Tandem multicomponent cycloaddition

In view of the multicomponent nature of the tandem [4 + 2] / [3 + 2] cycloaddition, the potential for a combinatorial approach to the synthesis of nitroso acetals has been investigated on solid-phase supports. The incorporation of either the dipolarophile or the starting nitroalkene on a Wang-type resin is compatible with the tandem cycloaddition promoted at high pressures (Schemes 2.28 and 2.29). The solid-supported nitroso acetals are subsequently liberated (in moderate yields from the staring nitroalkene) upon the addition of a catalytic amount of potassium cyanide in triethylamine and methanol or by reduction with lithium aluminum hydride (LAH) (261,264). 

For selected examples, see (a) G. Zhao, X. Sun, H. Bienayme, J. Zhu, J. Am. Chem. Soc. 2001, 123, 6700-6701. Activation of a terminal carboxylic acid by an internal oxazole a novel synthesis of macrocyclodepsipeptide. (b) P. Janvier, M. Bois-Choussy, H. Bienayme, J. Zhu, Angew. Chem. Int. Ed. 2003, 42, 811-814. A one-pot four-component (ABC ) synthesis of macrocycles, (c) L. A. Wessjohann, E. Ruijter, Mol. Divers 2005, 9, 159-169. Macrocycles rapidly produced by multiple multicomponent reactions including bifunctional building blocks (MiBs). (d) C. Bughin, G. Zhao, H. Bienayme, J. Zhu, Chem.-Eur. J. 2006, 12, 1174-1184. 5-Aminooxazole as an internal traceless activator of C-terminal carboxylic acid rapid access to diversely functionalized cyclodepsipeptides. (e) T. Pirali, G. C. Iron, J. Zhu, Org. Lett. 2006,8,4145 148. One-pot synthesis of macrocycles by a tandem three-component reaction and intramolecular [3 +2] cycloaddition. 

Additionally, Pd-catalyzed cross-coupling reactions were explored in pyridines synthesis also. In 2007, a multicomponent sequential process for the synthesis of trisubstituted pyridines was reported [59]. The reaction involves the formation of an enamine by Pd-catalyzed amination of an alkenyl bromide, formation of a 2-aza-1,3-butadiene by Pd-catalyzed cross-coupling of a trimethylsilylimine with an alkenyl bromide, and Lewis acid (Yb(OTf)3 (20mol%)) catalyzed cycloaddition between the enamine and the azadiene. Moderate yields can be achieved (Scheme 3.26). A zinc-mediated tandem reaction of nitriles... 

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