Microwave-Assisted Synthesis of 1-(5-Substituted-4-hydroxy-2-methyl-1<i>H</i>-pyrrol-3-yl)ethan-1-ones from 2-Amino Acid-Derived Enamine-Type Schiff Bases

Abstract

Pyrrole-type compounds are widely known for their potential biological activity. However, methods for synthesizing 2,3,4,5-tetrasubstituted pyrroles remain limited. This study explores an intramolecular cyclocondensation of 2-amino acid-derived enamines to yield novel 1-(5-substituted-4-hydroxy-2-methyl-1H-pyrrol-3-yl)ethan-1-ones. Using ʟ-alanine, ʟ-tyrosine, ʟ-phenylalanine, and ʟ-tryptophan, the corresponding 2-amino esters were synthesized, converted into enamines, and cyclized under microwave irradiation (55–86% yield). The highest yield was obtained from methyl ʟ-phenylalaninate (R1 = CH2Ph, R4 = Me). Steric hindrance from bulkier groups reduced yields, while the electronic nature of R1 influenced reactivity. Structural analysis (NMR, HR-ESI-MS) confirmed product identities, and a 5-exo-trig cyclization mechanism explained base-mediated deprotonation and steric effects. These findings highlight steric and electronic factors in this cyclocondensation, guiding reaction optimization for valuable heterocycles.

Keywords

• cyclocondensation
• microwave irradiation
• pyrrole
• Schiff bases
• 2-amino acid