An efficient synthesis of biaryls via noncatalysed anionic coupling of an arylsodium with haloarenes

Article abstract of DOI:10.1016/j.tetlet.2004.10.123

Noncatalysed anionic coupling of an arylsodium with haloarenes readily gives access to valuable biaryl structures. Compared to aryllithiums, the reaction with arylsodiums is faster and can be performed at lower temperature. The coupling with substituted haloarenes proceeds often with a high degree of regioselectivity. Since only cheap and readily available substrates are involved, this coupling is particularly suited for the large scale synthesis of basic biaryl building blocks.

Full text of DOI:10.1016/j.tetlet.2004.10.123

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9331–9333
An efficient synthesis of biaryls via noncatalysed anionic coupling
of an arylsodium with haloarenes
Jean-Michel Becht, Arnaud Gissot, Alain Wagner* and Charles Mioskowski*
´ ´ `
Universite Louis Pasteur de Strasbourg, UMR 7514 associee au CNRS, Laboratoire de Synthese Bioorganique,
Faculte de Pharmacie, 74 Route du Rhin, 67401 Illkirch-Graffenstaden, France
´
Received 11 October 2004; revised 22 October 2004; accepted 22 October 2004
Abstract—Noncatalysed anionic coupling of an arylsodium with haloarenes readily gives access to valuable biaryl structures. Com-
pared to aryllithiums, the reaction with arylsodiums is faster and can be performed at lower temperature. The coupling with sub-
stituted haloarenes proceeds often with a high degree of regioselectivity. Since only cheap and readily available substrates are
involved, this coupling is particularly suited for the large scale synthesis of basic biaryl building blocks.
Ó 2004 Published by Elsevier Ltd.
Biaryls have found many applications in the fields of
biologically active molecules,1 molecular recognition,2
nonlinear optic and ligands for catalysts.3 They are gen-
erally synthesised in high yields and under mild reaction
conditions through Pd- or Ni-catalysed cross coupling
reactions.4 Yet, Pd-catalysed cross couplings require
organoboronic or organostannane reagents which are
often tedious to prepare. Pd- or Ni-catalysts are also
expensive and therefore quite unsuitable for the large
scale preparation of basic biaryl building blocks. In this
regard, we recently reported a straightforward noncata-
lysed anionic coupling of aryllithiums with haloarenes
starting from readily available materials.5 We have
shown that the reaction of aryllithiums with substituted
haloarenes proceeds often either via a regioselective aro-
matic nucleophilic substitution or via a regioselective
addition of the aryllithium to an aryne intermediate.5,6
We also demonstrated that arylsodiums offer an inter-
esting alternative to aryllithiums especially in the large
scale preparation of functionalised aromatic com-
pounds.7 Indeed, arylsodiums are obtained via an effi-
cient one-pot ortho-metallation procedure of aromatic
substrates with a sodiated organic base generated in situ
from chlorooctane and stoichiometric amounts of
metallic sodium.7 Herein, we describe the reactivity
and selectivity of the anionic coupling between an aryl-
sodium and haloarenes and show the advantages associ-
ated with the use of an arylsodium in place of an
aryllithium.
The reactivity of arylsodiums was studied using 2-sodio-
1,3-dimethoxybenzene 1 and chlorobenzene (X = Cl) as
model substrates (Table 1). Inspired by our previous
Table 1. Optimisation of the reaction conditions
Entry
X
Temp [°C]
Time [min]
60
2a [%]
3a [%]
1
Cl
65
—
75
20Cl
3
2
60
4246
Cl
F
2
2
0
0
10
10
65
78
—
—
Keywords: Biaryls; Metallation; Arylsodiums; Aromatic substitution;
Arynes.
4
a Isolated overall yields after flash-chromatography on silica gel.
Starting materials were recovered.
*
Corresponding authors. Tel.: +33 3 90 24 42 95; fax: +33 3 90 24 43
06; e-mail: alwag@aspirine.u-strasbg.fr
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.10.123

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J.-M. Becht et al. / Tetrahedron Letters 45 (2004) 9331–9333
results,5a 1,3-dimethoxybenzene was in situ ortho-metal-
lated with the tandem chlorooctane/micronised sodium
in THF at rt for 3h.7,8 Using the same reaction condi-
tions than for aryllithiums,5a chlorobenzene was added
dropwise at rt and the reaction mixture was heated at
65°C for 60min. We observed the exclusive formation
of the biphenyl 3 in 75% yield, resulting probably from
the reduction of 2 by the metallic sodium present in situ
(entry 1). This hypothesis is supported by the excellent
electron scavenging properties of biaryls.9 Noteworthy,
3 was never observed with aryllithiums.5a Interestingly,
we found that 2 and 3 were obtained in a 42:46 ratio
when the coupling was carried out at rt for 60min (entry
2). By lowering the reaction time to 10min, 2 was ob-
tained in an improved 65% yield (entry 3). This result
is in accordance with an early report of Ehrhart.10 In
this case, no biphenyl was detected and the remaining
starting material was recovered. Finally, an improved
78% yield was obtained by reacting 1 with fluorobenzene
(entry 4).6f,11
able to those obtained with aryllithiums. This anionic
coupling was successfully carried out on a one mole
scale without any noticeable loss in efficacy starting
from readily available, stable and inexpensive starting
materials. This method is therefore particularly suited
for the large scale preparation of basic biaryls.
Acknowledgements
`
We thank the Ministere de lÕEducation Nationale, de la
Recherche et de la Technologie for financial support of
this work through MENRT grants to J.-M.B. and A.G.
References and notes
1. (a) Chrysselis, M. C.; Rekka, E. A.; Kourounakis, P. N. J.
Med. Chem. 2000, 43, 609–612; (b) Hallock, Y. F.;
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1998, 8, 1729–1734; (c) Milton, J.; Slater, M. J.; Bird, A.
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Med. Chem. Lett. 1998, 8, 2623–2628; (d) Bringmann, G.;
Next, we studied the regioselectivity in the anionic
coupling of 1 with 2-, 3- and 4-chloroanisole (Table 2).
Contrary to the report of Ehrhart,10 we found that 2-
chloroanisole afforded the ortho-biaryl in 62% yield
and 84% regioselectivity, through a chelation-driven
aromatic nucleophilic substitution mechanism (entry
1).5a 3-Chloroanisole gave the expected meta-biaryl with
94% regioselectivity and 58% yield, through a regioselec-
tive addition of 1 to an aryne intermediate (entry 3).5a
Finally, 4-chloroanisole (entry 5) led to a 3:2mixture
of meta- and para-biaryls in 48% yield. Compared to
2-lithio-1,3-dimethoxybenzene,5a 1 afforded the desired
biaryls with comparable regioselectivities (entries 2, 4,
6).
Holenz, J.; Weirich, R.; Rubenacker, M.; Funke, C.
¨
Tetrahedron 1998, 54, 497–512.
2. Schulte, J. L.; Laschat, S.; Vill, V.; Nishikawa, E.;
Finkelmann, H.; Nimtz, M. Eur. J. Org. Chem. 1998,
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65, 3154–3159.
´
4. (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. Rev. 2002, 102, 1359–1469; (b) Metal-
Catalyzed, Cross Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; (c)
Heck, R. F. Palladium reagents in organic synthesis;
Academic: New York, 1985; (d) Tsuji, J. Palladium
Reagents and Catalysis, Innovations in Organic Synthesis;
Wiley: Chichester, UK, 1995.
In summary, we have reported a straightforward anionic
coupling of an arylsodium with haloarenes. Compared
to aryllithiums, the reaction with arylsodiums requires
both shorter reaction time and lower temperature. The
regioselectivities with substituted haloarenes are compar-
5. (a) Becht, J.-M.; Gissot, A.; Wagner, A.; Mioskowski, C.
Chem. Eur. J. 2003, 9, 3209–3215; (b) Becht, J.-M.;
Ngouela, S.; Wagner, A.; Mioskowski, C. Tetrahedron
2004, 60, 6853–6857.
6. (a) Hoffmann, R. W. Chem. Rev. 1965, 98, 222–234; (b)
Wittig, G.; Hoffmann, R. W. Chem. Ber. 1962, 2729–2734;
(c) Benkeser, R. A.; Severson, R. G. J. Am. Chem. Soc.
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Am. Chem. Soc. 1952, 74, 3011–3014; (e) Adejare, A.;
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Table 2. Reaction of 1 with 2-, 3- and 4-chloroanisole
´ `
7. Gissot, A.; Becht, J.-M.; Desmurs, J. R.; Pevere, V.;
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8. All the reactions were performed using a 30% dispersion of
micronised sodium in toluene from Aldrich, reference
47,226-3, cas number : [7440-23-5].
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11. Typical procedure for the synthesis of 2. A solution
of chlorooctane (5.90mmol, 1.00mL, 1.0equiv) in anhy-
drous THF (8mL) was added dropwise at rt under an
atmosphere of argon to a suspension of micronised sodium
(30% in toluene, 16.5mmol, 379mg, 2.8equiv) and 1,3-
Entry
R
M
orthoa
metaa
paraa
Yieldb [%]
62
[%]
[%]
[%]
1
-OMe22 Li
2-OMe
82 18
Na
—
84
80
6
16
—
3
4
5
6
3-OMe
3-OMe
4-OMe
4-OMe
Na
Li
94
>95
60
—
—
40
50
58
82
48
53
—
—
—
Na
Li
50
a Determined by GC analysis of the crude reaction mixture.
b Isolated overall yields after flash-chromatography on silica gel.
Starting materials were recovered.

J.-M. Becht et al. / Tetrahedron Letters 45 (2004) 9331–9333
9333
dimethoxybenzene (5.90mmol, 0.77mL, 1.0equiv) in anhy-
drous THF (5mL). The reaction initiated within 5min and
was characterised by a slight increase in temperature. The
remaining chlorooctane solution was then added dropwise
at constant temperature. The reaction mixture was stirred
for 3h at rt. A solution of fluorobenzene (2.65mmol,
0.25mL, 0.45equiv) in anhydrous THF (2mL) was added
dropwise at rt. After stirring for 10min at rt, the reaction
mixture was quenched by addition of H2O (10mL). The
aqueous layer was extracted twice with Et2O (total 30mL)
and the combined organic layers were dried over MgSO4,
filtered under vacuum and concentrated under reduced
pressure. The residue was purified by flash-chromatogra-
phy on silica gel to afford 2 in 78% yield.