Synthesis of tetra-ortho-substituted biaryls using aryltriolborates

Article abstract of DOI:10.1055/s-0030-1260932

Tetra-ortho-substituted biaryls were synthesized by cross-coupling between 2,6-disubstituted bromoarenes and aryltriolborates possessing substituents at ortho carbon. The use of a copper(I) halide such as CuCl (20 mol%) with a palladium catalyst was found

Full text of DOI:10.1055/s-0030-1260932

LETTER
1769
Synthesis of Tetra-ortho-Substituted Biaryls Using Aryltriolborates
S
ynthesis of ortho
-
a
Substituted
o
B
iaryls -Qiang Li, Yasunori Yamamoto,* Norio Miyaura
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax +81(11)7066560; E-mail: yasuyama@eng.hokudai.ac.jp
Received 11 April 2011
boronic acid derivative.18 2-Pyridylboronic acid does not
give coupling products because of its very raid protodebo-
ronation.19 High performance of 2-pyridine triolborates
for metal-catalyzed bond-forming reactions was demon-
Abstract: Tetra-ortho-substituted biaryls were synthesized by
cross-coupling between 2,6-disubstituted bromoarenes and aryltri-
olborates possessing substituents at ortho carbon. The use of a cop-
per(I) halide such as CuCl (20 mol%) with a palladium catalyst was
found to be highly effective to give such sterically hindered biaryls strated in palladium- and copper-catalyzed cross-coupling
reactions.15b,c,16,17 Herein, we report a novel approach for
in good yields.
the synthesis of tri- or tetra-ortho-substituted biaryls using
ortho-substituted aryltriolborates (Scheme 1).
Key words: cross-coupling, palladium catalyst, aryltriolborates,
tetra-ortho-substituted biaryls
M+
O
Transition-metal-catalyzed cross-coupling reactions are
effective synthetic methods for the formation of C–C
bonds.1 Cross-coupling reaction between aryl metal com-
pounds and aryl electrophiles is a recent variant of tradi-
tional Ullman coupling for the synthesis of biaryls.
Although this protocol has been extensively studied using
a variety of organometallic reagents and electrophiles,1 in-
terest has recently been shown in the use of nonmetallic
boron compounds because of their high stability in air and
water and compatibility with a broad range of functional
groups. Tetra-ortho-substituted biaryls are important
fragments of organic functional materials2 and many bio-
logically active compounds such as michellamine and ste-
ganone.3 A recent advance is the use of electron-rich and
sterically demanding ligands, such as tri-tert-butylphos-
phine,4 dialkylarylphosphines,5–9 N-heterocyclic car-
benes,10–12 and other ligands,13,14 for the synthesis of
sterically hindered biaryl compounds. However, the use
of large amounts of a base, especially a strong base, may
be a major limitation for these applications. The develop-
ment of an efficient, mild, and operationally simple cata-
lyst system avoiding the use of large amounts of a base
remains a challenge and has becomes an urgent issue.
Pd(OAc)2 (5 mol%)
BIPHEP (5.5 mol%)
B–
Ar2
Br
Ar1
Ar2
+
O
O
CuCl (20 mol%)
DMF, 80 °C, 14 h
Ar1
1.5 equiv
M = Li, K
0.5 mmol
O
O
PPh2
PPh2
Ph2P PPh2
BIPHEP
PPh2
PPh2
DPEphos
Xantphos
OMe
i-Pr
i-Pr
i-Pr
OMe
Cy2P
Cy2P
S-phos
X-phos
Scheme
1
Synthesis of tetra-ortho-substituted biaryls using
aryltriolborates
The synthesis of cyclic triolborates has been reported in
our previous work.15 By using the same procedure, we
successfully synthesized ortho-substituted triolborates 7–
9 by treatment of hindered arylboronic acids with 1,1,1-
tris(hydroxymethyl)ethane, producing ester intermediates
that were further easily converted into aryltriolborates at
the work of potassium hydroxide (Scheme 2). 3-Methyl-
2-pyridyl triolborate 11 was synthesized by arylation of
B(Oi-Pr)3 with aryllithiums followed by ester exchange
with triol (Scheme 3). This protocol afforded high yields
for 2-pyridylboronates sensitive to B–C bond cleavage
with water.
We recently reported that aryltriolborates, which have air-
and water-stability and high solubility in organic solvents,
undergo very smooth transmetalation to various transi-
tion-metal complexes. The utility of these tetracoordinat-
ed arylboron compounds was demonstrated in palladium-
catalyzed cross-coupling,15 copper-catalyzed N-arylation
of amines,16 and rhodium-catalyzed 1,4-addition to
enones.17
The reaction under aqueous conditions gives undesirable
results due to competitive hydrolytic B–C bond cleavage.
Such cleavage is accelerated by ortho substituents and
significantly accelerated by adjacent heteroatoms in the
We chose 2,6-dimethylphenyltriolborates 7 and 1-bromo-
2-methoxynapthalene to undergo coupling to optimize the
reaction conditions (Table 1). Water proved to disfavor
the sterically demanding coupling (Table 1, entries1–4).
To our delight, the Pd(OAc)2/CuOAc condition using
Ph3P as a ligand gave 31% yield of the product (Table 1,
entry 5). Encouraged by this promising result, we further
SYNLETT 2011, No. 12, pp 1769–1773
x
x
.x
x
.2
0
1
1
Advanced online publication: 05.07.2011
DOI: 10.1055/s-0030-1260932; Art ID: U03311ST
© Georg Thieme Verlag Stuttgart · New York

1770
G.-Q. Li et al.
LETTER
HO
HO
Table 1 Optimization of Tetra-ortho-Substituted Biaryls
HO
K+
O
B–
O
O
O
B–
K+
O
HO
KOH
ArB(OH)2
Ar
B
O
O
O
– 2 H2O
– H2O
Ar
1 (Ar = 2,6-Me2C6H3-)
2 (Ar = 2,4,6-Me3C6H2-)
3 (Ar = 2-methyl-1-naphthalenyl-)
4 (99%)
5 (97%)
6 (99%)
7 (82%)
8 (73%)
9 (87%)
Pd(OAc)2 (3 mol%)
ligand (3.3 mol%)
7 (1.5 equiv)
OMe
+
solvent, 80 °C, 14 h
Scheme 2 Synthesis of ortho-substituted aryltriolborates
Br
13
OMe
HO
O
B–
O
HO
O
Br
N
Li–
12 (0.5 mmol)
B(OiPr)3
n-BuLi
HO
N
–78 °C to r.t.
12 h
reflux, 2 h
THF
–78 °C, 2 h
Entry Ligand
Additive (equiv) Solvent
Yield
(%)
10
11 (91%)
Scheme 3 Synthesis of 3-methyl-2-pyridyltriolborate
1
2
3
4
5
6
7
8a
9
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
X-phos
S-phos
none
DMF–H2O (5:1)
DMF–H2O (5:1)
0
none
0
examined the efficiency of CuI15b,c,20 and CuCl21 in this
hindered coupling reaction. CuCl gave the best yield, im-
proving the yield to 64% (Table 1, entry 7). When
Pd(dba)2 was used in the same reaction, a decreased yield
was observed (Table 1, entry 8). Next we screened the sol-
vent effects, and no desired coupling product was ob-
served in 1,4-dioxane and MeCN, which may be caused
by poor solubility for aryltriolborate in these solvents
(Table 1, entry 9). By examination of phosphine-based
ligands, BIPHEP gave the best result (84% yield, Table 1,
entry 14). By further investigations of the amounts of
Pd(OAc)2, CuCl, and BIPHEP, tetra-ortho-substituted bi-
aryl was obtained finally in 95% yield using 5 mol%
Pd(OAc)2/5.5 mol% BIPHEP in the presence of 20%
CuCl using DMF as a solvent at 80 °C for 14 hours
(Table 1, entry 16).
K3PO4 (1)
Cu(OAc)2 (0.3)
CuOAc (0.3)
CuI (0.3)
DMF–H2O (5:1) trace
DMF–H2O (5:1)
DMF
0
31
50
64
34
trace
trace
76
72
75
84
91
95
87
94
0
DMF
CuCl (0.3)
CuCl (0.3)
CuCl (0.3)
CuCl (0.3)
CuCl (0.3)
DMF
DMF
1,4-dioxane
DMF
10
11
DMF
12
Xantphos CuCl (0.3)
DPEphos CuCl (0.3)
BIPHEP CuCl (0.3)
BIPHEP CuCl (0.3)
BIPHEP CuCl (0.2)
BIPHEP CuCl (0.4)
BIPHEP CuCl (0.3)
BIPHEP none
DMF
13
DMF
No reaction was observed in the absence of CuCl
(Table 1, entry 19). There has not yet been a mechanistic
study; however, such an effect of copper salts has been
successfully utilized in analogous coupling reactions of 2-
heteroaryl boron compounds.15b,c,20,21The role of copper
salts seem to be facilitate the transmetalation of aryltriol-
borates to the arylpalladium bromides by the generation of
arylcopper species.21
14
DMF
15b
16b
17b
18c
19
DMF
DMF
DMF
DMF
Under the optimized reaction conditions, hindered cou-
plings occurred between aryltriolborates 7–9 and 11 and a
number of hindered aryl bromides (Table 2).22 All of the
ortho-substituted biaryls were obtained in excellent
yields. 2-Bromo-3-methylthiophene was also evaluated in
this hindered coupling. ortho-Substituted heterobiaryls
were successfully formed in excellent yields using 1.2
equivalents of aryltriolborate (Table 2, entries 6 and 15).
2,6-Disubsituted aryltriolborate and hindered electron-
deficient 1-bromo-2-naphthaldehyde gave the desired bi-
aryl in good yield using 2 equivalents of aryltriolborate
(Table 2, entry 12). To further demonstrate the efficiency
of this protocol, some arenes with a base-sensitive func-
tional group such as COOR or COR were also investigat-
ed and they smoothly yielded biaryls (Table 2, entries 7
and 8). Heteroaromatic boronic acids often fail to give bi-
DMF
a Pd(dba)2 (3 mol%) was used.
b Pd(OAc)2 (5 mol%)/BIPHEP (5.5 mol%) were used.
c Pd(OAc)2 (10 mol%)/BIPHEP (11 mol%) were used.
aryls due to the high sensitivity of the B–C bond of elec-
tron-deficient heteroaryl rings to hydrolytic B–C bond
cleavage with water.15,23 3-Methyl-2-pyridylboronic acid
is a typical example that undergoes very rapid cleavage
with water. Cross-coupling reaction of 3-methyl-2-
pyridyltriolborate (11) with 1-bromo-2-methoxynaph-
thalene or 4-bromo-1,3,5-trimethyl-1H-pyrazole gave
corresponding biaryls in high yields (Table 2, entries 23
and 24).
Synlett 2011, No. 12, 1769–1773 © Thieme Stuttgart · New York

LETTER
Synthesis of ortho-Substituted Biaryls
1771
Table 2 Hindered Coupling between Aryltriolborates and Aryl
Table 2 Hindered Coupling between Aryltriolborates and Aryl Bro-
Bromidesa
midesa (continued)
Ar1–Ar2
Yield (%)b
82
Entry
Ar1–Ar2
Yield (%)b
95
Entry
12d
OMe
CHO
1
13
14
24
25
OMe
OMe
13
84
2
88
14
26
27
99
83
3
4
15
16
83
81
15c
OMe
OMe
S
OMe
16
17
28
29
86
97
5
17
18
19
20
99
90
97
99
6c
7c
8c
S
O
18
30
82
OMe
O
OMe
OMe
19
20
21
31
14
22
78
84
91
OMe
9
21
22
92
90
10
11
23
87
Synlett 2011, No. 12, 1769–1773 © Thieme Stuttgart · New York

1772
G.-Q. Li et al.
LETTER
Table 2 Hindered Coupling between Aryltriolborates and Aryl Bro-
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midesa (continued)
Entry
22c
Ar1–Ar2
Yield (%)b
80
32
S
OMe
23d
24d
33
34
88
90
N
N
N
N
Me
a A mixture of Ar1B(OCH2)3CMe (0.75 mmol), Ar2Br (0. 5 mmol),
Pd(OAc)2 (5 mol%), BIPHEP (Pd/P = 1:1.1) and CuCl (0.1 mmol) in
anhyd DMF was stirred at 80 °C for 14 h.
(7) Tang, W.; Capacci, A. D.; Wei, X.; Ki, W.; White, A.; Patel,
N. D.; Savoie, J.; Gao, J. J.; Rodriguez, S.; Qu, B.; Haddad,
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C. H. Angew. Chem. Int. Ed. 2010, 49, 5879.
b Isolated yields by chromatography.
c 1.2 equiv aryltriolborate were used.
d 2.0 equiv aryltriolborate were used.
(8) So, C. M.; Chow, W. K.; Choy, P. Y.; Lau, C. P.; Kwong,
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In summary, we have described a novel and efficient cat-
alyst system for the synthesis of tetra-ortho-substituted bi-
aryls using aryltriolborates. Since the use of a base is
avoided, a variety of functional groups may be accommo-
dated in this reaction system.
(13) Ackermann, L.; Potukuchi, H. K.; Althammer, A.; Borm, R.;
Mayer, P. Org. Lett. 2010, 12, 1004.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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Acknowledgment
This work was supported in part by the Global COE Program (Pro-
ject No. B01, Catalysis as the Basis for Innovation in Materials Sci-
ence) from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
(16) Yu, X.-Q.; Yamamoto, Y.; Miyaura, N. Chem. Asian J.
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Synlett 2011, No. 12, 1769–1773 © Thieme Stuttgart · New York

LETTER
Synthesis of ortho-Substituted Biaryls
1773
(21) Deng, J. Z.; Paone, D. V.; Ginnetti, A. T.; Kurihara, H.;
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Anhyd DMF (5 mL) was added. The mixture was stirred at
80 °C for 14 h. After cooling to r.t., the crude mixture was
filtered through a plug of Celite and washed with Et2O. The
filtrate was then concentrated in vacuo to afford the crude
product, which was further purified by chromatography on
silica gel with hexanes–EtOAc (99:1 to 10:1).
(22) General Procedure for the Synthesis of ortho-Substituted
Biaryls
The aryl bromide (0.5 mmol), aryl triolborate (0.75 mmol),
Pd(OAc)2 (5 mol%), BIPHEP (5.5 mol%), and CuCl (0.1
mmol) were placed in a flash under nitrogen atmosphere.
(23) Tyrrell, E.; Brookes, P. Synthesis 2003, 469.
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