Modular Photochemical Flow Synthesis of Structurally Diverse Benzyne and Triazine Precursors

Abstract

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.

Light-Induced Generation and Cycloaddition Reactions of Benzyne: Synthesis of Naphthoxindoles E and Annulated Indolizines

“…More recently, Gann et al have used this for the photoinduced click reaction for the synthesis of substituted benzotriazoles . For our purpose, we have followed a reported procedure . Next, the optimization endeavor began with the irradiation of a reaction mixture of compounds 1a (3 equiv) and methylene indolinones 2g (1 equiv) in various solvents at room temperature with a 365 nM LED lamp in a Kessil photo reactor (PR160L-370 Gen 2) (Table , entries 1–6).…”

“…24 For our purpose, we have followed a reported procedure. 20 Next, the optimization endeavor began with the irradiation of a reaction mixture of compounds 1a (3 equiv) and methylene indolinones 2g (1 equiv) in various solvents at room temperature with a 365 nM LED lamp in a Kessil photo reactor (PR160L-370 Gen 2) (Table 1, entries 1−6). This was selected after screening the various LED sources.…”

“…Cyclization requires good compatibility between the LUMO and the HOMO orbitals. By virtue of possessing low LUMO, the benzyne intermediate reacts with various dienophiles to undergo [4 + 2], [2 + 2], and [3 + 2] cycloaddition reactions. – It is noteworthy that in recent times, there have been two reports of light-induced benzyne generation; however, their application has been limited to click reactions and cycloadditions with limited examples of their applications (Scheme e). – We envisioned the application of this photogenerated benzyne in reagent-free cycloaddition reactions with appropriate 1, 3-dipoles (Scheme f).…”

Continuous Flow Synthesis of Nitrosoarenes via Photochemical Rearrangement of Aryl Imines

“…18 These factors are responsible for shifting the attention of the pharmaceutical industry toward continuous manufacturing in recent years. 19 On the basis of our previous report, 16 we decided to investigate a similar photochemical process in flow mode involving a variety of different aldimines. We were interested in establishing whether products containing a carboxylic acid and a diazene or a cyclic hydroxylamine would form in analogy to our previous study.…”

“…Recently, our group developed a continuous flow procedure that involves a photochemical rearrangement of photoexcited nitroarenes to yield unusual acetyl triazene benzoic acid derivatives that are precursors to benzyne species (Scheme c) . This study showed that the mechanism proceeds through a transient nitroso species and an isolable cyclic hydroxylamine intermediate.…”