Polysubstituted benzenes, regioselective

Recent Advances In Fhe Transition Metal Catalyzed Regioselective Approaches To Polysubstituted Benzene Derivatives, Saito. S.-. Yamamoto. Y. Chem. Rev., 2000, 100, 294. 

Transition-metal-catalyzed intermolecular [2+2+2] cyclotrimerization of alkynes to benzenes has been extensively studied with several catalyst systems involving palladium, cobalt, nickel, rhodium, and other transition metals. This methodology can be applied to the preparation of polysubstituted benzenes. The major challenge of this transformation is control of regioselectivity of unsymmetrical alkynes, particularly in the cross-cyclotrimerization of two or three alkynes. 

Polysubstituted benzenes are widely used both in industry and in research laboratories. Regioselective construction of polysubstituted benzenes is usually achieved through the gradual introduction of substituents in the aromatic ring by Friedel-Crafts reaction or similar reactions of electrophilic substitution or through organometallic synthesis. In 1948, Reppe reported the [2+2+2] trimerization of substituted acetylenes in the presence of transition metals to form polysubstituted benzenes (Scheme 1.1) [1]. 

Regioselective Syntheses of Polysubstituted Benzenes Catalyzed by Transition Metal Complexes... 

Saito, S. and Yamamoto, Y. (2000) Recent advances in the transition-metal-catalyzed regioselective approaches to polysubstituted benzene derivatives. Chemical Reviews, 100(8), 2901-2916. 

Xi, C., Chen, C., Ling, J. and Hong, X. (2005) Pd-catalyzed one-pot multicomponent coupling reaction for the highly regioselective synthesis of polysubstituted benzenes. Organic Letters, 7 2), 347-349. 

Chapter 15 described the use of this transformation in the preparation of monosubstituted benzenes. In this chapter we analyze the effect of such a first substituent on the reactivity and regioselectivity (orientation) of a subsequent electrophilic substitution reaction. Specifically, we shall see that substituents on benzene can be grouped into (1) activators (electron donors), which generally direct a second electrophilic attack to the ortho and para positions, and (2) deactivators (electron acceptors), which generally direct electrophiles to the meta positions. We will then devise strategies toward the synthesis of polysubstituted arenes, such as the analgesics depicted on the previous page. 

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