Palladium-Catalyzed Highly Chemo- and Regioselective Formal [2 + 2 + 2] Sequential Cycloaddition of Alkynes: A Renaissance of the Well Known Trimerization Reaction? † Vladimir Gevorgyan,* ,‡ Ukkiramapandian Radhakrishnan, §,⊥ Akira Takeda, § Marina Rubina, ‡ Michael Rubin, ‡ and Yoshinori Yamamoto* ,§ Department of Chemistry, University of Illinois at Chicago, 845 Taylor Street, Chicago, Illinois 60607-7061, and Department of Chemistry, Graduate School of Science Tohoku University, Sendai 980-8578, Japan vlad@uic.edu Received January 13, 2001 A new concept of highly chemo- and regioselective formation of the benzene ring by a palladium- catalyzed formal [2 + 2 + 2] sequential intermolecular trimerization of alkynes is proposed. Homodimerization of terminal alkynes and subsequent [4 + 2] benzannulation with diynes gives tetrasubstituted benzenes in moderate to good yields. The introduction of two different alkynes (terminal and internal) in the first step of the sequence allows for construction of pentasubstituted benzenes from three different acyclic acetylenic units. In all cases the tetra- and pentasubstituted benzenes are formed as a single reaction product without being accompanied by any of regio- or chemoisomers. A significant acceleration of the sequential trimerization reaction in the presence of Lewis acid/phosphine combined system was observed. Mechanistic studies reveal that the Lewis acid assisted isomerization of the E-enyne formed in the first step of the sequence to the more reactive Z-isomer is responsible for the observed acceleration effect. The proposed methodology provides a conceptually new and synthetically useful route to multifunctional aromatic compounds. Introduction Transition metal catalyzed trimerization of alkynes is one of the most powerful and general methodologies used to assemble the benzene ring. 1 Though known for more than 50 years, 2 the intermolecular version of this process is still plagued by poor regio- and chemoselectivity, which severely limits the scope of this method. Vollhardt succeeded in solving these problems for several types of intramolecular 3a or partially intramolecular 3b modes of cyclotrimerization: three new bonds were formed under the cobalt catalysis affording a cyclophane-type aromatic product in a chemo- and regioselective manner. Indeed, a mixture of two regioisomers, 1,2,4- and 1,3,5-trisubsti- tuted benzenes, is usually obtained in the homotrimer- ization of terminal alkynes, whereas heterotrimerization of three different acetylenes can yield up to 38 possible regio- and chemoisomers. It is generally accepted that the variety of regio- and chemoisomeric products of transition metal catalyzed intermolecular trimerizations of alkynes arises from the variety of different modes of orientation of the alkynes in assembling the metallocy- clopentadiene intermediate i. 1 Despite enormous efforts to control regio- and chemoselectivity of formation of i, little success was achieved for the intermolecular [2 + 2 + 2] cycloaddition reaction. 4 Recently, Ladipo et al. succeeded in regioselectively trimerizing terminal alkynes to 1,2,4-substituted benzenes using a calixarene-bound titanium complex. 5 Though the regioselectivity in this cyclotrimerization reaction is rigorously controlled by the steric demand of the calixarene cavity, this method is applicable only to the homotrimerization of terminal alkynes. A different one-pot approach has been recently reported by Takahashi et al. 6 in which the multisubsti- tuted benzenes were regioselectively synthesized from zirconocyclopentadienes prepared in situ from two dif- ferent alkynes and a third alkyne. Yet, this method requires the use of stoichiometric amount of two transi- tion metals: Zr and either Cu 6a or Ni. 6b Consequently, alternative approaches that are both catalytic in transi- † Presented at the 219th American Chemical Society National Meeting, March 2000, San Francisco, CA. * Ph: (312) 355-3579. Fax: (312) 355-0836. ‡ University of Illinois at Chicago. § Tohoku University. ⊥ Present address: Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake Sity, UT 84112-0850. (1) For recent reviews, see: (a) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539. (b) Schore, N. E. Chem. Rev. 1988, 88, 1081. (c) Trost, B. M. Science 1991, 254, 1471. (d) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49. (e) Grotjahn, D. B. Transition Metal Alkyne Complexes: Transition Metal-Catalyzed Cyclotrimer- ization. In Comprehensive Organometallic Chemistry II; Wilkinson, Stone, Abel, Eds.; Pergamon: Oxford, 1995; Vol. 12, p 741. (f) Gevorgyan, V.; Yamamoto, Y. J. Organomet. Chem. 1999, 576, 232. (g) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901. (2) For the first transition metal catalyzed trimerization of alkynes, see: Reppe, W.; Schlichting, O.; Klager, K.; Toepel, T. Justus Liebigs Ann. Chem. 1948, 560, 1. (3) For selective intramolecular alkynes trimerization, see for example: (a) Lecker, S. H.; Nguen, N. H.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1986, 108, 856. For partially intramolecular trimerization, see: (b) Berris, B. C.; Hovakeemian, G. H.; Lai, Y.-H.; Mestdagh, H.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1985, 107, 5670. See also ref 1 and references therein. (4) For regioselective stoichiometric reactions of i with diphenyl- acetylene, see: (M ) Co) (a) Wakatsuki, Y.; Kuramitsu, T.; Yamazaki, H. Tetrahedron Lett. 1974, 4549. (M ) Pd) (b) Maitlis, P. M. Acc. Chem. Res. 1976, 9, 93. (5) Ozerov, O. V.; Ladipo, F. T.; Patrick, B. O. J. Am. Chem. Soc. 1999, 121, 7941. Ozerov, O. V.; Patrick, B. O.; Ladipo, F. T. J. Am. Chem. Soc. 2000, 122, 6423. (6) (a) Takahashi, T.; Xi, Z.; Yamazaki, A.; Liu, Y.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 1998, 120, 1672. (b) Takahashi, T.; Tsai, F.-Y.; Li, Y.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 1999, 121, 11093. 2835 J. Org. Chem. 2001, 66, 2835-2841 10.1021/jo0100392 CCC: $20.00 © 2001 American Chemical Society Published on Web 03/23/2001