-ro, Gwangjin-gu, Seoul 143-701, South Korea. Tel.: +82 2450 3520;
application of various novel concepts. The basic pillar of supramo-
lecular chemistry was built by Cram, Lehn and Pedersen,2
1–24
and
1
their study on host–guest chemistry between crown ethers and
cryptands merited the Nobel Prize for chemistry in the year 1987.
fax: +82 2452 3611.
E-mail address: shjung@konkuk.ac.kr (S. Jung).
http://dx.doi.org/10.1016/j.carres.2016.04.024
0008-6215/© 2016 Elsevier Ltd. All rights reserved.

86
S.D. Dindulkar et al. / Carbohydrate Research 430 (2016) 85–94
In particular, this host–guest property is more applicable in the field
of organometallic catalysts, where the host–guest interaction is a
powerful tool to enhance the efficiency of the catalyst in the cata-
2. Results and discussion
The catalyst 2-aminopyridine modified β-cyclodextrin sup-
2
5
lytic system.
ported palladium complex (PdL
consecutive steps which are depicted in Scheme 1. The synthesis
of 6-deoxy-6-(pyridin-2-ylamino)-β-cyclodextrin (L @β-CD) was pre-
viously reported by Ikenaka et al. But there are some drawbacks such
as low yield, harsh reaction conditions, and tedious work-up pro-
cedure that make this method counterproductive. So we modified
the protocol in two simple steps. The first step began with the re-
action of commercially available β-cyclodextrin with 1-(p-
toluenesulphonyl)imidazole to obtain mono-6-tosyl-β-cyclodextrin,
which was further reacted with 2-aminopyridine in anhydrous DMF
at 60 °C for 24 hours to afford functionalized ligand incorporated
β-cyclodextrin, i.e. 6-deoxy-6-(pyridin-2-ylamino)-β-cyclodextrin
n
@β-CD) was prepared in three
Among the various known host systems, the naturally occur-
ring cyclodextrin (CD) has attracted much attention due to its
hydrophobic cavities. Moreover, due to the specific binding con-
n
0
.5
5
−1
stant (10 –10 M ), CD could selectively bind substrates in the
33
aqueous phase and catalyze chemical reactions through non-
covalent host–guest complexation.2
6–28
The complexation capability
of CD with the water insoluble organic molecules is a well-known
alternative method to enhance the solubility of poorly soluble hy-
drophobic guest molecules.29 Due to this incredible property,
cyclodextrin and its derivatives are employed as phase transfer cata-
lysts in a variety of organic reactions.30 The substitution of CD at
the primary face with a ligand also demonstrates similar conjoint
(L
n
@β-CD). Subsequently, the synthesized 2-aminopyridine modi-
@β-CD) was treated with Pd(OAc) in
15,31
of hydrophobicity and molecule reorganization properties as CD.
fied β-cyclodextrin (L
n
2
Recently, chemists have had great interest in the development of
complexation abilities of CD with a specific structure. So different
synthetic modifications of CD was carried out for better complexing
host molecule. On the other hand, modification of CD as a ligand
has been explored far less in the field of organometallic catalysts
for various transformations in aqueous media. Recently, amino acid
modified β-cyclodextrins as ligand were applied successfully for Heck
reaction. However, this reported method shows varying degrees of
advantages, and the use of higher amount of ligand-β-CD (10 mol%)
and the use of external saturated β-CD water solution for solubil-
ity enhancement of reactant are some disadvantages associated with
anhydrous toluene overnight (12 hours) and the yellow coloured
target, 2-aminopyridine modified β-cyclodextrin supported palla-
dium complex (PdL @β-CD) was obtained. The prepared catalyst
n
displayed distinguished water solubility, which makes it more
advantageous.
The 2-aminopyridine modified β-cyclodextrin (L
n
@β-CD) and
Pd(OAc)
2
incorporated ligand-β-CD (PdL
n
@β-CD) were confirmed by
1
H NMR and the coordination of palladium in PdL
witnessed from the H NMR correlation (Fig. 1). It is important to
n
@β-CD was clearly
1
note that the proton signals of pyridine in PdL
shifted downfield with peak broadening as compared to the initial
2-aminopyridine modified β-cyclodextrin (L @β-CD). Moreover, a
marked effect was observed on the aromatic proton (b) of PdL
β-CD, which was markedly shifted and merged with a neighbouring
n
@β-CD marginally
3
2
this protocol.
n
In this context, we propose a new concept based on
-aminopyridine modified β-cyclodextrin supported palladium
n
@
2
complex (PdL
n
@β-CD) as a supramolecular reaction platform as well
aromatic proton (d). The characteristic acetyl peak of Pd(OAc)
2
was
1
as a catalytic system for Mizoroki–Heck cross-coupling reactions in
aqueous medium under aerobic conditions. The olefination of iodo-
and bromoarenes with different olefins under phosphine-free re-
action conditions results in cross-coupling products with good to
excellent yield. It is also important to note that the catalyst can be
easily recovered and reused several times.
n
observed in the H NMR of PdL @β-CD. Inductively coupled plasma
atomic emission spectrometry (ICP-MS) analysis was carried out to
determine the exact palladium content in the PdL @β-CD complex
n
−1
and notably, the catalyst was abundant at 0.387 mmol g . Conse-
1
quently, the H NMR correlation and ICP-MS analysis clearly proved
that the palladium was well coordinated with 2-aminopyridine
Scheme 1. Chemical and schematic representation of the synthetic path of 2-aminopyridine modified β-cyclodextrin supported palladium complex (PdLn@β-CD). Reaction
conditions: (a) 1-(p-Toluenesulphonyl)imidazole, NaOH, H2O 40%; (b) 2-aminopyridine, anhydrous DMF, 60 °C, 24 h, 24%; (c) Pd(OAc)2, toluene, r.t., 12 h.

S.D. Dindulkar et al. / Carbohydrate Research 430 (2016) 85–94
87
Fig. 1. 1H NMR of (a) ligand-β-CD (Ln@β-CD), (b) 2-aminopyridine modified β-cyclodextrin palladium complex (PdLn@β-CD).
modified β-cyclodextrin (L
n
@β-CD). The specific rotation is the prim-
an important role in the reaction. In order to find the most effec-
tive base for this coupling reaction, we screened different inorganic
itive characteristic property of optically active molecules. As
cyclodextrin (α-D-glucopyranose units) possesses the optical ac-
tivity, the polarimetric analysis was also carried out to find the
bases such as Na
(Table 1, entry 1–5). After screening various bases, we found that
Na CO , K CO , and Cs CO gave more than 80% yield (Table 1, entry
1, 3, 4). Comparatively, K CO was found to be the best operative
2 3 2 3 3 2 3 2 3 3
CO , N(CH CH ) , K CO , Cs CO , and NaHCO
differences in specific rotation of the L
complex) for further confirmation of the complex formation. The
specific rotation of L @β-CD and PdL @β-CD (complex) is +11.98
0.5 mg/mL) and +10.60° (10 mg/mL) respectively. The marked
n
@β-CD and PdL
n
@β-CD
2
3
2
3
2
3
(
2
3
n
n
base for this reaction due to successful improvement of the reac-
tion yield up to 88% (Table 1, entry 3). In the absence of a base, no
significant product formation was observed even after 12 hours of
reaction time (Table 1, entry 9). In searching for the optimal cata-
lyst loading, we increased the amount of catalyst loading to 2, 3 and
5 mol%. Notably, 3 mol% of catalyst was found to give the maximum
yield in minimum time (Table 1, entry 7). Further increasing the
(
change in the specific rotation of complexes was observed, which
suggests the incorporation of palladium acetate with ligand func-
tional group in PdL @β-CD complex.
n
The 2D ROESY NMR analysis was carried out to determine the
spatial correlation of the ligand proton with β-cyclodextrin in the
PdL
n
@β-CD. The spectrum clearly showed that there was no spatial
amount of the PdL
yield nor reduced the transformation time (Table 1, entry 8). When
the reaction was carried out in the absence of the catalyst (PdL
β-CD) or ligand-β-CD (L @β-CD) in aqueous medium, only a trace
amount of product was obtained even after 12 h (Table 1, entry 11).
After identifying the optimal catalyst and base loading condition,
the effect of temperature was also studied. When the reaction was
carried out below the reflux condition (80 °C), notably, the yield of
the desired product decreased from 94 to 76%, even after 12 h of
reaction (Table 1, entry 10). Our enthusiasm led us to evaluate the
efficiency of separate applications of aminopyridine modified
n
@β-CD catalyst (5 mol%) neither increased the
correlation among the aromatic proton of the pyridine ring with the
CD protons (β-cyclodextrin), which indicates that the pyridine ar-
omatic ring was not accommodated in the hydrophobic cavity of
the β-cyclodextrin (Fig. 2). The hydrophobic cavity is also fully avail-
able to the reactant during the reaction.
n
@
n
In our initial investigation, the catalytic behaviour of the water
soluble PdL @β-CD was investigated for Mizoroki–Heck cross-
n
coupling reactions. In the process of optimization for the best
operative experimental conditions, we selected iodobenzene and
styrene as the representative substrates; the results are depicted
in Table 1. The moderate yield (84%) of the desired product was ob-
tained when the reaction was carried out in water under reflux
n 2 2 3
β-cyclodextrin ligand (L @β-CD) with Pd(OAc) and K CO base in
aqueous medium at reflux conditions for 12 h. It is worthwhile to
note that an appreciable 92% yield was achieved with the use of
conditions with 1 mol% of PdL
n
@β-CD and Na
2 3
CO base for 12 h
n
(Table 1, entry 1), which indicates that the PdL @β-CD catalyst plays
n
3 mol% 2-aminopyridine modified β-cyclodextrin (L @β-CD) and

88
S.D. Dindulkar et al. / Carbohydrate Research 430 (2016) 85–94
Fig. 2. 2D ROESY NMR spectrum of saturated PdLn@β-CD in D2O (25 °C).
Table 1
Optimization of the reaction conditions
a
Entry
PdLn@β-CD
mol%)
Ln@β-CD/Pd(OAc)2
(mol%)
Base
Yieldb
(%)
(
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
1
1
2
3
5
—
—
—
—
—
—
—
—
Na2CO3
N(CH2CH3)3
K2CO3
Cs2CO3
NaHCO3
K2CO3
K2CO3
K2CO3
-
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
84
72
88
82
77
91
94
94
7
76
14
76
92
92
12
≤8
c
5
3
—
—
0/1
1/1
3/1
4/2
—/5
Adamantane
carboxylate
d
0
1
2
3
4
5
6
e
f
—
—
—
—
—
3
f
f
g
h
a
All the reactions were carried out under reflux in the presence of iodobenzene (3.0 mmol), styrene (3.2 mmol), PdLn@
β-CD, base (3.5 mmol), and H2O (4 mL), for 12 h, unless otherwise mentioned.
b
Isolated yields based on the amount of iodobenzene used.
Reaction is carried out for 4 h.
Reaction was carried out at 80 °C for 12 h.
Reaction was carried out only with the use of Pd(OAc)2 and K2CO3 base.
Reaction is carried out using Ln@β-CD and Pd(OAc)2 respectively for 12 h.
Reaction is carried out using β-CD (10 mol%) and Pd(OAc)2 (5 mol%) respectively for 12 h.
Reaction is carried out under reflux in the presence of iodobenzene (2.4 mmol), styrene (2.8 mmol), PdLn@β-CD,
c
d
e
f
g
h
base (3.6 mmol), adamantane carboxylate (2.4 mmol) and H2O (5 mL), for 12 h.

S.D. Dindulkar et al. / Carbohydrate Research 430 (2016) 85–94
89
1
mol% Pd(OAc)
2
(Table 1, entry 13). It is also imperative to mention
system in promoting aqueous Mizoroki–Heck cross-coupling reac-
tions. In this differentiation study, control experiments were carried
that instead of 1.0 equivalent alkene, the use of 1.2 equivalents of
alkene gives a better yield. In order to elucidate the role of
β-cyclodextrin (β-CD) for these reactions in aqueous media, a con-
out with different substrates using PdL
Pd(OAc) and the results are displayed in Table 3.
As seen in Table 3, when coupling reactions were carried out using
the PdL @β-CD catalytic system (A) and L @-β-CD/Pd(OAc) (B), L @-
β-CD/Pd(OAc) gave a marginally lower yield after prolonged reaction
times as compared to the PdL @β-CD catalytic system (A). On the
contrary, a lesser amount of PdL @β-CD catalyst is sufficient to ac-
celerate the reaction and gave a better yield in less time. From the
overall observations, we concluded that presynthesized PdL @β-
CD complex has better catalytic activity and catalytic efficiency
compared with the in-situ generated PdL @β-CD complex (Fig. 3).
Water solubility and easy recovery are the most important prop-
erties of this PdL @β-CD catalyst, which make the catalyst more
applicable in the field of reusable catalysts. This motivated us to in-
vestigate the reusability of the PdL @β-CD catalyst for a minimum of
n n
@β-CD and L @β-CD/
2
trolled reaction was carried out using β-CD (10 mol%) and Pd(OAc)
5 mol%). A very trace product formation was observed using un-
2
(
n
n
2
n
modified β-cyclodextrin as catalyst even after 12 hours of reaction
time (Table 1, entry 15), which indicates the importance of the ligand
group in CD to stabilize Pd(OAc)
important role of β-CD cavity for Mizoroki–Heck cross coupling re-
action was confirmed by the use of PdL @β-CD catalyst with its pre-
blocked cavity using adamantane carboxylate as competitive guest
for controlled reaction (Table 1, 16). As adamantane carboxylate is
well reported as standard guest which perfectly fits deep in the beta-
cyclodextrin cavity, the carboxylate group is exposed to solution at
the wider opening of β-cyclodextrin.34 There was no significant
product formation observed (on TLC), even after 12 hours of reac-
tion time (Table 1, entry 16). The effect of inhibitor (adamantane
carboxylate) on Mizoroki–Heck cross-coupling reactions clearly
suggest that the hydrophobic cavity of cyclodextrin plays a vital role
for this cross-coupling reaction.
2
n
2
in this reaction. Furthermore, the
n
n
n
n
n
n
three more reaction cycles. For this investigation, we carried out a
set of reusability tests using the recycled catalyst (Table 4). After com-
pletion of the reaction, extraction of the product was carried out using
ethyl acetate. The catalyst was simply reprecipitated from the aqueous
layer by the addition of 10 mL of acetone. The recovered catalyst was
filtered, washed with acetone (3 × 5 mL) and dried in a vacuum at
The overall optimization study clearly confirms the minimum
optimal reaction condition: 1.0 mmol aryl halide, 1.2 mmol alkene,
3
mol% of PdL
n
@β-CD, 1.5 mmol K
2
c
CO
3
, 4.0 mL H
2
O reflux under
n
70 °C for 5 h. The recovered PdL @β-CD catalyst was tested in up to
aerobic conditions (Table 1, entry 7 ).
three more reaction cycles. The cross-coupled product (E)-1,2-
diphenylethene was obtained in 90%, 90%, and 87% yields after
successive cycles. Recycling and reusability experiments showed neg-
ligible loss of activity.
After successful development of the optimal catalytic system, we
further proceeded to explore the generality and efficiency of the de-
veloped protocol using various aryl iodides and aryl bromides with
different aryl alkenes such as styrene and 4-bromo-styrene as well
as aliphatic alkenes, such as methyl acrylate, 5-hexene-2-one and
A possible mechanism for this Mizoroki–Heck cross-coupling re-
action is extrapolated from the obtained results and on the basis
1
5,41,42
5-hexenenitrile. Remarkably, PdL
n
@β-CD catalyst showed highly ef-
of reported literature (Scheme 2).
addition of an aryl halide to the PdL
In the first step, oxidative
n
@β-CD complex leads to the
ficient catalytic activity for these cross-coupling reactions, which
afforded good to excellent yield with a turnover number (TON) up
to 31.66 (Table 2). All new compounds were completely character-
formation of a Pd-chelated complex (intermediate-II). Subsequent
dissociation of halide from the formed intermediate leads to for-
mation of a cationic Π-complex (intermediate-III). Afterwards, syn-
insertion of the alkene occurs through a carbometallation reaction
to generate a palladium (II) alkyl complex (intermediate-IV) that
undergoes palladium hydride elimination (β-hydride elimination)
to furnish the Heck product, and base assisted elimination from the
hydridopalladium complex regenerates the catalytically active Pd
(0) complex for further reaction cycles.
1
ized by their analytical and spectral data. The melting point, H NMR,
and 1 C NMR data of the known compounds were in good agree-
3
ment with those in the literature.
The substrates with electron rich functionality, such as -CH
forded coupling products in good yield, but after long reaction times
Table 2, entries 14, 15). In contrast, aryl iodide-containing elec-
tron withdrawing groups, such as p-COCH and o-COCH , gave
excellent yields in short reaction times (Table 2, entries 16–18 and
3
, af-
(
3
3
2
4
1). On the other hand, electronegative substitutes such as 4-bromo,
-fluoro and 3,5-di-fluoro substitute on styrene and aryl halide gave
3. Conclusions
moderate to good yields after long reaction time (Table 2, entries
, 8, 9, 17, 19 and 20). The hydrophilic substitutes such as hy-
droxyl groups on aryl halide had a marked influence, which gives
biaryl compounds in moderate yield in relatively long reaction time
In summary, we designed and synthesized a novel water-
7
soluble palladium catalyst based aminopyridine modified
β-cyclodextrin (PdLn@β-CD). In this cross-coupling reaction,
olefination of iodo and bromoarenes using different aryl as well as
aliphatic olefins gave the corresponding coupling products good to
excellent yields without the use of an inert atmosphere. This cata-
lytic system was found to be sensitive to electronegative and
hydrophilic functional substrates. Moreover, the catalyst could be
easily recovered and reused without significant loss of activity. The
catalyst is proved to be an efficient and environmentally benign cat-
alyst for Mizoroki–Heck cross-coupling reactions in neat water and
could be an incredible approach in the field of water soluble cata-
lysts to mediate aqueous organic reactions.
(
Table 2, entries 5 and 6). We also performed coupling reactions
between bromobenzene and different olefins. Unlike iodobenzene,
bromobenzene did not give a satisfactory yield with the use of 3 mol%
PdL @β-CD catalyst. This poor yield of the biaryl product may be
n
due to the low reactivity of bromobenzene, poor water solubility,
or lack of β-CD hydrophobic cavities in the reaction system. So we
further optimized the reaction condition for bromobenzene and sig-
nificant results were obtained with 5 mol% PdL
8
1
n
@β-CD catalyst at
0 °C in a water/DMF (1:3) aqueous biphasic system (Table 2, entries
0–13). The catalytic system also gave excellent yields with the use
of substituted aryl olefin (Table 2, entries 8 and 17). This catalytic
system is not only efficient with the use of aryl olefin but ali-
phatic olefins like methyl acrylate, 5-hexene-2-one and
4. Experimental
5
-hexenenitrile also gave corresponding products in good yield
4.1. Materials and methods
(
Table 2, entries, 2–6, 9, 11–13, 15, 18, 20 and 21).
Furthermore, we also clarified the comparative catalytic effi-
All high purity chemicals and reaction solvents were pur-
chased from Sigma-Aldrich and used without further purification.
ciency and the catalytic activity of individual use of PdL
n
@β-CD over
the separate use of L @β-CD and the palladium acetate catalytic
n
2 5
Anhydrous DMF was prepared by vacuum distillation over P O and

90
S.D. Dindulkar et al. / Carbohydrate Research 430 (2016) 85–94
Table 2
Mizoroki–Heck reaction between aryl halides and olefins, catalyzed by using aminopyridine modified β-cyclodextrin supported palladium complex
a
Entry
1
Aryl halide
Olefins
Product
Time (h)
4
Yieldb (%)
94
TONc
31.33
M.p. (°C)
124–125
Reported
3a
(123–124)35
2
3
4
3b
3c
3d
6
12
4
92
89
95
30.66
29.66
31.66
Liquid
Liquid
Oil
—
—
—
5
6
3e
3f
8
86
88
28.66
29.33
134–135
130–132
—
12
(130–132)36
7
3g
9
93
30.99
125–126
(123–124)37
8
9
3h
3i
12
12
7
91
30.33
28.33
30.33
Liquid
—
—
—
85
Liquid
10
11
12
13
3j
91d
124–125
3k
3l
12
12
12
87d
90d
83d
28.99
29.99
27.66
Liquid
—
Liquid
—
3m
133–134
(133)38
1
4
5
3n
3o
8
95
92
31.66
30.66
34–35
Liquid
(30)37
1
12
—
1
6
7
3p
3q
7
95
87
31.66
28.99
104–105
Liquid
(105–107)39
1
12
—
(
continued on next page)

S.D. Dindulkar et al. / Carbohydrate Research 430 (2016) 85–94
91
Table 2 (continued)
Entry Aryl halide
Olefins
Product
Time (h)
5
Yieldb (%)
96
TONc
31.99
M.p. (°C)
62–63
Reported
(59–60)40
1
8
3r
1
9
3s
3t
9
10
4
94
92
93
31.33
30.66
30.99
107–108
Liquid
—
2
0
1
—
2
3u
93–94
(91–92)40
a
The reactions were carried out in refluxing water (4.0 mL) using aryl halide (3.0 mmol), olefins (3.2 mmol), catalyst PdLn@β-CD (3 mol%), and K2CO3 (3.5 mmol), unless
otherwise stated.
b
Isolated yields based on the amount of aryl halide used.
Turnover number (TON) based on the number of mole of isolated product.
Reaction is carried out using 5 mol% PdLn@β-CD catalyst at 80 °C in water/DMF (1:3).
c
d
The FT-IR spectra were recorded in the range of 400–4000 cm− using
a potassium bromide matrix with a Bruker IFS-66 spectrometer
(AMX, Germany). The palladium content was measured by induc-
tively coupled plasma mass spectrometry (ICP-MS) on Perkin-
Elmer SCIEX (USA), ELAN 6100. Matrix-assisted laser desorption
ionization mass spectrometer (MALDI TOF–TOF) was carried out on
1
stored over molecular sieves 3 Å under argon atmosphere. β-CD was
well dried in a vacuum oven at 70 °C overnight prior to use in the
reaction. Other solvents like n-hexane, iso-propyl alcohol, ethyl
alcohol, and ethyl acetate were purchased from Duksan Pure Chemi-
cals Co., Ltd., Korea. The progress of the reaction was monitored by
thin layer chromatography (using Merck silica gel 60 F-254 plates).
Distilled solvents were used for chromatographic separation while
water was purified using a Direct-Q Millipore water purification
system from SAM WOO S&T Co., Ltd., Korea. NMR spectral analy-
sis was carried out using a Bruker Avance spectrometer at 500 MHz.
™
a Voyager-DE STR bio-spectrometry workstation. Optical rota-
tion of compound was recorded using JASCO P-1020 polarimeter.
All melting points were determined using open capillaries on an
electrothermal-9100 (Japan) instrument.
Table 3
The effect of PdLn@β-CD and Ln@β-CD on Mizoroki–Heck cross-coupling reactionsa
Entry
1
Aryl halide
Product
A
B
Time (h)
4
Yield (%)b
94
Time (h)
12
Yield (%)b
92
2
3
4
7
5
9
95
96
94
12
12
12
87
90
85
a
All the reactions were carried out in refluxing water (4.0 mL) using aryl halide (1.0 mmol), olefins (1.2 mmol), catalyst PdLn@β-CD (3 mol%) or Ln@β-CD (3 mol%)/
Pd(OAc)2 (1 mol%), and K2CO3 (1.5 mmol).
b
Isolated yields based on the amount of aryl halide used.

92
S.D. Dindulkar et al. / Carbohydrate Research 430 (2016) 85–94
24 h. The formation of product was confirmed by using TLC in iso-
propyl alcohol:water:ethylacetate:ammonia (5:5:1:1) solvent system.
The reaction mixture was cooled to room temperature and 500 mL
of acetone was added to obtain a white precipitate. The resulting
white precipitate was filtered and dried under vacuum to give the
crude product. The crude product was purified using ion-exchange
column chromatography (CM Sephadex C25) using 200 mL water
(
triple distilled water) to remove the unreacted tosyl-CD and β-CD.
After that, pure product L @β-CD was isolated by eluting 300 mL
of 0.1 M NH HCO . The fractions containing L @β-CD were de-
salted (dialysis) and dried. Yield: 0.450 g (24.06%).
n
4
3
n
4
5
4.4. Synthesis of palladium acetate aminopyridine modified
β-cyclodextrin (PdL @β-CD)
n
The L
n 2
@β-CD 0.120 g (0. 099 mmol) and Pd(OAc) 0.0066 g
Fig. 3. Comparative yields of various derivatives using catalyst A and catalyst B.
(
0.0297 mmol) were dissolved in anhydrous toluene (16.0 mL). The
resulting reaction mixture was stirred at room temperature for 12
hours. Afterwards, the resulting solid was filtered, thoroughly washed
with plenty of acetone for removal of adsorbed palladium and dried
4
.2. Synthesis of
mono-6-(p-toluenesulphonyl)-6-deoxy-β-cyclodextrin
in vacuum at 30 °C. The light yellow colour Pd-L
n
@β-CD powder was
obtained (0.108 g). ICP-MS analysis showed 0.387 mmol g− palla-
1
The synthesis of mono-6-(p-toluenesulphonyl)-6-deoxy-β-
cyclodextrin was carried out using a previously reported
dium content in the complex.
4
3,44
procedure.
β-cyclodextrin (40.0 g, 35.2 mmol) was dissolved in deionized water
450 mL) at 60 °C with vigorous stirring. 1-(p-Toluenesulphonyl)-
In a 1 L double necked round-bottomed flask,
4.5. General procedure for Mizoroki–Heck cross-coupling reactions
of aryl halides with olefin using PdL @β-CD (3a-3u)
n
(
imidazole (12 g, 54 mmol) was added to the resulting milky
suspension at room temperature and stirred for 2 h. After that,
a solution of sodium hydroxide 9 g (225 mmol, in 25 mL water)
was added dropwise over 20 min. After addition of the
sodium hydroxide solution, the separation of unreacted 1-(p-
toluenesulphonyl)imidazole was carried out by simple filtration
using a sintered glass funnel. Finally the reaction was quenched
by the addition of ammonium chloride (24.1 g, 900 mmol), with
agitation to dissolve the added ammonium chloride. The resulting
mixture was concentrated to about half of its original volume by
blowing a stream of air over its surface. The resulting suspension
was filtered using a sintered-glass funnel and the collected solid
was washed twice using 200 mL ice-cold water and 100 mL of
acetone in one portion. The collected solid was well dried over-
A Schlenk flask equipped with asepta and a magnetic stir bar was
filled with aryl halide (3.0 mmol), alkene (3.2 mmol), K CO
3.5 mmol) and PdL @-β-CD 3 mol% catalyst in water (5 mL pure or
2
3
(
n
plain). The reaction was refluxed for the appropriate time under
aerobic conditions. After completion of the reaction was con-
firmed by TLC, the reaction mixture was cooled to room temperature.
The solvent was removed by rotary evaporator and extraction of the
product was carried out using ethyl acetate. The ethyl acetate frac-
tion was separated and dried over anhydrous sodium sulphate. The
resulting crude product was purified using flash column chroma-
tography of silica gel 60–120 mesh with n-hexane/ethyl acetate (8:2
ratio) as the eluent and afforded the pure desired product. After ex-
traction of product, catalyst was simply reprecipitated from the
aqueous layer by the addition of 10 mL of acetone. The recovered
catalyst was filtered, washed with acetone (3 × 5 mL) and dried in
a vacuum at 70 °C for 5 h and reused.
2
night in a vacuum at 60 °C and kept over CaCl in vacuum desiccators
yielding 18.30 g, or 40.26%.
4.3. Synthesis of 6-deoxy-6-(pyridin-2-ylamino)-
cyclomaltoheptaose (L @β-CD)
n
4.6. The effect of an inhibitor (adamantane carboxylate) on
Mizoroki–Heck cross-coupling reactions
In a two neck 100 mL round bottom flask, 6-monodeoxy-6-
monoazido-β-CD (2 g, 1.5 mmol) and 2-aminopyridine (0.583 g,
n
PdL @β-CD (0.073 mmol) was dissolved in 2 mL of water (pure
6
.20 mmol) were dissolved in 20 mL of anhydrous DMF under ni-
or plain), and then 1-adamantanecarboxylic acid (0.146 mmol) was
added. After stirring for 2 h at reflux temperature, iodobenzene
trogen atmosphere. The resulting mixture was stirred at 60 °C for
Table 4
The reuse of PdLn@β-CD catalyst for the synthesis of (E)-1,2- diphenylethene using styrene with bromobenzenea
Cycle
Time (h)
Yieldb (%)
Initial use
4
4
7
94
90
90
87
1
2
3
st cycle
nd cycle
rd cycle
10
a
The reactions were carried out in refluxing water (4.0 mL) using aryl halide (3.0 mmol), olefins (3.2 mmol), cata-
lyst PdLn@β-CD (3 mol% initially) and K2CO3 (3.5 mmol).
b
Isolated yields based on the amount of aryl halide used.

S.D. Dindulkar et al. / Carbohydrate Research 430 (2016) 85–94
93
Scheme 2. A possible mechanism for 2-aminopyridine modified β-cyclodextrin supported palladium complex (PdLn@β-CD) catalyzed Mizoroki–Heck reaction.
(
2.4 mmol), styrene (3.1 mmol) and K
2
CO
3
base (3.6 mmol) were
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