Angewandte
Chemie
DOI: 10.1002/anie.201210235
Cross-Coupling
Ligand-Accelerated Iron- and Cobalt-Catalyzed Cross-Coupling
Reactions between N-Heteroaryl Halides and Aryl Magnesium
Reagents**
Olesya M. Kuzmina, Andreas K. Steib, John T. Markiewicz, Dietmar Flubacher, and
Paul Knochel*
Transition-metal-catalyzed cross-coupling reactions are one
line can be used as a ligand to promote Fe-catalyzed cross-
À
of the most used C C bond-forming reactions in the
couplings in improved yield and reaction rate. Herein, we
report the scope of this new ligand-accelerated cross-coupling
and its extension from Fe catalysis to Co catalysis.
Thus, whereas the cross-coupling of 2-chloroquinoline
(1a) with PhMgCl (2a) in the presence of 3% FeBr3 in
tBuOMe/THF is completed at 258C in 5 min (producing the
phenylated product 3a in 90% yield; Scheme 1), the cross-
production of pharmaceuticals and agrochemicals.[1] Avariety
of Pd-catalyzed coupling reactions (for example, Suzuki,
Negishi, Kumada cross-coupling) dominate this field because
a large arsenal of bulky phosphine ligands lend generality to
these reactions, and virtually any cross-coupling can be
achieved by selecting the appropriate ligand.[2] However,
the use of Pd has some drawbacks, as its price and toxicity
(LD50 (PdCl2, rabbit) 18.6 mgkgÀ1) hamper its use in indus-
trial applications. Cross-coupling reactions employing alter-
native transition metals, such as Fe and Co, are a viable
alternative.[3] Recently, there has been much progress in Fe-
catalyzed coupling reactions between C(sp2) and C(sp3)
centers.[4] However, the formation of C(sp ) C(sp ) bonds
remains problematic because of homocoupling side reac-
tions.[5] Nakamura and co-workers have shown that N-
heterocyclic carbene (NHC) ligands can suppress the homo-
coupling reaction to less than 5% in conjunction with Fe- and
Co-catalyzed aryl–aryl cross-coupling reactions.[6–8] Although
this is a large improvement, NHC ligands are expensive, and
even under optimized conditions, elevated temperatures and
long reaction times are often required to complete the
coupling reaction. Clearly, there is a need to discover new
classes of ligands for Fe catalysis. Previously, we have
reported that the use of tBuOMe as a co-solvent leads to
a dramatic reduction of homocoupling and enables Fe-
catalyzed aryl–heteroaryl coupling reactions to proceed at
room temperature.[9] During the course of our work, we have
made the serendipitous discovery that quinoline or isoquino-
2
2
À
Scheme 1. Rate acceleration and improved yield of Fe-catalyzed cross-
couplings in the presence of quinoline.
coupling of the 2-chloropyrimidine 1b under the same
reaction conditions requires 2 h for completion and provides
the arylated pyrimidine 3b in 76% yield. However, carrying
out the same reaction in the presence of 7 mol% quinoline
leads to a reaction completion within 5 min (about 50 times
faster) and an increased yield of 3b (89% yield of isolated
product; Scheme 1).
Prompted by these results, we screened other ligands. We
noted that NMP and TMEDA, which have been traditionally
used for Fe catalysis, had a detrimental effect under our
conditions (compare entries 1–4 of Table 1).[4c,l] We system-
atically examined substituted quinolines. Erosion of the rate
enhancement occurs when a methyl group is attached to
either the 2- or 8-position (entries 5 and 6), and only a slight
improvement can be seen when a methyl group is placed at
position 6 (entry 7). Benzo[h]quinoline and acridine even led
to a decrease in yield (entries 8 and 9). Electron-donating
groups have a positive effect, whereas electron-withdrawing
groups decrease the catalytic activity of the quinoline core
(compare entries 10–14). Finally, we discovered that isoqui-
noline gave the best results with a 92% yield after 15 min
(entry 15). 1-Methyl isoquinoline had a similar catalytic
[*] Dipl.-Chem. O. M. Kuzmina, Dipl.-Chem. A. K. Steib,
Dr. J. T. Markiewicz, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilian-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Dr. D. Flubacher
Novartis Pharma AG
Novartis Campus, 4056 Basel (Switzerland)
[**] The research leading to these results has received funding from the
European Research Council under the European Community’s
Seventh Framework Programme (FP7/2007-2013) ERC Grant
Agreement No. 227763. We thank the Fonds der Chemischen
Industrie for financial support and are grateful to BASF AG, and
Rockwood Lithium GmbH for the generous gift of chemicals.
O.M.K. thanks the Novartis Pharma AG for financial support.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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