C À H Activation DOI: 10.1002/ange.200901484 Indoles from Simple Anilines and Alkynes: Palladium-Catalyzed C À H Activation Using Dioxygen as the Oxidant** Zhuangzhi Shi, Chun Zhang, Si Li, Delin Pan, Shengtao Ding, Yuxin Cui, and Ning Jiao* Indoles are ubiquitous bioactive heterocycles in nature. [1] Their importance in medicinal chemistry has stimulated considerable interest from organic chemists, and has encour- aged the development of new synthetic strategies to prepare these compounds. [2] In the past decades, transition-metal- catalyzed intermolecular cyclizations of ortho-halogenated anilines with internal alkynes have emerged as a powerful method for constructing indoles (Scheme 1 a). [3] However, ortho-halogenated anilines are required and halide byprod- ucts are produced in these methods. The C À H functionaliza- tion approach has received substantial attention because of its sustainable and environmentally benign features. [4] In this regard, preactivated intramolecular cyclization by C À H activation presents one of the most exciting and significant methods. [5] Very recently, in contrast to the requirement of the substrate preactivation procedure, Glorius et al. [6] described a one-pot indole synthesis from aniline and methyl acetoacetate involving an InBr 3 -catalyzed condensation and a Pd(OAc) 2 - catalyzed oxidative cyclization. Moreover, Fagnou and co- workers [7a] reported a significant rhodium-catalyzed intermo- lecular cyclization between alkynes and N-acetyl anilines, in which the acetyl species functioned as a directing group, [8, 9] assisting in the C ÀH activation (Scheme 1 b). Despite the significant advance, directing groups are required for the intermolecular approach. The direct approach from simple and readily available anilines by C À H activation remains a challenging task (Scheme 1 c). Furthermore, the oxidant plays an essential role in the catalytic cycle of C ÀH activation. Although oxidants such as Cu(OAc) 2 , AgOAc, PhI(OAc) 2 , BQ etc. have been proven to be excellent and practical, [4–9] dioxygen is an ideal oxidant and offers attractive industrial prospects in terms of green and sustainable chemistry. [10, 11] Herein, we demonstrate the first efficient and direct approach to indoles from simple and readily available anilines and alkynes by using C ÀH activation catalyzed by Pd(OAc) 2 and O 2 as the oxidant (Scheme 1 c). Initially we focused on the direct synthesis of the indole from simple aniline (1a) and dimethyl butynedioate (2a) through C À H activation in the presence of Pd(OAc) 2 in DMSO under 1 atmosphere of O 2 . Under these conditions, the desired product 3aa was observed in 18% yield (Table 1, entry 1). Gratifyingly, 62% of 3aa was achieved when DMA was employed as the solvent (Table 1, entry 2). Considering Scheme 1. Strategies involving C ÀH activation for the preparation of indoles. a) Type 1: Cyclization with ortho-halogenated anilines. b) Type 2: Directing group (DG) assisted approach. c) Type 3: Direct approach from simple anilines. Table 1: Direct indole synthesis from 1a and 2a by C ÀH activation. [a] Entry Catalyst Solvent t [h] Yield of 3aa [%] [b] 1 Pd(OAc) 2 DMSO 40 18 2 Pd(OAc) 2 DMA 40 62 3 Pd(TFA) 2 DMA 40 45 4 Pd(OAc) 2 PivOH 12 34 5 Pd(OAc) 2 DMA/AcOH (4:1) 12 73 6 Pd(OAc) 2 DMA/PivOH (4:1) 12 85 7 [c] Pd(OAc) 2 DMA/PivOH (4:1) 12 60 [a] Reaction conditions: 1a (0.24 mmol), 2a (0.2 mmol), Pd(OAc) 2 (0.02 mmol), in solvent (1.25 mL), 1 atm of O 2 . [b] Yield of isolated products. [c] The reaction was carried out under air. DMSO = dimethyl sulfoxide, DMA = N,N-dimethylacetamide, TFA = trifluoroacetate, Piv = pivaloyl. [*] Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Dr. Y. Cui, Dr. N. Jiao State Key Laboratory of Natural and Biomimetic Drugs Peking University, School of Pharmaceutical Sciences Peking University, Xue Yuan Rd. 38, Beijing 100083 (China) Fax: (+ 86) 10-8280-5297 E-mail: jiaoning@bjmu.edu.cn Dr. N. Jiao State Key Laboratory of Organometallic Chemistry Chinese Academy of Sciences, Shanghai 200032 (China) [**] Financial support from Peking University, the National Science Foundation of China (Nos. 20702002, 20872003), and the National Basic Research Program of China (973 Program 2009CB825300) are greatly appreciated. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.200901484. Zuschriften 4642  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2009, 121, 4642 –4646