A Direct Synthesis of Isocytosine Analogues by Carbonylative Coupling of α-Chloro Ketones and Guanidines

A valuable and direct method for the synthesis of 2-aminopyrimidin-4-one derivatives is described. The strategy relies on the Pd-catalysed carbonylation of alpha-chloro ketones in the presence of mono- and disubstituted guanidines. Although the strategy also gave 2-aminoimidazole derivatives as minor products, good chemoselectivity in favour of the six-membered ring was achieved in all experiments. The in-situ formation of a (beta-oxoacyl) palladium species has been invoked as the key step for the multicomponent process. Moreover, the method described could be of interest from a biological point of view, because it constitutes a straightforward strategy for the synthesis of structural analogues of the unnatural nucleobase iso-cytosine.