Communications
DOI: 10.1002/anie.200801968
Grignard Reagents
Convenient Preparation of Polyfunctional Aryl Magnesium Reagents
by a Direct Magnesium Insertion in the Presence of LiCl**
Fabian M. Piller, Prasad Appukkuttan, Andrei Gavryushin, Matthew Helm, and Paul Knochel*
Dedicated to Professor Gernot Boche on the occasion of his 70th Birthday
The preparation of complex polyfunctional organometallic
reagents is of pivotal interest in organic synthesis.[1] Recently,
functionalized organomagnesium reagents have become
accessible through a halogen/magnesium exchange[2] or a
directed metalation.[3] During these studies it became appar-
ent that aryl magnesium halides are compatible with impor-
tant functional groups, such as cyano, nitro, ester, or even keto
groups.[4] This observation prompted us to reinvestigate the
direct insertion of magnesium metal into aromatic and
heterocyclic halides pioneered by Grignard.[5] Such a direct
insertion reaction has several advantages: 1) It is atom
economical,[6] 2) magnesium turnings are one of the cheapest
reagents for the formation of organometallic species,[7] and
3) the low toxicity of magnesium makes organomagnesium
compounds particularly environmentally friendly. A signifi-
cant drawback of this well-known reaction is that the insertion
of magnesium metal into an aryl halide requires harsh
conditions: This transformation usually only takes place at
30–608C,[8] which is a serious limitation if functionalized
substrates are used. In pioneering studies, Rieke[9] prepared
highly activated magnesium powder by the treatment of
MgCl2 with lithium in the presence of naphthalene
(20 mol%); this highly activated magnesium powder was
used for the preparation of some functionalized aryl magne-
sium reagents at À788C.[10] Recently, we found that aryl zinc
halides can be obtained readily from aryl halides by using zinc
powder in the presence of LiCl.[11] LiCl serves several
purposes: 1) It solubilizes the resulting organozinc compound
and thus provides a constantly clean metal surface, 2) it
promotes the initial electron transfer by the electrophilic
activation of the aromatic ring through complexation,[11b] and
3) the high ionic strength of LiCl solutions facilitates charge
separation and accelerates the metal insertion.[12]
Herein, we report the direct preparation of a range of new
functionalized aryl and heteroaryl magnesium species 2 from
the corresponding chlorides and bromides 1 with commercial
magnesium turnings or powder (1.5–2.5 equiv) in the pres-
ence of LiCl (1.25 equiv)[13] under mild conditions
(Scheme 1).[14]
Scheme 1. LiCl-promoted insertion of magnesium into aryl and hetero-
aryl chlorides and bromides. FG=functional group.
Thus, the addition of 2-chloro- or 2-bromobenzonitrile
(1.0 equiv) to magnesium turnings (2.5 equiv)[15] and LiCl
(1.25 equiv) in THF at 258C led to 2-cyanophenylmagnesium
chloride or bromide (2a) within 30–45 min, as indicated by an
iodometric titration. In the absence of LiCl, a reaction time of
approximately 5 h was required for the insertion, and
considerable decomposition was observed. A palladium-
catalyzed Negishi cross-coupling reaction[16] with 4-iodoani-
sole then furnished the arylated benzonitrile 3a in 73–85%
yield (Table 1, entry 1). This remarkable compatibility of a
2
À
cyano group with a C(sp ) Mg bond at 258C was not limited
to this substitution pattern. The magnesium insertion into
various chloro- and bromobenzonitriles proceeded similarly
(258C, 45 min–3h) and led, after palladium-catalyzed cross-
coupling,[16] to the expected substituted benzonitriles 3b and
3c in 69–83% yield (Table 1, entries 2 and 3).
[*] F. M. Piller, Dr. P. Appukkuttan, Dr. A. Gavryushin, Dr. M. Helm,
Prof. Dr. P. Knochel
Ludwig-Maximilians-Universität München
Department Chemie und Biochemie
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)892-1807-7680
E-mail: paul.knochel@cup.uni-muenchen.de
Benzotrifluorides react violently with magnesium dust (no
reaction occurs with magnesium turnings). Therefore, the
synthesis of such magnesium reagents is dangerous owing to
possible runaway reactions.[17] However, the use of magne-
sium turnings in the presence of LiCl led to a safe magnesium
insertion into 4-bromobenzotrifluoride at 08C to produce the
magnesium reagent 2d within 30 min. Palladium-catalyzed
Negishi cross-coupling[16] with ethyl 4-iodobenzoate then
furnished the biphenyl derivative 3d in 97% yield (Table 1,
entry 4). Even a sensitive pivalate group was tolerated: The
[**] We thank the Fonds der Chemischen Industrie, the Deutsche
Forschungsgemeinschaft (DFG), and SFB 749 for financial support.
P.A. and M.H. thank the Alexander von Humboldt Foundation for a
fellowship. We also thank Chemetall GmbH (Frankfurt), Evonik
Industries AG (Hanau), and BASF AG (Ludwigshafen) for generous
donations of chemicals.
Supporting information for this article is available on the WWW
6802
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 6802 –6806