Synthesis of the 3-(3,4,5-Trimethoxyphenyl)-pyrrolidine: A New Conformationally Constrained Mescaline Analogue

A new mescaline analogue, 3-(3,4,5-trimethoxyphenyl)-pyrrolidine, was synthesized in four steps from N-Cbz-3-pyrrolidine with a 46% overall yield. The key step was a Heck arylation of a non-activated olefin using a diazonium salt. The resulting hemiaminal intermediate was converted through dehydration with trifluoroacetic anhydride, then hydrogenation and hydrogenolysis, to yield the final compound as a hydrochloride salt. This conformationally constrained analogue may have activity towards 5-HT2 dopamine receptors.

Study at a glance

Abstract

Abstract The total synthesis of the 3‐(3,4,5-trimethoxyphenyl)-pyrrolidine, a new and conformationally constrained mescaline analogue, was accomplished in a concise and efficient manner. The synthetic route encompassed only 4 steps from the starting N-Cbz-3-pyrrolidine, in 46% overall yield. The route features a highly effective Heck arylation of the non-activated olefin N-Cbz-3-pyrrolidine with the 3,4,5-trimethoxybenzene diazonium tetrafluoroborate. The hemiaminal (lactamol) Heck adduct was converted to the mescaline analogue in a sequence of reactions: (a) dehydration of the intermediate hemiaminal 3 with trifluoroacetic acid anhydride, (b) hydrogenation/hydrogenolysis of the endocyclic enecarbamate 6 with H2-Pd/C, and (c) formation of the rather stable mescaline analogue in the form of a hydrochloride salt. The target molecule constitutes a new mescaline analogue with potential activity towards 5‐HT2 dopamine receptors.