DOI: 10.1002/chem.201600107
Communication
&
Synthetic Methods |Hot Paper|
Cu/Fe Catalyzed Intermolecular Oxidative Amination of Benzylic
CÀH Bonds
Cong Liu,[a, b] Qi Zhang,[a] Hongbo Li,[a] Shuangxi Guo,[a] Bin Xiao,[b] Wei Deng,[c] Lei Liu,[b] and
Wei He*[a]
Abstract: We report a Cu/Fe co-catalyzed Ritter-type CÀH
activation/amination reaction that allows efficient and se-
lective intermolecular functionalization of benzylic CÀH
bonds. This new reaction is featured by simple reaction
conditions, readily available reagents and general sub-
strate scope, allowing facile synthesis of biologically inter-
esting nitrogen containing heterocycles. The Cu and Fe
salts were found to play distinct roles in this cooperative
catalysis.
Scheme 1. Intermolecular benzylic CÀH amination reactions.
Catalytic CÀH amination provides an appealing method for the
construction of CÀN bonds.[1] Metal nitrene insertion[2] is the
most exploited strategy for this purpose. Alternative methods
(i.e., nitriles), but also expand the toolbox for benzylic CÀH
including metal-free organonitrenoid,[3] CÀH activation/amina-
functionalization.
tion[4] and even enzyme catalysis[5] are also emerging. However,
Herein we report a Cu/Fe co-catalyzed Ritter-type intermo-
these methods are confronted with selectivity issues[6] in inter-
lecular oxidative CÀH amination of benzylic CÀH bonds ortho
molecular benzylic CÀH aminations due to the existence of
to a carboxylic group using acetonitrile as the nitrogen source
more reactive C(sp2)ÀH bonds. Oxidative CÀH activation/ami-
(Scheme 1b). This simple method is shown to be applicable to
nation reaction,[4] which takes advantage of the propensity of
a wide scope of substrates, providing rapid syntheses of a di-
the benzylic CÀH bonds in H-atom abstraction (HAA), has met
verse array of nitrogen-containing heterocycles including
with some encouraging success.[7]
a common synthetic precursor of two anxiolytic drugs Pago-
Ritter-type reactions[8] proceed through the nitrile capture of
a carbon cation intermediate, thus constituting another type
of oxidative CÀH amination strategy. For example, Li and co-
workers reported an interesting Rh-catalyzed diamination of al-
kenes by acetonitrile to access imidazolines.[9] Recently, Baran
clone and Pazinaclone. Our mechanistic studies suggested that
this reaction likely proceeds through a benzylic CÀH amina-
tion/lactamization cascade. We show that in such a cascade
[Cu] is required for the oxidative CÀH amination and [Fe] is re-
sponsible for the lactamization, while Selectfluor is necessary
et al. reported a remarkable Ritter-type intermolecular C(sp3)À for both processes.
H amination (Scheme 1a).[10] Given the rare examples[11,12] of in-
termolecular amination of benzylic CÀH bonds, new Ritter-type
oxidative amination of benzylic CÀH bonds would not only
benefit from the advantage of nonspecialized nitrogen sources
Our investigation started with a serendipitous finding that
treatment of 2-methylbenzoic acid (1a) with Selectfluor (F-
TEDA-BF4) under the catalysis of CuII in acetonitrile gives an un-
expected product in a low yield, which was subsequently iden-
tified as isoindolinone 2a by X-ray diffraction[13] (Table 1 and
Table 2). We further confirmed that acetonitrile was the nitro-
gen source by employing d3-acetonitrile (see the Supporting
Information). Interestingly, a number of intermolecular benzylic
CÀH amination reactions in acetonitrile were reported, but
amination product by acetonitrile trapping was not documen-
ted.[7d,11a] We thus decided to explore this surprising reactivity
to develop a new method for intermolecular benzylic CÀH ami-
nation.
[a] C. Liu, Q. Zhang, H. Li, S. Guo, Prof. Dr. W. He
School of Pharmaceutical Sciences, Tsinghua University
Beijing 100084 (P. R. China)
[b] C. Liu, B. Xiao, Prof. Dr. L. Liu
Department of Chemistry, Tsinghua University
Beijing 100084 (P. R. China)
[c] Prof. Dr. W. Deng
Reaction optimization was carried out using 1a as the
model substrate, with Selectfluor as the oxidant (Table 1 and
the Supporting Information). Initial screening showed that
20 mol% CuCl2 could give 2a in a moderate NMR yield (60%
School of Chemical and Environmental Engineering
Shanghai Institute of Technology, Shanghai 201418 (P. R. China)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2016, 22, 6208 – 6212
6208
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