Analytical chemistry of synthetic routes to psychoactive tryptamines : Part II. Characterisation of the Speeter and Anthony synthetic route to N,N-dialkylated tryptamines using GC-EI-ITMS, ESI-TQ-MS-MS and NMR

Summary

The degree of alkylation of the side chain nitrogen in tryptamines influences psychoactivity. The Speeter and Anthony method, which reduces a substituted indole-3-yl-glyoxalylamide to the desired tryptamine with metal hydride, was used to synthesize 12 symmetrically and 13 asymmetrically N,N-disubstituted glyoxalylamides and their corresponding tryptamine derivatives. These compounds were characterized by gas chromatography EI-ion trap mass spectrometry, electrospray-triple quadrupole-tandem mass spectrometry, and NMR spectroscopy. A solvent dependency in NMR chemical shifts must be considered for unambiguous assignment. The 1H-NMR study allowed evaluation of rotamer populations of asymmetrical glyoxalylamides. For forensic or clinical monitoring, appropriate ion transitions focus on beta-cleavage and alpha-cleavage fragmentations. The analytical data aid in spectral identification of psychoactive tryptamines.

Study at a glance

Abstract

The degree of alkylation of the side chain nitrogen in tryptamines is one important factor that affects psychoactivity. The method of Speeter and Anthony is considered to be one of the most important synthetic preparative methods. The final step in this reaction is based on the reduction of a (substituted) indole-3-yl-glyoxalylamide to the desired tryptamine with metal hydride. Twelve symmetrically and 13 asymmetrically N,N-disubstituted glyoxalylamides and their corresponding tryptamine derivatives have been synthesised and characterised by gas chromatography EI-ion trap mass spectrometry, electrospray-triple quadrupole-tandem mass spectrometry and NMR spectroscopy. Mass spectral and NMR similarities and differences between the investigated compounds are discussed. A solvent dependency is observed that has to be taken into consideration for the unambiguous assignment of (1)H- and (13)C-NMR chemical shifts. The (1)H-NMR study demonstrated that one can evaluate the rotamer populations of the asymmetrical glyoxalylamides. In a forensic or clinical scenario where single or multiple reaction monitoring approaches are contemplated, the appropriate ion transitions of choice may then focus on the two main fragmentations, namely beta-cleavage ([M+H](+)-->CH(2)N(+)R(2)R(3)) and/or alpha-cleavage ([M+H](+)-->[3-vinylindole](+)), respectively. The synthesis, NMR and MS analytical data presented provide the forensic analyst and clinical biochemist with a detailed and self-consistent body of information and mechanisms for the spectral identification of the more likely psychoactive tryptamines that may be met.