DOI: 10.1002/chem.201600680
Communication
&
CÀH Amidation
Cu-Catalyzed Intramolecular Amidation of Unactivated C(sp3)ÀH
Bonds To Synthesize N-Substituted Indolines
Fei Pan,[a] Bin Wu,[a] and Zhang-Jie Shi*[a, b]
Abstract: A copper-catalyzed intramolecular amidation of
unactivated C(sp3)ÀH bonds to construct indoline deriva-
tives has been developed. Such an amidation proceeded
well at primary CÀH bonds preferred to secondary CÀH
bonds. The transformation owned a broad substrate
scope. The corresponding indolines were obtained in
good to excellent yields. N-Formal and other carbonyl
groups were suitable and were easily deprotected and
transformed into methyl or long-chained alkyl groups. Pre-
liminary mechanistic studies suggested a radical pathway.
CÀN bond formation is regarded as one of major reactions in
Scheme 1. C(sp3)ÀN bond formation toward indolines.
organic synthesis because N-containing motifs are found as
core structures in natural products and drug molecules.[1] To
approach the goal of CÀN formation, Ullman reactions and
other efficient method to construct N-containing bioactive
Buchwald–Hartwig aminations/amidations have been well in-
molecules through a direct aliphatic CÀH amidation/amination
vestigated to construct C(sp2)ÀN bonds in the past several de-
with carboxyl amides as starting materials.
cades.[2] Other than traditional nucleophilic substitutions,[3]
We chose an indoline core structure as target product be-
such as Michael addition[4] with N-containing nucleophiles and
cause it is a common structural motif found in numerous natu-
Mannich reactions,[5] a direct amination/amidation of aliphatic
CÀH bonds has proved as another powerful method to con-
struct C(sp3)ÀN bonds.[6] Among the direct methods, Hof-
mann–Loffler–Freytag (HLF) reaction[7] and nitrene insertion[8]
were systematically surveyed. Recent advances to proceed the
oxidative CÀN formation of primary CÀH bonds have also been
investigated catalyzed by Pd,[9] Cu,[10] Ag,[11] and other metal
catalysts (Scheme 1a).[12] In most of these cases, complicated
amides, which might be used as directing groups in the desira-
ble transformations,[11] and trifluoromethylsulfonylamides (Tf)[13]
are broadly used to promote the efficacy of the reaction; how-
ever, such compounds are difficult to prepare and can compli-
cate further transformations. In contrast, the transformable car-
boxyl amides are hardly used as substrates for the direct CÀH
amidation in transition-metal catalysis, especially catalyzed by
earth-abundant transition metals. We planned to search for an-
ral products and bioactive molecules.[14] Among the methods
to approach such structure, the most conventional method is
based on an aryl CÀN bond formation through metal-catalyzed
CÀN cross-coupling reactions, such as Ullman coupling,[15]
Chan–Evans–Lam coupling,[16] Buchwald–Hartwig coupling,[2d,e]
and direct amination with C(sp2)ÀH bond.[17] Reductive or oxi-
dative dearomatization of indole derivatives also proceed to
construct complicated indoline derivatives.[18] A considerable
pathway to construct indolines is to construct C(sp3)ÀN bonds
through a direct amination/amidation of aliphatic CÀH bonds
(Scheme 1a). Up to date, one elegant example has been re-
ported by Glorius and co-workers to approach such a goal
though Pd catalysis from acetanilides.[19] Herein, we report for
the first time a copper-catalyzed intramolecular amidation of
unactivated C(sp3)ÀH bonds to construct indolines from ortho-
substituted carboxyl anilines (Scheme 1b).
As an initial trial, we performed the reaction with readily
available N-(2-tert-butylphenyl)acetamide (1a) to the corre-
sponding indoline 2a using copper acetate as the catalyst and
AgOAc as the oxidant (Table 1). A trace amount of product 2a
was obtained using DMSO as solvent (entry 1). Using other
polar solvents, such as MeCN, DMF, or dioxane, no desired
product 2a was obtained at all.[20] In contrast, the reaction pro-
ceeded well in nonpolar aromatic solvents (entries 4–8). After
an extensive solvent screening, m-xylene was proved optimal
(entry 6). Next, the investigation of copper catalysts was carried
[a] F. Pan, B. Wu, Dr. Z.-J. Shi
Beijing National Laboratory of Molecular Science (BNLMS) and Key Labora-
tory of Bioorganic Chemistry and Molecular Engineering of Ministry Educa-
tion, College of Chemistry and Molecular Engineering, Peking University,
Beijing, 100871 (P. R. China)
[b] Dr. Z.-J. Shi
State Key Laboratory of Organometallic Chemistry, CAS, Shanghai, 200032
(P. R. China)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2016, 22, 6487 – 6490
6487
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