Abstract

A series of seven new 2-tetrazolylmethyl-tetrahydro-1H-beta-carboline methane-linked bis-heterocycles including their fluorine-containing analogs were synthesized in good to excellent yields (74-97%) via one pot Ugi-azide / Pictet-Spengler strategy under mild thermal conditions. One intermediate (Ugi-azide product) was isolated and fully characterized in order to confirm the reaction pathway. The products herein described may find application in medicinal chemistry because they are formed by two heterocyclic frameworks (1,5-disubstituted-1H-tetrazole and tetrahydro-beta-carboline), which are present in a variety of bioactive compounds and drugs. In the same context, it has been reported that fluorine atoms placed suitably into structures of bioactive compounds enhances often very interesting features like bioavailability, lipophilicity and metabolic resistance.

Highlights

  • Bis-heterocycles are a special class of synthetic or naturally occurring products formed by two heterocyclic moieties in spaced, linked, fused, merged or bound manner,[1] which are of high interest for synthetic chemists because they have proven to be useful in various fields like agrochemistry, optics, material-polymer science, and mainly in medicinal chemistry.[2]

  • As a part of our ongoing program to develop Ugi-azide based methods to synthesize new methane-linked bis-heterocycles containing the 1,5-DS-T moiety,[12] we show our most recent results for the synthesis of 2-tetrazolylmethyl-tetrahydro-1H- -carbolines, which must be understood as a smart improvement and extension of our original work ‘synthesis of 2,3,4,9-tetrahydro- -carboline-1,5-1H-tetrazoles by a one pot Ugi-azide / Pictet-Spengler process’ published in Synthesis a couple of years back.[13]

  • We started the synthesis of bis-heterocycles 1a-g taking the fluorine-containing 2tetrazolylmethyl-tetrahydro-1H- -carboline 1a as model to optimize the Ugi-azide/PS process using the conditions previously reported by us as starting point (i-MeOH [1.0 M], rt, 6 h; ii-MeOH/PhMe 1/1 v/v [1.0 M], MW {90 °C, 60 W}, 5 h).[13]

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Summary

Introduction

Bis-heterocycles are a special class of synthetic or naturally occurring products formed by two heterocyclic moieties in spaced, linked, fused, merged or bound manner,[1] which are of high interest for synthetic chemists because they have proven to be useful in various fields like agrochemistry, optics, material-polymer science, and mainly in medicinal chemistry.[2].

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