Efficient Iron-Catalyzed N-Demethylation of Tertiary Amine-N-oxides under Oxidative Conditions

Abstract

An investigation into the influence of oxidative conditions on the efficiency of opiate N-demethylation using iron powder has been carried out under non-classical Polonovski conditions. This approach involves a two-step process of N-oxidation and subsequent treatment of the intermediate N-oxide hydrochloride with the redox catalyst. Significant improvements in rate and yield have been realized for these reactions in the presence of molecular oxygen. In this context, further rate enhancement was achieved by the judicious addition of small amounts of ferric ions, leading to a concomitant reduction in the amount of the zero-valent iron primary catalyst that is required. This has led to a generalized improved methodology for the N-demethylation of oripavine, codeine, morphine, and thebaine. This protocol can also be carried out in one-pot without the need to isolate the intermediate N-oxide.

A Multi-Step Continuous Flow Process for the N-Demethylation of Alkaloids

“…The non-classical Polonovski reaction has been used for the N-demethylation of a range of opiate alkaloids, [12][13][14][15][16][17][18][19][20] some of which are important precursors of semi-synthetic pharmaceuticals such as buphrenorphine, naltrexone and naloxone. For example, the oxidation of thebaine 2 to thebaine N-oxide followed by reaction with two molar equivalents of FeSO 4 •7H 2 O afforded N-northebaine in 74% yield.…”

“…[16,18] More recently, it was discovered that iron(0) in the form of iron powder as well as stainless steel can also serve as effective catalysts for Polonovski-type reactions. [17,19,20] A number of tertiary N-methylamines, including thebaine, codeine methyl ether and dextromethorphan and atropine, were N-demethylated in >80% yield using this methodology. Furthermore, the N-demethylation of the dopamine D2 receptor agonist, apomorphine 3, [21,22] the antipsychotic agent, cyamemazine 4, [23] processing.…”

Polonovski-Type N-Demethylation of N-Methyl Alkaloids Using Substituted Ferrocene Redox Catalysts

“…For example, we found that conducting these reactions in the presence of molecular oxygen markedly accelerates the rate of N-demethylation, suggesting that the crucial balance between the reduced and the higher oxidized iron species is important for a favorable outcome. 8 In the Fc/Fc + -mediated N-demethylations, we have found that different solvents (namely CHCl 3 , CH 2 Cl 2 , MeCN, MeOH, and i-PrOH) play a major role, with reaction outcomes generally better in halogenated solvents. 9 The latter solvent effects may be attributed to the relative ease of formation of the Fc + species in such solvents.…”

“…This was carried out via a two-step process: N-oxidation of the N-methyl alkaloid a and subsequent treatment of the N-oxide b with a redox catalyst, affording the N-nor product c (Scheme 1). A number of Fe(II) reagents such as FeSO 4 •7H 2 O 3,4 and the ferrous porphyrin Fe(II)TPPS 5 and, more recently, zero valent iron such as iron powder and stainless steel [6][7][8] have been found to be effective catalysts.…”

“…As shown in Scheme 2, N-demethylation under Polonovski-type conditions has been postulated to proceed via a series of one-electron transfers, implicating a Fe 2+ /Fe 3+ redox couple. 10 From our earlier studies with zerovalent iron catalysts, 7,8 it was apparent to us that tuning an appropriate balance of the primary catalyst and its oxidized form would be highly desirable for process optimization. For example, we found that conducting these reactions in the presence of molecular oxygen markedly accelerates the rate of N-demethylation, suggesting that the crucial balance between the reduced and the higher oxidized iron species is important for a favorable outcome.…”