Michael-type Addition as a Convenient Method for Regioselective N-Alkylation of Ambident Uracils

A review of the Michael-type addition as one of the convenient synthetic methods to N-functionalisation of the uracil ring - against the background of other typical alkylation methods - is presented. The topic of N1-versus N3-regioselectivity in alkylation reactions is emphasised since this differentiation is essential in the various, especially medicinal, applications of substituted uracils. Specifically, the addition of uracils to acrylic acceptors at the N1-position is frequently used in the first stage of the synthesis of pyrimidinic acyclic nucleosides. In turn, the N3-position of the uracil ring is useful in further transformations, like anchoring of biologically active fragments in conjugates for radiochemotherapy or carriage of covalently bonded drug molecules. Nevertheless, N3-substituted derivatives of pyrimidine nucleosides can, themselves, play various therapeutic roles. Fundamental theoretical premises are also detailed, with regard to the rationale behind the orientation of alkylation.