Mild Diarylmethylation of Indoles through Regioselective 1,6-Hydroarylation of para-Quinone Methides in Microdroplets/Thin Film

Diarylmethylated indoles constitute a basic framework in many pharmaceuticals, chiral catalysts/ligands, and important intermediates. A typical strategy by 1,6-conjugated addition between indoles and para-quinone methides (p-QMs) suffered from low efficiency (hours to days) and harsh conditions (expensive/toxic metals at high equivalents, high temperature, etc.) in conventional conversions. In this study, we developed a metal-free, efficient, mild, and wide microdroplet/thin film protocol to overcome these drawbacks. Catalyst-free indole diarylmethylation can be conducted only in microdroplet/thin film, although the conversion was incomplete (9% at room temperature but 24% yield at 45 degrees C) in a sharp contrast with no reactions in the bulk phase. By introducing 0.5-5 mol % phosphoric acid (4-40 times decreased in comparison with 20 mol % H3PO4 catalysis by a previous on-water strategy), good reaction yields (55-88%) were achieved for a wide range of substrates (12 indoles and 7 p-QMs) by microdroplet/thin film reactions. By spraying 0.5 mol L-1 reactants at 1 mL min(-1), the rate of the microdroplet/thin film product was scaled up to 6.70 g h(-1). Overall, the microdroplet/thin film method offered several advantages including high efficiency, mild conditions, wide substrate scope, and gram-scale ability, making it an attractive alternative for synthesizing diarylmethylindoles under the requirements of green and sustainable chemistry.