Radical Carbonylation Mediated by Continuous-Flow Visible-Light Photocatalysis: Access to 2,3-Dihydrobenzofurans Nenad Micic † and Anastasios Polyzos* ,‡ † School of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia ‡ CSIRO Manufacturing, Research Way, Clayton, Victoria 3168, Australia * S Supporting Information ABSTRACT: The annulative carbonylation of alkenyl- tethered arenediazonium salts using visible-light photo- catalysis in continuous flow is described. The method furnishes a diverse series of novel acetate-functionalized 2,3- dihydrobenzofurans at room temperature and moderate CO pressure (25 atm), delivering these products in a short time with straightforward scale-up. This continuous flow and free- radical approach overcomes the limitation of traditional Pd-catalyzed annulative carbonylation, giving valuable 2,3- dihydrobenzofurans in a predictable and regioselective manner. A nnulative carbonylation is an attractive strategy for the synthesis of carbonyl-containing N- or O-heterocycles. 1 The intramolecular Heck-type annulative carbonylation of allyl-2-iodophenyl ethers and amines provides a direct route to acetaldehyde-functionalized benzofuran, benzopyran, indoline, and tetrahydroisoquinoline derivatives. 2 A limitation of this approach relates to multiple product distribution derived from competitive biscarbonylation, carbometalation, and β-hydride elimination pathways following oxidative addition. 3 This protocol is particularly challenging for the synthesis of pharmaceutically relevant 2,3-dihydrobenzofurans (Scheme 1a). 4 Free-radical carbonylation offers an advantageous alternative to Pd-catalyzed carbonylation of aryl (pseudo)halides. 5 The radical-mediated carbonylation of alkenyl-tethered aryl halides has been applied to the synthesis of acetaldehyde-function- alized O-heterocycles using organostannane reagents (Scheme 1b). 6 The limitations of traditional free-radical carbonylation methods relate to the low regioselective control over the cyclization pathway, the requirement for high-pressure CO (>80 bar), and a strong radical acceptor coupling partner. These factors have encouraged the development of improved methods for radical carbonylation. In 2015, Xiao reported a single example of free-radical annulative alkoxycarbonylation of 2-allyloxybenzenediazonium salt mediated by organophotor- edox catalysis. 7 This marked a notably different reactivity manifold to previous radical methods, as simple nucleophiles could be engaged as coupling partners. Despite this milestone, the photoredox-mediated carbonylative cyclization of alkenyl- tethered aryl(pseudo)halides has not been developed. This is likely due to the practical and safety implications arising from the use of CO gas at high pressures (≥80 atm) and the requirement of specialized autoclave photoreactors, impairing accessibility and scalability. In this letter we report a method for the annulative carbonylation of alkenyl-tethered arenediazonium salts using visible-light photocatalysis in continuous flow processing (Scheme 1c). Our approach provides access to 3-acetate- substituted 2,3-dihydrobenzofurans under mild reaction conditions with significant chemo- and regioselectivity. The application of continuous flow processing permits short reaction times (200 s), low partial pressure of gaseous CO (25 atm), and straightforward scale-up. We proposed that the 3-acetate-functionalized 2,3-dihydro- benzofurans could be generated from allyloxy-tethered benzenediazonium tetrafluoroborate (I) via a photoredox catalysis manifold (Scheme 2). Diazonium tetrafluoroborates Received: June 24, 2018 Scheme 1. Synthesis of Acetate-Functionalized 2,3- Dihydrobenzofurans via Annulation/Alkoxycarbonylation Cascade Letter pubs.acs.org/OrgLett Cite This: Org. Lett. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.orglett.8b01971 Org. Lett. XXXX, XXX, XXX-XXX Downloaded via MIAMI UNIV on July 20, 2018 at 12:25:38 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.