Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Direct Access to Functionalized Indoles via Single Electron Oxidation Induced Coupling of Diarylamines with 1,3-Dicarbonyl Compounds Taoyuan Liang, He Zhao, Lingzhen Gong, Huanfeng Jiang, and Min Zhang* Key Lab of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Wushan Road 381, Guangzhou 510641, P.R. China Downloaded via NOTTINGHAM TRENT UNIV on August 13, 2019 at 14:39:27 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: Under aerobic copper catalysis, an unprecedented direct synthesis of functionalized indoles via single electron oxidation induced coupling of diarylamines with 1,3dicarbonyl compounds is presented. The protocol proceeds with good functional group and substrate compatibility, the use of readily available feedstocks and naturally abundant catalyst system, high step and atom efficiency, as well as selectivity, which offers a platform for accessing a new class of indoles with the potential for the discovery of functional molecules.
I
ndoles extensively exist in functional products.1 Due to the high binding affinity to many bioreceptors,2 they have been frequently found to exhibit diverse characteristics, including antibacterial and anticancer activities, and be potent inhibitors of tubulin polymerization.3 As such, indoles are considered to be privileged structures in the discovery of drugs. For instance, indomethacin and pravadoline are analgesic and nonsteroidal anti-inflammatory drugs.4 Arbidol is a drug used for the treatment of influenza viral infection.5 Due to the valuable applications, the construction of indoles has long been an attractive topic in organic chemistry. In general, the purpose is realized by utilizing Fischer,6 Larock,7 Nenitzescu,8 and Bartoli9 indole syntheses. Over the past decade, much attention has been directed toward the development of alternative approaches to access various indoles.10,11 Despite the significant utility, many of these transformations suffer from one or more limitations such as the need for preinstallation of specific coupling agents, the use of noble metal catalysts, and excess consumption of waste-generating oxidants or additives. From the viewpoint of step- and atom-economy, the search for effective synthesis of indole derivatives from readily available feedstocks, preferably naturally abundant oxidants and metal catalysts, would be highly desirable. Interestingly, easily available anilines and 1,3-dicarbonyl compounds have been elegantly employed for the construction of 3-carbonylindoles, a class of unique compounds with appealing biological and therapeutic activities. For instance, the Glorius group reported a palladium-catalyzed oxidative cyclization of enamines for the synthesis of indoles (Scheme 1, eq 1).12 Later, Njardarson and co-workers reported a metal-free synthesis of fluorinated indoles via an oxidative dearomatization−rearomatization strategy (eq 2) with the use of phenyliodine(III) diacetate as the oxidant.13 However, due to the low oxidative potential, anilines can easily undergo dehydrogenative dimeriza© XXXX American Chemical Society
Scheme 1. Previous Work and Our New Observation
tion to form azo compounds under oxidative conditions.14 So, it is understandable that preinstallation of enamines from anilines and 1,3-dicarbonyl compounds or the use of N-protected anilines is essential for the indole syntheses in these two examples (eqs 1 and 2). Due to our interest in selective functionalization of heterocyclic C−H bonds,15 we recently reported an aerobic copper-catalyzed synthesis of functionalized benzimidazoles from arylamines and primary alkylamines via tandem triple C−H aminations (eq 3).15a Received: July 8, 2019
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DOI: 10.1021/acs.orglett.9b02349 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
With the optimal conditions in hand, we examined the generality of the developed synthetic protocol (Scheme 2).
We developed a synthesis of functionalized indoles. As shown in eq 4 of Scheme 1, employing the coupling of diphenylamine 1a and 1-phenylbutane-1,3-dione 2a as a prototypical example, the single electron oxidation (SEO) of 1a initially forms aryl radical cation A, which is expected to be trapped by the carbo nucleophile 2a under the cooperative actions of electronic guidance and Hbonding and affords radical B. Indole product D is generated via SEO and deprotonation of B followed by intramolecular dehydration of C. This idea prompted us to carry out the reaction of 1a and 2a in i-butanol at 100 °C for 16 h with molecular O2 and a catalytic amount of CuCl2. Interestingly, although the anticipated 3-carbonyl indole D was not observed, a novel indole 3aa, by incorporating an additional diarylamino group at position 5 of D, was obtained in 23% yield. There are numerous methods reported for the construction of indoles,10,16 but direct synthesis of aminoindoles from easily available feedstocks has been rarely explored.17 Based on this observation, we report here, for the first time, an efficient synthesis of functionalized indoles via SEOinduced coupling of diarylamines with 1,3-dicarbonyl compounds. To formulate a more efficient reaction system, we synthesized 3aa from 1a and 2a as a model system to evaluate different reaction parameters (Table 1 and Table S1 in Supporting Information (SI)
Scheme 2. Variation of Diarylamines
Table 1. Optimization of the Reaction Conditionsa entry
catalyst
solvent
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
CuCl CuBr2 Cu(OTf)2 CuF2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2
i-butanol i-butanol i-butanol i-butanol toluene 1,4-dioxane t-amylalcohol t-butanol acetonitrile i-butanol i-butanol i-butanol i-butanol i-butanol i-butanol
ligand
yield (%) of 3aab
2,2′-bipyridine 1,10-phenanthroline pyridine pyridine
