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Copper(II)-Catalyzed Oxidative Cross-Coupling of Anilines, Primary Alkyl Amines and Sodium Azide Using TBHP: A Route to 2-Substituted Benzimidazoles Devulapally Mahesh, Pradeep Sadhu, and Tharmalingam Punniyamurthy J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00186 • Publication Date (Web): 18 Mar 2016 Downloaded from http://pubs.acs.org on March 18, 2016
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The Journal of Organic Chemistry
Copper(II)-Catalyzed Oxidative Cross-Coupling of Anilines, Primary Alkyl Amines and Sodium Azide Using TBHP: A Route to 2-Substituted Benzimidazoles Devulapally Mahesh, Pradeep Sadhu, and Tharmalingam Punniyamurthy* Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India.
Copper(II)-catalyzed oxidative cross-coupling of anilines, primary alkyl amines and sodium azide is described in the presence of TBHP at moderate temperature. This one-pot multicomponent protocol involves a domino C-H functionalization, transimination, ortho selective amination and cyclization sequence. The broad substrate scope and functional group compatibility are the significant practical features. The protocol can be extended to the coupling of benzyl alcohols with moderate yields. INTRODUCTION Recent advances in transition-metal-catalyzed C-H functionalization reactions using directing groups have led to the development of effective methods for the regioselective carbon-carbon and carbonheteroatom bonds formation.1 Among them, the C-N bond formation has attracted considerable attention due to the presence of this moiety in numerous compounds that are of biological, medicinal and material interests.2-5 More recently, ortho-selective C-H azidation of arene has been accomplished using -NH22c and imine2d as the directing groups. Herein, we report an efficient copper-catalyzed oxidative crosscoupling of anilines¸ primary alkyl amines and sodium azide to afford functionalized benzimidazoles via a domino transimination, ortho selective amination and cyclization sequence. The utilization of the readily accessible simple substrates and the broad substrate scope are the significant practical ACS Paragon Plus Environment
The Journal of Organic Chemistry
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advantages. These reaction conditions can be utilized for the coupling benzyl alcohols in moderate
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yields.
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Benzimidazoles are privileged structural scaffolds due to their interesting medicinal and biological
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properties.6 For examples, the compounds bearing benzimidazole motifs exhibit a broad spectrum of
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biological properties such as anti-viral,6a anti-cancer,6b anti-bacterial,6c anti-fungal6d and anti-HIV
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activities (Figure 1). In addition, benzimidazole structural frameworks are found to be useful for the
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fabrication of organic light-emitting diodes (OLEDs).7 Traditionally, the preparation of benzimidazoles
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is performed via condensation of 1,2-diaminoarene with aldehydes or carboxylic acids followed by
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oxidative cyclization. However, these methods often suffer due to the limited substrate scope and harsh
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reaction conditions.8 To overcome these drawbacks, transition-metal-catalyzed cross-coupling of aryl
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halides and their analogues with N-H nucleophiles has been explored.9 More recently, a few studies are
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focused on the C-H functionalization and C-N bond formation of amidines10and benzylamine with 2-
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aminoanilines11 to afford functionalized benzimidazoles (Scheme 1a). These reactions are attractive as
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they are effective under relatively mild conditions with broad substrates scope. Development of the
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oxidative coupling of the readily accessible substituted anilines, primary alkyl amines and sodium azide
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via a domino sp3 and sp2 C-H functionalization strategy would thus be valuable (Scheme 1b).
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Figure 1. Examples of Some Biologically Important Benzimidazoles.
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The Journal of Organic Chemistry
Scheme 1. Methods for Benzimidazoles Using Primary Alkyl Amines via Transimination.
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RESULTS AND DISCUSSION
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First, we commenced the optimization studies using aniline 1a and benzylamine 2a as model substrates
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with NaN3 employing different Cu-sources, oxidants and solvents (Table 1). Gratifyingly, the oxidative
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cross-coupling readily occurred to afford 2-phenylbenzimidazole 3a in a trace amount when the
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substrates 1a and 2a were stirred at 80 oC for 10 h with 10 mol % CuI, 3 equiv NaN3 and 2 equiv TBHP
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in DMSO (entry 1). The use of CH3COOH as an additive led an increase in the yield to 44%, whereas
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CF3COOH and (CH3)3CCOOH produced inferior results (entries 2-4). Subsequent screening of the
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copper sources led to further increase in the yield to 82% using Cu(OAc)2, whereas CuBr, CuCl and
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CuCl2 showed moderate catalytic activity (entries 5-8). In contrast, Cu(SO4)2·5H2O afforded 3a in a
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trace amount (entry 9). Similar results were observed using air, 30% H2O2 and DTBP as the oxidants
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(entries 10). DMSO was found to be the solvent of choice, whereas DMF, toluene, 1,4-dioxane and
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CH3CN furnished 3a in moderate yields (entries 11-14), varying the amount of the catalyst (5 mol %) or
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additive (10 equiv) led to drop the yield to
