Sterically demanding, water-soluble alkylphosphines as ligands for high activity Suzuki coupling of aryl bromides in Aqueous solvents

Article abstract of DOI:10.1021/ol0163629

(Equation presented) Sterically demanding, water-soluble alkylphosphines have been found to give highly active catalysts for Suzuki coupling of aryl bromides in aqueous solvents. A variety of aryl bromides and boronic acids were coupled in excellent yield

Full text of DOI:10.1021/ol0163629

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2757-2759
Sterically Demanding, Water-Soluble
Alkylphosphines as Ligands for High
Activity Suzuki Coupling of Aryl
Bromides in Aqueous Solvents
Kevin H. Shaughnessy* and Rebecca S. Booth
Department of Chemistry, The UniVersity of Alabama, Box 870336,
Tuscaloosa, Alabama 35487-0336
kshaughn@bama.ua.edu
Received June 28, 2001
ABSTRACT
Sterically demanding, water-soluble alkylphosphines have been found to give highly active catalysts for Suzuki coupling of aryl bromides in
aqueous solvents. A variety of aryl bromides and boronic acids were coupled in excellent yield. Turnover numbers up to 734 000 mmol/mmol
Pd have been achieved under mild conditions.
Aqueous-phase, palladium-catalyzed coupling reactions are
of interest as environmentally benign synthetic methods that
would decrease the use of volatile organic solvents and
simplify catalyst recovery.1 Water-soluble phosphines, such
as tris(3-sulfanotophenyl)phosphine (TPPTS, 1, Figure 1),
aryl bromides, but the activity of these systems remains too
low to be industrially viable. Water-soluble catalysts with
increased activity toward aryl bromides and chlorides are
necessary for wider application of aqueous-phase catalyst
systems. It has recently been shown that sterically demanding
alkylphosphines, such as tri-tert-butylphosphine (2), provide
high activity catalysts for a range of palladium-catalyzed
coupling reactions in organic solvents. Catalysts derived from
these ligands have allowed the first general couplings of aryl
bromides at room temperature and of unactivated aryl
(2) (a) Genet, J. P.; Blart, E.; Savignac, M. Synlett 1992, 715-717. (b)
Bumagin, N. A.; Bykov, V. V.; Beletskaya, I. P. Zh. Org. Khim. 1995, 31,
481-487. (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.
(3) Hessler, A.; Stelzer, O.; Dibowski, H.; Worm, K.; Schmidtchen, F.
P. J. Org. Chem. 1997, 62, 2362-2369.
Figure 1.
(4) (a) Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc. 1990, 112,
4324-4330. (b) Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi,
U. J. Org. Chem. 1997, 62, 7170-7173. (c) Uozumi, Y.; Danjo, H.; Hayashi,
T. J. Org. Chem. 1999, 64, 3384-3388. (d) Paetzold, E.; Oehme, G. J.
Mol. Catal. A: Chem. 2000, 152, 69-76.
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Chem. Commun. 1998, 1509-1510.
have been applied to aqueous-phase Heck,2 Sonogashira,3
Suzuki,2c,4 and Buchwald-Hartwig5 coupling reactions of
(1) Genet, J. P.; Savignac, M. J. Organomet. Chem. 1999, 576, 305-
317.
10.1021/ol0163629 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/17/2001

modestly air-sensitive solids. With ligands 3-5 in hand, their
ability to promote aqueous-phase Suzuki couplings was
compared to that of TPPTS under previously reported
conditions (Table 1, eq 1).4a At room temperature, TPPTS/
Pd(OAc)2 gave low conversion in the coupling of 4-bromo-
toluene and phenylboronic acid (entry 1). In contrast, ligands
3 and 4 gave nearly quantitative yields of 4-methylbiphenyl
at room temperature with 0.5 mol % Pd after 1 h (entries 2
and 4). Ligand 5 gave a less active catalyst than ligands 3
or 4 (entry 6). For each of the ligands prepared in this study,
a 1:1 ratio of ligand:Pd gave higher activity than a 2:1 ratio.
These results are consistent with those recently reported for
the t-Bu3P/Pd catalyst system.6c,g Catalysts derived from 3,
4, or 5/Pd(OAc)2 partitioned predominately in the organic
Table 1. Ligand Optimization in Aqueous-Phase Suzuki
Couplinga
entry
ligand
L:Pd
yieldb of 6 (%)
1
2
3
4
5
6
7
2
3
3
4
4
5
5
2:1c
1:1
2:1
1:1
2:1
1:1
2:1
2
98
73
99
32
46
2
a
Table 3. Scope of Suzuki Couplings with 3 or 4/Pd(OAc)2
a Reactions run on 0.2 mmol scale with 0.5 mol % Pd at room
temperature. b GC yield after 1 h. Mass balance was within 5%. c 2.5 mol
% Pd, 4 h.
chlorides under moderate conditions.6 To date, there have
been no examples of the application of sterically demanding,
water-soluble alkylphosphines to aqueous-phase coupling
reactions. Therefore, we have prepared a series of water-
soluble phosphines modeled on the steric and electronic
properties of t-Bu3P (3-5, Figure 1). Ligands 3 and 4
provided highly active catalysts for the Suzuki coupling of
aryl bromides at room temperature in aqueous solvents.
Table 2. Low Catalyst Loading Coupling Reactionsa
T
time yieldb of 6
entry ligand
mol % Pd
(°C)
(h)
(%)
TONc
1
2
3
4
5
3
4
3
4
4
9.92 × 10-3
9.80 × 10-3
1.03 × 10-3
1.01 × 10-3
9.95 × 10-5
23
23
80
80
80
24
24
4
4
4
99
>99
>99
>99
73
9 980
10 100
95 600
97 800
734 000
a See Supporting Information for the experimental procedure. b Average
GC yield (g2 runs) by comparison to mesitylene using response factors
from authentic samples. Mass balances were within 5%. c As mmol product/
mmol Pd.
Ligands 3 and 4 were prepared in analogy to the previously
reported synthesis of 57 and were isolated as water-soluble,
(6) (a) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10-11. (b) Bei,
X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S. J. Org. Chem. 1999,
64, 6797-6803. (c) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc.
2000, 122, 4020-4028. (d) Zapf, A.; Ehrentraut, A.; Beller, M. Angew.
Chem., Int. Ed. 2000, 39, 4153-4155. (e) Littke, A. F.; Fu, G. C. Angew.
Chem., Int. Ed. 1999, 38, 2411-2413. (f) Wolfe, J. P.; Tomori, H.; Sadighi,
J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158-1174. (g)
Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-
Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580. (h) Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473-1478. (i) Mann, G.;
Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999,
121, 3224-3225. (j) Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron
Lett. 1999, 40, 8837-8840. (k) Bo¨hm, V. P. W.; Herrmann, W. A. Eur. J.
Org. Chem. 2000, 3679-3681. (l) Baudoin, O.; Gue´nard, D.; Gue´rite, F. J.
Org. Chem. 2000, 65, 9268-9271. (m) Dai, C.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 2719-2724.
a 2 mol % Pd, 1:1 L:Pd, at room temperature. See Supporting Information
for complete reaction conditions. Reactions were complete in 1-2 h in all
cases. b Average yield of two runs that agreed within 5%. c Determined by
1H NMR of isolated material. Product was contaminated by 2,2′-dimeth-
ylbiphenyl (30% yield based on o-tolylboronic acid). d 4 mol % Pd, 2:1
L:Pd, 80 °C. e GC yield after 6 h.
2758
Org. Lett., Vol. 3, No. 17, 2001

phase of the reaction mixture, although addition of ether
drove the catalyst into the aqueous phase. Water-miscible
cosolvents that give homogeneous reaction mixtures, such
as methanol and DMF, could be used in place of acetonitrile
with no change in reaction yield or rate. Reactions carried
out in water alone occurred more slowly than when a
cosolvent was used, however.
1-4). The catalyst system also tolerated sterically demanding
aryl bromides and boronic acids (entries 5-8) to give mono-
and di-ortho-substituted biphenyl products in excellent yield
with no change in the reaction time. Preparation of 2,2′,6-
trimethylbiphenyl occurred in modest yield (67%), however,
along with a significant amount of aryl halide reduction to
m-xylene and boronic acid homocoupling to 2,2′-dimethyl-
biphenyl (entry 9). Water-soluble aryl bromides also gave
high yields of biphenyl products (entries 10 and 11) with
this system. Coupling of activated aryl chlorides with ligand
4 required high catalyst loading (4 mol %) and temperature
(80 °C) to achieve high yield (92%), while 3/Pd(OAc)2 gave
only 64% yield (66% conversion) under the same conditions
(entry 10). Both 3 and 4 gave low conversions (<30%) with
4-chlorotoluene and 4-chloroanisole under these conditions.
Catalysts derived from 3 and 4/Pd(OAc)2 are highly active
catalysts for Suzuki couplings of aryl bromides (Table 2).
The coupling of 4-bromotoluene and phenylboronic acid in
a 2:1 mixture of water and acetonitrile was used as a model
reaction. An increased ratio of water was used to avoid
precipitation of salts, which appeared to limit activity at
higher reaction concentrations. At room temperature, quan-
titative yields were obtained with as little as 0.01 mol % 3
or 4/Pd(OAc)2 after 24 h (entries 1 and 2), which is
comparable to the best turnover numbers reported for room-
temperature Suzuki couplings of aryl bromides in organic
solvents6c and is unprecedented for aqueous-phase systems.4d
At 80 °C, quantitative yields were obtained after 4 h using
1 × 10-3 mol % 3 or 4/Pd(OAc)2. No significant difference
was observed in the turnover number or frequency of
catalysts derived from 3 or 4. At ppm catalyst loadings of
4/Pd(OAc)2, 734 000 turnovers were achieved after 4 h at
80 °C (entry 5), but longer reaction times did not give further
conversion. The aVerage turnoVer frequency (TOF) was
184 000 h-1. This level of productivity is 2 orders of
magnitude higher than the most active aqueous-phase catalyst
system previously reported for the Suzuki coupling of aryl
bromides (TON ) 9 000 mmol/mmol Pd; TOF ) 5 400
mmol/h).8
In conclusion, we have shown that sterically demanding,
water-soluble alkylphosphines give highly active catalysts
for Suzuki couplings of aryl bromides in aqueous solvents.
Ligands 3 and 4 have provided the first room-temperature
aqueous-phase Suzuki couplings. Catalysts derived from 3
and 4 both showed high activity toward aryl bromides, while
the more sterically demanding ligand 4 gave catalysts with
activity toward aryl chlorides higher than that of 3. The more
facile synthesis of 3 makes it the preferred ligand for aryl
bromide couplings, however. These aqueous-phase catalysts
may prove useful in applications such as solution-phase
combinatorial library synthesis and modification of water-
soluble biomolecules, as well as in environmentally benign
synthesis. Preparation of ligands with improved water
solubility and activity, particularly toward aryl chlorides, are
currently being pursued.
Catalysts derived from 3 and 4 were used to couple a range
of aryl halides and boronic acids (eq 2, Table 3). Upon
completion of the reactions, extraction with ether gave the
biaryl products in >95% purity as determined by GC.
Excellent yields (>88%) were obtained with electron-rich,
-neutral, and -poor aryl bromides and boronic acids (entries
Acknowledgment. The authors acknowledge The Uni-
versity of Alabama and a DuPont Co. Aid to Education Grant
for support of this work.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for ligands 3 and 4 and the
products in Table 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
(7) (a) Mohr, B.; Lynn, D. M.; Grubbs, R. H. Organometallics 1996,
15, 4317-4325. (b) See Supporting Information for experimental proce-
dures.
(8) Beller, M.; Krauter, J. G. E.; Zapf, A. Angew. Chem., Int. Ed. Engl.
1997, 36, 772-774.
OL0163629
Org. Lett., Vol. 3, No. 17, 2001
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