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Article

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

by
Abdelaziz Ejjoummany
1,2,
Jonathan Elie
1,
Ahmed El Hakmaoui
2,
Mohamed Akssira
2,
Sylvain Routier
1,* and
Frédéric Buron
1,*
1
Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 7311, BP 6759, CEDEX 2, F-45067 Orléans, France
2
Faculté des Sciences et Technique, Université Hassan II-Casablanca, BP 146, Mohammedia 28800, Morocco
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(15), 5811; https://doi.org/10.3390/molecules28155811
Submission received: 6 July 2023 / Revised: 27 July 2023 / Accepted: 28 July 2023 / Published: 1 August 2023
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
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.

Graphical Abstract

1. 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 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).

2. Results

Based on diethyl acetylenedicarboxylate (DEAD) reactivity with arylhydrazine, new pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones were prepared in a few steps (Scheme 1) [21]. Condensation of the substituted phenylhydrazine chlorhydrate and diethyl acetylenedicarboxylate in ethanol led to 5-hydroxypyrazols 1 and 2 in 65 and 70% yields, respectively. In the next step, treatment of the derivatives 1 and 2 with POCl3 and DMF in DCE led to 4-formyl-5-chloropyrazoles 3 and 4 in yields of over 85%. A Pinnick oxidation using sodium chlorite under mild acidic conditions afforded the corresponding acids 5 and 6 in good yields [22,23,24]. An amide bond formation with HOBt and EDCI as peptide coupling reagents [25] was performed in the presence of several amines such as methylamine, aniline or PMBNH2 to afford the expected amides 7–10. Saponification of the ester function with KOH furnished acids 11–14 in good yields. Finally, the formation of the maleimide moiety was carried out from amines 11–14 in the presence of 1,1′-carbonyldiimidazole to access 2-aryl-3-chloropyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones 15–17 in yields of 80–86% [26]. Only the aromatic N-aryl derivative 18 was never observed, which is a limitation of this annellation method.
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 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 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 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.
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.

3. Materials and Methods

3.1. General Information

1H NMR and 13C 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 1H NMR, and 13C 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.

3.2. 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 Et3N (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 MgSO4, filtrated and concentrated; and the residue was precipitated and washed with Et2O to give the title product 1 (2.99 g, 65%) as a white solid. Rf = 0.3 (EtOAc:PE, 8:2). Mp: 194–196 °C. 1H NMR (250 MHz, DMSO-d6) δ 10.36 (s, OH), 7.19 (s, 4H), 6.20 (s, 1H), 4.10 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.3 (CO), 158.9 (CO), 138.1 (Cq), 137.6 (Cq), 133.4 (Cq), 129.3 (2 × CH), 125.7 (2 × CH), 97. 8 (CH), 61.2 (CH2), 21.1 (CH3), 14.3 (CH3). IR (ATR diamond, cm−1) ν: 2985, 1722, 1557, 1462, 813, 764, 514. HRMS: m/z [M + H]+ calculated for C13H15N2O3: 247.1074, found: 247.1077.

3.2.2. Ethyl 5-Hydroxy-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (2)

To a suspension of 4-nitrophenylhydrazine (4.5 g, 29.40 mmol, 1.00 eq.) in EtOH (50 mL) was added diethyl acetylenedicarboxylate (3.07 mL, 35.28 mmol, 1.2 eq.) and then slowly Et3N (8.15 mL, 58.80 mmol, 2.0 eq.). The mixture was stirred for 24 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 MgSO4, filtrated and concentrated; and the residue was precipitated and washed with Et2O to give the title product 2 (5.11 g, 70%) as a white solid. Mp: 246–248 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.9 Hz, 2H), 8.08 (d, J = 8.9 Hz, 2H), 5.96 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.9 (CO), 155.1 (Cq), 145.3 (Cq), 144.1 (Cq), 143.6 (Cq), 125.2 (2 × CH), 121.7 (2 × CH), 90.1 (CH), 60.9 (CH2), 14.6 (CH3). IR (ATR diamond, cm−1) ν: 2955, 1724, 1595, 1421, 1155, 1023, 854, 767. HRMS: m/z [M + H]+ calculated for C12H12N3O5: 278.0768, found: 278.0771.

3.2.3. Ethyl 5-Chloro-4-formyl-1-(p-tolyl)-1H-pyrazole-3-carboxylate (3)

To a suspension of compound 1 (2.20 g, 9.01 mmol, 1.0 eq.) in DCE (60 mL) was added DMF (2.13 mL, 34.8 mmol, 3.0 eq.) and POCl3 (1.51 mL, 15.76 mmol, 1.75 eq.). The mixture was stirred and refluxed for 1.5 h. After cooling, POCl3 (3.8 mL, 39.64 mmol, 4.4 eq.) was added a second time and stirred and refluxed for 18 h. After cooling, water was added slowly, and then the aqueous layer was extracted three times with DCM. Organic layers were combined, dried over MgSO4, filtrated and concentrated to give the title product 3 (2.63 g, 85%) as a white solid. Mp: 168–170 °C. 1H NMR (400 MHz, CDCl3) δ 10.51 (s, 1HAld), 7.41 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 2.43 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 185.2 (CHAld), 160.9 (CO), 144.1 (Cq), 140.4 (Cq), 134.0 (Cq), 131.8 (Cq), 129.9 (2 × CH), 125.6 (2 × CH), 119.4 (Cq), 62.1 (CH2), 21.3 (CH3), 14.3 (CH3). IR (ATR diamond, cm−1) ν: 2982, 2928, 1740, 1516, 1422, 1259, 1028, 827. HRMS: m/z [M + H]+ calculated for C14H14ClN2O3: 293.0685, found: 293.0687.

3.2.4. Ethyl 5-Chloro-4-formyl-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylate) (4)

To a suspension of compound 2 (3.00 g, 10.13 mmol, 1.0 eq.) in DCE (60 mL) was added DMF (2.4 mL, 30.39 mmol, 3.0 eq.) and POCl3 (1.71 mL, 17.72 mmol, 1.75 eq.). The mixture was stirred and refluxed for 1.5 h. After cooling, POCl3 (4.27 mL, 44.57 mmol, 4.4 eq.) was added a second time and stirred and refluxed for 18 h. After cooling, water was added slowly and then the aqueous layer was extracted three times with DCM. Organic layers were combined, dried over MgSO4, filtrated and concentrated to give the title product 4 (2.63 g, 86%) as a white solid. Mp: 174–176 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, HAld), 8.47 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 185.4 (CHAld), 160.8 (CO), 148.3 (Cq), 145.0 (Cq), 141.3 (Cq), 132.1 (Cq), 127.7 (2 × CH), 125.4 (2 × CH), 119.7 (Cq), 62.3 (CH2), 14.5 (CH3).IR (ATR diamond, cm−1) ν: 3115, 2988, 1723, 1535, 1321, 1025, 860, 687. HRMS: m/z [M + H]+ calculated for C13H11ClN3O5: 324.0378, found: 324.0381.

3.2.5. 5-Chloro-3-(ethoxycarbonyl)-1-(p-tolyl)-1H-pyrazole-4-carboxylic acid (5)

To a suspension of 3 (2.63 g, 9.01 mmol, 1.0 eq.) in a mixture of t-BuOH/H2O/2-methyl-2-butene (45 mL/45 mL/27 mL) was added NaH2PO4 (6.48 g, 54.06 mmol, 6.0 eq.) and NaClO2 (4.89 g, 54.06 mmol, 6.0 eq.). The mixture was stirred for 24 h at room temperature. Then, the mixture was poured into a funnel with EtOAc (50 mL) and water (30 mL). The aqueous layer was extracted twice with EtOAc. The aqueous layer was acidified with HCl 12 M, and the precipitate was filtrated, washed with cold water and dried with Et2O. Organics layers were combined, dried over MgSO4 and concentrated; the residue was triturated in EtOAc (2 mL); and Petroleum Ether (30 mL) was added. The resulting precipitate was filtrated and combined with the first solid to give the title compound 5 (2.77 g, 88%) as a white solid. Mp: 172–174 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 165.4 (CO), 163.1 (CO), 144.1 (Cq), 139.4 (Cq), 135.4 (Cq), 130.2 (2 × CH), 126.6 (Cq), 125.9 (2 × CH), 121.4 (Cq), 61.2 (CH2), 21.2 (CH3), 14.5 (CH3). IR (ATR diamond, cm−1) ν: 3011, 2752, 1734, 1452, 1300, 1223, 1027, 826, 763. HRMS: m/z [M + H]+ calculated for C14H14ClN2O4: 309.0999, found: 309.1000.

3.2.6. 5-Chloro-3-(ethoxycarbonyl)-1-(4-nitrophenyl)-1H-pyrazole-4-carboxylic acid (6)

To a suspension of 4 (2.00 g, 6.22 mmol, 1.00 eq.) in a mixture of t-BuOH/H2O/2-methyl-2-butene (45 mL/45 mL/27 mL) was added NaH2PO4 (4.48 g, 37.37 mmol, 6.00 eq.) and NaClO2 (3.38 g, 37.37 mmol, 6.00 eq.). The mixture was stirred for 24 h at room temperature. Then, the mixture was poured into a funnel with EtOAc (50 mL) and water (30 mL). The aqueous layer was extracted twice with EtOAc. The aqueous layer was acidified with HCl 12 M, and the precipitate was filtrated, washed with cold water and dried with Et2O. Organic layers were combined, dried over MgSO4 and concentrated; the residue was triturated in EtOAc (2 mL); and Petroleum Ether (30 mL) was added. The resulting precipitate was filtrated and combined with the first solid to give the title compound 6 (1.04g, 81%) as a white solid. Mp: 174–176 °C. 1H NMR (250 MHz, DMSO-d6) δ 8.44 (d, J = 8.9 Hz, 2H), 7.99 (d, J = 8.9 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.9 (CO), 161.5 (CO), 148.1 (Cq), 145.5 (Cq), 141.8 (Cq), 131.1 (Cq), 127.4 (2 × CH), 125.3 (2 × CH), 114.2 (Cq), 62.2 (CH2), 14.3 (CH3). IR (ATR diamond, cm−1) ν: 3086, 2662, 1746, 1414, 1302, 1234, 852, 753. HRMS: m/z [M + H]+ calculated for C13H11ClN3O6: 340.0331, found: 340.0330.

3.2.7. Ethyl 5-Chloro-4-(methylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylate (7)

To a suspension of 5 (2.00 g, 6.49 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H2O (1.043 g, 7.78 mmol, 1.20 eq.), methylamine (3.4 mL, 6.81 mmol, 1.05 eq.) and then EDCI (1.19, 7.13 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et2O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 7 (1.66 g, 80%) as a white solid. Mp: 190–192 °C. 1H NMR (400 MHz, CDCl3) δ 9.02 (q, J = 4.7 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 4.47 (q, J = 7.1 Hz, 2H), 2.99 (d, J = 4.7 Hz, 3H), 2.43 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 163.8 (CO), 160.9 (CO), 140.2 (Cq), 139.9 (Cq), 134.6 (Cq), 133.6 (Cq), 129.8 (2 × CH), 125.9 (2 × CH), 116.3 (Cq), 62.6 (CH2), 26.2 (NCH3), 21.3 (CH3), 14.2 (CH3). IR (ATR diamond, cm−1) ν: 3295, 1722, 1642, 1568, 1315, 1230, 1120, 1030, 826. HRMS: m/z [M + H]+ calculated for C15H17ClN3O3: 322.0958, found: 322.0952.

3.2.8. Ethyl 5-Chloro-4-[(4-methoxyphenyl)methylcarbamoyl]-1-(p-tolyl)-1H-pyrazole-3-carboxylate (8)

To a suspension of 5 (1.00 g, 3.25 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H2O (0.50 g, 3.89 mmol, 1.20 eq.), 4-methoxybenzylamine (0.50 mL, 3.41 mmol, 1.05 eq.) and then EDCI (0.59 mL, 3.36 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et2O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 8 (0.80 g, 75%) as a white solid. Mp: 168–170 °C. 1H NMR (400 MHz, CDCl3) δ 9.44 (t, J = 5.5 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.37–7.30 (m, 4H), 6.90 (d, J = 8.1 Hz, 2H), 4.60 (d, J = 5.5 Hz, 2H), 4.46 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 2.45 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 163.6 (CO), 160.0 (CO), 158.9 (Cq), 140.2 (Cq), 140.0 (Cq), 134.6 (Cq), 133.8 (Cq), 130.6 (Cq), 129.8 (2 × CH), 129.2 (2 × CH), 125.9 (2 × CH), 116.2 (Cq), 114.0 (2 × CH), 62.6 (CH2), 55.3 (OCH3), 43.0 (NCH2), 21.3 (CH3), 14.2 (CH3). IR (ATR diamond, cm−1) ν: 3557, 3304, 1721, 1636, 1302, 1255, 1041, 854, 838. HRMS: m/z [M + H]+ calculated for C22H23ClN3O4: 428.1369, found: 428.1371.

3.2.9. Ethyl 5-Chloro-4-(methylcarbamoyl)-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (9)

To a suspension of 6 (1.00 g, 3.05 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H2O (0.55 g, 3.65 mmol, 1.20 eq.), methylamine (1.60 mL, 3.20 mmol, 1.05 eq.) and then EDCI (0.79 mL, 4.42 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et2O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 9 (1.902 g, 82%) as a white solid. Mp: 156–158 °C. 1H NMR (250 MHz, DMSO-d6) δ 8.41–8.49 (m, 3H), 7.97 (d, J = 8.5 Hz, 2H), 4.31 (q, J = 6.8 Hz, 2H), 2.77 (d, J = 4.1 Hz, 3H), 1.28 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.8 (CO), 160.6 (CO), 147.9 (Cq), 142.3 (Cq), 141.9 (Cq), 128.2 (Cq), 126.9 (2 × CH), 125.4 (2 × CH), 120.4 (Cq), 61.7 (CH2), 26.4 (NCH3), 14.4 (CH3). IR (ATR diamond, cm−1) ν: 3086, 2662, 1746, 1414, 12341, 1157, 1040, 836. HRMS: m/z [M + H]+ calculated for C14H14ClN4O5: 353.0645, found: 353.0647.

3.2.10. Ethyl 5-Chloro-4-(phenylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylate (10)

To a suspension of 5 (1.00 g, 3.25 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H2O (0.50 g, 3.89 mmol, 1.20 eq.), phenylamine (0.55 mL, 3.41 mmol, 1.05 eq.) and then EDCI (0.59 mL, 3.36 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et2O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 10 (1.1 g, 89%) as a white solid. Mp: 176–178 °C. 1H NMR (400 MHz, CDCl3) δ 11.41 (s, 1H), 7.78 (d, J = 7.9 Hz, 2H), 7.37 (m, 6H), 7.13 (t, J = 7.9 Hz, 1H), 4.54 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 164.4 (CO), 158.0 (CO), 140.3 (Cq), 139.6 (Cq), 138.4 (Cq), 134.7 (Cq), 134.5 (Cq), 129.9 (2 x CH), 128.9 (2 × CH), 126.0 (2 × CH), 124.2 (CH), 120.1 (2 × CH), 116.5 (Cq), 63.0 (CH2), 21.3 (CH3), 14.2 (CH3). IR (ATR diamond, cm−1) ν: 3134, 3274, 172Ç, 1636, 1354, 1195, 1044, 879, 889. HRMS (EI-MS): m/z calculated for C20H19ClN3O3: 384.1013 [M + H]+, found: 384.1017.

3.2.11. 5-Chloro-4-(methylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylic acid (11)

To a suspension of 7 (0.56 g, 1.75 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (1.93 mL, 1.93 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12 M and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO4, filtered and concentrated to give the title compound 11 (0.51 g, 99%) as a white solid. Mp: 228–230 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (q, J = 3.9 Hz, 1NH), 7.46 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 2.76 (d, J = 3.9 Hz, 3H), 2.40 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 162.7 (CO), 161.41 (CO), 142.4 (Cq), 140.0 (Cq), 134.9 (Cq), 130.3 (2 × CH), 128.3 (Cq), 126.0 (2 × CH), 118.6 (Cq), 26.4 (NCH3), 21.2 (CH3). IR (ATR diamond, cm−1) ν: 3368, 1731, 1558, 1257, 1030, 824, 650. HRMS: m/z [M + H]+ calculated for C13H13ClN3O3: 294.0640, found: 294.0639.

3.2.12. 5-Chloro-4-((4-methoxybenzyl)carbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylic acid (12)

To a suspension of 8 (1.34 g, 3.25 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (2.83 mL, 3.57 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12 M, and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO4, filtered and concentrated to give the title compound 12 (1.19 g, 90%) as a white solid. Mp: 202–204 °C. 1H NMR (250 MHz, DMSO-d6) δ 12.11 (t, J = 5.3 Hz, 1NH), 7.30–735 (m, 4H), 7.26 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 4.39 (d, J = 5.3 Hz, 2H), 3.73 (s, 3H), 2.36 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 164.0 (CO), 160.7 (CO), 158.60 (Cq), 139.7 (Cq), 134.7 (Cq), 134.6 (Cq), 131.9 (Cq), 130.0 (2 × CH), 129.9 (Cq), 129.1 (2 × CH), 126.7 (Cq), 126.6 (2 × CH), 114.2 (2 × CH), 55.5 (OCH3), 42.1 (NCH2), 21.2 (CH3). IR (ATR diamond, cm−1) ν: 3347, 1752, 1560, 1338, 1176, 1001, 856, 765. HRMS: m/z [M + H]+ calculated for C20H19ClN3O4: 400.1059, found: 400.1058.

3.2.13. 5-Chloro-4-(methylcarbamoyl)-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylic acid (13)

To a suspension of 9 (0.470 g, 1.38 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (1.59 mL, 1.51 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12N, and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO4, filtered and concentrated to give the title compound 13 (0.45 g, 90%) as a white solid. Mp: 282–264 °C. 1H NMR (250 MHz, DMSO-d6) δ 8.54 (q, J = 4.5 Hz, 1NH), 8.46 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 8.6 Hz, 2H), 2.77 (d, J = 4.5 Hz, 3H). 13C NMR (400 MHz, DMSO-d6) δ 162.3 (CO), 161.0 (CO), 147.9 (Cq), 143.2 (Cq), 142.0 (Cq), 128.3(Cq), 126.9 (2 × CH), 125.4 (2 × CH), 120.0 (Cq), 26.5 (NCH3). IR (ATR diamond, cm−1) ν: 3128, 2924, 1767, 1606, 1500, 1356, 1005, 606. HRMS: m/z [M + H]+ calculated for C12H10ClN4O5: 325.0332, found: 325.0334.

3.2.14. 5-Chloro-4-(phenylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylic acid (14)

To a suspension of 10 (1.1 g, 2.87 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (3.16 mL, 3.16 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12 M, and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO4, filtered and concentrated to give the title compound 14 (886 mg, 87%) as a white solid. Mp: 218–220 °C. 1H NMR (250 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.12 (t, J = 7.9 Hz, 1H), 2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.6 (CO), 159.4 (CO), 142.2 (Cq), 140.1 (Cq), 139.5 (Cq), 134.9 (Cq), 130.4 (2 × CH), 129.3 (2 × CH), 128.5 (Cq), 125.9 (2 × CH), 124.2 (CH), 119.7 (2 × CH), 119.3 (Cq), 21.2 (CH3). IR (ATR diamond, cm−1) ν: 3145, 1761, 1569, 1588, 1170, 1007, 876, 744. HRMS (EI-MS): m/z calculated for C18H15ClN3O3: 356.0747 [M + H]+, found: 356.0749.

3.2.15. 3-Chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (15)

To a suspension of 11 (0.50 g, 1.7 mmol, 1.0 eq.) in dry DCM (10 mL) under inert gas was added CDI (0.830 g, 5.11 mmol, 3.0 eq.). The mixture was stirred for 24 h at room temperature. The solvent was removed, and the crude was purified by using flash chromatography with EP/EtOAc (9/1) as eluent to give 15 (0.403 g, 86%) as a white solid. Mp: 208–210 °C. 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 3.15 (s, 3H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.1 (CO), 160.5 (CO), 152.4 (Cq), 140.4 (Cq), 134.5 (Cq), 130.0 (2 × CH), 125.3 (2 × CH), 125.1 (Cq), 116.7 (Cq), 24.5 (NCH3), 21.3 (CH3). IR (ATR diamond, cm−1) ν: 3385, 1715, 1556, 1530, 1357, 1260, 1136, 1177. HRMS: m/z [M + H]+ calculated for C13H11ClN3O2: 276.0536, found: 276.0534.

3.2.16. 3-Chloro-5-(4-methoxybenzyl)-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (16)

To a suspension of 12 (0.4g, 1.00 mmol, 1.0 eq.) in dry DCM (10 mL) under inert gas was added CDI (0.486 g, 3.00 mmol, 3.0 eq.). The mixture was stirred for 24 h at room temperature. The solvent was removed, and the crude was purified by using flash chromatography with EP/EtOAc (7/3) as eluent to give 16 (0.306 g, 80%) as a white solid. Mp: 158–160 °C. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 4.73 (s, 2H), 3.78 (s, 3H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.5 (CO), 159.9 (CO), 159.1 (Cq), 152.0 (Cq), 140.2 (Cq), 134.2 (Cq), 130.1 (2 × CH), 129.8 (2 × CH), 128.4 (Cq), 125.1 (2 × CH), 125.0 (Cq), 116.4 (Cq), 113.8 (2 × CH), 55.1 (OCH3), 41.3 (NCH2), 21.1 (CH3). IR (ATR diamond, cm−1) ν: 2934, 2838, 1710, 1576, 1241, 1030, 916, 816, 760. HRMS: m/z [M + H]+ calculated for C20H17ClN3O3: 382.0952, found: 382.0952.

3.2.17. 3-Chloro-5-methyl-2-(4-nitrophenyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (17)

To a suspension of 13 (0.5g, 1.54 mmol, 1.0 eq.) in dry DCM (10 mL) under inert gas was added CDI (0.750 g, 4.62 mmol, 3.0 eq.). The mixture was stirred for 24 h at room temperature. The solvent was removed, and the crude was purified by flash chromatography with EP/EtOAc (7/3) as eluent to give 17 (0.366 g, 84%) as a white solid. Mp: 206–208 °C. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.7 Hz, 2H), 7.90 (d, J = 8.7 Hz, 2H), 3.20 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.4 (CO), 159.7 (CO), 153.3 (Cq), 148.0 (Cq), 141.6 (Cq), 125.8 (2 × CH), 125.2 (Cq), 124.9 (2 × CH), 117.7 (Cq), 24.7 (CH3). IR (ATR diamond, cm−1) ν: 3120, 3008, 1731, 1577, 1530, 1350, 982, 733, 674. HRMS: m/z [M + H]+ calculated for C12H8ClN4O4: 307.6605, found: 307.6610.

3.2.18. 5-Methyl-2,3-di-p-tolylpyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (19)

In a microwave vial, 0.5–2 mL with a stir bar was charged: 15 (0.05 g, 0.18 mmol, 1.00 eq.), p-tolylboronic acid (0.037 g, 0.27 mmol, 1.5 eq.), K2CO3 (0.075 g, 0.054, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh3)4 (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give 19 (0.048 g, 85%) as a white solid. M.p: 170–172 °C. 1H NMR (400 MHz CDCl3) δ 7.37 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 3.17 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.6 (CO), 162.11 (CO), 152.5 (Cq), 141.3 (Cq), 140.6 (Cq), 139.5 (Cq), 137.0 (Cq), 130.0 (2 × CH), 129.5 (2 × CH), 129.2 (2 × CH), 125.6 (2 × CH), 123.7 (Cq), 117.2 (Cq), 24.3 (NCH3), 21.4 (CH3), 21.2 (CH3). IR (ATR diamond, cm−1) ν: 2922, 2851, 1760, 1703, 1513, 1356, 1019, 851, 793. HRMS: m/z [M + H]+ calculated for C20H18N3O2: 332.1397, found: 332.1393.

3.2.19. 3-(4-Methoxyphenyl)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (20)

In a microwave vial, 0.5–2 mL with a stir bar was charged: 15 (0.05 g, 0.18 mmol, 1.00 eq.), 4-methoxyphenylboronic acid (0.042 g, 0.27 mmol, 1.5 eq.), K2CO3 (0.075 g, 0.054, mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh3)4 (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give 20 (0.048 g, 79%) as a white solid. M.p: 150–152 °C. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 3.10 (s, 3H), 2.37 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.7 (CO), 162.1 (CO), 161.0 (Cq), 152.5 (Cq), 141.2 (Cq), 139.5 (Cq), 137.1 (Cq), 130.9 (2 × CH), 130.0 (2 × CH), 125.7 (2 × CH), 118.8 (Cq), 116.7 (Cq), 114.2 (2 × CH), 55.35 (OCH3), 24.3 (NCH3), 21.3 (CH3). IR (ATR diamond, cm−1) ν: 2923, 2848, 1763, 1700, 1499, 990, 1180, 803, 517. HRMS: m/z [M + H]+ calculated for C20H18N3O3: 348.1343, found: 348.1342.

3.2.20. 3-(3-Methoxyphenyl)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (21)

In a microwave vial, 0.5–2 mL with a stir bar was charged: 15 (0.05 g, 0.18 mmol, 1.00 eq.), 3-methoxyphenylboronic acid (0.042 g, 0.27 mmol, 1.5 eq.), K2CO3 (0.075 g, 0.054, mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh3)4 (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give 21 (0.046 g, 67%) as a white solid. M.p: 168–170 °C. 1H NMR (400 MHz, CDCl3) δ 7.31–7.28 (m, 3H), 7.26 (d, J = 8.0 Hz, 2H), 7.15 (dd, J = 2.6, 1.6 Hz, 1H), 6.99–6.93 (m, 2H), 3.75 (s, 3H), 3.18 (s, 3H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.8 (CO), 162.3 (CO), 159.9 (Cq), 152.8 (Cq), 141.4 (Cq), 140.0 (Cq), 137.3 (Cq), 130.3 (2 × CH), 130.1 (CH), 127.9 (Cq), 126.0 (2 × CH), 121.7 (CH), 117.9 (Cq), 117.2 (CH), 114.5 (CH), 55.6 (OCH3), 24.6 (NCH3), 21.6 (CH3). IR (ATR diamond, cm−1) ν: 2929, 2921, 1758, 1705, 1448, 1360, 962, 787, 547 HRMS: m/z [M + H]+ calculated for C20H18N3O3: 348.1460, found: 348.1343.

3.2.21. 3-(4-Fluorophenyl)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (23)

In a microwave vial, 0.5–2 mL with a stir bar was charged: 15 (0.05 g, 0.18 mmol, 1.00 eq.), 4-fluorophenylboronic acid (0.038 g, 0.27 mmol, 1.5 eq.), K2CO3 (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh3)4 (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give 23 (0.038 g, 65%) as a white solid. M.p: 178–180 °C. 1H NMR (250 MHz, Chloroform-d) δ 7.50–7.41 (m, 2H), 7.22–7.24 (m, 4H), 7.12–6.97 (m, 2H), 3.15 (s, 3H), 2.42 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 163.49 (d, J = 252.5 Hz, Cq), 162.4 (CO), 161.9 (CO), 152.5 (Cq), 140.0 (Cq), 139.8 (Cq), 136.7 (Cq), 131.5 (d, J = 8.7 Hz, 2 × CH), 130.1 (2 × CH), 125.6 (2 × CH), 122.7 (d, J = 3.5 Hz, Cq), 117.5 (Cq), 116.1 (d, J = 22.1 Hz, 2 × CH), 24.3 (NCH3), 21.2 (CH3). IR (ATR diamond, cm−1) ν: 2924, 2920, 1767, 1710, 1448, 1356, 1107, 879, 643, 532. HRMS: m/z [M + H]+ calculated for C19H15FN3O2: 336.1144, found: 336.1142.

3.2.22. 3-(4-Cyanophenyl)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (24)

In a microwave vial, 0.5–2 mL with a stir bar was charged: 15 (0.050 g, 0.18 mmol, 1.00 eq.), 4-cyanophenylboronic acid (0.053 g, 0.27 mmol, 1.5 eq.), K2CO3 (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh3)4 (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give 24 (0.035 g, 60%) as a white solid. M.p: 178–180 °C. 1H NMR (250 MHz, CDCl3) δ 7.65 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 3.17 (s,3H), 2.44 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 162.1 (CO), 161.5 (CO), 152.7 (Cq), 140.4 (Cq), 138.6 (Cq), 136.3 (Cq), 132.5 (2 × CH), 130.8 (Cq), 130.4 (2 × CH), 129.8 (2 × CH), 125.6 (2 × CH), 118.7 (Cq), 117.9 (Cq), 113.7 (Cq), 24.5 (NCH3), 21.3 (CH3). IR (ATR diamond, cm−1) ν: 2923, 2227, 1764, 1709, 1494, 1352, 1279, 1105, 973, 643, 551. HRMS: m/z [M + H]+ calculated for C20H15N4O2: 343.1192, found: 343.1189.

3.2.23. 3-(FuraN-2-yl)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (25)

In a microwave vial, 0.5–2 mL with a stir bar was charged: 15 (0.05 g, 0.18 mmol, 1.00 eq.), 2-furanylboronic acid (0.030 g, 0.27 mmol, 1.5 eq.), K2CO3 (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh3)4 (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give 25 (0.042 g, 76%) as a white solid. M.p: 172–174 °C. 1H NMR (400 MHz CDCl3) δ 7.46 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 3.4 Hz, 1H), 6.49 (dd, J = 3.4, 1.8 Hz, 1H), 3.19 (s, 3H), 2.49 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.9 (CO), 161.8 (CO), 152.6 (Cq), 144.7 (CH), 141.7 (Cq), 140.1 (Cq), 137.0 (Cq), 131.5 (Cq), 129.8 (2 × CH), 126.0 (2 × CH), 115.5 (Cq), 115.0 (CH), 112.0 (CH), 24.3 (NCH3), 21.4 (CH3). IR (ATR diamond, cm−1) ν: 2926, 2920, 1770, 1712, 1445, 1355, 1116, 897, 647, 564. HRMS: m/z [M + H]+ calculated for C17H14N3O3: 308.1029, found: 308.1028.

3.2.24. 3-(FuraN-3-yl)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (26)

In a microwave vial, 0.5–2 mL with a stir bar was charged: 15 (0.05 g, 0.18 mmol, 1.00 eq.), 3-furanylboronic acid (0.030 g, 0.27 mmol, 1.5 eq.), K2CO3 (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh3)4 (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give 26 (0.039 g, 56%) as a white solid. M.p: 190–192 °C. 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.35–7.38 (m, 5H), 7.54 (d, J = 1.1 Hz, 1H), 3.16 (s, 3H), 2.48 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.5 (CO), 162.1 (CO), 152.6 (Cq), 143.8 (CH), 143.5 (CH), 140.8 (Cq), 136.7 (Cq), 134.5 (Cq), 130.3 (2 × CH), 126.4 (2 × CH), 116.1 (Cq), 113.6 (Cq), 109.6 (CH), 24.3 (NCH3), 21.4 (CH3). IR (ATR diamond, cm−1) ν: 2924, 2921, 1765, 1712, 1447, 1357, 1116, 977, 648, 594. HRMS: m/z [M + H]+ calculated for C17H14N3O3: 308.1029, found: 308.1032.

3.2.25. 5-Methyl-3-(thiopheN-3-yl)-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (27)

In a microwave vial, 0.5–2 mL with a stir bar was charged: 15 (0.05 g, 0.18 mmol, 1.00 eq.), 3-thienylboronic acid (0.041 g, 0.27 mmol, 1.5 eq.), K2CO3 (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh3)4 (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give 27 (0.026 g, 45%) as a white solid. M.p: 198–200 °C. 1H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 3.0, 1.3 Hz, 1H), 7.33–729 (m, 4H), 7.28 (dd, J = 5.2, 3.0 Hz, 1H), 7.21 (dd, J = 5.1, 1.3 Hz, 1H), 3.17 (s, 3H), 2.47 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.7 (CO), 162.0 (CO), 152.5 (Cq), 140.5 (CH), 137.0 (CH), 136.9 (Cq), 130.3 (2 × CH), 128.3 (CH), 127.5 (CH), 127.3 (Cq), 126.3 (2 × CH), 126.3 (CH), 116.3 (Cq), 24.3 (NCH3), 21.4 (CH3). IR (ATR diamond, cm−1) ν: 3087, 2923, 2921, 1759, 1700, 1498, 1356, 1116, 971, 792, 509. HRMS: m/z [M + H]+ calculated for C17H14N3O2S: 324.0802, found: 324.0801.

3.2.26. 5-(4-Methoxybenzyl)-2,3-di-p-tolylpyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (29)

In a microwave vial, 0.5–2 mL with a stir bar was charged: 16 (0.050 g, 0.114 mmol, 1.00 eq.), p-tolylphenylboronic acid (0.026 g, 0.171 mmol, 1.5 eq.), K2CO3 (0.047 g, 0.342 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh3)4 (0.013 g, 0.011 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (5/5) as eluent to give 29 (0.035 g, 70%) as a white solid. M.p: 160–162 °C. 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 7.5 Hz, 2H), 7.22–7.26 (m, 4H), 7.14 (d, J = 7.5 Hz, 2H), 6.84 (d, J = 7.7 Hz, 2H), 4.75 (s, 2H), 3.77 (s, 3H), 2.41 (s, 3H), 2.34 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 162.3 (CO), 161.7 (CO), 159.1 (Cq), 152.4 (Cq), 144.3 (Cq), 140.6 (Cq), 139.5 (Cq), 137.0 (Cq), 130.2 (2 × CH), 130.0 (2 × CH), 129.5 (2 × CH), 129.2 (2 × CH), 129.1 (Cq), 125.6 (2 × CH), 123.6 (Cq),117.2 (Cq), 114.0 (2 × CH), 55.3 (OCH3), 41.3 (CH2), 21.2 (CH3), 21.2 (CH3). IR (ATR diamond, cm−1) ν: 2922, 1764, 1707, 1513, 1313, 1150, 916, 845, 775. HRMS: m/z [M + H]+ calculated for C27H24N3O3: 438.1782, found: 438.1783.

3.2.27. 5-Methyl-2-(4-nitrophenyl)-3-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (30)

In a microwave vial, 0.5–2 mL with a stir bar was charged: 17 (0.050 g, 0.16 mmol, 1.00 eq.), p-tolylphenylboronic acid (0.033 g, 0.245 mmol, 1.5 eq.), K2CO3 (0.067 g, 0.489 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min and then Pd(PPh3)4 (0.022 g, 0.019 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give 30 (0.057 g, 84%) as a white solid. M.p: 222–224 °C. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 3.20 (s, 3H), 2.42 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 161.8 (CO), 161.5 (CO), 153.6 (Cq), 147.4 (Cq), 144.1 (Cq), 141.8 (Cq), 141.6 (Cq), 130.0 (2 × CH), 129.2 (2 × CH), 126.1 (2 × CH), 124.8 (2 × CH), 122.9 (Cq), 118.3 (Cq), 24.5 (NCH3), 21.5 (CH3). IR (ATR diamond, cm−1) ν: 3077, 2919, 1764, 1715, 1447, 1343, 1104, 988, 754, 504. HRMS: m/z [M + H]+ calculated for C19H15N3O4: 363.1083, found: 363.1087.

3.2.28. 5-Methyl-3-(phenylamino)-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (31)

A solution of the 3-chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-dione 15 (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the aniline (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd2dba3 (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give 31 (0.049 g, 83%) as a yellow solid. M.p: 214–216 °C. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.0 Hz, 2H), 7.43–7.34 (m, 4H), 7.20–7.16 (m, 3H), 6.37 (s, 1H), 3.08 (s, 3H), 2.46 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.2 (CO), 161.0 (CO), 153.0 (Cq), 140.1 (Cq), 139.2 (Cq), 138.1 (Cq), 134.3 (Cq), 130.7 (2 × CH), 129.3 (2 × CH), 125.2 (2 × CH), 124.6 (CH), 120.0 (2 × CH), 100.7 (Cq), 24.2 (CH3), 21.3 (CH3). IR (ATR diamond, cm−1) ν: 3375, 1781, 1707, 1553, 1341, 1133, 966, 885, 747. HRMS: m/z [M + H]+ calculated for C19H17N4O2: 333.1342, found: 333.1346.

3.2.29. 3-((4-Methoxyphenyl)amino)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (32)

A solution of the 3-chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-dione 15 (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the p-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd2dba3 (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give 32 (0.058 g, 88%) as a white solid. M.p: 204–206 °C. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 6.30 (s, 1H), 3.83 (s, 3H), 3.04 (s, 3H), 2.46 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.3 (CO), 161.0 (CO), 157.4 (Cq), 152.0 (Cq), 141.0 (Cq), 139.9 (Cq), 134.4 (Cq), 131.1 (Cq), 130.7 (2 × CH), 125.1 (2 × CH), 123.3 (2 × CH), 114.4 (2 × CH), 99.4 (Cq), 55.5 (OCH3), 24.1 (CH3), 21.3 (CH3). IR (ATR diamond, cm−1) ν: 3323, 1760, 1704, 1506, 1361, 1231, 822, 7444. HRMS: m/z [M + H]+ calculated for C20H19N4O3: 363.1451, found: 363.1452.

3.2.30. 3-((3-Methoxyphenyl)amino)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (33)

A solution of the 3-chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-dione 15 (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the m-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd2dba3 (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give 33 (0.055 g, 84%) as a white solid. M.p: 180–182 °C. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.26 (t, J = 9.8 Hz, 1H), 6.77 (s, 1H), 6.70 (t, J = 6.9 Hz, 2H), 6.39 (s, 1H), 3.83 (s, 3H), 3.09 (s, 3H), 2.46 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.2 (CO), 161.0 (CO), 160.5 (Cq), 152.0 (Cq), 140.1 (Cq), 139.3 (Cq), 138.7 (Cq), 134.3 (Cq), 130.7 (2 × CH), 129.9 (CH), 125.2 (2 × CH), 111.7 (CH), 109.8 (CH), 105.5 (CH), 101.0 (Cq), 55.4 (OCH3), 24.2 (CH3), 21.3 (CH3). IR (ATR diamond, cm−1) ν: 3302, 1755, 1699, 1552, 1366, 1199, 966, 764, 743. HRMS: m/z [M + H]+ calculated for C20H19N4O3: 363.1451, found: 363.1453.

3.2.31. 3-((2-Methoxyphenyl)amino)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (34)

A solution of the 3-chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-dione 15 (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the o-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd2dba3 (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (4/6) as eluent to give 34 (0.043 g, 65%) as a white solid. M.p: 218–220 °C. 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 7.3, 2.1 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.15–7.05 (m, 2H), 6.90 (dd, J = 7.3, 2.1 Hz, 1H), 6.86 (s, 1H), 3.82 (s, 3H), 3.12 (s, 3H), 2.48 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.2 (CO), 161.4 (CO), 152.0 (Cq), 148.7 (Cq), 139.8 (Cq), 138.6 (Cq), 134.5 (Cq), 130.6 (2 × CH), 127.7 (Cq), 125.0 (2 × CH), 123.9 (CH), 121.1 (CH), 118.7 (CH), 110.2 (CH), 100.7 (Cq), 55.7 (OCH3), 24.2 (CH3), 21.3 (CH3). IR (ATR diamond, cm−1) ν: 3390, 1757, 1707, 1550, 1357, 1196, 985, 748, 736. HRMS: m/z [M + H]+ calculated for C20H19N4O3: 363.1451, found: 363.1452.

3.2.32. 5-Methyl-2-(p-tolyl)-3-((4-(trifluoromethyl)phenyl)amino)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (35)

A solution of the 3-chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-dione 15 (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the o-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd2dba3 (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (4/6) as eluent to give 35 (0.030 g, 41%) as a blue solid. M.p: 190–192 °C. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 6.51 (s, 1H), 3.09 (s, 3H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.9 (CO), 161.1 (CO), 151.9 (Cq), 141.20 (q, J = 1.1 Hz, Cq), 140.5 (Cq), 137.1 (Cq), 134.0 (Cq), 130.8 (2 × CH), 126.6 (q, J = 3.7 Hz, 2 × CH), 125.6 (q, J = 32.7 Hz, Cq), 125.2 (2 × CH), 123.9 (CH), 118.0 (2 × CH), 102.4 (Cq), 24.3 (CH3), 21.3 (CH3). IR (ATR diamond, cm−1) ν: 3309, 1763, 1713, 1541, 1323, 1108, 1506, 831. HRMS: m/z [M + H]+ calculated for C20H16F3N4O2: 401.1220, found: 441.1219.

3.2.33. 5-(4-Methoxybenzyl)-3-(anilino)-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (39)

A solution of the 16 (0.113 mmol, 1.0 eq.), cesium carbonate (0.339 mmol, 3.0 eq.) and the aniline (0.226 mmol, 2.0 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd2dba3 (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give 39 (0.034g, 68%) as a yellow solid. M.p: 234–236 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 8.6 Hz, 2H), 7.29 (t, J = 7.9 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 7.03 (t, J = 7.3 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.30 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.9 (CO), 160.2 (CO), 159.0 (Cq), 152.7 (Cq), 142.3 (Cq), 140.9 (Cq), 140.9 (Cq), 140.2 (Cq), 133.0 (Cq), 129.5 (2 x CH), 129.3 (2 x CH), 129.2 (2 × CH), 129.10, 126.0 (2 × CH), 123.2 (CH), 119.3 (2 × CH), 114.4 (2 × CH), 102.3 (Cq), 55.5 (OCH3), 43.9 (CH3), 40.9 (CH2). IR (ATR diamond, cm−1) ν: 3174, 1786, 1707, 1553, 1356, 1133, 971, 885, 733. HRMS: m/z [M + H]+ calculated for C26H22N4O3: 439.1745, found: 439.1747.

3.2.34. 5-Methyl-2-(4-nitrophenyl)-3-(phenylamino)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (40)

A solution of the 17 (0.163 mmol, 1.0 eq.), cesium carbonate (0.326 mmol, 3.0 eq.) and the aniline (0.196mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd2dba3 (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give 40 (0.030 g, 51%) as a yellow solid. M.p: 240–242 °C. 1H NMR (400 MHz, Acetone-d6) δ 8.56 (s, 1H), 8.43 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 7.31 (t, J = 7.7 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.07 (t, J = 7.4 Hz, 1H), 2.99 (s, 3H). 13C NMR (101 MHz, Acetone-d6) δ 161.6 (CO), 160.1 (CO) 153.3 (Cq), 147.2 (Cq), 143.3 (Cq), 139.9 (Cq), 139.8 (Cq), 128.9 (2 × CH), 125.7 (2 × CH), 124.9 (2 × CH), 123.1 (CH), 119.0 (2 × CH), 103.1 (Cq), 23.3 (CH3). IR (ATR diamond, cm−1) ν: 3375, 1781, 1707, 1553, 1341, 1133, 966, 885, 747. HRMS: m/z [M + H]+ calculated for C18H14N5O4: 364.1033, found: 364.1036.

4. 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: 1H and 13C NMR of all synthesized compounds.

Author Contributions

F.B., S.R., A.E.H. and M.A. designed research; A.E. and J.E. performed research; A.E., J.E., F.B. and A.E.H. analyzed the data; F.B. and S.R. wrote the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Data will be available upon request to the corresponding author.

Acknowledgments

The authors gratefully acknowledge major financial support from the Ligue contre le Cancer du Grand Ouest (comités des Deux Sèvres, du Finistère, de l’Ille-et-Vilaine, du Loir-et-Cher, de Loire-Atlantique, du Loiret, de la Vienne), the Canceropôle Grand Ouest, INCA, Région Centre-Val de Loire, the SFR neuroimagerie (SFR FED 4224), which made this study possible, and also the projects CHemBio (FEDER-FSE 2014-2020-EX003677), Techsab (FEDER-FSE 2014-2020-EX011313), Valbiocosm (FEDER-FSE 2014-2020-EX003202), QUALICHIM (APR-IA-PF 2021-00149467) and RTR Motivhealth (2019-00131403) and the Labex programs SYNORG (ANR-11-LABX-0029) and IRON (ANR-11-LABX-0018-01) for their financial support of ICOA, UMR 7311, University of Orléans, CNRS. We also thank the SALSA platform for spectroscopic measurements (IR and UV-Vis) and spectrometric and chromatographic analyses (NMR, HPTLC, HPLC, MS and HRMS).

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

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Molecules 28 05811 g001
Figure 1. Some examples of pyrazole-based commercial drugs.
Figure 1. Some examples of pyrazole-based commercial drugs.
Molecules 28 05811 g001
Molecules 28 05811 g002
Figure 2. Access to polyfunctionalized pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones.
Figure 2. Access to polyfunctionalized pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones.
Molecules 28 05811 g002
Molecules 28 05811 sch001
Scheme 1. Steps in the synthesis of 2-aryl-3-chloropyrrolo[3,4-c]pyrazole-4,6-(2H, 5H)-diones 15–17.
Scheme 1. Steps in the synthesis of 2-aryl-3-chloropyrrolo[3,4-c]pyrazole-4,6-(2H, 5H)-diones 15–17.
Molecules 28 05811 sch001
Table 1. Optimization of Suzuki–Miyaura cross-coupling reaction.
Table 1. Optimization of Suzuki–Miyaura cross-coupling reaction.
Molecules 28 05811 i001
EntryCatalyst System
(10 mol %)		Base
(3.0 eq.)		T (°C)SolventTime (h)19, Yield (%) a
1PdCl2(PPh3)2K2CO3130Dioxane1.50
2Pd(OAc)2/Xantphos (0.2 eq.)K2CO3130Dioxane1.520
3Pd(PPh3)4K2CO3130Dioxane1.565
4Pd(PPh3)4K2CO3150Dioxane1.580
5Pd(PPh3)4K2CO3150Dioxane2.085
7Pd(PPh3)4Cs2CO3150Dioxane2.079
6Pd(PPh3)4K2CO3150Toluene2.00
a Isolated yield.
Table 2. Synthesis of 19–30.
Table 2. Synthesis of 19–30.
Molecules 28 05811 i002
EntryProductYield (%) aEntryProductYield (%) a
1Molecules 28 05811 i003
19		85%7Molecules 28 05811 i004
25		76%
2Molecules 28 05811 i005
20		79%8Molecules 28 05811 i006
26		56%
3Molecules 28 05811 i007
21		67%9Molecules 28 05811 i008
27		45%
4Molecules 28 05811 i009
22		Traces10Molecules 28 05811 i010
28		-
5Molecules 28 05811 i011
23		65%11Molecules 28 05811 i012
29		70%
6Molecules 28 05811 i013
24		60%12Molecules 28 05811 i014
30		84%
a Isolated yield.
Table 3. Optimization of the conditions for the formation of 31.
Table 3. Optimization of the conditions for the formation of 31.
Molecules 28 05811 i015
EntryCatalyst
(10 mol %)		Ligand
(20 mol %)		Base
(3.0 eq.)		T (°C)
M.W.		SolventTime (h)31, Yield (%) a
1Pd(OAc)2XantphosCs2CO3130Dioxane0.58
2Pd2dba3XantphosCs2CO3130Dioxane0.556
3Pd2dba3XantphosCs2CO3130Dioxane150
4Pd2dba3XantphosCs2CO3100Dioxane183
5Pd2dba3XantphosK2CO3100Dioxane176
6Pd2dba3XantphosCs2CO3100Toluene1N.D. b
7-XantphosK2CO3100Dioxane10
a Isolated yield. b Not detected.
Table 4. Synthesis of 31–40.
Table 4. Synthesis of 31–40.
Molecules 28 05811 i016
EntryProductYield (%) aEntryProductYield (%) a
1Molecules 28 05811 i017
31		83%6Molecules 28 05811 i018
36		-
2Molecules 28 05811 i019
32		88%7Molecules 28 05811 i020
37		-
3Molecules 28 05811 i021
33		84%8Molecules 28 05811 i022
38		-
4Molecules 28 05811 i023
34		65%9Molecules 28 05811 i024
39		68%
5Molecules 28 05811 i025
35		41%10Molecules 28 05811 i026
40		51%
a Isolated yield.
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MDPI and ACS Style

Ejjoummany, A.; Elie, J.; El Hakmaoui, A.; Akssira, M.; Routier, S.; Buron, F. Access and Modulation of Substituted Pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones. Molecules 2023, 28, 5811. https://doi.org/10.3390/molecules28155811

AMA Style

Ejjoummany A, Elie J, El Hakmaoui A, Akssira M, Routier S, Buron F. Access and Modulation of Substituted Pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones. Molecules. 2023; 28(15):5811. https://doi.org/10.3390/molecules28155811

Chicago/Turabian Style

Ejjoummany, Abdelaziz, Jonathan Elie, Ahmed El Hakmaoui, Mohamed Akssira, Sylvain Routier, and Frédéric Buron. 2023. "Access and Modulation of Substituted Pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones" Molecules 28, no. 15: 5811. https://doi.org/10.3390/molecules28155811

APA Style

Ejjoummany, A., Elie, J., El Hakmaoui, A., Akssira, M., Routier, S., & Buron, F. (2023). Access and Modulation of Substituted Pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones. Molecules, 28(15), 5811. https://doi.org/10.3390/molecules28155811

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