Phosphine-free Heck reactions in aqueous medium using hydroxypropylated cyclodextrins as supramolecular hosts

Article abstract of DOI:10.1016/j.tetlet.2007.09.095

It was made possible to carry out Heck reactions in aqueous media using hydroxypropylated cyclodextrins. Best yields were obtained with Pd/CaCO₃ as catalyst reservoir. Recycle of the whole system has been made possible up to three times.

Full text of DOI:10.1016/j.tetlet.2007.09.095

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8153–8156
Phosphine-free Heck reactions in aqueous medium using
hydroxypropylated cyclodextrins as supramolecular hosts
a
b
b
´
Jaqueline D. Senra, Luiz Fernando B. Malta, Andrea Luzia F. de Souza,
b
a
a,b,
*
´
Marta E. Medeiros, Lucia C. S. Aguiar and O. A. C. Antunes
aNu´cleo de Pesquisas de Produtos Naturais, CCS, Bloco H, Cidade Universita´ria, Rio de Janeiro RJ 21941-614, Brazil
bInstituto de Quı´mica, Universidade Federal do Rio de Janeiro, av. Athos da Silveira Ramos 149, CT Bloco A,
Cidade Universita´ria, Rio de Janeiro RJ 21941-909, Brazil
Received 15 August 2007; revised 12 September 2007; accepted 14 September 2007
Available online 20 September 2007
Abstract—It was made possible to carry out Heck reactions in aqueous media using hydroxypropylated cyclodextrins. Best yields
were obtained with Pd/CaCO3 as catalyst reservoir. Recycle of the whole system has been made possible up to three times.
Ó 2007 Elsevier Ltd. All rights reserved.
Palladium-catalyzed cross-coupling reactions are of
major importance in organic chemistry, providing good
protocols to the synthesis of elaborated organic com-
pounds from simpler blocks.1 From ecological and
process development perspectives, efforts to produce
cheaper and environmentally safe methods have recently
been the focus of attention in the scientific community.
In this respect, some processes have appeared to be effi-
ciently performed in aqueous environments,3 including
the Heck reaction for certain water-soluble aryl iodides
and bromides.4 In addition, there has been a great
search for phosphine-free approaches along with the
use of ligand-free palladium.2a–c Even though the latter
case offers advantages, most of these underligated sys-
tems have an inherent instability and the precise control
of the parameters that govern the efficiency in aqueous
catalytic reactions may be a difficult task. On the other
hand, the use of innovative additives, such as water-
soluble polymers, dendrimers, membranes and specific
ligands, have appeared as interesting alternatives to
increase the efficiency and selectivity, acting in the
stabilization of Pd nanoclusters.5
phobic internal cavity can include lipophilic molecules,
causing significant increase of their solubility in polar
solvents, for example, water, which allows better acces-
sibility to aqueous reactions. CDs show catalytic activity
in several reactions, including Diels–Alder reactions,6d
aromatic electrophilic substitution6e and hydrolysis of
DNA.6f
In the field of organometallic chemistry, the ability of
CDs is also involved in the formation of host–guest
adducts with organometallic complexes, which can be
used in technological applications.7 Indeed, the effect
of methylated cyclodextrins in biphasic Suzuki reactions
has recently been demonstrated, where their role as mass
transfer promoters appeared to be very efficient.8
In order to explore the potential of CDs as catalytic
promoters in aqueous Heck reactions and from the
standpoint of recycling, we report here the palladium-
catalyzed cross-coupling of aryl halides with methyl
acrylate in the presence of hydrophilic 2-hydroxy-propyl
a and b-CDs (a/b-HPCDs, Scheme 1). Our interest in
this work has been stimulated by the merging of three
Cyclodextrins (CDs), cyclic oligosaccharides consisting
of 6 (in a), 7 (in b) and 8 (in c) D-glucopyranose units
attached by a-1,4-linkages, have attracted substantial
attention in contemporary chemistry.6a–c Their hydro-
"Pd"
Ar
ArX +
CO2Me
CO2Me
alpha or beta HPCD
K2CO3, reflux, 4 h
X = I, Br
*
Corresponding author. Tel.: +55 21 25627818; fax: +55 21
25627559; e-mail: octavio@iq.ufrj.br
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.095

8154
J. D. Senra et al. / Tetrahedron Letters 48 (2007) 8153–8156
main factors: (i) the practical advantages on the use of
aqueous medium in Heck reactions,9 (ii) our continuous
attention in exploring host–guest supramolecular com-
plexes with CDs10 and (iii) the recently reported ability
of CDs to stabilize metal clusters.11
a
100
80
60
40
20
0
Firstly, the use of three different aqueous mixtures was
investigated in order to find the most appropriate condi-
tion. According to our successful results with the Pd/
CaCO3 catalyst,12b it was first used as a palladium
source. N,N-Dimethylformamide (DMF), an usual
solvent of choice for conventional Heck reactions, was
tested in proportions of DMF/H2O 1:9 and 1:2, respec-
tively. A biphasic medium was tested with CH2Cl2,
where the performance of hydroxypropylated CDs as
mass transfer agents could be evaluated.
0
0.005
0.01
0.015
0.02
alpha-HPCD / phenyl iodide
b
100
90
80
70
60
50
40
30
20
10
0
As shown in Figure 1, DMF/H2O ratio affects the cata-
lytic efficiency, probably because the increase in water
content reduces the ability of more hydrophilic CDs to
perform as mass transfer promoters. In addition, the
use of CH2Cl2/a or b-HPCD in a biphasic medium does
not appear to be a good condition to promote the Heck
reaction. Nevertheless, the presence of a or b-HPCD
always led to the highest yields, which means CDs
significantly enhanced the activity of the cross-coupling
reaction. When comparing the efficiency from the
viewpoint of CD cavity sizes, a-HPCD best performed
to improve the catalytic activity, as noticed by methyl
cinnamate yield after 4 h (74%).
0
0.01
0.02
0.5
1
alpha-HPCD/phenyliodide
Figure 2. Effect of the a-HPCD/phenyl iodide ratio on the yield of
methyl cinnamate after 4 h.
concentration to be used, which does not follow ‘the
greater, the better’ tendency.
To optimize phenyl iodide conversion, the a-HPCD-
to-phenyl iodide ratio was varied and its effect in reac-
tion yield was studied. All other reaction parameters
were kept constant (temperature, time and catalyst).
As observed in Figure 2, as a-HPCD-to-phenyl iodide
ratio was lowered from 1.0 to 0.01, the methyl cinna-
mate yield increased up to 92%. This can be explained
by another ratio, inclusion complex to free substrate,
that is, the stability constant of the inclusion compound,
which is significant for phenyl iodide with a-CDs
(>700 MÀ1).13 Then, the lowering of CD content frees
a part of this reactant from inclusion, which makes
them available to react. Although an equivalent
amount of a-HPCD contributes to the increase in the
efficiency, there seems to exist an optimum cyclodextrin
Control experiments with neat DMF in the presence and
in the absence of a-HPCD were also carried out. For the
latter, a good yield (80%) in a CD free medium was
observed, while very low methyl cinnamate yield was
noticed from DMF-a-HPCD solution. These results
show that in DMF there is no need of the addition of
a-HPCD to obtain a reasonable yield, by the contrary,
this addition jeopardizes the desired reaction.
The Heck reaction with CDs also proved to be influ-
enced by the palladium source used. Surprisingly, the
use of a homogeneous catalyst, Pd(OAc)2, resulted in
a low yield of the desired product. In addition, the most
classic supported catalyst (Pd/C) showed only a moder-
ate yield under the same conditions (Table 1, entries 1
and 2). Actually, a better dispersion in the aqueous
medium was noticed with the Pd/CaCO3 catalyst, which
can explain the outstanding increase in activity, com-
pared with Pd/C. This suggests a possible affinity by
adsorption of hydrophilic CDs on the surface of the
80
70
60
HP-alpha-CD
50
40
30
20
10
0
HP-beta-CD
without CD
Table 1. Effect of palladium source on the Heck reaction of phenyl
iodide with methyl acrylate in the presence of 1 mol % HPCD
Yielda (%)
DMF/H2O 1:2
DMF/H2O 1:9
CH2Cl2/H2O 1:1
Entry
Source (70 ppm Pd)
1
2
3
Pd(OAc)2
Pd/C
Pd/CaCO3
11
48
92
Figure 1. Methyl cinnamate yield (%) after 4 h with a- and b-HPCDs.
Reaction conditions: phenyl iodide (1.0 mmol), methyl acrylate
(1.3 mmol), K2CO3 (2.0 mmol), a- or b-HPCD (1.0 mmol), Pd/CaCO3
(5% w/w, 1 mol % Pd, 70 ppm), 15 mL, under reflux.
a Measured by GC–MS.

J. D. Senra et al. / Tetrahedron Letters 48 (2007) 8153–8156
8155
Pd/CaCO3 catalyst. A similar phenomenon was also
verified by Cassez and co-workers when using Pd/C in
the presence of methylated-b-CDs.8
by performing three consecutive runs. In this case, we
wanted to assure the presence of Pd(0)/Pd(II) soluble
species as the true catalysts, according to our previous
results.12 Therefore, after the convenient work-up, the
aqueous layer was reloaded and the coupling between
phenyl iodide and methyl acrylate was carried out in a
Pd/CaCO3 free solution. In all cases, no significant loss
of activity was observed between each run (Table 3).
Nevertheless, the small decrease in the methyl cinnamate
yield could be a consequence of the metal leaching from
the aqueous phase to the organic phase, whereas the
recovered organic phase was slightly coloured (entry 3).
In an attempt to extend the application of our system
under optimized conditions, the coupling of less reactive
halides, such as aryl bromide and chloride, with methyl
acrylate was carried out. As shown in Table 2, the
reactions with phenyl bromide and electron-deficient
or electron-rich aryl iodides resulted in moderate to
good yields (Table 2, entries 1, 3 and 4) but no appreciable
yield was obtained with the less reactive phenyl chloride
(entry 2).
In conclusion, the beneficial effect of sub-stoichiometric
amounts of a and b-HPCDs in aqueous Heck reactions,
using Pd/CaCO3 as catalyst reservoir, between aryl
halides and methyl acrylate was shown. In fact,
a-HPCD appeared to be the best supramolecular
mediator, contributing to a huge enhancement of
activity.
Some research groups have previously demonstrated the
beneficial effect of CDs in the presence of noble metals.
Recently, Luong and co-workers11d showed that the
presence of unmodified a,b and c-CDs limited the
coalescence of Au nanoparticles, allowing the synthesis
of very small (2–4 nm) clusters. Similar findings were
reported by Mandler and Willner14a and by the Kaifer’s
group14b involving the use of native or perthiolated
b-CDs as suitable Pd nanoparticle stabilizers.
The optimum performance of the system studied seems
to be a result of combining the cyclodextrin concentra-
tion and the choice of palladium source. As discussed,
the cyclodextrin to substrate (phenyl iodide) ratio of
0.01 gave the best yield along with the use of Pd/CaCO3
catalyst. In this regard, our results suggest a dual role of
a-HPCD whereas it increased the dispersion of the Pd/
CaCO3 and seems to stabilize Pd clusters, leached from
the support. So far, this is the first example of the use of
CDs in Heck reactions. Moreover, the catalytic system
can also be recovered and reused with reasonable
efficiency, which contributes to its versatility from an
industrial viewpoint. Further studies are currently
underway in our laboratory in order to better evidence
the interaction between a-HPCD and Pd colloids.
As an attempt to confirm the role of a-HPCD as a
stabilizer of possible clusters, the preparation of Pd
colloids was carried out by reduction of palladium chlo-
ride(II) with sodium borohydride in the presence and in
the absence of a-HPCD. After refluxing for 24 h, these
solutions were cooled to room temperature. At this
point, the reagents were added and the reaction mixtures
were refluxed for 4 h again. No appreciable yield of
methyl cinnamate was observed in the reaction carried
out in the absence of a-HPCD. Indeed, the formation
of Pd-black was detected in the end of the reaction, as
expected in the absence of stabilizing agents. On the
other hand, a moderate yield was obtained in the pres-
ence of CD (ꢀ50%), suggesting that the effectiveness in
the catalytic activity could be a result of CD-stabilized
Pd colloids. However, if compared to the results
discussed so far, the considerable lower methyl
cinnamate yield reveals that the conditions whereby Pd
colloids were prepared are not fully appropriate,
according to the preparation conditions described by
Mandler14a for reduction of bicarbonate to formate
mediated by Pd-b-CD colloids.
General procedure for Heck reactions: In a 100-mL two-
necked flask were placed aryl halide (1.0 mmol), methyl
acrylate (0.12 mL, 1.3 mmol), a-HPCD (11.8 mg,
0.01 mmol), potassium carbonate (276.4 mg, 2.0 mmol),
5 mL N,N-dimethylformamide and 10 mL distilled
water. After a complete homogeneity, Pd/CaCO3 pow-
der (5% w/w, 1 mol % Pd) was added to the flask and
the reaction was heated and stirred for 4 h at 120 °C.
Samples were then taken at regular time intervals and
analyzed by GC–MS. After centrifugation (5000 rpm),
the solid catalyst was recovered and the reaction
medium was washed three times with chloroform. The
organic phases were dried, evaporated and the isolated
products were collected and analyzed by GC–MS.15
The aqueous phase was stored for reusability.
Finally, to evaluate the possibility to recover our cata-
lytic system quantitatively, its reusability was examined
Table 2. Heck coupling of aryl halides with methyl acrylate using
a-HPCD
Entry
Aryl halide
Yieldc (%)
Reaction time (h)
Table 3. Recycling of the catalytic systema
1
2
3
4
PhBr
PhCl
p-MeOC6H4I
p-O2NC6H4I
60a (22)b
Traces
71a
7
24
4
Entry
Cycle
Yieldb (%)
1
2
3
0
1
2
92
85
77
75a
5
a Reaction conditions: 1.0 mmol halide, 1.3 mmol methyl acrylate,
2.0 mmol K2CO3, 0.01 mmol HPCD, Pd/CaCO3 (0.01 mmol), 15 mL
H2O–DMF (2:1) under reflux.
b Without HPCD.
c Measured by GC–MS.
a Reaction conditions: 1.0 mmol phenyl iodide, 1.3 mmol methyl
acrylate, 2 mmol K2CO3, recovered aqueous phase, 5 mL DMF
under reflux.
b Measured by GC–MS.

8156
J. D. Senra et al. / Tetrahedron Letters 48 (2007) 8153–8156
2003; (b) Reets, M. T.; de Vries, J. G. Chem. Commun.
2004, 1559; (c) Arvela, R. K.; Leadbeater, N. E. J. Org.
Chem. 2005, 70, 1786.
Recycling experiments: The first run was carried out as
described above. In a 100 mL flask containing the aque-
ous phase were poured phenyl iodide (0.11 mL,
1.0 mmol), methyl acrylate (0.12 mL, 1.3 mmol), potas-
sium carbonate (276.4 mg, 2.0 mmol) and 5 mL N,N-
dimethylformamide. The resulting mixture was stirred
and heated for 4 h at 120 °C.
3. Jeffery, T. Tetrahedron 1996, 52, 10113.
4. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009.
5. Astruc, D.; Lu, F.; Aranzaes, J. R. Angew. Chem., Int. Ed.
2005, 44, 7852.
6. (a) Wenz, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 803;
(b) Szejtli, J. Chem. Rev. 1998, 98, 1743; (c) Szejtli, J. In
Cyclodextrins and Their Inclusion Complexes; Akademiai
Kiado: Budapest, 1982; (d) Schneider, H.-J.; Sangwan, N.
K. Angew. Chem., Int. Ed. Engl. 1987, 26, 896; (e) Ye, H.;
Rong, D.; D’Souza, V. T. Tetrahedron Lett. 1991, 32,
5231; (f) Takahashi, C. F. K. Chem. Rev. 1998, 98,
2013.
(E)-Methyl cinnamate. 1H NMR (CDCl3, 200 MHz,
ppm): d 7.65 (d, J = 16.0 Hz, 1H), 7.57–7.53 (m, 2H),
7.41–7.39 (m, 3H), 6.49 (d, J = 16 Hz, 1H), 3.80 (s,
3H). 13C NMR (CDCl3, 50 MHz, ppm): d 167.1,
114.7, 134.2, 130.2, 128.8, 128.0, 117.7, 51.5. GC–MS:
162 m/z, 131 m/z, 103 m/z.
7. Hapiot, F.; Tilloy, S.; Monflier, E. Chem. Rev. 2006, 106,
767.
8. Cassez, A.; Ponchel, A.; Hapiot, F.; Monflier, E. Org.
Lett. 2006, 8, 4823.
9. For reviews see: (a) Sinou, D. Top. Curr. Chem. 1999, 206,
41; (b) Genet, J. P.; Savignac, M. J. Organomet. Chem.
1999, 576, 305; For recent reports of Heck couplings in
aqueous medium see: (c) Botella, L.; Najera, C. Tetra-
hedron Lett. 2004, 45, 1833; (d) Mukhopadhyay, S.;
Rothenberg, G.; Joshi, A.; Baidossi, M.; Sasson, Y. Adv.
Synth. Catal. 2002, 344, 348; (e) Uozumi, Y.; Kimura, T.
Synlett 2002, 2045.
(E)-Methyl 4-methoxycinnamate. 1H NMR (CDCl3,
200 MHz, ppm): d 7.7 (d, J = 16.0 Hz, 1H), 7.47–7.44
(m, 2H), 6.93–6.89 (m, 2H), 6.32 (d, J = 16 Hz, 1H),
3.83 (s, 3H), 3.79 (s, 3H). 13C NMR (CDCl3, 50 MHz,
ppm): d 167.6, 161.5, 144.5, 129.7, 127.2, 115.3, 114.4,
55.4, 51.5. GC–MS: 192 m/z, 161 m/z, 133 m/z.
(E)-Methyl 4-nitrocinnamate. 1H NMR (CDCl3,
200 MHz, ppm): d 8.23 (d, J = 8.7, 2H), 7.70 (d,
J = 16 Hz, 1H), 7.67 (d, J = 8.7 Hz, 2H), 6.55 (d,
J = 16 Hz, 1H), 3.84 (s, 3H). 13C NMR (CDCl3,
50 MHz, ppm): d 166.73, 149.2, 142.3, 141.3, 129.4,
124.9, 123.3, 51.6. GC–MS: 207 m/z, 176 m/z, 148 m/z.
10. Malta, L. F. B.; Senra, J. D.; Medeiros, M. E.; Antunes,
O. A. C. Supramol. Chem. 2006, 18, 327.
11. (a) Nowicki, A.; Zhang, Y.; Le’ger, B.; Rolland, J.-P.;
Bricout, H.; Monflier, E.; Roucoux, A. Chem. Commun.
2006, 296; (b) Palaniappan, K.; Xue, C.; Arumugam, G.;
Hackney, S. A.; Liu, J. Chem. Mater. 2006, 18, 1275; (c)
Giuffrida, S.; Ventimiglia, G.; Petralia, S.; Conoci, S.;
Sortino, S. Inorg. Chem. 2006, 45, 508; (d) Liu, Y.; Male,
K. B.; Bouvrette, P.; Luong, J. H. T. Chem. Mater. 2003,
15, 4172.
Acknowledgements
The authors acknowledge CAPES, CNPq and FAPERJ,
Brazilian Support Foundations, for financial support.
12. (a) Perez, R.; Veronese, D.; Coelho, F.; Antunes, O. A. C.
Tetrahedron Lett. 2006, 47, 1325; (b) Oliveira, B. L.;
Antunes, O. A. C. Lett. Org. Chem. 2007, 4, 13.
13. Guo, Q.-X.; Luo, S.-H.; Liu, Y.-C. J. Incl. Phenom. 1998,
30, 173.
References and notes
1. (a) Bra¨se, S.; de Meijere, A. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, Germany, 1998; (b) Beller, M.;
Riermeier, T. H.; Stark, G. In Transition Metals for
Organic Synthesis; Building Blocks and Fine Chemicals;
Beller, M., Bolm, C., Eds.; VCH: Weinheim, Germany,
1998.
14. (a) Willner, I.; Mandler, D. J. Am. Chem. Soc. 1989, 111,
1330; (b) Strimbu, L.; Liu, J.; Kaifer, A. E. Langmuir
2003, 19, 483.
15. 1H and 13C NMR spectra were recorded on a Bruker 200
and 50 MHz NMR spectrometer in CDCl3. The mass
spectra were obtained using a Shidmadzu instrument GC–
MS-26542. The chemicals were obtained from commercial
sources and used without previous purification.
2. (a) de Vries, A. H. M.; Mulders, J. M. C. A.; Mommers, J.
H. M.; Henderickx, H. J. W.; de Vries, J. G. Org. Lett.