Elsevier

Tetrahedron

Volume 75, Issue 15, 12 April 2019, Pages 2314-2321
Tetrahedron

A new practical synthesis of 3-amino-substituted 5-aminopyrazoles and their tautomerism

https://doi.org/10.1016/j.tet.2019.03.003Get rights and content

Highlights

  • An efficient hydrolysis-decarboxylation protocol.

  • A simple and scalable method for the aminopyrazole synthesis.

  • A microwave-assisted synthesis of pyrazoles.

  • Tautomeric preferences for pyrazoles in crystals.

Abstract

It was found that 3-amino-substituted 5-aminopyrazoles could be effectively prepared via hydrolytic decarboxylation of the corresponding 3,5-diaminopyrazole-4-carboxylates under microwave irradiation. The reactions required short time (4 min) and were successfully reproduced in a larger scale and under conventional heating mimicking the microwave heating pattern. X-ray crystallography identified two different types of tautomers in crystals of related 5-aminopyrazoles with p-toluidyl and p-anisidyl moieties at the position 3, respectively.

Introduction

5-Aminopyrazoles have been well recognised as biologically active compounds and efficient building blocks for the construction of fused heterocyclic molecules of high medicinal value [1]. Recent studies demonstrated an interesting biological profile for 3,5-diaminopyrazole (1) (Fig. 1) [2]. Hoffmann-La Roche patented 5-amino-3-arylaminopyrazoles (e.g. 2) as antiviral agents, particularly useful for the treatment of hepatitis C virus infection [3]. Some 3-amino-substituted 5-aminopyrazoles of general structure 3 were also mentioned in patents as building blocks for the construction of bioactive compounds [4]. Surprisingly, information on the synthesis of such non-symmetrically substituted 3,5-diaminopyrazoles is rather scarce. The methods earlier developed for the preparation of 3-amino-substituted 5-aminopyrazoles 3 are limited to heterocyclizations of N-substituted cyanoacetimidate esters or amides of cyanothioacetic acid in their reactions with hydrazine [5,6]. The main drawbacks of these synthetic approaches included relatively difficult accessibility of starting materials and low yields [3,5,6].

In our program on the synthesis of new purine-like heterocycles [7] we required 3-amino-substituted 5-aminopyrazoles 3 as synthons for further reactions [8]. That led us to the development of the described here practical method for the synthesis of compounds 3. Our interest towards prototropic tautomerism in azoles [9] prompted us to investigate this phenomenon viz. tautomeric preferences in the representative compounds 3 using X-ray crystallography.

Section snippets

Synthesis of 3-amino-substituted 5-aminopyrazoles (3)

For the synthesis of 3-amino-substituted 5-aminopyrazoles 3 we decided to employ readily accessible 3-amino-substituted 5-aminopyrazole-4-carboxylates 5, which can be conveniently prepared in good yields from 2-cyano-3-methylthioacrylates 4 using the previously described method (Scheme 1) [10]. The hydrolytic decarboxylation of 5 was suggested as a potential route to 3-amino-substituted 5-aminopyrazoles 3.

The initial optimization of reaction conditions for the synthesis 3 was performed using

Conclusion

A new efficient method for the synthesis of 3(5)-amino-substituted 5(3)-aminopyrazoles 3 was developed using hydrolytic decarboxylation of the ester group on the corresponding 3,5-diaminopyrazole-4-carboxylates 5 under microwave irradiation. The method was proven to be practical due to operational simplicity, short reaction time, good reproducibility and scalability. The X-ray crystallography performed on two representative aminopyrazoles 3g and 3i identified, on the basis of crystallographic

General information

Melting points (uncorrected) were determined on a Stuart™ SMP40 automatic melting point apparatus. 1H and 13C NMR spectra were recorded on a Bruker Fourier NMR spectrometer (300 MHz) using DMSO‑d6 as a solvent and TMS as an internal reference. IR spectra were recorded in KBr pellets using a Varian 640-IR spectrophotometer. Microwave-assisted reactions were carried out in the closed vessel focused single mode using a Discover SP microwave synthesizer (CEM, USA) monitoring reaction temperature by

Acknowledgements

The Research Centre for Crystalline Materials (Sunway University) is thanked for the X-ray intensity data. This work is supported by the Ministry of Higher Education, Malaysia under Fundamental Research Grant Scheme, grant number FRGS/1/2015/SG01/MUSM/03/1.

References (17)

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