Letter pubs.acs.org/OrgLett
Iridium(III)-Catalyzed Synthesis of Benzimidazoles via C−H Activation and Amidation of Aniline Derivatives Jintao Xia,†,‡ Xifa Yang,†,‡ Yunyun Li,†,‡ and Xingwei Li*,† †
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China University of Chinese Academy of Sciences, Beijing 100049, China
‡
S Supporting Information *
ABSTRACT: Ir(III)-catalyzed synthesis of benzimidazoles has been realized under redox-neutral conditions by annulation of aniline derivatives with dioxazolones. The reaction proceeded via a C−H activation−amidation−cyclization pathway with a decent substrate scope.
B
these studies, only simple amidation was realized. Subsequently, functionalizable (especially nucleophilic) DGs have been employed so that, following C−H bond amidation, the nucleophilicity of the DG triggered a subsequent cyclization tandem, as in the synthesis of quinazolines and their N-oxides reported by our group and others.10 Although different systems of Cp*Rh- and Cp*Co-catalyzed C−H amidation and annulation have been realized by following this strategy, the products were limited to six-membered azacycles.10,11 Synthesis of five-membered azacycles such as benzimidazoles via C−H activation and amidation of arenes has received limited attention.12 However, we and others have developed efficient synthesis of indoles by C−H activation of N-phenyl-2-aminopyridines and coupling with a diazo compound.13 This occurred via a C−H alkylation−nucleophilic cyclization tandem, which demonstrated the high reactivity of this arene substrate in the construction of five-membered rings.14 As a continuation of our interest in annulation reactions, we aimed to explore synthesis of benzimidazoles via C−H activation of N-phenyl-2-aminopyridines. However, challenges remain because the amidated intermediate is an o-phenylenediamine that may pose strong inhibition to the catalyst with formation of a stable fivemembered metallacyclic intermediate. In addition, the cyclization step might be challenging due to low electrophilicity of the amide carbonyl group. We now report the synthesis of benzimidazoles via the first C−H activation and intermolecular coupling process. With this concept in mind, the reaction parameters of the coupling of a dioxazolone with an aniline bearing a meta-Me blocking group (1b) were then examined to ensure mono selectivity (Table 1). The desired benzimidazole 3ba was isolated in 19% yield, with no amidation intermediate 3b being detected when [Cp*RhCl2]2/AgSbF6 was used as a catalyst (entry 1). Given high activity of Ir(III) catalysts in amidation reactions,15 an Ir(III) catalyst was then adopted. To our delight, the desired product 3ba was isolated in 72% yield using [Cp*IrCl2]2/
enzimidazoles are an important structural moiety that has found wide applications in biological and medicinal studies.1 Pharmaceutical molecules containing this significant heterocycle have exerted numerous biological effects including antimicrobial, antitubercular, anti-inflammatory, analgesic, and antiviral activities.2 Therefore, tremendous efforts have been devoted to the synthesis of benzimidazoles. The conventional synthetic methods include condensation of benzene-1,2-diamine with a C1 synthon3 and transition metal-catalyzed couplings of ortho-functionalized anilines (Scheme 1),4 but they generally Scheme 1. Synthesis of 1,2-Disubstituted Benzimidazoles
suffer from some limitations, such as functionalized starting materials, multiple steps, and harsh conditions. Thus, development of mild, straightforward, and ecofriendly processes to access benzimidazoles remains highly desirable. Over the past few years, direct amination/amidation of aryl C−H bonds has been established as a straightforward and stepeconomic process in the construction of various C−N bonds.5 Transition metal catalysts such as Mn, Co, Cu, Ru, Rh, and Ir have been employed to effect C−H activation−amination/ amidation using isocyanates, amines and amides, organic azides, hydroxylamines, and imidoiodinanes as nitrogen sources.6 In particular, the nitrene-transfer7 reagent 1,4,2-dioxazol-5-one8 is especially prominent with high reactivity, compatibility, and versatility. In 2015, Chang8 and our group9 independently reported Cp*Rh(III)- and Cp*Co(III)-catalyzed amidation of aryl and alkyl C−H bonds under mild reaction conditions. In © 2017 American Chemical Society
Received: May 5, 2017 Published: June 1, 2017 3243
DOI: 10.1021/acs.orglett.7b01356 Org. Lett. 2017, 19, 3243−3246
Letter
Organic Letters Table 1. Optimization Studies on Synthesis of Benzimidazolea
Scheme 2. Scope of Anilines in the Synthesis of Benzimidazolesa,b
yield (%)b entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 c
18
catalyst/silver [RhCp*Cl2]2/ AgSbF6 [IrCp*Cl2]2/ AgNTf2 [IrCp*Cl2]2 AgNTf2 [IrCp*Cl2]2/ AgBF4 [IrCp*Cl2]2/ AgOTf [IrCp*Cl2]2/ AgSbF6 [IrCp*Cl2]2/ AgNTf2 [IrCp*Cl2]2/ AgNTf2 [IrCp*Cl2]2/ AgNTf2 [IrCp*Cl2]2/ AgNTf2 [IrCp*Cl2]2/ AgNTf2 [IrCp*Cl2]2/ AgNTf2 [IrCp*Cl2]2/ AgNTf2 [IrCp*Cl2]2/ AgNTf2 [IrCp*Cl2]2/ AgNTf2 [IrCp*Cl2]2/ AgNTf2 [IrCp*Cl2]2/ AgNTf2
additive (equiv)
solvent
3b
DCE DCE
3ba 19
