Modular Photochemical Flow Synthesis of Structurally Diverse Benzyne and Triazine Precursors

• Published in: Advanced synthesis & catalysis Vol. 365; no. 15; pp. 2628 - 2635
• Main Authors: García‐Lacuna, Jorge, Baumann, Marcus
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 10.08.2023; Wiley Subscription Services, Inc
• Subjects: Amides; Amines; Aromatic compounds; Batch processing; benzyne; Carboxyl group; Chemistry; Chemistry, Applied; Chemistry, Organic; flow chemistry; Light sources; nitroarene; photochemistry; Physical Sciences; Precursors; Science & Technology; Synthesis; triazine; nitroarene; TRIAZENES; benzyne; photochemistry; triazine; CHEMISTRY; PHOTOLYSIS; ARYNES; flow chemistry; TOOL
• ISSN: 1615-4150; 1615-4169
• DOI: 10.1002/adsc.202300414

Benzyne and related arynes are classical high‐energy species with a rich history of widespread applications in synthesis. However, despite several synthetic routes being available to generate arynes and their precursors, none represents an ideal entry to benzyne chemistry in view of safety, scalability, and sustainability. Here we report a new photochemical flow process allowing for the generation of benzyne precursors in high yields, and throughput, with easy isolation of multigram quantities of products. This process leverages a catalyst‐free photochemical rearrangement via a photoexcited nitro arene which involves a cyclic hydroxylamine intermediate that has been fully characterized. The resulting precursors were converted to benzynes via a second photochemical flow process generating heterocyclic targets upon trapping with azide and sydnone partners. Remarkably, when reacting the benzyne precursors with secondary amines, a wide range of aryl triazines is obtained in good yields via a third photo‐flow transformation. This represents a modular approach to synthesize these species, that avoids the use of potentially explosive diazonium salts. Ultimately, three photochemical flow processes using a single high‐power LED light source (365 nm, adjustable in‐put power) are presented with manifest benefits compared to batch processing. Moreover, the functionalization of a pendent carboxyl group to form sets of biologically relevant aryl triazine‐based amides highlights further applications of these unique and industrially relevant triazine entities.