Hydrogen bonding network-enabled Brønsted acid-catalyzed Friedel–Crafts reactions: a green approach to access unsymmetrical diaryl- and triarylmethanes

Abstract

Unsymmetrical di-and triarylmethanes are generally synthesized through metal-catalyzed cross-coupling or Friedel–Crafts arylation using multistep harsh reaction conditions with pre-functionalized starting materials. These reaction protocols use pyrophoric materials such as Grignard reagents, metal hydrides, and toxic, hazardous, and problematic solvents like benzene, DMF, and THF. This affects the reaction mass efficiency, and atom economy and produces significant environmental wastes resulting in a high E-factor. As an alternative, herein, using a cheap, commercially available Brønsted acid-catalytic system (pTSA·H₂O)/HFIP, we describe a one-pot three-component approach for the synthesis of unsymmetrical polyarylated alkanes from renewable feedstock chemicals. Compared to conventional routes, we avoided using any pyrophoric reagents, metal catalysts, toxic solvents, or Grignard reagents and report many examples that are difficult to access using the reported methods. Calculation of different green metrics (atom economy (95%), atom efficiency (84.5%), reaction mass efficiency (77.1%), and E-factor (1.26 kg kg⁻¹ of the product without solvent recovery and 0.32 kg kg⁻¹ of the product considering solvent recovery) indicated the greenness of the described protocol. The developed method could also be scaled up and was applied for a short and efficient synthesis of a phenanthrene-based anti-breast cancer agent, which reduced the conventional six-step cross-coupling approach to the one step Friedel–Crafts approach. Also, the method was applied for the late-stage functionalization of various natural products such as thymol, menthol, and eugenol and the used HFIP was recovered, highlighting the suitability of the method for industrial applications.