Scale-up of Sodium Persulfate Mediated, Nitroxide Catalyzed Oxidative Functionalization Reactions

Background: Oxidation is a valuable tool in preparative organic chemistry. Oxoammonium salts and nitroxides have proven valuable as reagents and catalysts in this endeavor. Objective: The objective of this study is to scale up the oxidative amidation, ester formation, and nitrile formation using nitroxide as an organocatalyst. Methods: Oxidative functionalization reactions were scaled from the 1 mmol to the 1 mole level. Sodium persulfate was used as the primary oxidant, and a nitroxide was employed as a catalyst. The products of the reactions were isolated in analytically pure form by extraction with no need for column chromatography. Results: The oxidative amidation and esterification of aldehydes can be scaled up from 1 mmol to 1 mole effectively, with comparable product yields being obtained at each increment. This work shows that conditions developed on a small scale can be transferred to a larger scale without reoptimization. The oxidative functionalization of aldehydes to prepare nitriles is not amenable to direct scale-up due to the concomitant formation of significant quantities of the corresponding carboxylic acid, thereby compromising the product yield. Conclusion: Two of the three oxidative transformations studied here can be scaled up successfully from the 1 mmol to the 1 mole level.