Palladium-Catalyzed Cyclization of Propargylic Compounds

Abstract

Many groups have explored the scope of the palladium-based cyclization of propargylic compounds since Tsuji's first report in 1985. Through the proper positioning of an internal nucleophilic center and the judicious selection of an appropriate external nucleophile, the synthetic chemist can effectively assert control over the course of the reaction and its products. However, initial investigations were very limited: only heterocyclic compounds were originally synthesized. We have found the palladium-catalyzed cyclization of propargylic compounds to be a very efficient method for producing both carbocyclic and heterocyclic compounds. In this Account, we discuss the cyclization reactions of functionalized propargylic compounds with a variety of nucleophiles that we have developed over the past few years. We also review similar reactions reported by other groups. We focus here on the cyclization of functionalized propargylic compounds containing a carbon nucleophilic center that is in close proximity to the propargylic moiety. We conducted a detailed investigation of their cyclizations with carbon nucleophiles, with nitrogen nucleophiles, with oxygen nucleophiles, and without nucleophiles. We have developed several efficient and useful methods for the synthesis of indenes, naphthalenes, polycycles, and spirocyclic compounds. All of these reactions proceed satisfactorily under very mild conditions; high regio- and stereoselectivity have been observed as well. In the course of our studies, we provided the first demonstration of a novel tandem C-H activation/bis-cyclization reaction of propargylic compounds with terminal alkynes. In addition, we used external nucleophiles to investigate the cyclization of functionalized propargylic compounds that bear an unsaturated carbon-carbon or carbon-heteroatom bond. We presented the first report of the use of external nucleophiles to initiate a novel cyclization of functionalized propargylic compounds containing an electrophile. This revelation provided a fresh perspective through the discovery of a new type of domino cyclization of propargylic compounds. Metal-catalyzed cyclization of propargylic compounds can provide indenes, cyclopentanones, cyclic carbonates, benzofurans, and a range of other cyclic molecules. A thorough understanding of the mechanisms involved in this class of reaction affords exceptional synthetic control, as shown here by our development of efficient procedures and reagents for palladium-catalyzed propargylic cyclizations.