Pd(OAc)2-catalyzed fluoride-free cross-coupling reactions of arylsiloxanes with aryl bromides in aqueous medium

Article abstract of DOI:10.1021/jo070855v

(Chemical Equation Presented) Mild conditions have been developed to achieve the Pd-(OAc)₂-catalyzed fluoride-free cross-coupling between the aryl bromides and arylsiloxanes in good to high yields in aqueous medium. The success of the reactions requires the presence of poly(ethylene glycol) (PEG) and 3 equiv of sodium hydroxide. The product was easily separated with ethyl ether extraction, and the catalytic system can be reused eight times with high efficiency.

Full text of DOI:10.1021/jo070855v

noboranes can present hurdles to large-scale implementation.
The development of viable substitutes for organostannanes and
organoboranes becomes the important objective.
Pd(OAc)2-Catalyzed Fluoride-Free
Cross-Coupling Reactions of Arylsiloxanes with
Aryl Bromides in Aqueous Medium
Organosilanes (Hiyama) have emerged as premier agents for
effecting this type of cross-coupling reaction currently because
they are environmentally benign and stable to many reaction
conditions.7-9 The potential of the aqueous Hiyama reaction
was recognized with the development of sodium hydroxide as
an efficient promoter, and several examples of the Hiyama
reaction in aqueous medium were recently demonstrated.10 For
example, Wolf and Lerebours reported the Hiyama reaction in
water promoted by NaOH using a palladium-phosphinous acid
complex.11 Jesu´s et al. employed the palladium complex of
formula [PdCl2L2], where L was a crown-ether-containing
triarylphosphane ligand, to give the synthetically useful yields
of the Hiyama reaction in water.12 Very recently, the fluoride-
free Hiyama reaction was reported using palladium salts and
oxime-derived palladacycles in concentrated aqueous sodium
hydroxide solution under heating at 120 °C in a pressure tube
or under microwave irradiation.13 Although the aqueous Hiyama
reaction has been developed with significant success, the ligands
and/or high temperature (often in a sealed tube) are generally
required. Herein, we report the development of a practical and
efficient set of conditions for the fluoride-free Hiyama reaction
Shengyin Shi and Yuhong Zhang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou
310027, People’s Republic of China
yhzhang@zjuem.zju.edu.cn
ReceiVed April 24, 2007
Mild conditions have been developed to achieve the Pd-
(OAc)2-catalyzed fluoride-free cross-coupling between the
aryl bromides and arylsiloxanes in good to high yields in
aqueous medium. The success of the reactions requires the
presence of poly(ethylene glycol) (PEG) and 3 equiv of
sodium hydroxide. The product was easily separated with
ethyl ether extraction, and the catalytic system can be reused
eight times with high efficiency.
(7) (a) Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998;
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E.; DeShong, P. J. Org. Chem. 1999, 64, 3266. (g) Denmark, S. E.; Sweis,
R. F. Org. Lett. 2002, 4, 3771. (h) Hirabayashi, K.; Mori, A.; Kawashima,
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DeShong, P. J. Org. Chem. 2004, 69, 1137.
The palladium-catalyzed cross-coupling transformations be-
tween aryl halides and organometallic species constitute the most
efficient methodologies for the construction of biaryl subunits1-3
and are extensively used in the synthesis of pharmaceutical
intermediates, bioactive molecules, and functional materials.4
Among the various organometallic coupling partners, the
organoboranes (Suzuki)5 and organostannanes (Stille)6 are the
most routinely employed reagents because of their high reactiv-
ity and wide functional group tolerances. However, the toxicity
of organostannanes and the difficulty of purification of orga-
(1) For recent reviews, see: (a) Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-I., de Meijere, A., Eds.; Wiley: New
York, 2002. (b) Transition Metals for Organic Synthesis: Building Block
and Fine Chemicals, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, Germany, 2004.
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Luzikova, E. V. J. Organomet. Chem. 1997, 532, 271. (b) Fechtenkoetter,
A.; Saalwaechter, K.; Harbison, M. A.; Muellen, K.; Spiess, H. W. Angew.
Chem., Int. Ed. 1999, 38, 3039. (c) Huang, J.; Nolan, S. P. J. Am. Chem.
Soc. 1999, 121, 9889.
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(c) Hossain, K. M.; Shibata, T.; Takagi, K. Synlett 2000, 1137.
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Miyazawa, K.; Goto, Y. Chem. Commun. 1997, 1309. (c) Mowery, M. E.;
DeShong, P. J. Org. Chem. 1999, 64, 1684. (d) Mowery, M. E.; DeShong,
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2, 2053. (f) Correia, R.; DeShong, P. J. Org. Chem. 2001, 66, 7159. (g)
McElroy, W. T.; DeShong, P. Org. Lett. 2003, 5, 4779. (h) Wolf, C.;
Lerebours, R.; Tanzini, E. H. Synthesis 2003, 2069. (i) Seganish, W. M.;
DeShong, P. J. Org. Chem. 2004, 69, 6790. (j) Li, J.-H.; Deng, C.-L.; Liu,
W.-J.; Xie, Y.-X. Synthesis 2005, 3039. (k) Murata, M.; Yoshida, S.; Nirei,
S.-i.; Watanabe, S.; Masuda, Y. Synlett 2006, 118. (l) Mino, T.; Shirae, Y.;
Saito, T.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2006, 71, 9499. (m) Ju,
J.; Nam, H.; Jung, H. M.; Lee, S. Tetrahedron Lett. 2006, 47, 8673.
(10) (a) Hagiwara, E.; Gouda, K.; Hatanaka, Y.; Hiyama, T. Tetrahedron
Lett. 1997, 38, 439. (b) Murata, M.; Shimazaki, R.; Watanabe, S.; Masuda,
Y. Synthesis 2001, 2231.
(5) Selected papers on the Suzuki reaction: (a) Miyaura, N.; Suzuki, A.
Chem. ReV. 1995, 95, 2457. (b) Suzuki, A. J. Organomet. Chem. 1999,
576, 147. (c) Miao, W.; Chan, T. H. Org. Lett. 2003, 5, 5003. (d) Xiao,
J.-C.; Shreeve, J. M. J. Org. Chem. 2005, 70, 3072.
(11) Wolf, C.; Lerebours, R. Org. Lett. 2004, 6, 1147.
(6) Selected papers on the Stille reaction: (a) Milstein, D.; Stille, J. K.
J. Am. Chem. Soc. 1979, 101, 4992. (b) Stille, J. K. Angew. Chem., Int. Ed.
Engl. 1986, 25, 508. (c) Handy, S. T.; Zhang, X. Org. Lett. 2001, 3, 233.
(d) Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704.
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3517.
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10.1021/jo070855v CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/22/2007
J. Org. Chem. 2007, 72, 5927-5930
5927

TABLE 1. Effect of Solvent, Base, and Temperature on the
Hiyama Reactiona
TABLE 2. Cross-Coupling of Aryl Bromides with
Trimethoxy(phenyl)silane (a)a
Yield (%)
entry
solvent (g)
H2O (6)
conv (%)
Ab
Bb
Cc
22
3
5
4
0
0
trace
15
6
trace
0
0
3
8
1
2
3
4
5
6
7
8
9
10
11
12
13d
14e
15f
16g
17h
87
98
74
85
0
74
90
66
72
0
12
7
6
11
0
0
H2O:dioxane (3:3)
H2O:acetone (3:3)
H2O:THF (3:3)
H2O:[BMIM]BF4 (3:3)
H2O:[BMIM]PF6 (3:3)
H2O:PEG (3:3)
H2O:PEG (5:1)
H2O:PEG (4:2)
H2O:PEG (2:4)
H2O:PEG (1:5)
PEG (6)
H2O:PEG (3:3)
H2O:PEG (3:3)
H2O:PEG (3:3)
H2O:PEG (3:3)
H2O:PEG (3:3)
0
0
100
95
97
100
100
3
96
78
27
75
100
92
80
80
24
15
0
79
60
17
69
79
5
13
11
45
30
0
11
12
5
trace
10
4
6
16
a Reaction conditions: 1-bromo-4-methoxybenzene (1 mmol), trimethox-
y(phenyl)silane (1.2 mmol), NaOH (3 mmol), Pd(OAc)2 (1.8 mol %), 60
°C, 6 h. b GC yields based on 1-bromo-4-methoxybenzene. c Isolated yields
based on trimethoxy(phenyl)silane. d KOH (3 mmol). e NaOH (2 mmol).
f NaOH (1 mmol). g 25 °C, 24 h. h 80 °C, 4 h.
using Pd(OAc)2 as the catalyst in aqueous medium under mild
reaction conditions (60 °C).
The coupling reaction between 1-bromo-4-methoxybenzene
(1 mmol) and trimethoxy(phenyl)silane (1.2 mmol) was exam-
ined in pure water with 3 equiv of NaOH and 1.8 mol % of
Pd(OAc)2 at 60 °C for 6 h in air. The desired cross-coupling
product was obtained in 74% along with the formation of a
large amount of side products from the self-coupling of
1-bromo-4-methoxybenzene and trimethoxy(phenyl)silane (Table
1, entry 1). Various cosolvents were examined (Table 1, entries
2-7), and it was found that PEG 2000 significantly improved
the reaction, and the generation of the homocoupling byproducts
was suppressed markedly (Table 1, entry 7). Similar to the
Suzuki reaction in this catalytic system,14 the amount of the
PEG 2000 had a strong influence on the activity of the reaction,
and the low yields were obtained when an excess amount of
PEG was presented in the catalytic system (Table 1, entries
8-11). In the neat PEG, no reactions were observed (Table 1,
entry 12). Of the bases tested, KOAc, K2CO3, K3PO4, and
piperidine presented poor activity, and KOH was also inferior
compared to NaOH (Table 1, entry 13). In addition, KF and
TBAF, which were well-known promoters for the Hiyama
coupling in organic solvents, were inactive in the H2O-PEG
system, and no product was detected. The amount of the base
influenced the reactions, and the decrease of the amount of
NaOH led to poor yields (Table 1, entries 14 and 15). The excess
NaOH might have implications with the activation of arylsilanes
a Reaction conditions: aryl bromide (1 mmol), trimethoxy(phenyl)silane
(1.2 mmol), NaOH (3 mmol), Pd(OAc)2 (1.8 mol %), H2O:PEG 2000 )
3:3 g, 60 °C. b Isolated yields. c 100 °C.
and the hydrolysis of methoxysilane, which should be beneficial
to the increase of reaction rate. Raising or lowering the reaction
temperature did not improve the yields (Table 1, entries 16
and 17).
The scope and limitation of this catalytic system for various
aryl bromides were studied as summarized in Table 2. The
electronic property of the substituent group has a strong
influence on the reactivity of aryl bromides. The electron-
deficient aryl bromide showed the excellent reactivity and
furnished the products in high yields in short reaction times
(Table 2, entries 1-7), while prolonged reaction time was
required for the electron-rich aryl bromide (Table 2, entries
8-10). It was also noted that the catalytic system could tolerate
many functional groups, such as NO2, CF3, COMe, Me, and
(14) (a) Liu, L.; Zhang, Y.; Wang, Y. J. Org. Chem. 2005, 70, 6122. (b)
Xin, B.; Zhang, Y.; Liu, L.; Wang, Y. Synlett 2005, 20, 3083. (c) Xin, B.;
Zhang, Y.; Cheng, K. J. Org. Chem. 2006, 71, 5725.
5928 J. Org. Chem., Vol. 72, No. 15, 2007

TABLE 3. Hiyama Coupling Reaction of Aryl Bromide with
Various Arylsiloxanea
SCHEME 1
method for synthesizing polyaryls, which have wide appli-
cations in material and biological science, from di- and
tribromoaromatics.
The reactivity of various arylsiloxanes on the Hiyama reac-
tion was studied, and no obvious differences have been
found, as shown in Table 3. It can be seen that arylsiloxane
either with an electron-donating group or with an electron-
withdrawing group exhibited high reactivity and delivered
good yields (Table 3, entries 1-12). Satisfying results were
also obtained when triethoxy(phenyl)silanes were replaced
with trimethoxy(aryl)silanes (Table 3, entries 13-16).
Both aryl groups of dimethoxydiphenylsilane worked as a
coupling partner with aryl halides, and good to high yields
were obtained under the reaction conditions (Table 3, entries
17-20).
The fluoride is known to play the key role in the Hiyama
reaction via the in situ formation of the pentacoordinate
arylsilicate anion,15 which is found to be more reactive than
the corresponding tetracoordinated silane.16 In the absence of
fluoride, the generation of pentavalent silicate under basic
aqueous conditions through nucleophilic attack of a hydroxide
ion at the arylsiloxane is thought to play the key role to promote
the cross-coupling reaction. On the basis of the previous
studies,11 the following mechanism is proposed in the sodium
hydroxide aqueous solution. The initial oxidative addition of
aryl bromide to Pd(0) generates the arylpalladium inter-
mediate A, which reacts with the pentavalent silicate formed
in situ in sodium hydroxide solution to afford the (aryl)(aryl)-
palladium(II) species B. The subsequent reductive elimi-
nation liberates the biaryl product with the regeneration of the
active Pd(0) to complete the catalytic cycle (Scheme 1). For
practical applications, the level of reusability of the catalyst is
very important. To clarify this issue, we established the
experiments to test the reusability efficiency of the catalytic
system in the coupling reaction of 3-bromopyridine and
1-bromo-4-nitrobenzene with trimethoxy(phenyl)silane using 1.8
mol % of Pd(OAc)2. The product was easily isolated by
simple extraction with diethyl ether, and the Pd(OAc)2-PEG-
H2O was subjected to the second run by charging it with the
same substrates in the remnant. The catalytic system could be
recycled eight times with a small decrease in activity
without the need for activation or addition of the catalyst or
PEG (Scheme 2). The presence of water increased the solu-
a Reaction conditions: aryl bromide (1 mmol), siloxane (1.2 mmol),
NaOH (3 mmol), Pd(OAc)2 (1.8 mol %), H2O:PEG 2000 ) 3:3 g, 60 °C.
b Isolated yields. c Siloxane (0.6 mmol).
OMe. Furthermore, coupling of 4-bromochlorobenzene
with the trimethoxy(phenyl)silane gave exclusively 4-chloro-
biphenyl in 94% yield, showing the good chemoselectivity
(Table 2, entry 6). The sterically demanding aryl bromides
delivered poor yields even after prolonged the reaction time
(Table 2, entries 9 and 11), while the coupling of 1-bromo-2-
nitrobenzene with trimethoxy(phenyl)silane afforded the
desired product in nearly quantitative yield (Table 2, entry 3),
which might have implications with the strong electron-
withdrawing effect of NO2. 3-Bromopyridine was efficiently
coupled with trimethoxy(phenyl)silane to give 3-phenyl-
pyridine in 98% yield (Table 2, entry 14). The 2-bromopy-
ridine was less active and gave lower yield even at 100 °C
for 24 h (Table 2, entry 13). It should be noted that the
coupling of 1,4-dibromobenzene and 1,3,5-tribromobenzene
with trimethoxy(phenyl)silane afforded the polyaryls in
high yields in this catalytic system (Table 2, entries 15
and 16). Thus, the present reactions offered a convenient
(15) Hatanaka, Y.; Goda, K.; Hiyama, T. J. Organomet. Chem. 1994,
465, 97.
(16) Chuit, C.; Corriu, R. J. P.; Reye, C. In Chemistry of HyperValent
Compounds; Akiba, K.-Y., Ed.; Wiley-VCH: New York, 1999; pp 81-
146.
J. Org. Chem, Vol. 72, No. 15, 2007 5929

SCHEME 2
Experimental Section
General Procedure for the Hiyama Reaction: A mixture of
NaOH (0.120 g, 3 mmol), Pd(OAc)2 (4 mg, 1.8 mol %), aryl
bromide (1 mmol), arylsiloxane (1.2 mmol), distilled water (3 mL),
and PEG 2000 (3 g) was stirred at 60 °C for the indicated time.
Afterward, the reaction solution was cooled to room temperature
and extracted four times with diethyl ether (4 × 15 mL). The
combined organic phase was analyzed by GC and GC/MS. Further
purification of the product was achieved by flash chromatography
on a silica gel column.
In the recycling experiment, the residue was subjected to a second
run of the Hiyama reaction by charging it with the same substrates
(3-bromopyridine or 1-bromo-4-nitrobenzene, trimethoxy(phenyl)-
silane, NaOH) without further addition of Pd(OAc)2 or PEG 2000.
In the third, fifth, and seventh runs, another 0.5 mL of distilled
water was added to the reaction mixture.
3-Phenylpyridine12 [T2-14]: 1H NMR (400 MHz, CDCl3,
TMS) δ 8.83 (d, 1H), 8.55-8.56 (m, 1H), 7.80-7.83 (m, 1H),
7.53-7.55 (m, 2H), 7.42-7.45 (m, 2H), 7.29-7.38 (m, 2H); MS
(EI) m/z (%) 155 (100) [M+], 154 (22), 153 (15), 76 (9).
1,3,5-Triphenylbenzene18 [T2-16]: 1H NMR (400 MHz,
CDCl3, TMS) δ 7.85-7.86 (d, 3H), 7.76-7.78 (m, 6H), 7.52-
7.56 (m, 6H), 7.43-7.47 (m, 3H); MS (EI) m/z (%) 307 (81) [M+
+ 1], 306 (100) [M+], 289 (33), 276 (9), 228 (26), 202 (10), 153
(9), 77 (8).
bility of the sodium hydroxide in this catalytic system, which
should facilitate the coupling reaction, and indeed the reaction
was sluggish in the neat PEG (Table 1, entry 7). The reaction,
however, was not so successful in water alone (Table 1, entry
1). Thus, the combination of water and PEG was found to be
an efficient medium for the reaction. On the other hand, the
solubility of the organic substrates in water was greatly promoted
by PEG,17 which led to the enhancement of the reaction rate,
as well. In addition, PEG might act as the ligand and/or stability
reagent of palladium in the reaction process and construct the
recyclable catalytic system.17
In summary, the PEG-H2O solvent system was proved to
be a useful and alternative reaction medium for cross-coupling
of arylsiloxanes and aryl bromides, avoiding the use of fluoride.
The substrates show significant increase in reactivity, reducing
the reaction times and improving the yields substantially under
the mild reaction conditions. The simple experimental and
product isolation procedures combined with ease of recovery
and reuse of this reaction medium are expected to contribute to
the development of a green strategy for the preparation of
biaryls.
Acknowledgment. Funding from the Natural Science Foun-
dation of China (No. 20571063) is acknowledged.
Supporting Information Available: The experimental proce-
dure and spectroscopic data (1H NMR and MS) for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070855V
(17) (a) Che, J.; Spear, S. K.; Hunddleston, J. G.; Rogers, R. D. Green
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