Solid-Phase Synthesis of 2-Amino-2-thiazolines by the Cyclization of N-(2-Hydroxyethyl)thioureas Using TFA

Abstract

The 2-amono-2-thiazolines have recently gained significant interest as a scaffold that is applicable to the development of bioactive compounds such as pronounced antidepressant agents, potent human nitric oxide synthase inhibitors, octopaminergic-agonists, anthelmintics, and anti-inflammatory agents. The solid phase synthesis of small heterocycles have been considerably studied because it can be applied to the rapid generation of diverse libraries of drug-like compounds. Although there are many wellestablished reports on the solution phase synthesis of 2amino-2-thiazolines scaffolds because of their valuable pharmaceutical properties, very recently we first reported a solid phase synthetic method of 2-amino-2-thiazolines from the cyclization of N-(2-hydroxyethyl)thioureas using dicyclohexylcarbodiimide (DCC). The ring closure of N-(2hydroxyethyl)thioureas can furnish different products depending on the reaction conditions and substrates such as S-cyclized, N-cyclized, or O-cyclized products. Resinbound substrates 6 were designed as precursors to generate 2-amino-2-thiazolines by the S-cyclization, which were conveniently prepared from various commercially available aminoalcohols and isothiocyanates (Scheme 1). We wish to report an alternative and more effective way into the solid phase synthesis of 2-amino-2-thiazolines, using the cyclization of N-(2-hydroxyethyl)thioureas. Scheme 2 shows the synthetic route of the 2-amino-2thiazoline scaffold. The first step in solid phase reactions was the coupling of amino alcohol onto an ArgoGel-MBCHO resin via reductive amination, followed by the protection of the free alcohol 3 with tert-butyldimethylsilyl chloride (TBSCl) according to the previous procedures. Treatment of this intermediate with isothiocyanates afforded the thioureas resin 5, and subsequent deprotection of the silylated hydroxy group with tetrabutyl ammonium fluoride in THF yielded resin 6. The intramolecular cyclization of resin 6 using dicyclohexylcarbodiimide (DCC) gave mainly the required S-cyclized 2-amino-2-thiazolines resin 7 as reported. Then we turned to release the N-(2-hydroxyethyl)thioureas from the resin 6, key intermediate in Scheme 2, by the trifluoroacetic acid (TFA) cleavage to determine the loading capacity of the both amino alcohols and isothiocyanates. The desired thiourea was not obtained but the final product 2-amino-2-thiazoline was released in high yield and purity. This is that the cyclization and cleavage reaction in TFA simultaneously occurred at the same step, thereby saving one step procedure. The results using TFA for the cyclization and cleavage are summarized in Table 1. Resin 6 derived from either aliphatic (entry 7a-b) or aryl isothiocyanates (entry 7c-7k) furnished the required Salkylation products, but aminoalcohol was limited to the primary alcohol. In summary, a solid phase synthetic method was developed for the parallel synthesis of 2-amino-2-thiazolines, using the cyclization of N-(2-hydroxyethyl)thioureas and cleavage in TFA. This synthetic methodology is ideally suited for the automated applications, because all the reactions were carried out under ambient conditions.