Aerobic Transition‐Metal‐Free Synthesis of 2,3‐Diarylindoles and 5‐Aryluracils via Oxidative Nucleophilic Substitution of Hydrogen Pathway

Nucleophilic substitution of hydrogen in electron-deficient arenes has been extensively studied since the late 1970s. Addition of nucleophilic agents to electron-deficient arenes such as nitroarenes proceeds readily to the positions occupied by hydrogen atom to form the corresponding σ-adducts. Among various pathways for the conversion of σ-adducts to products, direct substitution of hydrogen via vicarious nucleophilic substitution (VNS) and oxidative nucleophilic substitution of hydrogen (ONSH) pathways are most frequently used. The ONSH (SNAr ) pathway with nitrobenzene, as an example, is shown in Scheme 1. For the oxidation of σadducts, many oxidants have been used including KMnO4 or AgNO3, 2 and aerobic oxidation with molecular oxygen has also been reported. A pioneering aerobic oxidative C C coupling between ketones and nitroarenes to α-arylated ketones has been reported by Kurti and co-workers. Later, Kumar et al. reported β-arylation of indoles under similar aerobic oxidation conditions. As 2,3-diarylindoles have been found in many biologically important compounds, the synthesis of this scaffold has receivedmuch attention.Most frequently, 2,3-diarylindoles have been prepared via palladium-catalyzed arylations of 2-arylindole with bromoarenes. During our recent transition metal-catalyzed arylations of indoles and uracils, we were interested in the arylation in the absence of an expensive transition metal catalyst. Reported aerobic ONSH pathway for 3-arylindoles was conducted most effectively in DMSO in the presence of KOBu. The arylation afforded 3-arylindoles in moderate yields with indole and 2-methylindole at room temperature. Unfortunately, the arylation of 2-arylindoles has not been examined. In these respects, we decided to examine the arylation of 2-arylindoles with electron-deficient arenes via an aerobic ONSH pathway, as shown in Scheme 2. At the outset of our experiment, the reaction of 2-phenylindole (1a) and 1,3-dinitrobenzene (2a) was examined in DMSO in the presence of KOBu under O2 balloon atmosphere at room temperature. The reaction was sluggish, and 3awas obtained in moderate yield (58%) after a long time (14 h) presumably due to steric hindrance around the reaction site (C-3 position of 1a). When we carried out the reaction at 50 C, reaction time was reduced to 8 h; however, the yield of 3a (60%) was not increased. The yield was slightly increased to 67% at 90 C in short time (2 h). To our delight, the yield could be further improved up to 78%byusingCs2CO3 (90 C, 2 h) instead of KOBu. The formation of polar side products was decreased in the reaction employingCs2CO3 as compared to the reaction using KOBu. Encouraged by the successful results, 3-arylations of 2-arylindoles via ONSH pathway with some electrondeficient arenes were examined. The results are summarized in Table 1. The reactions of 2-phenyl-5-chloroindole (1b) and 2-phenyl-5-methylindole (1c) with 2a afforded 3b and 3c in good yields (73 and 71%, respectively). The reactions of 2-(4-chlorophenyl)indole (1d), 2-(2-naphthyl)indole (1e), 2-(2-thienyl)indole (1f) also produced the corresponding products 3d–f in good yields (68-75%). The reaction of 1a and 1-nitronaphthalene (2b) showed somewhat sluggish reactivity, and 3g was obtained in moderate yield (40%) after a long time (10 h). For the synthesis of para-substituted compound 3g, no trace of the corresponding ortho-substituted derivative was detected. The reaction at elevated temperature showed the formation of many side products. Similarly, the