Competition between Alkenes in Intramolecular Ketene-Alkene [2 + 2] Cycloaddition: What Does It Take to Win? Guillaume Be´langer,* Franc¸ ois Le´vesque, Julie Paˆ quet, and Guillaume Barbe Laboratoire de synthe` se organique et de de´ veloppement de strate´ gies de synthe` se, De´ partement de Chimie, Universite´ de Sherbrooke, 2500 boulevard Universite´ , Sherbrooke, Que´ bec J1K 2R1, Canada guillaume.belanger@usherbrooke.ca Received September 17, 2004 In the course of developing a new synthetic methodology using ketenes in sequential cycloaddition steps, we were faced with a competition problem with molecules containing a ketene tethered to more than one reacting partner. To pinpoint the electronic and tethering requirements for a chemoselective reaction, we undertook a series of ketene-alkene [2 + 2] cycloaddition competition experiments. Those experiments were conducted on molecules containing either two identical alkenes having different tether lengths or two alkenes having the same tether length but being electronically different. We demonstrated that the reaction is much faster for forming five-membered rings than six-membered rings and calculated the Hammett constant F for intramolecular ketene-alkene [2 + 2] cycloadditions to be -1.39. Introduction Since their first preparation in 1905, 1 ketenes have been widely studied due to their unique reactivity. Many different ketene-alkene [2 + 2] cycloaddition mecha- nisms have been proposed, 2 and nowadays, two of them are commonly accepted: a stepwise mechanism involving sequential nucleophilic additions via a zwitterionic in- termediate 3 and a concerted cycloaddition. The latter is an antarafacial process, thermally allowed according to the frontier molecular orbital (FMO) theory, 4 and could be highly asynchronous. 2,5 It is also suggested that these two mechanisms may compete, depending on the nature of the alkene reacting with the ketene. 2 As we were developing a new synthetic strategy using ketenes in sequential cycloaddition steps, we were faced with a competition issue with molecules containing a ketene tethered to more than one reacting partner. In fact, our strategy is to build tricyclic skeletons of natural products in one step from linear precursors (Scheme 1). Because the first [2 + 2] cycloaddition would need to be chemoselective, we turned our attention to competition studies to determine the electronic and tethering require- ments for such a chemoselectivity. Intramolecular ketene-alkene [2 + 2] cycloadditions 6 were shown to form five-membered rings more easily than six-membered rings. 7 However, the only evidence supporting this affirmation is based on shorter reaction time and higher yields for the formation of five-membered rings. No competition experiments were run to quanti- (1) Staudinger, H. Chem. Ber. 1905, 38, 1735-1739. (2) For a review on proposed [2 + 2] cycloaddition mechanisms of ketenes with alkenes, see: Tidwell, T. T. Ketenes; Wiley: New York, 1995; pp 486-502, and references therein. (3) (a) Corey, E. J.; Arnold, Z.; Hutton, J. Tetrahedron Lett. 1970, 307-310. (b) Wagner, H. U.; Gompper, R. Tetrahedron Lett. 1970, 2819-2822. (c) Gompper, R. Angew. Chem., Int. Ed. Engl. 1969, 8, 312-327. (d) Becker, D.; Brodsky, N. C. J. Chem. Soc., Chem. Commun. 1978, 237-238. (4) (a) Fleming, I. Frontier Orbitals and Organic Chemical Reac- tions; Wiley: New York, 1976; pp 110-148. (b) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed, Engl. 1969, 8, 781-853. (c) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry; Verlag Chimie/Academic: New York, 1970. (5) For calculations of transition states for ketene-alkene [2 + 2] cycloadditions, see: (a) Bernardi, F.; Bottoni, A.; Robb, M. A.; Ven- turini, A. J. Am. Chem. Soc. 1990, 112, 2106-2114. (b) Wang, X.; Houk, K. N. J. Am. Chem. Soc. 1990, 112, 1754-1756. (6) For a review on intramolecular ketene-alkene [2 + 2] cycload- ditions, see: Snider. B. B. Chem. Rev. 1988, 88, 793-811. 10.1021/jo0483466 CCC: $30.25 © 2005 American Chemical Society J. Org. Chem. 2005, 70, 291-296 291 Published on Web 11/20/2004