Synthesis of Redshifted Azobenzene Photoswitches by Late-Stage Functionalization

• Published in: Chemistry : a European journal Vol. 22; no. 13; pp. 4364 - 4368
• Main Authors: Konrad, David B., Frank, James A., Trauner, Dirk
• Format: Journal Article
• Language: English
• Published: WEINHEIM Blackwell Publishing Ltd 18.03.2016; Wiley; Wiley Subscription Services, Inc
• Subjects: Activation; Azo Compounds - chemical synthesis; Azo Compounds - chemistry; azobenzene; Capsaicin receptors; Catalysis; Cations; Channels; Chemistry; Chemistry, Multidisciplinary; Chlorination; Construction; C−H activation; Halogenation; Hydrogen Bonding; ion channels; Isomerism; Isomerization; Light; Light effects; Optical control; Palladium; Photochemical Processes; photopharmacology; Physical Sciences; Red shift; Science & Technology; Synthesis; TRPV Cation Channels - chemistry; Wavelengths; azobenzene; RECEPTOR; COORDINATION; halogenation; ion channels; AZO-COMPOUNDS; OPTICAL CONTROL; ORTHO-HALOGENATION; C-H activation; CATALYTIC METHOD; CHANNEL; GLUTAMATE; IN-VIVO; FLUOROAZOBENZENES; photopharmacology; C−H activation
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201505061

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. A redshift in photopharmacology: Palladium(II) acetate effectively catalyzes the selective tetra‐ortho‐chlorination of azobenzenes. This methodology provides a straightforward and general approach towards the synthesis of these otherwise challenging redshifted photoswitches. This procedure is used to synthesize red‐AzCA‐4 (see scheme; NCS=N‐chlorosuccinimide), which is a potent photochromic agonist for the vanilloid receptor 1.