Angewandte
Chemie
DOI: 10.1002/anie.201106825
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C H Functionalization
Nickel- and Cobalt-Catalyzed Direct Alkylation of Azoles with
N-Tosylhydrazones Bearing Unactivated Alkyl Groups**
Tomoyuki Yao, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
The functionalization of heteroaromatic compounds has
received much attention from synthetic chemists because
heteroaromatic cores are ubiquitously found in pharmaceut-
icals, biologically active compounds, and functional materi-
als.[1] The transition-metal-catalyzed cross-coupling reaction
of heteroaryl halides or organometallic compounds is a
powerful and reliable strategy to obtain functionalized
heteroaromatic compounds.[2] On the other hand, recent
Our working hypothesis is inspired by our previous
success in the nickel-catalyzed direct alkylation of azoles
with primary alkyl halides[4f] and recent developments in the
use of N-tosylhydrazones in cross-coupling reactions
(Scheme 1).[9] An initial base-assisted direct nickelation of a
heteroarene[10] provides a heteroaryl nickel species A. On the
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advances in the metal-mediated C H functionalization pro-
vide a complementary and potentially more efficient method-
ology to heteroaromatic compounds, because additional
preactivation steps, such as the halogenation or stoichiometric
metalation of the parent heterocycles, to prepare the coupling
reagents can be avoided. Direct arylation, alkenylation, and
alkynylation have been widely explored.[3] However, the
alkylation reaction is relatively challenging,[4,5] despite the
fact that alkyl chains attached to aromatic nuclei are known to
generally enhance lipophilicity and solubility, and to tune the
aromatic p-stacking and p-conjugation of the corresponding
oligomers and polymers. In particular, direct introduction of
secondary alkyl side chains into heteroarenes remains elusive,
probably because of the difficulty in controlling an undesired
b-H elimination of an alkyl metal intermediate. A few
successful examples with alkyl halides are still restricted in
substrate scope to cyclic frameworks, such as cyclohexane and
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Scheme 1. Working hypothesis. HetAr=heteroaryl, Ts=p-toluenesul-
fonyl.
other hand, the N-tosylhydrazone is converted in situ to the
corresponding diazo compound B with concomitant elimina-
tion of the Ts group by the action of a base. Subsequent
decomposition of B by interaction with A[11] and 1,2 migration
of the heteroaryl group from Ni to the a carbon center afford
an alkyl nickel intermediate C. If protonation or ligand
cyclopentane.[4b,g,6]
A
metal-catalyzed C H insertion
approach with alkenes,[7] and a copper-catalyzed alkylation
with N-tosylhydrazones, which has very recently been
reported by Wang and co-workers (see below),[8] appear to
be good alternatives, however, these processes are limited to
activated systems, thus only enabling benzylation and allyla-
tion. Therefore, further developments for more general
alkylation methodologies are strongly desired. Herein, we
report nickel- and cobalt-based catalysts for the direct
alkylation of azoles with N-tosylhydrazones. The catalytic
systems are compatible with various unactivated secondary
alkyl groups, including cyclic and even more challenging
acyclic alkyl groups.
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exchange with the C H bond of the starting heteroarene
occurred much faster than the conceivable b-H elimination,
the desired heterocycles, which bear the secondary alkyl side
chain, would be obtained. In accordance with the above-
mentioned assumption, our study commenced with benzox-
azole (1a) and N-tosylhydrazone 2a, which was derived from
cyclohexanone as the model substrate (Table 1). In an early
experiment, treatment of 1a with 2a in the presence of
LiOtBu and a NiCl2/1,10-phenanthroline (phen) catalyst in
1,4-dioxane at 1008C gave 2-cyclohexylbenzoxazole (3aa) in
45% yield (determined by GC analysis; Table 1, entry 1).
With this intriguing result in hand, we investigated other first
transition elements. While the use of FeCl3 instead of NiCl2
was detrimental (Table 1, entry 2), CoCl2 catalyzed the
reaction with moderate efficiency (entry 3). In the course of
this study, Wang and co-workers reported a relevant CuI-
catalyzed coupling of azoles with N-tosylhydrazones on the
basis of a similar concept.[8] However, they reported only
formation of benzylated and allylated products. Indeed, under
copper-based conditions, only a trace amount of 3aa was
detected (Table 1, entry 4).[12] After additional evaluations of
nickel salts, ligands, and reaction stoichiometry (Table 1,
entries 5–12), a combination of NiBr2 and phen, and a 2:1
[*] T. Yao, Dr. K. Hirano, Prof. Dr. T. Satoh, Prof. Dr. M. Miura
Department of Applied Chemistry, Faculty of Engineering
Osaka University, Suita, Osaka 565-0871 (Japan)
E-mail: k_hirano@chem.eng.osaka-u.ac.jp
[**] This work was partly supported by Grants-in-Aid from the Ministry
of Education, Culture, Sports, Science, and Technology (Japan).
K.H. acknowledges the Kansai Research Foundation for the
Promotion of Science.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 775 –779
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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