Pyrimidine Synthesis via a Titanium-Catalyzed Multicomponent Reaction

Significance

A titanium-catalyzed synthesis of pyrimidines is reported. First, a three-component condensation of amines, an isocyanide, and alkynes leads to 1,3-diimine tautomers which, without isolation, are subjected to reaction with amidines to afford 2,4,5-trisubstituted pyrimi­dines. The basis of the reaction and the reason for the titanium catalyst choice lies in a previous report on 1,3-diimine synthesis (C. Cao, Y. Shi, A. L. Odom J. Am. Chem. Soc. 2003, 125, 2880). The substrate scope was adequately studied and the yields for the two-step, one-pot process range from poor to modest. In the case of unsymmetrical alkynes, the observed regioselectivity (R^² = Ar) is rationalized on the electronic effects stabilizing the formed azametallacyclobutene intermediate. In one case (R^² = n-Bu, R^³ = H) the ­regio­selectivity was controlled by changing the catalyst between [Ti(NMe)₂dpma] and [Ti(NMe)₂dpm].