Synthesis of 2-Quinolones via Thiolate-Mediated Cyclization of ( E )-2-Aminocinnamic Acid Derivatives

Overview

A synthetic protocol for the preparation of 2-quinolones and 2-aza-quinolones from 2-aminocinnamic acid derivatives utilizing thiolate-mediated cyclization has been developed. The method demonstrates broad substrate compatibility with high synthetic yields and favorable practical characteristics including straightforward product isolation and scalability.

Methods and approach

The synthetic strategy involves conjugate addition of thiolate nucleophiles to (E)-2-aminocinnamic acid derivatives, generating β-sulfide-substituted dihydrocinnamic acid intermediates as key synthetic intermediates. These intermediates permit conformational flexibility through rotation about the Cα–Cβ single bond, positioning the amino and carboxyl functionalities for subsequent intramolecular condensation. The condensation step is followed by elimination of hydrogen sulfide to furnish the quinolone core structure. The protocol extends to preparation of 2-aza-quinolone regioisomers through application to 2-amino-aza-cinnamate substrates.

Results

The cyclization protocol accommodates a broad substrate scope of 2-aminocinnamic acid derivatives with excellent product yields for the corresponding 2-quinolones. The aza-quinolone extension enables synthesis of multiple regioisomeric products from systematic variation of the heterocyclic precursor. Product isolation by recrystallization facilitates purification without chromatographic intervention. Gram-scale reactions demonstrate synthetic viability without significant yield or operational degradation.

Implications

The thiolate-mediated cyclization provides a practical alternative to existing 2-quinolone syntheses, with operational simplicity and high atom efficiency contributing to synthesis feasibility in both academic and industrial contexts. The broad substrate tolerance enables structural diversification of quinolone scaffolds through precursor variation without requiring protocol modification. Extension to aza-quinolone regioisomers expands the structural space accessible through a single synthetic platform, potentially supporting discovery programs requiring systematic variation across heterocyclic positions.