Angewandte
Communications
Chemie
À
C H Activation
Hot Paper
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A General Strategy for the Nickel-Catalyzed C H Alkylation of
Anilines
Zhixiong Ruan+, Sebastian Lackner+, and Lutz Ackermann*
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Abstract: The C H alkylation of aniline derivatives with both
primary and secondary alkyl halides was achieved with
a versatile nickel catalyst of a vicinal diamine ligand. Step-
economic access to functionalized 2-pyrimidyl anilines, key
structural motifs in anticancer drugs, is thus provided. The
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C H functionalization proceeded through facile C H activa-
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tion and SET-type C X bond cleavage with the assistance of
a monodentate directing group, which could be removed in
a traceless fashion.
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M
ethods for the functionalization of unreactive C H bonds
have emerged as transformative tools in synthetic chemistry,[1]
with applications to natural product syntheses,[2] drug discov-
ery,[3] or material sciences,[4] among others. Recently, consid-
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erable progress has been accomplished in C H alkylations
with alkyl halides for site-selective arene functionalizations
by chelation assistance.[5] In spite of undisputed advances,
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these C H alkylations have been dominated by expensive
catalysts of precious 4d and 5d transition metals.[6] In
consideration of the beneficial features associated with the
use of naturally abundant 3d transition metals, focus has
recently shifted to less expensive base-metal catalysts for
C H activations.[7] In this regard, considerable advances have
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been realized with versatile nickel[8] catalysts for powerful
arene[9] functionalizations, with major contributions by the
groups of Chatani[10] and Ge,[11] us,[12] and Shi, among
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Figure 1. Nickel-catalyzed C H activation for the assembly of bioactive
2-pyrimidyl anilines.
others.[13] A variety of nickel-catalyzed C H functionalization
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methods have thus been established that have proven
instrumental for organic synthesis. Unfortunately, nickel-
catalyzed arene functionalization has thus far been limited to
electron-deficient carboxylic amides derived from the biden-
tate auxiliaries 8-aminoquinoline (Q) or (pyridin-2-yl)iso-
propyl (PIP) amine. Within our program on step-economic
chemistry, such as the anticancer drug Gleevec (Figure 1).[15]
Notable features of our general strategy include 1) an
unparalleled broad substrate scope with both primary and
secondary alkyl halides, 2) an unusual ligand design based on
a vicinal diamine, 3) a rare six-membered[16] nickelacycle as
[14]
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C H activation for sustainable synthesis,
addressed this restriction by developing a nickel-catalyzed
we have now
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a key intermediate of the C H activation process, 4) a
C H alkylation of synthetically useful aniline derivatives
removable[17] monodentate directing group, and 5) in contrast
to previous reports on carboxylic acid derivatives, nickel-
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bearing monodentate directing groups. Our methods enables
the direct preparation of ortho-functionalized 2-pyrimidyl
anilines, which are key structural motifs of numerous
bioactive compounds used in crop protection and medicinal
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catalyzed C H functionalizations on inherently electron-rich
anilines. Moreover, this approach complements our recently
developed remote meta-alkylation by ruthenium(II) cataly-
sis.[6c]
At the outset, we probed various reaction conditions for
[*] Z. Ruan,[+] S. Lackner,[+] Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Gçttingen
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the envisioned C H alkylation of aniline 1a, which bears
a monodentate N-pyrimidyl substituent, with the primary
alkyl halide 2a (Table 1; see also the Supporting Information,
Table S1).[18] Interestingly, reaction conditions previously
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
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employed for nickel-catalyzed C H alkylations assisted by
the bidentate Q auxiliary[10e] proved ineffective for the C H
[+] These authors contributed equally to this work.
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activation of aniline 1a, reflecting the challenging nature of
Supporting information for this article is available on the WWW
transformations with monodentate groups via six-membered
Angew. Chem. Int. Ed. 2016, 55, 3153 –3157
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3153