scispace - formally typeset

Journal ArticleDOI

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

12 Apr 2019-Tetrahedron (Elsevier)-Vol. 75, Iss: 15, pp 2314-2321

AbstractIt 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.

Topics: Tautomer (54%), Decarboxylation (53%)

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.

Did you find this useful? Give us your feedback

...read more

Content maybe subject to copyright    Report

A new practical synthesis of 3-amino-substituted 5-aminopyrazoles
and their tautomerism
Felicia Phei Lin Lim,
a
Khai Ching Tan,
a
Giuseppe Luna,
b
Edward R. T. Tiekink,
c
Anton V.
Dolzhenko
a,b
*
a
School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway,
Selangor Darul Ehsan 47500, Malaysia
b
School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute,
Faculty of Health Sciences, Curtin University, GPO Box U1987 Perth, Western Australia 6845,
Australia
c
Research Centre for Crystalline Materials, School of Science and Technology, Sunway
University, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia
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 5
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.

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.
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.
Figure 1. Selected bioactive 3,5-diaminopyrazoles.

2 Results and discussion
2.1 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.
Scheme 1.
The initial optimization of reaction conditions for the synthesis 3 was performed
using ethyl 5-amino-3-phenylaminopyrazole-4-carboxylate (5a) (Table 1). The reaction
proceeded under microwave irradiation to form product 3a in 2 mL of 2M aqueous solution
of NaOH at 150 °C for 30 sec (Entry 1). Increasing the time of reaction (Entries 1-6) led to the
further improvement of yields with the yield of 81% achieved at 150 °C in 4 min (Entry 5).
Altering the concentration of NaOH did not led to an improvement in isolated yields (Entries
7 and 8). Conducting the reaction in 2M aqueous solution of K
2
CO
3
or Na
2
CO
3
led to lower
yields (Entries 9 and 10), while changing the base to an acid (Entry 11) resulted in the
isolation of the starting material 5a only.
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. However, an attempt to carry out the decarboxylation reaction of 5a in 2M
NaOH, imitating the optimised microwave irradiation conditions in the Monowave 50
reactor (Anton Paar), using sealed vessels under fast conventional heating successfully led

to the formation of equally pure 3a in 75% yield. Therefore, there was minimal (if any)
contribution of non-thermal microwave effects in promoting this reaction.
With the optimized conditions in hand, we decided to explore the scope of the
reaction with a diverse library of 3-amino-substituted 5-aminopyrazole-4-carboxylates (5) as
substrates. Compounds 5 were prepared according to the recently developed microwave-
assisted approach.
10
Subsequently, the base-catalysed decarboxylation of ethyl 5-
aminopyrazole-4-carboxylates 5 under microwave irradiation was found to proceed
efficiently with the formation of desired products 3a-3l in yields up to 85% (Table 2). A
variety of arylamino and arylalkylamino substituents on the pyrazole ring was well tolerated
with exclusive formation of compounds 3, which were isolated in high purity via simple
filtration. Using optimized conditions, we also attempted to carry out this reaction with
methyl 3,5-diaminopyrazole-4-carboxylates 5. For comparison purposes, 3a, 3h and 3j were
successfully prepared from the corresponding methyl esters 5. 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).
The structure assignments for the prepared 3,5-diaminopyrazoles 3 were made
based on their spectral data. When compared with the spectra of reported staring
materials,
10
we observed the disappearance of the characteristic
1
H NMR and
13
C NMR
signals of the ethoxycarbonyl and methoxycarbonyl groups in addition to the absence of a
C=O band in the IR spectra. Additionally, a signal assigned to H-4 atom of the pyrazole ring
appeared in
1
H NMR spectra of 3 at 4.62-5.07 ppm.
Annular prototropic tautomerism is an interesting phenomenon, which has been
widely investigated in aminopyrazoles.
11
In the
1
H 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. However, the tautomeric transformations were probably too fast
to be detected on the
1
H NMR time-scale under the experimental conditions and therefore
the tautomers were indistinguishable. For the compound 3l, two tautomeric forms (K
T
= 1.3)
were detected in the NMR spectra in DMSO solution with 1H-form of 5-amino-3-
phenethylaminopyrazole (3l) being predominant. Further study of the tautomeric
preferences was performed on pyrazoles 3g and 3i using X-ray crystallography. While to a

first approximation the molecular structures of 3g and 3i appeared to be similar, crucially
the compounds crystallized in the form of different tautomers as discussed in detail below.
Table 1. Optimization conditions for the synthesis of 5-amino-3-phenylaminopyrazole (3a)
a
Entry
Base/Acid
Temperature (°C)
Time (min)
Isolated yield (%)
1
2M NaOH
150
0.5
43
2
2M NaOH
150
1
40
3
2M NaOH
150
2
76
4
2M NaOH
150
3
80
5
2M NaOH
150
4
81
6
2M NaOH
150
5
72
7
1M NaOH
150
4
71
8
3M NaOH
150
4
64
9
2M K
2
CO
3
150
4
25
10
2M Na
2
CO
3
150
4
30
11
2M HCl
150
4
0
b
a
The reaction was performed using a Discover SP CEM microwave synthesizer with 0.325
mmol of 5a in 2 mL of the specified base or acid.
b
Only starting material 5a was isolated.

Figures (7)
Citations
More filters

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.

11 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
Abstract: 3-Amino-substituted 5-aminopyrazoles were found to be suitable substrates for the synthesis of new 4-aminopyrazolo[1,5-a][1,3,5]triazines (5-aza-9-deaza-adenines) when used in the one-pot, three-component reaction with cyanamide and triethyl orthoformate under microwave irradiation. The reaction proceeded selectively and its scope was demonstrated by the preparation of a library of 4-aminopyrazolo[1,5-a][1,3,5]triazines. Some structural aspects of the prepared compounds were investigated using dynamic NMR spectroscopy and X-ray crystallography. The operational simplicity, short reaction time, and good reproducibility are attractive features of the developed robust and practical approach for the synthesis of 7-amino-substituted 4-aminopyrazolo[1,5-a][1,3,5]triazines.

6 citations


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.

5 citations


Journal ArticleDOI
Abstract: By means of single crystal X-ray diffraction and DFT calculations the structural features of 3-(5-methyl-1H-pyrazol-3-yl)-2H-chromen-2-one and 3-(3-methyl-1H-pyrazol-3-yl)-2H-chromen-2-one obtained by condensing substituted 3-acetoacetyl-2Н-chromen-2-ones with semicarbazides are revealed. The possibility of the existence of the compound in different tautomeric and rotameric forms in the crystal is shown.

Journal ArticleDOI
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.

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.

77,177 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.

21,137 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.

12,245 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.

8,270 citations


Journal ArticleDOI
Abstract: 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. The tautomerism in the products was investigated using NMR spectroscopy and X-ray crystallography. The effects of the substitution, temperature, solvents, and concentration on the tautomerism were studied. The triazoles were found to exist in 1 H -forms, the 4 H -form was not observed either in solid state or in solution. In general, 5-amino-1,2,4-triazoles were electronically preferred in the tautomeric equilibrium, but some exceptions from the established relationship were also identified.

67 citations