TEMPO-Mediated Electrochemical N-demethylation of Opiate Alkaloids

A new TEMPO-mediated electrochemical method has been developed for N-demethylation of opiates using a home-made batch cell with low-cost porous glassy carbon electrodes. N-demethylation of opiates such as thebaine, codeine, morphine and oxycodone is a key step in the semi-synthesis of opioid medicines. The electrochemical N-demethylation using TEMPO as mediator enables the synthesis of noropiates, which is not possible with conventional Shono oxidation. Electrolysis was performed at a preparative scale in aqueous solvent at room temperature in a single step, yielding the desired products in good isolated yields (up to 83 %). Mechanistic studies suggest that the electrochemically generated oxoammonium species oxidizes the opiate to an iminium intermediate, which then hydrolyzes to the noropiate. The electrochemical reaction was also performed in a flow-cell without a supporting electrolyte and represents the first electrochemical N-demethylation of difficult opiates with an aminoxyl oxidant.

Automated summary

A new TEMPO-mediated electrochemical method has been developed for N-demethylation of opiates to synthesize noropiates, achieving good yields. The electrolysis was conducted in aqueous solvent at room temperature in a single step, and mechanistic studies suggest that the electrochemically generated oxoammonium species oxidizes the opiate to an iminium intermediate.