C–3 alkoxymethylation of 4-oxo-1,4-dihydroquinoline 2-carboxylic acid esters via organic additives

Abstract

Esters of kynurenic acid, a known neuroprotective agent were reacted with cyclic amino acids to yield novel alkoxymethylated products under optimized reaction conditions. The importance of amino acid based (primary, secondary, biogenic and synthetic) organic additives was proven by the conduction of numerous test reactions. Thoroughly extended investigations, directly focusing on amino acid catalysis, which is an emerging and up-to-date field of catalysis and green chemical processes, have been conducted. The mechanism of the alkoxymethylation reaction was proposed and later the findings supported the hypothesis of the first retro-Mannich step (formation of the ortho-quinone methide intermediate) and subsequent formation of the alkoxymethylated derivatives. As a preparative result, two novel kynurenic acid derivatives bearing an alkoxymethyl moiety and two additional derivatives having amino acid residues at the site C-3 were synthesized, thus setting the scope and limitations of the modified Mannich reaction of kynurenic acid derivatives using amino acid nucleophiles. The mechanistic investigations highlighted the significant physicochemical effects of used nucleophiles on the amino-acid driven one-pot retro-Mannich initiated alkoxylation of kynurenic acid.

Keywords

• Kynurenic acid
• Amino acid catalysis
• Mannich reaction
• Alkoxyalkylation