Synthesis of functionalised diarylmethanes via a cobalt-catalysed cross-coupling of arylzinc species with benzyl chlorides

Article abstract of DOI:10.1039/b809626k

A new cobalt-catalysed reductive coupling of aryl halides with benzyl chlorides is reported; a variety of diarylmethanes can be prepared in good to excellent yields under mild reaction conditions using CoBr₂ as catalyst and Zn dust; this new cobalt-catalysed coupling represents a practical and interesting alternative to previously known methods for the synthesis diarylmethanes. The Royal Society of Chemistry.

Full text of DOI:10.1039/b809626k

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Synthesis of functionalised diarylmethanes via a cobalt-catalysed
cross-coupling of arylzinc species with benzyl chloridesw
Muriel Amatorea and Corinne Gosmini*b
Received (in Cambridge, UK) 6th June 2008, Accepted 27th June 2008
First published as an Advance Article on the web 2nd September 2008
DOI: 10.1039/b809626k
A new cobalt-catalysed reductive coupling of aryl halides with
benzyl chlorides is reported; a variety of diarylmethanes can be
prepared in good to excellent yields under mild reaction condi-
tions using CoBr2 as catalyst and Zn dust; this new cobalt-
catalysed coupling represents
a practical and interesting
Scheme 1 Two-step procedure for the reductive cross-coupling of
p-EtO2CC6H4Br with PhCH2Cl.
alternative to previously known methods for the synthesis
diarylmethanes.
halides and benzylic chlorides in a very efficient manner. To
the best of our knowledge, this is the first cobalt-catalysed
reductive coupling of aryl halides and benzyl halides to form
diarylmethane. Our initial efforts were directed towards find-
ing an appropriate reaction using benzyl chloride as a model
substrate for coupling with various aryl bromides. Stemming
from our previous results concerning the reactivity of arylzinc
species obtained under cobalt catalysis,13 we believed that
methylene-linked biaryls could be obtained via the cross-
coupling of arylzinc derivatives with benzyl chlorides under
suitable conditions. We first investigated a two-step coupling
reaction, involving formation of 4-(ethoxycarbonyl)phenyl-
zinc bromide from ethyl 4-bromobenzoate and subsequent
coupling with benzyl chloride without further addition of
cobalt catalyst, leading to the corresponding diarylmethane
at room temperature. The coupling product was detected in
86% yield (GC), while the homocoupling product formed only
in a small amount (Scheme 1).
Diarylmethanes have been shown to possess interesting biologi-
cal and medicinal properties and are ubiquitous structural
constituents in pharmacologically important molecules1 such
as papaverine and beclobrate. These compounds also frequently
appear as subunits in supramolecular structures such as macro-
cycles, catenanes, and rotaxanes.2 A common synthetic method
for obtaining diarylmethanes includes the Friedel–
Crafts alkylation of aromatic compounds with benzylic halides.3
Additionally, transition metal-catalysed cross-coupling reactions
provide powerful tools for the formation of carbon–carbon
bonds.4 The most general procedures for diarylmethane synth-
esis are the transition metal-catalysed cross-coupling between
aryl halides and benzylic metals5 (usually prepared from benzylic
halides). However, cross-coupling reactions of an aryl-metal
with a benzyl halide or derivative such as benzyl phosphates
or carbonates are reported less frequently.6 The main difficulty
with these methods remains the preliminary preparation of the
organometallic reagent, especially when the aromatic ring bears
reactive functional substituents. These preformed organometal-
lic reagents often consist of a Grignard, borane, manganese,
stannane or zinc derivative and the cross-coupling generally
requires an expensive rhodium or palladium catalyst, or a toxic
nickel catalyst and typically sophisticated ligands. Some inter-
esting copper-catalysed reactions have also been shown to form
the methylene-linked biphenyl species.7 Alternatively, the use of
cobalt as a highly reactive catalyst for carbon–carbon bond-
forming reactions has been recently demonstrated by Cahiez,8
Knochel,9 Oshima,10 Cheng11 and our group.12
We next set our sights on developing an operationally
simplified Barbier-type procedure for the synthesis of diaryl-
methanes from aryl bromides or iodides without the need for
preforming the arylzinc reagent and avoiding the formation of
the corresponding homocoupling product (Ar–Ar). Since both
aryl and benzyl halides competitively form organozinc species
resulting in undesired homocoupled products, selective diaryl-
methane formation was pursued by using an excess (2 equiv.)
of the more reactive benzyl chloride coupling partner. Results
are reported in Scheme 2 and Table 1.
As shown, the reaction was broadly successful, affording
good yields with a range of electron-withdrawing or -donating
groups on the aryl halide. Interestingly, the substituent posi-
tion had no influence on yields as revealed in the case
Herein, we wish to report a new Co(II)-mediated cross-
coupling reaction devoted to the direct synthesis of
diarylmethanes, using variously functionalized aromatic
a
`
Equipe Electrochimie et Synthese Organique, Institut de Chimie et
des Materiaux Paris Est, ICMPE, C.N.R.S-Universite Paris 12 val
´
de Marne, UMR 7182, 2, rue Henri Dunant, 94320 Thiais, France
´ ´ ´ ´
b
Laboratoire ) Heteroelements et Coordination *, Ecole
Polytechnique, CNRS, 91128 Palaiseau Cedex, France.
E-mail: corinne.gosmini@polytechnique.edu; Fax: +33 1-6933-4440;
Tel: +33 1-6933-4412
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b809626k
Scheme 2 Reductive cross-coupling of ArX (X = Br or I) with
PhCH2Cl.
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Table
PhCH2Cl
1
Barbier-type reductive cross-coupling of ArBr with
Table 2 Reductive cross-coupling of ArZnBr with PhCH(Me)Cl
Isolated yield
vs. ArBr (%)
GC
yield (%)
Isolated
yield (%)
GC
yield (%)
Entry
FG
Entry
FG
15
16
17
18
19
20
p-CO2Et
o-CO2Et
p-CN
o-CN
p-CF3
p-OMe
75
60
67
—
70
65
77
61
74
0
79
68
1
2
3
4
5
6
7
8
9
p-CO2Et
m-CO2Et
o-CO2Et
p-CN
m-CN
o-CNa
p-COMe
p-CF3
77
75
75
71
74
76
75
85
77
77
71
—
68
70
88
85
80
92
97
81
87
91
86
86
76
70
76
90
rapid oxidative addition of cobalt in the corresponding C–Cl
bond and eventually to low selectivity. Under a Barbier-type
procedure, the cross-coupling of p-ethylbromobenzoate af-
forded the desired diarylmethane in a modest 61% yield
(GC). Alternatively, the cross-coupling could be conducted
in a two-step procedure. As highlighted in Table 2, the
corresponding diarylmethanes were generally obtained with
good yields regardless of the electronic nature of the substi-
tuents. However, sterics had small impact on the reaction,
especially in the case of o-bromobenzonitrile (Table 2, entries
15, 16 and 17, 18).
p-Cl
p-Clb
10
11
12
13
14
a
p-OMe
p-OMeb
o-OMe
p-NMe2
b
Reaction at 50 1C. X = I.
of ethyl bromobenzoate (Table 1, entries 1, 2 and 3), bromo-
benzonitrile (Table 1, entries 4, 5 and 6) and bromoanisole
(Table 1, entries 11 and 13). Aryl iodides lead to similar yields
(Table 1, entries 10 and 12). All the reactions were conducted
at room temperature except for o-bromobenzonitrile (Table 1,
entry 6). In this last case, the aryl bromide was totally
consumed only after 17 hours at room temperature. Heating
the medium to 50 1C led to a decrease in reaction time with a
similar yield (6 h instead of 17 h). This presumably reflects
steric and chelation effects.
Recently, we have established that cobalt catalysis allows
the simple and high-yielding preparation of a broad range of
functionalised arylzinc species from readily available corres-
ponding chlorides.14 To the best of our knowledge, there is no
previous example of any versatile chemical cobalt-catalysed
reductive coupling from arylzinc chlorides. Due to the low
reactivity of aryl chlorides as compared with aryl bromides,
homocoupling of the benzyl chloride was a potential issue.
However, it could be circumvented via a two-step procedure
without additional cobalt catalyst. In this case, the presence of
pyridine is required to avoid the fast disproportionation of
Co(I) and allow its oxidative addition into the C–Cl bond as
previously described.14a
We have shown that the behavior of our arylzinc com-
pounds synthesised via cobalt catalysis in acetonitrile was
similar to traditional arylzinc species obtained via a trans-
metallation reaction with ZnBr2 from the corresponding or-
ganomagnesium compound in tetrahydrofuran. In this case no
reaction was observed after adding benzyl chloride in the
medium. However, this last arylzinc species could react with
benzyl chloride due to the presence of CoBr2 to afford the
On the basis of this observation, the scope of aryl chlorides
bearing an electron-withdrawing group was investigated.
Results are reported in Scheme 5 and Table 3. Satisfactory
yields were observed and again the substituent position had
only a slight influence on yields.
cross-coupling product and Ar–Ar in
a large amount
(Scheme 3). These results demonstrate that in our case, cobalt
salts used for the preparation of arylzinc derivatives are also
involved in this Negishi-type cross-coupling.
In conclusion, we have developed a new, alternative method
for preparing diarylmethanes from the corresponding functio-
nalised aryl iodide, bromide or chloride via an intermediate
The reaction scope was then investigated with a secondary
benzylic chloride. Results are reported in Scheme 4 and
Table 2. Interestingly, the a-substitution considerably
modified the reactivity of the benzyl chloride, leading to a
Scheme 5 Reductive cross-coupling of ArZnCl with PhCH2Cl.
Table 3 Reductive cross-coupling of ArCl with PhCH2Cl
Scheme 3 Cross-coupling of ArZnBr derived from ArMgBr with
PhCH2Cl.
Isolated yield
vs. ArCl (%)
GC yield
vs. ArCl (%)
Entry
FG
21
22
23
24
p-CN
o-CN
p-CO2Me
p-COMe
57
55
68
83
87
85
77
93
Scheme 4 Reductive cross-coupling of ArBr with PhCH(Me)Cl.
5020 | Chem. Commun., 2008, 5019–5021
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arylzinc species and benzyl chloride using an eco-friendly and
inexpensive cobalt-catalyst. To the best of our knowledge, this
represents the first cobalt-catalysed reductive cross-coupling
involving a functionalised arylzinc chloride. Depending on the
nature of substrates involved, this versatile process even allows
the synthesis of a wide variety of diarylmethanes in a Barbier-
fashion for more convenience. Finally, this practical, efficient
and functional group tolerant procedure compares favorably
with other palladium or rhodium catalysed methods.
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Chem. Commun., 2008, 5019–5021 | 5021