Stereospecific N-Acylation Of Indoles And Corresponding Microwave Mediated Synthesis Of Pyrazinoindoles Using Hexafluoroisopropanol

We envisioned a facile construction of diversified pyrazinoindoles by using 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) as the solvent and catalyst, hence eliminating metal catalyzed routes for its development. The process is facilitated by HFIP that has emerged as a powerful tool for development of novel fused heterocycles. This cascade approach blends the asymmetric N-acylation with consecutive intramolecular cyclisation via Pictet-Spengler reaction as an efficient tool forming overall two stereogenic centers. Our approach deals with incorporation of L-amino acid on substituted indoles to provide the chiral N-acylated indole precursor followed by cyclisation to access pyrazinoindole derivatives in high enantiomeric excess up to > 99% in good to excellent yields, which have great potential as molecular scaffolds in drug discovery. We have also described the mechanistic course of the reaction based on density functional theory. (c) 2021 Elsevier Ltd. All rights reserved.