Science of Synthesis

Scammells, P. J., Science of Synthesis Knowledge Updates, (2013) 2, 444.

The N-demethylation of codeine using dimethyl azodicarboxylate was first reported in 1914.[‌45‌] Diethyl azodicarboxylate was later patented for the N-demethylation of thebaine,[‌46‌] a transformation that had previously proven problematic using other approaches. In this procedure, thebaine (‌16‌) is refluxed with diethyl azodicarboxylate to obtain N-[1,2-bis(ethoxycarbonyl)hydrazinomethyl]thebaine, which is subsequently hydrolyzed with saturated aqueous ammonium chloride to afford the deprotected amine ‌17‌ as its hydrochloride salt. A 60% yield of amine ‌17‌ is obtained over the two steps, although a higher yield (88%) has subsequently been reported.[‌47‌] Dialkyl azodicarboxylates have also been used to N-demethylate a range of other N-methylamines.[‌48‌–‌52‌] A relatively complex semisynthetic macrocyclic ketolide ‌18‌ has been cleanly mono-N-demethylated using diethyl azodicarboxylate to give ketolide ‌19‌ in 82% yield (‌Scheme 13‌).[‌53‌] Previous attempts to N-demethylate this sensitive substrate with iodine or alkyl chloroformates were unsuccessful.

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References