Synthesis of 2‐Aryl‐Substituted Indole‐3‐acetic Acid Derivatives via Intramolecular Imino‐Stetter Reaction of Aldimines with Cyanide

Abstract

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.

N‐Heterocyclic‐Carbene‐Catalyzed Umpolung of Imines

“…Specifically, NHC‐catalyzed cyclization of aldimines bearing a Michael acceptor afforded biologically important 2‐aryl indole 3‐acetic acid derivatives in moderate to good yields. Notably, the cyanide‐catalyzed umpolung of imines has recently been reported by Cheon and co‐workers . It is noteworthy that 2‐arylindole 3‐acetic acid derivatives are endowed with interesting biological properties and they are subunits in several natural products…”

Chemistry of Cyanide Adducts of Aldimines from Aniline Derivatives

“…Under these conditions, various 2‐aminocinnamic acid derivatives 26 and aromatic aldehydes 2 could be applied to this protocol and the desired 2‐aryl substituted indole‐3‐acetic acid derivatives 24 were obtained in high to excellent yields (Scheme ) …”

Reagent addition sequence and equivalent in N‐heterocyclic carbene‐catalyzed nonpolar inversion enable conversion from aldimine to benzoxazole

“…[ 19–21 ] Interestingly, catalysis using this concept has been extended to the umpolung reaction of Michael acceptors [ 22–25 ] and aldimines. [ 26–33 ] Detailed theoretical studies reported by our group [ 34–43 ] and other groups [ 44–52 ] have provided molecular‐level insight into the catalytic mechanism and chemo‐, regio‐, and/or stereo‐selectivities. [ 53,54 ]…”