N-lactam radicals: light-driven generation and application in APIs synthesis

We report the synthesis, the photocatalytic activation, and the application in APIs synthesis of a novel class of nitrogen-centred radicals (NCRs): N-lactam radicals. According to their structure, N-lactam radicals can be classified as electrophilic Amidyl NCRs, which can be generated by homolytic cleavage of a nitrogen-involving bond, after a single electron transfer (SET) triggered by light [1]. The great potentiality of NCRs is the possibility to be exploited as highly energetic synthetic intermediates, to introduce nitrogen-containing functional groups in complex target molecules, through a completely innovative strategy that relies on the combination of the chemistry of radicals with photocatalysis. The use of light in chemical transformations has been object of great studies in the last decades, enhancing the efficiency of radical-involving processes. Photochemistry underwent a great growth since it opened the door to the development of greener and more sustainable methods. The possibility to perform challenging reactions under milder conditions, using cheap and safe redox species made photocatalysis an appealing and powerful synthetic tool. The first goal of this work was the development of an efficient synthetic route for the radical precursor, the N-aminopyridinium salt 1. Taking inspiration from the work of Studer and coworkers, the desired precursor was successfully synthesised on a 10-gram scale, in 48% overall yield, through a five-step synthesis, starting from cheap and commercially available benzophenone hydrazone [2]. Once synthesised the precursor, a light-mediated process was exploited to generate the desired radical. The light-triggered addition of the radical to an electron-rich aromatic ring was the model reaction exploited to fine tune the conditions for the radical generation and it became the opportunity to study its reactivity [2]. Once achieved this result, the reactivity of the N-lactam radical was further explored testing a nucleophile of a different nature: the enamine of aldehydes [3]. This reaction was also developed in a stereoselective version, for the application in the synthesis of an API.