Efficient Fe-catalyzed homo-coupling of aryl Grignard reagents using O2 as the oxidant

Article abstract of DOI:10.1016/j.tetlet.2007.11.144

FeCl₃/Bipy catalyst system was found to be a good combination in the oxidative homo-coupling of aryl Grignard reagents directly using molecular oxygen as the oxidant. Moderate to good yields of desired corresponding symmetrical biaryls were obtained at room temperature in 10 min.

Full text of DOI:10.1016/j.tetlet.2007.11.144

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Tetrahedron Letters 49 (2008) 610–613
Efficient Fe-catalyzed homo-coupling of aryl Grignard reagents
using O2 as the oxidant
Wei Liu, Aiwen Lei *
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China
Received 26 October 2007; revised 22 November 2007; accepted 23 November 2007
Abstract
FeCl3/Bipy catalyst system was found to be a good combination in the oxidative homo-coupling of aryl Grignard reagents directly
using molecular oxygen as the oxidant. Moderate to good yields of desired corresponding symmetrical biaryls were obtained at room
temperature in 10 min.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Iron; Homo-coupling; Grignard reagents; Biaryls; Dioxygen
Biaryls as a central part of organic framework have been
found in a large number of natural products and widely
applied in many useful man-made materials.1–3 Transition
metal catalyzed oxidative homo-coupling reaction is one
of the efficient methods to construct symmetrical biaryls.
Palladium-catalyzed carbon–carbon coupling reactions
have been extensively studied and well established in the
past several decades.4 Our group have used a-halocarbonyl
compounds as oxidants in palladium-catalyzed oxidative
homo-coupling reactions and several important results
were achieved (Scheme 1).5–8 Although an excellent
chemo-selectivity in the reactions was given, we reconsid-
ered the applications and limitations of oxidative homo-
coupling reaction protocol. Palladium, a kind of expensive
noble metal, has a toxic effect on human and environment.
Moreover, using a stoichiometric amount of organic oxi-
dant is considered to be neither ‘green’ (environmentally
friendly) nor economical. Thus, with the urgent demand
for green chemistry process and sustainable development
in the chemistry industry, searching for cheap and nontoxic
catalysts as well as green and inexpensive oxidants obvi-
ously becomes one of the most important topics. And there
X
Palladium
R2
R2
R1
+
ArB(OH)2
Ar-Ar
R1
+
Homo-Coupling
O
O
X= Halogen (Cl,Br)
Scheme 1. Palladium-catalyzed oxidative homo-coupling reactions
involved a-halocarbonyl compounds as organic oxidants.
have been some examples carried out on palladium-cata-
lyzed homo-coupling reactions using molecular oxygen as
the oxidant.1,9–15 In addition, several other kinds of transi-
tion metal salts (CoCl2,16 TiCl4,17 VO(OEt)Cl2,18 and
CuCl219) were used in stoichiometric amount or catalytical
amount in the presence of reoxidant,9,14,18,20,21 such as oxy-
gen or other organic oxidants, to carry out the oxidative
coupling process. Iron is a very common and cheap metal,
which has been widely applied as a catalyst in carbon–car-
bon bond formation reactions22–33 and other types of reac-
tions.34–36 Recently, Nagano and Hayashi37 and Cahiez
38
et al. reported their iron-catalyzed oxidative homo-cou-
pling of aryl Grignard reagents using 1,2-dihalogeno-
ethanes as an oxidant. Undoubtedly, using cheap iron
salts as catalysts combined with oxidant in the synthesis
of biaryls is of great potential importance. However, 1,2-
dihalogenoethanes37,38 is not an ideal oxidant candidate
*
Corresponding author. Tel.: +86 27 68754672; fax: +86 27 68754067.
E-mail address: aiwenlei@whu.edu.cn (A. Lei).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.144

W. Liu, A. Lei / Tetrahedron Letters 49 (2008) 610–613
611
from both the sustainable and green point of view. Obvi-
ously, molecular oxygen should be the best choice of green
and environment-friendly oxidant for the oxidative homo-
coupling reactions and other oxidation processes. To the
best of our knowledge, directly using molecular oxygen
as an oxidant combined with catalytical amount of com-
mercially available and cheap iron salts was seldom39
reported in oxidative homo-coupling of aryl Grignard
reagents for the preparation of corresponding symmetrical
biaryls. Herein, we would like to present our results in this
area.
In our initial study on the iron-catalyzed oxidative
homo-coupling reactions using 4-methylphenyl magnesium
bromide 1a as a model substrate in the presence of catalyt-
ical amount of FeCl3 (5 mol %), at oxygen atmosphere
(bubbling by oxygen balloon), the result gave 4,40-di-
methyldiphenyl 2a as the main product, and 62% isolated
yield was obtained (Table 1, entry 3). And meanwhile a
little amount of phenol was observed from TLC. As we
know, without adding any transition metal salts, aryl
Grignard reagents could react directly with oxygen to give
ArOH as the oxidation products.16,40 In this experiment,
we found that the reaction proceeded so quickly that only
10 min was needed. Encouraged by the above promising
result, a series of experiments were carried out to optimize
the reaction conditions.
was proved to be more efficient than Fe(acac)3 (Table 1,
entries 3 and 4). On the basis of our experiments (Table
1, entries 1–4), the homo-coupling results were not satisfy-
ing due to the direct oxidation of aryl Grignard reagents
with oxygen, which acted as a main side reaction. To facil-
itate the oxidative homo-coupling reactions, we examined
the efficiency of FeCl3 as a catalyst with the aid of various
ligands (Table 1, entries 5–7), N,N,N,N-tetramethylethane-
1,2-diamine (TMEDA), 2,20-bipyridine (Bipy), and N-
butylpyridine-2-carbothioamide. TMEDA and Bipy were
commonly used as ligands in the iron-catalyzed coupling
reactions. The results indicated TMEDA was not efficient
in this reaction (Table 1, entry 5), as well as N-butylpyri-
dine-2-carbothioamide (Table 1, entry 7). We were glad
to find that FeCl3 in the presence of Bipy appeared much
more powerful (Table 1, entry 6), with 85% isolated yield
given in 10 min. Furthermore, we increased the amount
of catalyst used in this reaction and the yield of homo-cou-
pling product 2a was enhanced to 91% in 10 min when
6 mol % FeCl3 and 12 mol % Bipy were used (Table 1,
entry 8). In general, Table 1, entry 8 gave the best
condition.
Under the aforementioned optimized conditions and
promising results, we have examined the substrate scope
of this reaction.41 As shown in Table 2, our experiments
indicated that a variety of aryl Grignard reagents could
quickly transform to the desired corresponding symmetri-
cal biaryls. Using our new protocol, the oxidative homo-
coupling reactions could afford excellent yields (Table 2,
entries 1, 2, and 11). And moderate to good yields of biar-
yls (Table 2, entries 3–10) were also obtained with this new
efficient method. In the oxidative homo-coupling reaction
of ortho-methyl phenyl Grignard reagent 1d (Table 2, entry
4), because of the presence of ortho position, 72% homo-
coupling product 2d was obtained. In Table 2, entry 9,
4,40-dichlorobiphenyl 2j was given in 76% yield. Further-
more, when the methoxy group was present at the ortho
position, the yield of 2k was not apparently affected (Table
2, entry 10). And considering the catalyst loadings used in
our oxidative homo-coupling reactions and to enhance this
new method’s preparative meaning, we attempted to use
1 mol % catalyst system to carry out the reaction at
10 mmol scale, 86% isolated yield of 2b (Scheme 2) was
given in 15 min by dropping the phenyl Grignard reagent
1b into the reaction system. In addition, we directly used
dry air as the oxidant, a very good result (Scheme 3) was
observed after 2 h at room temperature, which made us
believe that this new method would be easily applied in
the synthesis of symmetrical biaryls under a very mild
condition.
As shown in Table 1, with no iron salts added, trace of
homo-coupling product was observed (Table 1, entry 1) at
oxygen atmosphere, which indicated that iron salts were
essential to this reaction. Then, iron salts were also evalu-
ated. When Fe(acac)3 (Table 1, entry 4) was added, only
46% homo-coupling product 2a was obtained. While FeCl3
Table 1
Optimizing the reaction conditions for the oxidative homo-coupling of
aryl Grignard reagent
O2
Fe Cat
MgBr
THF, r.t
2a
1a
homocoupling
Entry
Iron salt
Ligand
Yield (%)
1
2
3
4
5
6
No
No
No
No
No
<5a
47
62
46
35
85
FeCl3 (2 mol %)
FeCl3 (5 mol %)
Fe(acac)3 (5 mol %)
FeCl3 (3 mol %)
FeCl3 (3 mol %)
TMEDA (6 mol %)
Bipy (6 mol %)
(6 mol %)
H
N
7
FeCl3 (3 mol %)
57
N
In summary, we have developed a novel and practical
reaction system for oxidative homo-coupling reaction of
aryl Grignard reagents directly using molecular oxygen as
an oxidant and FeCl3 combined with Bipy as catalyst.
Moderate to good yields of desired corresponding symmet-
rical biaryls were obtained at room temperature in 10 min.
This reaction system is applicable to the quick preparation
S
8
9
FeCl3 (6 mol %)
FeCl3 (5 mol %)
Bipy (12 mol %)
Bipy (10 mol %)
91
87
Reactions were carried out with 1.0 mmol of 1a. All reactions completed
in 10 min at room temperature in THF.
a
The yield was checked by GC.

612
W. Liu, A. Lei / Tetrahedron Letters 49 (2008) 610–613
Table 2
FeCl3/Bipy catalyzed homo-coupling of aryl Grignard reagents using oxygen as an oxidant
O2
6 mol % FeCl3/12 mol % Bipy
MgBr
THF, r.t, 10 min
R
R
R
Entry
1
Aryl Grignard reagents
Product
Yield (%)
91
1a
2a
2b
MgBr
2
3
4
5
1b
1c
1d
1f
91
80
74
78
MgBr
MgBr
2c
2d
2f
MgBr
MgBr
6
7
1g
1h
2g
2h
82
80
MgBr
MeO
MeO
OMe
MeO
MeO
MgBr
OMe
8
9
1i
1j
2i
2j
84
76
MgBr
Cl
MgBr
Cl
Cl
OMe
OMe
MgBr
10
11
1k
2k
80
88
MeO
1m
2m
MgBr
All reactions were performed on a 2 mmol scale at room temperature.

W. Liu, A. Lei / Tetrahedron Letters 49 (2008) 610–613
613
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10 mmol
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2b
Scheme 2. Iron-catalyzed oxidative homo-coupling reaction using
1 mol % FeCl3/Bipy as catalyst.
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This work was supported by National Natural Science
Foundation of China (Grant No. 20502020) and the start-
up fund from Wuhan University.
Supplementary data
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.11.144.
39. Before we intended to submit this paper, we noted that Cahiez et al.
reported a similar Fe/O2 catalyzed homocoupling of ArMgCl without
the addition of ligand: Cahiez, G.; Moyeux, A.; Buendia, J.; Duplais,
C. J. Am. Chem. Soc. 2007. ASAP.
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