Communication
Abstract: A general catalytic protocol for the a-arylation
of aryl ketones has been developed. It involves the use of
a preformed, bench-stable Pd–N-heterocyclic carbene pre-
catalyst bearing IHept as an ancillary ligand, and allows
the coupling of various functionalized coupling partners
at very low catalyst loading. Careful choice of the solvent/
base system was crucial to obtain optimum catalyst per-
formance. The pre-catalyst was also successfully tested in
the synthesis of an industrially relevant compound.
Palladium-catalyzed bond-forming reactions are nowadays one
of the most common tools synthetic chemists employ, in in-
dustry as well as in academia.[1] Enormous resources have been
directed into the development of efficient methodologies to
perform this class of transformations in an environmentally
and economically advantageous
Figure 1. Mechanism of the ketone arylation reaction according to Hart-
wig.[4a,c]
manner. In the last two decades,
the design of electron-rich,
bulky ligands, has addressed
many challenges in this field, al-
lowing the coupling of highly
unactivated coupling partners
under mild conditions and using
low catalyst loadings.[2] The a-ar-
ylation of ketones, simultane-
ously disclosed by Buchwald
and Hartwig,[3] is potentially one
of the most powerful and atom-
economical CÀC bond formation
as it uses simple and widely
available substrates and gener-
Figure 2. Examples of Pd pre-catalysts for the a-arylation of carbonyl compounds.
ates a minimum amount of side
products; the general reaction
mechanism is depicted in Figure 1.[4]
Despite these important advances, only one example of
such methodology employing low catalyst loading (<0.1%) is
reported using bromides,[5d] and one single example of an ary-
lation reaction is reported using chlorides at low catalyst loa-
ding.[5g] Surprisingly, none of the “new generation” Pd–N-heter-
ocyclic carbene (NHC)-based pre-catalysts reported so far[10]
have been tested in this interesting reaction. We disclose
herein the first example of ketone arylation employing 200–
500 ppm catalyst loading for most cases examined, by using
the recently developed [Pd(ITent)] class of pre-catalysts
(Figure 3).[11]
Starting from the late years of the last millennium, our
group and many others devoted their efforts to the develop-
ment of catalysts for the a-arylation of ketones and other car-
bonyl-containing compounds; examples of which are shown in
Figure 2.[5,7] Mechanistic aspects of this reaction were studied
by Hartwig and co-workers,[5a,6a] and the latest advances in the
field were reported by the Stradiotto group, which developed
highly efficient methods for the use of challenging sub-
strates.[8] The recent development of useful synthetic strategies
involving this reaction as the key step further underlines the
importance of this class of couplings.[7b,9]
Our study began with the testing of various pre-catalysts in
the reaction between acetophenone and 4-chlorotoluene: IPr*-
based pre-catalysts (IPr*=1,3-bis(2,6-bis(diphenylmethyl)-4-
methylphenyl)imidazo-2-ylidene) showed poor catalytic activity
at low catalyst loading, whereas IPent (1,3-bis(2,6-di(pentan-4-
yl)phenyl)imidazo-2-ylidene) gave high conversions. Comparing
the entire ITent family, only [Pd(acac)Cl(IHept)] (2) (IHept: 1,3-
bis(2,6-di(heptan-4-yl)phenyl)imidazo-2-ylidene) was catalytical-
ly active at 100 ppm (see the Supporting Information). Notably,
as already reported, this pre-catalyst also proved to be the
most active in the Buchwald–Hartwig reaction.[11] The optimiza-
[a] E. Marelli, Dr. M. Corpet, S. R. Davies, Prof. Dr. S. P. Nolan
EaStCHEM, School of Chemistry, University of St Andrews
North Haugh, St Andrews, Fife, KY16 9ST (UK)
[b] Prof. Dr. S. P. Nolan
Chemistry Department, College of Science, King Saud University
Riyadh 11451 (Saudi Arabia)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404900.
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Chem. Eur. J. 2014, 20, 1 – 6
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!