Indolyl substituted 4-oxobut-2-enoic acids. Synthesis and aza-Michael additions

Abstract

Abstract:The synthesis of three new substituted 4-hetereoaryl-4-oxobut-2-enoic acids with indole ring substitutedin positions 3-, 5-and 7-is described. The addition of these Michael acceptors to 4-(1-phenylsulphonylpyrrol-3-yl)-4-oxobut-2-enoic acid in conjugate addition was explored using both racemic and chiral amines. In tandem with the crystallization-induced asymmetric transformation (CIAT) protocol the effective methodology for the synthesis of enantiomerically highly enriched substituted 2-amino-4-heteroaryl-4-oxobutanoic acids as multifunctional homotryptophan analogues was developed.

Regioselectivity of the Conjugate Addition of Amines to Dissymmetrical Pull‐Pull Alkenes

“…It was nevertheless demonstrated that several nitrogen nucleophiles add to β ‐nitroalkenoates to afford exclusively α ‐amino esters [9–16] . An analogous regioselectivity was observed when acrylic acid derivatives bearing a carbonyl group at the β ‐position were treated with primary or secondary amines [17–19] . On the contrary, only β ‐amino acid derivatives were formed in the reactions of amines or N,N‐ and N,O‐binucleophiles with β ‐trifluorocrotonic acid derivatives [20–22] .…”

“…However, a few articles published during the last decades on the reaction of nucleophiles on such derivatives (Scheme 2) bars generalization. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] It was nevertheless demonstrated that several nitrogen nucleophiles add to β-nitroalkenoates to afford exclusively α-amino esters. [9][10][11][12][13][14][15][16] An analogous regioselectivity was observed when acrylic acid derivatives bearing a carbonyl group at the β-position were treated with primary or secondary amines.…”

“…[9][10][11][12][13][14][15][16] An analogous regioselectivity was observed when acrylic acid derivatives bearing a carbonyl group at the β-position were treated with primary or secondary amines. [17][18][19] On the contrary, only β-amino acid derivatives were formed in the reactions of amines or N,N-and N,Obinucleophiles with β-trifluorocrotonic acid derivatives. [20][21][22] Finally, the aza-Michael addition of some primary amines and azoles to unsymmetrical fumaric esters led to the formation of the regioisomers mixture.…”

“…Doubly activated olefins bearing two different electron‐withdrawing groups in vicinal position (so‐called pull–pull olefins) [1b,8] could a priori be regarded as highly reactive compounds because of their global electron depletion. However, a few articles published during the last decades on the reaction of nucleophiles on such derivatives (Scheme 2) bars generalization [9–23] . It was nevertheless demonstrated that several nitrogen nucleophiles add to β ‐nitroalkenoates to afford exclusively α ‐amino esters [9–16] .…”

Pull‐Pull Alkenes in the Aza‐Michael Reaction

“…To facilitate the aza‐Michael addition of aromatic amines to methyl 4‐oxoenoate 1 b to form 3 , equimolar amount of the alkaline Al 2 O 3 [14] or catalytic amount of N‐heterocyclic carbenes (NHC) [15] were used. The aza‐Michael reaction of aroylacrylic acids with racemic or chiral primary amines [16] as well as benzimidazole and 2‐substituted anilines [17] was also reported. The nucleophilic attack was always directed towards to olefinic carbon attached to carboxylic group.…”