Towards Symmetric Thioamides: Microwave-Aided Synthesis of Terephthalic Acid Derivatives

Abstract

The multistep synthesis of novel bis-terephthalthioamides based on methyl esters of amino acids (AAs) was proposed using conventional heating and microwave-assisted approaches. In fact, the comparative case study on the thionation of new symmetrical diamides with Lawesson's reagent (LR) was performed. The microwave-accelerated small-scale methodology was successfully employed on the whole pathway from substrates (Gly, Ala, Val, Tyr, Ser) to products (symmetrical dithioamides of terephthalic acid), resulting in significantly reduced reaction time, energy requirements, and slightly increased reaction yields when compared to conventional heating. Moreover, the intermolecular similarity of novel terephthalic acid derivatives was estimated in the multidimensional space (mDS) of the structure/property-related in silico descriptors using principal component analysis (PCA) and hierarchical clustering analysis (HCA). The distance-oriented structure/property distribution was also correlated with the experimental lipophilic data.

Keywords: bis-terephthalthioamides; microwave-accelerated synthesis; terephthalic acid; thioamides; thionation.

Figure 1

The number of papers published in medicinal chemistry, where the name of the selected AAs was searched in the paper title or abstract according to Reaxys data.

Figure 2

Thioamide-based approved therapeutic agents according to DrugBank database.

Scheme 1

Direct thionation of amides by elemental sulfur using hydrochlorosilanes and amines.

Scheme 2

Spatial structure and dissociation mechanism of phosphorus decasulfide (P₄S₁₀).

Scheme 3

Mechanism of amide thionation via P₄S₁₀ agent.

Scheme 4

Lawesson (R = C₆H₄-OCH₃), Belleau (R = C₆H₄-OC₆H₅), and Davy (R = SCH₃) reagents.

Scheme 5

Mechanism of amide thiocarbonylation via Lawesson’s reagent.

Figure 3

Selected organosulfur families prepared with Lawesson’s reagent.

Scheme 6

Synthesis of dithioamides (5a–5e) according to conventional (I) and microwave-supported (II) procedures.

Figure 4

Projection of diamides (4a–4e) and dithioamides (5a–5e) of terephthalic acid on a plane defined by PC1 and PC2. Colors code the violations of Ro5 rule.

Figure 5

Dendrogram of diamides (4a–4e) and dithioamides (5a–5e) of terephthalic acid in descriptor-based space with a color-coded map of experimental lipophilic values (R_mo and logk).

Figure 6

Matrix of correlation coefficients of linear relationships between experimental lipophilicity (R_mo and logk) and calculated lipophilicity (clogP) for diamides (4a–4e) and dithioamides (5a–5e) of terephthalic acid.

Figure 7

Molecular structure of compound 5d.