Direct Photochemical Amination of Aromatics

The formation of aromatic carbon to nitrogen bonds is one of the most important processes used in the chemical industry. It is prevalent in many biologically-relevant molecules such as pharmaceuticals and agrochemicals. A modified Hofmann-Löffler-Freytag reaction, which allowed the direct functionalisation of aromatic C-H bonds using N-haloamines under UV-irradiation in highly acidic media, was first reported by Bock et al. in 1965.1 The reported conditions used concentrated sulfuric acid as solvent and demonstrated a minimal substrate scope.
Here, it has been shown that UV-irradiation of N-chloroamines with 10 equivalents of methanesulfonic acid in DCM allows for the intramolecular amination of unfunctionalised aryl C-H bonds to form tetrahydroquinolines. These novel conditions have been extended to 30 examples including in a concise synthesis of the alkaloid natural product angustureine. Furthermore, studies have helped elucidate a potential mechanism of the reaction and led to the discovery of a 1,2-alkyl migration reaction.
The reaction has also been shown to work in a continuous photochemical reactor. This was extended to work in a two-stage reactor where amines were chlorinated and reacted in situ to form tetrahydroquinolines directly.
Some of the substrates produced with the photochemical methodology have been tested in enzymatic deracemizations using genetically modified monoamine oxidase enzymes. Whilst modest activity was observed for a series of N-substituted tetrahydroquinolines, a group of natural products containing N-unsubstituted tetrahydroquinoline cores were successfully deracemized, with ee’s as high as 90% obtained.