Synthesis of Redshifted Azobenzene Photoswitches by Late-Stage Functionalization

Abstract

Azobenzenes are versatile photoswitches that can be cycled between their trans- and cis-configuration with light. The wavelengths required for this isomerization are substantially shifted from the UV to the visible range through tetra-ortho-chlorination. These halogenated azobenzenes display unique photoswitching characteristics, but their syntheses remain limited and inefficient. A new general method for the synthesis of tetra-ortho-chloro azobenzenes has been developed, which relies on direct palladium(II)-catalyzed C-H activation of pre-existing standard azobenzenes. This late-stage functionalization has a broad substrate scope and can be used to create a variety of useful building blocks for the construction of more elaborate redshifted photopharmaceuticals. This method is used to prepare red-AzCA-4, a photoswitchable vanilloid that enables optical control of the cation channel TRPV1 with visible light.

Keywords: C−H activation; azobenzene; halogenation; ion channels; photopharmacology.