1,2,3,4-Tetrahydroquinolines (THQ) and quinolines are nitrogen-containing heterocycles that play a vital role in the fields of medicinal chemistry and agrochemicals. Though versatile cyclisation methods such as the Povarov, Friedländer and Doebner-Miller reactions have been widely used in laboratories worldwide to access these motifs, modern advances in photoredox and radical chemistry have revitalized the field of cyclisation reactions and thus inspired chemists to discover new routes to diversely functionalized heterocycles. Control of stereochemistry and the incorporation of azaarene rings into products represent ongoing challenges in the development of new synthetic methodologies, particularly for application in medicinal chemistry.<br/><br/>We have developed an efficient light-mediated cyclisation starting from 2-vinylanilines and conjugated aldehydes to selectively yield either substituted tetrahydroquinoline products with typically high dr or, under photoredox conditions, quinoline derivatives. This atom economical process proceeds under mild conditions, with the scope giving excellent site selectivity and functional group tolerance, paying particular focus on azaarene containing substrates. A detailed mechanistic investigation using spectroscopic, experimental and DFT calculations explores divergent pathways and the key role of imine and iminium intermediates in the absorption of visible light to generate reactive excited states. The synthetic utility of the reactions is demonstrated by performing both methods on gram scale quantities in both batch and flow alongside further manipulation of the medicinally relevant heterocyclic products.

Visible light-mediated cyclization reaction for the synthesis of highly-substituted tetrahydroquinolines and quinolines

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