Reactions of CF3-enones with arenes under superelectrophilic activation: a pathway to trans-1,3-diaryl-1-CF3-indanes, new cannabinoid receptor ligands

Abstract

4-Aryl-1,1,1-trifluorobut-3-en-2-ones ArCHCHCOCF₃ (CF₃-enones) react with arenes in excess of Brønsted superacids (TfOH, FSO₃H) to give, stereoselectively, trans-1,3-diaryl-1-trifluoromethyl indanes in 35–85% yields. The reaction intermediates, the O-protonated ArCHCHC(OH⁺)CF₃ and the O,C-diprotonated ArHC⁺CH₂C(OH⁺)CF₃ species, have been studied by means of ¹H, ¹³C, ¹⁹F NMR, and DFT calculations. Both types of the cations may participate in the reaction, depending on their electrophilicity and electron-donating properties of the arenes. The formation of CF₃-indanes is a result of cascade reaction of protonated CF₃-enones to form chemo-, regio- and stereoselectively three new C–C bonds. The obtained trans-1,3-diaryl-1-trifluoromethyl indanes were investigated as potential ligands for cannabinoid receptors CB₁ and CB₂ types. The most potent compound showed sub-micromolar affinity for both receptor subtypes with a 6-fold selectivity toward the CB₂ receptor with no appreciable cytotoxicity toward SHSY5Y cells.