ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Iron-Catalyzed Oxidative C(3)ꢀH
Functionalization of Amines
Noriaki Takasu,† Kounosuke Oisaki,*,† and Motomu Kanai*,†,‡
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and ERATO, Japan Science and Technology
Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
oisaki@mol.f.u-tokyo.ac.jp; kanai@mol.f.u-tokyo.ac.jp
Received March 1, 2013
ABSTRACT
Fe-catalyzed direct dehydrogenative C(3)-functionalization of tertiary arylamines was developed via activation of the sp3 C(3)ꢀH bond. The reaction is
applicable to both cyclic and acyclic amines. The key process is the catalytic desaturative enamine formation from tertiary amines and position-selective
CꢀC bond formation (addition to nitro olefins) at the β-carbon. Products can be converted to versatile and unique nitrogen-containing molecules.
Many C(3)-functionalized amines have remarkable
biological activities,1 but access to such molecules gener-
ally requires multistep, indirect pathways.2,3 Direct C(3)-
functionalization of amines4,5 through catalytic conver-
sion of an sp3 C(3)ꢀH bond has scarcely been developed,
other than the recently reported catalyses.6,7 These poten-
tially useful reactions require further improvement for appli-
cation to the practical construction of carbon skeletons,
however, such as use of ubiquitous metals instead of precious
metals, expansion of the limited substrate scope, and
development of milder reaction conditions. Here we report
an iron-catalyzed C(3)ꢀH functionalization of amines that
is applicable to both cyclic and acyclic substrates under mild
conditions using nitroalkenes as a coupling partner.
We and others previously reported oxidative C(2)-
functionalizations of amines through the oxidation of
amines to electrophilic imines or iminium ions, followed
by addition of nucleophiles to the thus generated electro-
philes (Scheme 1a).8ꢀ11 In this general reaction profile, the
oxidatively generated iminium ions possessing a β-hydrogen
atom will isomerize to enamines in the absence of
† The University of Tokyo.
‡ Japan Science and Technology Agency (JST).
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r
10.1021/ol400568u
XXXX American Chemical Society