Novel Eco-friendly, One-Pot Method for the Synthesis of Kynurenic Acid Ethyl Esters

Abstract

The synthesis of kynurenic acid derivatives with potential biological effect was investigated and optimized for one-batch, two-step microwave-assisted reactions. Utilizing both chemically and biologically representative non-, methyl-, methoxy-, and chlorosubstituted aniline derivatives, in catalyst-free conditions, syntheses of seven kynurenic acid derivatives were achieved in a time frame of 2-3.5 h. In place of halogenated reaction media, tuneable green solvents were introduced for each analogue. The potential of green solvent mixtures to replace traditional solvents and to alter the regioisomeric ratio regarding the Conrad-Limpach method was highlighted. The advantages of the fast, eco-friendly, inexpensive analytic technique of TLC densitometry were emphasized for reaction monitoring and conversion determination in comparison to quantitative NMR. Moreover, the developed 2-3.5 h syntheses were scaled-up to achieve gram-scale products of KYNA derivatives, without altering the reaction time in the halogenated solvent DCB and more importantly in its green substitutes.

Scheme 1. Synthesis of Substituted Kynurenic Acid Ethyl Esters Using the CL Method

Scheme 2. CL Synthesis of C-6-Substituted KYNA Ethyl Esters

Figure 1

Factors taken into consideration while designing the MW-assisted reactions illustrated through an Ishikawa diagram.

Scheme 3. CL Syntheses of C-5- and C-7-Substituted KYNA Ethyl Esters

Figure 2

Quantitative NMR spectrum of the crude reaction mixture of the synthesis of compound 7 in GVL using p-methoxybenzoic acid as the internal standard (aromatic region).

Figure 3

TLC densitometric analysis of compound 7: record of the plate, densitogram, regression curve on a graph (quantity of desired compound [μg] → optical density divided by 1000), and calculated dissolved products given as conversion × selectivity [%].

Figure 4

¹H-NMR spectrum of 14a in DMSO-d₆ at 310 K, with a broad signal visible and a lack of multiplicity.

Figure 5

¹H-NMR spectrum of 14a in CDCl₃ at 285 K, with adequate multiplicity and the two tautomers visible.

Figure 6

Oxo–enol tautomerism of 14a, with full signal assignment.