Hydroxylated terphenylphosphine ligands for palladium-catalyzed ortho-selective cross-coupling of dibromophenols, dibromoanilines, and their congeners with Grignard reagents

Article abstract of DOI:10.1016/j.tet.2011.09.013

p-Terphenylphosphines bearing one or two hydroxy groups were used as ligands to palladium in the cross-coupling of dibromophenols, dibromoanilines, and their congeners with Grignard reagents. High ortho-selectivity that cannot be achieved using other phosphine ligands was observed. ortho-Preference was also observed in competitive cross-coupling reactions of two substrates. A significant effect of the concentration of the Grignard reagent on the ortho-selectivity was observed, when the hydroxylated terphenylphosphines were used. Kinetic studies on this effect showed that high concentrations of the Grignard reagent retard the cross-coupling reaction only at the para-position, but not at the ortho-position.

Full text of DOI:10.1016/j.tet.2011.09.013

Tetrahedron 67 (2011) 10156e10163
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Hydroxylated terphenylphosphine ligands for palladium-catalyzed ortho-selective
cross-coupling of dibromophenols, dibromoanilines, and their congeners with
Grignard reagents
,
,b,
Shunpei Ishikawa a y, Kei Manabe a
*
a Manabe Initiative Research Unit, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako 351-0198, Japan
b School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2011
Received in revised form 2 September 2011
Accepted 6 September 2011
Available online 10 September 2011
p-Terphenylphosphines bearing one or two hydroxy groups were used as ligands to palladium in the
cross-coupling of dibromophenols, dibromoanilines, and their congeners with Grignard reagents.
High ortho-selectivity that cannot be achieved using other phosphine ligands was observed. ortho-
Preference was also observed in competitive cross-coupling reactions of two substrates. A significant
effect of the concentration of the Grignard reagent on the ortho-selectivity was observed, when
the hydroxylated terphenylphosphines were used. Kinetic studies on this effect showed that high
concentrations of the Grignard reagent retard the cross-coupling reaction only at the para-position,
but not at the ortho-position.
Keywords:
Cross-coupling
Phosphine
Grignard reagent
Site-selective
Palladium
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
governed by electronic considerations. In these situations the cross-
coupling reactions occur at the more electron-poor carbon.
Transition metal-catalyzed cross-coupling of haloarenes with
organometals is an important preparation method of multi-
substituted benzenes.1 Despite its long history, there is still in-
tensive research underway to expand the current scope of cross-
coupling chemistry. Developing site-selective cross-coupling re-
actions is one such area that has attracted attention from synthetic
chemists.2 Site-selective cross-coupling of dihaloarenes, in which
one of the halo groups is selectively converted to another group,
can be a very useful method for efficient synthesis of multi-
substituted arenes. Many examples of site-selective cross-coupling
reactions have been reported for dihalogenated heteroarenes.2a,b
By contrast, there have been fewer examples documented for
dihalogenated benzene derivatives,3 thus there is a need to develop
new methods of site-selective cross-coupling for these types of
compounds. In the reactions that have been reported, the site-
selectivities are mainly controlled by the steric and electronic fac-
tors of the substrates. As expected, reactions occur at less sterically
hindered sites. In many cases the selectivity of the reactions is also
Therefore, it is generally difficult to realize site-selectivity in which
cross-coupling reactions preferentially occur at more electron-rich
carbons. Another drawback encountered during cross-coupling
reactions of dihaloarenes is the formation of di-cross-coupled
products, even when limited amounts of organometals are used.4
An efficient system for site-selective cross-coupling reactions
should be able to overcome this problem.
We have recently developed a new type of site-selective cross-
coupling in which reactions occur at the more electronically neg-
ative carbon and also at sterically hindered positions. In these re-
actions, dibromophenols or dibromoanilines react with excess
Grignard reagents preferentially at the bromo group ortho to hy-
droxy or amino groups (Scheme 1).5 These groups are strongly
electron-donating groups especially when deprotonated and ren-
der the ortho-positions electronically negative. The key of the re-
actions is the use of palladium catalysts bearing hydroxylated
terphenylphosphines,5,6 monohydroxyterphenylphosphine (HTP)
and dihydroxyterphenylphosphine DHTP (Fig. 1a). These phos-
phines were designed based on biphenylphosphines developed by
Buchwald and co-workers7 and were expected to perform as bi-
functional ligands.8 It is also worth noting that, in the reaction
system developed, the formation of di-cross-coupled products was
sufficiently suppressed in most cases.
* Corresponding author. Tel./fax: þ81 54 264 5754; e-mail address: manabe@
u-shizuoka-ken.ac.jp (K. Manabe).
y
Present address: Otsuka Pharmaceutical Co., Ltd.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.013

S. Ishikawa, K. Manabe / Tetrahedron 67 (2011) 10156e10163
10157
the corresponding free form in situ in the presence of the Grignard
reagent, para-selectivity was observed, albeit accompanied by sig-
nificant di-cross-coupling (entry 3). For 1,10-bis(diphenylphos-
phino)ferrocene (DPPF),
a highly para-selective, mono-cross-
coupling reaction occurred to give 3 as the major product (entry
4). Use of biphenylphosphines7 as shown in entries 5e7 resulted in
poor yields and selectivities. However, hydroxylated terphenyl-
phosphines, such as Cy-HTP (as its HBF4 salt) and Ph-HTP prefer-
entially afforded ortho-cross-coupled product 2 (entries 8 and 9).
Although small amounts of 4 were produced, 3 was not isolated at
all. In addition, the reactions were significantly accelerated and
completed in 2 h, compared with 24 h for the other entries. Ph-HTP
effectively suppressed formation of 4 compared with Cy-HTP. The
hydroxy group of HTP was found to be essential, since the corre-
sponding methylated compound6a resulted in poor yields and se-
lectivity (entry 10). A quaterphenyl analogue6b also gave low yields
and selectivity (entry 11), indicating that precise positioning of the
hydroxy group of HTP was also crucial for high ortho-selectivity. Ph-
DHTP, bearing two hydroxy groups, further improved the selectiv-
ity, affording 2 in 91% yield with only 2% of 4 produced (entry 12).
A reaction of 2-bromophenol with phenylmagnesium bromide
under the conditions shown in Table 1, entry 8 for 1 h gave
2-phenylphenol in 79% yield. On the other hand, a reaction of
Scheme 1. ortho-Selective cross-coupling of dibromophenol and dibromoaniline
derivatives with Grignard reagents.
Table 1
Effect of ligand on site-selective cross-coupling of
magnesium bromide
1 with 4-methoxyphenyl-
Fig. 1. (a) Hydroxylated terphenylphosphines. (b) Proposed intermediates responsible
for the ortho-selectivity in site-selective cross-coupling of
a dibromoarene with
a Grignard reagent.
Fig. 1b outlines the proposed intermediates through which the
ortho-selectivity achieved. The hydroxylated phosphines are
deprotonated by the Grignard reagent and presumably form pal-
ladium/magnesium bimetallic species in the presence of palladium.
The magnesium oxido moiety can then act as a binding site for the
substrate, which also exists as a magnesium salt, and situates the
ortho bromo group close to the palladium. Through this mecha-
nism, oxidative addition to the palladium should preferentially
occur at the position ortho to the oxido group of the substrate. Since
the oxidative addition step is considered as the rate-limiting and
the selectivity-determining step, both rate acceleration and ortho-
selectivity are expected.
Entry
Ligand
Time (h)
Yield (%)
2
3
4
1
2
3
4
PPh3
PCy3
P(t-Bu)3$HBF4
DPPF
24
24
24
24
22
21
0
16
14
40
77
14
38
25
1
1
The ortho-selectivity mentioned above was realized only when
these phosphines were used as ligands to palladium. Thus, this
catalyst-controlled site-selective cross-coupling results in a novel
synthetic route to multisubstituted benzenes. Herein, we detail
ortho-selective cross-coupling of dibromoarenes and ortho-selec-
tive competitive cross-coupling reactions between two substrates.
We also disclose an unusual dependence of the ortho-selectivity
upon the concentration of the Grignard reagent in the cross-
coupling using the hydroxylated terphenylphosphines.
5
24
5
5
1
6
7
24
24
8
2
12
8
3
0
2. Results and discussion
8
9
Cy-HTP$HBF4
Ph-HTP
2
2
71
89
0
0
16
4
2.1. ortho-Selective cross-coupling of dibromoarenes
To examine effects of ligands to palladium on site-selectivity, we
tested various phosphines for cross-coupling of 2,4-dibromophenol
(1) with 4-methoxyphenylmagnesium bromide in the presence of
tris(benzylideneacetone)dipalladium [Pd2(dba)3]. Triphenylphos-
phine and tricyclohexylphosphine gave ortho-cross-coupled prod-
uct 2, para-cross-coupled product 3, and di-cross-coupled product
4 all in modest yields (Table 1, entries 1 and 2). Selectivity was low
not only for ortho versus para, but also mono- versus di-cross-
coupling. For tri-tert-butylphosphine HBF4 salt,9 which generates
10
11
24
13
18
7
24
2
6
21
0
5
2
12a
Ph-DHTP
91
a
Grignard reagent (3 equiv) was used.

10158
S. Ishikawa, K. Manabe / Tetrahedron 67 (2011) 10156e10163
2-bromoanisole under the same conditions gave 2-methoxybiphenyl
in only 17% yield. This result indicates that the presence of the
hydroxy group of the substrate plays an important role in accelerat-
ing the reaction at the ortho-position.
We applied our catalytic system of palladiumeHTP or DHTP to
other dibromoarenes bearing a hydroxy or amino group (Table 2).
Although di-cross-coupling occurred to some extent, 2,5-
dibromophenol preferentially gave ortho-cross-coupled product A
when the hydroxylated terphenylphosphines were used (entries 1
and 2). It should be noted that the reaction occurred at the more
electronically negative carbon and at then more sterically hindered
position. In contrast, DPPF gave meta-cross-coupled product B as the
major product (entry 3). This result emphasizes the effectiveness of
the hydroxylated terphenylphosphines for ortho-selective cross-
coupling. In the case of 1,6-dibromo-2-naphthol, HTP was not effec-
tive at inducing site-selectivity (entry 6). However, phosphines with
Table 2
Site-selective cross-coupling with 4-methoxyphenylmagnesium bromide
Entry
Substrate
Ligand
PMPMgBr (equiv)
Temperature (ꢀC)
Time (h)
Yield (%)
A
B
C
1
2
3
Ph-HTP
Ph-DHTP
DPPF
4
3
4
25
25
25
2
2
65
64
0
0
0
10
25
<2a
24
61
4
5
Ph-DHTP
DPPF
3
3
25
25
5
93
2
0
2
1
24
<42a
6
Cy-HTP$HBF4
3
25
2
17
22
20
7
8
9
Cy-DHTP$HBF4
Ph-DHTP
DPPF
3
3
3
25
25
25
2
2
8
79
92
0
0
0
94
6
2
0
10
Cy-HTP$HBF4
4
25
10
71
0
12
11
12
13
Ph-HTP
Ph-DHTP
DPPF
4
3
4
25
25
25
10
10
10
76
90
9
0
0
15
13
0
2
14
Ph-HTP
4
25
10
63
0
<26a
15
16
Ph-DHTP
DPPF
4
4
25
50
10
10
36
15
0
32
<56a
<11a
17
18
Ph-DHTP
DPPF
4
3
35
25
24
18
70
29
0
9
21
36
19
20
Ph-DHTP
DPPF
3
3
25
50
13
13
81
0
0
5
37
55
21
22
Ph-HTP
4
4
50
50
2
2
58
80
4
0
22
5
Ph-DHTP
a
Contaminated with low levels of impurities.

S. Ishikawa, K. Manabe / Tetrahedron 67 (2011) 10156e10163
10159
two hydroxy groups, Cy-DHTP and Ph-DHTP, gave A with high se-
lectivities (entries 7 and 8), suggesting that DHTP is better at con-
trolling the selectivity when compared to HTP. Dibromoanilines and
dibromoindole also resulted in high ortho-selectivities, when HTP or
DHTP was used (entries 10e12, 14, 15, 17, and 19). To our surprise,
even 4-bromo-2-chlorophenol gave ortho-cross-coupled product A
with high selectivities (entries 21 and 22). This result clearly indicates
that the ortho-selectivity induced by the hydroxylated phosphines,
especially by DHTP, superseded the intrinsic reactivity order of the
halo groups (normally Br is more reactive than Cl).3f,10
Various Grignard reagents were tested for the ortho-selective
cross-coupling (Table 3). Both aryl and also heteroaryl Grignard
reagents worked well to give ortho-cross-coupled products A
(entries 1e5). By lowering the reaction temperature to 15 ꢀC, it
was possible to carry out the reaction with a Grignard reagent
having an ester functionality that was prepared following the
method by Knochel and co-workers11 (entry 6). An alkenyl
Grignard reagent gave A with excellent selectivity (entry 7).
Benzyl Grignard reagent showed different behavior. When Cy-
HTP was used, para-cross-coupled product B was the major
product (entry 8).12 When Ph-DHTP was employed, ortho-selec-
tivity was recovered, but with low product yield (entry 9). The
results in Table 3 indicate that Ph-DHTP was, in general, the best
ligand for these reactions.
The effectiveness of DHTP compared with HTP can be rational-
ized in terms of a conformational effect. The assumed catalytic
species formed from HTP is shown in Fig. 2a. This species has
flexibility in rotation of the CeC single bonds. The conformation in
which the palladium and the magnesium oxido moiety are located
close to each other is in equilibrium with the conformer in which
the palladium and the magnesium oxido groups are on the opposite
sides of the terphenyl group. In the latter conformation, the co-
operative effect of the palladium and the magnesium oxido groups
cannot function. On the other hand, in the case of DHTP, a magne-
sium oxido group is always located on the same side of the ter-
phenyl structure as the palladium, even if CeC bond rotation occurs
(Fig. 2b).13 Through this mechanism, cooperation between palla-
dium and the magnesium oxido moiety may be more effective for
DHTP, giving higher selectivities in the ortho-selective cross-
coupling reactions.
In the course of the investigation of the ortho-selective cross-
coupling reaction, we found that the amount of the Grignard re-
agent employed greatly affected the selectivity achieved. For the
reaction of 2,4-dibromophenol with 4-methoxyphenylmagnesium
bromide in the presence of palladium and Cy-HTP, the amount of
the Grignard reagent used was varied from 2.2 to 10 equiv (Table 4,
entries 1e4). Both the yields of 3 and 4 decreased, as the amount of
the Grignard reagent increased. Even when 10 equiv of the Grignard
Table 3
ortho-Selective cross-coupling with various Grignard reagents
Entry
Grignard reagent
(Equiv)
Ligand
Temperature (ꢀC)
Time (h)
Yield (%)
A
B
C
1
2
4
4
Cy-HTP$HBF4
25
25
2
2
60
84
0
0
17
5
Ph-HTP
3
3
Ph-DHTP
25
14
77
0
2
4
5
4
4
Cy-HTP$HBF4
25
35
72
22
66
98
0
0
17
1
Ph-DHTP
6
2a
Ph-DHTP
Ph-DHTP
15
25
20
18
73
83
0
2
0
7
8
3
0
4
3
Cy-HTP$HBF4
50
35
5
Trace
37
55
<21b
9
Ph-DHTP
20
<3b
15
a
Prepared from tert-butyl 4-iodobenzoate (2 equiv) with i-PrMgBr (3 equiv) in THF at ꢁ40 ꢀC.
b
Contaminated with low levels of impurities.

10160
S. Ishikawa, K. Manabe / Tetrahedron 67 (2011) 10156e10163
Table 5
Competitive cross-coupling of two substrates
Entry
1
Substrate
Ligand
PhMgBr Time (h) Yield (%)
(equiv)
A
B
Cy-HTP$HBF4
3
1
29 33
2
3
4
5
Cy-HTP$HBF4
Cy-DHTP$HBF4
Ph-DHTP
6
3
3
4
1
1
5
2
59
39
60
86
5
9
3
0
Fig. 2. CeC bond rotation for the species formed from (a) HTP and (b) from DHTP.
Ph-DHTP
Table 4
Effect of amount of the Grignard reagent
6
Ph-DHTP
3
2
96
2
7
8
Ph-DHTP
Ph-DHTP
4
4
5
85
88
2
1
Entry
Ligand
PMPMgBr (equiv)
Yield (%)
2
3
4
15
1
2
3
4
5
6
7
8
Cy-HTP$HBF4
Cy-HTP$HBF4
Cy-HTP$HBF4
Cy-HTP$HBF4
Ph-HTP
Ph-HTP
Ph-DHTP
Ph-DHTP
2.2
3
4
10
3
4
36
59
71
82
80
89
79
91
8
22
20
16
5
10
4
<2a
0
0
0
0
0
(entry 4). Further increases of the Grignard reagent suppressed
formation of B completely (entry 5). Ph-DHTP also worked well in
other competitive reactions, exhibiting high ortho-selectivity (en-
tries 6e8).
2.2
3
5
2
0
a
Contaminated with low levels of impurities.
reagent was used, the yield of 4 was only 5%. This counterintuitive
effect was also observed for reactions with Ph-HTP and Ph-DHTP as
ligands (entries 5e8). Although the mechanism for the effect is
unclear, kinetic studies14 of model compounds suggest that the
reaction at the para position to give 3 and 4 is retarded upon in-
creasing the concentration of the Grignard reagent (vide infra). The
results in Table 4 also indicate that large amounts of the Grignard
reagent are necessary for high selectivity when Cy-HTP is used. On
the other hand, when Ph-DHTP is employed, less amounts of the
Grignard reagent is sufficient.
2.3. Kinetic studies on the effect of concentration of Grignard
reagent
The results in Table 4 indicate that the amount of the Grignard
reagent employed affected the product selectivity in site-selective
cross-coupling of dibromophenol. Similar effects were also ob-
served in the competitive reactions between two substrates
(Table 5, entry 1 vs 2, 4 vs 5). The significant increase of selec-
tivity was observed for the hydroxylated terphenylphosphines,
but not for simple phosphines, such as tricyclohexylphosphine. To
gain insight into the mechanism of this effect, we conducted
kinetic studies on cross-coupling reactions of 4-bromophenol and
2-bromophenol with varying amounts of a Grignard reagent in
the presence of palladium and Cy-HTP or tricyclohexylphosphine
as a reference ligand. Fig. 3 shows a plot of the initial reaction
rate of 4-bromophenoxymagnesium bromide, prepared from
4-bromophenol in situ, versus the initial concentration of phe-
nylmagnesium bromide. This plot clearly indicates that, for both
the ligands, the reaction rate decreases as the concentration of
the Grignard reagent increases.
2.2. Competitive cross-coupling between two substrates
The high ortho-preference observed in the site-selective cross-
coupling mentioned above was also applied to competitive re-
actions between two substrates. For example, the reaction of
a 1:1:6 mixture of 2-bromophenol, 4-bromophenol, and phenyl-
magnesium bromide in the presence palladium and Cy-HTP affor-
ded ortho-cross-coupled product A in 59% yield and para-cross-
coupled product B in 5% yield (Table 5, entry 2). Interestingly, this
ortho-preference was not observed, when 3 equiv of the Grignard
reagent was used (entry 1). The larger amounts of the Grignard
reagent, the higher the selectivity, as already reported in Table 4.
On the other hand, when Ph-DHTP was used, 3 equiv of
the Grignard reagent was sufficient to induce ortho-selectivity
Results for 2-bromophenoxide exhibit different behavior
(Fig. 4). For tricyclohexylphosphine, the reaction rate decreases
upon increasing concentration of the Grignard reagent as in the
case of Fig. 3. For Cy-HTP, however, the reaction rate was found to
be independent of the concentration of the Grignard reagent

S. Ishikawa, K. Manabe / Tetrahedron 67 (2011) 10156e10163
10161
within this concentration range. Therefore, the rate difference
between ortho- and para-positions becomes greater at higher
concentrations of the Grignard reagent. Although a detailed
mechanism has not been elucidated, it is obvious that high
concentrations of Grignard reagent retard the cross-coupling re-
action only at the para-position, but not at the ortho-position, in
the HTP system.
3. Conclusions
Palladium-catalyzed ortho-selective cross-coupling of dibro-
moarenes with Grignard reagents has been realized using
hydroxylated terphenylphosphines as ligands to palladium.
Dibromophenols, dibromonaphthol, dibromoanilines, and dibro-
moindole reacted at the ortho-positions selectively. Formation of
di-cross-coupled products was sufficiently suppressed in many
cases. This catalytic system was also applied to ortho-selective
competitive cross-coupling between two substrates. The Grignard
reagent concentration had a profound influence on the ortho-se-
lectivity, when the hydroxylated terphenylphosphines were used.
In addition, the unaffected bromo groups of compounds produced
can be converted to various other groups, thus the catalyst-
controlled site-selective cross-coupling developed will provide
a novel efficient method for the preparation of multisubstituted
arenes.
4. Experimental section
4.1. Synthesis of ligands
Fig. 3. Double logarithm plot of the reaction rate v (M/min) versus the initial concen-
tration of PhMgBr [PhMgBr] (M) for Eq. 1. Open square: ligand¼Cy-HTP$HBF4 at 50 ꢀC.
Closed circle: ligand¼PCy3 at 35 ꢀC. The solid lines are calculated linear trendlines.
Cy-HTP$HBF4,6b Ph-HTP,5a Cy-DHTP$HBF4,5c and Ph-DHTP5c
were prepared according to previously reported methods.
4.2. General procedure of ortho-selective cross-coupling
reactions
To a solution of dibromo compound (0.42 mmol), Pd2(dba)3
(4.2 mmol), and ligand (10 mmol) in THF (0.42 mL) was added a THF
solution of Grignard reagent under argon at ꢁ78 ꢀC. After 10 min,
the reaction mixture was warmed to 25 ꢀC and stirred for the time
indicated. The reaction was quenched by the addition of a 10%
aqueous solution of HCl (5 mL), and the mixture was extracted with
ethyl acetate (5 mLꢂ3). The combined organic layers were washed
with brine (5 mL), dried over Na2SO4, filtered, and concentrated.
Purification by preparative TLC (silica gel) gave the desired product.
4.2.1. 5-Bromo-40-methoxy-(1,10-biphenyl)-2-ol (2, Table 1, Table 2,
entries 21 and 22). Mp 72.8e76.7 ꢀC; 1H NMR (400 MHz, CDCl3)
d
3.86 (3H, s), 5.16 (1H, s), 6.85 (1H, d, J¼8.4 Hz), 7.02 (2H, d,
J¼8.8 Hz), 7.32 (1H, dd, J¼2.4, 8.4 Hz), 7.33 (1H, d, J¼2.4 Hz), 7.35
(2H, d, J¼8.8 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d 55.4, 112.7,
114.9, 117.4, 127.7, 129.8, 130.1, 131.4, 132.6, 151.7, 159.7 ppm; IR
(ATR) 3421, 1487, 1232, 1182, 1030, 1011, 833, 800 cmꢁ1; HRMS (ESI)
m/z calcd for C13H10BrO2 ([MꢁH]ꢁ) 276.9859, 278.9839; found:
276.9852, 278.9837. Anal. Calcd for C13H11BrO2: C, 55.94; H, 3.97,
found: C, 56.00; H, 3.92%.
4.2.2. 4-Bromo-40-methoxy-(1,10-biphenyl)-2-ol (Table 2, entries 1
and 2). Mp 71.7e75.8 ꢀC; 1H NMR (400 MHz, CDCl3)
d 3.85 (3H, s),
5.27 (1H, s), 7.01 (2H, d, J¼8.8 Hz), 7.06 (1H, d, J¼8.4 Hz), 7.10 (1H,
dd, J¼2.0, 8.4 Hz), 7.14 (1H, d, J¼2.0 Hz), 7.34 (2H, d, J¼8.8 Hz) ppm;
13C NMR (100 MHz, CDCl3)
d 55.4, 114.9, 118.9, 121.6, 123.9, 126.9,
Fig. 4. Double logarithm plot of the initial reaction rate v (M/min) versus the initial
concentration of PhMgBr [PhMgBr] (M) for Eq. 2. Open square: ligand¼Cy-HTP$HBF4 at
128.0, 130.1, 131.2, 153.3, 159.5 ppm; IR (ATR) 3338, 1489, 1392,
1232, 1174, 999, 796 cmꢁ1; HRMS (ESI) m/z calcd for C13H10BrO2
0
ꢀC. Closed circle: ligand¼PCy3 at 15 ꢀC. The solid lines are calculated linear trendlines.

10162
S. Ishikawa, K. Manabe / Tetrahedron 67 (2011) 10156e10163
([MꢁH]ꢁ) 276.9859, 278.9839; found: 276.9858, 278.9840. Anal.
129.8, 130.2, 132.6, 159.4 ppm; IR (ATR) 3330, 1238, 827,
721 cmꢁ1; HRMS (EI) m/z calcd for C15H12BrNO ([M]) 301.0102,
303.0083; found: 301.0114, 303.0090. Anal. Calcd for
C15H12BrNO: C, 59.62; H, 4.00; N, 4.64, found: C, 59.64; H, 4.13; N,
4.65%.
Calcd for C13H11BrO2: C, 55.94; H, 3.97, found: C, 56.07; H, 4.04%.
4.2.3. 5-Bromo-3-isopropyl-40-methoxy-(1,10-biphenyl)-2-ol (Table 2,
entry 4). 1H NMR (500 MHz, CDCl3)
d
1.25 (6H, d, J¼7.0 Hz), 3.29
(1H, sept., J¼7.0 Hz), 3.86 (3H, s), 5.23 (1H, br s), 7.02 (2H, d,
J¼8.5 Hz), 7.16 (1H, d, J¼2.5 Hz), 7.27 (1H, dd, J¼0.5, 2.5 Hz), 7.34
4.2.9. 5-Bromo-30-methoxy-(1,10-biphenyl)-2-ol (Table 3, entries 1
(2H, d, J¼8.5 Hz) ppm; 13C NMR (125 MHz, CDCl3)
d
22.4, 27.3, 55.4,
and 2). Oil; 1H NMR (400 MHz, CDCl3)
d 3.83 (3H, s), 5.33 (1H, s),
112.6,114.9,128.0, 128.5, 129.4, 129.8, 130.3, 137.2,148.9,159.7 ppm;
IR (neat) 3537, 2962, 1609, 1514, 1455, 1250, 835 cmꢁ1; HRMS (EI)
m/z calcd for C16H17BrO2 ([M]) 320.0412, 322.0393; found:
320.0418, 322.0381. Anal. Calcd for C16H17BrO2: C, 59.83; H, 5.33,
found: C, 60.09; H, 5.40%.
6.86 (1H, d, J¼8.0 Hz), 6.94 (1H, d, J¼2.4 Hz), 6.95 (1H, ddd, J¼0.8,
2.4, 8.0 Hz), 7.00 (1H, dd, J¼0.8, 8.0 Hz), 7.34 (1H, dd, J¼2.4, 8.0 Hz),
7.36 (1H, d, J¼2.4 Hz), 7.40 (1H, t, J¼8.0 Hz) ppm; 13C NMR
(100 MHz, CDCl3) d 55.4, 112.6, 114.1, 114.3, 117.6, 120.9, 129.8, 130.6,
131.8, 132.4, 136.9, 151.6, 160.4 ppm; IR (neat) 3521, 3434, 1598,
1580, 1478, 1394, 1293, 1266, 1215, 1169, 1051, 1028, 817, 717 cmꢁ1
;
4.2.4. 6-Bromo-1-(4-methoxyphenyl)naphthalen-2-ol (Table 2, en-
HRMS (ESI) m/z calcd for C13H10BrO2 ([MꢁH]ꢁ) 276.9859, 278.9839;
found: 276.9859, 278.9841. Anal. Calcd for C13H11BrO2: C, 55.94; H,
3.97, found: C, 56.28; H, 4.00%.
tries 7 and 8). Mp 81.6e83.5 ꢀC; 1H NMR (500 MHz, CDCl3)
d 3.89
(3H, s), 5.20 (1H, s), 7.10 (2H, d, J¼9.0 Hz), 7.26 (1H, d, J¼9.0 Hz),
7.28 (1H, d, J¼9.0 Hz), 7.30 (2H, d, J¼9.0 Hz), 7.38 (1H, dd, J¼2.0,
9.0 Hz), 7.68 (1H, d, J¼9.0 Hz), 7.94 (1H, d, J¼2.0 Hz) ppm; 13C NMR
4.2.10. 5-Bromo-20-methyl-(1,10-biphenyl)-2-ol (Table 3, entry
(125 MHz, CDCl3)
d
55.4, 115.2, 117.0, 118.4, 120.9, 125.1, 126.5,
3). Oil; 1H NMR (500 MHz, CDCl3)
d 2.17 (3H, s), 4.76 (1H, br s), 6.88
128.3, 129.6, 129.9, 130.0, 132.2, 132.2, 150.7, 159.9 ppm; IR (ATR)
2964, 1246, 1171, 1028, 820 cmꢁ1; HRMS (ESI) m/z calcd for
C17H12BrO2 ([MꢁH]ꢁ) 327.0026, 329.0007; found: 327.0032,
329.0013. Anal. Calcd for C17H13BrO2: C, 62.03; H, 3.98, found: C,
62.09; H, 4.08%.
(1H, d, J¼8.5 Hz), 7.20e7.22 (1H, m), 7.25 (1H, d, J¼2.5 Hz),
7.28e7.31 (1H, m), 7.32e7.34 (2H, m), 7.37 (1H, dd, J¼2.5,
8.5 Hz) ppm; 13C NMR (125 MHz, CDCl3)
d 19.7, 112.4, 117.1, 126.6,
129.0, 129.7, 130.3, 130.8, 131.9, 132.6, 134.2, 137.3, 151.8 ppm; IR
(neat) 3495, 3428, 1480, 1258, 1233, 1175, 818, 767, 734 cmꢁ1
;
HRMS (EI) m/z calcd for C13H11BrO ([M]) 261.9993, 263.9974;
found: 261.9985, 263.9963. Anal. Calcd for C13H11BrO: C, 59.34; H,
4.21, found: C, 59.67; H, 4.47%.
4.2.5. 5-Bromo-40-methoxy-(1,10-biphenyl)-2-amine (Table 2, entries
10e12). Mp 89.1e90.6 ꢀC; 1H NMR (400 MHz, CDCl3)
d 3.74 (2H, br
s), 3.84 (3H, s), 6.62 (1H, d, J¼9.2 Hz), 6.97 (2H, d, J¼8.8 Hz), 7.19
(2H, m), 7.33 (2H, d, J¼8.8 Hz) ppm; 13C NMR (100 MHz, CDCl3)
4.2.11. 4-Bromo-2-(thiophen-2-yl)phenol (Table 3, entries 4 and
d
55.3, 110.1, 114.3, 116.9, 129.1, 130.0, 130.3, 130.7, 132.8, 142.8,
5). Mp 55.4e59.0 ꢀC; 1H NMR (400 MHz, CDCl3)
d 5.55 (1H, s), 6.84
159.1 ppm; IR (ATR) 3446, 3365, 1606, 1510, 1485, 1290, 1236, 1176,
1036, 818 cmꢁ1; HRMS (ESI) m/z calcd for C13H13BrNO ([MþH]þ)
278.0175, 280.0156; found: 278.0175, 280.0153. Anal. Calcd for
C13H12BrNO: C, 56.14; H, 4.35; N, 5.04, found: C, 56.23; H, 4.45; N,
4.96%.
(1H, d, J¼8.4 Hz), 7.14 (1H, dd, J¼3.6, 5.2 Hz), 7.28 (1H, dd, J¼1.2,
3.6 Hz), 7.31 (1H, dd, J¼2.4, 8.4 Hz), 7.42 (1H, dd, J¼1.2, 5.2 Hz), 7.53
(1H, d, J¼2.4 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d 112.8, 117.8,
122.9, 126.5, 126.9, 127.9, 131.9, 132.3, 137.0, 151.5 ppm; IR (neat)
3507, 1478, 1399, 1277, 1210, 1116, 818, 704 cmꢁ1; HRMS (ESI) m/z
calcd for C10H6BrOS ([MꢁH]ꢁ) 252.9317, 254.9296; found:
252.9325, 254.9308. Anal. Calcd for C10H7BrOS: C, 47.08; H, 2.77,
found: C, 47.00; H, 2.85%.
4.2.6. 4-Bromo-40-methoxy-(1,10-biphenyl)-2-amine (Table 2, entries
14 and 15). Mp 126.9e128.5 ꢀC; 1H NMR (400 MHz, CDCl3)
d 3.78
(2H, br s), 3.84 (3H, s), 6.88e6.94 (3H, m), 6.97 (2H, d, J¼8.8 Hz),
7.32 (2H, d, J¼8.8 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d
55.3,
4.2.12. tert-Butyl 50-bromo-20-hydroxy-(1,10-biphenyl)-4-carboxylate
114.3, 117.8, 121.3, 121.5, 126.1, 123.0, 130.6, 131.7, 145.0,
158.9 ppm; IR (ATR) 3452, 3363, 1604, 1481, 1238, 1174, 1032, 837,
795 cmꢁ1; HRMS (ESI) m/z calcd for C13H13BrNO ([MþH]þ)
278.0175, 280.0156; found: 278.0170, 280.0147. Anal. Calcd for
C13H12BrNO: C, 56.14; H, 4.35; N, 5.04, found: C, 56.10; H, 4.31; N,
4.91%.
(Table 3, entry 6). Mp 133.5e135.9 ꢀC; 1H NMR (500 MHz, CDCl3)
d
1.61 (9H, s), 5.50 (1H, s), 6.87 (1H, d, J¼8.5 Hz), 7.36 (1H, dd, J¼2.5,
8.5 Hz), 7.38 (1H, d, J¼2.5 Hz), 7.52 (2H, d, J¼8.5 Hz), 8.07 (2H, d,
J¼8.5 Hz) ppm; 13C NMR (125 MHz, CDCl3)
d 28.2, 81.5, 112.9, 118.0,
128.84, 129.3, 130.2, 131.5, 132.2, 132.6, 140.2, 151.7, 165.5 ppm; IR
(ATR) 3359, 1680, 1321, 1309, 1136, 1124, 818, 727 cmꢁ1; HRMS (ESI)
m/z calcd for C17H16BrO3 ([MꢁH]ꢁ) 347.0288, 349.0270; found:
347.0294, 349.0274.
4.2.7. N-Benzyl-5-bromo-40-methoxy-(1,10-biphenyl)-2-amine (Table
2, entry 17). Oil; 1H NMR (500 MHz, CDCl3)
d 3.83 (3H, s), 4.28
(2H, s), 4.50 (1H, br s), 6.49 (1H, d, J¼8.5 Hz), 6.97 (2H, d, J¼9.0 Hz),
4.2.13. 4-Bromo-2-(2-methylprop-1-en-1-yl)phenol (Table 3, entry
7.19 (1H, d, J¼2.5 Hz), 7.22 (1H, dd, J¼2.5, 8.5 Hz), 7.23e7.32 (5H, m),
7). Oil; 1H NMR (500 MHz, CDCl3)
d
1.68 (3H, d, J¼1.0 Hz), 1.94 (3H,
7.34 (2H, d, J¼9.0 Hz) ppm; 13C NMR (125 MHz, CDCl3)
d
48.1, 55.3,
d, J¼1.5 Hz), 5.04 (1H, br s), 6.05 (1H, m), 6.78 (1H, d, J¼8.5 Hz), 7.16
109.0, 112.3, 114.5, 127.0, 127.2, 128.6, 129.3, 130.0, 130.3, 130.8,
132.6, 138.8, 143.9, 159.1 ppm; IR (neat) 3425, 1497, 1295, 1246,
1176, 1038, 835 cmꢁ1; HRMS (EI) m/z calcd for C20H18BrNO ([M])
367.0572, 369.0554; found: 367.0577, 369.0538. Anal. Calcd for
C20H18BrNO: C, 65.23; H, 4.93; N, 3.80, found: C, 65.09; H, 4.97; N,
3.78%.
(1H, dd, J¼0.5, 2.5 Hz), 7.24 (1H, ddd, J¼0.5, 2.5, 8.5 Hz) ppm; 13C
NMR (125 MHz, CDCl3)
d 19.5 25.8, 112.1, 116.6, 117.5, 126.7, 130.9,
132.3, 142.0, 152.0 ppm; IR (neat) 3509, 2911, 1477, 1215, 822 cmꢁ1
;
HRMS (EI) m/z calcd for C10H11BrO ([M]) 225.9993, 227.9973;
found: 225.9994, 227.9981.
4.2.14. 4-Benzyl-2-bromophenol (Table 3, entry 8). Oil; 1H NMR
4.2.8. 5-Bromo-7-(4-methoxyphenyl)-1H-indole (Table 2, entry
(500 MHz, CDCl3)
d
3.89 (2H, s), 5.38 (1H, s), 6.93 (1H, d, J¼8.0 Hz),
19). Mp 132.4e142.5 ꢀC; 1H NMR (500 MHz, CDCl3)
d
3.87 (3H, s),
7.03 (1H, dd, J¼2.0, 8.5 Hz), 7.16 (2H, dd, J¼1.0, 7.5 Hz), 7.21 (1H, tt,
6.54 (1H, dd, J¼2.5, 3.0 Hz), 7.03 (2H, d, J¼9.0 Hz), 7.20 (1H, dd,
J¼2.5, 3.0 Hz), 7.27 (1H, d, J¼2.0 Hz), 7.51 (2H, d, J¼9.0 Hz), 7.72
(1H, dd, J¼1.0, 2.0 Hz), 8.37 (1H, br s) ppm; 13C NMR (125 MHz,
J¼1.0, 7.5 Hz), 7.27 (1H, d, J¼2.0 Hz), 7.29 (2H, t, J¼7.5 Hz) ppm; 13C
NMR (125 MHz, CDCl3) d 40.7, 110.1, 115.9, 126.3, 128.6, 128.8, 129.7,
132.0, 134.9, 140.7, 150.5 ppm; IR (neat) 3507, 1493, 1180, 698 cmꢁ1
;
CDCl3)
d
55.4, 102.7, 113.4, 114.7, 121.8, 124.2, 125.4, 126.9, 129.2,
HRMS (ESI) m/z calcd for C13H10BrO ([MꢁH]ꢁ) 260.9910, 262.9890;

S. Ishikawa, K. Manabe / Tetrahedron 67 (2011) 10156e10163
10163
found: 260.9907, 262.9890. Anal. Calcd for C13H11BrO: C, 59.34; H,
4.21, found: C, 59.34; H, 4.41%.
a Grant-in-Aid for Scientific Research on Priority Areas ‘Advanced
Molecular Transformations of Carbon Resources’ from the Min-
istry of Education, Culture, Sports, Science and Technology,
Japan.
4.2.15. 2-Benzyl-4-bromophenol (Table 3, entry 9). Oil; 1H NMR
(500 MHz, CDCl3)
d 3.95 (2H, s), 4.76 (1H, br s), 6.66 (1H, d,
J¼8.0 Hz), 7.21e7.24 (5H, m), 7.31 (2H, t, J¼7.5 Hz) ppm; 13C NMR
References and notes
(125 MHz, CDCl3) d 36.2,112.9,117.4,126.6,128.7,128.8,129.4,130.5,
133.4, 138.9, 152.8 ppm; IR (neat) 3533, 1492, 1410, 1266, 1105,
698 cmꢁ1; HRMS (EI) m/z calcd for C13H11BrO ([M]) 261.9993,
263.9974; found: 261.9999, 263.9982. Anal. Calcd for C13H11BrO: C,
59.34; H, 4.21, found: C, 59.26; H, 4.35%.
1. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F.,
Eds.; Wiley-VCH: Weinheim, 2004.
€
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Synthesis 2009, 1405.
3. For example: (a) Singh, R.; Just, G. J. Org. Chem. 1989, 54, 4453; (b) Ishii, Y.;
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4.3. General procedure of competitive cross-coupling
reactions between two substrates
To a solution of two substrates (0.47 mmol each), Pd2(dba)3
(4.7 mmol), and ligand (11 mmol) in THF (0.47 mL) was added a THF
solution of Grignard reagent under argon at ꢁ78 ꢀC. After 10 min, the
reaction mixture was warmed to 25 ꢀC and stirred for the time in-
dicated. The reactionwas quenched by the addition of a 10% aqueous
solution of HCl (5 mL), and the mixture was extracted with ethyl
acetate (5 mLꢂ3). The combined organic layers were washed with
brine (5 mL), dried over Na2SO4, filtered, and concentrated. Purifi-
cation by preparative TLC (silica gel) gave the desired products.
7. (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722; (b)
Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413; (c) Huang, X.;
Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 6653.
4.4. General procedure for kinetic studies
8. Examples of phosphines with a hydroxy group: (a) Hayashi, T.; Mise, T.; Ku-
mada, M. Tetrahedron Lett. 1976, 17, 4351; (b) Hatanaka, Y.; Goda, K.; Yamashita,
F.; Hiyama, T. Tetrahedron Lett. 1994, 35, 7981; (c) Matsui, K.; Takizawa, S.; Sasai,
H. Synlett 2006, 761; (d) Meng, X.; Huang, Y.; Chen, R. Chem.dEur. J. 2008, 14,
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9590.
To a THF solution of bromophenol and naphthalene as an in-
ternal standard was added a THF solution of the Grignard reagent at
rt. After letting the solution stand at an appropriate temperature for
5 min, a THF solution of Pd2(dba)3 and ligand was added to it. The
initial concentration of the components was as follows: bromo-
phenoxide, 0.0974 M; Pd, 0.0020 M (for Fig. 4, Cy-HTP$HBF4) and
0.0039 M (for the rest); ligand, 0.0020 M (for Fig. 4, Cy-HTP$HBF4)
and 0.0039 M (for the rest); Grignard reagent, 0.146e0.877 M. A
small amount of the reaction mixture was sampled via a syringe
every 10 min and poured into a saturated aqueous ammonium
chloride solution. The products were extracted with ethyl acetate,
and GC analysis was carried out to determine ratios of the products
and the internal standard.
9. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
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cross-coupling has been reported: (a) Blum, J.; Berlin, O.; Milstein, D.; Ben-
David, Y.; Wassermann, B. C.; Schutte, S.; Schumann, H. Synthesis 2000, 571; (b)
Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646;
(c) Mei, X.; August, A. T.; Wolf, C. J. Org. Chem. 2006, 71, 142; (d) Wang, T.;
Alfonso, B. J.; Love, J. A. Org. Lett. 2007, 9, 5629; (e) Arisawa, M.; Suzuki, T.;
Ishikawa, T.; Yamaguchi, M. J. Am. Chem. Soc. 2008, 130, 12214; (f) Wang, J.-R.;
Manabe, K. Org. Lett. 2009, 11, 741.
€
11. Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. 1998,
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12. Ishikawa, S.; Manabe, K. Chem. Lett. 2009, 38, 1206.
13. Similar conformational effects of 2,6-dihydroxyphenyl groups have been re-
ported for artificial receptors: Manabe, K.; Okamura, K.; Date, T.; Koga, K. J. Org.
Chem. 1993, 58, 6692.
Acknowledgements
14. Examples of kinetic studies on oxidative addition to palladium: (a) Jutand, A.
Chem. Rev. 2008, 108, 2300; (b) Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F.
J. Am. Chem. Soc. 2009, 131, 8141.
This work was partly supported by the Society of Synthetic
Organic Chemistry, Japan, Takeda Science Foundation, and