Green Halogenation of Indoles with Oxone–Halide

Abstract

Oxidative functionalization of indoles is one of the most widely used approaches to exploit the synthetic utility of indoles. In continuation of our research interest in the green oxidation of indoles, we further explore the oxidation of indoles with oxone–halide and discover that the protecting group on the nitrogen of indoles plays a decisive role in controlling the pathways of indole oxidation with oxone–halide. An electron-withdrawing group on the nitrogen of indoles (N-EWG) enables C2 halogenation with stoichiometric halide, while C3 halogenation could be selectively achieved by using stoichiometric halide without dependence on the electronic property of the protecting group on the indole nitrogen. Different from our previous results obtained by using catalytic halide, these findings lead to the development of an environmentally friendly, efficient, and mild protocol for access to 2- or 3-haloindoles (chloro and bromo). As compared to the previous synthetic methods for 2-/3-haloindoles, our method exploits the in situ-generated reactive halogenating species from oxone–halide for halogenation of indoles and thus eliminates the use of stoichiometric halogenating agents and the production of toxic and hazardous organic byproducts derived from oxidants.

Recent advances in oxidative chlorination

“…On the basis of the previous study on oxidative functionalization of indoles, Xu, Ma and Tong continued to establish a oxone/halide-mediated halogenation of indoles (Scheme 42). 68 The presence of electron-withdrawing groups on the N1 of indole enables C2 chlorination with oxone and KCl (22 examples, 50–88% yield). C3 chlorination of indoles can be reached selectively by the use of KCl and oxone, without dependence on the electronic nature of N1 protective groups (14 examples, 62–91% yield).…”