We have studied the Suzuki reaction extensively and found
that it is possible to perform couplings of aryl bromides in
neat water using microwave heating with as little as 50 ppb
palladium as a catalyst.9-12 The reaction involves the use of
tetrabutylammonium bromide (TBAB) as a phase transfer
agent. Although when using 0.4 mol % of Pd(OAc)2 as a
catalyst it is possible to couple some aryl chlorides, yields
are moderate at best. A review of the literature shows that
this is generally found to be the case for nonactivated
substrates whenever simple palladium sources such as
Pd(OAc)2, PdCl2, and palladium on carbon (Pd/C) are used
as catalysts either in water or in water/organic solvent
mixtures.13-21 Yields can be improved by using palladacyclic
complexes,22 palladium complexes of phosphine oxides,23 or
di(2-pyridyl)methylamine-based palladium complexes24 as
catalyst precursors. An objective of our recent work has been
Table 1. Coupling of 4-chlorotoluene with Phenylboronic
Acida
material recovered (mmol)
temp simultaneous product
entry (°C)
cooling
(mmol) 4-chlorotoluene
total
1
2
3
4
5
6
7
8
120
100
135
150
120
100
135
150
no
no
no
no
yes
yes
yes
yes
0.40
0.19
0.56
0.61
0.75
0.40
0.71
0.56
0.23
0.19
0.08
0.10
0.07
0.12
0.10
0.19
0.63
0.38
0.64
0.71
0.82
0.52
0.81
0.75
a Reactions were run in a sealed tube, using 1 mmol of 4-chlorotoluene,
1.3 mmol of phenylboronic acid, 1 mol % of Pd/C, 3.7 mmol of Na2CO3,
1 mmol of TBAB, and 2 mL of water. An initial microwave irradiation of
300 W was used, the temperature being ramped from room temperature to
the target temperature where it was then held until a total reaction time of
10 min had elapsed. Temperature was measured with a fiber-optic device
inserted into the reaction vessel.
(6) For a recent review see: Kappe, C. O. Angew. Chem., Int. Ed. 2004,
43, 6250.
(7) For other reviews on the general area of microwave-promoted organic
synthesis see: (a) Lidstro¨m, P.; Tierney, J. P.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225. (b) Caddick, S. Tetrahedron 1995, 51, 10403.
(8) A number of books on microwave-promoted synthesis have been
published recently: (a) Lidstro¨m, P.; Tierney, J. P., Eds. MicrowaVe-Assisted
Organic Synthesis; Blackwell, Oxford, UK, 2005 (b) Loupy, A., Ed.
MicrowaVes in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2002.
(c) Hayes, B. L. MicrowaVe Synthesis: Chemistry at the Speed of Light;
CEM Publishing: Matthews, NC, 2002.
(9) (a) Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 5660. (b)
Leadbeater, N. E.; Marco, M. Angew. Chem., Int. Ed. 2003, 42, 1407. (c)
Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 888. (d) Leadbeater,
N. E.; Marco, M. Org. Lett. 2002, 4, 2973.
(10) Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.; Williams, V. A.;
Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70, 161.
(11) For reports of microwave-promoted Suzuki couplings in organic
solvents or solvent free, see: (a) Hallberg, A.; Larhed, M. J. Org. Chem.
1996, 61, 9582. (b) Wang, Y.; Sauer, D. R. Org. Lett. 2004, 6, 2793. (c)
Kabalka, G. W.; Wang, L.; Pagni, R. M.; Hair C. M.; Namboodiri, V.
Synthesis 2003, 217 (d) Kabalka, G. W.; Pagni, R. M.; Wang, L.;
Namboodiri, V.; Hair, C. M. Green Chem. 2000, 2, 120.
(12) For reports of microwave-promoted Suzuki couplings in water,
see: (a) Blettner, C. G.; Konig, W. A.; Stenzel, W.; Schotten T. J. Org.
Chem. 1999, 64, 3885. (b) Han, J. W.; Castro, J. C.; Burgess, K. Tetrahedron
Lett. 2003, 44, 9359. (c) Appukkuttan, P.; Orts, A.; Chandran, R. P.;
Goeman, J. L.; Van der Eycken, J.; Dehaen, W.; Van der Eycken, E. Eur.
J. Org. Chem. 2004, 3277. (d) Gong, Y.; He, W. Org. Lett. 2002, 4, 3803.
(e) Namboodiri, V. V.; Varma, R. S. Green. Chem. 2001, 3, 146. (f) Zhang,
W.; Chen, C. H.-T.; Lu, Y.; Nagashima, T. Org. Lett. 2004, 6, 1473. (g)
Solodenko, W.; Scho¨n, U.; Messinger, J.; Glinschert, A.; Kirschning, A.
Synlett 2004, 1699.
(13) Marck, G.; Villiger, A.; Buchecker, R. Tetrahedron Lett. 1994, 35,
3277.
(14) LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R. Org. Lett.
2001, 3, 1555.
(15) Heidenreich, R. G.; Ko¨hler, K.; Krauter, J. G. E.; Pietsch, J. Synlett
2002, 1118.
(16) Gruber, M.; Chouzier, S.; Ko¨hler, K.; Djakovitch, L. Appl. Catal.
A 2004, 265, 161.
(17) Conlon, D. A.; Pipik, B.; Ferdinand, S.; LeBlond, C. R.; Sowa, J.
R.; Izzo, B.; Collins, P.; Hom, G.-J.; Williams, J. M.; Shi, Y.-J.; Sun, Y.
AdV. Synth. Catal. 2003, 345, 931.
(18) Sakurai, H.; Tsukuda, T.; Hirao, T. J. Org. Chem. 2002, 67, 2721.
(19) Gala, D.; Stamford, A.; Jenkins, J.; Kugelman, M. Org. Proc. Res.
DeV. 1997, 1, 163.
(20) Ennis, D. S.; McManus, J.; Wood-Kaczmar, W.; Richardson, J.;
Smith, G. E.; Carstairs, A. Org. Proc. Res. DeV. 1999, 3, 248.
(21) Mori, Y.; Seki, M. J. Org. Chem, 2003, 68, 1571.
(22) See for example: (a) Chen, C. L.; Liu, Y. H.; Peng, S. M.; Liu, S.
T. Tetrahedron Lett. 2005, 46, 521. (b) Alonso D. A.; Botella, L.; Na´jera,
C.; Pacheco, C. Synthesis 2004, 1713. (c) Botella, L.; Na´jera, C. J.
Organomet. Chem. 2002, 663, 46.
to develop a methodology for Suzuki couplings of aryl
chlorides in water but using just simple palladium sources
as catalysts. We report our initial results here.
We decided to focus attention on the use of Pd/C. This
has been used quite extensively as a catalyst for Suzuki
couplings in aqueous media as well as in organic solvents.25
Choice of cosolvent turns out to be very important, especially
when using aryl chlorides as substrates. The first report of
the use of Pd/C for the coupling in aqueous media was by a
group from Hoffmann La Roche.13 They showed that aryl
iodides and bromides can be effectively coupled in mixtures
of water and organic solvents, primarily ethanol. By changing
the cosolvent from ethanol to dimethylacetamide (DMA), it
is possible to favor the Suzuki cross coupling as opposed to
homocoupling pathway when using Pd/C with aryl chlorides
as substrates.14 With those bearing electron-withdrawing
groups, yields of between 79% and 95% are obtained with
5 mol % of Pd/C and a 20:1 mixture of DMA:water after 24
h. With those bearing electron-neutral or electron-donating
functionalities longer times (48 h) or higher catalyst loadings
(15 mol % of Pd/C) are required to obtain even moderate
yields of the desired products. Low catalyst loadings can be
sufficient when using Pd/C in NMP/water mixtures, p-
chloroacetophenone being coupled with phenylboronic acid
in high yields within 2 h at 120 °C with use of 0.05-0.25
mol % of Pd/C.15,16 However, this was the only aryl chloride
substrate cited.
To study reaction parameters, we used 4-chlorotoluene as
a substrate (Table 1). A 40% yield of the desired biaryl was
obtained when using phenylboronic acid as the coupling
partner, water as the solvent, sodium carbonate as the base,
1 mol % of Pd/C as the catalyst, TBAB as a phase transfer
agent, and microwave heating (Table 1, entry 1). We heated
(23) Miao, G.; Ye, P.; Yu, L.; Baldino, C. M. J. Org. Chem. 2005, 70,
2332.
(24) (a) Na´jera, C.; Gil-Molto´ J.; Karlstro¨m, S. AdV. Synth. Catal. 2004,
346, 1798. (b) Na´jera, C.; Gil-Molto´ J.; Karlstro¨m, S. Org. Lett. 2004, 5,
1451.
(25) For a representative example of use of nonaqeous solvent mixtures
see: Kabalka, G. W.; Namboodiri, V.; Wang, L. Chem. Commun., 2001,
775.
2102
Org. Lett., Vol. 7, No. 11, 2005