Reconstructive Methodology in the Synthesis of 2-Aminopurine

A fundamentally new synthetic approach to the synthesis of 2-aminopurine has been developed. It consists in the combination of the creation of a condensed polyazotic heterocyclic tetrazolopyrimidine structure, its transformation into triaminopyrimidine, and its subsequent cyclization into 2-aminopurine. The structure of the obtained compounds was established based on spectral characteristics, and the structure of the intermediate compound 5 was established directly by X-ray diffraction analysis.


Introduction
The compound 2-aminopurine, as a structural analog of guanine, represents a significant group of chemical materials-products of small molecules that are constructed based on modifications of biologically relevant natural compounds [1].These molecules include purines and their derivatives, such as nucleosides and nucleotides [2].The methods of structural modifications of purines and their derivatives are different, including the construction of purines and their glycosidic and/or nucleotide components.Initial studies have been limited to one of three structural modification options: heterocycle, glycoside, and phosphonate.All three techniques exhibited significant efficacy in terms of introducing innovative qualitative approaches for the development of antiviral and antitumor agents to combat-related diseases and infections.
The compound 2-aminopurine and its derivatives represent an important structural element for the creation of antagonists of nucleic acid monomers and their precursors.In addition, it is an intermediate in the biochemical pathways of purine and nucleic acid metabolism.It is also used as a marker to determine the activity of some enzymes involved in these processes [3].
The most significant representatives of this group of antiviral drugs are 2-aminopurines and non-natural nucleosides based on them (Figure 1).
Famciclovir is an antiviral medicine used to treat genital herpes and shingles.It works by preventing the viruses that cause these diseases from multiplying [4].Penciclovir is an antiviral medication used to treat infections caused by the herpes simplex virus.It works by preventing the virus from multiplying and can be used to treat both genital and oral herpes infections [5].Acyclovir is an antiviral medicine used to treat infections caused by the herpes simplex virus, such as herpes on the lips and genitals.It works by blocking the reproduction of the virus [6].Ganciclovir is a medicine used to treat viruses such as cytomegalovirus and herpes simplex virus.It works by stopping viruses from multiplying in the body [7].Abacavir is a medicine used to treat HIV infection.It works by blocking the activity of an enzyme that is needed for the virus to multiply [8].
such as cytomegalovirus and herpes simplex virus.It works by stopping viruses from multiplying in the body [7].Abacavir is a medicine used to treat HIV infection.It works by blocking the activity of an enzyme that is needed for the virus to multiply [8].Various methods for the preparation of 2-aminopurine are presented in the literature (Scheme 1).One of the methods for obtaining the target product is the hydrogenation of 6-chloraminopurine [9].In other publications [10,11], the authors use deamination methods.Thus, in [10], the dehalogenation of 6-chloropurine by microwave irradiation in water is used.In another study [11], the intermediate product is hydrazinopurine, which is formed by the deamination of 4,9-dihydro-purine-1,2-diamine.In this way, these two methods, which are described above, involve the removal of an amino group from the precursor compound to give 2-aminopurine.Alternatively, various cyclocondensation procedures have been reported in publications [12,13] to obtain the desired product.These methods involve the formation of a cyclic compound by the condensation of suitable precursors.The authors describe the one-pot synthesis of a large panel of nucleic bases and related compounds from formamide in the presence of iron-sulfur and iron-copper sulfur minerals as catalysts.Another paper reports the catalytic effect of several types of meteorites: iron, stony-iron, chondrites, and achondrites [14].Thus, meteorite technologies are considered as a potential method of synthesis of 2-aminopurine.These technologies involve the use of meteoritic materials or processes to facilitate the synthesis.Another approach to obtain the target product is the application of 2,4,6-triaminopyrimidine via the cyclization of the vicinal diamine group, with 5-nitrouracil as the starting reagent [15].
It is important to note that these methods represent some of the recognized approaches to the preparation of 2-aminopurine, and additional methods or variations of them may be found in the scientific literature.The aim of this work was to develop a simple synthetic approach that would reduce the number of steps so that it would not be difficult to obtain the target product.
In the present work, we propose a new method for the preparation of 2-aminopurine based on 2,4,6-triaminopyrimidine involving aminotetrazole and nitropyrimidine as key reagents.This approach is an alternative to the existing methods: aminoformylation and chlorodeoxygenation, which involve the use of phosphoryl chloride and subsequent hydrodechlorinatin.The last two steps are inconvenient in the synthetic application.The method developed by us is devoid of the described disadvantages.It should be noted that the target product is an important object for research and further transformations.Various methods for the preparation of 2-aminopurine are presented in the literature (Scheme 1).One of the methods for obtaining the target product is the hydrogenation of 6-chloraminopurine [9].In other publications [10,11], the authors use deamination methods.Thus, in [10], the dehalogenation of 6-chloropurine by microwave irradiation in water is used.In another study [11], the intermediate product is hydrazinopurine, which is formed by the deamination of 4,9-dihydro-purine-1,2-diamine.In this way, these two methods, which are described above, involve the removal of an amino group from the precursor compound to give 2-aminopurine.Alternatively, various cyclocondensation procedures have been reported in publications [12,13] to obtain the desired product.These methods involve the formation of a cyclic compound by the condensation of suitable precursors.The authors describe the one-pot synthesis of a large panel of nucleic bases and related compounds from formamide in the presence of iron-sulfur and iron-copper sulfur minerals as catalysts.Another paper reports the catalytic effect of several types of meteorites: iron, stony-iron, chondrites, and achondrites [14].Thus, meteorite technologies are considered as a potential method of synthesis of 2-aminopurine.These technologies involve the use of meteoritic materials or processes to facilitate the synthesis.Another approach to obtain the target product is the application of 2,4,6-triaminopyrimidine via the cyclization of the vicinal diamine group, with 5-nitrouracil as the starting reagent [15].
It is important to note that these methods represent some of the recognized approaches to the preparation of 2-aminopurine, and additional methods or variations of them may be found in the scientific literature.The aim of this work was to develop a simple synthetic approach that would reduce the number of steps so that it would not be difficult to obtain the target product.
In the present work, we propose a new method for the preparation of 2-aminopurine based on 2,4,6-triaminopyrimidine involving aminotetrazole and nitropyrimidine as key reagents.This approach is an alternative to the existing methods: aminoformylation and chlorodeoxygenation, which involve the use of phosphoryl chloride and subsequent hydrodechlorinatin.The last two steps are inconvenient in the synthetic application.The method developed by us is devoid of the described disadvantages.It should be noted that the target product is an important object for research and further transformations.
It is important to note that these methods represent some of the recognized approaches for the preparation of 2-aminopurine, and there may be additional methods or variations available in the scientific literature.
In the present work, we propose a new method for the preparation of 2-aminopurine based on 2,4,6-triaminopyrimidine involving aminotetrazole and nitropyrimidine as key reagents.
It is important to note that these methods represent some of the recognized approaches for the preparation of 2-aminopurine, and there may be additional methods or variations available in the scientific literature.In the present work, we propose a new method for the preparation of 2-aminopurine based on 2,4,6-triaminopyrimidine involving aminotetrazole and nitropyrimidine as key reagents.

Synthesis
As a novel approach for the preparation of purine systems, we propose a synthetic strategy based on the synthesis of tetrazolopyrimidines.
The interaction of 1H-tetrazol-5-amine 1 with morpholinoacrylonitrile 2 in a 1:1 mixture of pyridine and acetic acid leads to tetrazolo[1,5-a]pyrimidine-7-amine 3 (71%) (Scheme 2).Acetic acid and pyridine act as analogs of "ionic liquids", with the basic properties of pyridine and the acidic properties of acetic acid also favoring condensation reactions [16].The structure of the obtained tetrazolo[1,5-a]pyrimidine-7-amine 3 was confirmed by 1 H NMR, 13 C NMR, IR spectroscopy, and elemental analysis data.It should be noted that in the 1 H NMR spectrum, there are two characteristic doublets with a spin-spin interaction constant of J = 7.5 Hz in the region of δ = 6.59-6.61ppm and δ = 8.89-8.91 ppm, corresponding to the aromatic protons of the pyrimidine cycle.In turn, the protons of the primary amino group appear as a broadened singlet in the region of δ = 7.74 ppm.The presence of the primary amino group is also confirmed by infrared spectroscopy, as the corresponding spectra show a broadened band of low intensity in the region of 3100 cm −1 (Figures S1 and S5, see Supplementary Materials).The second step of the synthesis was the nitration of tetrazolo[1,5-a]pyrimidine-7-amine 3. The choice of a nitrating mixture with a molar ratio of 1:6 (HNO3:H2SO4) was due to the ability of excess sulfuric acid to reduce the oxidative properties of the mixture.The nitration process proceeds smoothly and in good yield (65%).No oxidation of the amino group was observed; thus, this Scheme 1. Literary approaches to 2-aminopurine [9][10][11][12][13][14][15].

Synthesis
As a novel approach for the preparation of purine systems, we propose a synthetic strategy based on the synthesis of tetrazolopyrimidines.
The interaction of 1H-tetrazol-5-amine 1 with morpholinoacrylonitrile 2 in a 1:1 mixture of pyridine and acetic acid leads to tetrazolo[1,5-a]pyrimidine-7-amine 3 (71%) (Scheme 2).Acetic acid and pyridine act as analogs of "ionic liquids", with the basic properties of pyridine and the acidic properties of acetic acid also favoring condensation reactions [16].The structure of the obtained tetrazolo[1,5-a]pyrimidine-7-amine 3 was confirmed by 1 H NMR, 13 C NMR, IR spectroscopy, and elemental analysis data.It should be noted that in the 1 H NMR spectrum, there are two characteristic doublets with a spin-spin interaction constant of J = 7.5 Hz in the region of δ = 6.59-6.61ppm and δ = 8.89-8.91 ppm, corresponding to the aromatic protons of the pyrimidine cycle.In turn, the protons of the primary amino group appear as a broadened singlet in the region of δ = 7.74 ppm.The presence of the primary amino group is also confirmed by infrared spectroscopy, as the corresponding spectra show a broadened band of low intensity in the region of 3100 cm −1 (Figures S1 and S5, see Supplementary Materials).The second step of the synthesis was the nitration of tetrazolo[1,5-a]pyrimidine-7-amine 3. The choice of a nitrating mixture with a molar ratio of 1:6 (HNO 3 :H 2 SO 4 ) was due to the ability of excess sulfuric acid to reduce the oxidative properties of the mixture.The nitration process proceeds smoothly and in good yield (65%).No oxidation of the amino group was observed; thus, this protocol eliminates the additional steps of the introduction and removal of protecting groups.As a result, 6-nitrotetrazolo[1,5-a]pyrimidine-7-amine 4 was obtained in 65% yield (Scheme 2).ppm and 8.27 ppm.
In the IR spectrum of compound 4, the valence vibration of the azide fragment can be observed, which corresponds to an intense band in the region of 2137 cm −1 .This shows that 6-nitrotetrazolo[1,5-a]pyrimidine-7-amine 4 is in an azide form in the solid state.The absorption band in the region of 3436 cm −1 corresponds to the amino group.In the region of 1633 cm −1 , 1329 cm −1 is the absorption band of nitro group.It is known that the nitro group can act both as a leaving group and as a cryptoform of the amino group [17].Thus, in the case of 6-nitroazolo[1,5-a]pyrimidines containing an amino group at the 5 or 7 position, it appears possible to complete the heterocyclic system to the corresponding purine.Therefore, the next stage of the study was the development of methods for the obtaining of pyrimidine-2,4,5-triamine 6.In our previous work, derivatives of (phenyldiazenyl)tetrazolo[1,5-a]pyrimidine-7-amine [16] were prepared by condensation of tetrazolo[1,5-a]pyrimidine-7-amine 3 with 2-oxo-N-phenylacetohydrazonoyl cyanide derivatives.As an alternative approach for the preparation of vicinal diamino derivatives of tetrazolopyrimidines, several attempts were made to reduce the (phenyldiazenyl)tetrazolo[1,5-a]pyrimidine-7-amine, which contains an azo fragment as a cryptoform of the amino group that can be obtained by reductive cleavage.However, we tried different reducing agents such as sodium dithionite, lithium aluminohydride, and zinc in acetic acid, but the initial azo compound was isolated from the reaction mass.
One of the synthetic strategies for obtaining 2-aminopurine is the synthesis of a tetrazolo[1,5-a]pyrimidine-6,7-diamine.To obtain it, it is necessary to reduce tetrazolo[1,5a]pyrimidine-7-amine 3, and this must be completed selectively.This heterocycle has two reaction centers capable of reduction: the nitro group and the tetrazole ring.However, we did not succeed in the selective reduction process of the nitro group without affecting the tetrazole cycle.We can assume that the tetrazole fragment is more reactive to reduction compared to the nitro group, which is located in the sixth position.The following reducing agents were used for this purpose: attempts to use zinc in acetic acid and in ethanol with ammonia did not lead to the formation of the desired intermediate.The typical reducing agent of iron and hydrochloric acid as a solvent failed to isolate 5-nitropyrimidine-2,4diamine 5. Sodium dithionite, which played the role of a reducing agent in the next step to obtain triaminopyrimidine, was ineffective in the selective reduction of tetrazole.In addition, H2/Pd, which is often used for the reduction of nitro groups, failed to yield an intermediate.In some cases, nothing happened, while in others, the tetrazole was reduced but the nitro group remained unreduced.
The construction of 5-nitropyrimidine-2,4-diamine 5 based on aminotetrazole is novel in the synthesis of nitrogenous heterocycles [18].Thus, we have developed the The structure of compound 4 was established based on 1 H, 13 C NMR spectroscopy, IR spectroscopy (Figures S2 and S6, see Supplementary Materials), and elemental analysis data.The 1 H NMR spectrum of compound 4 shows a single-proton signal in the region of δ 9.01 ppm.Corresponding to the resonance of the 5-H atom of the CH group, two single-proton singlet signals correspond to the protons of the amino group in the regions δ 8.89 ppm and 8.27 ppm.
In the IR spectrum of compound 4, the valence vibration of the azide fragment can be observed, which corresponds to an intense band in the region of 2137 cm −1 .This shows that 6-nitrotetrazolo[1,5-a]pyrimidine-7-amine 4 is in an azide form in the solid state.The absorption band in the region of 3436 cm −1 corresponds to the amino group.In the region of 1633 cm −1 , 1329 cm −1 is the absorption band of nitro group.
It is known that the nitro group can act both as a leaving group and as a cryptoform of the amino group [17].Thus, in the case of 6-nitroazolo[1,5-a]pyrimidines containing an amino group at the 5 or 7 position, it appears possible to complete the heterocyclic system to the corresponding purine.Therefore, the next stage of the study was the development of methods for the obtaining of pyrimidine-2,4,5-triamine 6.In our previous work, derivatives of (phenyldiazenyl)tetrazolo[1,5-a]pyrimidine-7-amine [16] were prepared by condensation of tetrazolo[1,5-a]pyrimidine-7-amine 3 with 2-oxo-Nphenylacetohydrazonoyl cyanide derivatives.As an alternative approach for the preparation of vicinal diamino derivatives of tetrazolopyrimidines, several attempts were made to reduce the (phenyldiazenyl)tetrazolo[1,5-a]pyrimidine-7-amine, which contains an azo fragment as a cryptoform of the amino group that can be obtained by reductive cleavage.However, we tried different reducing agents such as sodium dithionite, lithium aluminohydride, and zinc in acetic acid, but the initial azo compound was isolated from the reaction mass.
To obtain it, it is necessary to reduce tetrazolo[1,5-a]pyrimidine-7-amine 3, and this must be completed selectively.This heterocycle has two reaction centers capable of reduction: the nitro group and the tetrazole ring.However, we did not succeed in the selective reduction process of the nitro group without affecting the tetrazole cycle.We can assume that the tetrazole fragment is more reactive to reduction compared to the nitro group, which is located in the sixth position.The following reducing agents were used for this purpose: attempts to use zinc in acetic acid and in ethanol with ammonia did not lead to the formation of the desired intermediate.The typical reducing agent of iron and hydrochloric acid as a solvent failed to isolate 5-nitropyrimidine-2,4-diamine 5. Sodium dithionite, which played the role of a reducing agent in the next step to obtain triaminopyrimidine, was ineffective in the selective reduction of tetrazole.In addition, H 2 /Pd, which is often used for the reduction of nitro groups, failed to yield an intermediate.In some cases, nothing happened, while in others, the tetrazole was reduced but the nitro group remained unreduced.
It turned out that sodium sulfide nonahydrate, aqueous in alcoholic medium, undergoes a reduction of the tetrazole fragment to the amino group, which leads to the preparation of 5-nitropyrimidine-2,4-diamine 5 (32%) (Scheme 3. Route a).
It turned out that sodium sulfide nonahydrate, aqueous in alcoholic medium, undergoes a reduction of the tetrazole fragment to the amino group, which leads to the preparation of 5-nitropyrimidine-2,4-diamine 5 (32%) (Scheme 3. Route a).A selection of conditions was required to make the yields of the compounds preparative.The conditions were selected to make the yields of the target product preparative.The results obtained clearly demonstrated that the best activating reagent was triphenylphosphine (Scheme 3. Route b) when used in an amount of 1.0, equivalent in acetic acid for 2 h, leads to 5-nitropyrimidine-2,4-diamine 5 (77%) (Table 1, entry 4).Reaction conditions: 4 (4.9 mmol); 2 amount of solvent-10 mL; 3 conventional heating with an oil bath;4 autoclave; 5 isolated yield; and 6 10% Pd/C (5 wt %).
The 1 H spectrum of 5-nitropyrimidine-2,4-diamine 5 shows a single-proton signal in the region of 8.84 ppm corresponding to the resonance of the 6-H-atom of the pyrimidine fragment and two two-proton doublets corresponding to the protons of the amino group (δ = 7.98 ppm; 7.45 ppm) (Figures S3, see Supplementary Materials).In addition, the structure of 5-nitropyrimidine-2,4-diamine 5 was finally determined by X-ray diffraction analysis (Figure 2).A selection of conditions was required to make the yields of the compounds preparative.The conditions were selected to make the yields of the target product preparative.The results obtained clearly demonstrated that the best activating reagent was triphenylphosphine (Scheme 3. Route b) when used in an amount of 1.0, equivalent in acetic acid for 2 h, leads to 5-nitropyrimidine-2,4-diamine 5 (77%) (Table 1, entry 4).The 1 H spectrum of 5-nitropyrimidine-2,4-diamine 5 shows a single-proton signal in the region of 8.84 ppm corresponding to the resonance of the 6-H-atom of the pyrimidine fragment and two two-proton doublets corresponding to the protons of the amino group (δ = 7.98 ppm; 7.45 ppm) (Figure S3, see Supplementary Materials).In addition, the structure of 5-nitropyrimidine-2,4-diamine 5 was finally determined by X-ray diffraction analysis (Figure 2).Nitro compounds are important building blocks for further important transformations [19].
In the next step, we attempted the reduction of the nitro group to obtain the target pyrimidine-2,4,5-triamine 6.In the next step, we attempted the reduction of the nitro group to obtain the target pyrimidine-2,4,5-triamine 6.It is worth noting that reduction by tin or iron in an acidic medium leads to oil formation in the reaction mass (Table 2, Nitro compounds are important building blocks for further important transformations [19]. In the next step, we attempted the reduction of the nitro group to obtain the target pyrimidine-2,4,5-triamine 6.In the next step, we attempted the reduction of the nitro group to obtain the target pyrimidine-2,4,5-triamine 6.It is worth noting that reduction by tin or iron in an acidic medium leads to oil formation in the reaction mass (Table 2, entry 2,3).At the same time, in contrast to the reduction of 6-nitrotetrazolo[1,5-a]pyrimidin-7-amine 4, the use of sodium dithionite favors the reduction of the nitro group to the corresponding amine (Scheme 4. Route a), so pyrimidine-2,4,5-triamine 6 was obtained in 59% yield (Table 2, entry 1).Apparently, the energy barrier of this reaction is lower for pyrimidine than for its azoloannelated derivative.Nevertheless, the most successful result in this reaction was the reduction by hydrogen on palladium in dimethylformamide under heating at 20 bar, which gave the desired pyrimidine-2,4,5-triamine 6 in 75% yield (Scheme 4. Route b).Nitro compounds are important building blocks for further important transformations [19].
In the next step, we attempted the reduction of the nitro group to obtain the target pyrimidine-2,4,5-triamine 6.In the next step, we attempted the reduction of the nitro group to obtain the target pyrimidine-2,4,5-triamine 6.It is worth noting that reduction by tin or iron in an acidic medium leads to oil formation in the reaction mass (Table 2, entry 2,3).At the same time, in contrast to the reduction of 6-nitrotetrazolo[1,5-a]pyrimidin-7-amine 4, the use of sodium dithionite favors the reduction of the nitro group to the corresponding amine (Scheme 4. Route a), so pyrimidine-2,4,5-triamine 6 was obtained in 59% yield (Table 2, entry 1).Apparently, the energy barrier of this reaction is lower for pyrimidine than for its azoloannelated derivative.Nevertheless, the most successful result in this reaction was the reduction by hydrogen on palladium in dimethylformamide under heating at 20 bar, which gave the desired pyrimidine-2,4,5-triamine 6 in 75% yield (Scheme 4. Route b).The structure of compound 6 was justified by1 H, 13 C NMR spectroscopy, IR spectroscopy, and elemental analysis data.The 1 H NMR spectrum of compound 6 shows a singleproton signal in the region of δ 7.22 ppm.Corresponding to the resonance of the 6-H atom of the CH group, three single-proton singlet signals correspond to the protons of the amino group in the regions of δ 5.86 ppm, 4.95 ppm, and 3.59 ppm.The presence of the amino groups in the IR spectrum is also confirmed by the presence of a broadened band in the region of 3000-3400 cm −1 (Figures S4 and S8, see Supplementary Materials).The structure of compound 6 was justified by 1 H, 13 C NMR spectroscopy, IR spectroscopy, and elemental analysis data.The 1 H NMR spectrum of compound 6 shows a single-proton signal in the region of δ 7.22 ppm.Corresponding to the resonance of the 6-H atom of the CH group, three single-proton singlet signals correspond to the protons of the amino group in the regions of δ 5.86 ppm, 4.95 ppm, and 3.59 ppm.The presence of the amino groups in the IR spectrum is also confirmed by the presence of a broadened band in the region of 3000-3400 cm −1 (Figures S4 and S8, see Supplementary Materials).
Traube synthesis is a classic method to obtain purines through the annulation of the imidazole fragment into ortho-diaminopyrimidines [20].This method was not applicable to us.For the final cyclization of pyrimidine-2,4,5-triamine 6 to 2-aminopurine 8, we used different formylation reagents (Table 3).The use of triethylorthoformate, acetic acid as a catalyst, and N-formylmorpholine as a formylation agent in formic acid did not lead to the preparation of the target product 8.The results obtained clearly demonstrated that the best reagents were triethylorthoformate and acetic anhydride (Scheme 5), and 2-aminopurine 8 was obtained with a yield of 41%.The final step of the 2-aminopurine synthesis is the construction of the imidazole cycle.Despite the simplicity of the reaction, different derivatives of vicinal diamines may require different conditions [9][10][11][12][13][14].
Traube synthesis is a classic method to obtain purines through the annulation of the imidazole fragment into ortho-diaminopyrimidines [20].This method was not applicable to us.For the final cyclization of pyrimidine-2,4,5-triamine 6 to 2-aminopurine 8, we used different formylation reagents (Table 3).The use of triethylorthoformate, acetic acid as a catalyst, and N-formylmorpholine as a formylation agent in formic acid did not lead to the preparation of the target product 8.The results obtained clearly demonstrated that the best reagents were triethylorthoformate and acetic anhydride (Scheme 5), and 2-aminopurine 8 was obtained with a yield of 41%.

Crystallography
According to the XRD data, two independent molecules of the compound are crystallized with a molecule of H2O in the centrosymmetric space group of the triclinic system.In the result, the structurally independent unit C4H7ClN5O2.5 was used for all calculations.The geometry of the independent heterocyclic molecules has an insignificant distinction; however, all bond distances and angles are near expectations.Both molecules are planar, with insignificant dihedral angles between the NO2 group and the plane of the heterocycle.The general geometry of the molecules is shown in Figure 3.The crystal packing is ordered by the strong system of the H-bonds (Table S1, Supplementary Materials).Scheme 5. Synthesis of 2-aminopurine 8.

Crystallography
According to the XRD data, two independent molecules of the compound are crystallized with a molecule of H 2 O in the centrosymmetric space group of the triclinic system.In the result, the structurally independent unit C 4 H 7 ClN 5 O 2.5 was used for all calculations.The geometry of the independent heterocyclic molecules has an insignificant distinction; however, all bond distances and angles are near expectations.Both molecules are planar, with insignificant dihedral angles between the NO 2 group and the plane of the heterocycle.The general geometry of the molecules is shown in Figure 3.The crystal packing is ordered by the strong system of the H-bonds (Table S1, Supplementary Materials).

Chemical Experiment
Commercial reagents were obtained from Sigma-Aldrich, Acros Organics, or Alfa Aesar and used without any preprocessing.All workup and purification procedures were carried out using analytical-grade solvents.One-dimensional 1 H-and 13 C-NMR spectra were acquired on a Bruker DRX-400 instrument (Karlsruhe, Germany) (400 and 101 MHz, respectively) or a Bruker Avance NEO 600 instrument (151 MHz), utilizing DMSO-d6 as solvents and an external reference, respectively.Chemical shifts are expressed in δ (parts per million, ppm) values, and coupling constants are expressed in hertz (Hz).The following abbreviations are used for the multiplicity of NMR signals: s, singlet; d, doublet.IR spectra were recorded on a Bruker α spectrometer equipped with a ZnSe ATR accessory.Elemental analysis was performed on a PerkinElmer PE 2400 elemental analyzer (Waltham, MA, USA).Melting points were determined on a Stuart SMP3 (Staffordshire, UK) and are uncorrected.The monitoring of the reaction progress was performed using TLC on Sorbfil plates (Imid LTD, Krasnodar, Russia) (the eluent is EtOAc).
The resulting mixture was stirred at 135 °C for 4 h.The resulting precipitate was filtered

Chemical Experiment
Commercial reagents were obtained from Sigma-Aldrich, Acros Organics, or Alfa Aesar and used without any preprocessing.All workup and purification procedures were carried out using analytical-grade solvents.One-dimensional 1 H-and 13 C-NMR spectra were acquired on a Bruker DRX-400 instrument (Karlsruhe, Germany) (400 and 101 MHz, respectively) or a Bruker Avance NEO 600 instrument (151 MHz), utilizing DMSO-d6 as solvents and an external reference, respectively.Chemical shifts are expressed in δ (parts per million, ppm) values, and coupling constants are expressed in hertz (Hz).The following abbreviations are used for the multiplicity of NMR signals: s, singlet; d, doublet.IR spectra were recorded on a Bruker α spectrometer equipped with a ZnSe ATR accessory.Elemental analysis was performed on a PerkinElmer PE 2400 elemental analyzer (Waltham, MA, USA).Melting points were determined on a Stuart SMP3 (Staffordshire, UK) and are uncorrected.

Figure 3 .
Figure 3.The compound in the thermal ellipsoid of the 50% probability level.

Figure 3 .
Figure 3.The compound in the thermal ellipsoid of the 50% probability level.