Synthesis and functionalization of spirohydantoins with C(sp2)-N cross-coupling reactions

Abstract

Spirohydantoins are bicyclic compounds encountered in biologically active structures such as anticonvulsants and antibiotics. However, the synthesis of spirohydantoins is an underdeveloped field and is thus interesting to investigate. This study investigates the synthesis and functionalization of spirohydantoins, and is divided into three parts: The first part describes a microwave-assisted synthesis of spirohydantoins. The investigation showed compatibility with cyclic ketones of varying ring sizes and ketones with substituents on the β-carbon. With the right stoichiometry, a dispirohydantoin was formed using the same method. The second part describes a new, simple and efficient method for C(sp2)-N-bond formation on spirohydantoins using a Cu-catalyzed cross-coupling reaction with boronic acid as coupling partner. The method showed excellent regioselectivity and allowed for the synthesis of a diverse scope of products with good to excellent yields. The synthesis operated well with neutral, electron-rich and electron-poor aryl boronic acids, as well as with thiophenyl- and styrylboronic acid. Overall, the investigation produced 13 new N-3-substituted spirohydantoin structures. The third part describes an investigation into the underdeveloped synthesis of diarylated spirohydantoins. This investigation showed excellent results with a Cu-catalyzed cross-coupling using an aryl halide as coupling partner and resulted in the formation of a new diarylated spirohydantoin in 94 %.