Synthesis of Oxindole Derivatives via Intramolecular C–H Insertion of Diazoamides Using Ru(II)-Pheox Catalyst
Graphical abstract
This work presented the efficient intramolecular aromatic C–H bond insertion of diazoacetamide. The 1a–1o diazo compounds (except for 1k) were converted into their corresponding oxindoles via an intramolecular C–H insertion reaction in the presence of a Ru catalyst. The Ru-Pheox catalyst was shown to be highly efficient in this transformation in terms of the regioselectivity, producing the desired products in excellent yield (99%). The efficiency of the Ru catalyst reached 580 (TON) and 156 min−1 (TOF).
Introduction
The oxindole framework is prevalent as an important scaffold in numerous natural products and pharmaceutically active compounds due to its diverse biological activities, such as antifungal, antibacterial and antiviral, antimicrobial, and antioxidant activities [1].
Over the past few decades, the emerging therapeutic potential of the oxindole structural motif has encouraged the medicinal chemists to synthesize novel oxindole derivatives. Therefore, many reports on the approach toward the oxindole substructure include the derivatization of isatin and indoles [2], Heck reactions of aniline derivatives [3], and the Friedel–Crafts procedure using palladium (Pd)-catalyzed C–H functionalization [4].
However, these methods usually require harsh reaction conditions (strongly acidic conditions and high temperatures) and a multi-step synthesis of the corresponding starting materials as a functionalized precursor. Therefore, existing methods are limited in their scope and generality.
The oxindole framework can be constructed via intramolecular C–H insertion reactions of α-diazo compounds [5] using transition metals, such as Rh [6], Ru [7], Ag [8], and Pd [9], as catalysts. In this regard, Parul Garg et al. made a significant contribution in 2017, demonstrating a copper-catalyzed (5 mol%) ligand-free divergent route for synthesizing oxindoles and isatins via intramolecular cyclization of α-diazoanilide with a yield up to 93% (Scheme 1a) [10]. Recently, Solé and coworkers studied the Pd-catalyzed intramolecular carbene C–H insertion of α-diazo-α(methoxycarbonyl)acetamides for the preparation of oxindoles (yield up to 79%) (Scheme 1b) [9c]. Both of these established approaches for the procurement of oxindole derivatives remain challenging in certain areas, such as requiring large amounts of catalyst or special reaction conditions.
In the past several years, our group has been engaged in developing a Ru(II)-Pheox complex [11]. This catalyst was designed with a stereodirecting unit attached to the oxazoline ring and featuring various substituents on the ligand backbone to control the electron density on the metal center (Fig. 1).
Two factors cause different reactivities between Ru(II)−Pheox and traditional catalysts: (i) the design of the chiral ligand environment of the Ru(II)−Pheox catalyst, which allows much closer access to the substrate compared with traditional catalysts to provide a better reaction environment, and (ii) the strong electron-donating effect of the Csp2 anionic ligand on the Ru atom, which facilitates oxidative addition (usually the rate-limiting step of transition-metalcatalyzed reactions) [11b].
Moreover, we had achieved the highly regio- and enantioselective functionalization of unactivated primary C–H bonds, such as in the N-tert-butyl group of various diazoacetamides, using the Ru(II)-Pheox catalyst (Scheme 2a) [11g].
And in another our report, the oxindole derivatives particularly play an important role as starting materials for the synthesis of optically active spiro-cyclopropyl oxindole derivatives [11e].
Due to the interest in the catalytic C–H insertion reaction of diazoacetamide and the importance of the oxindole scaffold in natural product synthesis, we have recently described the results of experiments designed to probe the efficiency of Ru(II)-Pheox in the synthesis of oxindole. In this full paper, we describe in details the development of an intramolecular C-H insertion reaction of a variety of diazoacetamide derivatives in the presence of the Ru(II)-Pheox catalyst for the selective synthesis of oxindole derivatives (Scheme 2b), which based on our preliminary research in 2019 [11l].
Section snippets
Results and discussion
Initially, 2-diazo-N-methyl-N phenylacetamide 1a was chosen as the model substrate to screen the reaction conditions based on various catalysts. The results are shown in Table 1. Oxindole 2a was obtained at 91% yield and under the catalysis of 1 mol% Rh2(S-TBPTTL)4 [12] (Cat. 1) at room temperature (entry 1). For another Rh2(II) complex, Rh2(OAc)4 [13] (Cat.2), the intramolecular C–H insertion reaction also dominated, producing 2a at 83% yield after 24 h (entry 2).
Subsequently, the CuI [14]
Conclusion
In summary, we successfully developed an operationally simple protocol to regioselectively synthesize substituted oxindoles. In the presence of Ru(II)-Pheox, the intramolecular C–H insertion reaction proceeds smoothly under mild conditions, providing the corresponding oxindole derivatives in excellent yield (up to 99%). No other side reactions related to metal-carbene reactivity, such as dimerization, aromatic ring expansion, and Csp3-H on amide nitrogen insertion reaction, were observed.
General
All reactions were performed under an atmosphere of argon unless otherwise noted. DCM was purchased from Kanto Chemical Co., Inc. All reactions were monitored by thin-layer chromatography (TLC). Glass plates with a layer thickness of 0.2 mm were pre-coated with silica gel Merck KGaA 60 F254. The products were visualized either by ultraviolet (UV) light irradiation or by treatment with a phosphomolybdic acid solution or by treatment with a p-anisaldehyde solution. Flash column chromatography was
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work was supported by Japan Society for the Promotion of Science. The Grants-in-Aid for Scientific Research (C) (20K05583).
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