Modular Construction of Functionalized 2-CF₃-Indoles

Abstract

The reaction of α-CF3-β-(2-nitroaryl)enamines with benzaldehydes led to nitro-substituted α,β-diaryl-CF 3 -enones in high yield. Subsequent reduction of the nitro-group to the amino moiety by the Pd/C-NH 4 HCO 2 system resulted in intramolecular cyclization to form a 5-membered hemiaminal which is stabilized by the presence of a CF 3 -group. The reaction of this hemiaminal with various nucleophiles afforded functionalized 2-CF 3 -indoles isolated in up to quantitative yields. High efficiency and broad synthetic scope of all steps of the sequence were demonstrated. A possible mechanism of the reaction is discussed.

An Efficient Synthesis of 2-CF3-3-Benzylindoles

“…To start our investigation, we prepared a set of α-(2-nitroaryl)-β-aryl-CF 3 -enones using recently elaborated by us synthetic protocol [64]. Condensation of α-CF 3 -β-(2nitroaryl)enamines 1 with arylaldehydes 2 in acetic acid at 80-90 • C led to the corresponding α-(2-nitroaryl)-β-aryl-CF 3 -enones 3 in good to high yields.…”

“…CH 2 Cl 2 was removed in vacuo to give crude enamine, which was used without further purification. For characterization data of enamines 1 see [64].…”

“…Volatiles were evaporated in vacuo, the residue was purified by column chromatography, using mixtures of hexane and CH 2 Cl 2 (3:1, 1:1), CH 2 Cl 2 , mixture of CH 2 Cl 2 and MeOH (100:1) as eluents. For characterization data of ketones 3 see [64].…”

“…Using reduction of α-aryl-β-(2-nitroaryl)-CF 3enones a novel synthetic approach towards 2-CF 3 -3-arylquinolines was developed [63]. Shifting nitro group to α-aryl ring-opened a pathway to various functionalized 2-CF 3indoles by the reduction with ammonium formate followed by reactions with various nucleophiles [64]. One of the most reliable strategies for the synthesis of fluorinated heterocycles is using of fluorinated building blocks, highly reactive small-molecules.…”

“…Using reduction of α-aryl-β-(2-nitroaryl)-CF3-enones a novel synthetic approach towards 2-CF3-3arylquinolines was developed [63]. Shifting nitro group to α-aryl ring-opened a pathway to various functionalized 2-CF3-indoles by the reduction with ammonium formate followed by reactions with various nucleophiles [64].…”