Xin et al.
TABLE 1. Coupling Reaction of Phenylboronic Acid with Benzoic
Anhydride in Water with Different Basesa
mild conditions based on the cleavage of the C-O bond of
carboxylic anhydrides in the presence of palladium catalysts.
This method is superior to the previous methods in terms of
reaction conditions, efficiency, and functional group compat-
ibility. However, both Yamamoto’s and Goossen’s studies
showed that the phosphine ligands played a key role in the
successful execution of the reactions, and no ketone product
was obtained under the given conditions in the absence of
phosphine ligands.
Concerns over hazardous waste generated during the catalytic
reactions and separation of the products from the catalyst led
to increasing attention on the use of less toxic and environ-
mentally compatible materials in the design of new synthetic
methods. Recently, the reaction in water has attracted much
attention, and there is increasing recognition that organic
reactions carried out in water may offer advantages over those
in organic solvents.12 We have recently described the phosphine-
free palladium acetate-catalyzed Suzuki reaction in aqueous
media in the presence of poly(ethylene glycol) (PEG)13a or ionic
liquid.13b These catalytic systems are air-stable, insensitive to
moisture, and reusable with impressive reactivity for a wide
range of substrates. Herein, we report on the evaluation of
palladium-catalyzed cross-coupling of aryl boronic acid with
carboxylic anhydride or acyl chloride in the absence of
phosphine ligands in water. The method is straightforward, and
the ketones can be synthesized under mild reaction conditions
in high yields in short reaction times.
entry
base
solvent (g)b
H2O (6)
PEG (6)
PEG/H2O (3:2.5)
PEG/H2O (3:3)
PEG/H2O (3:3.5)
PEG/H2O (3:3)
PEG/H2O (3:3)
PEG/H2O (3:3)
PEG/H2O (3:3)
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
K3PO4
NaOAc
KOH
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
56
20
89
94
90
97c
99
90
78
39
63
71
50
9
PEG/H2O (3:3)
PEG/H2O (3:3)
PEG/H2O (3:3)
PEG/H2O (3:3)
KF
Et3N
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
[bmim][PF6]
[bmim][PF6]/H2O (3:2.5)
[bmim][BF4]/H2O (3:2.5)
[bmim][Cl]/H2O (3:2.5)
[bmim][PF6]/H2O (3:2.5)
82
20
NR
98d
a Reaction conditions: Benzoic anhydride (1.0 mmol), PhB(OH)2 (1.2
mmol), base (1.6 mmol). b Isolated yield. c Reaction temperature was 80
°C. d Pd(OAc)2 was 1.8 mol %.
PEG 600, PEG 1000, PEG 2000, PEG 4000, and PEG 6000,
PEG 2000 showed the best reactivity, and therefore PEG 2000
was used as the source of PEG throughout the studies. The
increase of temperature from 60 to 80 °C has a positive effect
on the acylation reaction (Table 1, entry 6), but more byproduct
of biphenyl from the self-coupling of phenylboronic acid was
observed. A prolongation of reaction time led to a profound
increase in yield of benzophenone without the increase of
biphenyl (Table 1, entry 7). The reaction under nitrogen
presented virtually the same yields of desired product, albeit
the amount of biphenyl was decreased. When the various bases
were screened, Na2CO3 and K2CO3 resulted in a good yield
(Table 1, entries 7 and 8). Moderate yields were afforded by
using the bases of K3PO4, KOH, and KF (Table 1, entries 9,
11, 12). NaOAc and Et3N gave the desired product with low
yields (Table 1, entries 10 and 13). It should be noted that the
reaction rate in this aqueous condition was faster than that in
organic solvent with the activation of phosphine ligands.10,11
As a new type of reaction media, ionic liquids have many
unique properties,14 and therefore we tested the palladium
acetate-catalyzed acylation reaction in water using ionic liquids
as the additives. It was found that hydrophobic 1-butyl-3-
methylimidazolium hexafluorophosphate ([bmim][PF6]) could
improve the cross-coupling reaction. Again, the ratio of water
and [bmim][PF6] acted on the reactivity, and best yield was
obtained when the ratio of [bmim][PF6] and water achieved 3:2.5
g (Table 1, entries 14 and 15). Compared with the Pd(OAc)2-
H2O-PEG system, more Pd(OAc)2 was required to complete
the reaction under the reaction conditions with the Pd(OAc)2-
H2O-[bmim][PF6] system (Table 1, entries 7 and 18). The
efficiency of the ionic liquid was strongly influenced by the
Results and Discussion
Our initial experiments comprised attempts to accomplish the
reaction in water in the presence of 0.5 mol % Pd(OAc)2. Similar
to the results of Suzuki reaction in aqueous media,13 the reaction
in pure water, pure PEG, or pure ionic liquid delivered poor
yields (Table 1, entries 1, 2, 14). The addition of PEG led to a
rapid increase of activity in the aqueous media (Table 1, entries
3-5), and the optimal ratio of water and PEG was 3:3 g (Table
1, entry 4). The catalytic system was perfectly stable to air,
and the reaction could be conducted without the rigorous
exclusion of oxygen. Among the PEG species tested, including
(8) (a) Rubottom, G. M.; Kim, C. W. J. Org. Chem. 1983, 48, 1550-
1552. (b) Zeysing, B.; Gosch, C.; Terfort, A. Org. Lett. 2000, 2, 1843-
1845. (c) Tatamidani, H.; Kakiuchi, F.; Chatani, N. Org. Lett. 2004, 6,
3597-3599.
(9) (a) Eberle, M. K.; Kahle, G. G. Tetrahedron Lett. 1980, 21, 2303-
2304. (b) Kazmierski, I.; Bastienne, M.; Gosmini, C.; Paris, J. M.; Pe´richon,
J. J. Org. Chem. 2004, 69, 936-942.
(10) (a) Kakino, R.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn.
2001, 74, 371-376. (b) Kakino, R.; Yasumi, S.; Shimizu, I.; Yamamoto,
A. Bull. Chem. Soc. Jpn. 2002, 75, 137-148. (c) Kakino, R.; Narahashi,
H.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn. 2002, 75, 1333-
1345. (d) Kakino, R.; Narahashi, H.; Shimizu, I.; Yamamoto, A. Chem.
Lett. 2001, 1242-1243.
(11) (a) Goossen, L. J.; Ghosh, K. Angew. Chem., Int. Ed. 2001, 40,
3458-3460. (b) Goossen, L. J.; Ghosh, K. Eur. J. Org. Chem. 2002, 3254-
3267. (c) Goossen, L. J.; Ghosh, K. Chem. Commun. 2001, 2084-2085.
(d) Goossen, L. J.; Winkel, L.; Doehring, A.; Ghosh, K.; Paetzold, J. Synlett
2002, 1237-1240.
(12) (a) Organic Synthesis in Water; Greico, P. A., Ed.; Blackie Academic
& Professional: London, 1998. (b) Li, C.-J.; Chen, T.-H. Organic Reactions
in Aqueous Media; Kluwer Academic Publishers: Dordrecht, The Neth-
erlands, 1997. (c) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 417, 2973-
2976. (d) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816-
7817. (e) Blettner, C. G.; Konig, W. A.; Stenzel, W.; Schotten, T. J. Org.
Chem. 1999, 64, 3885-3890.
(13) (a) Liu, L.-F.; Zhang, Y.-H.; Wang, Y.-G. J. Org. Chem. 2005, 70,
6122-6215. (b) Xin, B.-W.; Zhang, Y.-H.; Liu, L.-F.; Wang, Y.-G. Synlett
2005, 20, 3083-3086.
(14) (a) Dupont, J.; De Souza, R. F.; Suarez, P. A. Z. Chem. ReV. 2002,
102, 3667-3692. (b) Welton, T. Chem. ReV. 1999, 99, 2071-2083. (c)
Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller, S.; Hebel, A.; Haag,
R. Angew. Chem., Int. Ed. 2002, 41, 3964-4000. (d) Swatloski, R. P.;
Visser, A. E.; Reichert, W. M.; Broker, G. A.; Farina, L. M.; Holbrey, J.
D.; Rogers, R. D. Chem. Commun. 2001, 2070-2070.
5726 J. Org. Chem., Vol. 71, No. 15, 2006