Solid‐Supported [2+2+2] Cyclotrimerizations

Abstract

The transition-metal-catalyzed [2+2+2] cyclotrimerization of a diyne and an alkyne provides a convergent route to highly-substituted aromatic rings. This reaction possesses distinct drawbacks, especially low chemo- and regioselectivities, which hamper its application in combinatorial synthesis. These problems have been solved by the development of solid-supported [2+2+2]-cycloaddition reactions. If conducted on a solid-support, this reaction enables rapid combinatorial access to diverse sets of carbo- and heterocyclic small-molecule arrays. The scope of this methodology has been investigated by examining different immobilization strategies, different diyne precursors, and a variety of functionalized alkyne reaction partners. Overall, isoindoline, phthalan, and indan libraries were assembled in good to excellent yields and with high purities.

Cyclization Reactions for the Synthesis of Phthalans and Isoindolines­

“…In 2006, Deiters and co-workers reported the [RhCl(PPh 3 ) 3 ]catalyzed cycloaddition of polystyrene-supported dipropargylamines 149 and alkynes 47 to give the corresponding isoindolines 150 in excellent yields after deprotection with dilute HCl (Scheme 56). The experimental conditions used for these solid-supported cyclotrimerization reactions were compatible with a variety of functionalities such as alkyl chains, hydroxy and alkoxy groups, aromatic rings, cyano and silyl groups, chlorine, and esters.…”

Rhodium-Catalyzed [2+2+2] Cycloaddition of Alkynes for the Synthesis of Substituted Benzenes: Catalysts, Reaction Scope, and Synthetic Applications

“…The corresponding isoindolines (Scheme 26), indans (Scheme 27), and phthalans (Scheme 28) were obtained after deprotection. 47 Scheme 26…”

Chemo‐ and Regioselectivity Enhancement in Solid‐Supported Reactions

“…37 After cleavage from the resin, the isoindolines 70 were obtained in good to excellent yield and with high purity (Scheme 6.17). A similar chemoselective approach was also accomplished by Martinez and coworkers utilizing microwave irradiation and an iridium catalyst.…”