Convenient Synthesis of Thiohydantoins, Imidazole-2-thiones and Imidazo[2,1-b]thiazol-4-iums from Polymer-Supported α-Acylamino Ketones.

Petra Králová,Hiroyuki Koshino,Michal Maloň,Miroslav Soural

doi:10.3390/molecules23040976

Abstract

The preparation of 5-methylene-thiohydantoins using solid-phase synthesis is reported in this paper. After sulfonylation of immobilized Ser (t-Bu)-OH with 4-nitrobenzenesulfonyl chloride followed by alkylation with various bromoketones, the 4-Nos group was removed and the resulting polymer-supported α-acylamino ketones reacted with Fmoc-isothiocyanate. Cleavage of the Fmoc protecting group was followed by the spontaneous cyclative cleavage releasing the 5-methylene-thiohydantoin derivatives from the polymer support. Reduction with triethylsilane (TES) yielded the corresponding 5-methyl-thiohydantoins. When Fmoc-isothiocyanate was replaced with alkyl isothiocyanates, the trifluoroacetic acid (TFA) mediated cleavage from the polymer support, which was followed by the cyclization reaction and the imidazo[2,1-b]thiazol-4-iums were obtained. Their conversion in deuterated dimethylsulfoxide led to imidazole-2-thiones.

Highlights

The reaction of polymer-supported 2- or 4-nitrobenzensulfonamides with α-haloketones allows the simple production of many different heterocycles using the concept of diversity-oriented synthesis [1]
As a continuation of our ongoing research in the field of solid-phase syntheses of pharmacologically promising heterocycles, we suggested the application of immobilized α-acylamino ketones for preparing novel fused [5 + 6] heterocycles bearing a thiohydantoin scaffold. 2-Thiohydantoins are present in the structure of many natural and synthetic compounds that can serve as antiandrogens [8], immunomodulators [9], or agricultural agents [10,11]
Similar results were obtained for other 5-methyl-thiohydantoins 7{R1,1}, which were obtained in crude purities of

Summary

Introduction

The reaction of polymer-supported 2- or 4-nitrobenzensulfonamides with α-haloketones allows the simple production of many different heterocycles using the concept of diversity-oriented synthesis [1]. This chemistry was used to prepare morpholines and thiomorpholines from polymer-supported serine and cysteine via the corresponding α-acylamino ketones [2,3,4]. 2-thiohydantoins fused with morpholine or oxazine scaffolds and structurally related compounds have rarely been studied. Inspired by these findings, we attempted a simple synthesis to Molecules 2018, 23, 976; doi:10.3390/molecules23040976 www.mdpi.com/journal/molecules.

Results

Synthesis andand conditions:

Isomerization

Conclusions