Three-Component Synthesis of Functionalized Pyridines

Significance

Reported is a study of the scope of a three-component pyridine-forming reaction which was discovered earlier by Reissig and co-workers (Chem. Eur. J. 2004, 10, 4283). The reaction affords highly functionalized pyridines containing, for example, two differentiated oxygen functions, thus allowing opportunity for selective Pd-catalyzed cross-couplings. The scope of the reaction with respect to carboxylic acids, nitriles, and alkoxyallenes is reasonably broad and the products are obtained in poor to good yields. Furthermore, the use of dinitriles allows the synthesis of complex dipyridyl derivatives. The overall yields from the latter reaction are poor, but one has to consider that eight new bonds are formed in one transformation.

Comment

Pyridines are important structural units in many biologically important molecules, for example in the antileukemic and antineoplastic theonelladins C and D (T. Tsunoda et al. Tetrahedron Lett. 1999, 40, 7359). The reported unique methodology affords functionalized pyridines which may be useful building blocks since: a) they contain pharmaceutically interesting trifluoromethyl or perfluorophenyl groups, in addition to other functional groups (P. Lin, J. Jiang Tetrahedron 2000, 56, 3635), and may be readily connected via C-C cross-coupling reactions; b) they may provide new elements for supramolecular assemblies (see first review below); and c) they may be used for the construction of interesting ligands for asymmetric catalysis (see second review below). Studies concerning the application of the new methodology towards the construction of other heterocycles are anticipated.

Reviews

O. Mamula, A. von Zelewsky Coord. Chem. Rev. 2003, 242, 87; H.-L. Kwong et al. ­Coord. Chem. Rev. 2007, 251, 2188.