Mukaiyama became an assistant professor at the Tokyo Institute of Technology in 1958 and earned his full professorship in 1963. During this time, his main focus was on organophosphorus chemistry. While examining deoxygenation reactions involving phosphines, Mukaiyama found that the mercury(II) acetate employed as a catalyst would react with phosphorus(III) compounds to produce acetic anhydride. This initial example expanded into the concept of the redox condensation reaction, in which a weak acid and weak base catalyze a condensation by means of a redox reaction – this would become a primary research focus for Mukaiyama for much of his career. In the original reaction, the phosphine served as the reducing agent by accepting oxygen, while the mercury(II) was the oxidation agent that accepted hydrogens, resulting in the condensation of carboxylic acids with the loss of a molecule of water.
This framework was expanded to include the formation of a variety of other functional groups, including esters and amides, but the most significant was the synthesis of phosphoric esters using DEAD and an alcohol in 1967. The same year that paper was published, Mukaiyama's co-author and former student Oyo Mitsunobu attacked the products of the reaction with a carboxylic acid in the presence of triphenylphosphine to yield an ester, creating what is now known as the Mitsunobu reaction.