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Journal ArticleDOI

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

TL;DR: In this article, it was found that 3-amino-substituted 5-aminopyrazoles can be effectively prepared via hydrolytic decarboxylation of the corresponding 3-5-diaminopyrazole-4-carboxylates under microwave irradiation.
About: This article is published in Tetrahedron.The article was published on 2019-04-12 and is currently open access. It has received 8 citations till now. The article focuses on the topics: Tautomer & Decarboxylation.

Summary (2 min read)

1. 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.
  • 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 That led us to the development of the described here practical method for the synthesis of compounds 3.
  • The authors interest towards prototropic tautomerism in azoles9 prompted us to investigate this phenomenon viz.

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

  • For the synthesis of 3-amino-substituted 5-aminopyrazoles 3 the authors 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.
  • It should be noted that attempts to carry out the reaction under reflux for 12 h using 2M NaOH solution did not lead to the isolation of 3a but rather to the recovery of starting material 5a.
  • With the optimized conditions in hand, the authors decided to explore the scope of the reaction with a diverse library of 3-amino-substituted 5-aminopyrazole-4-carboxylates (5) as substrates.
  • In all cases, the hydrolytic decarboxylation of methyl and ethyl esters was efficiently performed in both 0.325 mmol and 3.25 mmol scales with similar outcomes (Table 2).
  • In the 1H NMR spectra of the prepared compounds, signals of protons of the exocyclic amino groups, C-H proton on the pyrazole ring and aromatic ring protons of 5-amino-3-arylaminopyrazoles 3a-3k adjacent to the pyrazole ring appeared as broad signals.

2.2 X-ray crystallography of 5-amino-3-arylaminopyrazoles 3g and 3i

  • The crystallographic asymmetric unit of 3g comprises two independent molecules, as shown in Figs. 2(a) and (b).
  • Quite similar molecular features as described for 3g are also evident in the structure of 3i.
  • The amine-N3/N3a‒H atoms form hydrogen bonds with the pyrazole-N1a/N1 atoms of the other independent molecules and are indicated with “iii” and “iv” in Fig. 4(a).
  • The most obvious contacts between the layers to consolidate the three-dimensional packing are methyl-C57‒H…π(C51a-C56a) interactions as highlighted in the unit cell diagram of ESI Fig. S2† from which it can be seen the phenyl groups project to either side of the layer.

3. 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 refinement, systematic variations of key geometric parameters and intermolecular interactions, the presence of two different tautomers: the 1H- and 2H-pyrazole, respectively.

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Journal ArticleDOI
TL;DR: A revision of data is provided on the present subject, based on investigations using theoretical and experimental methods, together with the applications of the compounds in synthesis, to contribute to a deeper understanding of structure/reactivity relationships in this class of heterocycles.
Abstract: Pyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex heterocyclic systems with relevance in the pharmaceutical field. Pyrazoles are also interesting compounds from a structural viewpoint, mainly because they exhibit tautomerism. This phenomenon may influence their reactivity, with possible impact on the synthetic strategies where pyrazoles take part, as well as on the biological activities of targets bearing a pyrazole moiety, since a change in structure translates into changes in properties. Investigations of the structure of pyrazoles that unravel the tautomeric and conformational preferences are therefore of upmost relevance. 3(5)-Aminopyrazoles are largely explored as precursors in the synthesis of condensed heterocyclic systems, namely pyrazolo[1,5-a]pyrimidines. However, the information available in the literature concerning the structure and chemistry of 3(5)-aminopyrazoles is scarce and disperse. We provide a revision of data on the present subject, based on investigations using theoretical and experimental methods, together with the applications of the compounds in synthesis. It is expected that the combined information will contribute to a deeper understanding of structure/reactivity relationships in this class of heterocycles, with a positive impact in the design of synthetic methods, where they take part.

31 citations


Cites background or methods from "A new practical synthesis of 3-amin..."

  • ...predominance of the form bearing the phenethylamine group, with higher electron donating properties, at the C3 position [111]....

    [...]

  • ...[111], using solution and solid-state NMR and X-ray crystallography, were in conformity with the aforementioned properties of pyrazoles regarding proton exchange....

    [...]

Journal ArticleDOI
TL;DR: These factors, pyrazole aromaticity and intra- and inter-molecular interactions, seem to have a considerable influence on the choice of tautomer.
Abstract: A series of disubstituted 1H-pyrazoles with methyl (1), amino (2), and nitro (3) groups, as well as ester (a) or amide (b) groups in positions 3 and 5 was synthesized, and annular tautomerism was investigated using X-ray, theoretical calculations, NMR, and FT-IR methods. The X-ray experiment in the crystal state showed for the compounds with methyl (1a, 1b) and amino (2b) groups the tautomer with ester or amide groups at position 3 (tautomer 3), but for those with a nitro group (3b, 4), tautomer 5. Similar results were obtained in solution by NMR NOE experiments in CDCl3, DMSO-d6, and CD3OD solvents. However, tautomer equilibrium was observed for 2b in DMSO. The FT-IR spectra in chloroform and acetonitrile showed equilibria, which can be ascribed to conformational changes of the cis/trans arrangement of the ester/amide group and pyrazole ring. Theoretical analysis using the M06-2X/6-311++G(d,p) method (in vacuo, chloroform, acetonitrile, and water) and measurement of aromaticity (NICS) showed dependence on internal hydrogen bonds, the influence of the environment, and the effect of the substituent. These factors, pyrazole aromaticity and intra- and inter-molecular interactions, seem to have a considerable influence on the choice of tautomer.

11 citations

Journal ArticleDOI
TL;DR: In this paper, 3-Amino-substituted 5-aminopyrazoles were found to be suitable substrates for the synthesis of new 4-AMR[1,5-a][1,3,5]triazines (5-aza-9deaza-adenines) when used in the one-pot, three-component reaction with cyanamide and triethyl orthoformate under microwave irradiation.

7 citations

Journal ArticleDOI
TL;DR: In this article , the synthesis and biological activity of a series of 1H-pyrazol-5-amine-based thrombin inhibitors with a serine-trapping mechanism of action was reported.
Abstract: New antithrombotic drugs are needed to combat thrombosis, a dangerous pathology that causes myocardial infarction and ischemic stroke. In this respect, thrombin (FIIa) represents an important drug target. We herein report the synthesis and biological activity of a series of 1H-pyrazol-5-amine-based thrombin inhibitors with a serine-trapping mechanism of action. Among synthesized compounds, flexible acylated 1H-pyrazol-5-amines 24e, 34a, and 34b were identified as potent 16–80 nM thrombin inhibitors, which showed practically no off-targeting effect against other physiologically relevant serine proteases. To prove that synthesized compounds are covalent thrombin inhibitors, the most potent derivative 24e (FIIa IC50 = 16 nM) was studied in a mass-shift assay, where it has been shown that 24e transfers its acyl moiety (pivaloyl) to the catalytic Ser195 of thrombin. Performed herein docking studies also confirmed the covalent mechanism of thrombin inhibition by synthesized compounds. Acylated aminopyrazoles found during this study showed only limited effects on plasma coagulation in activated partial thrombin time (aPTT) and prothrombin time (PT) in vitro assays. However, such thrombin inhibitors are expected to have virtually no effect on bleeding time and can be used as a starting point for developing a safer alternative to traditional non-covalent anticoagulants.

2 citations

Journal ArticleDOI
TL;DR: In this article, a matrix isolation IR spectra (in both argon and xenon matrices) was interpreted, and the observed bands were assigned to the tautomeric forms with help of vibrational calculations carried out at both harmonic and anharmonic levels.
Abstract: The prototropic tautomerism in 3(5)-aminopyrazoles was investigated by matrix isolation infrared (IR) spectroscopy, supported by DFT(B3LYP)/6-311++G(d,p) calculations. In consonance with the experimental data, the calculations predict tautomer 3-aminopyrazole (3AP) to be more stable than the 5-aminopyrazole (5AP) tautomer (calculated energy difference: 10.7 kJ mol−1; Gibbs free energy difference: 9.8 kJ mol−1). The obtained matrix isolation IR spectra (in both argon and xenon matrices) were interpreted, and the observed bands were assigned to the tautomeric forms with help of vibrational calculations carried out at both harmonic and anharmonic levels. The matrix-isolated compound (in argon matrix) was then subjected to in situ broadband UV irradiation (λ > 235 nm), and the UV-induced transformations were followed by IR spectroscopy. Phototautomerization of the 3AP tautomer into the 5AP form was observed as the strongly prevalent reaction.

2 citations

References
More filters
Journal ArticleDOI
TL;DR: This paper could serve as a general literature citation when one or more of the open-source SH ELX programs (and the Bruker AXS version SHELXTL) are employed in the course of a crystal-structure determination.
Abstract: An account is given of the development of the SHELX system of computer programs from SHELX-76 to the present day. In addition to identifying useful innovations that have come into general use through their implementation in SHELX, a critical analysis is presented of the less-successful features, missed opportunities and desirable improvements for future releases of the software. An attempt is made to understand how a program originally designed for photographic intensity data, punched cards and computers over 10000 times slower than an average modern personal computer has managed to survive for so long. SHELXL is the most widely used program for small-molecule refinement and SHELXS and SHELXD are often employed for structure solution despite the availability of objectively superior programs. SHELXL also finds a niche for the refinement of macromolecules against high-resolution or twinned data; SHELXPRO acts as an interface for macromolecular applications. SHELXC, SHELXD and SHELXE are proving useful for the experimental phasing of macromolecules, especially because they are fast and robust and so are often employed in pipelines for high-throughput phasing. This paper could serve as a general literature citation when one or more of the open-source SHELX programs (and the Bruker AXS version SHELXTL) are employed in the course of a crystal-structure determination.

81,116 citations

Journal ArticleDOI
TL;DR: New features added to the refinement program SHELXL since 2008 are described and explained.
Abstract: The improvements in the crystal structure refinement program SHELXL have been closely coupled with the development and increasing importance of the CIF (Crystallographic Information Framework) format for validating and archiving crystal structures. An important simplification is that now only one file in CIF format (for convenience, referred to simply as `a CIF') containing embedded reflection data and SHELXL instructions is needed for a complete structure archive; the program SHREDCIF can be used to extract the .hkl and .ins files required for further refinement with SHELXL. Recent developments in SHELXL facilitate refinement against neutron diffraction data, the treatment of H atoms, the determination of absolute structure, the input of partial structure factors and the refinement of twinned and disordered structures. SHELXL is available free to academics for the Windows, Linux and Mac OS X operating systems, and is particularly suitable for multiple-core processors.

28,425 citations

Journal ArticleDOI
TL;DR: This paper reports on the current status of structure validation in chemical crystallography and describes the current state of research in this area.
Abstract: Automated structure validation was introduced in chemical crystallography about 12 years ago as a tool to assist practitioners with the exponential growth in crystal structure analyses. Validation has since evolved into an easy-to-use checkCIF/PLATON web-based IUCr service. The result of a crystal structure determination has to be supplied as a CIF-formatted computer-readable file. The checking software tests the data in the CIF for completeness, quality and consistency. In addition, the reported structure is checked for incomplete analysis, errors in the analysis and relevant issues to be verified. A validation report is generated in the form of a list of ALERTS on the issues to be corrected, checked or commented on. Structure validation has largely eliminated obvious problems with structure reports published in IUCr journals, such as refinement in a space group of too low symmetry. This paper reports on the current status of structure validation and possible future extensions.

13,163 citations

Journal ArticleDOI
TL;DR: The WinGX suite provides a complete set of programs for the treatment of small-molecule single-crystal diffraction data, from data reduction and processing, structure solution, model refinement and visualization, and metric analysis of molecular geometry and crystal packing, to final report preparation in the form of a CIF.
Abstract: The WinGX suite provides a complete set of programs for the treatment of small-molecule single-crystal diffraction data, from data reduction and processing, structure solution, model refinement and visualization, and metric analysis of molecular geometry and crystal packing, to final report preparation in the form of a CIF. It includes several well known pieces of software and provides a repository for programs when the original authors no longer wish to, or are unable to, maintain them. It also provides menu items to execute external software, such as the SIR and SHELX suites of programs. The program ORTEP for Windows provides a graphical user interface (GUI) for the classic ORTEP program, which is the original software for the illustration of anisotropic displacement ellipsoids. The GUI code provides input capabilities for a wide variety of file formats, and extra functionality such as geometry calculations and ray-traced outputs. The programs WinGX and ORTEP for Windows have been distributed over the internet for about 15 years, and this article describes some of the more modern features of the programs.

9,479 citations

Journal ArticleDOI
TL;DR: In this paper, a catalyst-free highly efficient synthesis of 3(5)-amino-5(3)-(het)aryl-1,2,4-triazoles in aqueous medium was performed using conventional heating and microwave irradiation.

76 citations