Center for Magnetic Resonance

R.O. Iakovenko, A.N. Kazakova, V.M. Muzalevskiy, A.Yu. Ivanov, I.A. Boyarskaya, A. Chicca, V. Petrucci, J. Gertsch, M. Krasavin, G.L. Starova, A.A. Zolotarev, M.S. Avdontceva, V.G. Nenajdenko, A.V. Vasilyev

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

Org. Biomol. Chem., 2015, 13, 8827-8842

DOI:10.1039/c5ob01072a

4-Aryl-1,1,1-trifluorobut-3-en-2-ones ArCH=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=CHC(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.