5646
S. P. Singh et al. / Tetrahedron Letters 50 (2009) 5644–5646
Several combinations of functionalized unactivated alkyl bro-
Acknowledgments
mides, iodide, and tosylate with alkyl and phenyl Grignard
reagents were examined. As the polar functionalities, amide, ester,
ketone as well as acetal and ether groups were chosen and the
results are summarized in Table 1.
S.P.S. expresses his sincere thanks to the Global Education and
Research Center for Bio-Environmental Chemistry at Osaka Univer-
sity for the financial support.
Amide groups react only slowly with Grignard reagents3 and
haloalkanamides gave good to excellent yields of cross-coupling
products by the reaction with primary and secondary alkyl Grig-
nard reagents in the presence of a Ni salt and 1,3-butadiene (runs
1–3, 5–8, 10).4 GC analysis of these resulting mixtures showed
complete consumption of starting materials and no other large
peaks were observed except desired products. Isoprene also
showed a remarkable activity as a ligand precursor (run 4). Under
identical conditions, phenyl Grignard reagent afforded a moderate
yield (51%) of the desired product and 13% of biphenyl as a by-
product with recovery of 22% of the halide used (run 9). Bromides
and tosylate carrying tert-butyl or isopropyl ester groups also gave
alkylated products in good yields with butyl or isopropyl Grignard
reagents (runs 11–15). Unfortunately, reaction of isopropyl
6-bromohexanoic acid ester with secondary and tertiary butyl
Grignard reagent did not afford cross-coupling products.5 The
corresponding ethyl ester reacted with butyl Grignard reagent to
afford only 11% yield of the coupling product with 1 mol % of Ni
catalyst, probably due to the relatively fast direct addition of the
Grignard reagent at the carbonyl carbon. However, this problem
was overcome by using 5 mol % of NiCl2 to accelerate the coupling
process (runs 16 and 17). When an iodide was employed, even
ketone group can tolerate the present catalytic conditions to fur-
nish the cross-coupling predominantly (run 18). Under the same
conditions, acetal and ether groups did not affect the present
cross-coupling reaction (runs 19–21).
As demonstrated above, the present nickel/butadiene catalyst
system can successfully be applied to direct cross-coupling reac-
tion of primary and secondary alkyl and phenyl Grignard reagents
with functionalized alkyl halides and tosylate. This compatibility
arises from high catalytic activity of nickelate complexes as nucle-
ophiles toward sp3 carbons and the subsequent rapid reductive
elimination of the resulting Ni(IV) intermediates.2
Knochel and co-workers have pioneered the development of
methods for the preparation of functionalized aryl or vinyl Grig-
nard reagents and applied directly, or via transmetallation to more
stable organometallic reagents, to cross-coupling reaction.6
Although several interesting reactions have been reported to cou-
ple functionalized organic halides with Grignard reagents,7 only
three catalytic systems of alkyl–alkyl cross-coupling have been
developed by the aid of N-based pincer ligands or excess NMP.8
The present reaction proceeds with only 1–5 mol % of NiCl2 and
20 mol % of a 1,3-butadiene as an additive without such hetero-
atom ligands, and would provide a simple, convenient, and practi-
cal method for construction of carbon chains in organic synthesis.
References and notes
1. (a) For recent reviews, see for example: Catalytic Components for Coupling
Reactions; Molander, G. A., Ed.; John Wiley & Sons Ltd: West Sussex, 2008; (b)
Lipshutz, B. H.; Ghorai, S. Aldrichim. Acta 2008, 41, 57–72; (c) Negishi, E.-I.;
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4. A typical experiment is as follows. A dry nitrogen-flushed 50-mL flask equipped
with a stirring bar and a rubber septum was charged with anhydrous THF
(0.3 mL), 6-bromo-N,N-diethylhexanamide (250.18 mg, 1 mmol) and cooled to
ꢀ78 °C. Then nBuMgCl (0.6 mL, 1.82 M in THF, 1.1 mmol) (slowly) and 1,3-
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extracted with ether (3 ꢁ 15 mL). The combined organic layers were dried with
MgSO4, and evaporated to give
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