# A regioselective sustainable neat approach to naphtho[2,3-b]thiophene-4,9-dione: detailed mechanistic study and DFT analysis

## TL;DR

A sustainable, solvent-free method for making anticancer compounds called naphtho[2,3-b]thiophene-4,9-dione is developed and studied using detailed mechanisms and DFT analysis.

## Contribution

A new solvent-free, regioselective synthesis method for naphtho[2,3-b]thiophene-4,9-dione with a detailed mechanistic and DFT analysis is introduced.

## Key findings

- A solvent-free, one-pot three-component reaction successfully synthesizes naphtho[2,3-b]thiophene-4,9-dione derivatives.
- The reaction mechanism involves regioselective Michael addition, a domino reaction, and aromatization confirmed via DFT studies.
- The method is scalable and sustainable, with a wide substrate scope and confirmed biological activity.

## Abstract

An environment friendly simple, solvent-free, and lower E-factor technique has been developed for synthesizing anticancer property-containing substituted naphtho[2,3-b]thiophene-4,9-dione derivatives via a one-pot three-component reaction using active methylene compounds, alkyl/aryl isothiocyanate, and 1,4-naphthoquinone derivatives. The reaction proceeds through the regioselective Michael addition between the di-anionic intermediate and 1,4-naphthoquinone derivatives, followed by a domino reaction, which has been established via DFT study. Finally, it undergoes a Krapcho reaction followed by aromatization in a basic environment, yielding the desired product naphtho[2,3-b]thiophene-4,9-dione. The reluctant addition of a di-anionic intermediate to the naphthalene-1,4-dione or 2-bromonaphthalene-1,4-dione in the solvent medium has been overcome using a neat approach. Practicability of the methodology has been enhanced via gram scale solvent-free cascade reaction. The wide substrate scope, biological activity, sustainability, and detailed mechanistic study make our reaction more acceptable in the current scenario.

A regioselective sustainable neat approach to naphtho[2,3-b]thiophene-4,9-dione has been established via detailed mechanistic study and DFT analysis.