Selective monoarylation of naphthylpyrimidines with a variety of aryl chlorides through C–H bond activation in water was achieved by using a water-soluble [RuCl2-(η6-PhOCH2CH2OH)]2/phosphine catalytic system. The monoarylation occurred at the C-2 carbon of the naphthalene moiety, and selectively polysubstituted naphthylpyrimidines were obtained by a one-pot reaction involving a subsequent hetarylation with 2-pyridyl chlorides.