Selective alkylation of pyrimidine compounds.
Pyrimidines and pyrimidin-2(1H)-ones are used as starting materials for the synthesis of various compounds with pharmacological effects. For example, trihalomethyl-substituted pyrimidines show effects as hepatitis C inhibitors or against cancer and are therefore interesting substances for drug development. Chemists at IPB, together with partners from Brazil, have now developed new alkylation methods for these compounds. They report the direct and selective alkylation to prepare N- or O-alkylated trihalomethyl pyrimidines using 5-bromo enone/enaminone. By choosing specific substituents at position 6 of the pyrimidin-2(1H)-one ring the reaction could successfully be steered toward N- or O-alkylated products. A subsequent ring closure at the resulting enaminone moieties of the alkylated products yielded the corresponding di- and triheterocyclic conjugates. The new method has the advantage that it is less complex, since, for example, no protective groups have to be introduced to bring about selectivity. With the good to very good yields, important starting materials for further reactions can be produced in this way.
Original publication:
Mateus Mittersteiner, Genilson S. Pereira, Yuri Silva, Ludger A. Wessjohann, Helio G. Bonacorso, Marcos A. P. Martins, and Nilo Zanatta. Substituent-Driven Selective N-/O-Alkylation of 4-(Trihalomethyl)pyrimidin-2(1H)-ones Using Brominated Enones. J Org Chem 2022 87 (7), 4590-4602. DOI: 10.1021/acs.joc.1c02919
