Efficient Aqueous-Phase Heck and Suzuki Couplings of Aryl Bromides Using Tri(4,6-dimethyl-3-sulfonatophenyl)phosphine Trisodium Salt (TXPTS)

Article abstract of DOI:10.1021/ol0360288

(Matrix presented) Sterically demanding, sulfonated arylphosphines TXPTS and TMAPTS have been applied to the aqueous-phase Heck and Suzuki coupling of aryl bromides. TXPTS provides good yields of Heck coupling products from aryl bromides at 80°C, while both TMAPTS and TPPTS gave significantly less active catalysts. TXPTS is the first ligand to promote the aqueous-phase Heck coupling under such mild conditions. Both TXPTS and TMAPTS provide active catalysts for Suzuki couplings of aryl bromides at 50°C.

Full text of DOI:10.1021/ol0360288

ORGANIC
LETTERS
2004
Vol. 6, No. 2
225-228
Efficient Aqueous-Phase Heck and
Suzuki Couplings of Aryl Bromides
Using Tri(4,6-dimethyl-3-
sulfonatophenyl)phosphine Trisodium
Salt (TXPTS)
Lucas R. Moore and Kevin H. Shaughnessy*
Department of Chemistry and the Center for Green Manufacturing,
The UniVersity of Alabama, Tuscaloosa, Alabama 35487-0336
kshaughn@bama.ua.edu
Received October 16, 2003
ABSTRACT
Sterically demanding, sulfonated arylphosphines TXPTS and TMAPTS have been applied to the aqueous-phase Heck and Suzuki coupling of
aryl bromides. TXPTS provides good yields of Heck coupling products from aryl bromides at 80 °C, while both TMAPTS and TPPTS gave
significantly less active catalysts. TXPTS is the first ligand to promote the aqueous-phase Heck coupling under such mild conditions. Both
TXPTS and TMAPTS provide active catalysts for Suzuki couplings of aryl bromides at 50 °C.
Water continues to attract significant attention as an alterna-
tive solvent in organic synthesis due to its low cost, toxicity,
and environmental impact. Water is particularly attractive
in certain metal-catalyzed processes where a water-soluble
catalyst can be separated from an organic product stream
and potentially recycled.1 Water-soluble ligands are com-
monly used to give hydrophilic catalysts that will be retained
in the aqueous phase. The most commonly used water-
soluble ligand is tri(3-sulfonatophenyl)phosphine (TPPTS),
which was originally developed by Rhone-Poulenc for use
in the aqueous-phase hydroformylation of propylene.2
TPPTS has been successfully used as a water-soluble
replacement for triphenylphosphine in a variety of catalytic
processes. TPPTS in combination with palladium has modest
activity in the aqueous-phase Suzuki,3 Heck,3a,4 and Sonoga-
shira3a,4a,5 cross-coupling reactions. To date, these systems
have been largely limited to couplings of aryl iodides, while
couplings of aryl bromides have required high temperatures
or activated substrates. Modest activity for aqueous-phase
Suzuki couplings of unactivated aryl bromides has been
observed recently using high catalyst loadings of Pd/TPPTS,3c
while aqueous-phase Heck couplings of unactivated aryl
bromides require high temperatures (100-150 °C).6 The
Suzuki coupling of activated aryl chlorides using a nickel/
(3) (a) Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc. 1990, 112,
4324-4330. (b) Geneˆt, J. P.; Linquist, A.; Blard, E.; Mouries, V.; Savignac,
M.; Vaultier, M. Tetrahedron Lett. 1995, 36, 1443-1446. (c) Dupuis, C.;
Adiey, K.; Charruault, L.; Michelet, V.; Savignac, M.; Geneˆt, J.-P.
Tetrahedron Lett. 2001, 42, 6523-6526.
(4) (a) Geneˆt, J. P.; Blart, E.; Savignac, M. Synlett 1992, 715-717. (b)
Mirza, A. R.; Anson, M. S.; Hellgardt, K.; Leese, M. P.; Thompson, D. F.;
Tonks, L.; Williams, J. M. J. Org. Process Res. DeV. 1998, 2, 325-331.
(5) (a) Amatore, C.; Blart, E.; Geneˆt, J. P.; Jutand, A.; Lemaire-Audoire,
S.; Savignac, M. J. Org. Chem. 1995, 60, 6829-6839. (b) Dibowski, H.;
Scmidtchen, F. P. Tetrahedron Lett. 1998, 39, 525-528.
(1) (a) Geneˆt, J. P.; Savignac, M. J. Organomet. Chem. 1999, 576, 305-
317. (b) Joo´, F.; Katho´, AÄ . J. Mol. Cat A. Chem. 1997, 116, 3-26.
(2) Cornils, B.; Kuntz, E. G. J. Organomet. Chem. 1995, 502, 177-
186.
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1997, 36, 772-774.
10.1021/ol0360288 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/23/2003

TPPTS catalyst system has also been reported.7 Aqueous-
phase couplings of aryl bromides using high loadings of
ligand-free catalysts have also been reported in the presence
of surfactants.8 For this method to be more widely applicable,
catalysts with improved generality for coupling of unacti-
vated aryl bromide and chloride substrates under mild
conditions must be identified. Although a variety of water-
solubilizing groups have been appended to the tri-
phenylphosphine structure,6,9 little effort has been devoted
to modifying the steric and electronic properties of water-
souble arylphosphines. In contrast, electron-rich, water-
soluble alkylphosphines with a range of cone angles have
been prepared.10
Tri-o-tolylphosphine has been found to be superior to
triphenylphosphine in many palladium-catalyzed cross-
coupling reactions.11 In an effort to identify more efficient
ligands for aqueous-phase cross-coupling reactions, we have
prepared sulfonated triarylphosphine ligands containing ortho
substituents. The synthesis of tri(4,6-dimethyl-3-sulfonatophen-
yl)phosphine trisodium (TXPTS, Scheme 1) has been previ-
of halogenated nucleosides.13 Herein, we report the ability
of TXPTS and TMAPTS to promote Heck and Suzuki
couplings of simple aryl bromides.
The activity of catalysts TXPTS, TMAPTS, and TPPTS
in combination with Pd(OAc)2 were initially screened in the
Heck coupling of 1-ethyl-4-iodobenzene and styrene at 80
°C (eq 1, Figure 1). The catalyst derived from TXPTS gave
Scheme 1. Synthesis of TXPTS and TMAPTS
Figure 1. Comparison of GC yields for the Heck coupling of
1-ethyl-4-iodobenzene or 4-bromotoluene and styrene (eq 1).
ously reported.12 Tri(4-methoxy-6-methyl-3-sulfonatophen-
yl)phosphine trisodium salt (TMAPTS) was prepared in a
similar fashion as a more electron-rich analogue of TXPTS.
We have previously reported that TXPTS gave significantly
more active catalysts than TPPTS for the Suzuki coupling
complete conversion to product in 2 h. TPPTS and TMATPS
in combination with Pd(OAc)2 gave approximately 30%
yields of the stilbene product after 2 h, while Pd(OAc)2 alone
gave very little product. The screening was repeated with
4-bromotoluene under the same conditions. TXPTS/Pd-
(OAc)2 again gave a good yield (77%) of stilbene product
after 2 h at 80 °C. The catalysts derived from TMAPTS and
TPPTS gave lower yields of the desired product (40 and 28%,
respectively), while essentially no product was observed in
the absence of ligand. To our knowledge, this is the first
Heck coupling of unactivated aryl bromides to occur below
100 °C using water-soluble arylphosphine ligands.
The scope of the TXPTS/Pd(OAc)2 catalyst system was
explored using a series of aryl halides (Table 2). Coupling
of 1-ethyl-4-iodobenzene and styrene gave 4-ethylstilbene
in 90% isolated yield (entry 2). Good to excellent yields were
also obtained in the coupling of aryl bromides and styrene
to give substituted stilbenes. Both electron-donating and
electron-withdrawing substituents gave excellent yields of
(7) Galland, J.-C.; Savignac, M.; Geneˆt, J.-P. Tetrahedron Lett. 1999,
40, 2323-2326.
(8) Arcadi, A.; Cerichelli, G.; Chiarini, M.; Correa, M.; Zorzan, D. Eur.
J. Org. Chem. 2003, 4080-4086.
(9) (a) Wasserscheid, P.; Waffenschmidt, H.; Machnitzki, P.; Kottsieper,
K. W.; Stelzer, O. Chem. Commun. 2001, 451-452. (b) Uozumi, Y.; Danjo,
H.; Hayashi, T. J. Org. Chem. 1999, 64, 3384-3388. (c) Gelpke, A. E. S.;
Veerman, J. J. N.; Goedheijt, M. S.; Kamer, P. C. J.; van Leeuwen, P. W.
N. M.; Hiemstra, H. Tetrahedron 1999, 55, 6657-6670. (d) Parisot, S.;
Kolodziuk, R.; Goux-Henry, C.; Iourtchenko, A.; Sinou, D. Tetrahedron
Lett. 2002, 43, 7397-7400.
(10) (a) Bitterer, F.; Kucken, S.; Stelzer, O. Chem. Ber. 1995, 128, 275-
279. (b) Mohr, B.; Lynn, D. M.; Grubbs, R. H. Organometallics 1996, 15,
4317-4325. (c) Bartik, T.; Bartik, B.; Hanson, B. E. J. Mol. Catal. 1994,
88, 43-56. (d) Shaughnessy, K. H.; Booth, R. S. Org. Lett. 2001, 3, 2757-
2759.
(11) (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146-151. (b) Spencer,
A. J. Organomet. Chem. 1983, 258, 101-108. (c) DeVries, R. A.; Mendoza,
A. Organometallics 1994, 13, 2405-2411. (d) Louie, J.; Hartwig, J. F.
Tetrahedron Lett. 1995, 36, 3609-3612. (e) Guram, A. S.; Rennels, R. A.;
Buchwald, S. L. Angew. Chem., Int. Ed. 1995, 34, 1348. (f) Goodson, F.
E.; Wallow, T. I.; Novak, B. M. Macromolecules 1998, 31, 2047-2056.
(g) Vallin, K. S. A.; Emilsson, P.; Larhed, M.; Hallberg, A. J. Org. Chem.
2002, 67, 6243-6246.
(12) Gulya´s, H.; Szo¨llo¨sy, AÄ .; Hanson, B. E.; Bakos, J. Tetrahedron Lett.
2002, 43, 2543-2546.
(13) Western, E. C.; Daft, J. R.; Johnson, E. M., II; Gannett, P. M.;
Shaughnessy, K. H. J. Org. Chem. 2003, 68, 6767-6774.
226
Org. Lett., Vol. 6, No. 2, 2004

Table 1. Heck Coupling of Aryl Bromides with
Table 2. Scope of Suzuki Coupling with TXPTS or
TXPTS/Pd(OAc)2
TMAPTS/Pd(OAc)2
a See Supporting Information for experimental conditions.
functionalized stilbenes. Introduction of an ortho substituent
on the aryl halide resulted in a somewhat decreased yield of
product (entry 4). Attempts to couple 2-bromo-m-xylene with
styrene gave none of the desired product. Butyl acrylate was
slowly hydrolyzed under the coupling conditions, but sodium
acrylate gave good yields of cinnamic acid derivatives after
acidic workup. Again both electron-rich and moderately
sterically demanding aryl bromides gave good yields.
a See Supporting Information for experimental conditions.
more active than Pd(OAc)2 alone. At 50 °C, catalysts derived
from TXPTS and TMAPTS gave higher yields than the
catalyst derived from TPPTS. After 2.5 h, TXPTS gave a
78% yield (1600 mol product(mol Pd)-1, TOF ) 620 mol
product(mol Pd‚h)-1) and TMAPTS gave a 68% yield (1400
mol product(mol Pd)-1, TOF ) 540 mol product(mol
Pd‚h)-1), while TPPTS gave only a 48% yield (960 mol
product(mol Pd)-1, TOF ) 380 mol product(mol Pd‚h)-1).
After 5 h, the TXPTS system showed little additional
The activity of TXPTS and TMAPTS were next compared
to that of TPPTS in a standard Suzuki coupling of a
nonactivated aryl bromide, 4-bromotoluene, and phenyl-
boronic acid using Pd(OAc)2 (0.05 mol %), ligand (0.125
mol %), and sodium carbonate in a 1:1 mixture of water
and acetonitrile (eq 2). At 80 °C, all ligands gave complete
conversion within 1 h (Figure 2). Catalysts derived from Pd-
(OAc)2 and the sulfonated phosphines were only slightly
Org. Lett., Vol. 6, No. 2, 2004
227

4-bromo-3-methylanisole and phenylboronic acid at 80 and
50 °C gave excellent yields of the coupling product (entry
8). Couplings of 2-tolylboronic acid with 4-bromotoluene
using TMAPTS gave an 86% yield at 80 °C and a 67% yield
at 50 °C (entry 9). Similarly, couplings to give a 2,2′-
dimethylbiphenyl product occurred in excellent yield at 80
°C, but the yield dropped from 90 to 75 and 85%,
respectively, for the TXPTS and TMAPTS systems at 50
°C (entry 10). 2-Bromo-m-xylene gave somewhat lower
yields of 2,6-dimethyl-substituted biphenyl products (78-
87% yield) at both 50 and 80 °C. Attempts to prepare 2,2′,6-
trimethylbiphenyl from 2-bromo-m-xylene and o-tolylboronic
acid were unsuccessful.
In conclusion, TXPTS in combination with palladium
acetate provides active catalysts for Heck and Suzuki
couplings of aryl bromides at modest temperatures. TXPTS
is an air-stable ligand that can be prepared in two steps from
PCl3. While catalysts derived from TXPTS are only mod-
erately more active than those derived from TPPTS for the
Suzuki coupling, the TXPTS system provides a significant
advantage in the Heck coupling of aryl bromides. Using
TXPTS, we have achieved the first Heck couplings of
unactivated and deactivated aryl bromides under relatively
mild conditions in aqueous solvents.
Figure 2. Comparison of L/Pd(OAc)2 activity in the coupling of
4-bromotoluene and phenylboronic acid. 0 ) TXPTS, 80 °C; 4 )
TMAPTS, 80 °C; O ) TPPTS, 80 °C; ] ) no L, 80 °C; 9 )
TXPTS, 50 °C; 2 ) TMAPTS, 50 °C; b ) TPPTS, 50 °C; [ )
no L, 50 °C.
conversion, while both TMAPTS and TPPTS gave higher
yields than after 2.5 h. After 5 h, the TMAPTS system gave
a slightly higher yield than the TXPTS system. In the absence
of ligand, no product was formed at 50 °C.
Acknowledgment. We gratefully acknowledge financial
support of this work by the National Science Foundation
(CHE-0124255) and The University of Alabama through the
School of Mines and Energy Development (SOMED) and
the Research Activity Council. We thank Elizabeth C.
Western, who prepared the TXPTS used in this work.
The scope of Suzuki couplings catalyzed by TXPTS and
TMAPTS in combination with Pd(OAc)2 (2.5 mol %) was
tested for a variety of aryl bromide and arylboronic acid
combinations (Table 2). Both ligands gave very similar
results under these conditions. Excellent yields (90-99%)
were obtained with sterically unhindered, electron-rich
(entries 2 and 3) and electron-deficient (entries 5-7) aryl
bromides. Similarly, boronic acids with electron-withdrawing
(entry 3) or electron-donating substituents (entries 4 and 6)
gave high yields. For these sterically unhindered substrates,
similar yields were obtained at 50 and 80 °C.
Supporting Information Available: Experimental details
and compound characterization of TXPTS, TMAPTS, and
compounds in Tables 1 and 2. This material is available free
of charge via the Internet at http://pubs.acs.org.
Catalyst systems derived from TXPTS and TMAPTS do
show some sensitivity to ortho substituents. Coupling
OL0360288
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