Synthesis of 2-thioxoimidazolines via reaction of 1-unsubstituted 3-aminoquinoline-2,4-diones with isothiocyanates

doi:10.1016/j.tet.2009.09.048

Tetrahedron

Volume 65, Issue 45, 7 November 2009, Pages 9103-9115

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Abstract

3-Alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with alkyl/aryl isothiocyanates to give 3a-alkyl/aryl-1,2,3,3a-tetrahydro-9b-hydroxy-2-thioxo-5H-imidazo[4,5-c]quinolin-4(9bH)-ones in high yields. These compounds rearrange in boiling acetic acid or concd hydrochloric acid to give novel 4-(2-aminophenyl)-1H-imidazole-2(3H)-thiones, 1,3-bis(2-(2,3-dihydro-2-thioxo-1H-imidazol-5-yl)phenyl)ureas and minor N-(2-(2,3-dihydro-2-thioxo-1H-imidazol-4-yl)phenyl)acetamides. In the presence of ethanol, the starting compounds rearrange in boiling acetic acid to give ethyl 2-(2,3-dihydro-2-thioxo-1H-imidazol-4-yl)phenylcarbamates. All compounds were characterized by their ¹H, ¹³C, IR and MS spectra and some of them also by ¹⁵N NMR data. The structures of two compounds were supported by single-crystal X-ray diffraction.

Graphical abstract

Introduction

In our laboratory, much attention has been paid to the reactivity of 3-amino, 3-hydroxy and 3-thiocyanato-1H,3H-quinoline-2,4-diones. Recently, the behaviour of the products of the reaction of 3-amino-1H,3H-quinoline-2,4-diones with isocyanic acid and isocyanates was investigated. In an acidic medium, these compounds are subject to molecular rearrangement, leading to novel heterocycles. A brief survey of these transformations was given in our last paper on this topic.¹

The exceptional structural diversity of the products of the molecular rearrangement mentioned above gave us incentive to perform the analogous reaction of 3-amino-1H,3H-quinoline-2,4-diones with isothiocyanates and to examine how the products of this reaction would behave in an acidic environment. We anticipated the formation of new compounds containing a sulfur atom, which may be interesting, since many biologically active compounds contain a sulfur atom.2, 3

The structure of the rearrangement products of the adducts of 1 with isocyanates is largely dependent on the character of the substituents at the 1, 3 and 1′ positions of the starting compounds 1. Thus, according to this criterion, we divided the starting 3-amino-1H,3H-quinoline-2,4-diones into three different groups.⁴ The first group contained compounds substituted at the 1-position with an alkyl or aryl groups and at the 3-position with an alkyl group. In our latest paper,⁴ we demonstrated that compounds of this group afford—contrary to their reaction with isocyanates—a single cyclic addition product, which rearranges in an acidic environment to give three different types of spiro-imidazoline-4,3′-[3H]indole-2,2′(1H′)-diones, depending on the substituents at the 3 and 3a positions.

In this work, we demonstrate that the reaction of starting compounds 1 of the third group (compounds unsubstituted at the 1-position) also provides a single cyclic adduct, 3, which rearranges in an acidic environment to give novel 4-(2-aminophenyl)-1H-imidazole-2(3H)-thiones (4), 1,3-bis(2-(2,3-dihydro-2-thioxo-1H-imidazol-5-yl)phenyl)ureas (6) and minor N-(2-(2,3-dihydro-2-thioxo-1H-imidazol-4-yl)phenyl)acetamides (7) (Scheme 1).

Section snippets

Results and discussion

Reactions of 3-amino-1H,3H-quinoline-2,4-diones 1 with isothiocyanates were performed by refluxing the reaction components in chloroform (Scheme 1).

Methylisothiocyanate and phenylisothiocyanate were chosen as model isothiocyanates. Starting aminoketones 1 were obtained from the corresponding 3-chloro derivatives, in accordance with the procedures described.⁵

As in the reaction of the 1-substituted compounds 1 with isothiocyanates,⁴ only cyclic 1,2,3,3a-tetrahydro-9b-hydroxy-2-thioxo-5H

Conclusions

In conclusion, the described molecular rearrangement of compounds 3 is not merely interesting from a theoretical point of view but, owing to the simple reaction protocol, presents an easy pathway for the preparation of novel heterocyclic systems containing 2-thioxoimidazoline fragment. A number of 2-thioxoimidazolines and their derivatives exhibit significant biological activities11, 12 including inflammatory activity,¹³ gentamycin nephrotoxicity,¹⁴ dopamine β-hydroxylase inhibitory activity

General considerations

Melting points were determined on a Kofler block or Gallencamp apparatus. Elemental analyses (C, H, N) were performed with an EA 1108 Elemental Analyzer (Fisons Instrument). IR (KBr) spectra were recorded on a Mattson 3000 spectrophotometer. NMR spectra were recorded on a Bruker Avance spectrometer (500.13 MHz for ¹H, 125.76 MHz for ¹³C, 50.68 MHz for ¹⁵N) in DMSO-d₆. ¹H and ¹³C chemical shifts are given on the δ scale (ppm) and are referenced to internal TMS. ¹⁵N chemical shifts were referred to

Acknowledgements

This study was supported by the Ministry of Education, Youth and Sports of the Czech Republic (Grant No. MSM 7088352101) and the Czech Science Foundation (Grant No. 203/07/0320). The authors thank Mrs. H. Geržová (Faculty of Technology, Tomas Bata University in Zlín) for technical help.

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Synthesis of 2-thioxoimidazolines via reaction of 1-unsubstituted 3-aminoquinoline-2,4-diones with isothiocyanates

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

General considerations

Acknowledgements

Tetrahedron

Tetrahedron

J. Appl. Crystallogr.

Helv. Chim. Acta

Chem. Rev.

Nat. Prod. Rep.

Heterocycles

J. Heterocycl. Chem.