Temperature-Controlled Divergent Synthesis of Pyrazoles and 1-Tosyl-1H-pyrazoles under Transition-Metal-Catalyst- and Oxidant-Free Conditions

Herein, a general and practical temperature-controlled approach for the divergent synthesis of pyrazoles and 1-tosyl-1H-pyrazoles via electrophilic cyclization in the absence of transition-metal catalysts and oxidants was developed. The desired products were obtained in moderate to excellent yields from common starting materials in both ionic liquids and ethanol by simply tuning the reaction temperature. This strategy employs easily synthesized substrates, mild reaction conditions, and excellent functional-group tolerance.

Advances in the development of electrophilic cyclization strategies over the past few decades have led to many studies on the synthesis of substituted pyrazoles under mild reaction conditions with excellent regioselectivity [17][18][19][20].In 2011, Zora and co-workers developed a method for the electrophilic cyclization of α,β-alkynic hydrazones mediated by CuI in the presence of trithylamine [21].They also reported another study on the preparation of 4-iodopyrazoles promoted by molecular iodine [22].In the same year, Liu, Xu, and co-workers declared a Au(I)-catalyzed tandem aminofluorination method to furnish fluoropyrazoles with the addition of selectfluor [23].In 2017, Tsui et al. achieved a copper-mediated method for the synthesis of 4-(trifluoromethyl)pyrazoles [24].In 2020, Niu and Gao et al. pioneered a facile method for the synthesis of 4-chalcogenylated pyrazoles [25].Then, Wang and Ji's group successfully utilized the strategy to synthesize 4-(arylselanyl)-1H-pyrazoles [26].
Despite such remarkable achievements, transition-metal catalysts and oxidants were always indispensable.Along with the concept of green chemistry, the significance of the green and sustainable development of chemical systems has gained increased attention; in particular, the development of eco-friendly synthesis methods that conform to the demands of green chemistry is of critical importance [27,28].Thus, considerable effort has been devoted to the investigation of the green solvent system.Therefore, ionic liquids (ILs) have sparked great interest among chemists because of their unique physical and chemical properties, such as easy recyclability and high stability [29][30][31].Inspired by the synthesis potential of ILs, we sought to develop a green and economical strategy to prepare useful pyrazoles with potential applications in various fields.
Herein, we report the solvent-switchable, metal-and oxidant-free divergent synthesis of 1H-and 1-tosyl-1H-pyrazoles via electrophilic cyclization, affording the desired products in moderate to excellent yields under mild conditions (Figure 1).green and sustainable development of chemical systems has gained increased attention; in particular, the development of eco-friendly synthesis methods that conform to the demands of green chemistry is of critical importance [27,28].Thus, considerable effort has been devoted to the investigation of the green solvent system.Therefore, ionic liquids (ILs) have sparked great interest among chemists because of their unique physical and chemical properties, such as easy recyclability and high stability [29][30][31].Inspired by the synthesis potential of ILs, we sought to develop a green and economical strategy to prepare useful pyrazoles with potential applications in various fields.
Herein, we report the solvent-switchable, metal-and oxidant-free divergent synthesis of 1H-and 1-tosyl-1H-pyrazoles via electrophilic cyclization, affording the desired products in moderate to excellent yields under mild conditions (Figure 1).

anions like [HDBU][NHS], [HTMG][NHS], [HDBU][OAc][NHS], and [HTMG][HDBU]
[OAc]-[NHS] were then investigated, and excellent product yields were obtained at room temperature (entries 5-9).It was noticed that this transformation could also be realized in EtOH with the addition of 1.0 equivalent DBU (entry 4).Moreover, the desired product could be obtained via filtration rather than column chromatography, thus avoiding the wastage of organic solutions and silica gel (see Supporting Information).Since temperature is also a crucial factor in facilitating the reaction, different temperatures were investigated.To our surprise, when the temperature increased to 95 °C, no 2a was detected, but 3a was obtained in 85% yield, and further studies showed that 3a began to be produced at 40 °C.This result indicates that a divergent synthesis pathway could be achieved by regulating the reaction temperature.Further experiments showed that the transformation could also be achieved in different solvents, with [HDBU][OAc] demonstrating superior performance (entries 5-9).We also performed

anions like [HDBU][NHS], [HTMG][NHS], [HDBU][OAc][NHS], and [HTMG][HDBU]
[OAc]-[NHS] were then investigated, and excellent product yields were obtained at room temperature (entries 5-9).It was noticed that this transformation could also be realized in EtOH with the addition of 1.0 equivalent DBU (entry 4).Moreover, the desired product could be obtained via filtration rather than column chromatography, thus avoiding the wastage of organic solutions and silica gel (see Supporting Information).Since temperature is also a crucial factor in facilitating the reaction, different temperatures were investigated.To our surprise, when the temperature increased to 95 • C, no 2a was detected, but 3a was obtained in 85% yield, and further studies showed that 3a began to be produced at 40 • C.This result indicates that a divergent synthesis pathway could be achieved by regulating the reaction temperature.Further experiments showed that the transformation could also be achieved in different solvents, with [HDBU][OAc] demonstrating superior performance (entries 5-9).We also performed the reaction in the presence of different additives and reaction temperatures, and the yields decreased to varying degrees (see Supporting Information).Considering the green synthetic properties of EtOH, both pathways were executed in the following investigations.
With the aforementioned optimized reaction protocol in hand, the scope of cyclizations was first screened (Table 2).A wide range of substrates containing diverse substituents was evaluated using both optimal approaches, and the expected products were obtained in up to 98% (2a-2u) yields.No significant difference between substrates containing electrondonating (-Me, and -OMe) and electron-withdrawing groups (-F, -Cl, and -Br) on R1 and R2 rings was observed.Ulteriorly, 2-naphthyl, 2-thienyl, and saturated t-butyl (2l-2n) also gave satisfying yields of 67-83%.Furthermore, bis-pyrazoles (2o) could also be obtained with a maximum yield of 93%.However, it is a pity that the phenylhydrazine-substituted substrate (2q) could not take place in this transformation.the reaction in the presence of different additives and reaction temperatures, and the yields decreased to varying degrees (see Supporting Information).Considering the green synthetic properties of EtOH, both pathways were executed in the following investigations.With the aforementioned optimized reaction protocol in hand, the scope of cyclizations was first screened (Table 2).A wide range of substrates containing diverse substituents was evaluated using both optimal approaches, and the expected products were obtained in up to 98% (2a-2u) yields.No significant difference between substrates containing electron-donating (-Me, and -OMe) and electron-withdrawing groups (-F, -Cl, and -Br) on R1 and R2 rings was observed.Ulteriorly, 2-naphthyl, 2-thienyl, and saturated tbutyl (2l-2n) also gave satisfying yields of 67-83%.Furthermore, bis-pyrazoles (2o) could also be obtained with a maximum yield of 93%.However, it is a pity that the phenylhydrazine-substituted substrate (2q) could not take place in this transformation.Subsequent studies were conducted to investigate the application scope for the synthesis of pyrazole derivatives under the standard reaction conditions (Table 3).Surprisingly, the reaction exhibited remarkable differences from the cyclization reaction, specifically manifested as follows: (1) the yields in ILs (35-88%) were significantly higher than those in EtOH (17-76%); (2) the substrates with electron-donating groups showed inferior reactivity to the electron-withdrawing ones, indicating that the substituent effect strongly influences the transformation; (3) none of corresponding products were obtained with aliphatic substrates and the corresponding cyclization product was retained.Subsequent studies were conducted to investigate the application scope for the synthesis of pyrazole derivatives under the standard reaction conditions (Table 3).Surprisingly, the reaction exhibited remarkable differences from the cyclization reaction, specifically manifested as follows: (1) the yields in ILs (35-88%) were significantly higher than those in EtOH (17-76%); (2) the substrates with electron-donating groups showed inferior reactivity to the electron-withdrawing ones, indicating that the substituent effect strongly influences the transformation; (3) none of corresponding products were obtained with aliphatic substrates and the corresponding cyclization product was retained.Subsequent studies were conducted to investigate the application scope for the synthesis of pyrazole derivatives under the standard reaction conditions (Table 3).Surprisingly, the reaction exhibited remarkable differences from the cyclization reaction, specifically manifested as follows: (1) the yields in ILs (35-88%) were significantly higher than those in EtOH (17-76%); (2) the substrates with electron-donating groups showed inferior reactivity to the electron-withdrawing ones, indicating that the substituent effect strongly influences the transformation; (3) none of corresponding products were obtained with aliphatic substrates and the corresponding cyclization product was retained.Subsequent studies were conducted to investigate the application scope for the synthesis of pyrazole derivatives under the standard reaction conditions (Table 3).Surprisingly, the reaction exhibited remarkable differences from the cyclization reaction, specifically manifested as follows: (1) the yields in ILs (35-88%) were significantly higher than those in EtOH (17-76%); (2) the substrates with electron-donating groups showed inferior reactivity to the electron-withdrawing ones, indicating that the substituent effect strongly influences the transformation; (3) none of corresponding products were obtained with aliphatic substrates and the corresponding cyclization product was retained.Subsequent studies were conducted to investigate the application scope for the synthesis of pyrazole derivatives under the standard reaction conditions (Table 3).Surprisingly, the reaction exhibited remarkable differences from the cyclization reaction, specifically manifested as follows: (1) the yields in ILs (35-88%) were significantly higher than those in EtOH (17-76%); (2) the substrates with electron-donating groups showed inferior reactivity to the electron-withdrawing ones, indicating that the substituent effect strongly influences the transformation; (3) none of corresponding products were obtained with aliphatic substrates and the corresponding cyclization product was retained.Subsequent studies were conducted to investigate the application scope for the synthesis of pyrazole derivatives under the standard reaction conditions (Table 3).Surprisingly, the reaction exhibited remarkable differences from the cyclization reaction, specifically manifested as follows: (1) the yields in ILs (35-88%) were significantly higher than those in EtOH (17-76%); (2) the substrates with electron-donating groups showed inferior reactivity to the electron-withdrawing ones, indicating that the substituent effect strongly influences the transformation; (3) none of corresponding products were obtained with aliphatic substrates and the corresponding cyclization product was retained.Subsequent studies were conducted to investigate the application scope for the synthesis of pyrazole derivatives under the standard reaction conditions (Table 3).Surprisingly, the reaction exhibited remarkable differences from the cyclization reaction, specifically manifested as follows: (1) the yields in ILs (35-88%) were significantly higher than those in EtOH (17-76%); (2) the substrates with electron-donating groups showed inferior reactivity to the electron-withdrawing ones, indicating that the substituent effect strongly influences the transformation; (3) none of corresponding products were obtained with aliphatic substrates and the corresponding cyclization product was retained.Subsequently, a Gram-scale reaction was conducted under standard conditions, and the cyclization product 2a was obtained in 93% and 85% yields.Additionally, the 1H-parazole (3a) could be furnished in 75% and 53% yields, respectively (Scheme 1a).Next, a range of control experiments were carried out to research the reaction mechanism.Initially, the cyclization was conducted in IL at room temperature for 12 h, and there was no 3a produced, revealing that the reaction temperature is the key to triggering subsequent reactions (Scheme 1b).Then, 3a was obtained at a 90% yield when 2a was employed as the starting material under 95 °C, in IL for 12 h (Scheme 1c).Finally, none of the expected products were detected when 1,3-diphenylprop-2-yn-1-one and 4-methylbenzenesul-fonohydrazide were selected as initial materials (Scheme 1d).Subsequently, a Gram-scale reaction was conducted under standard conditions, and the cyclization product 2a was obtained in 93% and 85% yields.Additionally, the 1H-parazole (3a) could be furnished in 75% and 53% yields, respectively (Scheme 1a).Next, a range of control experiments were carried out to research the reaction mechanism.Initially, the cyclization was conducted in IL at room temperature for 12 h, and there was no 3a produced, revealing that the reaction temperature is the key to triggering subsequent reactions (Scheme 1b).Then, 3a was obtained at a 90% yield when 2a was employed as the starting material under 95 °C, in IL for 12 h (Scheme 1c).Finally, none of the expected products were detected when 1,3-diphenylprop-2-yn-1-one and 4-methylbenzenesul-fonohydrazide were selected as initial materials (Scheme 1d).Subsequently, a Gram-scale reaction was conducted under standard conditions, and the cyclization product 2a was obtained in 93% and 85% yields.Additionally, the 1H-parazole (3a) could be furnished in 75% and 53% yields, respectively (Scheme 1a).Next, a range of control experiments were carried out to research the reaction mechanism.Initially, the cyclization was conducted in IL at room temperature for 12 h, and there was no 3a produced, revealing that the reaction temperature is the key to triggering subsequent reactions (Scheme 1b).Then, 3a was obtained at a 90% yield when 2a was employed as the starting material under 95 °C, in IL for 12 h (Scheme 1c).Finally, none of the expected products were detected when 1,3-diphenylprop-2-yn-1-one and 4-methylbenzenesul-fonohydrazide were selected as initial materials (Scheme 1d).Subsequently, a Gram-scale reaction was conducted under standard conditions, and the cyclization product 2a was obtained in 93% and 85% yields.Additionally, the 1H-parazole (3a) could be furnished in 75% and 53% yields, respectively (Scheme 1a).Next, a range of control experiments were carried out to research the reaction mechanism.Initially, the cyclization was conducted in IL at room temperature for 12 h, and there was no 3a produced, revealing that the reaction temperature is the key to triggering subsequent reactions (Scheme 1b).Then, 3a was obtained at a 90% yield when 2a was employed as the starting material under 95 °C, in IL for 12 h (Scheme 1c).Finally, none of the expected products were detected when 1,3-diphenylprop-2-yn-1-one and 4-methylbenzenesul-fonohydrazide were selected as initial materials (Scheme 1d).Subsequently, a Gram-scale reaction was conducted under standard conditions, and the cyclization product 2a was obtained in 93% and 85% yields.Additionally, the 1H-parazole (3a) could be furnished in 75% and 53% yields, respectively (Scheme 1a).Next, a range of control experiments were carried out to research the reaction mechanism.Initially, the cyclization was conducted in IL at room temperature for 12 h, and there was no 3a produced, revealing that the reaction temperature is the key to triggering subsequent reactions (Scheme 1b).Then, 3a was obtained at a 90% yield when 2a was employed as the starting material under 95 °C, in IL for 12 h (Scheme 1c).Finally, none of the expected products were detected when 1,3-diphenylprop-2-yn-1-one and 4-methylbenzenesul-fonohydrazide were selected as initial materials (Scheme 1d).Subsequently, a Gram-scale reaction was conducted under standard conditions, and the cyclization product 2a was obtained in 93% and 85% yields.Additionally, the 1H-parazole (3a) could be furnished in 75% and 53% yields, respectively (Scheme 1a).Next, a range of control experiments were carried out to research the reaction mechanism.Initially, the cyclization was conducted in IL at room temperature for 12 h, and there was no 3a produced, revealing that the reaction temperature is the key to triggering subsequent reactions (Scheme 1b).Then, 3a was obtained at a 90% yield when 2a was employed as the starting material under 95 °C, in IL for 12 h (Scheme 1c).Finally, none of the expected products were detected when 1,3-diphenylprop-2-yn-1-one and 4-methylbenzenesul-fonohydrazide were selected as initial materials (Scheme 1d).Subsequently, a Gram-scale reaction was conducted under standard conditions, and the cyclization product 2a was obtained in 93% and 85% yields.Additionally, the 1H-parazole (3a) could be furnished in 75% and 53% yields, respectively (Scheme 1a).Next, a range of control experiments were carried out to research the reaction mechanism.Initially, the cyclization was conducted in IL at room temperature for 12 h, and there was no 3a produced, revealing that the reaction temperature is the key to triggering subsequent reactions (Scheme 1b).Then, 3a was obtained at a 90% yield when 2a was employed as the starting material under 95 °C, in IL for 12 h (Scheme 1c).Finally, none of the expected products were detected when 1,3-diphenylprop-2-yn-1-one and 4-methylbenzenesul-fonohydrazide were selected as initial materials (Scheme 1d).Subsequently, a Gram-scale reaction was conducted under standard conditions, and the cyclization product 2a was obtained in 93% and 85% yields.Additionally, the 1H-parazole (3a) could be furnished in 75% and 53% yields, respectively (Scheme 1a).Next, a range of control experiments were carried out to research the reaction mechanism.Initially, the cyclization was conducted in IL at room temperature for 12 h, and there was no 3a produced, revealing that the reaction temperature is the key to triggering subsequent reactions (Scheme 1b).Then, 3a was obtained at a 90% yield when 2a was employed as the starting material under 95 °C, in IL for 12 h (Scheme 1c).Finally, none of the expected products were detected when 1,3-diphenylprop-2-yn-1-one and 4-methylbenzenesul-fonohydrazide were selected as initial materials (Scheme 1d).Subsequently, a Gram-scale reaction was conducted under standard conditions, and the cyclization product 2a was obtained in 93% and 85% yields.Additionally, the 1Hparazole (3a) could be furnished in 75% and 53% yields, respectively (Scheme 1a).Next, a range of control experiments were carried out to research the reaction mechanism.Initially, the cyclization was conducted in IL at room temperature for 12 h, and there was no 3a produced, revealing that the reaction temperature is the key to triggering subsequent reactions (Scheme 1b).Then, 3a was obtained at a 90% yield when 2a was employed as the starting material under 95 • C, in IL for 12 h (Scheme 1c).Finally, none of the expected products were detected when 1,3-diphenylprop-2-yn-1-one and 4-methylbenzenesul-fonohydrazide were selected as initial materials (Scheme 1d).Finally, the recyclable experiment was further studied in order to assess the recyclability of IL (Figure 2).After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate.The organic layer containing the product was kept for purification, and the aqueous phase was placed in a drying cabinet to remove the excess water.Satisfactorily, only a minimal decline in activity was noted during five runs.Finally, the recyclable experiment was further studied in order to assess the recyclability of IL (Figure 2).After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate.The organic layer containing the product was kept for purification, and the aqueous phase was placed in a drying cabinet to remove the excess water.Satisfactorily, only a minimal decline in activity was noted during five runs.Finally, the recyclable experiment was further studied in order to assess the recycla bility of IL (Figure 2).After the reaction was completed, the reaction mixture was poure into water and extracted with ethyl acetate.The organic layer containing the product wa kept for purification, and the aqueous phase was placed in a drying cabinet to remove th excess water.Satisfactorily, only a minimal decline in activity was noted during five run Based on the aforementioned experiments and previous related reports, a plausibl mechanism for this reaction was proposed (Scheme 2).Primarily, in the presence of DBU 1a initiated electrophilic cyclization via nucleophilic attack of the secondary nitrogen atom to furnish protonated product 2a, which ulteriorly underwent the nucleophilic attack o DBU triggered by thermal energy to obtain intermediates B and C. Eventually, B de spoiled the hydrogen proton from the solvent to provide 3a.Based on the aforementioned experiments and previous related reports, a plausible mechanism for this reaction was proposed (Scheme 2).Primarily, in the presence of DBU, 1a initiated electrophilic cyclization via nucleophilic attack of the secondary nitrogen atom to furnish protonated product 2a, which ulteriorly underwent the nucleophilic attack of DBU triggered by thermal energy to obtain intermediates B and C. Eventually, B despoiled the hydrogen proton from the solvent to provide 3a.

Experimental Section
All the chemicals were obtained commercially and used without any prior purification. 1H NMR and 13 C NMR spectra were recorded on Bruker Avance II 400 or 500 spectrometers (See Supplementary Materials).All products were isolated by short chromatography on a silica gel (200-300 mesh) column using petroleum ether (60-90 °C) and ethyl acetate, unless otherwise noted.All compounds were characterized by 1 H NMR and 13 C Scheme 2. Plausible mechanistic pathway.

Experimental Section
All the chemicals were obtained commercially and used without any prior purification. 1H NMR and 13 C NMR spectra were recorded on Bruker Avance II 400 or 500 spectrometers (See Supplementary Materials).All products were isolated by short chromatography on a silica gel (200-300 mesh) column using petroleum ether (60-90 • C) and ethyl acetate, unless otherwise noted.All compounds were characterized by 1 H NMR and 13 C NMR, which are consistent with those reported in the literature.

Experimental Section
All the chemicals were obtained commercially and used without any prior purification. 1H NMR and 13 C NMR spectra were recorded on Bruker Avance II 400 or 500 spectrometers (See Supplementary Materials).All products were isolated by short chromatography on a silica gel (200-300 mesh) column using petroleum ether (60-90 °C) and ethyl acetate, unless otherwise noted.All compounds were characterized by 1 H NMR and 13 C NMR, which are consistent with those reported in the literature.

Figure 1 .
Figure 1.Strategies for the synthesis of pyrazole derivatives.

Figure 1 .
Figure 1.Strategies for the synthesis of pyrazole derivatives.

Scheme 3 .
Scheme 3. Preparation of the Starting Materials.

Scheme 3 .
Scheme 3. Preparation of the Starting Materials.

Table 1 .
Optimization of reaction conditions a,b .

Table 1 .
Optimization of reaction conditions a,b .

Table 2 .
Scope of cyclization substrates a,b .

Table 2 .
Scope of cyclization substrates a,b .

Table 2 .
Scope of cyclization substrates a,b .

Table 2 .
Scope of cyclization substrates a,b .
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Table 2 .
Scope of cyclization substrates a,b .

Table 2 .
Scope of cyclization substrates a,b .
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Table 2 .
Scope of cyclization substrates a,b .
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Table 2 .
Scope of cyclization substrates a,b .
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Table 2 .
Scope of cyclization substrates a,b .

Table 2 .
Scope of cyclization substrates a,b .

Table 2 .
Scope of cyclization substrates a,b .
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Table 2 .
Scope of cyclization substrates a,b .

Table 2 .
Scope of cyclization substrates a,b .

Table 2 .
Scope of cyclization substrates a,b .
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Table 2 .
Scope of cyclization substrates a,b .

Table 3 .
Scope of pyrazole substrates a,b .

Table 3 .
Scope of pyrazole substrates a,b .

Table 3 .
Scope of pyrazole substrates a,b .

Table 3 .
Scope of pyrazole substrates a,b .

Table 3 .
Scope of pyrazole substrates a,b .

Table 3 .
Scope of pyrazole substrates a,b .

Table 3 .
Scope of pyrazole substrates a,b .

Table 3 .
Scope of pyrazole substrates a,b .

Table 3 .
Scope of pyrazole substrates a,b .

Table 3 .
Scope of pyrazole substrates a,b .

Table 3 .
Scope of pyrazole substrates a,b .