Angewandte
Chemie
DOI: 10.1002/anie.200803730
Synthetic Methods
Radical Catalysis of Kumada Cross-Coupling Reactions Using
Functionalized Grignard Reagents**
Georg Manolikakes and Paul Knochel*
In memory of Jay K. Kochi
The Kumada cross-coupling allows direct Pd-catalyzed
carbon–carbon bond formation between unsaturated halides
and organomagnesium reagents (without further transmeta-
lation steps)[1,2] and is therefore a highly atom-economical
cross-coupling reaction.[3] Most of these cross-couplings
follow a standard mechanism (oxidative addition, ligand
exchange, reductive elimination),[4] although an alternative
pathway is possible, as was shown by Kambe et al. for
Kumada cross-couplings in the presence of dienes.[5] Recently,
Buchwald and co-workers have shown that when an appro-
priate phosphine ligand[6] and low temperatures are used,
functionalized aryl and heteroaryl iodides undergo a smooth
cross-coupling with functionalized arylmagnesium halides.[7,8]
Herein, we wish to report a new radical catalysis which
makes it possible to perform a Kumada cross-coupling using
aryl bromides at room temperature within a few minutes in
the presence of an alkyl iodide. In preliminary experiments
Scheme 1. Accelerating effect of iPrI in the Kumada coupling reaction.
[a] Conversion determined by GC using tetradecane as the internal
standard. [b] Yield of isolated, analytically pure product.
we observed that the reaction of PhMgCl (1a), prepared by
the insertion of magnesium in the presence of lithium
chloride,[9] reacts slowly with 4-bromoanisole (2a) in the
presence of Pd(OAc)2 and S-Phos (S-Phos = 2-dicyclohexyl-
phosphanyl-2’,6’dimethoxyphenyl)[10] or PEPPSI (PEPPSI =
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloro-
pyridyl)palladium(II) dichloride),[11] leading to 4-methoxybi-
phenyl (3a). A conversion of only 8% was observed at 08C
after 15 minutes. In strong contrast, the reaction of PhMgCl
(1a), prepared by I/Mg exchange using iPrMgCl·LiCl,[12]
provided 3a with 82% conversion after 15 minutes
(Scheme 1, top). This difference was attributed to the
presence of 1.1 equivalents of iPrI obtained as a side product
in the I/Mg exchange. Thus, the cross-coupling of arylmagne-
sium halide 1b, prepared from 3-iodobenzotrifluoride (4a) by
I/Mg exchange with the bromoaryl ketone 2b, furnished the
functionalized biphenyl 3b within 5 min at 258C as a single
product (87% yield, Scheme 1, bottom). Interestingly, when
the Grignard reagent 1b was prepared from the correspond-
ing aryl bromide 4b by Br/Mg exchange, no acceleration was
observed and the biphenyl 3b was isolated in only 46% yield
after 1 hour.[13] This demonstrates the accelerating effect of
iPrI. We have found that a range of alkyl iodides such as MeI,
1-iodoadamantane, neopentyl iodide, and cyclohexyl iodide
give similar rate enhancement.[14] In subsequent experiments,
however, we used isopropyl iodide (1.1–1.2 equiv),[15] since it
is produced in the I/Mg exchange and since the above-
mentioned iodides displayed comparable catalytic activity.
As shown in the bottom equation of Scheme 1, the
presence of iPrI considerably enhances the functional-group
tolerance of this Kumada cross-coupling. By using this
procedure, a range of functionalized arylmagnesium species
were efficiently coupled with functionalized aryl and hetero-
aryl bromides. Thus, the reaction of 3-trifluoromethylphenyl-
magnesium chloride (1b, 1.1 equiv) with 2-bromobenzonitrile
(2c, 1.0 equiv) in the presence of PEPPSI (2 mol%) provided
the coupling product 3c within 5 minutes at 258C in 92%
yield (Table 1, entry 1). Interestingly, this method can be
extended to functionalized arylmagnesium reagents having
low stability at room temperature. Thus, the ester-substituted
organomagnesium compound 1c (1.1 equiv),[16] prepared by I/
Mg exchange at À208C,[11] reacted with the functionalized
bromobenzenes 2d and 2e (1.0 equiv) in the presence of
Pd(OAc)2 (2 mol%) and S-Phos (3 mol%) or PEPPSI
(2 mol%)[17] to afford the biphenyls 3d and 3e in 82 and
[*] G. Manolikakes, Prof. Dr. P. Knochel
Ludwig-Maximilians-Universitꢀt Mꢁnchen, Department Chemie
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)892-1807-7680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the Deutsche
Forschungsgemeinschaft (DFG), and SFB 749 for financial support.
We also thank Chemetall GmbH (Frankfurt), Evonik GmbH
(Hanau), W. C. Heraeus GmbH (Hanau), and BASF AG (Ludwig-
shafen) for generous gifts of chemicals.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2009, 48, 205 –209
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
205