Controlled monoarylation of dibromoarenes in water with a polymeric palladium catalyst

Article abstract of DOI:10.1055/s-2005-871540

A highly selective monoarylation of dibromoarenes was performed via the Suzuki-Miyaura cross-coupling with arylboronic acids with an amphiphilic polystyrene-poly(ethylene glycol) (PS-PEG) resin-supported phosphine-palladium complex in water under heteroge

Full text of DOI:10.1055/s-2005-871540

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1775
Controlled Monoarylation of Dibromoarenes in Water with a Polymeric
Palladium Catalyst
?
????
?
asuhiro Uozumi,* Makoto Kikuchi1
Institute for Molecular Science, Higashiyama 5-1, Myodaiji, Okazaki 444-8787, Japan
Fax +81(564)595574; E-mail: uo@ims.ac.jp
Received 19 April 2005
cross-coupling
Abstract: A highly selective monoarylation of dibromoarenes was
+
Ar'-M
Ar'
2
X
performed via the Suzuki–Miyaura cross-coupling with arylboronic
acids with an amphiphilic polystyrene-poly(ethylene glycol) (PS-
PEG) resin-supported phosphine–palladium complex in water
under heterogeneous conditions to give bromobiaryls in high yields.
Introduction of two different aryl groups on a aromatic moiety was
achieved in a one-pot reaction by successive addition of two kinds
of arylboronic acids under similar conditions. The polymeric
palladium catalyst can be readily recovered and recycled.
X
1
+
Ar'
X
Ar'
4 (double cross-coupling product)
3
Key words: Suzuki–Miyaura coupling, cross-coupling, biaryl
formation, dibromoarenes
Ar'
FG
Scheme 1
Biaryls have sparked considerable interest due to their
presence in a number of biologically active compounds
and stereoselective agents, and in the field of materials
science, where they have been recognized as the parent
unit of dendritic or polycyclic oligoaryl compounds.2
Among biaryl formations, the transition metal-catalyzed
cross-coupling arylation of halobenzenes (or pseudo-ha-
lobenzenes) is one of the most versatile and efficient
methods to produce biaryl compounds.3 Consequently, a
vast amount of research has been devoted to the catalytic
cross-coupling of a variety of haloarenes. However, sur-
prisingly, only scattered attention has been paid to the
highly controlled monoarylation of arenes having equally
reactive mutiple halogeno groups to provide monohalobi-
aryls 34,5 as potentially useful synthetic intermediates
(Scheme 1).
showed nearly statistical ratios of the non-/mono-/bis-
arylated products, even though in principle the reactivity
of the halogeno group of the halobiaryl 3 toward a succes-
sive second cross-coupling reaction should be lowered by
the electron-donating property8 of the aromatic substitu-
ent (Ar¢ in Scheme 1). Thus, the cross-coupling of dibro-
mobenzene 1a and p-tolylboronic acid 2A in aqueous
toluene and in aqueous THF with Pd(PPh3)4 (1 mol%) as
a catalyst provided the desired monoarylation product
3aA; however, the yields for both were 40% at best and
the selectivities were only 59% and 76%, respectively
(Scheme 2).
[Pd] (1 mol%)
+
K2CO3, H2O/co-solvent
105 °C (reflux), 15 h
Br
Br
(HO)2B
1a
2A
Moreover, we have recently developed amphiphilic poly-
styrene-poly(ethylene glycol) (PS-PEG) resin-supported
transition metal catalysts which promote various catalytic
transformations including the cross-coupling of halo-
arenes with arylboronic acids (the so-called Suzuki–
Miyaura coupling)6 smoothly in water under heteroge-
neous conditions.7 We wish to report here a new practical
protocol for the palladium-catalyzed controlled monoary-
lation of dibromoarenes with arylboronic acids to give
bromobiaryls with excellent selectivity which was
achieved under heterogeneous aqueous conditions by use
of a PS-PEG resin-supported palladium–phosphine com-
plex.
+
Br
3aA
4aA
Cat
Yield (%)
of 3aA
Co-solvent Conversion
Ratio
of 3:4
(%) of 1a
Pd(PPh3)4
Pd /PPh3
75
40
40
76/24
59/41
Toluene
68
THF
94
90
98/2
Toluene
O
Ph2
=
O
O
N
H
C
P
Pd
PS
n
Preliminary studies on the cross-coupling of dihaloarenes
were carried out using standard methods. The results
Pd
Cl
5
Scheme 2
SYNLETT 2005, No. 11, pp 1775–1778
0
7
.0
7
.2
0
0
5
Advanced online publication: 14.06.2005
DOI: 10.1055/s-2005-871540; Art ID: Y00905ST
© Georg Thieme Verlag Stuttgart · New York

1776
Y. Uozumi, M. Kikuchi
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After extensive experimentation, we have found that di- gave an 80% yield of the biaryl 3gA along with 19% of the
bromobenzene 1a undergoes controlled cross-coupling terphenyl 4gA where one of two reactive bromides in the
with 2A with a PS-PEG resin-supported palladium–phos- desired 3gA underwent further coupling with 2A to give 4
phine catalyst 57,9 to give the bromobiaryls 3aA with high (entry 12). The dibromopyridines 1h and 1i also under-
monoarylation selectivity under aqueous conditions. went cross-coupling with 2A to give 3hA and 3iA, respec-
Thus, 1,3-dibromobenzene (1a) reacted with 1.0 equiva- tively, with exclusive selectivity under similar reaction
lent of p-tolylboronic acid (2A) with 1 mol% palladium of conditions (entries 13 and 14). It is noteworthy that the
the polymeric catalyst 5 in the presence of 8 mol% of polymeric palladium catalyst was readily recovered and
triphenylphosphine and 1% (v/v) of toluene as the co-sol- reused without any loss of activity and selectivity to meet
vent in aqueous potassium carbonate (2 M solution) under green chemical requirements. The recycling experiments
reflux for 24 hours to give a 90% yield of 3-bromo-4¢- were examined for the cross-coupling of 1a and 2A
methylbiphenyl (3aA) along with <1% of the terphenyl (entries 15–17). Thus, after being recovered and rinsed,
4aA (GC-MS analysis: 3aA/4aA = >99/<1; Scheme 2).10 the resin catalyst was subjected to the next series of
The cross-coupling presumably takes place in the toluene- reactions to give quantitative yields of 3aA with 98–99%
swollen resin matrix generated in situ to afford the desired selectivity.
monoarylation product. The biphasic system comprised of
water and toluene-swollen resin might cause the resulting
With this efficient monoarylation protocol to provide
bromobiaryls 3 in hand, we were eager to examine the
introduction of a second alkyl group via a one-pot
monoarylation and a subsequent second cross-coupling
biaryl 3 to precipitate out from the resin matrix to retard a
successive cross-coupling giving the teraryl 4,11 in coop-
eration with electronic deactivation of the bromo group of
reaction (Scheme 3).21,22
3 by an aryl substituent on the bromoarene moiety.
Table 1 shows that various combinations of the dibro-
(HO)2B
Me
2A
moarenes 1 and the arylboronic acids 2 undergo cross-
coupling to give the halobiaryls 3 with high selectivity
using this monoarylation catalyst system.12–20 Thus, m-
dibromobenzene (1a) reacted with p-, m-, and o-tolyl-
boronic acids (2A–C) to give the 2-, 3-, and 4-methylbi-
aryls 3aA, 3aB, and 3aC in 90%, 92%, and 90% yields,
respectively, where excellent selectivities were obtained
in forming biaryls 3 (entries 1–3). Exclusive monoaryla-
tion took place with both electron–rich and electron–defi-
cient arylboronic acids 2D and 2E to give 95% and 84%
yields of 3aD and 3aE (entries 4 and 5). A combination of
o-dibromobenzene (1b) and o-tolylboronic acid (2C)
gave >99% selectivity of monoarylation although the
chemical yield of the biaryl 3bC was relatively low (77%
yield), presumably due to steric hindrance of the substrate
and/or the reactant (entry 6). Excellent monoarylating se-
lectivities (>98%) were also achieved in the cross-cou-
pling reactions of the p-dibromoarenes 1c, 1d, and 1e
(entries 7–10) under similar conditions. 1,3-Dibromo-5-
fluorobenzene (1f) gave an 88% yield of 3-bromo-5-fluo-
ro-4¢-methylbiphenyl (3fA) where the bromoaryl group of
the arylated product 3fA is activated by the 5-fluoro sub-
stituent to result in formation of 12% of the terphenyl 4fA
via successive cross-coupling (entry 11). Cross-coupling
of tribromobenzene (1g) with p-tolylboronic acid (2A)
Br
X
(1.0 equiv)
Br
X
Br
Me
1a (X = CH)
1h (X = N)
3aA (X = CH)
3hA (X = N)
OMe
(HO)2B
2D
MeO
(1.5 equiv)
X
Me
6 (X = CH): 83% yield
7 (X = N): 76% yield
Scheme 3
When 1.5 equivalents of 3-methoxyphenylboronic acid
(2D) was added to a reaction mixture of the monoaryl-
ation of 1,3-dibromobenzene (1a) with p-tolylboronic
acid (2A; 2 mol% Pd of 5, 16 mol% of PPh3, 1.0 equiv of
2A, 105 °C, 24 h), and the resulting mixture was stirred
for an additional 15 hours, the successive arylation–aryl-
ation product 3-methoxy-3¢¢-methylterphenyl (6) was ob-
tained in 83% isolated yield. 2,6-Dibromopyridine (1h)
reacted with 2A and 2D successively under similar condi-
tions to afford 2-(3-anisyl)-6-(4-tolyl)pyridine (7) in 76%
isolated yield.
X1
Br
X1
F
Me
X1
X2
X1
X2
X1
X1
N
X2
X1
X2
X1
X2
X2
X1
X2
N
X2
X2
Me
i
h
a
b
c
d
g
e
f
Me Me
OMe
COMe
1: X1 = X2 = Br, 3: X1 = R, X2 = Br, 4: X1 = X2 = R
R:
Me
E
D
A
B
C
Figure 1
Synlett 2005, No. 11, 1775–1778 © Thieme Stuttgart · New York

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Controlled Monoarylation of Dibromoarenes in Water
1777
Table 1 Monoarylation of Di- or Trihaloarenesa
References
(1) Present address: Graduate school of Engineering, Nagoya
University, Nagoya, Japan.
Entry
1
2
Product
Yield (%) Ratio of
of 3b
90
92
90
95
84
77d
93
90
88
81
88
81
75
89
3:4c
(2) For reviews, see: (a) Martin, R. E.; Diederich, F. Angew.
Chem. Int. Ed. 1999, 38, 1350. (b) Watson, M. D.;
Fechtenkotter, A.; Mullen, K. Chem. Rev. 2001, 101, 1267.
(3) For reviews, see: (a) Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998. (b) Cross-Coupling Reactions: A
Practical Guide, In Top. Curr. Chem., Vol. 219; Miyaura,
N., Ed.; Springer-Verlag: Berlin-Heidelberg, 2002. (c) J.
Organomet. Chem. Vol. 653 (Special Issue), 30 Years of
Cross-Coupling Reaction; Tamao, K.; Negishi, E.-i.;
Hiyama, T., Eds.; 2002.
1
2
1a
1a
1a
1a
1a
1b
1c
1c
1d
1e
1f
A
B
C
D
E
C
C
E
A
A
A
A
A
A
3aA
3aB
3aC
3aD
3aE
3bC
3cC
3cE
3dA
3eA
3fA
3gA
3hA
3iA
98:2
98:2
3
96:4
4
>99:<1
>99:<1
>99:<1
98:2
5
6
(4) Monoarylating cross-couplings affording halobiaryls have
been performed with arenes bearing different halogeno (or
pseudo-halogeno) groups. For examples, see:
7
8
>99:<1
>99:<1
99:1
(a) Kamikawa, T.; Hayashi, T. Tetrahedron Lett. 1997, 38,
7087. (b) Kamikawa, T.; Hayashi, T. J. Org. Chem. 1998,
63, 8922. (c) Sengupta, S.; Sadhukhan, S. K. Tetrahedron
Lett. 1998, 39, 715.
9
10
11
12
13
14
(5) Monoalkylation of 1-[2,6-bis(trifluoromethanesulfonyl-
oxy)phenyl]naphthalene has been achieved with high
chemo- and stereoselectivity via Grignard cross-coupling,
see: (a) Hayashi, T.; Niizuma, S.; Kamikawa, T.; Suzuki, N.;
Uozumi, Y. J. Am. Chem. Soc. 1995, 117, 9101.
88:12
81:19
>99:<1
>99:<1
1g
1h
1i
(b) Kamikawa, T.; Uozumi, Y.; Hayashi, T. Tetrahedron
Lett. 1996, 37, 3161.
(6) For reviews, see: (a) Modern Arene Chemistry; Astruc, D.,
Ed.; Wiley-VCH: Weinheim, 2002. (b) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147. (c) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457. (d)SuzukiCoupling,
Organic Syntheses via Boranes, Vol. 3; Suzuki, A.; Brown,
H. C., Eds.; Aldrich: Milwaukee, 2003.
Recycle experimentse
1a
A
3aA
15
16
17
1st re-use
2nd re-use
3rd re-use
89
94
87
98:2
98:2
99:1
(7) For studies on polymer-supported palladium catalysts from
the author’s group, see the following. p-Allylic substitution:
(a) Uozumi, Y.; Danjo, H.; Hayashi, T. Tetrahedron Lett.
1997, 38, 3557. (b) Danjo, H.; Tanaka, D.; Hayashi, T.;
Uozumi, Y. Tetrahedron 1999, 55, 14341. Cross-coupling:
(c) Uozumi, Y.; Danjo, H.; Hayashi, T. J. Org. Chem. 1999,
64, 3384. Carbonylation reaction: (d) Uozumi, Y.;
Watanabe, T. J. Org. Chem. 1999, 64, 6921. Suzuki–
Miyaura coupling: (e) Uozumi, Y.; Nakai, Y. Org. Lett.
2002, 4, 2997. Heck reaction: (f) Uozumi, Y.; Kimura, T.
Synlett 2002, 2045. Sonogashira reaction: (g) Uozumi, Y.;
Kobayashi, Y. Heterocycles 2003, 59, 71. Asymmetric
alkylation: (h) Uozumi, Y.; Shibatomi, K. J. Am. Chem. Soc.
2001, 123, 2919. Asymmetric amination: (i) Uozumi, Y.;
Tanaka, H.; Shibatomi, K. Org. Lett. 2004, 6, 281.
Asymmetric catalysis: (j) Hocke, H.; Uozumi, Y. Synlett
2002, 2049. (k) Hocke, H.; Uozumi, Y. Tetrahedron 2003,
59, 619. (l) Hocke, H.; Uozumi, Y. Tetrahedron 2004, 60,
9297. Asymmetric cycloisomerization: (m) Nakai, Y.;
Uozumi, Y. Org. Lett. 2005, 7, 291.
a Reaction conditions: All reactions were carried out with 1.0 equiv of
2, 1–2 mol% Pd of 5 and 8 mol equiv to Pd of PPh3 in 2 M aq K2CO3
in the presence of 1% (v/v) of toluene at 105 °C (reflux) for 12–24 h,
unless otherwise noted: 1 (0.4 mmol), H2O (0.4 mL).
b GC yield (internal standard: biphenyl).
c Determined by GC-MS analysis.
d 23% (GC) of 1b was recovered.
e Used polymeric catalyst resin was recovered by filtration and
washed with EtOAc before re-using. PPh3 (8 mol equiv to Pd) was
added to each re-use run.
In summary, we have developed a selective monoaryl-
ation of dibromoarenes with arylboronic acids using a PS-
PEG resin-supported palladium catalyst to give various
bromobiaryls. One-pot successive double cross-coupling
provided a practical protocol for preparing unsymmetri-
cally substituted teraryls. Simple starting materials, a
readily recyclable catalyst, and aqueous conditions should
make the present method very useful from a synthetic
viewpoint.
(8) The s/s+ value of bromo and phenyl groups: sm/sm+ (Br) =
+0.391/+0.405; sp/sp+ (Br) = +0.232/+0.150; sm/sm+ (Ph) =
+0.06/+0.109; sp/sp+ (Ph) = +0.01/–0.179.
(9) Argo Gel NH2 (F = 130 mm, loading value = 0.3 mmol/g)
was used as a polymer support.
(10) General Procedure for Monoarylation of
Dibromoarenes.
Acknowledgment
A mixture of the dibromoarene 1 (0.4 mmol), the arylboronic
acid 2 (0.4 mmol), 1 mol% palladium of 5 (4 mmol Pd), 8.4
mg of PPh3 (32 mmol), and 40 mL of toluene in 4 mL of 2 M
aqueous solution of K2CO3 was refluxed for 24 h. After
being cooled, the mixture was filtered and collected resin
beads were extracted with EtOAc. The GC yield and the
This work was supported by the CREST program, sponsored by
the JST. We also thank the JSPS (GRANT-in-AID for Scientific
Research, No.15205015) and the MEXT (Scientific Research on
Priority Areas, No. 420) for partial financial support of this work.
Synlett 2005, No. 11, 1775–1778 © Thieme Stuttgart · New York

1778
Y. Uozumi, M. Kikuchi
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(17) 1-Bromo-4-(4-methylphenyl)naphthalene (3eA).
ratio of 3:4 were determined by GC-MS analysis (internal
standard: biphenyl) of the organic extract, and an
analytically pure product was isolated by silica gel
chromatography.
1H NMR (400 MHz, CDCl3): d = 8.31 (d, J = 8.4 Hz, 1 H),
7.89 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 7.6 Hz, 1 H), 7.57 (t,
J = 6.8 Hz, 1 H), 7.44 (t, J = 6.8 Hz, 1 H), 7.32 (d, J = 8.0
Hz, 2 H), 7.27 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 7.6 Hz, 1 H),
2.43 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 140.2, 137.1,
136.8, 132.8, 131.9, 129.7, 129.3, 128.9, 127.3, 127.0 (2 C),
126.6, 126.5, 121.9, 21.4. MS: m/z = 296, 215, 202, 189,
107, 94.
(11) During the reaction, generation of precipitates on the resin
surface was observed microscopically.
(12) CAS Registry numbers of biaryl products: 3aA, 844856-52-
6; 3aB, 844856-54-8; 3aD, 337535-27-0; 3bC, 251320-87-
3; 3cC, 106475-19-8; 3iA, 675590-28-0.
(13) 3-Bromo-2¢-methylbiphenyl (3aC).
(18) 3-Bromo-5-fluoro-4¢-methylbiphenyl (3fA).
1H NMR (400 MHz, CDCl3): d = 7.49–7.50 (m, 1 H), 7.41
(d, J = 8.0 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 7.16–7.21 (m,
2 H), 3.14 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 164.0,
161.5, 144.7, 144.6, 138.3, 135.6 (2 C), 130.0, 126.8, 125.8,
125.7, 122.8, 122.7, 117.3, 117.1, 112.8, 112.6, 21.2. MS:
m/z = 264, 183, 165, 91.
Compound 3aC was not isolated as an analytically pure
sample. Characterization of 3aC was performed by GC-MS
analysis: MS: m/z = 248, 246 [M+], 167 [M – Br] (base
peak), 152, 139, 115, 82.
(14) 1-(3¢-Bromobiphen-3-yl)ethanone (3aE).
1H NMR (400 MHz, CDCl3): d = 8.12 (s, 1 H), 7.94 (d,
J = 6.8 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.48–7.55 (m, 3
H), 7.31 (t, J = 8.0 Hz, 1 H), 2.65 (s, 3H). 13C NMR (100
MHz, CDCl3): d = 197.4, 142.0, 139.9, 137.4, 131.4, 130.5,
130.2, 130.0, 129.0, 127.6, 126.6, 125.6, 122.8, 26.8. MS:
274, 259, 231, 152, 76.
(15) 1-(4¢-Bromobiphen-3-yl)ethanone (3cE).
Compund 3cE was not isolated as an analytically pure
sample. Characterization of 3cE was performed by GC-MS
analysis: MS: m/z = 276, 274 [M+], 261, 259 [M – CH3], 233,
231 [M – COCH3], 152 [M – COCH3-Br] (base peak), 126,
76.
(19) 3,5-Dibromo-4¢-methylbiphenyl (3gA).
1H NMR (500 MHz, CDCl3): d = 7.58–7.61 (m, 3 H), 7.38–
7.40 (m, 2 H), 7.21–7.24 (m, 2 H), 2.38 (s, 3 H). 13C NMR
(125 MHz, CDCl3): d = 144.5, 138.2, 135.2, 123.0, 129.5,
128.5, 126.7, 123.0, 21.3. MS: m/z = 326, 245, 165, 139,
115, 82.
(20) 2-Bromo-6-(4-methylphenyl)pyridine (3hA).
1H NMR (500 MHz, CDCl3): d = 7.88 (d, J = 8.5 Hz, 2 H),
7.64 (d, J = 7.0 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.36 (d,
J = 8.0 Hz, 1 H), 7.26 (d, J = 8.5 Hz, 2 H), 2.40 (s, 3 H). 13
NMR (125 MHz, CDCl3): d = 158.4, 141.9, 139.5, 138.6,
C
(16) 4-Bromo-2,5,4¢-trimethylbiphenyl (3dA).
1H NMR (400 MHz, CDCl3): d = 7.42 (s, 1 H), 7.20 (d,
J = 8.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 7.06 (s, 1H), 2.38
(s, 3 H), 2.36 (s, 3 H), 2.19 (s, 3 H). 13C NMR (100 MHz,
CDCl3): d = 140.8, 137.7, 136.5, 134.7, 134.5, 133.5, 133.4,
131.9 (2 C), 128.7 (2 C), 123.1, 22.4, 21.3, 19.8. MS: m/z =
274, 195, 180, 165, 89.
134.7, 129.3 (2 C), 126.7 (2 C), 125.7, 118.4, 21.5. MS:
m/z = 247, 168, 153, 141, 115, 83.
(21) 3-Methoxy-4¢¢-methyl[1,1¢:3¢,1¢¢]terphenyl(6).
1H NMR (500 MHz, CDCl3): d = 7.77 (br s, 1 H), 7.51–7.54
(m, 4 H), 7.45 (t, J = 7.5 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 1 H),
7.20–7.24 (m, 3 H), 7.16 (t, J = 2.0 Hz, 1 H), 6.89 (dd,
J = 7.5, 2.0 Hz, 1 H), 3.81 (s, 3 H), 2.37 (s, 3 H). 13C NMR
(125 MHz, CDCl3): d = 159.7, 142.6, 141.4 (2 C), 138.0,
136.9, 129.5, 129.3, 128.9, 126.9 (2 C), 125.8, 125.7, 125.6,
119.6 (2 C), 112.9, 112.6, 55.3, 21.2. MS: m/z = 274, 215,
137, 115, 101.
(22) 2-(3-Methoxyphenyl)-6-(4-methylphenyl)pyridine(7).
1H NMR (500 MHz, CDCl3): d = 8.03 (d, J = 8.0 Hz, 2 H),
7.76 (t, J = 2.5 Hz, 1 H), 7.70 (t, J = 8.0 Hz, 1 H), 7.67 (br d,
J = 8.0 Hz, 1 H), 7.59 (t, J = 7.5 Hz, 2 H), 7.37 (t, J = 8.0 Hz,
1 H), 7.26 (d, J = 8.0 Hz, 2 H), 6.95 (dd, J = 7.5, 2.5 Hz, 1
H), 3.86 (s, 3 H), 2.38 (s, 3 H). 13C NMR (125 MHz, CDCl3):
d = 159.7, 156.4, 156.1, 140.8, 138.6, 137.0, 136.4, 129.3,
129.1, 126.6, 119.2, 118.2, 114.4, 112.5, 55.3, 21.4. MS:
m/z = 274, 245, 137.
Synlett 2005, No. 11, 1775–1778 © Thieme Stuttgart · New York