Intramolecular Diels-alder and Alder Ene Reactions

Abstract

Enhancing synthetic efficiency requires the development of synthetic reactions that, to the extent possible, are simple additions wherein everything else is required only in catalytic amounts. The Alder ene reaction constitutes a classical reaction that meets this requirement that has much unrealized potential. A transition-metal-catalyzed version helps to increase that potential by permitting this reaction to proceed under mild conditions. A significant benefit of transition metal catalysis is the feasibility of diverting the reaction along pathways not feasible under thermal conditions. The synthesis of 1,3-dienes rather than 1,Cdienes is a very important diversion because of the utility of 1,3-dienes as reaction partners in the Diels-Alder reaction, another highly atom economical process. A catalyst derived from palladium acetate cycloisomerizes 1,6-and 1,7-enynes to dialkylidenecyclopentanes and-cyclohexanes. 1,3-Diene formation is favored over the Alder ene process by both steric and electronic effects. The reaction is highly chemoselective-tolerating a wide diversity of functionality including hydroxyl groups, ketones, esters, alkynyl and enol ethers, alkynyl and vinyl silanes, and enones. Many of the substrates are available by palladium-catalyzed alkylation reactions-highlighting the effectiveness of palladium catalyzed methodology in organic synthesis. The atom-economical nature of these reactions combined with the Diels-Alder reaction permit butadiene and dimethyl propargylmalonate to be molded into a polyhydro-as-indacene. The mechanism of this reaction may involve a tautomerization of an enynePd(+2) complex to a pallada(+4)cyclopentene intermediate as a key step. The Alder ene reaction (eq 1, X = carbon) has a great deal of promise yet to be realized in complex synthesis.' Like its electronic relative, the Diels-Alder reaction, this simple addition typifies the kind of synthetic reaction that maximizes atom economy. Unlike the Diels-Alder reaction, selectivity issues have restricted its applicability. The limitations stem, in part, from the high temperatures required and low chemoselectivity of the thermal process. The oxaene reaction (eq 1, X = 0) has drawn more attention because of the ease with which it can be catalyzed by Lewis acids, thereby lowering the requisite temperatures of reaction and enhancing the chemoselectivity.2 An additional benefit of Lewis acid catalysis has been the feasibility of catalytic asymmetric induction.3 Catalysis for the Alder ene reaction could bring similar benefits.' Indeed, recent efforts in these laboratories have revealed the feasibility of using transition-metal complexes to catalyze both the inter-4 and intramolecular5 versions-the latter being cycloisomerizations.6 A major additional benefit of a transition-metal-catalyzed process is the feasibility of diverting the reaction to new pathways not feasible in the thermal reaction. Consider one of the mechanistic rationales of the palladium catalyzed cycloisomer-ization of enynes (Scheme 1, path a). Assuming a palladacy-clopentene intermediate (eg., l), the Alder ene product derives Scheme 1. Path for the Pd(+2)-Catalyzed Cycloisomerization of Enynes 1 from preferential @-elimination of the C-H, bond to generate the 1,Cdiene product 2. This rationale suggests that a 1,3-diene product 3 may be possible if @-elimination of the C-Ht, bond would dominate. While the geometry of the palladacycle 1 may favor path a, path b need not be impossible.' The general importance of 1,3-dienes in cycloadditions makes path b of prime interest. The mechanism of the Alder ene reaction precludes formation of such a product in a thermal process. Dialkyli-denecycloalkenes are normally particularly difficult 1,3-dienes (4) Trost, B. M.; Indolese, A. Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, TheNetherlands, 1991; pp 277-282. (7) Cf. Pd: Diversi, P.; Fasce, D.; Santini, R. J. Orgonomet. Chem. 1984, 269, 285. Diversi, P.; Ingrosso, G.; Lucherini, A.; Martas, S. J. Chem. SOC., Dalton Trans. 1980, 1633. Diversi, P.; Ingrosso, G.; Lucherini, A. Chem. Commun. 1978, 735. Pt: Whitesides, G.; White, J.; McDermott, J. J. Am. Chem. SOC. 1976,98,6521. Grubbs, R.; Erick, H.; Biefield, C. Inorg. Chem. 1973,12,2166. Ni: Grubba, R. H.; Miyeshita, A,; Liu, M.; Burk, P. J. Am. Chsm. Soc. 1978,100,2418. Doyle, M. J.; McMwking, J.; Binger, P. Chrm. Commun. 1976,376, Ru: Mitaudo, T,; Zhang, S.; Nogao, M.; Wotonabe, Y.