C–H activation: A strategic approach toward lactams using transition metals

Abstract

The presence of lactam motif in surrounding biological and pharmaceutical arenas themselves calls for an easy and synthetically viable route toward its synthesis. There are multiple ways to achieve molecular targets; however, activating a C–H bond has attracted the chemical community for decades. Recent advances introduce a spectrum of mild routes to activate very inert C–H bonds, and here, it becomes highly important for the manufacturing of lactam moieties. Even the activation of distal-located C–H bonds can generate a chance of synthesizing macromolecules. In this review, we discuss the ways in which C–H activation can help to create molecular complexities containing lactam skeleton. Lactams are ubiquitous in various industrial sectors, especially the pharmaceutical sectors. Different classes of inhibitors from the earliest β-lactamase inhibitors to the most recent SARS-CoV-2 embodies (mainly) four- or five-membered lactam scaffolds. Traditional synthetic routes have been used to carry out the development of diverse lactam derivatives but the synchronous C–N coupling and ring closure has not been a very facile process. Thus, lactam formation has been undertaken via the transition metal-mediated C–H activation technique, which not only provides a milder and functional group-tolerant method but also traverses an expeditious route to carry out the synthesis of small membered rings. This review discusses various modus operandi such as alkylation, alkenylation, carbamoylation, amidation, and amination, each of which can be a linchpin in the formal synthesis or semi-synthesis of a diverse range of pharmacophores as well as several classes of potential drug candidates. The review focuses mainly on the routes to synthesize differently sized lactam motifs by exploiting different avenues of C–H functionalization strategies. Lactam motifs are ubiquitous in various drug candidates and biologically active motifs. C–H activation establishes itself as a sustainable method to synthesize these strained rings via alkylation, alkenylation, amidation, amination, and carbonylation. Also, the utility of lactam rings has been demonstrated by the recent discovery by Pfizer of an anti-COVID-19 drug.