Development of Ti-mediated multicomponent syntheses via cycloaddition and insertion reactions

Abstract

Nitrogen-containing compounds are extremely prevalent in bioactive molecules, dyes, electronics, and other materials. Thus, the development of practical synthetic routes to a diverse library of N-containing compounds is vital. Condensation reactions have been traditionally employed to access highly functionalized N-containing compounds. However, these reactions typically exhibit poor chemoselectivity, and frequently require extensive pre-construction of carbon skeletons. These limitations make the development of metal-mediated or -catalyzed multicomponent reactions from simple starting materials an attractive alternative. Given its high abundance and low-cost, Ti is an excellent candidate for facilitating these reactions. Herein, efforts to develop new Ti-mediated or -catalyzed multicomponent transformations for the synthesis of N-containing organic compounds and N-heterocycles are presented. The modular construction of unsymmetrical α-diimines has been achieved through the diimination of alkynes using Ti imidos, nitrosos, and nitriles. This reaction features a key diazatitanacyclohexadiene intermediate, generated ¬in-situ, that undergoes a series of cycloaddition and retrocyclization reactions. The reactivity of this titanacycle towards other unsaturated substrates and electrophiles has been explored, culminating in the development of a multicomponent method for the synthesis of 1,2-dihydropyrimidines. Finally, a newly developed Ti-catalyzed multicomponent synthesis of 2,3-annulated pyrroles from alkynes, 1,2-cyclononadiene, and azobenzene is presented, and the selectivity of other allenes has been assessed. Importantly, all of these Ti-mediated reactions feature key electrocyclic mechanistic steps, and it is becoming increasingly clear that these are a general feature of titanium’s reactivity that can be exploited for the design of new synthetic methods.