Ag eneral method to generate umpolung of aldimines with cyanide was developed via the addition of cyanide to aldiminesf ollowed by ap roton transfer from the carbon atom to the nitrogen atom in the resulting cyanide adducts.T hisn ovel method was successfully applied to the first imino-Stetter reaction of aldimines obtainedf rom 2-aminocinnamic acid derivatives anda romatic aldehydes with cyanide,a ffording 2-aryl-substituted indole-3-acetic acid derivatives.F urthermore,t he usefulness of this method wass uccessfully demonstratedb yt he synthesis of an FPTase inhibitor, one of the biologically important2-arylindole-3-acetic acid derivatives.
A new method for the synthesis of 2-vinylindole-3-acetic acid derivatives from aldimines, which are derived from 2-aminocinnamic acid derivatives and α,β-unsaturated aldehydes, via a cyanide-catalyzed imino-Stetter reaction is described. Various types of 2-aminocinnamic acid derivatives and α,β-unsaturated aldehydes could be used in this protocol, and the desired 2-vinyl substituted indole-3-acetic acid derivatives were obtained in high yields. This cyanide-catalyzed imino-Stetter reaction was further extended to the preparation of indole-3-acetic acid derivatives bearing a carboxylic acid functionality at the 2-position, using aldimines obtained from glyoxylates and 2-aminocinnamic acid derivatives.
A new protocol for the direct formation of amides from imines derived from aromatic aldehydes via metal-free aerobic oxidation in the presence of cyanide is described. This protocol was applicable to various aldimines, and the desired amides were obtained in moderate to good yields. Mechanistic studies suggested that this aerobic oxidative amidation might proceed via the addition of cyanide to imines followed by proton transfer from carbon to nitrogen in the original imines, leading to carbanions of α-amino nitriles, which undergo subsequent oxidation with molecular oxygen in air to provide the desired amide compounds.
The total synthesis of rutaecarpine (1) and luotonin A (2) is described through controlled cyclization of a common aldimine intermediate 5 derived from ethyl-2-aminocinnamate and quinazolinone-2-carbaldehyde. The cyanide-mediated imino-Stetter reaction of aldimine 5 provided the corresponding indole derivative 3, from which the total synthesis of rutaecarpine (1) was completed via the formation of a 6-membered C-ring. On the other hand, microwave-assisted thermal 6π-electrocyclization of the common intermediate 5, followed by the formation of a 5-membered C'-ring, allowed the completion of the total synthesis of luotonin A (2).
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