C-H arylation of unactivated arenes with aryl halides catalyzed by cobalt porphyrin

Article abstract of DOI:10.1016/j.tetlet.2010.12.092

A general procedure for cobalt-catalyzed direct C-H arylation of unactivated arenes has been discovered. This method employs aryl halides as the direct coupling partners with arenes without using any Grignard-type reagents. This catalysis opens a new methodology for the preparation of symmetrical as well as unsymmetrical biaryls in a user-friendly approach.

Full text of DOI:10.1016/j.tetlet.2010.12.092

Tetrahedron Letters 52 (2011) 1023–1026
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Tetrahedron Letters
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C–H arylation of unactivated arenes with aryl halides catalyzed
by cobalt porphyrin
⇑
Ching Tat To, Tek Long Chan, Bao Zhu Li, Ying Ying Hui, TSZ Yiu Kwok, Suet Yu Lam, Kin Shing Chan
Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A general procedure for cobalt-catalyzed direct C–H arylation of unactivated arenes has been discovered.
This method employs aryl halides as the direct coupling partners with arenes without using any Grig-
nard-type reagents. This catalysis opens a new methodology for the preparation of symmetrical as well
as unsymmetrical biaryls in a user-friendly approach.
Received 9 November 2010
Revised 15 December 2010
Accepted 21 December 2010
Available online 29 December 2010
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
C–H arylation
Unactivated arenes
Cobalt porphyrin
Biaryls
Carbon–carbon bond forming reaction is a backbone in organic
synthesis. Transition metal complexes have been used to catalyze
homo- and cross-coupling of carbon–carbon bonds. Among the cat-
alytic carbon–carbon bond formations, aryl–aryl bond formation to
construct biaryls is important as biaryls are widely present in
ligands, natural products, drugs, and materials.1
cobalt(II) porphyrin catalyzed cross-coupling reactions between
Ar–X (X = I, Br) and unactivated Ar -H to synthesize biaryls
(Tables 1 and 2).
0
To our delight, 4-iodotoluene (1 equiv) in the presence of
5 mol % Co(t4-OMepp) (t4-OMepp = tetrakis-4-methoxyphenylpor-
t
phyrinato dianion), KOH (10 equiv) and BuOH (10 equiv) reacted
Since the discovery of Ullmann reaction in 1901 for the synthe-
sis of symmetrical biaryls from aryl halides,2 more efficient cata-
lytic systems have been developed in the past few decades to
obtain symmetrical and unsymmetrical biaryls from aryl halides
2
with benzene (100 equiv) at 200 °C under N to yield the 4-meth-
ylbiphenyl in 63% isolated yield (Table 1, entry 2). Trace amounts
0
of biphenyl (<5%) and 4,4 -dimethylbiphenyl (<1%) were also de-
tected by GCMS. The coupling protocol is general for aryl iodides.
Iodobenzene reacted well to give biphenyl in 70% yield (Table 1,
entry 1). Both electron rich and electron poor aryl iodides were
compatible under the reaction conditions and the desired biaryls
were obtained in good yields (Table 1, entries 3–6). To our delight,
aryl bromides also reacted successfully to afford biaryls in moder-
ate yields (Table 1, entries 7–11). The longer reaction times were
consistent with the stronger C–Br bond. Sterically hindered 2-bro-
motoluene and 2-bromoanisole also produced the corresponding
biaryls though in 36% and 15% yields, respectively (Table 1, entries
9 and 11).
3
4
5
and aryl organometallics, such as the Kumada, Negishi, Stille,
6
7
Suzuki, and Hiyama coupling reactions. These established meth-
ods however require expensive palladium catalysts, preparation
and handling of air and moisture sensitive Grignard type or related
reagents, making the reaction less user-friendly. Therefore, an
alternative convenient method is desired. Recently, there are
increasing reports employing 1st row transition metal catalysts,
8
8c,9
10
11
for example, Fe, Co,
Ni and Cu, for cross-coupling reactions
to obtain biaryl compounds. These complexes are much cheaper in
price and less toxic, making them much more attractive.
Furthermore, direct C–H arylation of arenes with aryl halides
partners is an attractive approach for aryl–aryl bond formation
as Grignard type reagents are avoided. Examples using palladium
as catalysts have been reported.12 1st row transition metal cata-
lysts have also appeared very recently. To the best of our knowl-
edge, cobalt catalyzed arylation is scarce and direct arylation of
unactivated arenes is unprecedented. Herein, we report a novel
We further examined the coupling reactions of 4-iodotoluene
with substituted arene derivatives (Table 2). Toluene and anisole
were arylated to afford a mixture of ortho-, meta-, and para-substi-
tuted isomers in 43% and 53% total yields, respectively (Table 2, en-
tries 1 and 2). The regioisomeric ratios (o/m/p = 1.6:1.0:2.0 for
toluene and o/m/p = 3.3:1.0:2.3 for anisole) imply that the elec-
tronic effect of substituent does not affect the regioselectivity of
arylation much. However, steric hindrance was again proved to
be important. p-Xylene required 6 h for completion of the reaction
to give the coupling product in 24% yield
8
⇑
Corresponding author. Tel.: +852 26096376; fax: +852 26035057.
E-mail address: ksc@cuhk.edu.hk (K.S. Chan).
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.092

1
024
C. T. To et al. / Tetrahedron Letters 52 (2011) 1023–1026
Table 1
Cobalt-catalyzed arylation of benzene with various aryl halides
5
mol% CoII(t -OMepp)
4
1
0 equiv KOH
X
H
t
10 equiv BuOH
FG
+
o
FG
200 C, N
2
,
dark, time
1
100 equiv
2
Entry
1
Aryl halide
Time (h)
2
Product
Yielda (%)
70(66)
I
1
a
2a
2c
2
3
I
2
2
79(63)
65(51)
1
b
2b
I
1
c
4
5
6
7
MeO
F
I
4
2
2
4
MeO
F
60(57)
69(45)
85(60)
63(56)
1
d
2d
I
1
e
2e
2f
2b
Cl
I
Cl
1
f
Br
1
g
Br
8
9
4
62(34)
1
h
2
g
5
4
36(27)
58(52)
Br
1
i
2c
1
0
1
MeO
OMe
Br
MeO
1
j
2d
OMe
1
4
15(3)
Br
1
k
2h
a
GC yield. Isolated yield is in parentheses.
II
5
mol% Co (t4-OMepp)
1
0 equiv KOH
I
t
1
0 equiv BuOH
+
+
d6
50 equiv
+
o
2
00 C, N2,
dark, 2 h
ð1Þ
50 equiv
d
5
k
H
kD
=
1.03 0.01
only (Table 2, entry 3). In comparison, the less hindered o-xylene
and m-xylene reacted faster (Table 2, entries 4 and 5). Besides,
dibenzyl and diarylmethane derivatives were detected when tolu-
ene and xylenes were employed as coupling partners. Arylation at
the methoxy carbon of anisole was also observed. The detection of
these products provides mechanistic insight of the reaction. As the
In order to gain further understanding of the reaction mecha-
nism, a competition experiment using an equimolar mixture of
benzene and benzene-d with 4-iodotoluene was carried out and
6
yielded the KIE of 1.03 ± 0.01 (by GCMS) (Eq. 1). This indicates that
the C–H bond cleavage is not rate-determining.
Based on the above data, we propose the reaction mechanism as
ꢀ
1
II
benzylic C–H bond (89.7 kcal mol ) and the anisyl C–H bond
shown in Figure 1. The Ar–X bond is first activated by Co (t4-OMepp)
ꢀ
1
III
(
(
92.0 kcal mol
)
are weaker than the aromatic C–H bond
via a formal halogen atom abstraction to give Co (t4-OMepp)X and
112.9 kcal mol 1),13 competitive arylations through a radical pro-
ꢀ
generate an Ar radical. The Ar radical intermediate then adds onto
14
cess are very likely.
the arene. Biaryl is released by abstraction of a hydrogen atom from

C. T. To et al. / Tetrahedron Letters 52 (2011) 1023–1026
1025
Table 2
Cobalt-catalyzed arylation of unactivated arenes with 4-iodotoluene
mol% CoII(t4-OMepp
)
5
1
0 equiv KOH
FG
I
t
1
0 equiv BuOH
+
FG
o
200 C, N
2
,
dark, time
arene
00 equiv
1
Entry
1
Arene
Time (h)
2
Product
Yielda (%)
43(54)
o : m : p = 1.6 : 1.0 : 2.0
OMe
OMe
2
3
4
2
6
4
53(52)
24(18)
27(25)
o : m : p = 3.3 : 1.0 : 2.3
4
.2
:
1.0
5
4
20(14)
3
.8
:
1.0
a
GC yield of desired biaryl only. Total isolated yield with other arylation products is in parentheses.
1
2
H O
H O +
O2
2
2
2
H2
Ar-Ph
III
Co (t4-OMepp)H
CoII(t4-OMepp)
II
Co (t4-OMepp)
ArX
Ar
H
III
Co (t4-OMepp)OH
Ar
+ CoIII(t4-OMepp)X
KX
KOH
Figure 1. Proposed reaction mechanism.
II
III
II
.16
Co (t4-OMepp). The resultant Co (t4-OMepp)H generated quickly
undergoes dehydrogenation to give back the active catalyst
Co (t4-OMepp) and H
2
O
2
H
2
O
2
then decomposes to give water
1
7
II
and oxygen by base. Co (t4-OMepp) is regenerated to complete
the catalytic cycle.
II
15
III
Co (t4-OMepp) with release of H
2
.
Meanwhile, Co (t4-OMepp)X
undergoes fast ligand substitution reaction with KOH to give a tran-
sient intermediate Co (t4-OMepp)OH, which rapidly produces the
In summary, we have successfully demonstrated a cheap and
user-friendly Co(II) porphyrin catalyzed cross-coupling between
III

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C. T. To et al. / Tetrahedron Letters 52 (2011) 1023–1026
aryl halides with unactivated arenes to prepare biaryls. Prelimin-
ary mechanistic study suggests that the reaction operates by a rad-
ical mechanism. Further studies are ongoing.
3. (a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374;
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Acknowledgment
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7
.
.
Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 866.
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We thank the Research Grants Council (No. 400308) of the
HKSAR, the People’s Republic of China for the financial support.
This Letter is dedicated to Professor H. N. C. Wong on the occasion
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