α-Hydroxydimethylacetal/ketal as an α-hydroxycarbonyl equivalent in interrupted Heyns/Amadori rearrangement: regioselective synthesis of substituted C2- and C3-acylindoles

Abstract

Heyns/Amadori rearrangement allows the synthesis of α-aminocarbonyl compounds from α-hydroxycarbonyls and amines via the generation of an aminoenol intermediate. In the present work, the in situ generated aminoenol intermediate has been efficiently trapped with ketones/aldehydes for the construction of N-heterocycles. This method offers access to various substituted indole derivatives with a high level of regioselectivity through the intramolecular trapping of the aminoenol intermediate derived from o-acyl/formylanilines and α-hydroxydimethylacetals/ketals followed by rearrangement/aromatization in the presence of acid. Important features include the use of α-hydroxydimethylacetal/ketal as an α-hydroxycarbonyl equivalent, excellent regiocontrol, good functional group tolerance, selective synthesis of acylindoles, gram-scale synthesis, and synthesis of higher analogues of indoles and anti-tumor agent.