Metal-promoted intermediate-driven and multicomponent organic transformations

Abstract

Multicomponent reactions are in the forefront of synthetic methodology because they allow multiple transformations to occur in a single step. These reactions maintain high atom and step-economy, increasing synthetic efficiency and allowing for a decrease in chemical waste from things such as workups and purification. Herein, efforts to expanding the use of phenonium ions, azatitanacyclobutenes, and Pauson-Khand type reactions to further multicomponent reactions are reported. First, benzylic or homobenzylic stereocenters are present in many biorelevant natural products. These stereocenters are commonly installed via cross-coupling reactions employing expensive and/or inefficient transition metal catalysis. Mechanistic studies on an already established system to form these stereocenters via phenonium ions reveal the reaction to be complete in under 3 minutes and attempts to slow the reaction down to perform kinetic studies resulted in a change of mechanism. Next, the selective manipulation of C−C bonds is a growing area of research. We reported a formal insertion of diazo compounds into the sp2−sp3 C−C bond of benzyl bromide derivatives catalyzed by a simple Lewis acid. This regioselective reaction proceeds via a phenonium ion intermediate. Second, we report a new hydroaminative cyclization for 1,6 and 1,7 enynes using a simple Ti-imido precatalyst, [py2TiCl2(NPh)]2. The well-known [2+2] azatitanacyclobutadiene cycloadduct intermediate is intercepted by tethered alkenes, followed by protonolysis of the resultant metallacycle. Next, previously reported by the Tonks group was the synthesis of pyrazoles by a Ti-mediated multiple-component reaction using alkynes and nitriles. This work herein studies the effects of the intramolecular reaction of alkynes and nitriles under these conditions as well as using alkyne-nitriles under Fe/Ru catalysis conditions to form pyrazoles. Finally, precedented Ti-catalyzed Pauson-Khand reactions use expensive or non-commercially available Ti-catalysts which are not benchtop stable. We proposed that inexpensive commercially available TiCl4(THF)2 could be capable of catalyzing a Pauson-Khand reaction, based on previous reports on benchtop Ti-catalyzed pyrrole synthesis.