Acid-Promoted Reaction of Trifluoromethylated Allyl Alcohols with Arenes. Stereoselective Synthesis of CF₃‑Alkenes and CF₃‑Indanes

Reaction of 4-aryl-1,1,1-trifluorobut-3-en-2-ols [CF₃-allyl alcohols, ArCHCHCH­(OH)­CF₃] with arenes under activation with anhydrous FeCl₃ or FSO₃H was studied. We found that the transformation led to trifluoromethylated alkenes [Ar­(Ar′)­CHCHCHCF₃] or 1-trifluoromethylated indanes (CF₃-indanes). The formation of these two types of reaction products strongly depends on the nucleophilicity of the starting arene and the electrophilicity of cationic intermediates generated from CF₃-allyl alcohols under reaction conditions. Benzene, anisole, veratrole, and <i>ortho-</i>xylene lead exclusively to CF₃-alkenes with an <i>E-</i>configuration. More π-donating polymethylated arenes (pseudocumene, mesitylene) afford only CF₃-indanes with a predominantly <i>cis-</i>orientation of substituents at positions 1 and 3 of the indane ring. <i>Meta-</i> and <i>para-</i>xylenes show an intermediate behavior; they may form both CF₃-alkenes and/or CF₃-indanes. The mechanisms of the investigated transformations are discussed

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

4-Aryl-1,1,1-trifluorobut-3-en-2-ones ArCH[double bond, length as m-dash]CHCOCF3 (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 ArCH[double bond, length as m-dash]CHC(OH(+))CF3 and the O,C-diprotonated ArHC(+)CH2C(OH(+))CF3 species, have been studied by means of (1)H, (13)C, (19)F 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