Synthesis of four members heterocycles via photochemical and multicomponent reactions

During the three years of my PhD, I focused my research on the development of novel methodologies for the synthesis of four members cycles, taking advantage of photochemical and multicomponent approaches and alternative operating systems. All these processes involve the visible light-mediated Wolff Rearrangement of α-diazoketones into ketenes. The Ketene Two Photons Four Component Reaction is a useful and direct synthetic method to obtain oxetanes. It derives from the combination of the Ketene Three Component Reaction (and its silylative version) and the Paternò-Büchi Reaction. The versatility and the selectivity of the process in terms of regioselectivity, diastereoselectivity and siteselectivity were investigated. Furthermore, an optimization of the reaction through a Design of Experiment (DoE) was carried out. A Paternò-Büchi Reaction between a ketene and a 1,2-diketone was studied for the synthesis of β-lactones. An investigation of the optimal reaction conditions was performed realizing many designs (DoE), screening the parameters both in batch and in a continuous flow system. The reaction was also successfully tested with different diazoketones and mixed benzils, showing remarkable versatility and a complete regioselectivity. The development of a flow procedure of the photoinduced Ketene 3-Component Staudinger Reaction was achieved for the synthesis of β-lactams. This methodology displays the use of a packed column with a dehydrating agent directly connected to a photoreactor. Flowing across the system the mixture of aldehyde, amine and diazoketone, it is possible to promote the imine formation in the packed-bed and the consequent Staudinger cycloaddition thanks the visible-light irradiation. The optimization of the conditions and the fine-tuning of the set-up for the three-component reaction were carried out in flow, achieving a performance much higher than the batch one. Moreover, a library of compounds was realized, isolating them in a moderate and high yield.