Simple and selective one-pot replacement of the N-methyl group of tertiary amines by quaternization and demethylation with sodium sulfide or potassium thioacetate: an application to the synthesis of pergolide

Abstract

The paper describes a mild, selective, and rapid replacement of an N-methyl group of tertiary amines with other alkyl groups via a simple one-pot procedure. This transformation is easily achieved by preparation of the appropriate quaternary ammonium salt in sulfolane and in situ treatment with sodium sulfide or potassium thioacetate. The protocol is successfully applied to the transformation of dihydrolysergol, dextromethorphan and laudanosine (as models of ergot and opium N-methyl alkaloids) into various N-alkyl congeners.

N-Demethylation of Alkaloids

“…The selective, one-pot exchange of the N-methyl group for ethyl, propyl or octyl groups on laudanosine (56), an ergot alkaloid, and the opiate agonist, dextromethorphan (6a), was achieved using the nucleophile potassium thioacetate (MeCOSK) ( Table 4) [72]. Use of Na 2 S or MeSNa as nucleophiles in these cases favoured Hofmann elimination products, over one-pot N-alkylation.…”

“…Procedures for the direct replacement of an N-methyl group with an alternative N-alkyl substituent have also been reported [71,72]. Such methodologies do not require the formation of a secondary amine intermediate and are thus potentially concise routes to N-alkyl substituted alkaloids.…”

Characterization of the Molecular Fragment That Is Responsible for Agonism of Pergolide at Serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A Receptors

“…(Cernosice, Czech Republic) according to previously published procedures with minor modifications (Misner et al, 1997;Anastasia et al, 2001;Cabri et al, 2006).…”

Synthesis of deuterated dextromethorphan derivatives

“…8 The yield of the sodium sulfide or potassium thioacetate method is not high enough and undesired side reactions could be noticed. 9 N-demethylation of the tertiary amine alkaloids e.g.…”