Expedient Lewis Acid Catalyzed Synthesis of a 3-Substituted 5-Arylidene-1-methyl-2-thiohydantoin Library

Abstract

An efficient and rapid solution phase combinatorial synthesis of a 3-substituted 5-arylidene-1-methyl-2-thiohydantoin library was developed. The salient feature for this library production procedure is the addition of the Lewis acid catalyst, indium(III) trifluoromethanesulfonate, which serves to facilitate the direct condensation of aldehydes with 3-substituted 1-methyl-2-thiohydantoins. Use of this Lewis acid catalyst has resulted in faster reaction times, higher conversions and better purity profiles for these condensation reactions as compared to traditional uncatalyzed reactions. The resulting 315 member library of 3-substituted 5-arylidene-1-methyl-2-thiohydantoin is described.

Diverse Applications of Biomass‐Derived 5‐Hydroxymethylfurfural and Derivatives as Renewable Starting Materials

“…HMF-derived hydantoins with interesting biological properties. [28,29] SW480 (colorectal cancer). This synthetic strategy was also utilized by other groups, such as Meguellati et al, who reported the synthesis of B-ring-modified Aurones via nucleophilic addition of a β-oxo ketone to HMF.…”

“…In a similar synthetic fashion, Gregg et al. reported an In III ‐catalyzed combinatorial synthesis towards 3‐substituted 5‐arylidene‐1‐methyl‐2‐thiohydantoins, including an HMF‐derived substrate (Scheme 4, compound 12 ) [29] . The efficient synthesis and straightforward purification of this protocol allowed for the rapid production of a diverse library of compounds with potential application as antimycobacterial agents.…”

5-Hydroxymethylfurfural (HMF) in Organic Synthesis: A Review of its Recent Applications Towards Fine Chemicals

“…[48] Scheme 9. Condensation of cyanoamides and nitriles derivatives with 5-HMF Cyclic amides such as rhodanine 28 [49] and thiohydantoins 30 [50] have been employed for the preparation of 5hydroxymethylfurfurylidene-substituted heterocycles, designed for pharmacological tests (Scheme 10). The furfurylidene-rhodanine 29 was obtained in the presence of ethylenediammonium diacetate with 73% yield whereas the thiohydantoin 31 was formed in the presence of pyrrolidine and indium triflate as Lewis acid.…”

New frontiers in the transition-metal-free synthesis of heterocycles from alkynoates: an overview and current status

“…This method is different from the classical approach which involves two-step synthesis, aiming at the preparation of the thiohydantoin moiety followed by a Knoevenagel condensation with aldehydes. 305,306 This concept originates from the dual reactivity of thioureas where α-N-addition occurs at aryl propiolates under Bu 3 P catalysis followed by cyclization to produce thiohydantoins. With the optimized reaction conditions in hand, a range of thioureas were employed as coupling partners with aryl propiolates to afford numerous 5-arylidene-2-thiohydantoins.…”