A Knoevenagel condensation of various aldehydes with malononitrile effectively proceeded in the presence of hydroquinone/benzoquinone mixed catalysts at room temperature in H2O. Furthermore, γ-deuterium-labeled α,β-unsaturated nitrile derivatives were also constructed via a deuteration of an aliphatic aldehyde in D2O using a basic resin and the subsequent Knoevenagel condensation.