This review explores the innovative strategies for synthesizing bis(indolyl)methanes and C3-alkylated indoles using alcohols as green alkylating agents. Focusing on borrowing hydrogen (BH) and interrupted BH pathways, we highlight the role of transition and earth-abundant metal catalysts and key mechanisms, including BH, ADC, and MLC, that drive efficient, selective, and sustainable CC and CN bond formation.

Abstract

Bis(indolyl)methanes (BIMs) and C3-alkylated indole derivatives are crucial scaffolds in bioactive natural products and pharmaceuticals. However, traditional synthetic methods often rely on hazardous reagents, generating waste, and necessitating greener alternatives. In recent years, transition metal-catalyzed borrowing hydrogen (BH) and interrupted borrowing hydrogen (IBH) strategies have emerged as sustainable, atom- and step-economic approaches for C─C and C─heteroatom bond formation using alcohols as alkylating agents. This review explores recent advances in the homogeneous catalytic synthesis of BIMs and C3-alkylated indoles, focusing on transition and earth-abundant metal catalysts that leverage BH, acceptorless dehydrogenative coupling (ADC), and metal-ligand cooperative (MLC) strategies. We discuss key catalytic systems, emphasizing their efficiency, regioselectivity, functional group tolerance, and mechanistic insights. Furthermore, we highlight the role of alcohols as renewable and versatile alkylating agents, underscoring their impact on sustainable synthesis. Finally, we discuss future catalyst design and industrial applications, highlighting the practical importance of these methods in industry.