Angewandte
Chemie
DOI: 10.1002/anie.200704092
À
C H Activation
À
Multiple C H Activations To Construct Biologically Active Molecules
in a Process Completely Free of Organohalogen and Organometallic
Components**
Bi-Jie Li, Shi-Liang Tian, Zhao Fang, and Zhang-Jie Shi*
À
C H functionalization is the most sustainable and straight-
forward method to construct complicated structures and has
received significant attention in the past several decades.[1]
catalyzed by palladium has been relatively well developed.[8]
Cross dehydrogenative coupling (CDC)[9] of different arenes
is still a big challenge for organic chemists, especially with
control of chemo-, regio-, and even stereoselectivity. A recent
article reported an improvement in selectivity of this cross-
coupling reaction by tuning the high ratio of two different
arenes, although the reaction proceeded with lower effi-
ciency.[10] The groups of Fagnou[11]and DeBoef[12] reported the
arylation of electron-rich N-acetylindoles and benzofurans by
À
À
À
Through direct C H functionalization, C C and C X bonds
(X = B, N, O, etc.) could be directly constructed by methods
utilizing ruthenium, rhodium, palladium, iridium, and other
metal complexes as catalysts.[2] Compared with the activation
3
À
of sp C H bonds, many efforts have been made to activate
2
À
sp C H bonds, especially aromatic ones, since unsaturated
À
rings form the main scaffold in many natural products,
cross-coupling through dual C H activation in systems in
synthetic drugs, and materials.[3] Among various methods to
which homocoupling is inhibited. The regioselectivity of this
cross-coupling was relatively well-controlled by electrophilic
features of the heterocyclic scaffold; however, the process is
still limited to N-acetylindoles and benzofurans and cannot be
II
À
activate C H bonds of aromatic rings, Pd -catalyzed electro-
philic substitution is one of the most important.[4] Despite
previous research, efficient methods to construct complicated
scaffolds are still rare.[5] We present herein a new
pathway to approach highly selective cross-coupling
of arenes controlled by directing groups. This effective
method is applied to prepare fully functionalized
II
À
carbazoles through Pd -catalyzed multiple C H func-
tionalization in the absence of halides and organome-
tallic reagents.
General methods to construct biaryls typically use
transition-metal-catalyzed coupling reactions in which
the arenes are functionalized with boron (or other
metals) and halides.[6] Recent efforts have made this
coupling more efficient by avoiding the use of one of
the coupling partners through direct activation of
Scheme 1. Construction of biaryls by different cross-coupling methods.
[7]
À
aromatic C H bonds. Homocoupling of arenes DG=directing group
[*] Z.-J. Shi
Beijing National Laboratory of Molecular Sciences (BNLMS)
applied to other arenes to construct, for example, function-
alized biphenyls. Our strategy to overcome this challenge and
to gain high regioselectivity is to initiate cross-coupling with a
directing group (Scheme 1).
PKU Green Chemistry Centre and Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education
College of Chemistry
We first tried the arylation of N-acetyl-1,2,3,4-tetrahydro-
quinoline (1a), which had shown relatively high reactivity in
previous studies.[13] We found that the arylation between 1a
and o-xylene (2a) took place smoothly in the presence of
Pd(OAc)2 (10 mol%) as a catalyst with Cu(OTf)2 (20 mol%)
as an oxidative cocatalyst [Eq. (1)]. Gratifyingly, dioxygen
(O2, 1 atm) could be applied as the terminal oxidant to
complete this transformation. The desired ortho-arylated
product 3aa could be isolated in 78% yield using 6.0 equiv-
alents of 2a. Only a single product was isolated, and the highly
regioselective reaction proceeded at the ortho position of 1a
and the meta position of 2a. In the proposed mechanism
(Scheme 2), the selectivity in this arylation was most likely
Peking University, Beijing 100871 (China)
and
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
Fax: (+86)10-6276-0890)
E-mail: zshi@pku.edu.cn
B.-J. Li, S.-L. Tian, Z. Fang
College of Chemistry
Peking University, Beijing 100871 (China)
[**] Support of this work by a starter grant fromPeking University and
the grant fromNational Sciences Foundation of China (No.
20542001, 20521202, 20672006) is gratefully acknowledged.
Supporting information for this article is available on the WWW
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controlled by the acetamino directing group in the first C H
Angew. Chem. Int. Ed. 2008, 47, 1115 –1118
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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