bromides in the presence of phosphines and high palladium
loadings. In the case of aryl chlorides, only a general method
has been described using Pd(OAc)
phosphine S-Phos, under MeOH reflux.
2
and the electron-rich
9
,10
1
1
The use of water in transition-metal catalysis has many
advantages for the recycling of the catalyst and product
recovery and also concerning safety and environmental
aspects. The beneficial effects of the presence of water,
especially in Suzuki-Miyaura reactions with boronic acids,
K
1
2
CO
3
as base under refluxing water, and using palladacycle
(0.01 mol % of Pd) as precatalyst (Table 1, entry 1). The
reaction took place efficiently with complex 1 after 20 h in
2% yield, which could be increased to 91% in 7 h reaction
time using 0.05 mol % Pd loading (Table 1, entry 2). When
the same reaction was performed with 1 equiv of PhBF K,
aa was obtained in a lower 62% yield. Under microwave
8
2
,11
are well documented.
Another important aspect for
industrial application is the use of the less expensive and
easily available aryl chlorides. Our group has described the
first cross-coupling of aryl chlorides and arylboronic acids
in refluxing water using an oxime-derived carbapalladacycle
3
2
heating (MW) at 100 °C, 4-acetylbiphenyl (2aa) was
obtained in 87% yield in only 15 min (Table 1, compare
entries 1 and 3). However, using 0.01 mol % of Pd(OAc)
under conventional or MW heating, 28 and 19% yields were
observed (Table 1, entries 4 and 5). A lower 16% yield was
1
2
1
as precatalyst for the general synthesis of biphenyls. In
2
addition, allyl and benzyl chlorides could be cross-coupled
with arylboronic acids at room temperature in aqueous
acetone. However, attempts to use neat water as solvent in
the case or potassium organotrifluoroborates succeed only
measured using PdCl
2
under MW heating (Table 1, entry
6
). Different activated and deactivated aryl chlorides were
1
3
with aryl iodides and bromides. We envisage that the
presence of water would increase the reactivity of aryltrif-
luoroborates facilitating its hydrolysis to the corresponding
cross-coupled with aryltrifluoroborates under conventional
and MW heating in neat water using palladacycle 1 (1 mol
%
) as precatalyst (Table 1). Deactivated potassium 4-(trif-
luoromethyl)phenyltrifluoroborate reacted with 4-chloroac-
etophenone under reaction conditions similar to PhBF
14
arylboronic acids. In the present communication, we report
for the first time the cross-coupling of potassium aryltrif-
3
K
1
5
luoroborates with aryl chlorides in neat water and with allyl
affording biphenyl 2ab in 78% yield (Table 1, compare
entries 2 and 7). The anti-inflammatory 4-biphenylacetic acid
1
6
and benzyl chlorides in aqueous acetone using the pre-
catalyst 1 under phosphine-free conditions.
(felbinac) (2ba) was obtained in 55 and 86% yield under
Initially, 4-chloroacetophenone was cross-coupled with
potassium phenyltrifluoroborate (1.5 equiv) in the presence
of 0.5 equiv of tetra-n-butylammonium bromide (TBAB),
conventional and MW heating, respectively (Table 1, entries
8 and 9). In the cross-coupling of 2-chlorobenzonitrile with
potassium 4-tolyltrifluoroborate, the antihypertensive drug
1
7
(sartans) intermediate 2cc was obtained in 96 and 88% crude
(
8) For reviews, see: (a) Darses, S.; Gen eˆ t, J.-P. Chem. ReV. 2008, 108,
yield, respectively (Table 1, entries 10 and 11). When the
same chloride was allowed to react with a hindered potassium
2-tolyltrifluoroborate, biphenyl 2cd was obtained in good
yields but in longer reaction time (16 h) than the 4-tolyl (5
h) (Table 1, entries 12 and 13). Deactivated aryl chlorides
such as 4-methoxychlorobenzene and 4-chloroaniline reacted
with potassium phenyltrifluoroborate under standard reaction
conditions providing compounds 2da and 2ea, respectively,
in good yields (Table 1, entries 14-17). Nitrogenated
heterocyclic chlorides, such as 3-chloropyridine, 4,5-dichloro-
2-methyl-3(2H)-pyridazinone, and 2,4,6-trichloropyrimidine
were mono-, di-, and triphenylated, respectively, affording
compounds 2fa, 2ga, and 2ha in good yields (Table 1, entries
2
88–325. (b) Doucet, H. Eur. J. Org. Chem. 2008, 201, 3–2030. (c)
Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286. (d) Stefani,
H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623–3658. (e)
Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49–56. (f)
Darses, S.; Gen eˆ t, J.-P. Eur. J. Org. Chem. 2003, 431, 3–4327.
(
(
9) Border, T. E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649–2652.
10) Pd2(dba)3 (1 mol %) and PCy3 have been used as catalysts in the
reaction of potassium 3-pyridinetrifluoroborate with 4-n-butylchlorobenzene
at 100 °C in aqueous dioxane: (a) Kudo, N.; Perseghini, M.; Fu, G. Angew.
Chem., Int. Ed. 2006, 45, 1282–1284. A palladium N-heterocyclic carbene
has been used as catalyst in refluxing MeOH: (b) O’Brien, C. J.; Kantchen,
A. A. B.; Valente, C.; Hadei, N.; Chass, G. A.; Lough, A.; Hopkinson,
A. C.; Organ, M. G. Chem.-Eur. J. 2006, 12, 4743–4748.
(11) For recent reviews, see: (a) Capek, P.; Vr a´ bel, M.; Hasn ´ı k, Z.; Pohl,
R.; Hocek, M. Synthesis 2006, 3515–3526. (b) Saughnessy, K. H. Eur. J.
Org. Chem. 2006, 1827–1835. (c) Li, C.-J. Chem. ReV. 2005, 105, 3095–
165. (d) Saughnessy, K. H.; DeVasher, R. B. Curr. Org. Chem. 2005, 9,
85–604. (e) Aqueous-Phase Organometallic Catalysis; Cornils, B., Her-
3
5
18-23). These results are rather similar to the cross-coupling
rmann, W. A., Eds.; Wiley-VCH: Weinheim, 2004.
12) (a) Botella, L.; N a´ jera, C. Angew. Chem., Int. Ed. 2002, 41, 179–
81. (b) Botella, L.; N a´ jera, C. J. Organomet. Chem. 2002, 663, 46–57.
13) (a) Arvela, R. K.; Leadbeater, N. E.; Mack, T. L.; Kormos, C. M.
reactions performed with arylboronic acids and the same aryl
chlorides under these phosphine-free aqueous conditions, the
reaction rates being slightly lower than with potassium
(
1
(
Tetrahedron Lett. 2006, 47, 217–220. (b) Lipshutz, B. H.; Petersen, T. B;
Abela, A. R. Org. Lett. 2008, 10, 1333–1336. (c) Wang, L.; Li, P.-H. Chin.
J. Chem. 2006, 24, 770–774.
1
2
aryltrifluoroborates.
Next, we studied the cross-coupling reactions of allyl and
benzyl chlorides with potassium aryltrifluoroborates using
KOH as base and 0.1 mol % Pd loading in aqueous acetone,
a reaction condition previously described for arylboronic
(
14) (a) Batey, R. A.; Quach, T. D. Tetrahedron Lett. 2001, 42, 9099–
9
(
103. (b) Molander, G. A.; Biolatto, B. J. Org. Chem. 2002, 4, 1867–1870.
c) Ting, R.; Harwig, C. W.; Lo, J.; Li, Y.; Adam, M. J.; Ruth, T. J.; Perrin,
D. M. J. Org. Chem. 2008, 73, 4662–4670.
15) Allyl chlorides have been coupled with potassium vinyltrifluorobo-
(
1
2
rates using PdCl2(dppf) as catalyst in aqueous isopropanol under microwave
acids. Initially, the reaction of cinnamyl chloride with
potassium phenyltrifluoroborate was performed at room
heating: Kabalka, G. W.; Dadush, E.; Al-Masum, M. Tetrahedron Lett. 2006,
4
7, 7459–7461.
(16) Diarylmethanes have been prepared by reaction of benzyl bromides
and chlorides with potassium aryltrifluoroborates using PdCl2(dppf) as
catalyst in aqueous cyclopentyl methyl ether: Molander, G. A.; Elia, M. D.
J. Org. Chem. 2006, 71, 9198–9202.
(17) TBAB can act as a phase-transfer catalyst and also can stabilize
palladium nanoparticles avoiding aggregation: Reetz, M. T.; Westermann,
E. Angew. Chem., Int. Ed. 2000, 39, 165–168.
5012
Org. Lett., Vol. 10, No. 21, 2008