.
Angewandte
Communications
DOI: 10.1002/anie.201303911
Synthetic Methods
À
Palladium/Copper-Catalyzed Oxidative C H Alkenylation/N-
Dealkylative Carbonylation of Tertiary Anilines**
Renyi Shi, Lijun Lu, Hua Zhang, Borui Chen, Yuchen Sha, Chao Liu, and Aiwen Lei*
Dedicated to Professor Xiyan Lu on the occasion of his 85th birthday
Anilines are valuable commodity chemicals and useful
synthetic building blocks for agrochemicals, active pharma-
ceutical ingredients, and process chemicals. Although anilines
have been widely utilized in chemical synthesis, the ortho-
exhibit extraordinary biological and pharmaceutical proper-
ties (for example protein kinase inhibitors, phosphodiesterase
inhibitors, and anti-rheumatic agents).[4] For example, Suni-
tinib was commercialized by Pfizer, Inc. in 2006 to treat renal
cell carcinoma and gastrointestinal stromal tumors.[5] Tenidap
(commercialized in 1993; Pfizer, Inc.) is an anti-inflammatory
medicine for the therapy of arthritis and other ailments.[6]
Moreover, 3-methyleneindolin-2-ones could be easily utilized
to synthesize important indolin-2-one derivatives.[7] Conse-
quently, considerable efforts have been made to develop
efficient methods for the synthesis of oxindole derivatives.
However, most of these methods involve multistep proce-
dures under harsh reaction conditions.[8] Herein, we have
developed an efficient and straightforward approach for the
synthesis of 3-methyleneindolin-2-one derivatives by using
commercial and simple tertiary anilines, olefins, and CO gas
as the substrates.
À
selective C H bond functionalization of anilines still remains
an outstanding challenge.[1] During the past decade, Pd-
À
À
catalyzed aromatic C H functionalization to form C C and
[2]
À
C X bonds has been intensively investigated. However, to
our best knowledge, the oxidative alkenylation of anilines
À
through the ortho-selective direct C H bond functionaliza-
tion have never been achieved. On the other hand, activation
À
of the C N bond has become a hot topic in organic synthesis
recently, in which most efforts were focused on the amination
transformation.[3] As a typical example of tertiary amines,
À
tertiary anilines have also been utilized in C N bond cleavage
transformations.[3g,i] However, the utilization of tertiary ani-
lines as nitrogen nucleophiles with alkyl as leaving group in
oxidative carbonylation has remained undeveloped. Herein,
Our experiment was initiated by treating 4-methylstyrene
(2a) with N,N-dimethylaniline (1a) in the presence of 1 atm
CO/O2 (Table 1). By optimizing various reaction parameters,
the combination of a catalytic amount of [PdCl2(PPh3)2],
Cu(OAc)2·H2O, dppp, and AcOH in a solvent mixture of
toluene and DMF using O2 as the terminal oxidant at 1008C
was found to be the best reaction conditions for this trans-
formation (Table 1, entries 1, 13, and 14). No product was
detected without the addition of Cu(OAc)2·H2O (entry 2).
Removing dppp or replacing dppp with PPh3 both decreased
the yield dramatically (entries 3 and 11). The carbonylation
reaction afforded lower yield when AcOH was removed
(entry 4). The variation of the mixed solvent also led to less
efficiency in terms of chemical yields (entries 5 and 10). When
[PdCl2(PPh3)2] was replaced by Pd(OAc)2 or PdCl2, a rela-
tively low yield of corresponding product was obtained
(entries 6 and 7). The use of a copper salt is essential for the
reaction. No product was detected with CuCl2 as the co-
catalyst, while Cu(OAc)2 showed less efficiency (entries 8 and
9). Decreasing the reaction temperature slowed the reaction,
affording 46% yield of 3a (entry 12). With lower loading of
[PdCl2(PPh3)2], 71% yield of 3a was obtained by lowering the
amount of Cu(OAc)2·H2O, dppp, and solvent accordingly
(entry 13). When the carbonylation was conducted under
mixed gas outside the CO/O2 explosion limits (CO/O2 = 1:7),
74% yield of desired product was obtained (entry 14).
With the above optimized conditions in hand, the carbon-
ylation of a variety of styrene derivatives with N,N-dimethyl-
aniline were tested (Scheme 2). The products obtained are
mixtures of Z- and E-isomer because of the isomerization
between them.[9] In general, both electron-donating and
À
we present the first palladium/copper-catalyzed oxidative C
H alkenylation/N-dealkylative carbonylation of tertiary ani-
lines towards the synthesis of 3-methyleneindolin-2-ones
derivatives (Scheme 1).
3-Methyleneindolin-2-ones are recognized as a particu-
larly useful class of compounds in medicinal chemistry that
Scheme 1. Strategies towards syntheses of indolin-2-ones.
[*] R. Shi, L. Lu, H. Zhang, B. Chen, Y. Sha, C. Liu, Prof. A. Lei
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan 430072, Hubei (P. R. China)
E-mail: aiwenlei@whu.edu.cn
Prof. A. Lei
Laboratory of Chemical Genomics
School of Chemical Biology and Biotechnology
Peking University Shenzhen Graduate School
Shenzhen 518055 (P. R. China)
[**] This work was supported by the 973 Program (2012CB725302), the
National Natural Science Foundation of China (21025206 and
21272180), and the Research Fund for the Doctoral Program of
Higher Education of China (20120141130002). We are also grateful
for support from the Program for Changjiang Scholars and
Innovative Research Team in University (IRT1030).
Supporting information for this article is available on the WWW
10582
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 10582 –10585