DOI: 10.1002/chem.201100909
Nickel-Catalyzed Cross-Coupling of Aryl Bromides with Tertiary Grignard
Reagents Utilizing Donor-Functionalized N-Heterocyclic Carbenes (NHCs)
Claudia Lohre, Thomas Drçge, Congyang Wang, and Frank Glorius*[a]
Metal-catalyzed cross-coupling reactions are among the
most important transformations in organic synthesis, allow-
ing the efficient construction of complex structures from
simpler, readily available building blocks.[1] Many applica-
tions in large and small-scale synthesis can be found in dif-
ferent areas such as agrochemicals, pharmaceuticals and
supramolecular chemistry. Whereas the coupling of sp2-hy-
bridized carbon atoms in either reaction partner is well es-
tablished, the use of CACTHNUTRGNEUNG
(sp3)-hybridized substrates presents
some challenges.[2] Catalytic cross-coupling of sterically hin-
dered tertiary alkyl substrates is especially difficult, general-
ly resulting in low yields, and thus, only few reports exist.[2–7]
A big challenge in this field is not only to get the required
level of reactivity, but also to overcome competing pathways
like b-hydride elimination, hydrodehalogenation or isomeri-
zation.[8]
Scheme 1. Challenging cross-couplings of tertiary alkyl Grignard re-
agents.
In an early report, Kumada et al.[4] have shown a nickel-
catalyzed cross-coupling of tertiary alkyl Grignard reagents
with b-bromostyrene. Cahiez et al.[5] could obtain the same
product in similar yield using an Fe catalyst, however, b-hy-
dride elimination became competitive. Furthermore, the
group of Bell used a stoichiometric amount of a copper(I)
salt to alkylate pyridines and quinolines.[6] Recently, Hinter-
mann et al. reported an impressive selective copper-cata-
lyzed cross-coupling of tertiary Grignard reagents of certain
azacyclic electrophiles, but this protocol is limited to chlor-
oazacycles such as pyridines, pyrimidines, quinazolines and
quinoxalines (Scheme 1).[7]
A general method for the coupling of tertiary alkyl metal
reagents with aryl halides would be very desirable. Due to
their attractive properties[9] N-heterocyclic carbene (NHC)
ligands have found widespread applications in organometal-
lic chemistry and transition-metal catalysis.[10] NHCs have al-
ready been successfully applied in Kumada–Corriu–
Tamao[11] reactions.[12] Herein we report the Kumada–
Corriu–Tamao-type nickel-catalyzed cross-coupling of aryl
halides with tertiary Grignard reagents. This practical ad-
vance provides selective access to highly substituted tertiary
alkyl benzene derivatives, an interesting class of chemical
compounds. The coupling of 4-bromobiphenyl with
tBuMgCl was used as the initial model system. The high re-
activity of Grignard reagents is desirable in this coupling, as
is their easy accessibility. Functional group compatibility,
often a problem in reactions of Grignard reagents, can be
expanded, if sufficiently mild reaction conditions can be re-
alized. Using NHC ligands, we tried to prevent the forma-
tion of undesired side products. Thus, the sterically demand-
ing easily synthesized ligand precursor L1, IAd·HBF4, was
selected for the first screening reactions.
Screening of L1 together with various commercial Ni, Pd
and Cu sources showed [NiACTHNUTRGNE(UNG acac)2] to be a uniquely suited
metal precursor, with all other complexes giving lower or no
catalytic activity (Table 1, entries 1 and 3). Naturally, no
product was obtained in the absence of any metal source
(entry 2). In addition, different solvents, bases and reaction
temperatures were evaluated.[13] The reaction can be suc-
cessfully run at 08C, and changing the temperature to +40
or À788C did lower the yield significantly (entries 4 and
5).[13] The solvent played an important role, non-coordinat-
ing solvents only afforded poor or no conversion. On the
contrary, ethers, especially THF, were suitable (entries 7, 14,
16). Without an NHC ligand, the desired product could be
obtained in decreased yield and selectivity after rather long
reaction time (entry 8).[13] For many other substrates this
effect was even more pronounced, as became obvious upon
studying the substrate scope of this reaction (see below).
[a] C. Lohre, T. Drçge, Dr. C. Wang, Prof. Dr. F. Glorius
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Organisch-Chemisches Institut, Corrensstrasse 40
48149 Mꢁnster (Germany)
Fax : (+49)251-833-3202
Supporting information for this article is available on the WWW
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Chem. Eur. J. 2011, 17, 6052 – 6055