Synthesis of biaryls and polyaryls by ligand-free Suzuki reaction in aqueous phase

Article abstract of DOI:10.1021/jo060122v

A highly efficient palladium acetate-catalyzed ligand-free Suzuki reaction in aqueous phase was developed in short reaction times (0.5-1 h) at 35 °C in air. The key for such a successful catalytic system was the use of a suitable amount of cosolvents in the aqueous phase. The method could be extended to the consecutive multi-Suzuki coupling, and polyaryls were prepared in a single one-pot step in high selectivity and excellent yield under mild reaction conditions (60 °C).

Full text of DOI:10.1021/jo060122v

been successfully applied in the Suzuki reaction as useful
promoters,5 the Suzuki reaction in the absence of additives and
ligands is greatly limited by the substrate solubility and reactivity
in aqueous media.6 For example, Belestkaya and co-workers
reported the Suzuki reaction in water with water-soluble aryl
halides with the catalyzing of a simple palladium salt, but the
reaction was sluggish with water-insoluble aryl halides under
the reaction conditions.7
Synthesis of Biaryls and Polyaryls by
Ligand-Free Suzuki Reaction in Aqueous Phase
Leifang Liu,† Yuhong Zhang,*,† and Bingwei Xin†,‡
Department of Chemistry, Zhejiang UniVersity,
Hangzhou 310027, People’s Republic of China, and
Department of Chemistry, Dezhou UniVersity,
Dezhou 253023, People’s Republic of China
Wallow and co-workers8 have reported an improved method
for ligandless Suzuki coupling using 1:1 acetone/water as
solvent. However, the attractiveness of their protocol is limited
by the painstaking measures used to exclude oxygen, including
a total of 15 freeze-pump-thaw degassing cycles at various
stages of the reaction.8a In our previous studies, we found that
the amount of water was crucial to the success of the Suzuki
coupling reaction in aqueous media in the presence of PEG and
ionic liquid.9 Herein we present the reassessment of the ligand-
free Suzuki reaction in water-cosolvent. We have reinvestigated
the procedure with respect to four key variables: (1) solvent
composition, (2) nature of the base, (3) catalyst loading, and
(4) reaction temperature. During the course of these studies,
we have discovered that the reaction can be run in air thus
improving its operational simplicity. Moreover, we have ex-
tended the scope of useful coupling partners to di- and
trihaloaromatics, providing an improved synthesis of polyaryls.
Polyaryls are of current interest,10-12 and their synthesis by
conventional means is often inefficient.13,14 Recently, polyaryls
have been prepared via Suzuki coupling using palladium
phosphine complexes.15,16 However, to the best of our knowl-
yhzhang@zjuem.zju.edu.cn
ReceiVed January 19, 2006
A highly efficient palladium acetate-catalyzed ligand-free
Suzuki reaction in aqueous phase was developed in short
reaction times (0.5-1 h) at 35 °C in air. The key for such a
successful catalytic system was the use of a suitable amount
of cosolvents in the aqueous phase. The method could be
extended to the consecutive multi-Suzuki coupling, and
polyaryls were prepared in a single one-pot step in high
selectivity and excellent yield under mild reaction conditions
(60 °C).
The Suzuki cross-coupling reaction is one of the most
important methods for the selective construction of biaryls,1
which has found extensive use in the synthesis of natural
products, pharmaceuticals, and advanced materials.2 The utility
of the Suzuki reaction comes from its high stability, broad
functional group tolerance, as well as low toxicity associated
with boron compounds. Recently, the use of water as solvent
for the Suzuki reaction received much attention.3 Water has clear
advantages as a solvent in organic synthesis considering its
safety, cost, and significance to environmentally benign pro-
cesses.4 Although many additives and water-soluble ligands have
(5) (a) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 4, 2973. (b)
Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 5660. (c) Badone,
D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi, U. J. Org. Chem. 1997,
62, 7170. (d) Bedford, R. B.; Blake, M. E.; Butts, C. P.; Holder, D. Chem.
Commun. 2003, 466. (e) Blettner, C. G.; Ko¨nig, W. A.; Stenzel, W.;
Schotten, T. J. Org. Chem. 1999, 64, 3885.
(6) Jackson, W. R.; Marcuccio, S. M.; Naeslund, C. G. M. Chem.
Commun. 1994, 2395.
(7) Bumagin, N. A.; Bykov, V. V.; Beletskaya, I. P. Bull. Acad. Sci.
USSR, DiV. Chem. Sci. (Engl. Transl.) 1989, 38, 2206.
(8) (a) Goodson, F. E.; Wallow, T. I.; Novak, B. M. Org. Synth. 1998,
75, 61. (b) Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034.
(9) (a) Liu, L.; Zhang, Y.; Wang, Y. J. Org. Chem. 2005, 70, 6122. (c)
Xin, B.; Zhang, Y.; Liu, L.; Wang, Y. Synlett 2006, 20, 3083.
(10) (a) Watson, M. D.; Fechtenkotter, A.; Mullen, K. Chem. ReV. 2001,
101, 1267. (b) Gary, G. W.; Winsor, P. A. Liquid Crystals and Plastic
Crystals 1; John Wiley and Sons: New York, 1974. (c) Heeger, A. J. J.
Phys. Chem. B 2001, 105, 8475. (d) Yang, S.-M.; Shie, J.-J.; Fang, J.-M.;
Nandy, S. K.; Chang, H.-Y.; Lu, S.-H.; Wang, G. J. Org. Chem. 2002, 67,
5208.
† Zhejiang University.
‡ Dezhou University.
(1) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Hassan,
J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002,
102, 1359. (c) Miyaura, N. Top. Curr. Chem. 2002, 11.
(2) (a) Nicolaou, K. C.; Boddy, C. N. C.; Brase, S.; Winssinger, N.
Angew. Chem., Int. Ed. 1999, 38, 2096. (b) Baudoin, O.; Cesario, M.;
Guenard, D.; Gueritte, F. J. Org. Chem. 2002, 67, 1199. (c) Pu, L. Chem.
ReV. 1998, 98, 2405. (d) Tsuji, J. In Palladium Reagents and Catalysts;
John Wiley and Sons: NewYork, 1995.
(3) Suzuki reaction in water: (a) Shaughnessy, K. H.; Booth, R. S. Org.
Lett. 2001, 3, 2757. (b) Dupuis, C.; Adiey, K.; Charruault, L.; Michelet,
V.; Savignac, M.; Gene´t, J.-P. Tetrahedron Lett. 2001, 42, 6523. (c) Uozumi,
Y.; Nakai, Y. Org. Lett. 2002, 4, 2997. (d) Zou, G.; Wang, Z.; Zhu, J.;
Tang, J.; He, M. Y. J. Mol. Catal. A: Chem. 2003, 206, 193. (e) Arcadi,
A.; Cerichelli, G.; Chiarini, M.; Correa, M.; Zorzan, D. Eur. J. Org. Chem.
2003, 10, 4080. (f) Moore, L. R.; Shaughnessy, K. H. Org. Lett. 2004, 6,
225. (g) Leadbeater, N. E. Chem. Commun. 2005, 2881.
(11) (a) Shirakawa, H. Chem. Commun. 2003, 1. (b) Karl, N. Synth. Met.
2003, 133, 649. (c) Dimitrakopoulos, C. D.; Malenfant, P. R. L. AdV. Mater.
2002, 14, 99. (d) Pron, A.; Rannou, P. Prog. Polym. Sci. 2002, 27, 135. (e)
Katz, H. E.; Bao, Z.; Gilat, S. L. Acc. Chem. Res. 2001, 34, 359. (f) Crone,
B.; Dodabalapur, A.; Llin, Y.-Y.; Filas, R. W.; Bao, Z.; LaDuca, A.;
Sarpeshkar, R.; Katz, H. E. Nature 2000, 403, 521. (g) Tour, J. M. Acc.
Chem. Res. 2000, 33, 791.
(12) (a) Inf. Disp. 2003, 19 (6), special OLED issue. (b) Tullo, A. H.
Chem. Eng. News 2000, 26 (June 26), 20-21.
(13) (a) Li, S.; Wei, B.; Low, P. M. N.; Lee, H. K.; Hor, T. S. A.; Xue,
F.; Mak, T. C. W. J. Chem. Soc., Dalton Trans. 1997, 1289. (b) Minato,
A.; Tamao, K.; Hayashi, T.; Suzuki, K.; Kumada, M. Tetrahedron Lett.
1980, 21, 845.
(4) Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media; Wiley:
New York, 1997; In Organic Synthesis in Water; Grieco, P.A., Ed.; Thomson
Science: Glasgow, 1998; In Aqueous-Phase Organometallic Catalysis,
Concepts and Applications; Cornils, B., Herrmann, W. A., Eds.; Wiley-
VCH: Weinheim, Germany, 1998.
(14) Nakada, M.; Miura, C.; Nishiyama, H.; Higashi, F.; Mori, T. Bull.
Chem. Soc. Jpn. 1989, 62, 3122B.
(15) (a) Sinclair, D. J.; Sherburn, M. S. J. Org. Chem. 2005, 70, 3730.
(b) Paul, S.; Clark, H. Green Chem. 2003, 5, 635. (c) Basu, B.; Das, P.;
Bhuiyan, M. M. H.; Jha, S. Tetrahedron Lett. 2003, 44, 3817.
10.1021/jo060122v CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/19/2006
3994
J. Org. Chem. 2006, 71, 3994-3997

TABLE 1. Effect of Solvent, Base, and Amount of Catalyst on the
Suzuki Coupling Reactiona
TABLE 2. Suzuki Cross-Coupling Reaction of Aryl Halides with
Arylboronic Acida
entry
X
R1
R2
time (min)
yieldb (%)
entry
base
solvent (mL)
catalyst (mol %) yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
I
I
I
4-CH3
4-OCH3
4-NO2
4-Cl
4-COCH3
4-CN
4-Me
2-Me
3-OH
4-OMe
H
H
H
H
H
H
H
H
H
H
H
20
30
20
30
20
20
30
30
30
40
30
45
30
45
45
60
45
30
30
45
97
90
98
98
98
98
97
94
97
98
97
94
98
81
94
92
91
98
98
98
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Na2CO3 pure H2O (6)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
9
93
97
98
97
73
7
97
97
97
95
97
96
96
94
68
72
66
Na2CO3 acetone/H2O (3:6)
Na2CO3 acetone/H2O (3:4)
Na2CO3 acetone/H2O (3:3.5)
Na2CO3 acetone/H2O (3:3)
Na2CO3 acetone/H2O (3:1)
Na2CO3 pure acetone (6)
K2CO3
NaOH
KOH
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
acetone/H2O (3:3.5)
acetone/H2O (3:3.5)
acetone/H2O (3:3.5)
acetone/H2O (3:3.5)
4-OCH3
4-CF3
4-OCH3
4-CF3
4-OCH3
4-CF3
4-CF3
4-OCH3
4-OCH3
4-CF3
H
K3PO4
4-CH3
4-CH3
4-OCH3
4-OCH3
4-Cl
4-Cl
4-CN
4-CN
Na2CO3 ethanol/H2O (3:3.5)
Na2CO3 propanol/H2O (3:3.5) 0.5
Na2CO3 DMF/H2O (3:3.5)
Na2CO3 acetone/H2O (3:3.5)
Na2CO3 acetone/H2O (3:3.5)
Na2CO3 acetone/H2O (3:3.5)
Na2CO3 acetone/H2O (3:3.5)
0.5
0.25
0.002 (6 h)
0.0002 (10 h)
0.000 02 (24 h)
a Reaction conditions: bromotoluene (1 mmol), PhB(OH)2 (1.5 mmol),
base (2 mmol). b GC yields based on bromotoluene.
a Reaction conditions: aryl halide (1 mmol), ArB(OH)2 (1.5 mmol),
Na2CO3 (2 mmol), H2O/acetone ) 3.5:3 mL, 35 °C (external temperature).
b Isolated yields.
edge, ligand-free one-pot consecutive cross-couplings in aqueous
media have not yet been reported.
mixture of water and acetone in the absence of any ligand or
additive (Table 1, entries 15-18). A quantitative yield of desired
product was obtained in the presence of 0.5 mol % Pd(OAc)2
for 0.5 h. Decreasing the catalyst loading to 0.25 mol % gave
a respectable 94% yield of the product for 0.5 h. Pd(OAc)2 in
the amount of 0.002 mol % was found to be sufficient to give
a moderate conversion with a 68% isolated yield of the product
after 6 h. A yield of 66% was obtained after 24 h when the
loading of Pd was decreased to 0.000 02 mol %, which
corresponds to a turnover number of 3 000 000, indicating that
the Pd(OAc)2-H2O-acetone catalytic system is highly active
for the mono-Suzuki coupling reaction.
The catalytic system was applicable to a wide range of aryl
iodides and bromides (Table 2). The coupling of aryl iodides
was superior and afforded the desired product in excellent yields
(Table 2, entries 1-3). The electron-deficient aryl bromides
showed an excellent reactivity and furnished the products in
high yields in short reaction times (Table 2, entries 4-6). A
little prolongation of the reaction time was required for the
electron-rich aryl bromides (Table 2, entries 7-10). It is worth
noting that the catalytic system was tolerant to a broad range
of functional groups, such as NO2, OMe, OH, COMe, and CN.
The coupling of 4-bromochlorobenzene with the phenylboronic
acid gave exclusively 4-chlorobiphenyl in 98% yield, showing
good selectivity (Table 2, entry 4). Both the electron-rich and
the electron-deficient arylboronic acids delivered the products
with high yields (Table 2, entries 11-20). The sterically
demanding aryl bromide also gave a high yield (Table 2, entry
8), but the aryl chlorides were almost inactive.
We initially studied the effect of acetone as a cosolvent on
the Suzuki reaction in water. We employed the coupling reaction
of 4-bromotoluene with phenylboronic acid as a model reaction
to study the effect of acetone on the reaction. The reactions
were carried out using Na2CO3 as base in the presence of 0.5
mol % Pd(OAc)2 at 35 °C (external temperature) in air. As is
evidenced from Table 1, the reaction in pure water afforded
4-methylbiphenyl in a very low yield after 0.5 h (Table 1, entry
1). However, the addition of incremental amounts of acetone
led to a very rapid increase in the activity, and nearly quantitative
yield was obtained when the ratio of water and acetone was
between 3:3 and 4:3 mL (Table 1, entries 3-5). The reaction
in pure acetone was sluggish (Table 1, entry 7). These results
suggest that the ratio of water and acetone plays the key role in
the ligand-free Suzuki reaction. Different bases, including Na2-
CO3, K2CO3, K3PO4, NaOH, and KOH, delivered the desired
product in high yields (Table 1, entries 4, 8-11). In addition,
a profound solvent effect on the reaction was observed. The
use of ethanol, propanol, and DMF as cosolvent gave almost
identical results as acetone (Table 1, entries 12-14), whereas
toluene, CH2Cl2, dioxane, DMSO, THF, and CH3CN delivered
very low yields (<40%).
The efficiency of the catalytic system was evaluated by the
coupling of 4-bromotoluene and phenylboronic acid in a 3.5:3
(16) (a) Cammidge, A.; Gopee, H. Chem. Commun. 2002, 966. (b) Wong,
K.-T.; Hung, T. S.; Lin, Y.; Wu, C.-C.; Lee, G.-H.; Peng, S.-M.; Chou, C.
H.; Su, Y. O. Org. Lett. 2002, 4, 513. (c) Bo, Z.; Schlueter, A. D. J. Org.
Chem. 2002, 67, 5327. (d) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am.
Chem. Soc. 2002, 124, 13179. (e) Berthiol, F.; Kondolff, I.; Doucet, H.;
Santelli, M. J. Organomet. Chem. 2004, 689, 2786. (f) Sailer, M.; Gropeanu,
R.-A.; Mueller, T. J. J. J. Org. Chem. 2003, 68, 7509. (g) Simoni, D.;
Giannini, G.; Baraldi, P. G.; Romagnoli, R.; Roberti, M.; Rondanin, R.;
Baruchello, R.; Grisolia, G.; Rossi, M.; Mirizzi, D.; Invidiata, F. P.;
Grimaudo, S.; Tolomeo, M. Tetrahedron Lett. 2003, 44, 3005.
The application of the above aqueous catalytic systems in
the synthesis of polyaryls was studied, and the results are
summarized in Table 3. Among the solvents tested, DMF
afforded the best selectivity to the product of terphenyl as the
cosolvent in the coupling of 1-bromo-2-iodobenzene with phenyl
J. Org. Chem, Vol. 71, No. 10, 2006 3995

TABLE 3. Double Coupling of Dihaloaryls with Phenyl Boronic Acida
a Reaction conditions: dihalide (1 mmol), PhB(OH)2 (4-6 mmol), Na2CO3 (4 mmol), H2O/solvent ) 3.5:3 mL. b GC yield based upon dihalide.
TABLE 4. Coupling of Di- and Trihaloaryls with Phenyl Boronic Acids
a Isolated yield. b Reaction conditions: dihalide (1 mmol), ArB(OH)2 (6 mmol), Na2CO3 (4 mmol), Pd(OAc)2 (1 mol %), H2O/DMF ) 3.5:3 mL, 60 °C
(external temperature), 12 h. c Reaction conditions: trihalide (1 mmol), ArB(OH)2 (9 mmol), Na2CO3 (6 mmol), Pd(OAc)2 (1.5 mol %), H2O/DMF ) 3.5:3
mL, 60 °C (external temperature), 12 h.
boronic acid (Table 3, entry 1). Acetone and ethanol also
presented high activity as cosolvents, but showed relatively
lower selectivity to terphenyl (Table 3, entry 1). An increase in
the amount of phenyl boronic acid and the prolongation of the
reaction time have a slight impact upon the selectivity toward
terphenyl (Table 3, entry 2). The temperature was found to be
the strongest effect on the selectivity, and the excellent yield
and selectivity to terphenyl was obtained when the temperature
was increased to 60 °C (Table 3, entry 3). Changes to the
aromatic substituent location have little function to the activity
3996 J. Org. Chem., Vol. 71, No. 10, 2006

mol %; for trihalides, Pd(OAc)2 ) 1.5 mol %), aryl halides (1
mmol), arylboronic acid (1.5 mmol; for dihalides, boronic acid was
6 mmol; for trihalides, boronic acid was 9 mmol), distilled water
(3.5 mL) and solvent (3 mL) was stirred for the indicated time.
Afterward, the reaction solution was extracted four times with
diethyl ether (4 × 10 mL). The combined organic phase was
analyzed by GC and GC/MS. The further purification of the product
was achieved by flash chromatography on a silica gel column.
and selectivity (Table 3, entries 4-9). In all cases, the mixture
of water and DMF afforded the best selectivity to terphenyls
(Table 3).
In the study of single and double Suzuki couplings with
dihalobenzene, Sinclair and Sherburn15a reported that the halogen
was the major factor in determining the selectivity for the
coupling of aryl boronic ester in the presence of Pd(PPh3)4 and
Ag2CO3. They found that diiodobenzenes were the best choice
for the double coupling and that dibromobenzenes mainly
delivered the single coupling products. In the case of the Pd-
(OAc)2-H2O-DMF system, the identity of the halogen pre-
sented little effect on the selectivity, as shown in Table 4. For
each di- or trihalobenzene substrate examined, regardless of the
halide substituent location and type, the major products resulted
from the multiple coupling under the reaction conditions (Table
4, entries 1-14). The electron-rich, electron-poor, and electron-
neutral aryl boronic acids presented essentially the same
reactivity and selectivity patterns.
In conclusion, we have developed a general and high-yielding
methodology for the Suzuki reaction in aqueous phase in a short
reaction time under mild conditions. The high efficiency and
use of only cosolvent without other additives and ligands make
the method useful and attractive for the synthesis of biaryls.
Furthermore, the method can be extended to the consecutive
multi-coupling Suzuki reaction involving di- and trihaloaro-
matics, which allows the access of a variety of polyaryls in high
selectivity and high yield under mild aqueous reaction condi-
tions.
1
4,4′′-Trifluoromethyl-1,1′:3′,1′′-terphenyl [T4-8]: H NMR (500
MHz, CDCl3, TMS) δ 7.79 (s, 1H), 7.73 (m, 8H), 7.64-7.56 (m,
3H); 13C NMR (125 MHz, CDCl3) δ 144.6, 140.9, 130.0 (q, J )
32.3 Hz), 129.9, 127.8, 127.4, 126.6, 126.1 (q, J ) 3.8 Hz), 124.5
(q, J ) 270.3 Hz). MS (EI, %) m/z: 366 (100) [M+], 347 (12),
296 (10), 228 (10), 183 (8); HRMS (EI) calcd for C20H12F6,
366.0838; found, 366.0835; IR (KBr) V 1616, 1573, 1482, 1410,
1389, 1323, 1249, 1173, 1126, 1070, 1059, 1023, 844, 796, 755,
737, 698, 601, 430 cm-1
.
2,4,6-Tris(4-trifluoromethylphenyl)phenol [T4-14]: 1H NMR
(500 MHz, CDCl3, TMS) δ 7.79 (d, 4H, J ) 8.5 Hz), 7.73 (d, 4H,
J ) 8.0 Hz), 7.70 (s, 4H), 7.55 (s, 2H), 5.33 (s, 1H); 13C NMR
(125 MHz, CDCl3) δ 149.7, 143.7, 140.9, 133.3, 130.6 (q, J )
32.3 Hz), 130.0, 129.6 (q, J ) 32.3 Hz), 129.6, 128.7, 127.3, 126.3
(q, J ) 3.4 Hz), 126.1 (q, J ) 3.6 Hz), 124.5 (q, J ) 270.1 Hz),
124.3 (q, J ) 270.9 Hz). MS (ESI) m/z: 525.0 ([M - H]+). HRMS
(ESI) calcd for C27H15F9O, 525.0895; found, 525.0893. IR (KBr)
V 3447, 1617, 1394, 1328, 1228, 1164, 1112, 1067, 837 cm-1
.
Acknowledgment. Funding from Natural Science Founda-
tion of China (No. 20373061 and No. 20571063) is acknowl-
edged.
Supporting Information Available: The experimental proce-
dure and spectroscopic data (1H NMR, 13C NMR, and MS) for the
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
Experimental Section
General Procedure for the Suzuki Reaction: A mixture of Na2-
CO3 (0.212 g, 2 mmol; for dihalides, 4 mmol; for trihalides, 6
mmol), Pd(OAc)2 (1 mg, 0.5 mol %; for dihalides, Pd(OAc)2 ) 1
JO060122V
J. Org. Chem, Vol. 71, No. 10, 2006 3997