A solvent free mechanochemical route to indole synthesis

Abstract

Indole is a bicyclic aromatic heterocyclic compound consisting of a benzene ring fused with a nitrogen-containing pyrrole ring. It is a core structural motif present in many synthetic and natural bioactive molecules. Owing to its versatile structure, indole has become a privileged scaffold in medicinal chemistry. It holds immense importance in both synthetic drug development and natural product design, primarily because of its exceptional ability to engage in diverse biological interactions.

Indole derivatives are indispensable in the pharmaceutical sector due to their potent activities as anticancer, antibacterial, antiviral, and anti-inflammatory agents, as well as their role as precursors to psychoactive and neuroprotective compounds. The indole moiety enables rational drug design by enhancing therapeutic efficacy and molecular selectivity.

Mechanochemistry is an emerging and influential area of research that employs mechanical forces such as grinding, milling, or shearing to initiate and sustain chemical reactions. Its significance stems from its alignment with the principles of green chemistry, as it minimizes the need for highly volatile and often toxic organic solvents while greatly improving the sustainability and energy efficiency of synthetic processes. The integration of mechanochemical methods into indole synthesis is an important advancement, largely due to their potential to enable solvent-free reactions.

Mechanochemical conditions have been successfully applied to numerous indole-forming reactions, often resulting in enhanced efficiencies characterized by shorter reaction times and improved product yields.

Therefore, the aim of this study is to review the various mechanochemical approaches employed in the synthesis of indole and its pharmaceutically relevant derivatives.