Unexpected multifunctional effects of methylated cyclodextrins in a palladium charcoal-catalyzed Suzuki-Miyaura reaction

Article abstract of DOI:10.1021/ol061836v

(Chemical Equation Presented) Native and modified cyclodextrins (CDs) have shown polyvalent properties in a biphasic Pd/C-catalyzed Suzuki-Miyaura reaction. In addition to their mass transfer ability, the CDs favored the dispersion of the catalyst in water. With the randomly methylated CDs (RaMe-β-CD), the gains of initial activities were multiplied by factors between 3.8 and 343 depending on the nature of the substrates. The reusability of the system was also demonstrated.

Full text of DOI:10.1021/ol061836v

ORGANIC
LETTERS
2
006
Vol. 8, No. 21
823-4826
Unexpected Multifunctional Effects of
Methylated Cyclodextrins in a Palladium
4
Charcoal-Catalyzed Suzuki
Reaction
−Miyaura
Andy Cassez, Anne Ponchel,* Fr e´ d e´ ric Hapiot, and Eric Monflier
Laboratoire de Physico-Chimie des Interfaces et Applications, FRE CNRS 2485,
F e´ d e´ ration CheVreul FR CNRS 2638, Facult e´ des Sciences Jean Perrin,
UniVersit e´ d’Artois, rue Jean SouVraz, S.P.18-62307 LENS C e´ dex, France
anne.ponchel@uniV-artois.fr
Received July 25, 2006
ABSTRACT
Native and modified cyclodextrins (CDs) have shown polyvalent properties in a biphasic Pd/C-catalyzed Suzuki
−Miyaura reaction. In addition
to their mass transfer ability, the CDs favored the dispersion of the catalyst in water. With the randomly methylated CDs (RaMe-
â
-CD), the
gains of initial activities were multiplied by factors between 3.8 and 343 depending on the nature of the substrates. The reusability of the
system was also demonstrated.
The formation of C-C bonds has long remained a difficult
task until the recent development of the Suzuki-Miyaura
palladium-catalyzed reaction. A large number of biaryl
In this context, efforts have been made to develop ecological
ligandless Pd-catalyzed processes. Nevertheless, the indus-
trial tonne-scale production is still limited by the low
activities (due to the opposite solubilities of both reactants),
the severe experimental conditions, and the presence of
byproducts resulting from homocoupling reactions.6
5
1
compounds are now at hand that find applications in many
fields including pharmaceutics, cosmetics, agrochemistry,
liquid crystalline materials, and conducting polymers. Ex-
perimentally, the coupling reactions between aryl halides and
arylboronic derivatives were mainly performed using a
(4) (a) Datta, A.; Plenio, H. Chem. Commun. 2003, 1504-1505. (b)
Strimbu, L.; Liu, J.; Kaifer, A. E. Langmuir 2003, 19, 483-485. (c)
McNulty, J.; Capretta, A.; Wilson, J.; Dyck, J.; Adjabeng, G.; Robertson,
A. Chem. Commun. 2002, 1986-1987. (d) Moreno-Manas, M.; Pleixats,
R.; Villarroya, S. Organometallics 2001, 20, 4524-4528. (e) Li, Y.; Hong,
X. M.; Collard, D. M.; El-Sayed, M. A. Org. Lett. 2000, 2, 2385-2388. (f)
Hapiot, F.; Lyskawa, J.; Bricout, H.; Tilloy, S.; Monflier, E. AdV. Synth.
Catal. 2004, 346, 83-89. (g) Nishimura, M.; Ueda, M.; Miyaura, N.
Tetrahedron 2002, 58, 5779-5787. (h) Shaughnessy, K. H.; Booth, R. S.
Org. Lett. 2001, 3, 2757-2759.
(5) (a) Sakurai, H.; Tsukuda, T.; Hirao, T. J. Org. Chem. 2002, 67, 2721-
2722. (b) Artok, L.; Bulut, H. Tetrahedron Lett. 2004, 45, 3881-3884. (c)
Shimizu, K.; Kan-no, T.; Kodama, T.; Hagiwara, H.; Kitayama, Y.
Tetrahedron Lett. 2002, 43, 5653-5655. (d) Gruber, M.; Chouzier, S.;
Koehler, K.; Djakovitch, L. Appl. Catal. A: General 2004, 265, 161-169.
(e) Lipshutz, B. H.; Sclafani, J. A.; Blomgren, P. A. Tetrahedron 2000, 56,
2139-2144. (f) Lu, G.; Franz e´ n, R.; Zhang, Q.; Xu, Y. Tetrahedron Lett.
2005, 46, 4255-4259. (g) Bhattacharya, S.; Srivastava, A.; Sengupta, S.
Tetrahedron Lett. 2005, 46, 3557-3560.
2
phosphine-palladium catalyst in homogeneous, heteroge-
3
4
neous, or biphasic systems. Though the activities were
generally good and the reusability of these systems was often
demonstrated, the use of phosphine ligands did not constitute
an eco-friendly alternative from an industrial point of view.
(
1) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. AdV. Synth. Catal. 2006,
48, 609-679. (c) Farina, V. AdV. Synth. Catal. 2004, 346, 1553-1582.
3
(
2) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168.
(
3) (a) Varma, R. S.; Naicker, K. P. Tetrahedron Lett. 1999, 56, 8661-
8
664. (b) Inada, K.; Miyaura, N. Tetrahedron 2000, 40, 439-442. (c)
Paetzold, E.; Jovel, I.; Oehme, G. J. Mol. Catal. 2004, 214, 241-247. (d)
Paetzold, E.; Oehme, G.; Fuhrmann, H.; Richter, M.; Eckelt, R.; Pohl, M.-
M.; Kosslick, H. Microporous Mesoporous Mater. 2001, 44-45, 517-
5
22.
1
0.1021/ol061836v CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/22/2006

Our continual exploration of the use of modified R- and
â-cyclodextrins (cyclic oligomers made of six or seven
glucopyranose units, respectively; Scheme 1) as mass transfer
Scheme 1. Native and Modified â-Cyclodextrins7
Figure 1. Phenyl iodide conversion (%) after a 24 h reaction with
differently shaped CDs. Native â-CD: R ) H. RaMe-R-CD and
3
RaMe-â-CD: R ) H or CH (random distribution, 1.8 methyl
promoters in biphasic catalytic processes 4f,8 led us to report
here their beneficial contribution to the performances of a
Suzuki-Miyaura reaction between aryl iodides and phenyl-
boronic acid in mild experimental conditions using Pd/C as
the catalyst. The activity, selectivity, and reusability of the
catalyst have been studied, and an unexpected role of
cyclodextrins (CDs) was clearly identified.
groups on average per glucopyranose unit). HP-â-CD: R ) H or
CH CH(OH)-CH (5.6 substituents on average per cyclodextrin
on the C-2 position). CrysMe-â-CD: R ) H or CH (5 methyl
groups on average per cyclodextrin on the C-2 or C-3 position).
TriMe-â-CD: R ) CH . 1-SBE-â-CD: R ) H or (CH -SO Na
one sulfobutyl group per cyclodextrin on the C-6 position).
HPTMA-â-CD: R ) H or CH CH(OH)-CH -N(CH ) Cl (1.1
2
3
3
3
2
)
4
3
(
2
2
3 3
substituents on average per cyclodextrin on the C-2). Reaction
conditions: C I (0.5 mmol), C B(OH) (0.65 mmol), Na CO
1.5 mmol), native or modified cyclodextrins (0 or 0.25 mmol),
internal standard C12 26 (0.3 mmol), Pd/C (5 mg, 9%, 4.2 µmol of
Pd) in H O (3 g) and heptan (3 g) at 40 °C.
H
6 5
H
6 5
2
2
3
First, several cyclodextrins have been considered to
determine the impact of their structure on the conversion
and initial activity of a cross-coupling reaction between
(
H
2
9
phenyl iodide and phenylboronic acid. When comparing the
conversions after 24 h (Figure 1), methylated cyclodextrins
cationic (HPTMA-â-CD) cyclodextrins proved inadequate
to improve the performance of the system. Finally, when
the reaction was performed with the constitutive building
blocks of the CD (methyl-R-D-glucopyranoside), the conver-
sion was only slightly better (12%) than that measured
without CD (10%) proving that the CD cavity was respon-
sible for the better performance of the system. In terms of
initial activities, it could be noticed that RaMe-â-CD
remained the best carrier to promote the Suzuki reaction (44
(RaMe-R-CD and RaMe-â-CD) appeared to be the most
efficient (64 and 62% biphenyl, respectively).
Nevertheless, RaMe-R-CD does not appear to be a
valuable mass transfer promoter because a precipitate is
observed in the end of the reaction, compromising the
reusability of the catalytic system. Indeed, NMR analysis
proved that RaMe-R-CD precipitates in a heptan/biphenyl
mixture. Interestingly, the efficacy of methylated cyclodex-
trins strongly depended on their substitution rate. Indeed,
the permethylated TriMe-â-CD gave a lower 38% conversion
and the partially methylated CrysMe-â-CD led to 30% of
biphenyl in the same experimental conditions. The more
hydrophilic hydroxypropylated HP-â-CD was slightly less
efficient (28% biphenyl), whereas anionic (1-SBE-â-CD) or
-
1
mol h /mol Pd).
To investigate the scope of limitations of the RaMe-â-
CDs as supramolecular carriers, the cross-coupling reaction
of various monosubstituted phenyl iodide derivatives with
phenylboronic acid has been performed. The results are
gathered in Table 1.
Whatever the substrate, addition of RaMe-â-CD always
improved the catalytic activity, but the relative reaction rate
(
6) LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R., Jr. Org. Lett.
2
001, 3, 1555-1557.
(
7) Szejtli, J. Chem. ReV. 1998, 98, 1743-1753.
(ratio of the initial activity with RaMe-â-CD to that without
(8) (a) Hapiot, F.; Tilloy, S.; Monflier, E. Chem. ReV. 2006, 106, 767-
RaMe-â-CD) proved sensitive to both the nature and the
position of the substituent. For example, though the activity
measured for the p-acetylphenyl iodide was higher than that
7
81. (b) Cassez, A.; Ponchel, A.; Bricout, H.; Fourmentin, S.; Landy, D.;
Monflier, E. Catal. Lett. 2006, 108, 209-214. (c) Kirschner, D.; Green,
T.; Hapiot, F.; Tilloy, S.; Leclercq, L.; Bricout, H.; Monflier, E. AdV. Synth.
Catal. 2006, 348, 379-386. (d) Leclercq, L.; Hapiot, F.; Tilloy, S.;
Ramkisoensing, K.; Reek, J. N. H.; van Leeuwen, P. W. N. M.; Monflier,
E. Organometallics 2005, 24, 2070-2075. (e) Blach, P.; Landy, D.;
Fourmentin, S.; Surpateanu, G.; Bricout, H.; Ponchel, A.; Hapiot, F.;
Monflier, E. AdV. Synth. Catal. 2005, 347, 1301-1307.
-
1
measured for the biphenyl iodide (116 vs 24 mol h /mol
Pd, respectively), the relative reaction rate for the latter was
much higher than that obtained for the former (343 vs 6.1,
respectively). These results are clearly connected to the water
(9) The cross-coupling reaction tests have been performed as follows:
in a Schlenk tube, 105 mg of phenyl iodide (0.5 mmol) and 52 mg of
dodecane in 3 g of heptan were poured under a N2 atmosphere on an aqueous
solution (3 g) containing cyclodextrin (0.25 mmol), 81 mg of phenylboronic
acid (0.65 mmol), 160 mg of sodium carbonate (1.5 mmol), and 5 mg of
Pd/C powder (9%, 4.2 µmol of Pd). The reaction was heated at 40 °C and
stirred for 24 h. Conversion in biphenyl was measured by GC and carried
out on a Perkin-Elmer Clarus GC500 gas chromatograph equipped with a
10
solubility of the substrate. In fact, the more water insoluble
the substrate is, the more important the mass transfer
promoter contribution is.
(10) The water solubility denoted by W (mol L-1) in Table 1 has been
evaluated for the different iodide derivatives using an interactive analysis
predictor method described in the following paper: Tetko, I. V.; Tanchuk,
V. Y.; Kasheva, T. N.; Villa, A. E. P. J. Chem. Inf. Comput. Sci. 2001, 41,
1488-1493.
5
% diphenyl/95% dimethyl silicone capillary column (25 m × 0.25 mm)
and a flame ionization detector. The nature of the products was determined
by comparison of their retention times with those of the commercial
products.
4824
Org. Lett., Vol. 8, No. 21, 2006

Table 1. Suzuki-Miyaura Reaction Using Monosubstituted
6 4
Aryl Iodides (R′C H
I) and Phenyl Boronic Acid as Substratesg
log10
a
i
without b
a
i
with
relative
a
b
c
conversiond
65
R′
p-H
(W)
RaMe-â-CD RaMe-â-CD
rate
-3.07
-3.41
-4.05
-2.74
-2.00
-2.12
-5.28
-3.26
-3.23
-3.75
5.1
18
0.5
19
2.2
0.98
0.07
0.48
0.76
0.45
47
9.2
6.0
15.6
6.1
3.8
e
p-CN
108
100
p-CF
3
7.8
86
100
f
p-COCH
3
116
8.4
p-NH
2
75
49
31
15
26
37
p-OCH
p-Ph
3
34
24
5.6
7.0
8.2
34.7
343
11.7
9.2
o-CH
3
m-CH
3
p-CH
3
18.2
a
10
b
Logarithm of calculated water solubility (W) at 20 °C.
Initial
-
1
c
activities in mol h /mol Pd. Defined as the ratio of the initial catalytic
activity in the presence of cyclodextrin to the initial catalytic activity without
d
cyclodextrin. Conversion in the presence of RaMe-â-CD (%) after 24 h.
Figure 2. Reusability of the catalytic system. Reaction condi-
tions: p-CH COC H I (0.5 mmol), C H B(OH) (1.65 mmol), Na -
e
Conversion in the presence of RaMe-â-CD (%) after 1.5 h of reaction.
3
6
4
6
5
2
2
f
Conversion in the presence of RaMe-â-CD (%) after 2 h of reaction.
CO
0.3 mmol), Pd/C (5 mg, 9%, 4.2 µmol of Pd) in H
n-dibutyl ether (3 g) at 40 °C.
3
(1.5 mmol), RaMe-â-CD (0.25 mmol), internal standard C12
H
26
g
Reaction conditions: R′C6H4I (0.5 mmol), C6H5B(OH)2 (0.65 mmol),
(
2
O (3 g) and
Na2CO3 (1.5 mmol), RaMe-â-CD (0.25 mmol), internal standard C12H26
(
0.3 mmol), Pd/C (5 mg, 9%, 4.2 µmol of Pd) in H2O (3 g) and n-dibutyl
ether (3 g) at 40 °C.
preciable loss of activity was observed after three consecutive
runs. The initial activities were only slightly decreased (229
vs 187 mol h /mol Pd for the first and third runs,
respectively), and 98% conversion was still achieved after
2 h in the third experiment.
In terms of conversion, substrates with an electron-
-
1
withdrawing substituent (CN, CF
rapidly converted than the substrates having an electron-
donor group (CH , NH , OCH ). For instance, although the
3
, or COCH
3
) were more
3
2
3
water solubility of p-trifluoromethylphenyl iodide and p-
cyanophenyl iodide is close to that of p-methylphenyl iodide,
the conversions reached 100 and 86% for the substrates with
an electron-withdrawing substituent and only 37% for the
substrates containing an electron donor group. This reactivity
tendency was in line with that generally observed for
palladium-catalyzed cross-coupling reactions.11
All the above results have been first rationalized in terms
of molecular recognition processes between the aryl iodides
and the cyclodextrins. Indeed, it was initially postulated that
the beneficial effect of CDs was due to their capacity to
transfer organic substrates in the aqueous phase via the
formation of inclusion complexes. Nevertheless, the differ-
13
ences in the formation constant values between phenyl
In terms of chemoselectivity, RaMe-â-CD strongly favored
the selective formation of cross-coupling compounds. Thus,
the percentage of homocoupling products remained low (1-
iodide and the CD derivatives are too low to explain the
differences in activity and conversion (K
f
(â-CD/C
6
H
5
I) )
-1
-1
6
22 M ; K
f
(HP-â-CD/C
6 5
H I) ) 716 M ; K
f
(RaMe-â-CD/
5%) regardless of the substrate.
-1
6 5
C H I) ) 785 M ). Consequently, the recognition process
Interestingly, it is worth mentioning that RaMe-â-CD was
could not constitute the only explanation of the above results.
In fact, we have unexpectedly found that the cyclodextrins
can improve the dispersion of the Pd/C catalyst in water.
As an example, the triphasic organic/aqueous/catalyst system
without CD and with native â-CD or RaMe-â-CD are
displayed in Figure 3. Even though the Pd/C catalyst was
located at the organic/aqueous interface without CD, a
homogeneous distribution of the Pd/C catalyst appeared in
the aqueous phase when the CD was added to the medium.
Moreover, the homogeneity of the Pd/C catalyst suspension
depends on the nature of the CD. Indeed, a much more
homogeneous distribution of the Pd/C catalyst in the aqueous
phase was obtained with the RaMe-â-CD compared to the
native â-CD.
also shape-selective because the three methylphenyl iodide
isomers gave different initial activities. The best relative
reaction rate was measured for the p-methylphenyl iodide
(18.2 vs 11.7 for the o-methylphenyl iodide and 9.2 for the
m-methylphenyl iodide) whose structure seemed more ap-
propriate for the inclusion in the CD cavity to occur.
Finally, the reusability of the catalytic system has been
evaluated on p-acetylphenyl iodide (Figure 2).12 No ap-
(
11) Beleskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009-
066.
12) Catalytic experiments for reusability were carried out as follows:
in a Schlenk tube under a nitrogen atmosphere were poured 5 mg of Pd/C
9%, 4.2 µmol of Pd), 160 mg of Na2CO3 (1.5 mmol), 205 mg of
phenylboronic acid (1.65 mmol), 327 mg of RaMe-â-CD (0.25 mmol), and
g of water. The mixture was kept at 40 °C for 10 min. In another Schlenk
3
(
(
3
This phenomenon could be explained by assuming an
adsorption of the cyclodextrin on the surface of the Pd/C
catalyst. Indeed, adsorption of CD increases the hydrophilic
tube were dissolved 125 mg of p-acetylphenyl iodide (0.5 mmol) and 52
mg of dodecane (0.3 mmol) in n-dibutyl ether (3 g). The solution was
transferred by cannula into the previous one. The resulting mixture was
stirred for 2 h at 40 °C. After decantation, the organic phase was recovered
by cannula and the aqueous phase was washed three times with 10 mL of
diethyl ether. The aqueous phase was then gently pumped in a vacuum to
remove any trace amount of diethyl ether and reloaded with phenylboronic
acid, p-acetylphenyl iodide, dodecane, and n-dibutyl ether as described
above.
(13) Formation constants have been determined as described in the
following paper: Fourmentin, S.; Outirite, M.; Blach, P.; Landy, D.; Ponchel,
A.; Monflier, E.; Surpateanu, G. J. Hazard. Mater. 2006, in press, doi:
10.1016/j.jhazmat.2006.06.090.
Org. Lett., Vol. 8, No. 21, 2006
4825

on the carbons also widely contributes to the increase in the
catalytic activity. The performances of the studied catalytic
system are likely a consequence of a combination of two
effects: the well-known mass transfer promoter properties
of the CDs and their dispersing role on the Pd/C catalyst.
Experiments are currently underway to understand how
cyclodextrins interact with the Pd/C particles and which of
them constitutes the best dispersing agent. Though the
interactions between CDs and metallic nanoparticles have
1
5
already been explored, this is the first example of CD-
stabilized Pd/C particles for a catalytic application.
Figure 3. Pd/C distribution in a mixture of water/heptan (10 mg/
0 mL/10 mL): (a) without CD; (b) with 57 mg of native â-CD
0.05 mmol); (c) with 66 mg of RaMe-â-CD (0.05 mmol).
1
(
Nowhere else could such a combination of beneficial
functional properties be found. As a matter of fact, RaMe-
â-CD appeared to be a multifunctional supramolecular entity
capable of dispersing and stabilizing Pd/C particles in water,
transferring the substrate from the organic to the aqueous
phase, recognizing selectively the substrate structure (shape
selectivity), and avoiding homocoupling side reactions.
Moreover, the advantages of this CD-involving catalytic
system also lie in its reusability, the low cost of their
constituents, and the low temperature at which it proceeds.
All these features give the above triphasic catalytic system
a substantial advantage over its main rivals.
character of the support, making its dispersion easier in the
aqueous phase. It should be noticed that a previous study
has recently shown that cyclodextrins can be adsorbed on
activated carbons and that this adsorption is dependent on
the number of glucose units of the CD and the size of the
carbon pores.14 In our case, the affinity of the RaMe-â-CD
for the Pd/C catalyst has been confirmed by isothermal
adsorption studies. Thus, the adsorption isotherm is of
Langmuir type and the sorption capacity of the RaMe-â-
-
1
CD on the Pd/C catalyst reaches 175 µmol g at the
monolayer.
OL061836V
Concurrently to the enhancement of activity due to the
CD mass transfer promoter, this dispersing effect of CDs
(15) (a) Nowicki, A.; Zhang, Y.; L e´ ger, B.; Rolland, J.-P.; Bricout, H.;
Monflier, E.; Roucoux, A. Chem. Commun. 2006, 296-298. (b) Palaniap-
pan, K.; Xue, C.; Arumugam, G.; Hackney, S. A.; Liu J. Chem. Mater.
2
006, 18, 1275-1280. (c) Giuffrida, S.; Ventimiglia, G.; Petralia, S.; Conoci,
(
14) Abe, I.; Kukuhara, T.; Kawasaki, N.; Hitomi, M.; Kera, Y. J. Colloid
S.; Sortino, S. Inorg. Chem. 2006, 45, 508-510. (d) Liu, Y.; Male, K. B.;
Bouvrette, P.; Luong J. H. T. Chem. Mater. 2003, 15, 4172-4180.
Interface Sci. 2000, 229, 615-619.
4826
Org. Lett., Vol. 8, No. 21, 2006