Transition Metal Free Catalytic Aerobic Oxidation of Methyl-α-d-Glucopyranoside Under Mild Conditions Using Stable Nitroxyl Free Radicals

Abstract

The selective oxidation of alcohols to the corresponding aldehydes, ketones or acids is an essential transformation in organic synthesis and a large number of reagents have been developed for this reaction (Kirk-Othmer, Encyclopedia of chemical technology, 1992; Hudlicky, Oxidations in organic chemistry, 1990; Sheldon and Kochi, Metal-catalyzed oxidations of organic compounds, 1981). Many of these well established procedures require the use of a toxic stoichiometric oxidant, transition metal catalyst and/or halogenated solvents. In this respect, the TEMPO (2,2,6,6,-tetramethylpiperidine-N-oxyl) based compositions have emerged as highly selective catalyst systems for the oxidation of primary alcohols to the corresponding aldehydes or acids (Holum, J Org Chem 26:4814, 1961; Lee and Spitzer, J Org Chem 35:3589, 1970). Here, we report on a new catalyst composition for the aerobic oxidation of methyl-α-d-glucopyranoside (1) to the corresponding methyl-α-d-glucuronic acid (2). The catalyst system is based on 4-acetamido-2,2,6,6-tetramethylpiperidine N-oxyl (AA-TEMPO, 3b) and a nitrate source. It utilizes ecologically friendly solvents and does not require any transition metal co-catalyst. It has been shown that the described process represents an efficient oxidation protocol that can easily and safely be scaled up to commercial scale. The influence of the most critical reaction parameters such as the nature of the substituent on the TEMPO structure, the nitrate source and the temperature–pressure matrix have been studied. By a detailed analysis of the effect of each of the reaction variables on the oxidation rate, a reaction pathway including a multistep cascade is presented.