New chemical synthesis of functionalized arylzinc compounds from aromatic or thienyl bromides under mild conditions using a simple cobalt catalyst and zinc dust

Article abstract of DOI:10.1021/ja0289494

A new chemical method for the preparation of arylzinc intermediates is described in acetonitrile, on the basis of the activation of aryl bromides by low-valent cobalt species arising from the reduction of cobalt halide by zinc dust. This procedure allows for the synthesis of a variety of functionalized aryl- and thienylzinc species in good to excellent yields. The versatility and the simplicity of that original method represent an alternative to most known procedures.

Full text of DOI:10.1021/ja0289494

Published on Web 03/08/2003
New Chemical Synthesis of Functionalized Arylzinc
Compounds from Aromatic or Thienyl Bromides under Mild
Conditions Using a Simple Cobalt Catalyst and Zinc Dust
Hyacinthe Fillon, Corinne Gosmini,* and Jacques Pe´richon
Contribution from the Laboratoire d’Electrochimie, Catalyze et Synthe`se Organique,
UMR 7582 CNRS-UniVersite´ Paris 12 2, rue Henry-Dunant 94320 Thiais, France
Received October 15, 2002; E-mail: gosmini@glvt-cnrs.fr
Abstract: A new chemical method for the preparation of arylzinc intermediates is described in acetonitrile,
on the basis of the activation of aryl bromides by low-valent cobalt species arising from the reduction of
cobalt halide by zinc dust. This procedure allows for the synthesis of a variety of functionalized aryl- and
thienylzinc species in good to excellent yields. The versatility and the simplicity of that original method
represent an alternative to most known procedures.
Introduction
Among the numerous topics developed in our laboratory, the
synthesis of organozinc reagents is of current interest. In the
past few years, arylzinc compounds have been successfully
synthesized from aryl bromides or chlorides in high yields under
mild conditions by two electrochemical procedures. The former
one was based on the catalytic activity of a nickel complex in
DMF as solvent.8 More recently, we have developed a simpler
catalytic system involving cobalt halides in DMF or acetonitrile
associated to pyridine.9 The use of cobalt allowed us both to
achieve the synthesis of organozinc reagents using the sacrificial
anode process with a wide variety of solvents and to use a less
toxic catalyst. To develop a pyridine-free process, the last
electrochemical process has been carried out in pure acetonitrile
from aryl bromides.10 These electrochemical methods favorably
compare with known chemical processes. Yet all of the
electrochemical reactions are generally considered as being more
difficult to handle than conventional chemical methods. Thus,
electrochemical syntheses are poorly applied by organic chem-
ists, and, although they were found successful on the laboratory
scale, they are not used on a larger (industrial) scale.
The preparation of functionalized organometallic compounds
has been the subject of increased research activity over the past
decades,1 due to the versatility of such key intermediates in
organic synthesis. Indeed, organozinc species have received
much attention because of their mildness resulting in high
functional group compatibility.2 Numerous methods devoted to
carbon-zinc bond formation have been developed. Prior to the
discovery of Rieke zinc,3 zinc was found unreactive toward
alkyl, vinyl, and aryl bromides or chlorides except in the well-
known Reformatsky reaction.4 The preparation of these organo-
zinc compounds was formerly achieved only by a transmeta-
lation reaction of a zinc halide from preformed organolithium
or magnesium counterparts. Although some functionalized
magnesium reagents have been prepared via an iodine-
magnesium exchange,5 they need to be transmetalated with
copper or zinc to undergo the cross-coupling reaction. Organo-
lithium compounds can also bear a reactive group, providing
they are prepared at low temperature.6 Alternatively, Rieke
reported on a general approach for preparing highly reactive
metals such as zinc by reducing the corresponding metal halide.7
This Rieke zinc is generally reactive toward aryl or heteroaryl
bromides at elevated temperature but reacts neither on aryl
chlorides nor on some aryl bromides (e.g., 3-bromothiophene).
Despite its indisputable synthetic utility, the use of such activated
zinc requires specific conditions together with careful handling.
Given the importance of arylzinc species in chemical
synthesis, we developed a new chemical reaction aimed at
preparing aromatic zinc species. This process relies on our recent
discoveries and demonstrates that in some cases a purely
chemical reaction could be extended from our initial electro-
chemical process. Indeed, we have established that chemical
reducing agents could advantageously replace electricity for the
preparation of arylzinc compounds catalyzed by cobalt in
acetonitrile.11 The low-valent cobalt generated from the chemical
(1) (a) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem., Int.
Ed. 2000, 39, 4414. (b) Rieke, R. D.; Hanson, M. V. Tetrahedron 1997,
53, 1925.
(2) (a) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117. (b) Knochel,
P.; Jones, P. In Organozinc Reagents, A Practical Approach; Harwood, L.
M., Moody, C. J., Eds.; Oxford University Press: Oxford, 1999.
(3) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991, 56, 1445.
(4) Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210.
(5) Jensen, A. E.; Dohle, W.; Sapountzis, Y.; Lindsay, D. M.; Vu, V. A.;
Knochel, P. Synthesis 2002, 4, 565.
(8) Sibille, S.; Ratovelomanana, V.; Perichon, J. J. Chem. Soc., Chem. Commun.
1992, 283.
(9) Gosmini, C.; Rollin, Y.; Nedelec, J.-Y., Pe´richon, J. J. Org. Chem. 2000,
65, 6024.
(10) Fillon, H.; Le Gall, E.; Gosmini, C.; Pe´richon, J. Tetrahedron Lett. 2002,
(6) Tucker, C. E.; Majid, T. N.; Knochel, P. J. Am. Chem. Soc. 1992, 114,
3983.
43, 5941.
(11) Fillon, H.; Gosmini, C.; Pe´richon, J. Patent application in France (4. july
(7) Rieke, R. D. Aldrichimica Acta 2000, 33, 52.
2001) n°01/08880.
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10.1021/ja0289494 CCC: $25.00 © 2003 American Chemical Society
J. AM. CHEM. SOC. 2003, 125, 3867-3870
3867

A R T I C L E S
Fillon et al.
Table 1. Preparation of Aryl-Zinc Compounds Substituted by
Electron-Donating Groups
reduction of cobalt halide can unprecedentedly activate aryl
bromides in acetonitrile.
Herein, we describe that, in the presence of zinc bromide
and zinc dust, the cobalt catalyst is also suitable for the efficient
chemical conversion of various aryl bromides to the corre-
sponding arylzinc intermediates (eq 1).
entry
FG−C H −FG
X
% ArZnX
% ArH
% Ar−Ar
conv. %
6
4
1
2
3
4
5
6
7
8
9
H
H
Cl
Br
Br
Br
Br
I
Br
Br
Br
Br
Br
0
77
86
70
93
88
71
40
65
6
0
8
8
7
7
8
9
52
16
94
13
0
15
6
23
0
3
20
0
0
100
100
100
100
100
100
100
100
100
100
p-CH3O
m-CH3O
o-CH3O
p-CH3O
p-CH3
p-NH2
p-N(Me)2
p-OH
19
0
7
10
11
p-OCOMe
80
Results and Discussion
Arylzinc bromides are readily prepared by the reaction of
aryl bromides with commercially available zinc dust activated
by traces of acid in the presence of cobalt halide (0.1 equiv)
and zinc halide (0.1 equiv) in acetonitrile at room temperature.
The conversion is complete after a reaction time of ca. 30 min,
affording the corresponding organozinc species. The resulting
organozinc species are converted into aromatic iodide by
addition of iodine. The amount of the aromatic iodide is
measured by GC using an internal standard (alcane). In the
beginning of the reaction, ArH is formed. To decrease the
amount of the reduction product, a catalytic amount of bro-
mobenzene (10% vs ArX) is added in the solution before the
introduction of the functionalized aryl bromide, allowing this
side reaction to proceed on bromobenzene rather than on more
functionalized aryl halides used as substrates. Bromobenzene
is readily converted into the reduced product, no corresponding
organozinc is detected, and only benzene is formed. The aryl
bromide is added in a second time (eq 2). An inert atmosphere
is not required in this process as long as ArZnX is consecutively
engaged in a coupling reaction.
dried ZnBr2 leads to a slight decrease in dimer ArAr formation.
ZnBr2 stabilizes cobalt(I) as reported before in an electrochemi-
cal study12 and by electrochemical synthesis of arylzinc
compounds from aryl bromides.10 In the chemical synthesis
described herein, ZnBr2 is generated by chemical reduction of
cobalt halide with zinc dust. Several other parameters such as
the nature of the solvent or the presence of a cosolvent have
been studied. The use of dimethylformamide (DMF), dimethyl-
acetamide (DMAC), or tetrahydrofuran (THF) instead of ac-
etonitrile does not lead to organozinc formation. Considering
the fact that in the presence of pyridine, the rate of formation
of organozinc compounds is very low and could have negative
effects in some coupling reaction, we decided to carry out the
reactions without any ligand in the following synthesis. The
optimized conditions developed for aromatic bromides bearing
either electron-donating or electron-withdrawing groups have
been applied to the conversion of heteroaromatic bromides into
the corresponding organozinc species. In some cases, the
arylzinc species has been coupled with aryl iodide using PdCl2-
(PPh3)2 as catalyst. The resulting product has been isolated.
The results obtained in acetonitrile from phenyl halides
substituted by an electron-donating substituent are reported in
Table 1.
These results show that this new original chemical method
gives the expected organozinc species in high yields with
aromatic bromides (entries 2-5, 7-9, 11) and iodides (entry
6). However, as already observed in the electrochemical process
in pure acetonitrile, no organozinc compound could be detected
from chlorobenzene (entry 1), which was not consumed. This
indicates that Co(I) reacts too slowly with aryl chlorides.
Bromophenol (Table 1, entry 10) reacts with Co(I), but the
complexation of the alcoholate to the zinc proceeds so fast that
transmetalation is no longer observed, leading to the formation
of the reduction product. However, the corresponding protected
alcohol (Table 1, entry 11) affords the organozinc species in
good yield. On the contrary, p-bromoaniline (entry 8) can be
converted in moderate yield without protecting the amino group.
The results obtained with aromatic halides substituted by an
electron-withdrawing group are reported in Table 2.
Different aryl bromides have been tested in the first step
instead of bromobenzene, such as p-Br-Ph-COOEt, p-Br-
Ph-CN, m-Br-Ph-CF3, p-Br-Ph-Me, and 3-bromo pyridine,
giving similar results; only the reduction product appears.
However, with an aryl bromide substituted in the ortho position,
such as o-Br-Ph-CN, the corresponding organozinc compound
is detected. For greater convenience, bromobenzene was used.
In this protocol, PhBr and CoBr2 are introduced in equimolar
amount. If the PhBr/CoBr2 ratio is increased, the organozinc
PhZnBr is formed and does not affect the yield in ArZnBr. The
large excess of zinc dust enhances the rate of the reaction, but
a slight excess is sufficient to consume all of the starting product.
Using 2 or 3 equiv of Zn dust has no effect on the yields. The
results are similar when the zinc dust is activated either by CF3-
COOH or by CH3COOH. Replacement of these Bro¨nsted acids
by iodine was attempted but led to poorly reproducible results.
CoCl2 can be used instead of CoBr2. A few years ago, we
described an electrochemical method catalyzed by nickel, but
no organozinc compound was detected when CoBr2 was
replaced by NiCl2 in this protocol. At the beginning of the
reaction, the presence of ZnBr2 which undergoes transmetalation
with ArCoBr is not required according to the mechanism which
will be discussed later on. Nevertheless, a little amount of freshly
These results show that the yields obtained in the standard
reaction conditions described above are good to excellent with
aromatic bromides substituted by COOEt, CF3, X, or CN (entries
14-22) in the ortho, meta, or para position except when FG is
a carbonyl group (Table 2, entries 23 and 24). With these last
substituents, poor yields are obtained under these conditions.
(12) Seka, S.; Buriez, O.; Nedelec, J. Y.; Pe´richon, J. Chem.-Eur. J. 2002, 8,
2534.
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3868 J. AM. CHEM. SOC. VOL. 125, NO. 13, 2003

Synthesis of Functionalized Arylzinc Compounds
A R T I C L E S
Table 4. Formation of Dizinc Species from Dibromobenzenes
Table 2. Preparation of Aryl-Zinc Compounds Substituted by
Electron-Withdrawing Groups
entry
FG−C H −FG
X
% ArZnX
conv. %
% ArH
% ArAr
6
4
12
13
14
15
16
17
18
19
20
21
22
23
24
p-CH3SO2
p-C2H5OCO
p-C2H5OCO
p-C2H5OCO
p-CF3
m-CF3
p-Cl
p-F
p-CN
m-CN
o-CN
p-CHO
p-CH3CO
Cl
Cl
Br
I
Br
Br
Br
Br
Br
Br
Br
Br
Br
41
6
63
29
23
23
6
11
4
12
6
9
3
4
0
13
10
0
0
13
14
10
3
5
21
2
0
0
65
38
80
75
86
80
89
70
95
96
100
22
52
100
100
100
100
100
100
100
100
100
100
100
Table 3. Formation of Organozinc Species from Bromothiophenes
To our knowledge, there is no example of any direct versatile
chemical synthesis of thienylzinc species from bromothiophene.
3-Thienyl organozinc reagents can be prepared by direct
oxidative addition of active zinc to 3-iodothiophene.13 However,
3-iodothiophene is rather difficult to prepare. A few years ago,
we reported the first direct preparation of 3-thienylzinc bromide
from 3-bromothiophene by a simple electrochemical method
using nickel catalyst and the sacrificial anode process.14
In the standard conditions described for aromatic bromides,
the arylzinc species is obtained in 67 or 50% yield from 3- or
2-thienyl bromide, respectively. 3-Thienyl bromide is partially
consumed, and 2-thienyl bromide, which is more reactive, gives
a large amount of the reduction product. To increase these yields,
20% of CoCl2 was used instead of the standard reaction
condition (entries 26 and 28). These results are similar to those
obtained previously using our electrochemical process, using
more simple conditions. The 3-thienylzinc bromide can be
coupled with aromatic halides in the same medium using the
classical catalyst PdCl2(PPh3)2. The coupling was found efficient
with iodobenzene (70% isolated vs 3-thienyl bromide) or with
ethyl 4-iodobenzoate (68% isolated vs 3-thienyl bromide),
underlining the high efficiency of the thienylzinc bromide
formation.
Therefore, this new method has also been applied to the
formation of organodizinc compounds from aromatic or het-
eroaromatic dibromides. We have already described that these
compounds can be synthesized using a cobalt catalysis by our
electrochemical process in acetonitrile or DMF associated to
pyridine.15 These compounds are of interest in the preparation
of π-conjugated alternating copolymers, which has already been
carried out from electrochemically prepared aryldizinc species.16
In Table 4, we have reported the results obtained with various
aryl or heteroaryl dibromides.
Surprisingly, these organozinc species quickly evolve, resulting
in dimer formation. It can be pointed out that the position of
the substituent has again a slight influence on the yields as
revealed in entries 16 and 17 or 20-22. When the halogen on
ArX is chlorine instead of bromine, the consumption of the aryl
chloride is partial even if the aromatic nucleus is substituted
by an electron-withdrawing group (Table 2, entries 12 and 13).
Such compounds were found to be poorly reactive toward zinc.
Some aromatic organozinc species mentioned in Table 2
(entries 14, 20, 22) have been coupled with iodo anisole (1 equiv
vs ArX) in the presence of a catalytic amount of PdCl2(PPh3)2
(eq 3).
Starting from ethyl 4-bromobenzoate, 4-bromobenzonitrile,
and 2-bromobenzonitrile, the corresponding biaryls are obtained
in 66, 76, and 61% vs ArX, respectively. The last yield increases
when 2 equiv of iodo anisole is introduced in the medium (74%).
The corresponding organozinc species were iodolyzed for GC
titration of the resulting aryl diiodide using an internal standard
(alcane). In all cases, the analysis of the solution showed the
formation of a mixture of the desired organodizinc compound
(BrZnArZnBr), the monoorganozinc corresponding to the reduc-
tion product (ArZnBr), and the organodizinc species of the dimer
(BrZnAr-ArZnBr). The latter product was never observed by
In the following series of experiments, we tried to apply this
method to heteroaromatic halides. The results are reported in
Table 3 and show that the method affords the formation of
heteroarylzinc compounds such as bromothiophene. Unfortu-
nately, results were disappointing with bromo pyridine, because
all of the reactant ArX is converted into the reduction compound
ArH. On the other hand, the thienylzinc bromide can be
generated from bromothiophene.
(13) Wu, X.; Rieke, R. D. J. Org. Chem. 1995, 60, 6658.
(14) Gosmini, C.; Nedelec, J. Y.; Perichon, J. Tetrahedron Lett. 1997, 38, 1941.
(15) Fillon, H.; Gosmini, C.; Nedelec, J. Y.; Perichon, J. Tetrahedron Lett. 2001,
42, 3843.
(16) Cecile, C.; Mellah, M.; Labbe´, E.; Nedelec, J. Y.; Pe´richon, J. New J. Chem.
2002, 26, 787.
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A R T I C L E S
Fillon et al.
Scheme 1
Experimental Section
GC analysis was carried out using a 25 m DB-1 capillary column.
Mass spectra were recorded with an ITD spectrometer coupled to a
gas chromatograph (DB1, 30 m). Column chromatography was
performed on silica gel 60, 70-230 mesh. 1H, 13C NMR spectra were
recorded in CDCl3 at 200 MHz with TMS as an internal standard.
Unless indicated, all solvents and reagents were purchased and used
without further purification. Acetonitrile was stored under argon.
Cobalt bromide and zinc bromide were used as obtained com-
mercially.
General Procedure for the Preparation of Arylzinc Halide. A
dried 100 mL three-necked flask is charged with acetonitrile (20 mL),
cobalt bromide (330 mg, 1.5 mmol), zinc bromide (340 mg, 1.5 mmol),
phenyl bromide (0.16 mL, 1.5 mmol), zinc dust (3.25 g, 50 mmol),
and 50 µL of trifluoroacetic acid. The mixture is stirred at room
temperature until PhBr is consumed (ca. 15 min). The functionalized
aromatic bromide (15 mmol) is then added to the solution, and the
reaction mixture is allowed to stir at room temperature. The formation
of the arylzinc species is monitored by GC by addition of iodine and
is run until whole consumption of the aromatic halide (ca. 30 min).
The amount of the corresponding aryl iodide is measured by GC using
an internal reference and compared with the commercial product. Some
arylzinc species are directly used for the cross-coupling reactions with
aryl iodide.
General Procedure for the Preparation of Thienylzinc Halide.
A dried 100 mL three-necked flask is charged with acetonitrile (20
mL), cobalt bromide (660 mg, 3 mmol), zinc bromide (340 mg, 1.5
mmol), anisole bromide (0.2 mL, 1.5 mmol), zinc dust (3.25 g, 50
mmol), and 50 µL of trifluoroacetic acid. The mixture is stirred at room
temperature until MeOPhBr is consumed (ca. 15 min). Thienyl bromide
(15 mmol) is then added to the solution, and the reaction mixture is
allowed to stir at room temperature. The formation of the thienylzinc
species is monitored by GC by addition of iodine and is run until the
bromothiophene was totally consumed (ca. 1 h). The thienyl iodides
are measured by GC using an internal reference and are directly used
for the cross-coupling reactions with aryl iodide.
General Procedure for Coupling with Phenyl Iodide. After
consumption of the aryl bromide, aryl iodide (15 mmol, i.e., in a 1:1
ratio vs initial aryl bromide) and PdCl2(PPh3)2 (110 mg, 0.15 mmol)
are added at room temperature. The reaction is monitored by GC and
is run until the consumption of aromatic zinc halide (ca. 2 h). The
reactions are then quenched with 1 N HCl and extracted with diethyl
ether (3 × 40 mL). The extracts are dried over MgSO4, and the solvent
is removed under reduced pressure. The product was isolated by silica
gel column chromatography eluted with 95:5 or 90:10 pentane/diethyl
ether.
The following compounds are identified by comparison of their
physical and spectral data with those given in the cited references:
4-methoxy-biphenyl-4-carboxylic acid ethyl ester,17a 4-methoxy-biphen-
yl-4-carbonitrile,17b 4-methoxy-biphenyl-2-carbonitrile,17a and 3-phenylthio-
phene.17c
electrosynthesis. The reaction conditions are the same as those
described for the monozinc compounds, but the reaction time
is longer, ca. 1h 30 min.
We observed that all carbon-bromine bonds are reactive,
even those arising from the resulting dimer, which was not
observed with the electrochemical method. However, yields are
similar for the desired diorganozinc compound (BrZnArZnBr).
This behavior was expected, considering the higher reaction rate
in the chemical reaction, and is consistent with the fact that all
of the products are converted into organozinc species. This
discovery prompted us to apply this procedure to 2,5-dibro-
mothiophene (Table 4, entry 32).
From a mechanistic point of view, we based our procedure
on the mechanism described recently in the case of the
electrochemical conversion of aryl halides to arylzinc com-
pounds by cobalt catalysis in DMF/pyridine.12 The catalytic
cycle is initiated by the reduction of CoBr2 by zinc dust, which
needs to be activated previously by acid traces. The resulting
CoIBr undergoes an oxidative addition with aryl halides to afford
the trivalent cobalt complex ArCoIIIBr2. That latter species is
reduced into ArCoIIBr by the excess of zinc dust. The cycle is
completed by a transmetalation reaction between ArCoIIBr and
ZnBr2 formed in the previous steps, leading to the arylzinc
compound and regenerating divalent cobalt (Scheme 1).
In summary, we have established that readily available cobalt
halide and zinc dust are convenient for the facile preparation
of arylzinc species from the corresponding bromides in aceto-
nitrile. This new and versatile process can be applied to the
preparation of 3-thienylzinc bromide in a single operation from
3-bromothiophene. The efficient preparation of these organozinc
compounds makes this new chemical method an excellent
alternative to our electrochemical processes. The cobalt-
catalyzed chemical conversion of aryl or thienyl bromides to
arylzinc species generally gives excellent yields. The zinc dust
acts as the reducing agent, providing the required zinc salt by
reaction with the CoX2. This chemical synthesis using a cobalt
catalyst must now be extended to aryl chlorides, and the
mechanism requires a thorough study to be clearly elucidated.
Currently, studies of the reactivity of these organozinc species
are in progress.
Acknowledgment. We gratefully acknowledge the financial
support provided by Rhodia Industry.
JA0289494
(17) (a) Gomes, P.; Fillon, H.; Gosmini, C.; Labbe´, E.; Pe´richon, J. Tetrahedron
2002, 58, 8417. (b) Hassan, J.; Hathroubi, C.; Gozzi, C.; Lemaire, M.
Tetrahedron 2001, 57, 7845. (c) Rieke, R. D.; Kim, S.-H.; Wu, X. J. Org.
Chem. 1997, 62, 6921.
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3870 J. AM. CHEM. SOC. VOL. 125, NO. 13, 2003