A convenient method for the preparation of aromatic ketones from acyl chlorides and arylzinc bromides using a cobalt catalysis

Article abstract of DOI:10.1016/j.tet.2003.08.032

Aromatic ketones are synthesized efficiently via cobalt catalyzed cross-coupling reaction between arylzinc bromides and acid chlorides. Arylzinc bromides prepared chemically via a cobalt catalysis undergo coupling without additional catalyst unlike their electrochemical analogs.

Full text of DOI:10.1016/j.tet.2003.08.032

Tetrahedron 59 (2003) 8199–8202
A convenient method for the preparation of aromatic ketones
from acyl chlorides and arylzinc bromides using a cobalt catalysis
*
Hyacinthe Fillon, Corinne Gosmini and Jacques Perichon
´
` ´
Laboratoire d’Electrochimie, Catalyse et Synthese Organique, UMR 7582, Universite Paris 12-C.N.R.S, 2, Rue Henri Dunant,
F-94320 Thiais, France
Received 13 June 2003; revised 16 July 2003; accepted 19 August 2003
Abstract—Aromatic ketones are synthesized efficiently via cobalt catalyzed cross-coupling reaction between arylzinc bromides and acid
chlorides. Arylzinc bromides prepared chemically via a cobalt catalysis undergo coupling without additional catalyst unlike their
electrochemical analogs.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
at low temperature followed by lithium-manganese trans-
metallation7 and coupling with acyl chlorides with a
catalytic amount of CuCl.
Many synthetic methods have been developed for the
synthesis of aromatic ketones which are important building
blocks included in a large number of natural products and
active pharmaceutical ingredients. The reaction of acid
chlorides with organometallic reagents provides a direct and
convenient method for the synthesis of ketones.1 Although a
variety of alkali, alkaline earths, transition metal and main
group organometallic reagents react with acid chlorides to
give ketones, the most useful synthetic methods generally
utilize organocopper reagents or palladium catalyzed routes.
In most cases, the organocopper species arise from the
reaction of an organolithium or Grignard reagents with an
appropriate copper (I) salt.2 This approach exhibits severe
restrictions toward the type of functional groups, except in
the case of low temperature iodine magnesium or bromide–
lithium exchange reaction.3 Alternatively, this drawback
can be overcome by using a higher reactive zerovalent
copper that undergoes fast oxidative addition on the aryl
halide.4 Despite its indisputable synthetic utility, the use of
such activated Rieke metal powders requires specific
conditions together with careful handling.5 In the same
way, highly reactive manganese prepared by Rieke’s
method reacts with 3-bromothiophene to yield the corre-
sponding organomanganese reagent.6 These compounds are
very interesting since they can be used to perform various
useful synthetic reactions notably acylation without involv-
ing any additive. More recently, functionalized organo-
manganese have also been one-pot synthesized according to
a two step procedure, involving halogene–lithium exchange
Functionalized organozinc species can be transmetalled into
organocopper reagents in order to react with acid chlorides.8
However, like organostannanes9 and arylboronic acids,10
arylzinc compounds can also be acylated to produce ketones
if the reaction is catalyzed by palladium11 complexes.
In the past few years, we have successfully synthetized
arylzinc compounds from aryl bromides by an electro-
chemical method using a simple catalytic system involving
cobalt halide in acetonitrile as solvent. In a second step,
these compounds undergo coupling, with acetyl chloride in
quantitative yields using a palladium catalyst (Eq. (1)).12
ð1Þ
In this paper, we report our investigations on the cobalt-
catalyzed coupling reaction of arylzinc compounds with
acid chlorides, leading to aromatic ketones in acetonitrile.
Indeed, cobalt halides have also been employed as catalyst
in the acylation of dialkylzinc reagents by Knochel at 08C in
THF-NMP.13
Keywords: arylzinc; acyl chloride; cobalt catalysis.
*
Corresponding author. Tel.: þ33-1-49-78-11-39; fax: þ33-1-49-78-11-
48; e-mail: gosmini@glvt-cnrs.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.032

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H. Fillon et al. / Tetrahedron 59 (2003) 8199–8202
2. Results and discussion
Table 1. Coupling of electrochemical aryl zinc compound with acid
chlorides
Several new approaches have been developed depending on
the preparation of arylzinc species leading to aromatic
ketones.
2.1. Coupling of acyl chlorides with electrosynthetized
arylzinc compounds using a cobalt catalysis in
acetonitrile
Entry
FG
RCOCl
Yielda (isolated yieldb)
1
2
3
4
5
6
7
8
H
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
PhCOCl
PhCOCl
PhCOCl
74 (40) [1]
87 (68) [2]
87 (58) [3]
69 (51) [4]
73 (55) [5]
67 (60) [6]
63 (48) [7]
93 (40) [8]
42 (30) [9]
69 (58) [10]
84 (67) [11]
33(26) [12]
90 (77) [13]
49 (39) [14]
66 (50) [15]
p-MeO
o-MeO
p-Me
p-EtOCO
m-CF3
p-Cl
p-F
p-MeCO
p-CN
m-CN
o-CN
p-CN
A previous report from our laboratory has shown that
arylzinc species formed by our electrochemical method
could not be activated using a mixture of cuprous cyanide
and lithium chloride to form aromatic ketones. In fact, these
assays led quantitatively upon work up to the hydro-
dehalogenation product (ArH). Therefore, we tried to
achieve the coupling reaction between electrogenerated
organozinc species and acid chlorides using a cobalt halide
as catalyst (Eq. (2)).
9
10
11
12
13
14
15
m-CN
p-EtOCO
a
Yields calculated with respect to ArZnBr (titrated by quenching with I2).
Isolated yields obtained for the 2 steps reported with respect to ArBr.
b
2.2. Coupling of acyl chlorides with aryl zinc compound
formed by our chemical process using a cobalt catalysis
in acetonitrile
ð2Þ
Recently, we have reported a new simple chemical method
for the preparation of arylzinc intermediates based on the
activation of aryl bromides by low-valent cobalt species
arising from the reduction of cobalt (II) halides by zinc
dust15 in acetonitrile as solvent. The versatility and the
simplicity of that original method represent an alternative to
most known procedures. Moreover, the chemical formation
of these aryl zinc compounds proceeds faster than in the
case of the electrochemical preparation (Eq. (3)). In these
conditions, a supplementary catalyst is not necessary to
form the corresponding aromatic ketone. Cobalt (I)
produced in the medium, was found effective to catalyze
the acylation reaction (Eq. (3)).
All reactions are carried out in an undivided cell already
described14 fitted with a consumable zinc anode and a
stainless steel cathode. The ionic conductivity of the
medium is ensured by addition of NBu4BF4 as supporting
electrolyte. Electrolyses are run at constant current intensity
of 0.2 A (0.01 A/cm2), at room temperature and under inert
atmosphere of argon. The consumption of ArX is monitored
by GC analysis. Electrolyses are stopped after total
consumption of ArX. Then, 0.13 equiv. of CoCl2 and
1 equiv. of RCOCl vs ArX are introduced into the medium
at room temperature. The solution is stirred until total
consumption of the organozinc compound and formation of
the aromatic ketone.
The use of a supplementary amount of cobalt catalyst
(0.05 equiv. vs ArX) is sufficient to consume all the starting
products in the acylation step. In this case, the reaction is
slower than with 0.13 equiv. of catalyst. CoBr2 could
replace CoCl2. Acylation of the electrochemically prepared
arylzinc species does not occurs in the absence of CoX2
added in the second step. Results are reported in Table 1.
ð3Þ
The mechanism of the reaction can be explained from a
catalytic sequence already proposed for other metals:1
oxidative addition of RCOCl to a Co(I) complex formed in
the previous step (formation of the arylzinc species)
provides RCOCo(III)Cl. Reaction between this acyl cobalt
complex and the arylzinc reagent, followed by reductive
elimination, affords the expected ketone and regenerates the
Co(I) species (Scheme 1).
The yields are moderate to excellent, ranging from 33 to
93%. The overall yields vs initial aromatic bromides are
moderate to good (26–77%). These yields decrease when
the substituent is in ortho position (Table 1, entries 3 and
12). Moreover, an electron-donating or withdrawing group
on the aryl bromide does not affect the yield in the coupling
reaction. No further optimization of that process has been
undertaken, since pure chemical conditions afford the
coupling product without supplementary cobalt catalyst, as
described in the next paragraph.
On the contrary to the acylation of aryl zinc bromides
formed by our electrochemical method, no supplementary
cobalt catalyst was necessary (Eq. (4)). The rate of the
chemical formation of the arylzinc species is faster than the
analog electrochemical reaction (20–30 min in comparison
with 2 h 30 min). So, the low-valent Co(I) species, which is

H. Fillon et al. / Tetrahedron 59 (2003) 8199–8202
8201
Table 2. Coupling of chemically prepared aryl zinc compound with acid
chlorides
Entry
FG
RCOCl
Yielda (isolated yieldb)
16
17
18
19
20
21
22
23
24
26
27
m-MeO
o-MeO
p-Me
p-EtOCO
m-CF3
p-Cl
p-F
p-CN
m-CN
p-CN
m-CN
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
C8 H17COCl
PhCOCl
87 (61) [16]
74 (64) [3]
66 (47) [4]
83 (63) [5]
98 (80) [6]
72 (64) [7]
93 (65) [8]
71 (67) [10]
66 (63) [11]
60 (57) [17]
51(48) [14]
Scheme 1.
a
Yields calculated with respect to ArZnBr (titrated by quenching with I2).
Isolated yields obtained for the 2 steps reported with respect to ArBr.
b
necessary for the coupling reaction with acyl chloride, is
present in the medium and most likely evolves into a cobalt
(III) carbonyl intermediate. In fact, disproportionation of
Co(I) occurs in the case of the electrochemical reaction
considering the reaction is very slower.
4. Experimental
GC analysis was carried out using a 25 m DB1 capillary
column. Mass spectra were recorded with an ITD spectro-
meter coupled to a gas chromatograph (DB1, 30 m).
Column chromatography was performed on silica gel 60,
70–230 mesh. H, 13C and 19F spectra were recorded in
1
CDCl3 at 200 MHz with TMS as an internal standard.
ð4Þ
The electrochemical cell was similar to that described
previously.12 All solvents and reagents were purchased and
used without further purification. Acetonitrile was stored
under argon.
These yields in ketone are good but can be improved by
adding a catalytic amount of CoBr2 (10% vs ArBr).
4.1. General procedure
1-Coupling of aryl zinc compounds formed electrochemi-
cally using a cobalt catalysis in pure acetonitrile with acid
chlorides. All the reactions were carried out in an undivided
cell fitted using a consumable zinc anode and a stainless
steel cathode. In a mixture of solvent (acetonitrile 45 mL)
containing 7.5 mmol of ArX (0.16 M), 1 mmol of CoCl2
(0.02 M) and 9 mmol of ZnBr2 (formed by electroreduction
of 1-2 dibromoethane in the presence of a zinc anode) we
applied a constant current intensity of 0.2 A (0.01 A/cm2) at
room temperature. The reactions are stopped after con-
sumption of 2F per mole of ArX. The yields of organozinc
compounds thus obtained were estimated as follows:
samples of the electrolysis solutions were iodinated, then
hydrolyzed with sodium thiosulfate and extracted with
diethyl ether. Amounts of iodinated compounds were
compared to the amounts of starting phenyl bromides via
an internal standard by gas chromatography. Then, 1 mmol
of CoCl2 and 7.5–14 mmol of RCOCl vs ArX were
introduced into the medium at room temperature. The
solution was stirred until total consumption of the
organozinc compound. The reaction mixture was poured
into a solution of 2 M HCl (50 mL) and extracted with
diethyl ether (2£25 mL). The combined extracts were dried
over MgSO4. Evaporation of ether and purification by
column chromatography on silica gel (pentane/ether, 9/1)
afforded the aromatic ketones and were characterized by
NMR (1H, 13C, 19F) and mass spectrometry.
In a typical experiment, the suitable acyl chloride
(1–1.9 equiv. vs ArBr) and CoBr2 (0.1 equiv. vs ArBr) were
added into the solution of the arylzinc reagent formed via a
cobalt catalysis in the same solvent at room temperature.
After hydrolysis with aqueous HCl, the organic layers,
extracted with diethyl ether, give the crude product in good
chemical yield. The yields of the corresponding ketone
obtained are even higher than those obtained using
electrochemically prepared aryl zinc compounds. The
preparation of various functionalized ketones is reported
in Table 2.
3. Conclusion
We have developed a new cobalt-catalyzed two components
cross-coupling reaction between arylzinc species and acyl
chlorides. As observed for the palladium catalyzed cross-
coupling reaction, cobalt salts also catalyze the cross
coupling reaction between an arylzinc species and acyl
chlorides. Acylation proceeds in short reaction times
(30 min to convert 15 mmol of ArZnBr) and gives good
yields in aromatic ketones. Although the yields are
increased in the presence of 0.1 equiv. CoBr2, additional
cobalt is not necessary to obtain the ketone in good yields
when arylzinc species are prepared by the chemical process.

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H. Fillon et al. / Tetrahedron 59 (2003) 8199–8202
2-Coupling of aryl zinc compound formed by our chemical
process using a cobalt catalysis in pure acetonitrile with acid
chlorides. A dried 100 mL three-necked flask is charged
with acetonitrile (20 mL), cobalt bromide (1.5 mmol), zinc
bromide (1.5 mmol), phenyl bromide (1.5 mmol), zinc dust
(50 mmol), 50 ml of trifluoroacetic acid. The mixture is
stirred at room temperature until PhBr is consumed (ca.
15 min). Then the functionalized aromatic bromide
(15 mmol) is added to the solution and the reactions 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. Then, CoCl2 (1.5 mmol) and
acyl chloride (15–20 mmol) were introduced into the
medium at room temperature. The solution was stirred
until total consumption of the organozinc compound. The
reaction mixture was poured into a solution of 2 M HCl
(50 mL) and extracted with diethyl ether (2£25 mL). The
combined extracts were dried over MgSO4. Evaporation of
ether and purification by column chromatography on silica
gel (pentane/ether, 9/1) afforded the aromatic ketones and
were characterized by NMR (1H, 13C, 19F) and mass
spectrometry.
benzoyl-benzoic acid ethyl ester (15), 15165-27-2; 1-(3-
methoxy-phenyl)-ethanone (16),586-37-8; 4-nonanoyl-
benzonitrile (17), 1279928-59-0.
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references. 1-Phenyl-ethanone (1), 98-86-2; 1-(4-methoxy-
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