Green Halogenation of Indoles with Oxone-Halide

Oxidative functionalization of indoles is one of themost widelyused approaches to exploit the synthetic utility of indoles. In continuationof our research interest in the green oxidation of indoles, we furtherexplore the oxidation of indoles with oxone-halide and discoverthat the protecting group on the nitrogen of indoles plays a decisiverole in controlling the pathways of indole oxidation with oxone-halide.An electron-withdrawing group on the nitrogen of indoles (N-EWG) enablesC2 halogenation with stoichiometric halide, while C3 halogenationcould be selectively achieved by using stoichiometric halide withoutdependence on the electronic property of the protecting group on theindole nitrogen. Different from our previous results obtained by usingcatalytic halide, these findings lead to the development of an environmentallyfriendly, efficient, and mild protocol for access to 2- or 3-haloindoles(chloro and bromo). As compared to the previous synthetic methodsfor 2-/3-haloindoles, our method exploits the in situ-generated reactivehalogenating species from oxone-halide for halogenation ofindoles and thus eliminates the use of stoichiometric halogenatingagents and the production of toxic and hazardous organic byproductsderived from oxidants.

Automated summary

Oxidative functionalization of indoles is widely used in synthetic chemistry. In this study, we explored the oxidation of indoles using oxone-halide and found that the protecting group on the nitrogen of indoles determines the pathways of oxidation. An electron-withdrawing group on the nitrogen enables C2 halogenation, while C3 halogenation can be achieved without dependence on the protecting group. This environmentally friendly and efficient method allows for the synthesis of 2- or 3-haloindoles without the use of stoichiometric halogenating agents or production of toxic byproducts.