Step-Economical Synthesis and Evaluation of Furyl(indolyl)methanes: Chemoselective Activation, Furan Functionalization, and Antiproliferative Activity

Di(hetero)arylmethane represents a valuable chemical motif in natural products and pharmaceuticals. Bis(indolyl)methane is a valuable member of this class of compounds with diverse bioactivity profiles. Many other indolyl(heteroaryl)methane have also shown promising bioactivity, which necessitates development of expedient methods for the synthesis and biological evaluation of previously underexplored scaffolds. Herein, we report the development of a step-economical and highly practical synthesis of furyl(indolyl)methane using feedstock chemical DMSO as a C1 synthon under metal-free conditions. This methodology represents a significant advantage over the known methods, which use Au catalysts and highly functionalized substrates. The reaction conditions enabled excellent cross-selectivity through chemoselective activation of indole in the presence of highly nucleophilic furan. The reaction displayed excellent scope with the rare possibility to use completely unsubstituted indole as well as furan as viable substrates. Additionally, we also demonstrate two vital applications of the methodology─first, through direct functionalization of biomass-derived platform chemicals such as 2-methylfuran (2-MF) and furan and second, through the biological evaluation and disclosure of furyl(indolyl)methane as novel antiproliferative agents in a breast cancer cell line with comparable activity as compared to corresponding bis(indolyl)methanes.