Access and Modulation of Substituted Pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones

The first access to polyfunctionnalized pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione derivatives is reported. The series were generated from diethyl acetylenedicarboxylate and arylhydrazines, which afforded the key intermediates bearing two functional positions. The annellation to generate the maleimide moiety of the bicycle was studied. Moreover, an efficient palladium-catalyzed C-C and C-N bond formation via Suzuki–Miyaura or Buchwald–Hartwig coupling reactions in C-6 position was investigated from 6-chloropyrrolo[3,4-c]pyrazole-4,6-(2H,5H)–diones. This method provides novel access to various 1,6 di-substituted pyrrolo[3,4-c] pyrazole-4,6-(2H,5H)–diones.


Introduction
Pyrazole derivatives are an important class of five-membered heterocyclic compounds, which are widely encountered as the central core in a large panel of products used in various therapeutic areas such as antibacterial and antifungal agents, antibiotics and pesticides [1][2][3][4][5][6][7][8][9]. For example, the pyrazole ring is present in a variety of drugs such as Celebrex, Sildenafil (Viagra), Rimonabant and Difenamizole ( Figure 1). For these reasons, their use as pharmacophores in medicinal chemistry programs has grown, in particular with a view to increasing molecular diversity and exploring innovative chemical spaces.

Introduction
Pyrazole derivatives are an important class of five-membered heterocyclic compounds, which are widely encountered as the central core in a large panel of products used in various therapeutic areas such as antibacterial and antifungal agents, antibiotics and pesticides [1][2][3][4][5][6][7][8][9]. For example, the pyrazole ring is present in a variety of drugs such as Celebrex, Sildenafil (Viagra), Rimonabant and Difenamizole ( Figure 1). For these reasons, their use as pharmacophores in medicinal chemistry programs has grown, in particular with a view to increasing molecular diversity and exploring innovative chemical spaces. In contrast, bicyclic heterocycles containing a pyrazole moiety are relatively rare in nature but nonetheless prevalent in the pharmaceutical industry. Such a class is well represented by ring-contracted [5,5] bicyclic aromatic rings [10][11][12][13][14][15][16]. Among this heterocyclic family, the pyrrolo [3,4-c]pyrazole-4,6-(2H,5H)-dione nucleus stands out through the little attention it has been given, despite previous reports of interesting biological activities as a phosphatase inhibitor [16][17][18]. The classic and main method available to date to access In contrast, bicyclic heterocycles containing a pyrazole moiety are relatively rare in nature but nonetheless prevalent in the pharmaceutical industry. Such a class is well represented by ring-contracted [5,5] bicyclic aromatic rings [10][11][12][13][14][15][16]. Among this heterocyclic family, the pyrrolo [3,4-c]pyrazole-4,6-(2H,5H)-dione nucleus stands out through the little attention it has been given, despite previous reports of interesting biological activities as a phosphatase inhibitor [16][17][18]. The classic and main method available to date to access this bicyclic system involves building the maleimide moiety using the appropriate functionalized pyrazole moiety [19,20]. Despite the apparent efficiency of this step, molecular diversity cannot be easily managed under this synthetic pathway due to the limitation in terms of access or commercial availability of pyrazole derivatives. In order to introduce this bicyclic system involves building the maleimide moiety using the appropriate functionalized pyrazole moiety [19,20]. Despite the apparent efficiency of this step, molecular diversity cannot be easily managed under this synthetic pathway due to the limitation in terms of access or commercial availability of pyrazole derivatives. In order to introduce a wide range of functional groups and to explore its multiple substitutions, a promising solution is to find an efficient method to selectively functionalize polyfunctionalized pyrrolo [3,4-c]pyrazole-4,6-(2H,5H)-diones at the C-3 position, an indispensable step to designing future original bioactive molecules ( Figure 2).
With these three compounds in hand, we then achieved the chlorine displacement by Suzuki-Miyaura cross-coupling to explore their reactivity and also access C-3 substituted pyrrolo [3,4-c]pyrazole-4.6-(2H,5H)-diones [27]. This prompted us to propose to the community a general and efficient catalytic system by optimizing the main reaction parameters (Table 1). First, we used 15 as starting material, Pd(OAc) 2 as the palladium source, Xantphos as a ligand, K 2 CO 3 as a base and 1.4-dioxane as the solvent under microwave irradiation at 130 • C for 1.5 h [28]. With these conditions, the desired product 19 was isolated in a low but encouraging yield (20%, entry 2), in contrast with PdCl 2 (PPh 3 ) 2 as a catalytic system, which totally inhibited reactivity (entry 1). When the palladium system was switched for Pd(PPh 3 ) 4 , the reactivity was improved, and the desired compound 19 was obtained in 65% yield. A fine adjustment of the temperature coupled with an increase in the reaction time improved the reactivity, and the compound was isolated in 85% yield. In the following experiment, we used Cs 2 CO 3 as a base, which induced a slight decrease in yield. Finally, the nature of the solvent was investigated, showing that toluene induced a drastic inhibition of the reactivity. With these three compounds in hand, we then achieved the chlorine displacement by Suzuki-Miyaura cross-coupling to explore their reactivity and also access C-3 substituted pyrrolo [3,4-c]pyrazole-4.6-(2H,5H)-diones [27]. This prompted us to propose to the community a general and efficient catalytic system by optimizing the main reaction parameters (Table 1). First, we used 15 as starting material, Pd(OAc)2 as the palladium source, Xantphos as a ligand, K2CO3 as a base and 1.4-dioxane as the solvent under microwave irradiation at 130 °C for 1.5 h [28]. With these conditions, the desired product 19 was isolated in a low but encouraging yield (20%, entry 2), in contrast with PdCl2(PPh3)2 as a catalytic system, which totally inhibited reactivity (entry 1). When the palladium system was switched for Pd(PPh3)4, the reactivity was improved, and the desired compound 19 was obtained in 65% yield. A fine adjustment of the temperature coupled with an increase in the reaction time improved the reactivity, and the compound was isolated in 85% yield. In the following experiment, we used Cs2CO3 as a base, which induced a slight decrease in yield. Finally, the nature of the solvent was investigated, showing that toluene induced a drastic inhibition of the reactivity. Next, the scope and potential limitations of the Pd-coupling step were investigated by modulation of the boron derivatives ( Table 2). The use of electron-donating substituents as a methoxy group was well tolerated and afforded the derivative 20 in 79% yield. In contrast, the presence of electron-withdrawing substituents slightly decreased the effi-   With these three compounds in hand, we then achieved the chlorine displacement by Suzuki-Miyaura cross-coupling to explore their reactivity and also access C-3 substituted pyrrolo [3,4-c]pyrazole-4.6-(2H,5H)-diones [27]. This prompted us to propose to the community a general and efficient catalytic system by optimizing the main reaction parameters (Table 1). First, we used 15 as starting material, Pd(OAc)2 as the palladium source, Xantphos as a ligand, K2CO3 as a base and 1.4-dioxane as the solvent under microwave irradiation at 130 °C for 1.5 h [28]. With these conditions, the desired product 19 was isolated in a low but encouraging yield (20%, entry 2), in contrast with PdCl2(PPh3)2 as a catalytic system, which totally inhibited reactivity (entry 1). When the palladium system was switched for Pd(PPh3)4, the reactivity was improved, and the desired compound 19 was obtained in 65% yield. A fine adjustment of the temperature coupled with an increase in the reaction time improved the reactivity, and the compound was isolated in 85% yield. In the following experiment, we used Cs2CO3 as a base, which induced a slight decrease in yield. Finally, the nature of the solvent was investigated, showing that toluene induced a drastic inhibition of the reactivity. Next, the scope and potential limitations of the Pd-coupling step were investigated by modulation of the boron derivatives ( Table 2). The use of electron-donating substituents as a methoxy group was well tolerated and afforded the derivative 20 in 79% yield. In contrast, the presence of electron-withdrawing substituents slightly decreased the efficiency of the reaction, and compounds 23 and 24 were isolated in 65% and 60% yields, respectively. Next, we investigated the influence of steric hindrance using the methoxy Next, the scope and potential limitations of the Pd-coupling step were investigated by modulation of the boron derivatives ( Table 2). The use of electron-donating substituents as a methoxy group was well tolerated and afforded the derivative 20 in 79% yield. In contrast, the presence of electron-withdrawing substituents slightly decreased the efficiency of the reaction, and compounds 23 and 24 were isolated in 65% and 60% yields, respectively. Next, we investigated the influence of steric hindrance using the methoxy position switch on the phenyl ring. While the ortho orientation induced a dramatic decrease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a π-electron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 Molecules 2023, 28, 5811 4 of 18 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. position switch on the phenyl ring. While the ortho orientation induced a dramatic decrease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a πelectron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. position switch on the phenyl ring. While the ortho orientation induced a dramatic decrease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a πelectron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. position switch on the phenyl ring. While the ortho orientation induced a dramatic decrease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a πelectron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. position switch on the phenyl ring. While the ortho orientation induced a dramatic decrease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a πelectron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. position switch on the phenyl ring. While the ortho orientation induced a dramatic decrease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a πelectron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. position switch on the phenyl ring. While the ortho orientation induced a dramatic decrease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a πelectron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. position switch on the phenyl ring. While the ortho orientation induced a dramatic decrease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a πelectron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. crease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a πelectron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. crease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a πelectron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. crease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a πelectron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. crease in yield (only traces of 22 were observed), the meta orientation led to the desired compound 21 in 67% yield. The introduction of electron-rich heterocycles was also studied with 2-or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products 25-27 were isolated in satisfactory yields. The only identified limit concerned the use of a πelectron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound 29 was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded 30 in 84% yield. We next focused our attention on creating a C-N bond instead of a C-C bond under palladium catalysis by chlorine displacement [29]. We started with conditions that had proved their efficiency in the imidazodiazole series [30,31], namely Pd(OAc)2/Xantphos as a catalytic system, Cs2CO3 as a base and dioxane at 130 °C under microwave irradiation. However, in this case, with aniline as a partner, the desired product 31 was isolated in only 8% of yield (Table 3, entry 1). When the catalyst was switched for Pd2dba3, the reactivity was improved, and the desired compound 31 was obtained in an encouraging 56% yield (entry 2). The fine adjustment of the temperature and reaction time showed that 1h We next focused our attention on creating a C-N bond instead of a C-C bond under palladium catalysis by chlorine displacement [29]. We started with conditions that had proved their efficiency in the imidazodiazole series [30,31], namely Pd(OAc)2/Xantphos as a catalytic system, Cs2CO3 as a base and dioxane at 130 °C under microwave irradiation. However, in this case, with aniline as a partner, the desired product 31 was isolated in only 8% of yield (Table 3, entry 1). When the catalyst was switched for Pd2dba3, the reactivity was improved, and the desired compound 31 was obtained in an encouraging 56% yield (entry 2). The fine adjustment of the temperature and reaction time showed that 1h 30 84% a Isolated yield.
We next focused our attention on creating a C-N bond instead of a C-C bond under palladium catalysis by chlorine displacement [29]. We started with conditions that had proved their efficiency in the imidazodiazole series [30,31], namely Pd(OAc) 2 /Xantphos as a catalytic system, Cs 2 CO 3 as a base and dioxane at 130 • C under microwave irradiation. However, in this case, with aniline as a partner, the desired product 31 was isolated in only 8% of yield (Table 3, entry 1). When the catalyst was switched for Pd 2 dba 3 , the reactivity was improved, and the desired compound 31 was obtained in an encouraging 56% yield (entry 2). The fine adjustment of the temperature and reaction time showed that 1h at 100 • C was the best condition, and 31 was isolated in 83% of yield (entry 4). Modifications of the nature of other parameters, such as the base or solvent, did not improve the efficiency of the reaction. Finally, to show that the amination follows a palladium-assisted mechanism without a concomitant S N Ar reaction, we carried out the transformation without any catalyst ( Table 3, Entry 7), and, as expected, no reaction occurred. We next focused our attention on creating a C-N bond instead of a C-C bond under palladium catalysis by chlorine displacement [29]. We started with conditions that had proved their efficiency in the imidazodiazole series [30,31], namely Pd(OAc)2/Xantphos as a catalytic system, Cs2CO3 as a base and dioxane at 130 °C under microwave irradiation. However, in this case, with aniline as a partner, the desired product 31 was isolated in only 8% of yield (Table 3, entry 1). When the catalyst was switched for Pd2dba3, the reactivity was improved, and the desired compound 31 was obtained in an encouraging 56% yield (entry 2). The fine adjustment of the temperature and reaction time showed that 1h at 100 °C was the best condition, and 31 was isolated in 83% of yield (entry 4). Modifications of the nature of other parameters, such as the base or solvent, did not improve the efficiency of the reaction. Finally, to show that the amination follows a palladium-assisted mechanism without a concomitant SNAr reaction, we carried out the transformation without any catalyst (Table 3, Entry 7), and, as expected, no reaction occurred. Next, the scope and limitations of the amination were investigated by modulating the nature of the amines ( Table 4). The use of electron-rich anilines was well tolerated and afforded derivative 32 in good yields (entries 2). In contrast, the presence of electron-withdrawing substituents such as trifluoromethyl slightly decreased the efficiency of the reaction, and compound 35 was isolated in 41% of yield. We next investigated the influence of steric hindrance using the methoxy position switch on the phenyl ring. While the ortho orientation induced a slight decrease in yield (34, 65% versus 32, 88%), the meta orientation did not alter the efficiency of the cross-coupling reaction, as product 33 was isolated in high yield. The only identified limit concerned the nature of the amine. The use of poorly nucleophilic lactams or morpholine as well as secondary alkylamines or 3-aminopyridine was prohibited.  Next, the scope and limitations of the amination were investigated by modulating the nature of the amines ( Table 4). The use of electron-rich anilines was well tolerated and afforded derivative 32 in good yields (entries 2). In contrast, the presence of electronwithdrawing substituents such as trifluoromethyl slightly decreased the efficiency of the reaction, and compound 35 was isolated in 41% of yield. We next investigated the influence of steric hindrance using the methoxy position switch on the phenyl ring. While the ortho orientation induced a slight decrease in yield (34, 65% versus 32, 88%), the meta orientation did not alter the efficiency of the cross-coupling reaction, as product 33 was isolated in high yield. The only identified limit concerned the nature of the amine. The use of poorly nucleophilic lactams or morpholine as well as secondary alkylamines or 3-aminopyridine was prohibited.
Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.  Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl3 and DMSO-d6. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13   Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl3 and DMSO-d6. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13   Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl3 and DMSO-d6. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13   Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl3 and DMSO-d6. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13   Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl3 and DMSO-d6. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13   Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl3 and DMSO-d6. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13   Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl3 and DMSO-d6. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13   Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl3 and DMSO-d6. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13   Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl3 and DMSO-d6. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13   Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl3 and DMSO-d6. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13   Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds 39 and 40 were isolated in 68% and 51% of yields, respectively.

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl3 and DMSO-d6. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13

General Information
1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl 3 and DMSO-d 6 . The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by 1 H NMR, and 13 C NMR, which are consistent with those reported in the literature (Supplementary Materials). Melting points are uncorrected. IR absorption spectra were obtained on a PerkinElmer PARAGON 1000 PC, and the values are reported in inverse centimeters. HRMS spectra were acquired in positive mode with an ESI source on a Q-TOF mass by the "Fédération de Recherche" ICOA/CBM (FR2708) platform, and NMR data were generated on the Salsa platform. Monitoring of the reactions was performed using silica gel TLC plates (silica Merck 60 F 254). Spots were visualized by using UV light (254 nm and 356 nm). Column chromatography was performed using silica gel 60 (0.063-0.200 mm, Merck, Darmstadt, Germany). Microwave irradiation was carried out in sealed vessels placed in a Biotage Initiator or Biotage Initiator + system (400 W maximum power). The temperatures were measured externally by using IR. Pressure was measured by using a non-invasive sensor integrated into the cavity lid. All reagents were purchased from commercial suppliers and were used without further purification.

Synthesis and Characterization
3.2.1. Ethyl 5-Hydroxy-1-(p-tolyl)-1H-pyrazole-3-carboxylate (1) To a suspension of p-tolylphenylhydrazine hydrochloride (5.0 g, 31.5 mmol, 1.0 eq.) in EtOH (50 mL) was added diethyl acetylenedicarboxylate (6.05 mL, 37.83 mmol, 1.2 eq.) and then slowly Et 3 N (8.72 mL, 63.05 mmol, 2.0 eq.). The mixture was stirred for 20 h at room temperature. The solvent was removed, the residue was taken in EtOAc, and the organic layer was washed with aqueous HCl 6 M. The aqueous layer was extracted twice with EtOAc; organic layers were combined, dried over MgSO 4 , filtrated and concentrated; and the residue was precipitated and washed with Et 2 O to give the title product 1 (2.99 g, 65%) as a white solid. Rf

Conclusions
In summary, we have described in this work a synthetic pathway for the preparation of an original pyrrolo [3,4-c]pyrazole-4,6-(2H,5H)-dione platform and have developed several arylations/amination at its C-3 position. First, a reactivity study of these derivatives with respect to Suzuki-Miyaura coupling reactions has shown that the reaction is compatible with various arylboronic acids. A strong influence of electronic effect and steric hindrance has also been shown. A study of the Buchwald-Hartwig cross-coupling in C-3 position was also performed. The scope was investigated and showed its limitation to aniline derivatives. Secondly, this work allows access to a novel class of substituted pyrrolo [3,4-c]pyrazole-4,6-(2H,5H)-diones, which will undoubtedly have a major impact on the further synthesis of new bioactive compounds that contain the rare pyrrolo [3,4-c]pyrazole scaffold as the central skeleton. Finally, efforts to achieve these objectives, and particularly to study the reactivity of the maleimide moiety involved in the bicyclic system, are currently in progress.

Supplementary Materials:
The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules28155811/s1, Figures S1-S34: 1 H and 13 C NMR of all synthesized compounds. Data Availability Statement: Data will be available upon request to the corresponding author.