Boronic Acid Coupling Reactions in Water
J . Org. Chem., Vol. 62, No. 21, 1997 7171
that hydrophobic effects16 also play a role. Under “clas-
sical” conditions, the slow step when using aryl bromides
has been shown to be the oxidative addition,17 whereas
the transmetalation step seems to be rate-determining
here.
In summary, we found that tetrabutylammonium
bromide in water without organic cosolvent considerably
enhances the rate of the Suzuki coupling of aryl bromides
with aryl and vinyl boronic acids. A wide variety of
functional groups, including base-sensitive ones (i.e.
ester), can be tolerated.
Ta ble 1. Effects of Solven t on Cr oss-Cou p lin g of 1 a n d 2
Ca ta lyzed by Liga n d less P d (OAc)2.a
entry
solvent
time (h) 1 (%)b 3 (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
DMFc
DMF
1
1
2
1
1
1
1
1
1
3
3
1
1
>95
20
20
15
>95
85
95
60
65
65
65
d
d
80
80
85
d
DMF
DMFe
CH3CN
NMP
15
5
DMSO
DMSO +4 equiv H2O
EtOH
40
35
35
35
>95
>95
H2O
H2O + nBu4NBr (10%)
H2O + nBu4NBr (1 equiv)
H2O + nBu4NBr (1 equiv) f
Exp er im en ta l Section
d
Gen er a l. All reactions were carried out under argon. NMR
spectra were recorded at 200 MHz using CDCl3 or DMSO-d6
as both solvent and reference. Coupling constants are given
in hertz (Hz). IR spectra were recorded an a dispersion
instrument. Elemental analysis were performed by the mi-
croanalytical laboratory of the Redox S.n.C. in Cologno Monz-
ese, Italy.
a
All couplings were carried out at 70 °C in the presence of 2%
Pd(OAc)2 and 2.5 equiv of K2CO3. b 1H NMR yields determined
c
by integration on the crude reaction mixture. Et3N employed
d
as base instead of K2CO3. None detected. e Carried out at 100
°C. f 0.2% Pd(OAc)2.
Ar yl Iod id e Cou p lin g. In the palladium-catalyzed
Suzuki9 and Stille10 coupling of aryl halides, the order of
reactivity is usually I > Br >> Cl. Under our conditions,
aryl iodides gave incomplete conversion (Table 4). Reac-
tions stopped after about 1 h.
The cross-coupling of 4-iodoanisole with phenylboronic
acid under aqueous conditions with water-soluble Pd-
TTPS (meta-sulfonated triphenylphosphine) catalyst has
been reported to give good yields.11 Moreover, it is well
known that aryl iodides do not give complete conversion
in simple displacement reactions (i.e. SN2) in the LL-PTC
system.12 This suggests that an effective phase-transfer
process is pivotal under our conditions.
Ar yl Tr ifla te Cou p lin g. Suzuki coupling of aryl
triflates with aryl boronic acids in a toluene/water
biphasic system is reported to give high yields of biphenyl
when an electron-withdrawing group is present on the
aryl triflate.13 Lower yields and/or incomplete conversion
are reported with nonactivated aryl triflates.14 No
substantial improvement is observed in water in the
presence of tetrabutylammonium bromide (Table 5). Low
conversion is obtained with 4-acetamidophenyl triflate
(entry 1). Cross-coupling proceeds rapidly with 4-acetyl-
phenyl triflate, but there is significantly hydrolysis to
phenol (entry 2).
The mechanism of the Pd-catalyzed Suzuki reaction
of aryl halides with aryl boronic acids involves oxidative
addition of Pd(0) to aryl halide, transmetalation of the
Ar-Pd-X with Ar1B(OH)3-M+ and reductive elimination
to give Ar-Ar1.15 The high acceleration rate in the
presence of tetrabutylammonium bromide is presumably
due to the formation of an Ar1B(OH)3-Bu4N+ species
which partitions back into the organic phase, although
the behavior observed with cosolvent (Table 3) suggests
Ch em ica ls. Unless otherwise specified, all reagents were
commercially available from Aldrich, Fluka, or Lancaster.
Organic solvents were dried by distillation from CaH2 and
stored over molecular sieves (4 Å). Aryl triflates were prepared
from the corresponding phenols by reported standard meth-
ods.18 (E)-1-octenyl-1-boronic acid was prepared as described
by Brown.19
Rep r esen ta tive Cou p lin g Rea ction s. 6-Meth oxy-2-p h e-
n yln a p h th a len e (Ta ble 3, en tr y 4). To a 5 mL flask were
added a stir-bar, 474.2 mg (2 mmol) of 2-bromo-6-methoxy-
naphthalene, 268 mg (2.2 mmol) of phenylboronic acid, 0.9 mg
(0.2 mol %) of Pd(OAc)2, 691 mg (5 mmol) of powdered K2CO3,
and 644.8 mg (2 mmol) of Bu4NBr. The flask was flushed with
argon and equipped with a rubber septum. Water (2.2 mL)
was added with a syringe, and the resulting suspension was
energetically stirred and degassed to remove O2. The mixture
was stirred and heated for 1 h at 70 °C under argon. It was
then cooled to room temperature, diluted with water, and
extracted with EtOAc. The solution was dried (Na2SO4) and
concentrated to yield a white solid. Chromatography on silica
(1% EtOAc in hexane) afforded 465 mg (99% yield) of the title
compound: mp 149-151 °C (lit.20 mp 148 °C). Anal. Calcd
for C17H14O: C, 87.14; H, 6.02. Found: C, 86.84; H, 6.00.
4-Meth oxy-3′-(tr iflu or om eth yl)-1,1′-bip h en yl (Table 1,
entry 13). Obtained as a colorless oil after flash-chromatog-
raphy (5% EtOAc in cyclohexane). IR (film) 2839, 1337, 1263,
1166, 1124 cm-1 1H NMR (CDCl3) δ 7.81 (m, 1H), 7.72 (m,
;
1H), 7.6-7.5 (m, 4H), 7.01 (m, 2H), 3.88 (s, 3H). Anal. Calcd
for C14H11F3O: C, 66.67; H, 4.40. Found: C, 66.65; H, 4.38.
4-(2-Hyd r oxyet h yl)-3′-(t r iflu or om et h yl)-1,1′-b ip h en yl
(Table 2, entry 3). Obtained as a colorless oil after flash-
chromatography (10% EtOAc in cyclohexane). IR (film) 2941,
1336, 1166, 1128 cm-1; 1H NMR (CDCl3) δ 7.88-7.71 (m, 2H),
7.67-7.50 (m, 4H), 7.40-7.28 (m, 2H), 3.92 (t, J ) 6, 2H), 2.93
(t, J ) 6, 2H). Anal. Calcd for C15H13F3O: C, 67.67; H, 4.92.
Found : C, 67.91; H, 4.91.
3-(2-Cya n om et h yl)-3′-(t r iflu or om et h yl)-1,1′-b ip h en yl
(Table 2, entry 4). Obtained as a colorless oil after flash-
chromatography (10% EtOAc in cyclohexane). IR (film) 2253,
1338, 1165, 1124 cm-1; 1H NMR (CDCl3) δ 7.83-7.32 (m, 8H),
3.82 (s, 2H). Anal. Calcd for C15H10F3N: C, 68.96; H, 3.86; N,
5.36. Found: C, 68.82; H, 3.85; N, 5.34.
3-(1,3-Dioxa -2-cyclop en tyl)-3′-(tr iflu or om eth yl)-1,1′-bi-
p h en yl (Table 2, entry 5). Obtained as a colorless oil after
flash-chromatography (10% EtOAc in cyclohexane). IR (film)
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