Light-induced N-Lactam radicals generation under continuous flow conditions

Nitrogen-containing structures are widespread in both natural and synthetic organic compounds, including pharmaceutical products. Finding novel synthetic approaches for forming C-N bonds in a mild, sustainable, and potentially stereoselective way is a subject that captivates synthetic organic chemists. Over the past twenty years, photoredox catalysis[1] and flow chemistry [2] emerged as powerful methods for generating radical species in such conditions. The possibility to use light as traceless reagent plays a pivotal role in the development of green synthetic strategies, and flow setups can further enhance the performances of light-induced reactions. Additionally, the characteristics of flow reactors offers advantages in terms of both process scalability and safety, making flow chemistry an indispensable tool for organic chemists. Among the various nitrogen radical species, amidyl radicals[3] have interesting properties for synthetic purposes. The light-induced generation of N-lactam radicals, which are not know in literature, and their reactivity with aromatic substrates under flow conditions are the focus of this work. The N-radical precursor was synthesized by taking inspiration from the literature.[4] Different indole derivatives were successfully tested. The reaction proceeds in mild conditions, and the use of an organic photocatalyst makes this approach interesting since the use of expensive and polluting metal-based catalysts is avoided. The development of a flow setup permitted to achieve better results compared to a conventional batch reactor, significantly reducing the time required to complete the reaction. [1] M.H. Shaw, J. Twilton, D.W.C. MacMillan; J. Org. Chem. 2016, 81, 6898-6926 [2] M.B. Plutschack, B. Pieber, K. Gilmore, P.H. Seeberger; Chem. Rev. 2017, 117, 11796−11893 [3] J. Davies, S.P. Morcillo, J.J. Douglas, D. Leonori; Chem. Eur. J. 2018, 24, 12154–12163 [4] WO2021/013712A1; T.W. Greulich, C.G. Daniliuc, A. Studer; Org. Lett. 2015, 17, 254−257