Microwave-assisted N-Arylation of Indoles via C(sp2)–N(sp2) Bond Formation by Aromatic Nucleophilic Substitution Reactions

The N-arylindole subunit is an important species in many biologically active and pharmaceutically important compounds, which display antiestrogen [1], analgesic [2], antiallergy [3], antimicrobial [4], and neuroleptic activity [5]. Although the traditional coppercatalyzed coupling of an aryl halide with a heteroatombased nucleophile, the Ullmann-type coupling reaction, has remained a standard method for the construction of N-arylindoles, it requires high temperatures, generally 140 ◦C or more, and often the use of two or more equivalents of the aryl halide to obtain optimal yields. Buchwald reported some improved N-arylation of indoles, but still using expensive palladium or copper [6]. Another reaction of the CuOAc catalyzed Narylation of indoles has been reported recently [7]. On the other hand, the nucleophilic aromatic substitution of aryl halides, activated by electron-withdrawing substituents, with indoles represents yet another route to N-arylindoles for certain substrate combinations. Smith has described the N-arylation of indole by aromatic nucleophilic substitution, however, this SNAr reaction was catalyzed by 18-crown-6 at high temperature (120 ◦C), and no examples of reactions of substituted indoles were reported [8]. Maiorana described N-arylation of indoles by aromatic nucleophilic substitution on haloarenes, but using chromium tricarbonyl complexes [9]. Therefore, a simple and general method for SNAr reactions, including easy work-up and a wide scope of substrates, for the preparation of N-arylindoles is highly desirable.