Ligandless Suzuki-Miyaura reaction in neat water with or without native β-cyclodextrin as additive

Article abstract of DOI:10.1016/j.catcom.2012.12.004

Efficient green ligand-free Suzuki cross coupling in neat water was developed by using low loading of catalyst (0.5 mol%) in neat water in the presence or not of β-cyclodextrin (0.5 mol%) as additive at 25 C and 100 C respectively.

Full text of DOI:10.1016/j.catcom.2012.12.004

Ligandless Suzuki-Miyaura reaction in neat water with or without native
β-cyclodextrin as additive
Audrey Decottignies, Aziz Fihri, Geoffrey Azemar, Florence Djedaini-
Pilard, Christophe Len
PII:
DOI:
Reference:
S1566-7367(12)00461-X
doi: 10.1016/j.catcom.2012.12.004
CATCOM 3356
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
4 October 2012
3 December 2012
4 December 2012
Please cite this article as: Audrey Decottignies, Aziz Fihri, Geoffrey Azemar, Florence
Djedaini-Pilard, Christophe Len, Ligandless Suzuki-Miyaura reaction in neat water with
or without native β-cyclodextrin as additive, Catalysis Communications (2012), doi:
10.1016/j.catcom.2012.12.004
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ACCEPTED MANUSCRIPT
Ligandless Suzuki-Miyaura reaction in neat water with or without
native -cyclodextrin as additive
Audrey Decottigniesa, Aziz Fihrib, Geoffrey Azemarc, Florence Djedaini-Pilardc, Christophe
Lena,*
aTransformations Intégrées de la Matière Renouvelable - EA 4297 UTC/ESCOM, Université
de Technologie de Compiègne, Centre de Recherches de Royallieu, BP 20529, rue Personne
de Roberval, F-60205 Compiègne cedex, France
bKAUST Catalysis Center (KCC), King Abdullah University of Science and Technology
Thuwal 23955, Kingdom of Saudi Arabia
cLaboratoire des Glucides - FRE 3517 CNRS, Université de Picardie Jules Verne, 33 rue Saint
Leu, F-80033 Amiens, France
Corresponding author. Tel.: +33 3 4424 8828; fax: +33 3 4497 1591.
E-mail address: christophe.len@utc.fr .

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Abstract
Efficient green ligand-free Suzuki cross coupling in neat water was developed using low
loading of catalyst (0.5 mol%) in neat water in presence or not of -cyclodextrin (0.5 mol%)
as additive at 25°C and 100°C respectively.
Keywords
-cyclodextrin – Suzuki – aqueous catalysis

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1. Introduction
Among the carbon-carbon bond-forming reactions using palladium: the Suzuki-Miyaura
reaction, the Heck reaction, the Kumada reaction, the Stille reaction, the Negishi reaction, and
the Sonogashira reaction, the palladium-catalyzed Suzuki coupling reaction has found wide
applications in modern synthetic organic chemistry for the preparation of unsymmetrical
biaryl compounds. The major advantages of the Suzuki-Miyaura reactions were the low-cost
and commercial availability of a large number of boronic acids, as well as their nontoxic
nature and stability to heat, air, and moisture. These reactions are usually carried out with
palladium in the presence of auxiliary ligands using heterogeneous catalytic systems [1,2] and
homogeneous catalytic systems [3]. Although the use of homogeneous catalysis provided
environmental and economic problems in large scale-synthesis, it also afforded high
reactivity, high turnover numbers, and milder reaction conditions. For example, a large
variety of organic molecules was obtained in different scales from academic laboratories and
industries such as Felbinac, Losartan, Boscalid, and Diovan.
Due to recent efforts in developing green chemistry and sustainable development for
academic and industrial research, chemists have recently established a catalytic Suzuki-
Miyaura protocol based on atom economy, less hazardous chemical syntheses, safer solvents
and auxiliaries. In this respect, the Suzuki-Miyaura reaction was developed in safe,
economical and environmentally benign aqueous media such as a cosolvent mixture in water
[4] or neat water [5-8]. When the initial substrates were unsoluble in water, the most attractive
choice was the use of surfactants [9] or inverse phase-transfer catalysts such as cyclodextrin
[10-12] or calixarene [12] permitting the phase transfer of water-insoluble substrates.
In regard with the 12 green chemistry principles, the development of a ligandless protocol in
an aqueous medium was recently reported [13-21]. Different mixtures such as EGME-water
[13], PEG-water [14,15], ethanol-water [16], NMP-water [17,18], acetone-water [19], THF-
water [20] and DMF-water [21] were successfully investigated. Only few ligandless Suzuki-
Miyaura reactions in neat water with high yield were described. Starting from arylbenzoic
acid and methyl arylbenzoate, the use of tetraalkylborate as a new type of borate source in
presence of palladium charcoal-catalyzed Suzuki coupling reaction in water and without
ligand could be achieve in good yield [22]. A reverse order of addition of reagents was
developed starting from arylbenzoic acid and the corresponding methyl ester [23]. Recently,
Mondal and Bora described an efficient protocol for palladium-catalyzed ligand-free Suzuki-
Miyaura coupling in water with or without additive [24]. The primary advantage of the
ligandless methodology is its ability to eliminate one reagent (e.g. phosphine derivatives).

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This provides a less hazardous chemical syntheses and atom economy. The second key
advantage is a marked improvement in reaction efficiency that allows for shorter reaction
time, milder conditions and greater catalytic turnover.
To the best of our knowledge, only one report has described the Suzuki-Miyaura reaction in
neat water using water unsoluble starting materials and ligand-free in the presence of
modified -cyclodextrin-capped palladium nanoparticles [25]. In this work, Antunes et al.
used 2-hydroxypropyl--cyclodextrin as a reductant and capping agent for the Suzuki-
Miyaura reaction and obtained different unsymmetrical biaryl compounds in high yields with
significant catalytic activity [25]. Starting from modified -cyclodextrin did not permit a
phase transfer due to the little size of the hydrophobic internal cavity. In an attempt to expand
the sustainable aspect of the Suzuki-Miyaura reaction, our group developed a successful
ligand-free water-based method using a natural -cyclodextrin (-CD) promoter.
2. Experimental
2.1 General
All reactants were obtained from Acros Organics and were used as received without further
purification. Solvents were purchased from Carlo Erba and were dried and freshly distilled
under nitrogen. Water (deionized) was degassed by sparging with nitrogen. Chromatography
was performed on a neutral silica gel. All reactions and workup procedures were performed
under an inert atmosphere using conventional vacuum-line and glasswork techniques.
2.2. Characterization
NMR spectra of Suzuki coupling products were recorded on a Bruker instrument operating at
400.13 MHz for proton and 100.62 MHz for carbon. The qualitative and quantitative analysis
of the reactants and products was performed by gas chromatography. Products were identified
by a comparison with authentic samples. Conversion and GC yields were calculated with
dodecane as an internal standard. NMR spectra for the complexation analysis were recorded
on a Bruker instrument operating at 600.17 MHz.
An isothermal calorimeter (ITC200, MicroCal Inc., USA) was used for determining the
stoichiometry and the binding constant of the complex between different substrates and the
cyclodextrin. Aliquots (0.5 µL to 2 µL) of titrant solution (11.1 to 38.3 mM) was added with
syringe to titrate solution (200 µL, 0.38 to 2.83 mM) at 25 °C. Data analysis was carried out
using Origin 7 software.

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Samples for TEM analyses were prepared by depositing one drop of diluted nanoparticles
aqueous dispersion on PVP-coated copper grids. After drying, the images were obtained by a
Hitachi H 600 transmission electron microscopy (100 kV).
XPS studies were carried out in a Kratos Axis Ultra DLD spectrometer equipped with a
monochromatic Al Ka-X-ray source (hν = 1486.6 eV) operating at 150 W, a multi-channel
plate and delay line detector under 1.0 x10-9 Torr vacuum. The survey and high-resolution
spectra were collected at fixed analyzer pass energies of 160 and 20 eV, respectively. The
instrument work function was calibrated to give an Au4f7/2 metallic gold binding energy of
83.95 eV. The spectrometer dispersion was adjusted to give a binding energy of 932.63 eV for
metallic Cu 2p3/2. Samples were mounted in floating mode in order to avoid differential
charging, charge neutralization was required for all samples. Binding energies were
referenced to the C 1s binding energy of adventitious carbon contamination which was taken
to be 284.80 eV [26,27]. The data were analyzed with commercially available software,
CasaXPS. The individual peaks were fitted by a Gaussian (70%)-Lorentzian (30%) (GL30)
function after Shirley type background subtraction.
2.3. Typical procedure for the Suzuki-Miyaura reaction
A 10 mL Schlenk flask was charged with bromoarene (0.25 mmol), phenylboronic acid
(0.375 mmol, 1.5 eq), base (0.5 mmol, 2 eq), -cyclodextrin (1.25 10-3 mmol, 0.5 mol %). A
solution of Pd (1.25 10-3 mmol, 0.5 mol %) in water (2 mL) was added. The mixture was
flushed with nitrogen, capped and placed in a pre-heated oil bath. The reaction mixture was
stirred at the specified temperature for the specified time. Then the reaction mixture was
extracted with ethyl acetate (3 x 3mL) and the combined organic layers were dried over
MgSO4, filtered and evaporated under reduced pressure. The crude product was analyzed by
GC or purified by flash chromatography on silica gel.
3. Results and discussion
-CDs are a family of cyclic oligosaccharides composed of -(1→4)-linked D-glucopyranose
units in 4C1 chair conformation that have seven glucopyranose units. As a consequence of the
non-modified -CD structure, the molecule is hydrophilic and features a conical cavity that is
essentially hydrophobic in nature with a size of the internal cavity permitting the phase
transfer of water-unsoluble substrates. The best method consisted of obtaining an inclusion
complex between a model initial substrate such as 4-bromacetophenone (1) and native -CD

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and not or weak inclusion complex between target compounds such as 4-acetylbiphenyl (3)
and -CD. NMR spectroscopy is one of the most reliable techniques for studying -CD
1
inclusion complexes. In our case, the H NMR spectra of the native -CD, -CD-4-
bromoacetophenone (1) mixture and -CD-4-acetylbiphenyl (3) mixture were realized in
D2O. The mixture of the -CD and 4-bromoacetophenone (1) showed apparent chemical shift
changes of the -CD cavity protons, H-3 and H-5. The H-3 and H-5 protons were shifted
downfield in the range from 3.889 ppm; 3.782 ppm to 3.782 ppm; 3.661 ppm respectively. In
1
contrast, the shifts of -CD outside H-2 and H-4 could be neglected. The analysis of the H
NMR spectrum showed that the 4-bromoacetophenone (1) or a part of it was included into the
-CD cavity, thus, confirming the formation of an inclusion complex.
The T-ROESY spectrum of the -CD (10 mM) and 4-bromoacetophenone (1) (10 mM)
mixture showed that the protons peaks of the phenyl core (a, b) were highly correlated with
the proton peaks of -CD (H-3 and H-5). This confirmed that the phenyl ring was included
into the -CD cavity. In this case, two potent inclusion complexes could exist depending on
the orientation of the 4-bromoacetophenone (1) inside the cavity; one with the bromide atom
oriented in the primary face and the other with the bromide atom in the secondary face. The
same experiments were realized with the replacement of 4-bromoacetophenone (1) by 4-
1
acetylbiphenyl (3) in D2O. The H NMR spectrum of the mixture did not show apparent
chemical shift change. To gain better insight into the complexation phenomena, experiments
were also conducted with Isothermal Titration Calorimetry (ITC) [28].
Figure 1 describes the ITC enthalpogram for addition of -CD with 4-bromoacetophenone (1)
in pure water at 25°C. Negative peaks were observed for each addition as a consequence of
the formation of inclusion complex. The intensities decreased as such association weakens as
the host concentration inside the cell increased. The fit of these data to the theoretical model
allowed the determination of the thermodynamic parameters. The stoichiometry was 1:1 and
association constant was equal to 634 (± 19) M-1 at 25°C. In our hands, the same experiments
performed with 4-acetylbiphenyl (3) used as guest in pure water failed. However in a mixture
of water and acetone (50:50), a low value of inclusion constant could be obtained (155 ± 36
M-1 at 25°C).

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Fig. 1. Representative observed heats (left part) and corresponding binding isotherm (right
part) for ITC complexation experiments between native -CD and 4-bromoacetophenone (1).
Solid line represents the best theoretical fit to experimental points.
Even if the structure of compound 3 could form an inclusion complex the association constant
was low in our conditions. These results demonstrated that native -CD could be used as a
mass transfer promoter for the initial compound in the Suzuki reaction. The results also
showed that the target hydrophobic biphenyl core could be easily extracted.
In the first set of experiments, the reaction of 4-bromoacetophenone (1) (1 equiv) with
phenylboronic acid (2) (1.5 equiv) was carried out as a model reaction in sole water at 100°C
with K2CO3 (2 equiv) using Pd(OAc)2 (0.5 mol%) as the catalyst and native -CD (0.5 mol%)
(Table 1, entry 1). It was notable that in the literature the amount of -CD was higher and
often similar with the concentration of the starting material.
In our conditions, the target aryl analogue 3 was obtained with a 97% yield after 1 hour. In
order to know the potent role of mass transfer of the native -CD, Suzuki coupling was
conducted without -CD and the target 4-acetylbiphenyl compound 3 was obtained after 1
hour with a 87% yield (Table 1, entry 1). A longer reaction time (2 hours vs 1 hour) did not
increase the yield of biaryl compound 3 (Table 1, entry 2). Lowering the temperature from
100°C to 25°C in the presence of -CD did not decrease the yield of the target biphenyl
analogue 3 but extended reaction time (24 hours vs 1 hour) (Table 1, entry 3). At 100°C, the
yields of the biaryl derivatives were higher than 87% (Table 1, entries 1 and 2) and the use of
-CD permitted to increase the yield by 10% (Table 1, entries 1 and 2). At 25°C, the

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difference in yield was higher than at 100°C (94% vs 63%,  = 31%) (Table 1, entry 3). The
inclusion complex between native -CD and compound 1 was more stable at 25°C than at
100°C affording a better reactivity for the Suzuki-Miyaura coupling in neat water.
Table 1
Variation of temperature with and without -CD (0.5 mol%) for the Suzuki-Miyaura coupling
starting from 4-bromoacetophenone (1).
PhB(OH)2 (2) 1.5 equiv
Pd(OAc)2 0.5 mol%
-CD 0-0.5 mol%
O
O
K2CO3 2 equiv
Br
H2O
25-100°C, 1-24 h
1
3
Yielda
(%)
97b (87)c
99b (88)c
94b (63)c
Temp.
(°C)
100
Time
(h)
1
Entry
1
2
3
100
2
25
24
a
Determined by GC methods. Products were compared with authentic samples.
b Reaction conditions: 1 (0.25 mmol), PhB(OH)2 (0.375 mmol), Pd(OAc)2 (0.5 mol%), -CD
(0.5 mol%), K2CO3 (0.50 mmol), water (2 mL), 25-100°C, 1-24 h.
c Reaction conditions: 1 (0.25 mmol), PhB(OH)2 (0.375 mmol), Pd(OAc)2 (0.5 mol%), K2CO3
(0.50 mmol), water (2 mL), 25-100°C, 1-24 h.
Different bases, including K2CO3, Na2CO3, Cs2CO3, CsF, K3PO4, NaOH, KOH and Et3N
were tested with the optimized conditions described in Table 2. On the one hand, at 100°C for
1 hour, with or without -CD, the different bases afforded the target biaryl compound 3 in
good to excellent yield (Table 2). When CsF was used, the yield of the Suzuki-Miyaura
product was lower (Table 2, entry 7). On the other hand, at 25°C for 24 hours, the bases had
dramatic effects on the yields of the cross-coupling product 3 (from 7% to 99%). At 25°C and
in the presence of -CD (0.5 mol%), only K2CO3, Na2CO3, Cs2CO3, K3PO4, NaOH and KOH
gave the biaryl structure 3 in good yield. At 25°C and without the presence of -CD, the
target 4-acetylbiphenyl compound 3 was obtained in a lower yield. This was particularly

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evident with CsF, K3PO4 and Et3N (Table 2, entries 8, 10 and 16). Considering the
economical and environmental advantages, K2CO3 was chosen as the base.

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Table 2
Variation of the nature of base for the Suzuki-Miyaura coupling starting from 4-
bromoacetophenone (1) with or without -CD.
PhB(OH)2 (2) 1.5 equiv
Pd(OAc)2 0.5 mol%
-CD 0-0.5 mol%
O
O
Base 2 equiv
Br
H2O
25-100°C, 1-24 h
1
3
Yielda
(%)
Base
Temp.
(°C)
Time
(h)
Entry
(2 equiv)
K2CO3
K2CO3
Na2CO3
Na2CO3
Cs2CO3
Cs2CO3
CsF
1
2
100
25
1
97b (87)c
94b (63)c
99b (97)c
99b (86)c
93b (85)c
99b (81)c
75b (72)c
43b (32)c
90b (86)c
96b (29)c
95b (91)c
99b (94)c
85b (83)c
94b (93)c
95b (94)c
60b (7)c
24
1
3
100
25
4
24
1
5
100
25
6
24
1
7
100
25
8
CsF
24
1
9
K3PO4
K3PO4
NaOH
NaOH
KOH
100
25
10
11
12
13
14
15
16
24
1
100
25
24
1
100
25
KOH
24
1
Et3N
100
25
Et3N
24
a
Determined by GC methods. Products were compared with authentic samples.
b Reaction conditions: 1 (0.25 mmol), PhB(OH)2 (0.375 mmol), Pd(OAc)2 (0.5 mol%), -CD

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(0.5 mol%), K2CO3 (0.50 mmol), water (2 mL), 25-100°C, 1-24 h.
c Reaction conditions: 1 (0.25 mmol), PhB(OH)2 (0.375 mmol), Pd(OAc)2 (0.5 mol%), K2CO3
(0.50 mmol), water (2 mL), 25-100°C, 1-24 h.
In search of a more efficient catalyst, the next step consisted of examining different PdII-based
species. Palladium sources were screened by using the same amount of catalyst (0.5 mol% of
either PdI2, PdCl2, Na2PdCl4, [Pd(C3H5)Cl]2 or Pd(PhCN)2Cl2), and by varying the
concentration of native -CD (0 or 0.5 mol%), as well as the temperature and time (25°C for
24 hours and 100°C for 1 hour). Even though all the palladium derivatives promoted the
formation of biaryl analogues, none of these palladium derivatives was as good as Pd(OAc)2
for the four methods tested (table 3). It was notable that PdCl2 permitted the Suzuky-Miyaura
coupling with a 96% yield in the presence of -CD (0.5 mol%) at 25°C for 24 hours (table 3,
entry 6). Pd(PhCN)2Cl2 also afforded the biaryl compound 3 in 98% yield in the presence of
-CD (0.5 mol%) at 100°C for 1 hour (table 3, entry 11).

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Table 3
Variation of the nature of PdII-based species for the Suzuki-Miyaura coupling starting from 4-
bromoacetophenone (1) with or without -CD.
PhB(OH)2 (2) 1.5 equiv
PdII 0.5 mol%
-CD 0-0.5 mol%
K2CO3 2 equiv
O
O
Br
H2O
25-100°C, 1-24 h
1
3
Yielda
(%)
PdII
Amount
Temp.
(°C)
Time
(h)
Entry
based species (mol%)
1
2
Pd(OAc)2
Pd(OAc)2
PdI2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
100
25
1
97b (87)c
94b (63)c
64b (61)c
4b (1)c
24
1
3
100
25
4
PdI2
24
1
5
PdCl2
100
25
93b (85)c
96b (14)c
91b (78)c
25b (8)c
39b (28)c
1b (1)c
6
PdCl2
24
1
7
Na2PdCl4
Na2PdCl4
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
100
25
8
24
1
9
100
25
10
11
12
24
1
100
25
98b (77)c
68b (8)c
24
a
Determined by GC methods. Products were compared with authentic samples.
b Reaction conditions: 1 (0.25 mmol), PhB(OH)2 (0.375 mmol), Pd(OAc)2 (0.5 mol%), -CD
(0.5 mol%), K2CO3 (0.50 mmol), water (2 mL), 25-100°C, 1-24 h.
c Reaction conditions: 1 (0.25 mmol), PhB(OH)2 (0.375 mmol), Pd(OAc)2 (0.5 mol%), K2CO3
(0.50 mmol), water (2 mL), 25-100°C, 1-24 h.

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As a result of the previous experiments, four methods were defined in order to establish
different optimized reaction conditions (variations in the nature of the base and palladium
source, the temperature, the time and the presence or absence of the mass transfer promoter -
CD) (Table 4).
Table 4
Four optimized reaction conditions for the Suzuki-Miyaura coupling starting from aryl
bromide with or without -CD.
Amount
Temp.
(°C)
Time
(h)
Entry
of -CD
(mol%)
A[a]
B[b]
C[c]
D[d]
0.5
-
100
100
25
1
1
0.5
-
24
24
25
a
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), PdII (0.5
mol%), -CD (0.5 mol%), K2CO3 (0.50 mmol), water (2 mL), 100°C, 1 h.
b
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), PdII (0.5
mol%),
K2CO3
(0.50
mmol),
water
(2
mL),
100°C,
1
h.
c
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), PdII (0.5
mol%), -CD (0.5 mol%), K2CO3 (0.50 mmol), water (2 mL), 25°C, 24 h.
d
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), PdII (0.5
mol%), K2CO3 (0.50 mmol), water (2 mL), 25°C, 24 h.
Using these four methods (Table 4), a range of arylboronic acids with different electronic and
steric demands in the Suzuki-Miyaura reaction were screened. Arylbromides with various
functional groups efficiently reacted with boronic acids (Table 5) to give the Suzuki-Miyaura
product with good to excellent yield. Using methods A and B at 100°C for 1 hour, the Suzuki-
Miyaura products were obtained with higher yields than those that used methods C and D at
25°C for 24 hours, respectively, except for the 4-bromobenzaldehyde without -CD (Table 5,
entries 5 and 6). The presence of native -CD often gave better yields for the Suzuki-Miyaura
coupling than the reaction without the mass transfer promoter (Table 5). The yields should be

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a function of the solubility of the starting material and reagents in water. Nevertheless, the
presence of an electron withdrawing group in the 4- position of the aryl bromide afforded the
biaryl derivatives in high yields using methods A and C (Table 5, entries 1, 2 and 5-8).
However, the presence of a donating group often gave weaker yields (Table 5, entries 4, 9 and
10) with the exception of the methoxy group at 100°C (Table 5, entry 3). The substitution of
phenylboronic acid (Table 5, entries 1, 2, 5 and 6) by 4-acetylphenylboronic acid (Table 5,
entries 13-16) gave the target biaryl compounds in lower yields (46-83% vs 90-99%). Our
methodology did not permit to obtain the biaryl compound starting from aryl chlorides (Table
5, entries 11 and 12). Starting from 2-bromotoluene and 2-bromoanisole in the presence of
phenylboronic acid, the use of methods A-D permitted the synthesis of the target biaryl
derivatives in low yields (Table 5, entries 17-20). In our conditions, the steric hindrance did
not allow the C-C coupling with yields higher than 22%. In addition, the use of 2-
bromotoluene led to an unseparable mixture of the target compound and biphenyl obtained by
homocoupling. In our hands, the best result for the synthesis of 2-methylbiphenyl was 19%
yield and determined by NMR estimation.
Table 5
Suzuki-Miyaura coupling of various aryl bromides with arylboronic acids with or without -
CD.
Pd(OAc)2 0.5 mol%
X
B(OH)2
-CD 0-0.5 mol%
K2CO3 2 equiv
+
R2
R1
H2O
R1
R2
25-100°C, 1-24 h
Yielda
(%)
X
R1
Entry
R2

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1
2
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
4-(CO)CH3
4-(CO)CH3
4-OCH3
4-OCH3
4-CHO
H
H
H
H
H
H
H
H
H
H
H
H
95b (84)c
90d (59)e
97b (68)c
22d (10)e
99b (55)c
90d (84)e
91b (76)c
84d (34)e
60b (51)c
8d (3)e
3
4
5
6
4-CHO
7
4-CN
8
4-CN
9
4-NH2
10
11
12
13
14
15
16
17
18
19
20
4-NH2
4-(CO)CH3
4-(CO)CH3
2b (1)c
1d (1)e
4-(CO)CH3 4-(CO)CH3
4-(CO)CH3 4-(CO)CH3
62b (58)c
46d (42)e
80b (78)c
83d (36)e
19b,f (10)c,f
14d,f (7)e,f
22b (12)c
19d (7)e
4-CHO
4-CHO
2-CH3
4-(CO)CH3
4-(CO)CH3
H
H
H
H
2-CH3
2-OCH3
2-OCH3
Isolated
a
yields.
b
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), Pd(OAc)2
(0.5 mol%), -CD (0.5 mol%), K2CO3 (0.50 mmol), water (2 mL), 100°C, 1 h.
c
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), Pd(OAc)2
(0.5
mol%),
K2CO3
(0.50
mmol),
water
(2
mL),
100°C,
1
h.
d
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), Pd(OAc)2
(0.5 mol%), -CD (0.5 mol%), K2CO3 (0.50 mmol), water (2 mL), 25°C, 24 h.
e
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), Pd(OAc)2

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(0.5
mol%),
K2CO3
(0.50
mmol),
water
(2
mL),
25°C,
24
h.
f The yield was determined by NMR estimations.
Starting from 2-bromothiophene and 2-bromonaphthalene in the presence of phenylboronic
acid, the use of methods A-D afforded the target biaryl compounds (Table 6). In all cases, the
presence of native -CD permitted to obtain the target biaryl compounds in better yield (at
100°C, 41 vs 18% and at 25°C 61 vs 1%) (Table 6). It was notable that, using method A, 2-
bromonaphthalene did not afford the higher yield (Table 6, entry 1) as observed for the other
aryl bromide (Table 5). One plausible explanation was that the inclusion complex between
native -CD and 2-bromonaphthalene was more stable at 25°C than at 100°C affording a
better reactivity for the Suzuki-Miyaura coupling in neat water. 2-Bromothiophene gave no
coupling product due to a potent instability in water (Table 6, entries 3 and 4). Moreover, it
should be possible that a potent interaction between the sulphur atom and the palladium
complex afforded a desactivation effect on the rate of the reaction.
Table 6
Suzuki-Miyaura coupling starting from 2-thiophene and 2-bromonaphthalene with or without
-CD.
Yielda
R1
Entry
(%)
1
2
3
4
2-naphthyl 41b (18)c
2-naphthyl
2-thienyl
2-thienyl
Isolated
62d (1)e
3b (0)c
2d (1)e
a
yields.
b
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), Pd(OAc)2
(0.5 mol%), -CD (0.5 mol%), K2CO3 (0.50 mmol), water (2 mL), 100°C, 1 h.
c
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), Pd(OAc)2
(0.5
mol%),
K2CO3
(0.50
mmol),
water
(2
mL),
100°C,
1
h.
d
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), Pd(OAc)2
(0.5 mol%), -CD (0.5 mol%), K2CO3 (0.50 mmol), water (2 mL), 25°C, 24 h.

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e
Reaction conditions: aryl bromide (0.25 mmol), arylboronic acid (0.375 mmol), Pd(OAc)2
(0.5 mol%), K2CO3 (0.50 mmol), water (2 mL), 25°C, 24 h.
In order to study the variations of the size of the internal cavity and the hydrophily of the
oligosaccharides, the replacement of -CD by -CD, -CD, DIMEB of -CD, per-methylated
-CD and per-methylated -CD was effected using methods A and C. In our hand, none of the
CD analogues gave the Suzuki-Miyaura coupling products with yields higher than those
obtained with native -CD. Moreover, the replacement of cyclodextrin by D-glucose in
different concentrations (0.5 mol% to 3.5 mol%) did not permit an increase in the yield of the
target compound.
The addition of phenylboronic acid (2, 0.37 mM) and Pd(OAc)2 (0.5mol%) in neat water as
solvent afforded spherical nanoparticules, 4.63-8.25 nm in size (Figure 2). Similar
nanoparticules were observed during the Suzuki-Miyaura reactions. In our study, the
dispersibility of nanoparticules in water was neglected.
Fig. 2. TEM micrographs obtained from a mixture of phenylboronic acid (2, 0.37 mM) and
Pd(OAc)2 (0.5mol%) in H2O at 25°C.
The X-ray photoelectron spectroscopy (XPS) analysis of the nanoparticules obtained by: (i)
addition of phenylboronic acid (2, 0.37 mM) and Pd(OAc)2 (0.5mol%) in water; (ii) after our
Suzuki-Miyaura methods (methods A-D) revealed that among the palladium species detected,
Pd(II) and Pd(0), the latter was formed as a major phase.

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4. Conclusion
In summary, the Suzuki-Miyaura reaction was used to obtain a large range of commercial
compound with high added value. From the view point of green chemistry, different methods
have been developed to produce biaryl derivatives with various steric and electronic
substituents in good yields. Our optimization furnished four efficient methods for the
ligandless Suzuki-Miyaura reaction using Pd(OAc)2 as a catalyst (0.5 mol%) in neat water at
25°C and 100°C : two methods without additive and two methods with the presence of low
amount of native -CD (0.5 mol%). In the literature the amount of -CD was higher and often
similar with the concentration of the starting material. In our hands, the use of native -CD
often gave better yield than the reaction without the mass transfer promoter. Starting from
hindered aryl bromide such as 2-bromonaphthalene, the presence of native -CD permitted to
furnish the target compound with a significant enhancement of the yield (at 100°C, 41 vs 18%
and at 25°C 61 vs 1%). Using our methodology, Pd(OAc)2 is reduced in situ to form
catalytically Pd(0) species in nanoparticle forms and the catalytic system cannot be recycled.
To the best of our knowledge, this is the first time that the Suzuki-Miyaura reaction has been
performed under such green conditions.
Acknowledgements
Authors are grateful to the Région Picardie and Europe (FEDER) for their financial support.
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Graphical abstract
100°C
1 h
Pd(OAc)2 0.5 mol%
Ligandless
O
Br
O
-CD 0 or 0.5 mol%
+
25°C
24 h
K2CO3
H2O
(HO)2B

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Highlights
Suzuki cross-coupling reactions using ligand-free palladium Pd(OAc)2
Suzuki cross-coupling was performed in water
The method was applied successfully to a number of brom substituted reactants
The presence of low amount of native b-CD (0.5 mol%)