Multicomponent alkene azidoarylation by anion-mediated dual catalysis

Molecules that contain the beta-arylethylamine motif have applications in the modulation of pain, treatment of neurological disorders and management of opioid addiction, among others, making it a privileged scaffold in drug discovery(1,2). De novo methods for their assembly are reliant on transformations that convert a small class of feedstocks into the target compounds via time-consuming multistep syntheses(3-5). Synthetic invention can drive the investigation of the chemical space around this scaffold to further expand its capabilities in biology(6-9). Here we report the development of a dual catalysis platform that enables a multicomponent coupling of alkenes, aryl electrophiles and a simple nitrogen nucleophile, providing single-step access to synthetically versatile and functionally diverse beta-arylethylamines. Driven by visible light, two discrete copper catalysts orchestrate aryl-radical formation and azido-group transfer, which underpin an alkene azidoarylation process. The process shows broad scope in alkene and aryl components and an azide anion performs a multifaceted role both as a nitrogen source and in mediating the redox-neutral dual catalysis via inner-sphere electron transfer(10,11). The synthetic capabilities of this anion-mediated alkene functionalization process are likely to be of use in a variety of pharmaceutically relevant and wider synthetic applications. A streamlined synthesis of beta-arylethylamines using two distinct copper catalysts is reported, and an azide anion is proposed to both react to form the product and facilitate catalyst regeneration.

Automated summary

A dual catalysis platform has been developed for the multicomponent coupling of alkenes, aryl electrophiles, and a simple nitrogen nucleophile to provide access to synthetically versatile and functionally diverse beta-arylethylamines in a single step.