Stereospecific N-acylation of indoles and corresponding microwave mediated synthesis of pyrazinoindoles using hexafluoroisopropanol. (26th March 2021)

• Record Type: Journal Article
• Authors: Singh, Aarushi; Singh, Snigdha; Sewariya, Shubham; Singh, Nidhi; Singh, Prashant; Kumar, Ajay; Bandichhor, Rakeshwar; Chandra, Ramesh
• Is Part Of: Tetrahedron. Volume 84(2021)
• Publication Date: 2021-03-26
• Subjects: Hexafluoroisopropanol -- Stereospecific -- Pictet-spengler reaction -- Microwave; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2021.132017
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: 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. Graphical abstract: Image 1 Highlights: This article elucidates the Stereoselective N - acylation of Indoles and synthesis of corresponding Pyrazinoindoles and its derivatives. Amongst the widely distributed fused indole heterocycles in various alkaloids and natural product synthesis, pyrazinoindoles are attractive targets for synthetic organic chemists due to their biological activity including receptor agonist, CNS depressant, protein kinase C inhibitor, antibacterial and ubiquitous structural motifs in natural products. The enantiomerically reinforced indole-based heterocycles have a crucial role in medicinal chemistry. This paper attempts to identify a simple route to generate enantiomerically pure pyrazinoindoles from chiral amines, aryl aldehydes and HFIP that plays dual role under the reaction. In this paper we present, operationally straightforward, metal-free and an efficient microwave assisted route to access pyrazinoindole using HFIP as a solvent. The reaction features readily available substrate, mild reaction conditions and good tolerance to functional group. A one-pot, highly enantioselective Pictet-Spengler reaction was used to direct the synthesis under microwave-assisted approach. A plausible mechanism for role of HFIP as a solvent and catalyst has also been discussed, which explains the most likely pathway for synthesis of these scaffolds. For the first time, the mechanistic course of the reaction based on density functional theory (DFT) has been described.