Exploring Three Avenues: Chemo- and Regioselective Transformations of 1,2,4-Triketone Analogs into Pyrazoles and Pyridazinones

A convenient approach to substituted pyrazoles and pyridazinones based on 1,2,4-triketones is presented. Chemo- and regiocontrol in condensations of t-Bu, Ph-, 2-thienyl-, and CO2Et-substituted 1,2,4-triketone analogs with hydrazines are described. The direction of preferential nucleophilic attack was shown to be switched depending on the substituent nature in triketone as well as the reaction conditions. The acid and temperature effects on the selectivity of condensations were revealed. Regiochemistry of heterocyclic core formation was confirmed by NMR and XRD studies. The facile construction of heterocyclic motifs bearing acetyl and (or) carbethoxy groups suggests them as promising mono- or bifunctional building blocks for subsequent transformations.

Since the structural features have extremely significant effects on the physical and drug-like properties of pyrazole and pyridazine derivatives, the starting materials for the synthesis of promising pharmaceuticals and agrochemicals based on these motifs should have a flexible structure for the fine tuning of the desired characteristics.In this context, the building block strategy has been proven to be a convenient approach to modified heterocycles with two adjacent nitrogen atoms.The classical method for creating pyrazoles is based on the condensation reaction of 1,3-dicarbonyl compounds (β-diketones and 3-ketoesters [45][46][47][48]) or α,β-unsaturated ketones [49,50] with hydrazines.One further route affording the pyrazole core formation involves [3+2] cycloaddition reactions of diazocompounds, nitrilimines with alkenes or alkynes [51][52][53][54][55].For the synthesis of pyridazine ring systems, condensation reactions of 1,4-bifunctional reagents (4-oxocarboxylic acids or furan-2(5H)-ones [56][57][58][59], cyclic anhydrides [60,61]) with hydrazines commonly used as well as the Diels-Alder cycloaddition approach [62,63].The ability of these heterocycles to act as effective agrochemicals also highlights their potential for the selective targeting of biological systems [36,37].For crop growth control photosynthesis inhibitors norflurazon [38], chloridazon [39], and pyridate [37] are used as pyridazine-based herbicides along with insecticides (pyridaben [40]).The pesticidal activity of the 1,2-diazole core can be illustrated by a range of N-phenylpyrazoles [41], among which fipronil [42] is the most popular insecticide, and also by methyl-substituted analogs such as cyenopyrafen [43], tebufenpyrad, and fenpyroximate [2,44] (Figure 2).The ability of these heterocycles to act as effective agrochemicals also highlights their potential for the selective targeting of biological systems [36,37].For crop growth control photosynthesis inhibitors norflurazon [38], chloridazon [39], and pyridate [37] are used as pyridazine-based herbicides along with insecticides (pyridaben [40]).The pesticidal activity of the 1,2-diazole core can be illustrated by a range of N-phenylpyrazoles [41], among which fipronil [42] is the most popular insecticide, and also by methyl-substituted analogs such as cyenopyrafen [43], tebufenpyrad, and fenpyroximate [2,44] (Figure 2).Since the structural features have extremely significant effects on the physical and drug-like properties of pyrazole and pyridazine derivatives, the starting materials for the However, there are some limitations associated with reactions of unsymmetrical diketones and their synthetic equivalents with substituted hydrazines.The major difficulty is that they can sometimes suffer from regioselectivity issues, leading to the formation of multiple isomeric products [64][65][66][67][68].In some cases, using specific catalysts along with varying the reaction parameters allow for the precise manipulation of the reactivity of different carbonyl groups.
Nevertheless, β-diketones are overwhelmingly used as easily available and highly reactive compounds, offering a straightforward and versatile approach to accessing a wide range of five-and six-membered nitrogen containing heterocycles [69,70].One important benefit comes from the modification of 1,3-diketones with various substituents including functional groups, which makes it possible to directly introduce them into the desired positions of heterocycles when it is problematic to do otherwise.This opens up new possibilities for the construction of more complex molecules as well as fused heterocycles with improved biological activities [8,71].
The synthetic potential of β-diketones can be further expanded by incorporating an additional keto group and thereby turning to a 1,2,4-triketone scaffold.The literature provides scarce data on the synthesis and transformations of such triketones, in contrast to closely related class of 2,4-diketoesters [72,73].Substantially more attention has been paid to the 1,2,4-triketone analogs, mainly fluorine-containing [74][75][76][77][78].These compounds combine the reactivity of α-, β-, and γ-dicarbonyl systems, opening the route to a wider range of possible products via interaction with binucleophiles [79].Previously fluorinated acetal-containing lithium β-diketonates and their cyclic derivatives-furan-3(2H)-oneswere found to be the polyfunctional building blocks for the preparation of 3-R F and 5-R F pyrazoles, pyridazine-4(1H)-ones, and β-diketohydrazones during condensations with arylhydrazines [80][81][82] (Figure 3).In this case, the solvent-dependent regiocontrol strategy turned out to be effective.Overall, the nature of a fluoroalkyl substituent in 1,2,4-triketones was responsible for the distinctive reaction pattern, leading to three different routes [79].In this regard, similar transformations of non-fluorinated derivatives must be considered for in-depth study and the achievement of regio-and chemocontrol in reactions of tricarbonyl compounds with hydrazines.Moreover, revealing the electronic effects of the substituents and evaluating steric control provide access to specific isomers.Overall, the nature of a fluoroalkyl substituent in 1,2,4-triketones was responsible for the distinctive reaction pattern, leading to three different routes [79].In this regard, similar transformations of non-fluorinated derivatives must be considered for in-depth study and the achievement of regio-and chemocontrol in reactions of tricarbonyl compounds with hydrazines.Moreover, revealing the electronic effects of the substituents and evaluating steric control provide access to specific isomers.
With this aim in mind, we designed a series of novel 1,2,4-triketone analogs bearing alkyl, aryl, heteroaryl, and functional groups and explored how they affect the direction of condensations with hydrazines compared to fluorinated substituents (Figure 3).Here, we discuss the ability to control their influence to access either pyridazines or pyrazoles of isomeric structure with high selectivity.This work will ensure the use of 1,2,4-triketones as polyfunctional starting materials for the synthesis of multiple heterocyclic scaffolds that can be subsequently functionalized.

Results and Discussion
The base-promoted Claisen condensation was chosen as the main approach to novel 1,2,4-triketone analogs.Acetal-and ester-functionalized β-diketone 1 was obtained by the reaction of 3,3-dimethoxybutan-2-one with ethyl oxalate in the presence of sodium hydride (Scheme 1).Since sodium β-diketonates are highly soluble in organic solvents and water, we used a convenient method to isolate compound 1.This procedure includes the formation of the copper(II) complex by adding Cu(OAc) 2 to the rection mixture and the further treatment of the Cu(II) chelate with Na 2 EDTA (disodium ethylenediamine tetraacetate) [75].The same access has been successfully applied to the synthesis of tricarbonyl derivatives containing alkyl, aryl, and heteroaryl fragments.Ethyl 2,2-dimethoxypropanoate was reacted with a series of methyl ketones giving 1,2,4-triketone analogs 2a-c bearing tert-butyl, phenyl, and 2-thienyl substituents (Scheme 2).It was found that using oxalic acid instead of Na2EDTA for the decomposition of the Cu(II) complex based on 2-thienylsubstituted diketone led to the formation of cyclic product 3.Moreover, the partial crystallization of 1,2,4-triketone 2b to 2-hydroxy-2-methyl-5-phenylfuran-3(2H)-one 5 occurred during storage in air, affording a few crystals suitable for XRD studies.In this regard, the acid-catalyzed intramolecular cyclization of compounds 1, 2a-c was attempted.However, only aryl-substituted triketones 4a,b, existing in enolized form, were isolated and characterized (Scheme 2).In the case of the tert-butyl 2a and ester 1 substituents, small amounts of 1,2,4-triketones and furanones were observed in a mixture with the decomposition products according to GC-MS analysis.It should be noted that although 2-hydroxyfuran-3(2H)-one 5 is stable in a solid state, it is mainly observed in the open-chain form when dissolved in a nonpolar solvent (CDCl3).β-Diketones 2с and 4a,b and furan-3(2H)ones 3 and 5 are also stable as powders, while the other 1,2,4-tricarbonyl analogs exist as oils at normal conditions.The same access has been successfully applied to the synthesis of tricarbonyl derivatives containing alkyl, aryl, and heteroaryl fragments.Ethyl 2,2-dimethoxypropanoate was reacted with a series of methyl ketones giving 1,2,4-triketone analogs 2a-c bearing tert-butyl, phenyl, and 2-thienyl substituents (Scheme 2).It was found that using oxalic acid instead of Na 2 EDTA for the decomposition of the Cu(II) complex based on 2-thienyl-substituted diketone led to the formation of cyclic product 3.Moreover, the partial crystallization of 1,2,4-triketone 2b to 2-hydroxy-2-methyl-5-phenylfuran-3(2H)-one 5 occurred during storage in air, affording a few crystals suitable for XRD studies.In this regard, the acidcatalyzed intramolecular cyclization of compounds 1, 2a-c was attempted.However, only aryl-substituted triketones 4a,b, existing in enolized form, were isolated and characterized (Scheme 2).In the case of the tert-butyl 2a and ester 1 substituents, small amounts of 1,2,4triketones and furanones were observed in a mixture with the decomposition products according to GC-MS analysis.It should be noted that although 2-hydroxyfuran-3(2H)-one 5 is stable in a solid state, it is mainly observed in the open-chain form when dissolved in a nonpolar solvent (CDCl 3 ).β-Diketones 2c and 4a,b and furan-3(2H)-ones 3 and 5 are also stable as powders, while the other 1,2,4-tricarbonyl analogs exist as oils at normal conditions.
As previously mentioned, hydrazine dihydrochloride is a convenient reagent providing for the formation of heterocyclic products in the absence of acid catalysis [80].The transformations of acetal-containing 2,4-diketoester 1 were considered starting from reaction with this binucleophile.As a result of reflux in EtOH, the NH-pyrazole 6 was formed (Scheme 3, see Section 3.2.Method A).Turning to the methyl-and phenylhydrazines, 5-acetylpyrazoles 7a,b as the sole products were obtained.Likewise, reactions between 1,2,4-triketone 1 and the substituted arylhydrazines proceeded in a regiospecific manner.A large series of N-aryl-5-acetyl-1H-pyrazole-3-carboxylates 7c-l was synthesized (Scheme 3).The pyrazoles 7c-l were easily isolated with the high yields as the precipitates from reaction mixtures.
curred during storage in air, affording a few crystals suitable for XRD studies.In this regard, the acid-catalyzed intramolecular cyclization of compounds 1, 2a-c was attempted.However, only aryl-substituted triketones 4a,b, existing in enolized form, were isolated and characterized (Scheme 2).In the case of the tert-butyl 2a and ester 1 substituents, small amounts of 1,2,4-triketones and furanones were observed in a mixture with the decomposition products according to GC-MS analysis.It should be noted that although 2-hydroxyfuran-3(2H)-one 5 is stable in a solid state, it is mainly observed in the open-chain form when dissolved in a nonpolar solvent (CDCl3).β-Diketones 2с and 4a,b and furan-3(2H)ones 3 and 5 are also stable as powders, while the other 1,2,4-tricarbonyl analogs exist as oils at normal conditions.As previously mentioned, hydrazine dihydrochloride is a convenient reagent providing for the formation of heterocyclic products in the absence of acid catalysis [80].The transformations of acetal-containing 2,4-diketoester 1 were considered starting from reaction with this binucleophile.As a result of reflux in EtOH, the NH-pyrazole 6 was formed (Scheme 3, see Section 3.2.Method A).Turning to the methyl-and phenylhydrazines, 5acetylpyrazoles 7a,b as the sole products were obtained.Likewise, reactions between 1,2,4-triketone 1 and the substituted arylhydrazines proceeded in a regiospecific manner.А large series of N-aryl-5-acetyl-1H-pyrazole-3-carboxylates 7c-l was synthesized (Scheme 3).The pyrazoles 7c-l were easily isolated with the high yields as the precipitates from reaction mixtures.Accordingly, the direction of the initial nucleophilic attack is strongly determined by influence of the ethoxycarbonyl group, despite the hydrazine structure.It provides a wide range of bifunctional pyrazole derivatives, which are of interest for further modification via the acetyl and ester fragments.
In order to compare the electron-withdrawing and -donating effects of the substituents in 1,2,4-triketones, the chemical properties of tert-butyl, phenyl-, and 2-thienyl-substituted analogs were also examined in reactions with different binucleophiles.Herewith, unsubstituted hydrazine, methyl-, and phenylhydrazines were used as the most illustrative examples.
It was found that both β-diketone 2c and the furan-3(2H)-one 3 bearing the 2-thienyl analogs were also examined in reactions with different binucleophiles.Herewith, unsubstituted hydrazine, methyl-, and phenylhydrazines were used as the most illustrative examples.
It was found that both β-diketone 2c and the furan-3(2H)-one 3 bearing the 2-thienyl fragment give pyridazine-4(1H)-ones 8 and 9 during reflux with binucleophiles in EtOH (Scheme 4).To improve the conversion in reactions with substituted hydrazines, hydrochloric acid was used as a catalyst.In these cases, binucleophiles attack the acetal carbon atom, leading to cyclization or recyclization of compounds 2c and 3 to six-membered products 8 and 9. Similarly to CO 2 Et-functionalized β-diketone 1, the reaction pathway is affected by the nature of the substituent near the 1,3-dicarbonyl fragment and does not depend upon the hydrazine structure.When t-Bu-substituted 1,2,4-triketone 2a was refluxed with hydrazine dihydrochlo ride, both five-and six-membered products were obtained.According to 1 H NMR data pyridazin-4(1H)-one 10a and NH-pyrazole 10b were formed in the ratio 3:2 (Scheme 5).I is worth noting that attempts to separate the product mixture by recrystallization were unsuccessful, thus column chromatography was required.The high chemoselectivity o the process was achieved during the reflux of t-Bu-containing β-diketone 2a with substi tuted hydrazines.Being the strongest nucleophile, MeNHNH2 transforms compound 2a into pyridazin-4(1H)-one 11 through interaction with the carbon atom of the acetal group (Scheme 5).At the same time, phenylhydrazine provides the formation of 3-regioisomeric acetylpyrazole 12 in accordance with the spectral and XRD studies.When t-Bu-substituted 1,2,4-triketone 2a was refluxed with hydrazine dihydrochloride, both five-and six-membered products were obtained.According to 1 H NMR data, pyridazin-4(1H)-one 10a and NH-pyrazole 10b were formed in the ratio 3:2 (Scheme 5).It is worth noting that attempts to separate the product mixture by recrystallization were unsuccessful, thus column chromatography was required.The high chemoselectivity of the process was achieved during the reflux of t-Bu-containing β-diketone 2a with substituted hydrazines.Being the strongest nucleophile, MeNHNH 2 transforms compound 2a into pyridazin-4(1H)-one 11 through interaction with the carbon atom of the acetal group (Scheme 5).At the same time, phenylhydrazine provides the formation of 3-regioisomeric acetylpyrazole 12 in accordance with the spectral and XRD studies.
Turning to Ph-containing 1,2,4-triketone 2b, its cyclization with hydrazine was accompanied by the formation of two nitrogen heterocycles 13a and 13b, as in the case of tert-butyl analog 2a.In addition, only one product was obtained by using PhNHNH 2 •HCl, which was not pyrazole but pyridazinone 14 (Scheme 6).Although the reaction between diketone 2b and methylhydrazine proceeded mainly via the 1,4-addition pathway under reflux, 3-acetylpyrazole 15b was isolated along with pyridazinone 15a in the ratio of 1:3, respectively.The yields of the products are presented in Table 1.
is worth noting that attempts to separate the product mixture by recrystallization were unsuccessful, thus column chromatography was required.The high chemoselectivity of the process was achieved during the reflux of t-Bu-containing β-diketone 2a with substituted hydrazines.Being the strongest nucleophile, MeNHNH2 transforms compound 2a into pyridazin-4(1H)-one 11 through interaction with the carbon atom of the acetal group (Scheme 5).At the same time, phenylhydrazine provides the formation of 3-regioisomeric acetylpyrazole 12 in accordance with the spectral and XRD studies.Turning to Ph-containing 1,2,4-triketone 2b, its cyclization with hydrazine was accompanied by the formation of two nitrogen heterocycles 13a and 13b, as in the case of tert-butyl analog 2a.In addition, only one product was obtained by using PhNHNH2•HCl, which was not pyrazole but pyridazinone 14 (Scheme 6).Although the reaction between diketone 2b and methylhydrazine proceeded mainly via the 1,4-addition pathway under Scheme 5. Acid-catalyzed condensations of t-Bu-substituted triketone 2a with hydrazines.
Int. J. Mol.Sci.2023, 24, x FOR PEER REVIEW 8 of 28 reflux, 3-acetylpyrazole 15b was isolated along with pyridazinone 15a in the ratio of 1:3, respectively.The yields of the products are presented in Table 1.
Scheme 6.Multiple products obtained via the heterocyclization of Ph-containing building blocks 2b and 4.
Table 1.Summary of the data of the reactions between compounds 2b/4a and the hydrazines.Since methylhydrazine is a strong nucleophile, we decreased the reaction temperature to enhance the selectivity of its initial attack.Nevertheless, similar transformations were observed with the predominant formation of a 1,3-addition product.Moreover, we turned to 1,2,4-triketone 4a to evaluate the effect of the acetal group on the reaction pathway.During refluxing 4a with MeNHNH2, the mixture of heterocycles 15a and 15b was observed in the same ratio as in the case of acetal-functionalized analog 2b (Table 1).

Compound
One might conclude that hydrazine can attack either one or several positions of the 1,2,4-triketone concurrently.It depends only on the substituent nature in the building block and the nucleophilicity of hydrazine, and is not affected by the presence of a protecting group.Besides, the temperature has been found to be a significant and potent tool Since methylhydrazine is a strong nucleophile, we decreased the reaction temperature to enhance the selectivity of its initial attack.Nevertheless, similar transformations were observed with the predominant formation of a 1,3-addition product.Moreover, we turned to 1,2,4-triketone 4a to evaluate the effect of the acetal group on the reaction pathway.During refluxing 4a with MeNHNH 2 , the mixture of heterocycles 15a and 15b was observed in the same ratio as in the case of acetal-functionalized analog 2b (Table 1).
One might conclude that hydrazine can attack either one or several positions of the 1,2,4-triketone concurrently.It depends only on the substituent nature in the building block and the nucleophilicity of hydrazine, and is not affected by the presence of a protecting group.Besides, the temperature has been found to be a significant and potent tool for directing the nucleophilic attack.
Based on these results, attempts have been made to gain control over the direction of the preferential nucleophile attack by varying the reaction conditions.Firstly, the influence of temperature was analyzed in condensations of 1,2,4-triketone analogs 1 and 2a-c with hydrazine hydrate in the presence of HCl as a catalyst.This choice was made in light of the low solubility of RNHNH 2 •HCl in ethanol at room temperature.Herewith, the corresponding NH-pyrazoles 6, 10b, 13b, and 17 were obtained (Scheme 7, see Section 3.2.Method B).Only in the case of Ph-substituted β-diketone was the intermediate pyrazolidine 16 precipitated from the reaction mixture, preventing its further dehydration.According to the 1 H NMR spectrum of compound 16, protons of two NH-and two OH-groups appeared as multiplets in the ranges of 7.15-7.25 ppm and 13.45-13.55ppm, respectively.In addition, signals of the acetyl group as well as CH 2 fragment were observed at δ H = 2.33-2.39ppm.It was found that compound 16 could be converted to acetylpyrazole 13b upon reflux in the excess of glacial acetic acid.Next, the heterocyclization of compounds 2a-c under acid-free conditions was investigated (Scheme 7).Recently, it has been demonstrated that fluorine-containing 1,2,4triketone analogs can be easily cyclized to NH-pyrazoles in MeOH under the action of aqueous hydrazine while retaining the acetal group [83].The behavior of t-Bu, Ph, and 2thienyl-substituted β-diketones was not an exception, whereby heterocyclic compounds 18a-c were obtained.It should be noted that the products 18a-c open an alternative route to acetylpyrazoles 10b, 13b, and 17 via acid-catalyzed hydrolysis of the acetal fragment (see Section 3.2.Method C).
Following this method, the regiocontrolled transformations of 1,2,4-triketones 2a-c to 5-acetyl-N-methylpyrazoles 20a-c were performed without catalysis (Scheme 8).The selectivity of the methylhydrazine attack was found to increase when the reaction mixture was cooled, providing the formation of the acetal-containing pyrazoles 19a-c.Further hydrolysis of compounds 19a-c carried out in formic acid led to the target products.For triketone 1, regiospecific condensation with methylhydrazine afforded 5-acetylpyrazole-3-carboxylate 7a as well as the reaction with the salt form of binucleophile.Next, the heterocyclization of compounds 2a-c under acid-free conditions was investigated (Scheme 7).Recently, it has been demonstrated that fluorine-containing 1,2,4triketone analogs can be easily cyclized to NH-pyrazoles in MeOH under the action of aqueous hydrazine while retaining the acetal group [83].The behavior of t-Bu, Ph, and 2-thienyl-substituted β-diketones was not an exception, whereby heterocyclic compounds 18a-c were obtained.It should be noted that the products 18a-c open an alternative route to acetylpyrazoles 10b, 13b, and 17 via acid-catalyzed hydrolysis of the acetal fragment (see Section 3.2.Method C).
Following this method, the regiocontrolled transformations of 1,2,4-triketones 2a-c to 5-acetyl-N-methylpyrazoles 20a-c were performed without catalysis (Scheme 8).The selectivity of the methylhydrazine attack was found to increase when the reaction mixture was cooled, providing the formation of the acetal-containing pyrazoles 19a-c.Further hydrolysis of compounds 19a-c carried out in formic acid led to the target products.For triketone 1, regiospecific condensation with methylhydrazine afforded 5-acetylpyrazole-3carboxylate 7a as well as the reaction with the salt form of binucleophile.
Following this method, the regiocontrolled transformations of 1,2,4-triketones 2a-c to 5-acetyl-N-methylpyrazoles 20a-c were performed without catalysis (Scheme 8).The selectivity of the methylhydrazine attack was found to increase when the reaction mixture was cooled, providing the formation of the acetal-containing pyrazoles 19a-c.Further hydrolysis of compounds 19a-c carried out in formic acid led to the target products.For triketone 1, regiospecific condensation with methylhydrazine afforded 5-acetylpyrazole-3-carboxylate 7a as well as the reaction with the salt form of binucleophile.Scheme 8. Two-step method for the preparation of 5-acetyl-N-methylpyrazoles 7a and 20a-c.
Accordingly, there was no interaction of hydrazine with the carbon atom of the acetal group under mild conditions, since the formation of six-membered products was not detected.Furthermore, different regioisomeric pyrazoles are derived during condensation Scheme 8. Two-step method for the preparation of 5-acetyl-N-methylpyrazoles 7a and 20a-c.
Accordingly, there was no interaction of hydrazine with the carbon atom of the acetal group under mild conditions, since the formation of six-membered products was not detected.Furthermore, different regioisomeric pyrazoles are derived during condensation reactions with substituted hydrazines depending on whether the acid is used.This confirms that chemo-and regioselectivity of conversions is dictated not only by the structure of the reagents but can be definitely ruled by the temperature as well as by the catalysts.
Finally, to ensure that the substituent effect on the preferred reaction pathway is mainly of an electronic nature, a series of condensations was carried out involving hydrazine functionalized with the CO 2 Me group.While the reflux of triketones 2a-c with methyl carbazate in the presence of HCl, 3-acetylpyrazole-1-carboxylates 21a-c were formed, notwithstanding the substituent in the building block (Scheme 9).The compounds 21a-c can also be considered as precursors for the preparation of NH-pyrazoles via base-induced ester group hydrolysis (see Section 3.2.Method D). reactions with substituted hydrazines depending on whether the acid is used.This confirms that chemo-and regioselectivity of conversions is dictated not only by the structure of the reagents but can be definitely ruled by the temperature as well as by the catalysts.Finally, to ensure that the substituent effect on the preferred reaction pathway is mainly of an electronic nature, a series of condensations was carried out involving hydrazine functionalized with the CO2Me group.While the reflux of triketones 2a-c with methyl carbazate in the presence of HCl, 3-acetylpyrazole-1-carboxylates 21a-c were formed, notwithstanding the substituent in the building block (Scheme 9).The compounds 21a-c can also be considered as precursors for the preparation of NH-pyrazoles via base-induced ester group hydrolysis (see Section 3.2.Method D).In contrast, acetal-containing 2,4-diketoester 1 did not yield pyrazole during the reaction with NH2NHCO2Me.The formation of pyridazinone 22 was observed as a result of the initial nucleophilic attack on the carbon atom of the acetal group, followed by step-bystep acid hydrolysis of the CO2Me fragment, decarboxylation, and intramolecular cyclization through the NH2 group interaction with the electrophilic center adjacent to the ester substituent (Scheme 10).In contrast, acetal-containing 2,4-diketoester 1 did not yield pyrazole during the reaction with NH 2 NHCO 2 Me.The formation of pyridazinone 22 was observed as a result of the initial nucleophilic attack on the carbon atom of the acetal group, followed by step-by-step acid hydrolysis of the CO 2 Me fragment, decarboxylation, and intramolecular cyclization through the NH 2 group interaction with the electrophilic center adjacent to the ester substituent (Scheme 10).
Int. J. Mol.Sci.2023, 24, x FOR PEER REVIEW 10 of 28 reactions with substituted hydrazines depending on whether the acid is used.This confirms that chemo-and regioselectivity of conversions is dictated not only by the structure of the reagents but can be definitely ruled by the temperature as well as by the catalysts.Finally, to ensure that the substituent effect on the preferred reaction pathway is mainly of an electronic nature, a series of condensations was carried out involving hydrazine functionalized with the CO2Me group.While the reflux of triketones 2a-c with methyl carbazate in the presence of HCl, 3-acetylpyrazole-1-carboxylates 21a-c were formed, notwithstanding the substituent in the building block (Scheme 9).The compounds 21a-c can also be considered as precursors for the preparation of NH-pyrazoles via base-induced ester group hydrolysis (see Section 3.2.Method D).In contrast, acetal-containing 2,4-diketoester 1 did not yield pyrazole during the reaction with NH2NHCO2Me.The formation of pyridazinone 22 was observed as a result of the initial nucleophilic attack on the carbon atom of the acetal group, followed by step-bystep acid hydrolysis of the CO2Me fragment, decarboxylation, and intramolecular cyclization through the NH2 group interaction with the electrophilic center adjacent to the ester substituent (Scheme 10).The 2-thienyl-triketone was found to exhibit a high chemoselectivity of transformations, which decreased when passing to the Ph and t-Bu-substituted analogs.During all reactions, hydrazines preferentially attacked the charged keto group of intermediate A (path c), providing pyridazinones 8, 9a,b, 10a, 11, 13a,14, and 15a, apart from the condensation of t-Bu-triketone with PhNHNH2.This exception can be induced by steric hindrances when the bulky t-Bu and Ph substituents approach one another as well as by the weak nucleophilicity of the -NHPh fragment, which prevents rapid dikethohydrazone B cyclization.Therefore, the second phenylhydrazine molecule can be attached via path b to form intermediate C, followed by the pyrazole ring closure and the cleavage of the first hydrazine molecule from pyrazolyl hydrazone D. This mechanism of the formation of 3acetylpyrazoles 12 and 15b corresponds to the conversions of fluorinated 1,2,4-triketones to 5-R F -pyrazoles by reactions with substituted arylhydrazines under similar conditions [81].In other cases, the reaction temperature appeared to be the main decisive factor.It was found that 1,4-addition of binucleophiles (path c) proceeds by kinetic control, whereas path b is favored at lower temperatures, leading to pyrazoles as more thermodynamically stable products.
The features of the reactions involving NH2NHCO2Me should be considered separately.Methyl carbazate is a weak nucleophile and a harder base than other hydrazines, so it primarily attacks the positively charged keto group (the harder acid) of intermediate A. However, the formed dikethohydrazone B undergoes intramolecular cyclization to pyridazinone 22 only in the case of the strong acceptor CO2Et substituent.This confirms that the increased donor effects of the substituents and the reduced nucleophilicity of the NH group prevent the cyclization of both fluorinated [80] and non-fluorinated diketohydrazones.Thus, compounds 2a-c give 3-acetylpyrazoles 21a-c via a series of transfor-Scheme 11.Proposed mechanism of acid-catalyzed heterocyclization of 1,2,4-triketone analogs 1 and 2a-c into regioisomeric 3-and 5-acetylpyrazoles and pyridazinones.
The 2-thienyl-triketone was found to exhibit a high chemoselectivity of transformations, which decreased when passing to the Ph and t-Bu-substituted analogs.During all reactions, hydrazines preferentially attacked the charged keto group of intermediate A (path c), providing pyridazinones 8, 9a,b, 10a, 11, 13a,14, and 15a, apart from the condensation of t-Bu-triketone with PhNHNH 2 .This exception can be induced by steric hindrances when the bulky t-Bu and Ph substituents approach one another as well as by the weak nucleophilicity of the -NHPh fragment, which prevents rapid dikethohydrazone B cyclization.Therefore, the second phenylhydrazine molecule can be attached via path b to form intermediate C, followed by the pyrazole ring closure and the cleavage of the first hydrazine molecule from pyrazolyl hydrazone D. This mechanism of the formation of 3acetylpyrazoles 12 and 15b corresponds to the conversions of fluorinated 1,2,4-triketones to 5-R F -pyrazoles by reactions with substituted arylhydrazines under similar conditions [81].In other cases, the reaction temperature appeared to be the main decisive factor.It was found that 1,4-addition of binucleophiles (path c) proceeds by kinetic control, whereas path b is favored at lower temperatures, leading to pyrazoles as more thermodynamically stable products.
The features of the reactions involving NH 2 NHCO 2 Me should be considered separately.Methyl carbazate is a weak nucleophile and a harder base than other hydrazines, so it primarily attacks the positively charged keto group (the harder acid) of intermediate A. However, the formed dikethohydrazone B undergoes intramolecular cyclization to pyridazinone 22 only in the case of the strong acceptor CO 2 Et substituent.This confirms that the increased donor effects of the substituents and the reduced nucleophilicity of the NH group prevent the cyclization of both fluorinated [80] and non-fluorinated diketohydrazones.Thus, compounds 2a-c give 3-acetylpyrazoles 21a-c via a series of transformations, similar to those described above for the reaction between t-Bu-triketone and PhNHNH 2 .
It seems that the chemical behavior of non-fluorinated 1,2,4-triketones corresponds to β-diketones upon removing the acid from the reaction sphere.The nature of the substituent did not define the main route of these reactions, which was path a.Nevertheless, the selectivity of 5-acetylpyrazole formation from the t-Bu-, Ph-, and 2-thienyl-triketones was influenced by the temperature.
Taking this into account, one can highlight the key features.In contrast to the fluorine-containing 1,2,4-triketones, it does not matter in which form the non-fluorinated analogs react with hydrazines: acetal-functionalized β-diketones, 1,2,4-triketones, or furan-3(2H)-ones give identical products.Furthermore, these conversions tend to proceed nonselectively, although the reaction conditions are the same as for R F -triketones.Nevertheless, chemo-and regioselectivity have been demonstrated to be achievable.
Analyzing the NMR spectroscopy data, the structure of the isomeric heterocyclic products can be proven.In 1 H spectra registered in DMSO-d 6 solution, the chemical shifts of the methyl groups of pyridazinones 8, 10a, 11, 13a, 14, 15a, 22 and acetylpyrazoles 7a, 10b, 12, 13b, 15b, 20a-c, and 21a were observed in the ranges of 2.1-2.4 ppm and 2.4-2.6 ppm, respectively.The singlets of methine protons related to pyrazoles also appeared in a weaker field (δ H = 6.4-7.6 ppm) than in the case of six-membered products (δ H = 6.1-7.2 ppm).According to the 13 C NMR data, for pyridazinones, the signals of the CH 3 (15-17 ppm) and C=O groups (164-171 ppm) were upfield in comparison with the corresponding ranges detected for pyrazoles of δ Me = 26-28 ppm and δ C=O = 189-194 ppm.Likewise, these characteristic signals were used to correlate the regioisomeric structure of 3-and 5-acetylpyrazoles 7a, 15b, and 20a-c, obtained as N-methyl derivatives (Figure 4).One can see clearly how δ C values of the carbon atoms in the acetyl fragment depend upon its position in a pyrazole ring, along with the signals of the CH-group in both the 1 H and 13 C NMR spectra.
the selectivity of 5-acetylpyrazole formation from the t-Bu-, Ph-, and 2-thienyl-triketones was influenced by the temperature.
Taking this into account, one can highlight the key features.In contrast to the fluorine-containing 1,2,4-triketones, it does not matter in which form the non-fluorinated analogs react with hydrazines: acetal-functionalized β-diketones, 1,2,4-triketones, or furan-3(2H)-ones give identical products.Furthermore, these conversions tend to proceed nonselectively, although the reaction conditions are the same as for R F -triketones.Nevertheless, chemo-and regioselectivity have been demonstrated to be achievable.
For instance, the crystal packing differences were determined by H-contacts between the oxygen and nitrogen atoms of the functional groups, heterocyclic rings with hydrogen atoms of methyl groups and C-H fragments in (het)aromatic systems (Figures S110-S120, Table S6).
In contrast to 3-acetylpyrazoles 12, 15b, and 21b, the carbonyl group in 5-substituted pyrazoles 7а and 7l was oriented toward the methyl or aryl substituent at the nitrogen atom.
In the case of heterocycles 7а, 7l, 9a, 9b, 12, 14, 15b, and 21b, the deviation of aromatic substituents from either pyrazole or pyridazine plane was observed (Table S3), which affects their crystal packing features (Figures S102-S109).Almost all compounds exhibited the formation of stacks due to the orientation of aryl or heterocyclic rings.However, not all of them corresponded to π-π stacking.It should be noted that π-π interactions with characteristic values of ~3.4 Å were observed for only one aromatic fragment among the products.As an exception, compound 7l was found to realize π-π-stacking with a minimum value for the difluorophenyl rings while the interplanar distances between the pyrazole rings were increased to 3.6 Å.The enolic form of compound 2c adopted a mostly planar conformation.The pseudo hexagonal cycle of the β-dicarbonyl fragment is characterized by the presence of the methine proton and intramolecular hydrogen bond between the oxygen atom and hydroxy group.Herewith, the values of the bond lengths and angles between carbon atoms of the enolic form 2c corresponded to sp 2 hybridization (Table S1).
The difference between methoxy-and hydroxy-substituted furanones 3 and 5 was found.In the case of compound 3, the carbon atom bearing methoxy and methyl groups extended ~0.4 Å beyond the plane of the furan ring.In contrast, the furan ring of product 5 was in the same plane as the aryl substituent.The formation of intermolecular hydrogen bonds between the hydroxy and keto groups of compound 5 provided zigzag chains in which there were no π-π interactions between the aromatic fragments (Figure S112).
For pyrazoles 7a, 7l, 12, 15b, and 21b, the crystal structure data provides an accurate determination of the substituent position at the nitrogen atom of the heterocyclic system.In contrast to 3-acetylpyrazoles 12, 15b, and 21b, the carbonyl group in 5-substituted pyrazoles 7a and 7l was oriented toward the methyl or aryl substituent at the nitrogen atom.
In the case of heterocycles 7a, 7l, 9a, 9b, 12, 14, 15b, and 21b, the deviation of aromatic substituents from either pyrazole or pyridazine plane was observed (Table S3), which affects their crystal packing features (Figures S102-S109).Almost all compounds exhibited the formation of stacks due to the orientation of aryl or heterocyclic rings.However, not all of them corresponded to π-π stacking.It should be noted that π-π interactions with characteristic values of ~3.4 Å were observed for only one aromatic fragment among the products.As an exception, compound 7l was found to realize π-π-stacking with a minimum value for the difluorophenyl rings while the interplanar distances between the pyrazole rings were increased to 3.6 Å.
Synthesis of compounds 2a-c and 3: Sodium hydride (100 mmol; 60% in mineral oil) was slowly added at 0-5 • C to a solution of ethyl 2,2-dimethoxypropanoate (0.1 mol) and corresponding methyl ketone (0.1 mol) in 100 mL of 1,2-dimethoxyethane.The suspension was stirred at room temperature (25 • C) for 1 h and then at 60 • C for 3 h.The products were isolated similarly to β-diketone 1 via the formation of Cu(II) chelates, decomposed by stirring with Na 2 EDTA or oxalic acid dihydrate (0.05 mol) at r.t.(25 • C) for 1 h.In the case of compounds 2c, 3 the solvent was removed by evaporation.
Synthesis of compounds 4a,b: 1,2,4-Triketone analogs 2b,c (10 mmol) were refluxed in an excess of formic acid for 4 h.Then, water was added, the precipitate formed was filtered off, dried, and recrystallized from hexane.
Synthesis of compound 6 (method A): A mixture of 1,2,4-triketone analog 1 (3 mmol) and hydrazine dihydrochloride (3 mmol) was refluxed in 10 mL of EtOH for 3 h.Then, water was added, the mixture was extracted by Et 2 O (2 × 5 mL), the organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated.
Synthesis of compounds 7a-l: A mixture of 1,2,4-triketone analog 1 (3 mmol) and the corresponding hydrazine hydrochloride (3 mmol) was refluxed in 10 mL of EtOH for 3 h.The precipitate formed was filtered off, washed with NaHCO 3 aqueous solution, and dried to give products 7b-l.In the case of 7a, the water was added to the reaction mixture, the precipitate formed was filtered off, and recrystallized from hexane.
Synthesis of compounds 11, 12, and 14: A mixture of 1,2,4-triketone analogs 2a,b (3 mmol) and the substituted hydrazine (3 mmol) was refluxed in 10 mL of EtOH for 4 h.The solvent was evaporated, and the residue was recrystallized from hexane or Et 2 O.
Synthesis of compounds 6, 10b, 13b, and 17 (method B): A mixture of 1,2,4-triketone analogs 1 and 2a-c (3 mmol) and hydrazine monohydrate (3 mmol) was stirred in 10 mL of EtOH and 0.5 mL of HCl at room temperature (25 • C) for 8 h.The solvent was evaporated and the residue was recrystallized from an appropriate solvent.In the case of Ph-substituted products, the precipitate formed in the reaction mixture was filtered off to give pyrazolidine 16, then the filtrate was evaporated, and the residue was washed by hexane and recrystallized from EtOAc to give 13b.
Synthesis of compounds 18a-c: A mixture of 1,2,4-triketone analogs 2a-c (5 mmol) and hydrazine hydrate (5 mmol) was refluxed in 12 mL of MeOH for 3 h.The solvent was evaporated and the residue was recrystallized from hexane.
Synthesis of compounds 10b, 13b, and 17 (method C): An appropriate pyrazole bearing the acetal group 18a-c (3 mmol) was heated at 50 • C with stirring in an excess of formic acid for 3 h.Then, water was added, and the precipitate formed was filtered off and dried without further purification.
Synthesis of compounds 19a-c: To a solution of 1,2,4-triketone analogs 2a-c (5 mmol) in 15 mL of EtOH methyl hydrazine was added dropwise at 0-5 • C. The mixture was stirred for 3 h, then the solvent was evaporated, and the residue was recrystallized from hexane.
Synthesis of compounds 20a-c: An appropriate pyrazole bearing the acetal group 19a-c (3 mmol) was heated at 50 • C with stirring in an excess of formic acid for 3 h.Then, water was added, the mixture was extracted by CHCl 3 (2 × 7 mL), the organic layer was separated, dried over sodium sulfate, and the solvent was evaporated.
Synthesis of compounds 21a-c and 22: A mixture of 1,2,4-triketone analogs 1 and 2a-c (5 mmol) and methyl carbazate (5 mmol) was refluxed in 15 mL of EtOH and 1 mL of HCl for 8 h.Then, the solvent was evaporated, and the residue was recrystallized from an appropriate solvent to give 21a and 22.In the case of 21b,c the precipitate formed was filtered off, dried, and recrystallized from Et 2 O.
Synthesis of compound 10b (method D): Pyrazole bearing the methyl ester group 21a (3 mmol) was dissolved in 5 mL of THF, then an aqueous solution of NaOH (5 mmol) was added and the mixture was heated at 50 • C with stirring for 8 h.The solution was neutralized with 0.1 M HCl and extracted with THF, the organic layer was separated, dried over sodium sulfate, and the solvent was evaporated.

Figure 1 .
Figure 1.Representative examples of drugs containing pyrazole and pyridazine moieties.

Scheme 10 .Scheme 9 .
Scheme 10.Unexpected formation of six-membered product 22 during the reaction between acetalfunctionalized 2,4-diketoester 1 and methyl carbazate.The acid-catalyzed reactions between 1,2,4-triketone analogs 2a-c and 3 and hydrazines can be described by the general mechanism proposed in Scheme 11.It includes three possible directions leading to the formation of regiosomeric 3-and 5-acetylpyrazoles (paths a and b) or pyridazinones (path c).The acid cleavage of the acetal fragment provides intermediate A. Herewith, two enolic forms of diketone A can exist, one of which becomes dominant depending on the nature of the substituent.Path a, yielding 5-

Scheme 10 .Scheme 10 . 28 Scheme 11 .
Scheme 10.Unexpected formation of six-membered product 22 during the reaction between acetalfunctionalized 2,4-diketoester 1 and methyl carbazate.The acid-catalyzed reactions between 1,2,4-triketone analogs 2a-c and 3 and hydrazines can be described by the general mechanism proposed in Scheme 11.It includes three possible directions leading to the formation of regiosomeric 3-and 5-acetylpyrazoles (paths a and b) or pyridazinones (path c).The acid cleavage of the acetal fragment provides intermediate A. Herewith, two enolic forms of diketone A can exist, one of which becomes dominant depending on the nature of the substituent.Path a, yielding 5-Scheme 10.Unexpected formation of six-membered product 22 during the reaction between acetalfunctionalized 2,4-diketoester 1 and methyl carbazate.The acid-catalyzed reactions between 1,2,4-triketone analogs 2a-c and 3 and hydrazines can be described by the general mechanism proposed in Scheme 11.It includes