Interrupted Intramolecular Hydroaminomethylation of N-Protected-2-vinyl Anilines: Novel Access to 3-Substitued Indoles or Indoline-2-ols.

Frank Hochberger-Roa,José G López-Cortés,Jean-Claude Daran,M Carmen Ortega-Alfaro,Martine Urrutigoïty,Maryse Gouygou,Perla H García-Ríos

doi:10.3390/molecules27031074

Abstract

A new synthetic alternative to the synthesis of 3-methyl indoles and 3-methyl indoline-2-ols with an excellent atomic economy is presented in this study. It is demonstrated that the intramolecular interrupted hydroaminomethylation (HAM) reaction is a powerful tool for the formation of these compounds, which exhibit wide-ranging biological activity. Several N-Protected-2-vinyl anilines were synthesized and involved in the reaction producing the corresponding 3-methylindole or 3-methyl indoline-2-ol depending on the nature of the N-protecting groups.

Highlights

The indole ring system is one important motif widely present in nature [1,2,3]
Since most of the conventional methods to yield this heterocycle require highly functionalized starting materials and suffer from low atom economy and harsh reaction conditions, transition metal catalysis has become an excellent alternative for the production of the indole
Starting from 2-nitrobenzaldehyde (1), 2-vinyl aniline (3a) was synthetized in two steps according to a procedure adapted from the literature [25]

Summary

Introduction

The indole ring system is one important motif widely present in nature [1,2,3]. With great structural diversity, many drugs and bioactive compounds include this ring (Figure 1) [4,5,6]. The importance of indoles as structural elements in natural products and pharmaceuticals is reflected in the perpetual development of new synthetic methods. Since most of the conventional methods to yield this heterocycle require highly functionalized starting materials and suffer from low atom economy and harsh reaction conditions, transition metal catalysis has become an excellent alternative for the production of the indole. The reaction catalysed by rhodium has proved to be a very effective synthetic route for the formation of amines through olefins. This one-pot, atom-efficient reaction consists of hydroformylation of olefin to an aldehyde and the subsequent formation of an enamine or imine, followed by hydrogenation. The interrupted version should be a method for the access to imines and enamines (Scheme 1)

Methods

Results

Conclusion