Mizoroki-Heck arylation of α,β-unsaturated acids with a hybrid fluorous ether, F-626: Facile filtrative separation of products and efficient recycling of a reaction medium containing a catalyst

Article abstract of DOI:10.1021/jo049028+

The Mizoroki-Heck reaction was carried out using a fluorous ether F-626 as the solvent and a fluorous Pd carbene complex as the catalyst. When carboxylic acids are the products, separation of both the F-626 and the Pd catalyst from the products can be conveniently carried out by simple filtration. The F-626 filtrates containing the Pd catalyst can be recycled.

Full text of DOI:10.1021/jo049028+

SCHEME 1. Protocols for Separation of Fluorous
Catalyst and Solvent in Fluorous Biphasic
Catalysis (FBC)
Mizoroki-Heck Arylation of
r,â-Unsaturated Acids with a Hybrid
Fluorous Ether, F-626: Facile Filtrative
Separation of Products and Efficient
Recycling of a Reaction Medium
Containing a Catalyst
Takahide Fukuyama, Masashi Arai,
Hiroshi Matsubara, and Ilhyong Ryu*
Department of Chemistry, Faculty of Arts and Sciences,
Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
ryu@ms.cias.osakafu-u.ac.jp
Received June 9, 2004
Abstract: The Mizoroki-Heck reaction was carried out
using a fluorous ether F-626 as the solvent and a fluorous
Pd carbene complex as the catalyst. When carboxylic acids
are the products, separation of both the F-626 and the Pd
catalyst from the products can be conveniently carried out
by simple filtration. The F-626 filtrates containing the Pd
catalyst can be recycled.
perature-dependent miscibilities of the fluorous catalyst
to the organic solvent, such as octane,4a,b xylene,4c,d
toluene,4e and DMF,5 at higher temperature, but the
catalyst precipitates when the solution is cooled and can
be recovered by simple solid/liquid separation.
Fluorous biphasic catalysis (FBC), since the pioneering
studies of Vogt and Kaim1a as well as the work of Horva´th
and Ra´bai were reported,1c has provided an elegant
solution to a long-standing problem associated with
homogeneous metal catalysis, namely the separation of
the catalysts from the products and their reuse.2,3 This
protocol, depicted typically as A in Scheme 1, exploits
the thermomorphic nature of fluorous solvents which
form a monophasic solution with an organic solvent when
heated. After the reaction, the catalyst, having fluorous
ligands, can be separated from the products by means of
an organic/fluorous liquid/liquid biphasic workup. A
protocol for fluorous catalysis, B, has also recently been
reported in which ordinary organic solvents are used
exclusively as a reaction medium for reactions using
fluorous catalysts.4,5 This protocol B exploits the tem-
It occurred to us that the use of a fluorous monophasic
system6,7 would be also promising. In such, if the products
have a low solubility in the fluorous solvent, they would
precipitate during the reaction, which would allow for a
homogeneous solution containing fluorous catalysts via
simple solid/liquid separation of the products (protocol
C). In this paper, we report on the successful use of the
protocol C where a fluorous ether, F-626, 1H,1H,2H,2H-
perfluorooctyl 1,3-dimethylbutyl ether7 was used as the
sole reaction medium in the Mizoroki-Heck arylation8
of R,â-unsaturated acids. It should be noted that fluorous
versions of Mizoroki-Heck arylations have already been
reported by other groups. Whereas many of these proto-
cols can be classified as A-type,9,10 Gladysz and Rocaboy
recently reported on the B-type protocol using a highly
effective fluorous palladacycle catalyst, which can be
conducted with DMF as the exclusive solvent.5,11
(1) (a) Vogt, M. Ph.D. Thesis, University of Aachen, 1991. (b) Keim,
W.; Vogt, M. Wassercheid, P. Driessen-Ho¨lscher, B. J. Mol. Catal. A:
Chem. 1999, 139, 171. (c) Horva´th, I. T.; Raba´i, J. Science 1994, 266,
72.
(2) For reviews on fluorous chemistry, see: (a) Horva´th, I. T. Acc.
Chem. Res. 1998, 31, 641. (b) Curran, D. P. Angew. Chem., Int. Ed.
1998, 37, 1175. (c) Cornils, B. Angew. Chem., Int. Ed. Engl. 1997, 36,
2057. (d) Yoshida, J.; Itami, K. Chem. Rev. 2002, 102, 3693. (e) Otera,
J. Acc. Chem. Res. 2004, 37 288. (f) A thematic issue of fluorous
chemistry: Gladysz, J. A.; Curran, D. P. Tetrahedron 2002, 58, 3823.
(g) Gladysz, J. A., Curran, D. P., Horva´th, I. T., Eds. Handbook of
Fluorous Chemistry; Wiley-VCH: Weinheim, 2004.
(3) For recent examples, see: (a) Klement, I.; Lu¨tjens, H.; Knochel,
P. Angew. Chem., Int. Ed. Engl. 1997, 36, 1454. (b) Schneider, S.;
Bannwarth, W. Angew. Chem., Int. Ed. 2000, 39, 4142. (c) Mikami,
K.; Mikami, Y.; Matsumoto, Y.; Nishikido, J.; Yamamoto, F.; Nakajima,
H. Tetrahedron Lett. 2001, 42, 289. (d) Sinou, D.; Maillard, D.; Aghmiz,
A.; Masdeu. B. A. M. Adv. Synth. Catal. 2003, 345, 603. (e) Yao, Q.;
Zhang, Y. J. Am. Chem. Soc. 2004, 126, 74. See also ref 2f.
(4) (a) Wende, M.; Meier, R.; Gladysz, J. A. J. Am. Chem. Soc. 2001,
123, 11490. (b) Wende, M.; Gladysz, J. A. J. Am. Chem. Soc. 2003,
125, 5861. (c) Ishihara, K.; Kondo, S.; Yamamoto, H. Synlett 2001,
1371. (d) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Synlett 2002, 1299.
(e) Xiang, J.; Orita, A.; Otera, J. Adv. Synth. Catal. 2002, 344, 84. Also
see a recent variation using a catalyst immobilized to fluorous reversed-
phase silica: Tzschucke, C. C.; Markert, C.; Glantz, H.; Bannwarth,
W. Angew. Chem., Int. Ed. 2002, 41, 4500.
Fluorous Pd carbene complex I was prepared from Pd-
(OAc)2, fluorous ionic liquid II,12 and PPh3 in the presence
of LiCl and was used in an initial test (Scheme 2).13 Thus,
the reaction of iodobenzene (1a) with acrylic acid (2a) was
(5) (a) Rocaboy, C.; Gladysz, J. A. Org. Lett. 2002, 4, 1993. (b)
Rocaboy, C.; Gladysz, J. A. New J. Chem. 2003, 27, 39.
(6) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
(7) Matsubara, H.; Yasuda, S.; Sugiyama, H.; Ryu, I.; Fujii, Y.; Kita,
K. Tetrahedron 2002, 58, 4071.
10.1021/jo049028+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/09/2004
J. Org. Chem. 2004, 69, 8105-8107
8105

TABLE 1. Mizoroki-Heck Arylation of r,â-Unsaturated
SCHEME 2. Mizoroki-Heck Arylation Catalyzed
by a Fluorous Pd-Carbene Complex in F-626 and
Photographs of the Reaction Using Pd Catalyst Ia
Carboxylic Acids and Esters Using F-626 as a Solventa
a Conditions: (A) before heating, with undissolved I and acylic
acid (2a); (B) homogeneous solution after heating at 120 °C for 5
min; (C) after the reaction, with precipitated cinnamic acid (3a)
and amine salts.
carried out in the presence of 2 mol % of I and tripropy-
lamine (1.5 equiv, bp 155-158 °C) in F-626 (0.5 mL) at
120 °C (bath temperature). Changes in the appearance
of the reaction mixture are demonstrated by three
photographs (Scheme 2). At room temperature, even after
stirring for 10 min, the Pd carbene complex I was present
on the bottom, and the acrylic acid floated to the top of
the F-626, whereas iodobenzene (1a) was soluble in F-626
(photograph A). On heating at 120 °C, however, the
mixture became a homogeneous solution (photograph B)
and the coupling product and amine salts began to
precipitate as the reaction progressed. After cooling to
room temperature, the coupling product, cinnamic acid,
and amine salts precipitated in the bottom of the test
(8) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
44, 581. (b) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320.
For reviews, see: (c) Bra¨se, S.; de Meijere, A. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New
York, 1998; pp 99-166. (d) Beletskaya, I. P.; Cheprakov, A. V. Chem.
Rev. 2000, 100, 3009.
(9) Moineau, J.; Pozzi, G.; Quici, S.; Sinou, D.; Tetrahedron Lett.
1999, 40, 7683.
(10) Nakamura, Y.; Takeuchi, S.; Zhang, S.; Okumura, K.; Ohgo,
Y. Tetrahedron Lett. 2002, 43, 3053.
(11) Very recently, Curran and co-workers reported the Heck
reaction using fluorous sulfur-carbon-sulfur pincer palladacycle as
a catalyst and DMA as a solvent, in which the catalyst was recovered
by fluorous solid-phase extraction using fluorous reversed-phase silica
gel. Curran, D. P.; Fischer, K.; Moura-Letts, G. Synlett 2004, 1379.
(12) Fluorous ionic liquid II was prepared from 1-methylimidazole
and 2-(perfluorodecyl)ethyl iodide. For other examples of fluorous ionic
liquids, see: (a) Davis, J. H., Jr.; Forrester, K. J.; Merrigan, T. L.
Tetrahedron Lett. 1998, 39, 8955. (b) Merrigan, T. L.; Bates, E. D.;
Dorman, S. C.; Davis, J. H., Jr. Chem. Commun. 2000, 2051.
(13) For reviews on Pd carbene complex catalyzed C-C coupling
reactions, see: (a) Herrmann, W. A.; O¨ fele, K.; v. Preysing, D.;
Schneider, S. K. J. Organomet. Chem. 2003, 687, 229. (b) Hillier, A.
C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.; Yang, C.; Nolan, S. P. J.
Organomet. Chem. 2002, 653, 69. Also see recent examples: (c)
Weskamp, T.; Bo¨hm, V. P. W.; Herrmann, W. A. J. Organomet. Chem.
1999, 585, 348. (d) Herrmann, W. A.; Bo¨hm, V. P. W.; Gsto¨ttmayr, C.
W. K.; Grosche, M.; Reisinger, C.-P.; Weskamp, T. J. Organomet. Chem.
2001, 617, 616. (e) Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002,
4, 1411. (f) Fukuyama, T.; Shinmen, M. Nishitani, S.; Sato, M.; Ryu,
I. Org. Lett. 2002, 4, 1691. (g) McLachlan, F.; Mathews, C. J.; Smith,
P. J.; Welton, T. Organometallics 2003, 22, 5350.
a Method A: 1 (1 mmol), 2 (1.3 mmol), Pd(OAc)2 (2 mol %), PPh3
(2 mol %), II (2 mol %) Pr3N (1.5 equiv), F-626 (0.5 mL), 120 °C,
2 h. Method B (without PPh3): 1 (1 mmol), 2 (1.3 mmol), Pd(OAc)2
(2 mol %), II (2 mol %) Pr3N (1.5 equiv), F-626 (0.5 mL), 120 °C,
2 h. b Yields isolated by flash chromatography on SiO2. Only the
E isomer was obtained unless otherwise noted. c Recovered F-626
contains the Pd catalyst whose weight % is less than 2%.
d Phosphine ligand having a perfluoro alkyl chain, P(p-(C6H4)-
CH2CH2C6F13)3, was used instead of PPh3. e Recovered F-626
contained 1.7% of the coupling product. f Reaction was carried out
for 3 h. g Recovered F-626 contained 12% p-methoxy-R-methylsty-
rene, decarboxylation product of 3l, as a byproduct.
8106 J. Org. Chem., Vol. 69, No. 23, 2004

tube (photograph C). The F-626 solution, containing the
Pd catalyst,14 was separated from the precipitates by
filtration under argon (96% solvent recovery by weight).
The precipitates were subjected to an organic/aqueous
biphasic workup to remove the salts, and the organic
layer, containing the coupling product, was purified by
short silica gel chromatography, to give pure cinnamic
acid (3a) in 93% yield.15 The reaction with the Pd carbene
complex, prepared in situ from Pd(OAc)2, PPh3, and II,
also occurred smoothly to give the coupling product in
comparable yield. Later we also found that triphenylphos-
phine can be omitted without affecting the product
yield.16 The use of pefluorohexanes in place of F-626 was
unsuccessful because of the low solubility of substrates.
Scheme 3 shows that the recovered F-626 phase,
containing the Pd catalyst, can be successfully reused for
further five runs without any detectable loss in catalytic
activity. Contamination of the product in the recovered
F-626 solution was negligible (less than 0.8% by 1H
NMR).
arylation of R,â-unsaturated acid ester products did not
precipitate in F-626 (entries 11 and 13). For these cases,
a traditional fluorous/organic biphasic workup using
ethanol/FC-72 (perfluorohexanes) was carried out to
separate the products and fluorous ether F-626 contain-
ing the fluorous catalyst. To suppress the partial leaching
of Pd catalyst to organic phase, it was necessary to use
P(p-(C6H4)CH2CH2C6F13)3 as a phosphine ligand in place
of PPh3 (entry 12).
In summary, the Mizoroki-Heck arylation of R,â-
unsaturated carboxylic acids and esters proceeds ef-
ficiently in a fluorous/organic hybrid solvent, F-626,
without the use of an organic cosolvent. The insolubilities
of the acid-type coupling products in the F-626 allows
for the facile separation of the F-626 and the products,
by simple filtration. The recovered F-626 phase, contain-
ing the Pd catalyst, can be successfully recycled for
further runs.
Experimental Section
Typical Experimental Procedure for Mizoroki-Heck
Arylation in F-626 (Method A). F-626 was degassed under
reduced pressure at room temperature for 30 min, and then
nitrogen gas was introduced. Pd(OAc)2 (4.5 mg, 0.02 mmol),
fluorous ionic liquid II (16 mg, 0.02 mmol), PPh3 (5.2 mg, 0.02
mmol), tripropylamine (215 mg, 1.5 mmol), iodobenzene (1a) (204
mg, 1 mmol), and acrylic acid (2a) (93 mg, 1.3 mmol) were added
to F-626 (0.5 mL, 850 mg). The resulting mixture was heated at
120 °C for 2 h under nitrogen. After cooling to room temperature,
the precipitate was filtered and washed with FC-72 (perfluoro-
hexanes) (5 × 1 mL) under argon. The filtrate was evaporated
under reduced pressure to give F-626 (820 mg, 96%, containing
less than 2% of Pd catalyst). The precipitate was dissolved in
EtOAc (30 mL) and washed with 2 M HCl aqueous solution (20
mL). The aqueous layer was extracted with EtOAc (2 × 20 mL),
and the combined organic layer was dried over MgSO4. After
filtration, the solvent was removed under reduced pressure, and
the residue was purified by short column chromatography on
SiO2 to afford the trans-cinnamic acid (3a) (130 mg, 88%, mp
133-134 °C (lit.17 mp 132-135 °C)) as a white solid. The
recovered F-626 containing the Pd catalyst was used in the next
experiment.
Cinnamic acid (3a) was also obtained by washing the pre-
cipitates, consisting of cinnamic acid and the amine salt, with 2
M HCl aqueous solution instead of organic/aqueous biphasic
workup. After the reaction, F-626 was decanted off and the
precipitates were washed with FC-72. HCl (2 M) aqueous
solution (3 mL) was added, and the mixture was stirred for 30
min at room temperature. After filtration, the precipitates were
washed with water and dried under reduced pressure at 50 °C
for 2 h to give cinnamic acid (3a) (135 mg, mp 129-132 °C).
SCHEME 3. Recycling Study of Fluorous Medium
and Catalyst
As shown in Table 1, using in situ generated Pd
catalysts (method A, with PPh3; method B, without PPh3),
the present filtrative separation of the catalyst and
solvent could be applied to the synthesis of a variety of
â-arylated R,â-cinnamic acids (entries 1-10). The aryla-
tion of crotonic acid (2c) and methacrylic acid (2d) also
proceeded to give the corresponding â-arylated R,â-
unsaturated carboxylic acids 3k, 3l, and 3m, although
the yields are not uniform (entries 14-16). Unlike the
case of the arylation of R,â-unsaturated acids, in the
(14) To investigate if the Pd nanoparticles5 are active species in our
system, we carried out mercury poisoning experiments by addition of
mercury(0) (12.5: 1, Hg/Pd) to the reaction system. The addition of
mercury(0) did not suppress the catalysis, which suggests the nano-
particles are not key species in the present system. For recent examples
for the Heck reaction promoted by Pd nanoparticles, see: (a) de Vries,
A. H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.; Hendrickes, H. J.
W.; de Vries, J. G. Org. Lett. 2003, 5, 3285. (b) Consorti, C.; Zanini, M.
L.; Leal, S.; Eberling, G.; Dupont, J. Org. Lett. 2003, 5, 983. (c)
Nowotny, M.; Hanefeld, U.; van Konigsveld, H.; Maschmeyer, T. Chem.
Commun. 2000, 1877. See also ref 11.
Acknowledgment. H.M. thanks the Japan Society
for the Promotion of Science (JSPS) for financial sup-
port. I.R. thanks the Noguchi Foundation for partial
financial support of this work. We thank the Kao Corp.
for the generous gift of F-626.
Supporting Information Available: Experimental pro-
cedures and characterizations for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) Cinnamic acid (3a) was also obtained by washing the precipi-
tates with 2 M HCl aqueous solution instead of organic/aqueous
biphasic workup. See the Experimental Section.
(16) For Mizoroki-Heck reaction using phosphine-free carbene
complexes, see: (a) Xu, L.; Chen, W.; Xiao, J. Organometallics 2000,
19, 1123. (b) Selvakumar, K.; Zapf, A.; Beller, M. Org. Lett. 2002, 4,
3031. See also ref 13a,b.
JO049028+
(17) Britteri, D. R. J. Org. Chem. 1981, 46, 2514.
J. Org. Chem, Vol. 69, No. 23, 2004 8107