Synthesis of Nororipavine and Noroxymorphone via N- and O-Demethylation of Iron Tricarbonyl Complex of Thebaine

Abstract

Thebaine was converted into its iron tricarbonyl complex, which underwent successive N-and O-demethylation with BrCN and BBr 3 , respectively. Decomplexation of the iron tricarbonyl moiety was accomplished with ammonium cerium(IV) nitrate (CAN) and base-catalyzed hydrolysis furnished nororipavine. When excess CAN was used the methoxydiene unit was converted into its C-14 nitrate that on hydrogenation and further hydrolysis furnished noroxymorphone. Full experimental and spectral data are provided for all key compounds.

TEMPO‐Mediated Electrochemical N‐demethylation of Opiate Alkaloids

“…[3,7] The most challenging step in the reaction sequence, from natural opiates to opiate-like therapeutics, is the selective N-demethylation of the highly functionalized morphinan structure. [1][2][3][4][5][6][8][9][10][11] The classical route for selective Ndemethylation involves the application of chloroformates [12,13] and cyanogen bromide [14][15][16] (von Braun reaction), forming carbamate and cyanamide intermediates, respectively, which subsequently hydrolyze to the desired secondary amine (Figure 1, b). Although these methods produce secondary amines in good yields, the requirement of highly toxic reagents at elevated temperature and the need to protect the phenol moiety in the morphinan structure limits their application.…”

Toward the Synthesis of Noroxymorphone via Aerobic Palladium-Catalyzed Continuous Flow N-Demethylation Strategies

“…1 A number of methods to accomplish the N-demethylation of tertiary amines have been reported, but none of them are entirely satisfactory. Standard procedures for the removal of the N-methyl group involve the use of electrophilic reagents such as cyanogen bromide (von Braun reaction), 2 or chloroformates. 3 These reactions produce cyanamides and carbamates, respectively, which can be readily hydrolyzed to the corresponding amines.…”