TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6991–6993
CꢀC Bond activation with selective functionalization:
preparation of unsymmetrical biaryls from benzonitriles
Joseph A. Miller*
DSM Catalytica Pharmaceuticals, 430 Ferguson Drive, Mountain View, CA 94043-5272, USA
Received 3 August 2001; accepted 6 August 2001
Abstract—For the first time, benzonitriles have been shown to participate in metal-catalyzed cross coupling reactions via
activation of the CꢀCN bond. Thus, reaction of a benzonitrile with an aryl Grignard derivative in the presence of a Ni catalyst
can readily provide the corresponding unsymmetrical biaryl in high yield and with high selectivity. © 2001 Elsevier Science Ltd.
All rights reserved.
We recently described the synthesis of unsymmetrical
biaryls via Ni- and Pd-catalyzed cross coupling of aryl
cross coupling with benzonitriles can proceed selectively
without significant imine formation or homocoupled
side products. Thus, reaction of PhMgCl with LiOBu-t
in THF (60°C, 1 h), followed by treatment with 4-
methoxybenzonitrile and Cl Ni(PMe ) catalyst under
1
a
1b
zincs and aryl Grignard reagents with functionally
substituted aryl halides. For example, coupling of
PhZnCl with 4-chlorobenzonitrile takes place at room
temperature in the presence of a Ni(acac) /PPh catalyst
2
3 2
similar reaction conditions gave 4-methoxybiphenyl
(1.59 mmol) and 4-methoxybenzophenone imine (0.05
mmol), along with residual 4-methoxybenzonitrile (0.12
2
3
to afford 4-phenylbenzonitrile selectively and in high
yield. During the course of catalyst optimization for
7
this transformation, we found that use of Me P-based
mmol). By comparison, similar derivatization of the
3
Ni catalysts resulted in phenyl coupling occurring at
both the CꢀCl and CꢀCN bonds of 4-chlorobenzonitrile
to yield 4-chlorobiphenyl, 4-phenylbenzonitrile, p-ter-
PhMgCl with LiOEt prior to the coupling reaction gave
the imine side product in slightly higher amounts. On
the other hand, treatment of PhMgCl with LiSPh or the
lithium salt of BHT resulted in only trace amounts, if
any, of the corresponding imine being formed.
2
phenyl, and many other higher oligomers. We now
report that this heretofore unknown reactivity of
3
benzonitriles has been parlayed into an efficient syn-
2 3 2
Cl Ni(PMe ) catalyst
Ar CN+Ar MgX/‘‘LiZR’’ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢁAr ꢀAr
1
2
1
2
thesis of unsymmetrical biaryls via their Ni-catalyzed
coupling with aryl Grignard reagents (Eq. (1)).
(1)
Several features of this biaryl synthesis are worth not-
ing. First, use of 2 equiv. of aryl Grignard derivative
relative to the benzonitrile substrate generally provides
higher yields of biaryl product and lower amounts of
imine byproduct. Second, use of LiSPh as Grignard
modifier gives very high yields of biaryl products with
virtually no imine formation. In addition, this reagent
may be easily removed from the product mixture dur-
ing workup via base extraction. Third, essentially
equivalent results are obtained using an in situ-pre-
pared catalyst derived from Ni(acac) and PMe (Table
Reaction of 4-methoxybenzonitrile (2.0 mmol) with
phenylzinc chloride (3.0 mmol, prepared in situ from
4
PhMgCl and ZnCl ) and Cl Ni(PMe ) (5 mol%) in
2
2
3 2
THF at 60°C for 8 h gave a product mixture containing
-methoxybiphenyl (0.90 mmol), 4,4%-dimethoxy-
biphenyl (0.23 mmol), biphenyl (0.82 mmol), anisole
0.38 mmol), and residual 4-methoxybenzonitrile (0.09
4
(
6
mmol). Interestingly, substitution of PhMgCl for the
corresponding zinc reagent in the otherwise same reac-
tion gave negligible amounts of anisole and homocou-
pled side products, producing 4-methoxybiphenyl (1.42
mmol) and 4-methoxybenzophenone imine (0.36 mmol)
in the amounts indicated. If this Grignard reagent is
first treated with an alkoxide, however, its Ni-catalyzed
2
3
1, entry 2). Use of Me P is important to the success of
3
this cross coupling reaction; significantly lower yields
9
are obtained from substitution of other phosphines.
Fourth, use of sodium- or potassium t-butoxide pro-
vides cross coupling results similar to those derived
from use of LiOBu-t as Grignard modifier. Finally,
from a preparative standpoint, the small amount of imine
*
0
Fax: 650-254-0153; e-mail: joe.miller@dsm.com
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01476-9