Installing fluoroalkyl motifs into biorelevant indoles is particularly interesting due to their ubiquitous presence in drug molecules. Herein, we demonstrate the regioselective C4 fluoroalkoxylation of indoles using fluoroalcohols via palladium-catalyzed chelation-assisted C & horbar;H activation. The weak chelating benzoyl moiety at the C3 position acts as a directing group for remote C(4)& horbar;H fluoroalkoxylation of diversely substituted indoles. This methodology demonstrates a high level of regioselectivity and tolerates a range of crucial functional groups, yielding diverse trifluoroalkoxylated indoles in moderate to good yields. Removal of directing/protecting groups and further functionalization established the synthetic utility of the methodology. A preliminary mechanistic investigation is conducted by isolating the palladacycle intermediate and performing the deuterium scrambling study. The regioselective C4 fluoroalkoxylation of indoles with various fluoroalcohols is achieved by the palladium-catalyzed weak chelation assistance strategy. The reaction is compatible for a range of important functionalities and proceeds via the intermediacy of a six-membered palladacycle following a Pd(II)/Pd(IV) pathway. image

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