Efficient Synthesis of Racemic α-Aryl-α-amino Acid Esters via Aminoalkylation with in situ Generated Glycine Cation Equivalents

Abstract

Iminium salts generated in situ from ethyl glyoxylate, secondary amines and 1-H-benzotriazole are demonstrated to be excellent reagents for the regioselective mono-aminoalkylation of indoles, phenols, furans and pyrroles. This method provides a simple and straightforward "one-pot" reaction sequence to a variety of ethyl α-aryl-α-amino acid esters 5 and 8 in high yields.

Efforts towards an On‐Target Version of the Groebke–Blackburn–Bienaymé (GBB) Reaction for Discovery of Druglike Urokinase (uPA) Inhibitors

“…[55][56][57][58] Such adducts have been used, among others, in the Strecker reaction [55] and the alkylation of (hetero)aromatic systems. [59] Interestingly,t his strategy has also been reported for the synthesis of functionalized imidazo[1,2-a]pyridines. [60,61] Althougha lso involvingt he GBB reaction, the latter examples differ from the strategy applied here in that they require an intermediate methylation step and am etal catalyst.…”

A Modified Mannich-Type Reaction Catalyzed by VO(acac)2

“…Ours is the first metal-catalyzed modified Polonovsky reaction and provides a new entry to α-aryl-α-amino acids. Recently the Risch group reported in situ generation of ternary iminium salts from benzotriazole-based ethyl glyoxylate aminals by using a stoichiometric amount of Lewis acid (AlCl 3 or TiCl 4 ) in the synthesis of α-aryl-α-amino acid esters . The classical Mannich reaction had limited applicability in the synthesis of these amino acids …”

“…Recently the Risch group reported in situ generation of ternary iminium salts from benzotriazole-based ethyl glyoxylate aminals by using a stoichiometric amount of Lewis acid (AlCl 3 or TiCl 4 ) in the synthesis of α-aryl-α-amino acid esters . The classical Mannich reaction had limited applicability in the synthesis of these amino acids 5 3 VO(acac) 2 -Catalyzed Modified Mannich-Type Reactions of 3° Amine Oxides with Naphthols …”

Arylglycine-derivative synthesis via oxidative sp3C–H functionalization of α-amino esters

“…Among these, the addition reaction of a carbon nucleophile to imines or iminium ions through Mannich-type reaction appears more useful (Scheme 1, reactions 1–3). However, these reactions need expensive arylboronic acids (Petasis reaction) [4–9] and suitable leaving groups [10–12] as well as a metal catalyst (Polonovsky reaction; this route requires the preparation of amine N -oxide in advance) [13–14]. …”