Utility of iron nanoparticles and a solution-phase iron species for the N-demethylation of alkaloids

Abstract

N-Demethylation of selected N-methylalkaloids using a modified Polonovski reaction can be accomplished employing nanoscale zero-valent iron, nZVI, in isopropanol.

ElectrochemicalN-demethylation of tropane alkaloids

“…13 Over the past decade, modifications of the reaction based on iron cata-lysts have been developed for the N-demethylation of tropane and opiate alkaloids. 2,3,6,8,[14][15][16][17][18][19] These reactions are based on a multi-step process, comprising the oxidation of the tertiary amine using m-chloroperbenzoic acid (m-CPBA) or H 2 O 2 to the corresponding N-oxide, which is then isolated as the HCl salt. The N-oxide salt is N-demethylated with iron-based catalysts such as FeSO 4 •7H 2 O, FeCl 2 •4H 2 O, or Fe(NH 4 SO 4 ) 2 , 14,15 iron porphyrin complex, 16,17 ferrocene, 8 and iron powder 2 which need to be separated from the reaction mixture by chelating with EDTA or TPPS (meso-tetra(4-sulfophenyl)porphyrin) 14,15 or by filtration.…”

“…The N-oxide salt is N-demethylated with iron-based catalysts such as FeSO 4 •7H 2 O, FeCl 2 •4H 2 O, or Fe(NH 4 SO 4 ) 2 , 14,15 iron porphyrin complex, 16,17 ferrocene, 8 and iron powder 2 which need to be separated from the reaction mixture by chelating with EDTA or TPPS (meso-tetra(4-sulfophenyl)porphyrin) 14,15 or by filtration. [16][17][18] Recent works have focused on using greener solvents such as ethanol and isopropanol, instead of chloroform, in the N-demethylation of N-oxides. 3,6,18,20 In one approach, iron nanoparticles have been studied as catalyst for the N-dealkylation of various alkaloids reporting a yield of 85% for the synthesis of noratropine.…”

“…[16][17][18] Recent works have focused on using greener solvents such as ethanol and isopropanol, instead of chloroform, in the N-demethylation of N-oxides. 3,6,18,20 In one approach, iron nanoparticles have been studied as catalyst for the N-dealkylation of various alkaloids reporting a yield of 85% for the synthesis of noratropine. 18 However, chloroform is still in use for N-oxide formation in the first step of the reaction.…”

“…3,6,18,20 In one approach, iron nanoparticles have been studied as catalyst for the N-dealkylation of various alkaloids reporting a yield of 85% for the synthesis of noratropine. 18 However, chloroform is still in use for N-oxide formation in the first step of the reaction. 18 Do Pham et al studied the N-demethylation of atropine and scopolamine using Fe(III)-TAML (tetra-amidato macrocyclic ligand) as catalyst in ethanol without isolation of the N-oxide as the hydrochloride salt, reporting a yield of about 80% for noratropine and norscopolamine.…”

“…18 However, chloroform is still in use for N-oxide formation in the first step of the reaction. 18 Do Pham et al studied the N-demethylation of atropine and scopolamine using Fe(III)-TAML (tetra-amidato macrocyclic ligand) as catalyst in ethanol without isolation of the N-oxide as the hydrochloride salt, reporting a yield of about 80% for noratropine and norscopolamine. 3,6 However, this method uses 50 equivalents of H 2 O 2 , which must be deactivated at the end of the process by treatment with MnO 2 .…”