Flow Microreactors and Photochemistry as Enabling Technologies for the Straightforward Preparation of Four-Membered Azaheterocycles

Azaheterocycles are ubiquitous and essential in a plethora of biologically active natural derivatives and marketed drugs. Although less studied than the higher homologous counterparts, four-membered aza-heterocycles are emerging motifs in drug discovery programs. Indeed, molecules that incorporate the azetidine core display a variety of pharmacological activities, such as anticancer, antibacterial, antimicrobial, antischizophrenic, antimalarial, antiobesity, anti-inflammatory, antidiabetic, antiviral, antioxidant, analgesic, and dopamine antagonist activities, and are also used for the treatment of central nervous system disorders. Accordingly, the development of efficient and general synthetic methods for the construction and decoration of the azetidine ring constitutes a hot topic in modern synthetic chemistry. In this contribution, our recent efforts on the use of continuous flow microreactors and photochemistry as valuable tools to access functionalized azetidines are described. In particular, a light-mediated hydrothiolation of C2-functionalized azetines to prepare 2,3-disubstituted azetidines will be detailed. Furthermore, C2-functionalized azetines were also subjected to convenient continuous flow hydrogenation using a Pd/C packed-bed reactor to produce the corresponding C2-functionalized azetidines. The use of flow technology allows us to improve reaction productivity and address sustainability concerns.