Activation of Aryl Chlorides for Suzuki Cross-Coupling by Ligandless, Heterogeneous Palladium

Article abstract of DOI:10.1021/ol015850d

matrix presented We demonstrate that Pd/C without added ligands catalyzes the Suzuki cross-coupling reaction with aryl chlorides. The ability of heterogeneous Pd to activate the C-Cl bond is explained in terms of a synergistic anchimeric and electronic effect that occurs between the Pd surface and the aryl chloride. Furthermore, the importance of selectivity control following C-Cl bond activation is illustrated by the striking role that solvents play in determining homo- vs cross-coupling pathways of the aryl chlorides.

Full text of DOI:10.1021/ol015850d

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1555-1557
Activation of Aryl Chlorides for Suzuki
Cross-Coupling by Ligandless,
Heterogeneous Palladium
,†
,‡,§
Carl R. LeBlond,†,‡ Arthur T. Andrews,† Yongkui Sun,* and John R. Sowa, Jr.*
Merck Research Laboratories, P.O. Box 2000, RY818-B328,
Rahway, New Jersey 07065, and Department of Chemistry and Biochemistry,
Seton Hall UniVersity, South Orange, New Jersey 07079
yongkui_sun@merck.com
Received March 15, 2001
ABSTRACT
We demonstrate that Pd/C without added ligands catalyzes the Suzuki cross-coupling reaction with aryl chlorides. The ability of heterogeneous
Pd to activate the C−Cl bond is explained in terms of a synergistic anchimeric and electronic effect that occurs between the Pd surface and
the aryl chloride. Furthermore, the importance of selectivity control following C−Cl bond activation is illustrated by the striking role that
solvents play in determining homo- vs cross-coupling pathways of the aryl chlorides.
There is great interest in developing catalysts that use aryl
chlorides in Suzuki cross-coupling reactions1,2 because aryl
chlorides are readily available, inexpensive, and environ-
mentally strategic reagents. However, they are much more
difficult to activate than aryl bromides and iodides. The key
to success in homogeneous catalysis1 and recent examples
of Ni/C-catalyzed coupling3 is the use of ligands that facilitate
activation of the C-Cl bond in aryl chlorides. A recently
reported ligandless Pd system catalyzes Suzuki cross-
coupling with electron-deficient aryl chlorides but fails to
work for neutral and electron-rich aryl chlorides.4 We chose
to investigate heterogeneous Pd catalysts to activate aryl
chlorides for Suzuki cross-coupling because of their inherent
activity toward C-Cl bonds. This inherent activity is
manifest in the cleavage of the C-Cl bond of chlorobenzene
over a metallic Pd surface at room temperature,5 hydro-
dechlorination,6 and reductive homo-coupling reactions of
aryl chlorides over supported Pd catalysts.7 Furthermore,
excellent cross-coupling efficiency is possible over hetero-
geneous Pd in the cases of aryl bromides and iodides.8
† Merck Research Laboratories.
‡ Seton Hall University.
§ E-mail: sowajohn@shu.com.
We report here that ligandless, heterogeneous Pd catalysts
activate C-Cl bonds in aryl chlorides under Suzuki cross-
(1) (a) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000,
39, 4153-4155. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998,
37, 3387-3388. (c) Stu¨rmer, R. Angew. Chem., Int. Ed. 1999, 38, 3307-
3308. (d) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722-9723. (e) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S.
P. J. Org. Chem. 1999, 64, 3804-3805. (f) Bohn, V. P. W.; Gstottmayr,
C. W. K.; Weskamp, T.; Herrmann, W. A. J. Organomet. Chem. 2000,
595, 186-190.
(2) Reviews of Suzuki Coupling: (a) Suzuki, A. J. Organomet. Chem.
1999, 576, 147-168. (b) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457-2483. (c) Buchwald, S. L.; Fox, J. M. Strem Chemiker 2000, 1, 1-12.
(3) (a) Lipshutz, B. H.; Sclafani, J. A.; Blomgren, P. A. Tetrahedron
2000, 56, 2139-2144. (b) Lipshutz, B. H.; Blomgren, P. A. J. Am. Chem.
Soc. 1999, 121, 5819-5820. (c) Lipshutz, B. H.; Tomioka, T.; Blomgren,
P. A.; Sclafini, J. A. Inorg. Chim. Acta 1999, 296, 164-169. (d) Lipschutz,
B. H.; Ueda, H. Angew. Chem., Int. Ed. 2000, 39, 4492-4494.
(4) Zim, D.; Monteiro, A. L.; Dupont, J. Tetrahedron Lett. 2000, 41,
8199-8202.
(5) Aarts, J. F. M.; Phelan, K. G. Surf. Sci. 1989, 222, L853.
(6) (a) Rajagopal, S.; Spatola, A. F. J. Org. Chem. 1995, 60, 1347-
1355. (b) Coq, B.; Ferrat, G.; Figueras, F. J. Catal. 1986, 101, 434-445.
(c) LaPierre, R. B.; Wu, D.; Kranich, W. L.; Weiss, A. H. J. Catal. 1978,
52, 59-71. (d) Wiener, H.; Blum, J.; Sasson, Y. J. Org. Chem. 1991, 56,
6145-6148. (e) Margues, C. A.; Selva, M.; Tundo, P. J. Org. Chem. 1994,
59, 3830-3837.
(7) (a) Mukhopadhyay, S.; Rothenberg, G.; Wiener, H.; Sasson, Y.
Tetrahedron 1999, 55, 14763-14768. (b) Mukhopadhyay, S.; Rothenberg,
G.; Gitis, D.; Sasson, Y. J. Org. Chem. 2000, 65, 3107-3110.
10.1021/ol015850d CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/07/2001

coupling reaction conditions. More importantly, with prudent
choice of solvent system, we block the homo-coupling
pathway of aryl chlorides and selectively obtain the Suzuki
cross-coupling product.9
A previous study of Pd/C in Suzuki cross-coupling
reactions with aryl chlorides reported a 6% yield using EtOH/
H2O as solvent.8a Indeed, under similar conditions, we found
a disappointing 11% yield of the desired cross-coupling
product between phenylboronic acid and p-chlorotrifluoro-
methylbenzene (Figure 1). However, the aryl chloride had
Table 1. Pd/C-Catalyzed Suzuki Cross-Couplings with Aryl
Chlorides9
entry p-XC6H4Cl p-YC6H4B(OH)2 yield (%)a
convn (%)
1
2
3
4
5
6
7
NO2
CF3
CN
COCH3
H
OCH3
CH3
H
H
H
H
OCH3
H
H
93
95
83
79
45
32
36,b 54c
100
100
100
100
61
37
65,b 76c
a DMA:water (20/1), 80 °C, K2CO3 (2 equiv), Pd/C (5 mol %), 24 h.
b Conditions as cited in (a) except 48 h reaction time was used. c 15 mol %
of Pd/C, 24 h.
electron-withdrawing groups and give 79-95% yields of
cross-coupled products (Table 1). Moderate yields are
obtained with neutral or electron-rich aryl chlorides which
can be improved using greater amounts of catalyst. Thus, a
simple change in the solvent system dramatically diverts a
reaction pathway that gives almost entirely undesired prod-
ucts to a pathway that gives desired products in high yield.
The striking role played by solvents in directing homo-
vs cross-coupling pathways highlights the importance of
selectivity control following C-Cl bond activation in
heterogeneous catalysis. The solvent effect on the cross-
coupling efficiency is likely related to the reductive homo-
coupling pathway with the alcohol solvent11 and/or boronic
acid12 as reductive reagent. The use of the nonreducing
solvent DMA averts the former problem. The mechanism
for the striking sensitivity of cross-coupling selectivity on
water concentration is currently under investigation.
In homogeneous Pd chemistry, the choice of the ligand
plays a critical role in Suzuki cross-coupling reactions of
aryl chlorides.1 In contrast, the Pd/C catalysts activate aryl
chlorides for Suzuki coupling reactions under mild conditions
without added ligands. In comparison, a recently reported
ligandless catalytic method using homogeneous complexes
PdCl2(SEt)2 or Pd(OAc)2 that also catalyzes Suzuki cross-
coupling with electron-withdrawing aryl chlorides “failed”
with electron-rich or neutral substrates.4 Although the Ni/C
system is active for Suzuki coupling of aryl chlorides,
triphenylphosphine (4 equiv with respect to Ni) is required.3
In contrast, we find that added phosphines are deleterious
to the Pd/C-catalyzed reaction. Addition of phosphines such
as P(t-Bu)3 or PPh3 in the amount of one equivalent with
respect to surface palladium9 brought the coupling reaction
to a halt. Thus, Pd/C is unique in its ability to activate aryl
chlorides for Suzuki couplings without added ligands.
Figure 1. Effect of solvent mixture on cross-coupling yield.
completely reacted, producing mainly homo-coupled prod-
ucts. The results were encouraging because they indicated
Pd/C is sufficiently reactive to activate aryl chlorides under
Suzuki cross-coupling conditions. However, activation itself
is not sufficient for high-yielding Suzuki cross-coupling due
to the presence of a competing homo-coupling pathway.
We find that an appropriately chosen solvent system
strongly favors the cross-coupling pathway. For example,
the cross-coupling yield (Figure 1) increased to 95% in
dimethylacetamide (DMA) and water (20/1). The DMA/
water volumetric ratio is critical to the success of the cross-
coupling reaction. High water concentrations (e.g., DMA/
water, 5/1) had a deleterious effect, resulting in significant
amounts (74%) of homo-coupling products. Without water,
the reaction was highly selective to cross-coupling, but very
slow (46% conversion after 24 h). The optimal volumetric
ratio was found to be 20/1, under which conditions the cross-
coupling proceeded to completion in 1.5 h without observa-
tion of homo-coupling product from the aryl chloride.10 These
conditions are generally applicable toward aryl chlorides with
(8) Suzuki coupling: (a) Marck, G.; Villiger, A.; Buchecker, R.
Tetrahedron Lett. 1994, 35, 3277-3280. (b) Gala, D.; Stamford, A.; Jenkins,
J.; Kugelman, M. Org. Proc. Res. DeV. 1997, 1, 163-164. (c) Sengupta,
S.; Bhattacharyya, S. J. Org. Chem. 1997, 62, 3405-3406. (d) Bykov, V.;
Bumagin, N. Russ. Chem. Bull. 1997, 46, 1344-1345. (e) Ennis, D.;
McManus, J.; Wood-Kaczmar, W.; Richardson, J.; Smith, G.; Carstairs, A.
Org. Proc. Res. DeV. 1999, 3, 248-252. (f) Kabalka, G. W.; Pagni, R. M.;
Hair, C. M. Org. Lett. 1999, 1, 1423-1425. Heck Coupling: (g) Augustine,
R. A.; O’Leary, S. T. J. Mol. Catal. 1992, 72, 229-242. (h) Eisenstadt, A.
In Catalysis of Organic Reactions; Herkes, F. E., Ed.; Marcel Dekker: New
York; pp 415-427. Stille Coupling: (i) Liebeskind, L. S.; Pena-Cabrera,
E. Org. Synth. 1999, 77, 135-140.
(9) General procedure: Under a N2 atmosphere, Pd/C (85.0 mg, 5 wt
%, 5 mol % total Pd vs aryl chloride, obtained from PMC, 20% Pd
dispersion), phenylboronic acid (120 mg, 0.96 mmol), K2CO3 (221 mg,
1.60 mmol), 5 mL of solvent and water at a desired v/v ratio, and a magnetic
stir bar were combined. This mixture was degassed with 5 vacuum/N2 purge
cycles and the reaction initiated by the addition of the aryl halide (0.8 mmol)
and placed in an oil bath at 80 °C for 24 h. The catalyst was filtered off
and washed with 75 mL of acetonitrile. The filtrate and wash were combined
and diluted for HPLC yield analysis. All products had the same retention
time as authentic materials and the correct mass by GC/MS. All products
(10) A small amount of biphenyl identified in the reaction correlates
with the number of surface palladium atoms and suggests that the
phenylboronic acid plays a role in reducing the surface palladium. Thus,
reactions are performed with a 20% excess of aryl boronic acid.
(11) (a) 2-Propanol is used as reducing reagent in homo-coupling of aryl
halides. See: Hassan, J.; Penalva, V.; Lavenot, L.; Gozzi, C.; Lemaire, M.
Tetrahedron 1998, 54, 13793-13804. (b) Postreaction NMR of the ethanol
solvent revealed a complex mixture including the presence of aldehydic
protons (δ 9.74, q, J ) 2.5 Hz) indicating oxidation of ethanol.
(12) Aramendia, M. A.; Lafont, F.; Moreno-Manas, M.; Pleixats, R.;
Roglans, A. J. Org. Chem. 1999, 64, 3592-3594.
1
were isolated and their H NMR were identical to authentic samples.
1556
Org. Lett., Vol. 3, No. 10, 2001

On the basis of findings from surface science studies, we
hypothesize that the extraordinary reactivity of the ligandless
heterogeneous Pd catalyst results from a property unique to
heterogeneous catalysts, i.e., synergistic anchimeric and
electronic effects occurring upon adsorption of aryl chlorides
on Pd surfaces. In contrast to the single-site Pd catalysts
employed in homogeneous catalysis, heterogeneous Pd
catalysts have reactive sites adjacent to one another. Surface
science studies show that aryl chlorides adsorb on Pd(111)
surfaces mainly via π-electrons, resulting in a nearly parallel
orientation of the ring with the surface.13 Adsorption of the
aryl moiety to the Pd surface serves as an anchor, enhancing
the chemical interaction of the C-Cl bond with a separate
but nearby Pd site (i.e., an anchimeric effect). Furthermore,
the adsorption of aryl chlorides influences the electronic
properties of the catalytic surface. It leads to a decrease in
the work function of the metal surface,14 implying a net
electron flow from the adsorbed aryl group to the Pd
surface.15 The Pd surface acts effectively as an electron-
withdrawing substituent on the aryl ring which facilitates
C-Cl bond activation.16 The corresponding increase in
electron density on Pd, in turn, facilitates C-Cl bond
activation. These cooperative anchimeric and electronic
effects are absent with single-site homogeneous catalysts,
which explains the excellent reactivity of heterogeneous Pd
catalysts, even with electron-rich aryl chlorides.
homogeneous catalysts often presents a significant practical
problem. Extra chromatographic, precipitation, or extraction
steps are often required.17 However, after catalyst filtration
we observe less than 1.0 ppm Pd (<0.10% loss based on
the initial palladium) in the reaction mixtures, which lends
support that the reaction is heterogeneously catalyzed.18
Because added ligands are unnecessary, product isolation is
simplified and potential side reactions between aryl groups
of the phosphines and the boronic acid19 are eliminated.
In summary, we demonstrate the first high-yielding use
of ligandless Pd/C as an effective catalyst for Suzuki cross-
coupling using aryl chlorides. A synergistic anchimeric and
electronic effect, indigenous to heterogeneous catalysts, is
proposed to be responsible for the high reactivity. We also
show that activating the C-Cl bond is not sufficient, but
prudent selection of reaction medium is essential for the
cross-coupling pathway. Potential applications of this syn-
ergistic effect will be further explored, and efforts to
understand the reaction mechanism and to improve the cross-
coupling efficiency for electron-neutral and -rich aryl
chlorides are in progress.
Acknowledgment. The authors thank Dr. T. Wang and
J. Wu for atomic absorption analysis, Drs. S. Krska, M.
Palucki, and D. G. Blackmond for helpful discussions, and
Dr. F. Gortsema for catalyst characterization. C.R.L. and
J.R.S. thank Merck & Co., Inc. for support.
A salient advantage of heterogeneous catalysts is the ease
with which they are separated from the reaction products.
The Suzuki reaction is often used in the last steps in
convergent synthesis of bioactive molecules. That it is
difficult to remove both the residual metal and ligands of
OL015850D
(17) Tsuji, J. Palladium Reagents and Catalysts; Wiley: Chichester,
1995.
(18) For the reaction of p-chloronitrobenzene with phenylboronic acid
at 80 °C with 5 mol % of Pd/C, after filtration through 0.45 mm filter, we
found 1.0 ppm of palladium by atomic absorption spectroscopy. If the
reaction were to occur exclusively on palladium that leached into solution,
a turnover number (TON) of 16 000 would be required. Catalytic palladium-
catalyzed cross-couplings with TON greater than 10 000 have only been
demonstrated in few cases ((a) Murray, W. V. Chemtracts-Org. Chem. 1993,
6, 263-284. (b) Hsieh, K.-H.; Hsieh; LaHann, T.; Speth, R. J. Med. Chem.
1989, 32, 898-903. (c) Williams, D.; Kannan, R. J. Org. Chem. 1987, 52,
5435-5437) and those which utilize aryl chlorides to the best of our
knowledge are nonexistent.
(13) Richardson, N. V.; Palmer, N. R. Surf. Sci. 1982, 114, L1-L6.
(14) Somorjai, G. A.; Gland, J. L. AdV. Colloid Interface Sci. 1976, 5,
203-243.
(15) Work function is defined as the minimum work that must be done
to remove an electron from the metal at 0 K. See: (a) Lang, N. D.; Kohn,
W. Phys. ReV. B 1971, 3, 1215-1223. (b) Somorjai, G. A. Introduction to
Surface Chemistry; Wiley: New York, 1994; Chapter 5.
(16) This is analogous to the acceleration of oxidative addition of aryl
chlorides to Pd(0) via coordination of an electron-withdrawing tricarbon-
ylchromium group to the arene ring. See: Uemura, M.; Nishimura, H.;
Kamikawa, K.; Nakayama, K.; Hayashi, Y. Tetrahedron Lett. 1994, 35,
1909-1912.
(19) O’Keefe, D.; Dannock, M.; Marcuccio, S. Tetrahedron Lett. 1992,
33, 6679-6680.
Org. Lett., Vol. 3, No. 10, 2001
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