Organocatalyzed C2-Friedel-Crafts alkylation of 1,3-disubstituted indoles with acrolein: efficient synthesis of 3-(1H-indol-2-yl)propanals.

Abstract

An organocatalyzed C2-Friedel-Crafts alkylation of 1,3-disubstituted indoles with acrolein was developed for the efficient synthesis of 3-(1H-indol-2-yl)propanals (30 examples, 38-95% yields). This strategy is operationally simple and avoids the use of metal catalysts, stoichiometric oxidants, and directing-group-containing substrates. The resulting 3-(1H-indol-2-yl)propanals exhibit the characteristic multifunctional reactivity of 3-arylpropanals, enabling the construction of valuable molecular architectures, including C2-functionalized indoles, pyrido[1,2-a]indoles, and [1,3]oxazepino[3,4-a]indoles. More importantly, several of the synthesized 3-(1H-indol-2-yl)propanals and their derivatives demonstrated promising antiproliferative activity against NCI-H1703 and AGS cells, with IC50 values of up to 1.488 ± 0.19 μM and 1.202 ± 0.09 μM, respectively.

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