Angewandte
Chemie
DOI: 10.1002/anie.201202797
Cross-Coupling
Iron-Catalyzed Alkyl–Alkyl Suzuki–Miyaura Coupling**
Takuji Hatakeyama, Toru Hashimoto, Kalum K. A. D. S. Kathriarachchi, Takeshi Zenmyo,
Hirofumi Seike, and Masaharu Nakamura*
The Suzuki–Miyaura coupling reaction is one of the most
practical and reliable synthetic reactions for the production of
functional molecules, such as drug/agrochemical intermedi-
ates and organic electronic materials.[1] Although palladium,
nickel, and iron can catalyze the Suzuki–Miyaura coupling
reaction, catalysts based on the nontoxic and most abundant
transition metal, iron, have not been studied extensively.
Despite the renaissance of iron-catalyzed cross-coupling
reactions,[2–4] there are only a few reports on iron-catalyzed
Suzuki–Miyaura coupling. Although three iron-catalyzed
biaryl cross-coupling reactions have been reported, two
have been retracted.[5] Bedfordꢀs research group and our
group have reported iron-catalyzed Suzuki–Miyaura coupling
reactions of aryl- or alkenylboron reagents with the aid of
iron-bisphosphine catalysts.[6] Herein we report the first iron-
catalyzed alkyl–alkyl Suzuki–Miyaura coupling reaction
wherein alkylboron compounds and non-activated alkyl
halides are cross-coupled in high yields with a catalyst
combination of an iron salt and a bisphosphine with a large
bite angle, Xantphos (9,9-dimethyl-4,5-bis(diphenylphosphi-
no)xanthene), thereby providing a new method for the most
challenging combination of cross-coupling partners.[7]
rizes the screening results of various iron salts, ligands, and
activators used in the coupling reaction between tri(n-
butyl)borane and 7-bromoheptanenitrile (1; Scheme 1). As
shown in entry 1 of Table 1, the optimum yield (82%) of the
desired butylation product 3 was achieved by using a stoichio-
Scheme 1. Iron-catalyzed Suzuki–Miyaura coupling between 1 and 2
(R=alkyl).
metric amount of iPrMgCl in the presence of [Fe(acac)3]
(3 mol%) and Xantphos (6 mol%), previously reported as
the unselective catalyst combination for cross-coupling of
alkyl Grignard reagents and alkyl halides.[7e] The cyano group
remained untouched under the reaction conditions, thereby
reflecting the quantitative formation of magnesium tetraal-
kylborate 2.[9] The other secondary alkyl Grignard reagents
also gave the desired product 3 but in slightly lower yields.[10]
The reaction with nBuMgCl gave a high yield (85%) although
it was inapplicable to other trialkylboranes (Table 1,
entry 2).[11] Notably, the reaction with nBuLi did not give
any product (Table 1, entry 3). We confirmed the formation of
lithium tetrabutylborate ([nBu4B][Li]),[9] suggesting that the
lithium borate is stable and unreactive toward the trans-
metalation step. Interestingly, the reaction with MeMgBr
gave methylation product 4 (73%) rather than 3 (8%,
Table 1, entry 4). These results clearly show that the transfer
rate of alkyl groups from the boron center to the iron center
decreased in the order of methyl > primary alkyl > secondary
alkyl group.[12] The reaction of a magnesium borate prepared
with TMSCH2MgBr did not give 3 but gave heptanenitrile 5
and hept-6-enenitrile 6 in 19% and 49% yields, respectively,
thus suggesting the selective transfer of the TMSCH2 group
from the borate [nBu3(TMSCH2)B][MgCl] (Table 1,
entry 5).[13] Similarly, the reaction with tBuMgCl did not
give 3 but gave 5 and 6 (19% and 12% yields, respectively,
Table 1, entry 6). NMR spectroscopy studies indicate that
tBuMgCl partially reacts with nBu3B to give a small amount
of the corresponding borate ([nBu3tBuB][MgCl]).[9] We
assumed that the reaction with the remaining tBuMgCl took
place prior to the coupling reaction with the activated alkyl
boron compound, leading to the production of 5 and 6. Note
During our studies on Suzuki–Miyaura coupling under
iron catalysis,[6b,c] we identified transmetalation in the cata-
lytic cycle as a critical step, requiring combinations of
a carbanionic activator and a Lewis acidic metal salt. There-
fore, to accomplish alkyl–alkyl coupling, we carefully
screened organoboron reagents and their activators and
found that iso-propylmagnesium chloride (iPrMgCl) acts as
an efficient activator for trialkylboranes.[8] Table 1 summa-
[*] Dr. T. Hatakeyama, T. Hashimoto, Dr. K. K. A. D. S. Kathriarachchi,
T. Zenmyo, Dr. H. Seike, Prof. M. Nakamura
International Research Center for Elements Science
Institute for Chemical Research
Kyoto University
Uji, Kyoto 611-0011 (Japan)
E-mail: masaharu@scl.kyoto-u.ac.jp
Dr. T. Hatakeyama
PRESTO (Japan) Science and Technology Agency (Japan)
[**] This work was funded by the Japan Society for the Promotion of
Science (JSPS) through the “Funding Program for Next Generation
World-Leading Researchers (NEXT Program),” initiated by the
Council for Science and Technology Policy (CSTP). Financial
support from Tosoh Finechem Corporation is also acknowledged.
The synchrotron X-ray absorption measurement was performed at
the BL14B2 in the SPring-8 with the approval of JASRI (2009A1848,
2009B1783, 2011B1945, 2012A1595). M.N. thanks Prof. K. Fukase
and Dr. Y. Fujimoto for valuable discussion on the coupling reaction
with long-chain alkyl substrates.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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