Efficient cobalt-catalyzed formation of unsymmetrical biaryl compounds and its application in the synthesis of a sartan intermediate

Article abstract of DOI:10.1002/anie.200704402

(Chemical Equation Presented) No prior preparation of the organometallic reagent is required in a cobalt-catalyzed coupling of two different aryl halides under mild conditions (see scheme). A broad spectrum of valuable biaryl compounds can be prepared in this way. Not only may a variety of reactive substituents be present, but heteroaryl halides and aryl triflates are also suitable substrates. DMF = N,N-dimethylformamide, FG = functional group.

Full text of DOI:10.1002/anie.200704402

Angewandte
Chemie
DOI: 10.1002/anie.200704402
À
C C Coupling
Efficient Cobalt-Catalyzed Formation of Unsymmetrical Biaryl
Compounds and Its Application in the Synthesis of a Sartan
Intermediate
Muriel Amatore and Corinne Gosmini*
Unsymmetrical biaryl compounds are of considerable interest
in organic chemistry. The biaryl structural motif is encoun-
tered in a wide variety of organic processes, from supra-
molecular chemistry[1] to natural products synthesis.[2] Among
the innumerable methods for the construction of aryl–aryl
bonds, transition-metal-mediated reactions constitute one of
the main strategies used.[3] Generally, such reactions involve
the coupling of an organometallic reagent (ArM; M = B,[4]
Sn,[5] Si,[6] Zn,[7] Mg,[8] Mn[9]) with an aryl halide or pseudo-
halide. They all require the preparation of a stoichiometric
organometallic reagent and typically the presence of a Ni or
Pd complex as a catalyst. More recently, it has been shown
that iron[10] and cobalt[11] catalysts might be employed as
alternatives to expensive precious metals, such as palladium,
or toxic metals, such as nickel,[12] in coupling reactions with
organometallic reagents. Studies within the realms of metal
catalysis have provided several direct aryl–aryl bond-forming
electrochemical methods, we carried out studies aimed at
broadening the use of this type of catalyst in the direct cross-
coupling of aryl compounds. These transformations with aryl
halides or even aryl triflates are of particular interest owing to
their high functional-group tolerance and the ready avail-
ability of the aryl species. In line with our previous experience
in cobalt-mediated coupling reactions, we found that the low-
valent cobalt species generated from the chemical reduction
of a cobalt halide associated with a ligand can activate
functionalized aryl (or heteroaryl) halides or triflates in an
unprecedented manner to provide unsymmetrical biaryl
compounds. The results of our previous studies demonstrated
the activation efficiency of a cobalt halide associated with 2,2’-
bipyridine in dimethylformamide in the presence of pyri-
dine.[19a,c] Herein, we describe the details of a similar cobalt-
catalyzed cross-coupling reaction, in which another cobalt
complex is used in combination with manganese dust as a
reducing agent, and establish its scope and synthetic utility for
the efficient formation of a variety of unsymmetrical biaryl
compounds (Scheme 1).
transformations for organic synthesis. Catalytic direct arene
[13]
À
C H cross-coupling and the decarboxylative coupling of
aromatic carboxylates[14] with aryl halides can be very
efficient; however, these methods often require the use of a
base, high temperatures, and expensive catalysts. Other
reaction pathways include the palladium-catalyzed reductive
coupling of two aryl halides in combination with a reducing
agent.[15]
In an attempt to couple two different aryl halides, we
previously developed electrochemical methods involving
either Ni[16] or Co[17] catalysis. However, the transformation
is less efficient with aryl chlorides than with aryl bromides,
and no reaction was observed with aryl pseudohalides.
Moreover, nickel is environmentally hazardous, and a large
quantity of the catalyst was required when a cobalt catalyst
was used. Motivated by the interest in cobalt-catalyzed
reactions[18] and our early success in the use of new cobalt-
catalyzed direct procedures[19] as an efficient alternative to
Scheme 1. Cross-coupling of two aryl halides. DMF = N,N-dimethyl-
formamide, FG = functional group.
Our initial studies involving an activated aryl bromide and
a non-activated aryl iodide were highly encouraging. We
determined that [CoBr2(PPh3)] (0.1 equiv) in the presence of
manganese dust (4 equiv) activated by traces of acid pro-
moted the cross-coupling of the two aryl halides in DMF/
pyridine at 508C within 12 h. However, we chose to increase
the amount of [CoBr2(PPh3)] to 0.2 equivalents to reduce the
reaction time to 5 h.
The choice of ligand had a substantial impact on the
course of the reaction. In contrast to other cross-coupling
reactions of aryl compounds, the product was produced in
higher yield when triphenylphosphane was used as the ligand
than with any other ligand tested; 1,2-bis(diphenylphospha-
nyl)ethane and 2,2’-bipyridine were less effective. In the
absence of PPh3 or with only 5 mol% of the catalyst, the
desired product was still formed, although more slowly. An
increase in the temperature led to the formation of the
product in lower yield despite a coinciding decrease in the
[*] Dr. C. Gosmini
Laboratoire “HØtØroØlØments et Coordination”
Ecole Polytechnique, CNRS
91128 Palaiseau Cedex (France)
Fax : (+33)1-6933-4440
E-mail: corinne.gosmini@polytechnique.edu
M. Amatore
ESO, Institut de Chimie et des MatØriaux Paris Est
UniversitØ Paris
12 Val de Marne, CNRS
2, rue Henri Dunant, 94320 Thiais (France)
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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reaction time. From an extensive survey of solvents, a 6:1
sartan derivatives (Scheme 2). Chemical modifications of the
resulting biaryl compound, which was isolated in 70% yield,
lead to a large range of biologically active compounds, such as
losartan, irbesartan, and valsartan.[20]
mixture of DMFand pyridine emerged as the best choice. The
cross-coupling was not efficient in pure DMF, acetonitrile,
THF, or other solvent mixtures, such as acetonitrile/pyridine.
Interestingly, in contrast to other cobalt-catalyzed reactions
developed recently, zinc (used instead of manganese) was not
able to reduce the phosphine-associated cobalt species in this
solvent mixture to form either the biaryl compound or the
organozinc species. Not surprisingly, the results depended on
the amount of manganese dust used. After a few attempts, we
found that the minimum manganese loading required for the
conversion of all aryl halides into the corresponding products
in optimal yields was 4 equivalents with respect to the limiting
halogenated aryl substrate. In contrast to palladium-catalyzed
reactions,[15] the more reactive aryl halide was used in excess
(2 equiv).
This novel method generally gives the expected cross-
coupling product in good yield with good selectivity, both
when an aryl bromide and an aryl iodide are used (Table 1,
entries 1–5) and with two aryl bromide substrates (Table 1,
entries 8–16). However, a significant difference in the reac-
tivity of the two substrates results in a decrease in the yield of
the product when an aryl bromide and an aryl iodide are used
(Table 1, entry 6).
Scheme 2. Synthesis of a key intermediate for the preparation of sartan
derivatives.
An array of aryl bromides and chlorides also underwent
the desired coupling reaction with one another (Table 1,
entries 17–22). Indeed, activated aryl chlorides can be cou-
pled successfully with non-activated aryl bromides and
activated aryl chlorides, albeit in modest yields in the latter
case. To the best of our knowledge, this is the first example of
a chemical cross-coupling reaction of two aryl chlorides
(Table 1, entries 23–29).
Recently, we reported that phenol derivatives react with
low-valent cobalt complexes with a 2,2’-bipyridine ligand
either to form an aryl zinc species[19d] or to form an
intermediate that undergoes conjugate addition to activated
olefins.[19c] Cobalt bromide associated with PPh3 is also a
suitable catalyst for the formation of an aryl cobalt species
upon treatment with an aryl triflate. The resulting organo-
metallic reagent can undergo cross-coupling with an aryl
bromide to provide a biaryl compound in very good yield
(Scheme 3). Efforts are currently under way towards the
comprehensive development of this aryl bromide–aryl triflate
coupling.
These results prompted us to attempt the synthesis of 2-(4-
tolyl)benzonitrile, a key intermediate in the synthesis of
Table 1: Cross-coupling of various aryl halides.[a]
Entry
FG1
X
FG2
Y
Ar1–Ar2
Ar2–Ar2
(Ar1)
(Ar2)
Yield[%] [b]
Yield[%] [c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
p-OMe
H
H
p-OMe
p-CO2Et
p-CO2Et
H
I
I
I
I
I
I
I
p-CO2Et
m-CO2Et
p-CN
p-CN
p-CN
OMe
OMe
H
p-CF3
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
77
70
8
19
10
10
15
60
40
13
14
12
15
3
46 [72][c]
54 [88][c]
57 [75][c]
[48][c]
[47][c]
73
p-OMe
p-CO2Et
p-CO2Et
p-CO2Et
p-CO2Et
m-CO2Et
o-CO2Et
p-CO2Et
p-CO2Et
p-OMe
p-NMe2
H
m-OMe
o-OMe
p-Me
p-CO2Me
p-CO2Me
p-CO2Me
p-CO2Me
m-CO2Me
o-CO2Me
p-SO2Me
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
68
63
p-F
p-CN
o-CN
56 [75][b]
60 [92][b]
60
Scheme 3. Cross-coupling of 4-trifluoromethanesulfonyloxybenzoic acid
ethyl ester with 4-bromoanisole.
p-OMe
p-OMe
m-OMe
o-OMe
p-CO2Me
p-CO2Me
p-CO2Me
p-CO2Me
p-CO2Me
o-CN
p-CN
o-CN
p-CF3
m-CF3
p-CF3
19
7
16
9
52
64
65
84
71
70
72
89
As a further test of the flexibility of this cobalt-catalyzed
synthesis of unsymmetrical biaryl compounds, we investigated
the suitability of heteroaromatic halides as substrates in
reactions with aryl bromides (Table 2). The cross-coupling of
aryl bromides with an electron-withdrawing or electron-
donating substituent with 4-chloroquinoline derivatives
afforded the desired products in good to excellent yields,
regardless of the position of the substituent (Table 2,
entries 3–6). However, moderate yields were observed with
6
12
12
12
3
10
13
6
24
32
24
13
17
72
47 [72][b]
66
60 [73][b]
50
3-bromothiophene and
a
2-chloropyridine derivative
(Table 2, entries 1 and 2). The lower yields can be rationalized
by the propensity of the heteroaromatic ring to act as a strong
ligand in the reaction medium for reduced cobalt (CoI or Co0)
and prevent it undergoing oxidative addition at a sufficient
rate. Studies are in progress towards the extension of these
63
71
60
p-CF3
p-CO2Me
[a] See Scheme 1. [b] Yield of the isolated product. [c] Yield determined
by GC.
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Chemie
Table 2: Cross-Coupling of aryl bromides with heteroaryl halides.
valuable compounds, including heterocyclic biaryl com-
pounds, in satisfactory to high yields under simple and mild
conditions. This catalytic process involves a simple, inexpen-
sive, and environmentally friendly cobalt halide salt and the
ligand triphenylphosphane. This combination affords an
extremely powerful catalyst for the coupling of a large variety
of aromatic reagents, which range from halides to triflates,
functionalized with reactive groups. Further studies are in
progress to elucidate the mechanism of this reaction and to
extend this process to vinylic and other heterocyclic systems.
Entry
ArBr
HetArX
Ar–HetAr
[%][a]
HetAr–HetAr
[%][b]
1
2
50
49
2
10
3
4
5
6
60
71
70
94
21
19
20
2
Experimental Section
General procedure: A mixture of CoBr2 (20 mol%; 220 mg, 1 mmol)
and PPh3 (20 mol%; 262 mg, 1 mmol) in DMF (6 mL) and pyridine
(1 mL) was stirred at room temperature for 15 min. Manganese
powder (20 mmol, 1.098 g) and the two aryl halides (5 mmol for less
reactive and 10 mmol for more reactive compounds) were added
successively to the resulting deep blue solution. The manganese dust
was activated with trifluoroacetic acid (100 mL), and the mixture was
stirred at 508C. The amounts of the corresponding heterocoupling,
homocoupling, and reduction products were measured by GC by
using an internal reference (dodecane, 200 mL). The reaction mixture
was poured into a solution of 2n HCl and extracted with diethyl ether.
The organic layer was washed with a saturated solution of NaCl, and
dried over MgSO4. Evaporation of the solvents and purification by
column chromatography on silica gel (pentane/ethyl acetate)
afforded the corresponding unsymmetrical biaryl compound, which
was characterized by 1H and 13C NMR spectroscopy and mass
spectrometry.
[a] Yieldof the isolatedproduct. [b] Yielddeterminedby GC.
cross-coupling reactions to other heteroaromatic halide sub-
strates.
The proposed mechanism in Scheme 4 is comparable to
that described for the nickel-catalyzed formation of biaryl
compounds, which is favored in the presence of excess
reductant.[21] A radical pathway can be ruled out; however,
the presence of a radical inhibitor (galvinoxyl free radical)
leads to similar results.
Received: September 24, 2007
Revised: October 29, 2007
Published online: February 7, 2008
À
Keywords: biaryls · C C coupling · cobalt ·
homogeneous catalysis · P ligands
.
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