Thermal Heteroannulation Route to Pyrido[4,3-d]pyrimidines

Significance

Reported is the synthesis of substituted pyrido[4,3-d]pyrimidines by thermolysis of 2,4-disubstituted 6-alkynylpyrimidine-5-carbaldehydes in the presence of tert-butylamine. The mechanism of the reaction was shown to proceed via the imine-enamine shown, which then undergoes cyclization to form the product. Three examples of the intermediate imines were isolated by heating the reaction mixture at only 80-90 ˚C. These were subjected to both heating in DMSO and in tert-butylamine to give the expected products. The only common amine to participate in this reaction was shown to be tert-butylamine. The method is precedented by the work of Larock and co-workers (e.g., Q. Huang, J. A. Hunter, R. C. Larock J. Org. Chem. 2002, 67, 3437) in which the tert-butyl cation stability dictates the cleavage of the incipient iminium species.