Elsevier

Tetrahedron

Volume 57, Issue 9, 25 February 2001, Pages 1671-1675
Tetrahedron

Study of N-benzoyl-activation in the HgCl2-promoted guanylation reaction of thioureas. Synthesis and structural analysis of N-benzoyl-guanidines

https://doi.org/10.1016/S0040-4020(00)01168-6Get rights and content

Abstract

In this work, it is demonstrated that the benzoyl group is an activating group for thioureas in the HgCl2-guanylation reaction. Thus N-benzoyl-thioureas containing electronically neutral and even electron-withdrawing or electron-releasing substituents are converted into guanidines with reasonable yields. In addition, NMR and X-ray structural analyses were performed to understand the intra- and intermolecular features of the synthesized guanidines.

Introduction

Recently, we initiated a research program aimed at the synthesis of anticonvulsant agents. In this context, we became interested in the preparation of guanidine derivatives since these substances proved to be potential anticonvulsant compounds.1 The guanidinium group is also present in many natural and synthetic biologically active compounds.2., 3., 4. Due to its large spectrum of activity such as antibacterial, antidiabetic, antihistaminic, anti-inflammatory and cardiovascular activity,4 the guanidine unit has been intensively studied as a synthetic goal and a diversity of new methods has been developed. Advances have been described both in solid5., 6., 7., 8., 9. and solution10., 11., 12., 13., 14., 15., 16., 17., 18. phase synthesis of guanidine and, in the latter case, thioureas are the most versatile starting material because they can be obtained in high yield from easily available precursors. However, to efficiently convert thiourea into guanidine by the HgCl2 protocol the thiourea should be activated by a strong electron-withdrawing group, and the most general approach to achieve this is by the use of N,N′-bis-Boc-protected thioureas (Scheme 1).12., 13., 16., 17.

Herein, we described our study of the N-benzoyl-group as an alternative activation group for thiourea in the guanylation reaction promoted by HgCl2. To the best of our knowledge, only one example of N-benzoyl-thiourea conversion into guanidine has been described in the literature but that case was limited to electronically and sterically neutral substituents.13

Section snippets

Results and discussion

While N,N′-bis-Boc-thioureas and N-Boc-thiourea are easily converted into guanidines by the HgCl2 method,12., 13., 16., 17. the use of this starting material can be a drawback if guanidines containing different N-substituents need to be synthesized, because deprotection/protection steps are necessary. With N-benzoyl activation this limitation can be overcome, in principle, by reacting benzoyl isothiocyanate with an appropriate amine followed by the reaction of the resulting N-benzoyl-thiourea

Experimental

Melting points were determined on a Karl Kolb apparatus and are uncorrected. Infrared spectra were recorded as KBr discs on an FT-IR BOMEM MB100 instrument. NMR spectra were obtained for 1H at 300 or 400 MHz and for 1C at 75 or 100 MHz using a Varian Gemini 300, a Bruker AC300P and a Bruker ARX400 spectrometers at Instituto de Quı́mica/UNICAMP and at Instituto de Quı́mica/UFSCar. Chemical shifts are reported in ppm units downfield from reference (internal TMS). MS spectra were measured on a

Acknowledgements

The authors thank the Brazilian Agencies for fellowships to MBC (PIBIC-UFG/CNPq), IV (CNPq) and HBN (CAPES), and financial support from FUNAPE-UFG, PADCT-III/QEQ (No. 620166/97-5). The authors also thank Instituto de Quı́mica—UNICAMP (NMR and elemental analyses), Instituto de Quı́mica—UFSCar (NMR) for measurements, and Departamento de Quı́mica—UFSC for the X-ray single crystal data collection.

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