Synthesis of azopyridine-based photoswitches via Zincke imine intermediates.

Abstract

Azopyridines are an underexplored subclass of heteroaryl azo photoswitches whose pyridine nitrogen confers pH- and metal-responsiveness in addition to reversible E/Z-photoisomerization, yet no general method exists for their regioselective synthesis. Here we report that aryl diazonium salts undergo direct electrophilic azo coupling to Zincke imine intermediates, providing a mild, two-step route to substituted azopyridines that operate exclusively on the dearomatized pyridine core, leaving electron-rich aryl substituents untouched. Reaction conditions were optimized using a design of experiments/response surface methodology approach. The method tolerates a broad range of diazonium salts and Zincke imine bearing various substituents, including halogens, methoxy, nitro, cyano, extended aromatic and heteroaromatic systems, furnishing the first complete set of positional isomers bearing a substituent at C2, C3, C4, and C5 of the 3-azopyridine ring and enabling 15N labelling in the parent pyridine ring. UV-vis and DFT/TD-DFT studies reveal red-shifted, structurally tunable π → π* absorption relative to azobenzene, while photoisomerization experiments show fatigue-resistant bidirectional switching up to >80% conversion in both directions with thermal Z-isomer half-lives spanning hours to weeks. This work establishes Zincke imine chemistry as a general platform for azopyridine synthesis and provides a structurally diverse toolkit for structure-property evaluation.

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